N-(2-Arylethyl)Benzylamines as Antagonists of the 5-HT6 Receptor

专利摘要:
The present invention provides a compound of formula (I) which is an antagonist of 5-HT 6 receptor. <Compound I> <Formula II>
公开号:KR20030090694A
申请号:KR10-2003-7012694
申请日:2002-03-15
公开日:2003-11-28
发明作者:자오겐 첸；마이클 필립 코헨；매튜 조지프 피셔；브루노 지에틀렝；제임스 로날드 길리그；제퍼슨 레이 맥코완；션 크리스토퍼 밀러；존 메너트 샤우스
申请人:일라이 릴리 앤드 캄파니；
IPC主号:

专利说明:

N- (2-Arylethyl) benzylamines as Antagonists of the 5-HT6 Receptor} as antagonist of 5-HT6 receptor
[2] The 5-HT ₆ receptor is a member of the G-protein coupled receptor superfamily of serotonin receptors and, like the 5-HT ₄ and 5-HT ₇ receptors, is clearly coupled to adenylate cyclase ¹ . Rat (rat) 5-HT ₆ receptor was first cloned in 1993 ^2,3, cloning of the human homologue having a sequence identity of 89% and it was reported in 1996, ^4. Localization of 5-HT ₆ receptors in the rat brain has been studied using Northern analysis and RT-PCR mRNA quantification, immunohistochemistry and autoradiography ^{2, 3, 5, 6, 7 , 8} . These methods consistently found high levels of receptors in the olfactory process, hippocampus, striated body, nucleus accumbens and cortical sites. Peripheral tissues may or may not have very low levels of 5-HT ₆ receptors ^{2, 3} .
[3] To date, high affinity selective antagonists for the 5-HT ₆ receptor are unknown. Serotonin by itself has only moderate affinity for the 5-HT ₆ receptor (Ki = 65 nM), and N, N-dimethyl-2-ethyl-5-meth, the most selective antagonist reported to date. Oxytryptamine has a Ki of 81 nM and has only 3.5 fold selectivity over the 5-HT _2A receptor ⁹ .
[4] 5-HT ₆ receptor for the recent interest is due to the observation that several psychotropic Mars antagonists for repairing agent is a human 5-HT ₆ receptor ^{4, 10.} Such compounds include amitriptyline (Ki = 65 nM) and atypical antipsychotic clozapine (Ki = 9.5 nM), olanzapine (Ki = 10 nM) and quetiapine (33 nM). However, all of these compounds are not selective. The first reported selective 5-HT ₆ receptor antagonists are Ro 04-6790 and Ro 63-0563. Their usefulness is limited by their moderate affinity (Ki = 50 nM and 12 nM, respectively) and poor pharmacokinetics ¹¹ . A series of 5-HT ₆ receptor antagonists was reported, peaking at SB-271,046 ¹² . This compound has high affinity (Ki = 1.2 nM) and selectivity (more than 200-fold for more than 55 receptors, enzymes and ion channels) and bioavailability of 80%. Selective radioligand [ ¹²⁵ I] -SB-258,585 has been used for radioligand binding and self-radiation studies ^{13, 14} . These compounds are useful tools for preclinical studies on 5-HT ₆ receptors.
[5] The rationale for the treatment of cognitive dysfunction with selective 5-HT ₆ receptor antagonists is based on three arguments: the ability to modulate cholinergic and glutamate neuronal function of selective 5-HT ₆ receptor antagonists and atypical antipsychotic clozapine for cognitive function. And clinical studies of olanzapine, the activity of selective 5-HT ₆ receptor antagonists in animal models of cognitive function.
[6] Selective 5-HT ₆ receptor antagonists modulate cholinergic and glutamate neuronal function. Cholinergic and glutamate neuronal systems play an important role in cognitive function. Cholinergic neuronal pathways are known to be important for memory formation and reinforcement. Anticholinergic agents acting on the central nerve impair cognitive function in animal and clinical studies, and loss of cholinergic neurons is one of the hallmarks of Alzheimer's disease. In contrast, stimulation of cholinergic function has been known to improve cognitive performance, and the only two agents currently approved for the treatment of cognitive deficiency in Alzheimer's disease, tacrine and donepezil, are both acetylcholinesterase inhibitors. The glutamate system of the forehead cortex is also known to be associated with cognitive functions ^{26, 27} .
[7] Blockade of 5-HT ₆ receptor function has been shown to cause procholine effects in vivo. Administration of antisense oligonucleotides targeting the 5-HT ₆ receptor sequence (icv) in mice induced yawning and stretching behavior, which was blocked by cholinergic antagonist atropine ¹⁵ . The selective 5-HT ₆ receptor antagonist Ro 04-6790 induced stretching behavior in a dose dependent manner. It was blocked by the anticholinergic agents scopolamine and atropine acting on the central nerve, but this behavior was not blocked by the dose of methylscopolamine known to be peripherally selective ¹⁶ . Ro 04-6790 has also been shown to block the rotational behavior induced by scopolamine administration in rats with one black line 6-OH-DA lesion. This did not block the rotational behavior induced by L-DOPA or amphenamine ¹⁷ . Scopolamine, reversed to Ro 04-6790, induced performance deficiency in object recognition tests, a model of cognitive function. Another selective 5-HT ₆ receptor antagonist, SB-271,046, enhanced the yawn behavior induced by the cholinesterase inhibitor physostigmine ¹⁸ . These studies suggest that 5-HT ₆ receptor blockade facilitates cholinergic delivery. In in vivo microdialysis studies, SB-271,046 (10 mg / kg sc) increases glutamate release in the forehead cortex via neuronal mechanisms ²⁵ .
[8] Clinical Study of Atypical Antipsychotic Clozapine and Olanzapine on Cognitive Function. Atypical antipsychotics Clozapine and Olanzapine are both high-affinity, non-selective, non-selective 5-HT ₆ receptor antagonists ⁴ . On the other hand, risperidone and the orthopedic antipsychotic haloperidol do not have great affinity for the 5-HT ₆ receptor. Clinical differences seen in these drug groups may be due to 5-HT ₆ receptor blockade. Goldberg et al reported no beneficial cognitive effects of clozapine treatment in small-scale (N = 5) trials of treatment-resistant schizophrenia ¹⁹ . In contrast, the melt teujeo (Meltzer) and the like than in the study of patients with large-scale treatment resistant schizophrenia (N = 36), 6 weeks and 6 months after therapy, clozapine observed improvements in several areas of neuropsychological function ²⁰ . In schizophrenic patients with no treatment resistance, clozapine was more effective than placebo in improving cognitive function by some measures ²¹ . This effect appeared at 6 months and lasted for the 12 month study period. The effects of olanzapine, risperidone, and haloperidol on cognitive function were compared by multicenter double blinding in schizophrenia ²² . The olanzapine group showed statistically significant improvement in cognitive function compared to haloperidol or risperidone treatment. This effect was evident after 6 weeks of treatment and lasted for the 54 week study period. Animal studies suggest that this effect can be mediated through the release of acetylcholine in the forehead cortex ²³ .
[9] Activity of Selective 5-HT ₆ Receptor Antagonists in Animal Models of Cognitive Function. With the recent development of selective 5-HT ₆ receptor antagonists Ro-04,6790 and SB-271,046, there are several reports on the activity of these compounds in models of cognitive function. The selective 5-HT ₆ receptor antagonist SB-271,046 improved performance in Morris water maze ²⁴ . These results are consistent with results ¹⁶ that prolonged icv administration of antisense oligonucleotides directed at the 5-HT ₆ receptor sequence resulted in significant performance improvements in the Morris water maze. SB-271,046 treatment also induced improvement in the spatial shift manipulation behavioral test in older mice ²⁴ .
[10] The compounds of the invention are selective high affinity antagonists of 5-HT ₆ receptor, and thus provides a useful therapeutic agents for the 5-HT ₆ receptor mediated disorders.
[11] references
[12]
[13]
[14] The present invention provides compounds of formula I and pharmaceutically acceptable salts thereof.
[15]
[16] Where
[17] X is selected from the group consisting of -O-, -NH-, -S-, -SO _2- , -CH _2- , -CH (F)-, -CH (OH)-and -C (O)- ;
[18] R ₁ is an optionally substituted 5- and 6-membered monocyclic aromatic heterocyclo having one heteroatom selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, nitrogen, oxygen and sulfur and optionally benzofused Selected from the group consisting of;
[19] R ₂ is selected from the group consisting of hydrogen and C ₁ -C ₃ alkyl;
[20] R ₃ is selected from the group consisting of hydrogen, fluoro and methyl;
[21] R ₄ is selected from the group consisting of hydrogen, allyl, C ₂ -C ₄ alkyl, fluorinated C ₂ -C ₄ alkyl, optionally substituted phenyl, optionally substituted phenylsulfonyl, optionally substituted benzyl, and nitrogen, oxygen and sulfur Optionally selected from the group consisting of optionally substituted 5- and 6-membered monocyclic aromatic heterocycles with one or two heteroatoms selected, wherein X is -SO _2- , -CH _2- , -CH (F)-, Or -CH (OH) or -C (O)-, it is not an optionally substituted phenylsulfonyl.
[22] The present invention also provides compounds of formula II and pharmaceutically acceptable salts thereof.
[23]
[24] Where
[25] Y is selected from the group consisting of O, NH and NR ₉ , wherein R ₉ is selected from the group consisting of C ₁ -C ₄ alkyl and optionally substituted phenyl;
[26] R ₅ and R ₆ are hydrogen, or combine with the atoms to which they are attached to form a benzo ring, but when Y is NR ₉ , it is hydrogen;
[27] R ₇ is an optionally substituted 5- and 6-membered monocyclic aromatic heterocyclo having one heteroatom selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, nitrogen, oxygen and sulfur and optionally benzofused Selected from the group consisting of;
[28] R ₈ is selected from the group consisting of hydrogen and C ₁ -C ₃ alkyl.
[29] The present invention also provides novel pharmaceutical compositions comprising a compound of Formula I or II and a pharmaceutically acceptable diluent.
[30] Since the compounds of formulas (I) and (II) are antagonists of the 5-HT ₆ receptor, the compounds of formulas (I) and (II) are useful for the treatment of various disorders. Accordingly, another embodiment of the present invention provides a method of treating a disorder associated with a 5-HT ₆ receptor comprising administering an effective amount of a compound of Formula I or II to a patient in need. That is, the present invention provides the use of a compound of formula (I) or (II) and a pharmaceutical composition thereof for the treatment of a disorder associated with 5-HT ₆ . More specifically, the present invention comprises administering to a patient in need thereof an effective amount of a compound of formula (I) or an effective amount of a compound of formula (II), mild cognitive impairment, mood disorders (depression, mania, bipolar Disorders), psychosis (particularly schizophrenia), anxiety (including generalized anxiety disorders, panic disorders and obsessive compulsive disorders), idiopathic and drug-induced Parkinson's disease, epilepsy, cramps, migraine headaches (migraine headaches Substance withdrawal (including substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, sleeping pills, etc.), sleep disorders (including narcolepsy), attention deficit / hyperactivity disorders, behavioral disorders , Learning disabilities, dementia (including Alzheimer's disease and AIDS-induced dementia), Huntington's chorea, cardiac bypass composition surgery and cognitive deficiency after seizures, seizures, cerebral infarction, spinal cord trauma, head trauma, emergence Provided are methods of treating disorders selected from the group consisting of prenatal hypoxia, cardiac arrest and hypoglycemic neuronal damage, vascular dementia, multiple infarct dementia, amyotrophic lateral sclerosis and multiple sclerosis.
[31] The present invention also provides a process for the preparation of the compounds of formulas (I) and (II).
[32] As used herein, the meanings of the following terms are as follows.
[33] The term "C ₁ -C ₃ alkyl" refers to a straight or branched chain alkyl chain of 1 to 3 carbon atoms and includes methyl, ethyl, propyl and iso-propyl.
[34] The term "optionally substituted phenyl" refers to a radical of the formula
[35]
[36] Wherein R _a is hydrogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, benzyloxy, carboxy, C ₁ -C ₄ alkoxycarbonyl, amido, N- (C _1- C ₄ alkyl) amido, sulfonylamido, cyano, trifluoromethyl, trifluoromethoxy, nitro, and C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, cyano and trifluoro 1 to 3 groups independently selected from the group consisting of phenyl optionally substituted with methyl.
[37] The term "optionally substituted naphthyl" refers to a radical of the formula
[38]
[39] Wherein R _c is 1 or 2 groups independently selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, cyano, trifluoromethyl and nitro.
[40] The term “optionally substituted 5-membered and 6-membered monocyclic aromatic heterocycle having one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur” refers to a radical of the formula:
[41] And
[42] Wherein Q ₁ is selected from the group consisting of —O—, —S— and —NR _g —, wherein R _g is selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl; Q ₂ is -N = and R _d , each R _e and R _f are each independently from the group consisting of hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, cyano and trifluoromethyl Or R _d and R _e (or one of R _e ) are each combined together with the atoms to which they are attached to form a benzo ring, which is hydrogen, hydroxy, C ₁ -C ₄ alkyl, C _1- C ₄ alkoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, halogen, carboxy, C ₁ -C ₄ alkoxycarbonyl, amido, N- (C ₁ -C ₄ Alkyl) amido, amino, (C ₁ -C ₄ alkyl) amino, acylamino selected from the group consisting of C ₁ -C ₄ alkyl and phenyl; Cyano, nitro, sulfonylamido; Phenyl optionally substituted with C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, cyano and trifluoromethyl; Phenoxy, benzyloxy, -NHS (O) ₂ R _h , wherein R _h is selected from the group consisting of C ₁ -C ₄ alkyl and phenyl, and -S (O) _p R _i , wherein p is 0, 1 or 2, R _i is selected from C ₁ -C ₄ alkyl, and C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, cyano, and the group consisting of optionally substituted phenyl as trifluoromethyl) Optionally substituted with 1 to 4 substituents independently selected from the group consisting of R _f is selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, trifluoromethyl and halogen. This term specifically includes furyl, thienyl, pyrrolyl, pyridyl, benzofuryl, benzothienyl, indolyl and quinolinyl, each optionally substituted as described above.
[43] The term "fluorinated C ₂ -C ₄ alkyl" refers to a straight or branched chain alkyl chain of 2 to 4 carbon atoms substituted with one or more fluorine atoms. This term refers to 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3- Trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, 2,2,3,3-tetrafluoropropyl, 4,4,4-trifluorobutyl, 3,3,4, 4,4-pentafluorobutyl and the like.
[44] The term "optionally substituted phenylsulfonyl" refers to a radical of the formula
[45]
[46] Wherein R _j is 1 to 3 groups independently selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, cyano, trifluoromethyl, nitro and phenyl.
[47] The term "optionally substituted benzyl" refers to a radical of the formula
[48]
[49] Wherein R _k is 1 to 3 groups selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, cyano, nitro, trifluoromethyl and halogen.
[50] The term "optionally substituted 5- and 6-membered monocyclic aromatic heterocycle having one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur" denotes a radical of the formula:
[51] And
[52] Wherein Q ₃ is selected from the group consisting of -O-, -S- and NR _{g '} -wherein R _g' is selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl; Q ₄ and Q ₅ are —CR _m , wherein each R _m is independently selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, halogen and trifluoromethyl, or one of Q ₄ and Q ₅ or Both are -N =; One or two of Q ₆ is —N =, while the others are —CR _n (where each R _n is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, cyano, nitro and Independently selected from the group consisting of trifluoromethyl). The term specifically refers to furyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, thiisoxazolyl, pyridyl, pyrimidyl, optionally substituted as described above. , Pyridazinyl and pyrazindinyl.
[53] The term "C ₁ -C ₄ alkyl" refers to a straight or branched chain alkyl chain of 1 to 4 carbon atoms and includes methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, isobutyl and t-butyl .
[54] The term "C ₂ -C ₄ alkyl" refers to a straight or branched chain alkyl chain of 2 to 4 carbon atoms and includes ethyl, propyl, iso-propyl, butyl, sec-butyl, isobutyl and t-butyl.
[55] The term “C ₁ -C ₄ alkoxy” refers to a straight or branched chain alkyl chain of 1 to 4 carbon atoms, attached to an oxygen atom, which includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and t-butoxy.
[56] The term "halogen" refers to chloro, fluoro, bromo and iodo atoms.
[57] The term "pharmaceutically acceptable addition salts" refers to acid addition salts.
[58] Compounds and intermediates of formula (I) or (II) described herein form pharmaceutically acceptable acid addition salts with a wide variety of organic and inorganic acids and include physiologically acceptable salts commonly used in pharmaceutical chemistry. Such salts are also part of the present invention. Pharmaceutically acceptable addition salts are formed from pharmaceutically acceptable acids as is well known in the art. Such salts include pharmaceutically acceptable salts known to those skilled in the art, listed in the Journal of Pharmaceutical Science, 66, 2-19 (1977). Typical inorganic acids used to form these salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, superphosphoric acid, metaphosphoric acid, pyrophosphoric acid, and the like. Salts derived from organic acids such as aliphatic monocarboxylic and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic acids and hydroxyalkanedic acids, aromatic acids, aliphatic and aromatic sulfonic acids can also be used. Thus, the pharmaceutically acceptable salts include chloride, bromide, iodide, nitrate, acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, Hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, isobutyrate, phenylbutyrate, α-hydroxybutyrate, butyne-1,4-dicarboxylate, hexin-1,4- Dicarboxylate, caprate, caprylate, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hypofurlate, lactate, malate, maleate, hydroxymaleate, malonate , Mandelate, mesylate, nicotinate, isonicotinate, oxalate, phthalate, terraphthalate, propiolate, phthalate Cypionate, Phenylpropionate, Salicylate, Sebacate, Succinate, Suberate, Benzenesulfonate, p-Bromobenzenesulfonate, Chlorobenzenesulfonate, Ethylsulfonate, 2-hydroxyethylsulfonate, Methylsulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, naphthalene-1,5-sulfonate, p-toluenesulfonate, xylenesulfonate, tartrate and the like.
[59] For any group of pharmaceutically active compound, some groups may be desirable for end use applications of the compound. Preferred embodiments of the invention are given as compounds of formula (I)
[60] Preferred are compounds wherein X is selected from the group consisting of -O-, -NH- and -S-, more preferably compounds wherein X is -O-.
[61] Preference is given to compounds wherein R ₁ is optionally substituted phenyl or one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and optionally benzofused, optionally substituted 5- and 6-membered monocyclic aromatic heterocycles. .
[62] When R ₁ is optionally substituted phenyl, preferred substituents are hydrogen, C ₁ -C ₄ alkyl, halogen, benzyloxy, carboxy, C ₁ -C ₄ alkoxycarbonyl, amido, N- (C ₁ -C ₄ alkyl Optionally as amido, sulfonylamido, cyano, trifluoromethyl, trifluoromethoxy, nitro, and C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, cyano and trifluoromethyl 1 to 3 groups independently selected from the group consisting of substituted phenyl.
[63] When R ₁ is optionally substituted phenyl, more preferred substituents are 1 to 3 groups independently selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, halogen, cyano and trifluoromethyl.
[64] Preference is given to compounds wherein R ₃ is hydrogen or fluorine.
[65] When R ₁ is a compound having one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and optionally benzofused, optionally substituted 5- and 6-membered monocyclic aromatic heterocycles, benzo fused compounds are preferred. Indolyl is preferred, and indol-3-yl is even more preferred.
[66] When R ₁ is indol-3-yl, preferred groups are shown as the following radicals.
[67]
[68] a) R _o is selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl, more preferably hydrogen;
[69] b) R _p is selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl, more preferably hydrogen;
[70] c) R _q is selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy and halogen, more preferably hydrogen;
[71] d) R _{q '} is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, halogen, and -S ( O) _p R _i , wherein p is 2 and R _i is C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, phenyl optionally substituted with trifluoromethyl, with halogen being most preferred;
[72] e) R _{q ''} is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, nitro, cyano, trifluoromethyl and —S (O) _p R _i where p is 2 , R _i is phenyl optionally substituted with C ₁ -C ₄ alkyl, more preferably halogen;
[73] f) R _{q '''} is selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, trifluoromethyl, cyano and nitro, with hydrogen and halogen being preferred.
[74] Preference is given to compounds in which R ₄ is selected from the group consisting of C ₂ -C ₄ alkyl, fluorinated C ₂ -C ₄ alkyl and optionally substituted phenyl.
[75] When R ₄ is C ₂ -C ₄ alkyl, particularly preferred groups include propyl, isopropyl and butyl.
[76] When R ₄ is fluorinated C ₂ -C ₄ alkyl, preferred groups are 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3,3-difluoro Propyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl and 2,2,3,3-tetrafluoropropyl.
[77] When R ₄ is optionally substituted phenyl, preferred groups are 1 to 3 independently selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, cyano and trifluoromethyl Groups are included.
[78] Preferred embodiments of the invention are given as compounds of formula II as follows:
[79] Preference is given to compounds wherein R ₇ is optionally substituted phenyl or one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and is optionally benzofused, optionally substituted 5- and 6-membered monocyclic aromatic heterocycles. .
[80] When R ₇ is optionally substituted phenyl, preferred substituents are independently selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, cyano, trifluoromethoxy and trifluoromethyl 1 to 3 groups.
[81] When R ₇ is a compound which has one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and is optionally benzofused, optionally substituted 5- and 6-membered monocyclic aromatic heterocycles, benzofused compounds are preferred. Indolyl is preferred, indol-3-yl is even more preferred, and indol-3-yl as depicted in formula (I) above.
[82] Preferred compounds of formula (II) have points of attachment shown below:
[83] And
[84] Although only compounds of formula I are shown, both compounds of formulas I and II are prepared as described in Schemes A and B below. In the schemes below, all substituents are as defined above, unless otherwise indicated, and all starting materials and agents are well known and understood in the art and can be readily available or prepared by the methods described herein. In the following schemes, it should be understood that protecting groups may be used as appropriate to prepare parts of formula (I) or (II). Selective use and removal of suitable protecting groups are well known and well known in the art [Protection Groups in Organic Synthesis, Theodora Greene (Wiley-Interscience)].
[85]
[86] Scheme A illustrates an alternative method for preparing a compound of Formula I by reductive amination.
[87] In one alternative of step a of Scheme A, a suitable compound of formula (1) is contacted with a suitable compound of formula (2) in a reductive amination reaction to produce a compound of formula (I). Suitable compounds of formula (1) are those in which R ₁ and R ₂ are those required for the final product of formula (I) or give rise to the groups required for the final product of formula (I). Suitable compounds of formula (2) are those in which X, R ₃ and R ₄ are those required for the final product of formula (I) or give rise to the groups required for the final product of formula (I).
[88] In another alternative to step a of formula A, a suitable compound of formula (3) is contacted with a suitable compound of formula (4) in a reductive amination reaction to produce a compound of formula (I). Suitable compounds of formula (3) are those in which R ₁ and R ₂ are required for the final product of formula (I) or generate groups required for the final product of formula (I). Suitable compounds of formula (4) are those in which X, R ₃ and R ₄ are those required for the final product of formula (I) or give rise to the groups required for the final product of formula (I).
[89] The reductive amination shown in step a of Scheme A can be carried out under various conditions such as hydrogenation with a suitable catalyst or a suitable reducing agent.
[90] For example, a suitable amine of formula (1) is contacted with a suitable aldehyde of formula (2) (or alternatively suitable amine of formula (4) and a suitable aldehyde of formula (3)) and a suitable reducing agent to form a compound of formula (I) Create The reaction is carried out in a suitable solvent such as methanol, ethanol, tetrahydrofuran or a mixture of methanol or ethanol and tetrahydrofuran, dichloromethane and 1,2-dichloroethane. The reaction can be carried out in the presence of a desiccant, for example sodium sulfate, cupric disulphate, or molecular sieve. The reaction is carried out in the presence of about 1 to 20 molar equivalents of a suitable reducing agent such as sodium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride. It may be advantageous to proceed with Schiff base formation before adding a suitable reducing agent. When using sodium cyanoborohydride, it may be advantageous to monitor and adjust the pH during the course of the reaction as is known in the art. The reaction is generally carried out at 0 ° C. to the reflux temperature of the solvent. In general, the reaction takes 1 to 72 hours. The product can be isolated and purified by techniques well known in the art such as filtration, extraction, evaporation, trituration, chromatography and recrystallization.
[91] In any step b of step A not shown, the pharmaceutically acceptable acid is used to form an acid addition salt of the compound of formula (I). The formation of acid addition salts is well known and known in the art.
[92]
[93] Scheme B shows an alternative process for the preparation of compounds of formula I by formation and reduction of amides.
[94] In one alternative, step a of Scheme B depicts contacting a suitable compound of formula (1) with an appropriate compound of formula (5) in an amide forming reaction to produce a compound of formula (6). Suitable compounds of formula (1) are as described in Scheme A. Suitable compounds of formula (5) are those in which A is an acid halide, activated ester, activated amide or anhydride form and X, R ₃ and R ₄ are required for the final product of formula (I) or To generate the required groups for the final product.
[95] In another alternative, step a of Scheme B illustrates contacting a suitable compound of formula (7) with an appropriate amide formation reaction to produce a compound of formula (8). Suitable compounds of formula (7) are those wherein A is an activating group as described above and R ₁ is required for the final product of formula (I). Suitable compounds of formula (5) are as described in Scheme A. Suitable compounds of formulas (4) and (7) are generally available from commercial suppliers and may be prepared by the methods described herein and by the methods described in the literature.
[96] The amide formation reaction shown in step a of Scheme B is readily carried out in a variety of ways readily available to those skilled in the art, including those commonly performed for peptide synthesis. This method can be carried out on acids, acid halides, activated esters, activated amides and anhydrides.
[97] For example, acid amide formation is facilitated using well-known coupling agents such as carbodiimide, with or without well-known additives such as N-hydrosuccinimide, 1-hydroxybenzotriazole, and the like. It can be done. Such coupling reactions typically use from about 1 to 1.5 molar ratios of acid, amine and coupling agent, typically pyridine, dimethylformamide, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, tetrahydrofuran In an inert aprotic solvent such as the like. It may be advantageous to use a suitable base such as triethylamine or N, N-diisopropylethylamine in the coupling reaction. The reaction is preferably carried out at about 0 ° C. to about 60 ° C. until completion of the reaction, which is typically achieved within 1 to about 48 hours. After completion of the reaction, the product can be isolated and purified by methods well known in the art such as filtration, extraction, evaporation, trituration, chromatography and recrystallization.
[98] Alternatively, for example, acid halides can be used in the reaction. It may be advantageous to use a suitable base to remove the acid generated during the reaction, and suitable bases include, for example, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine and the like. do. Typically, about 1 to 1.5 molar ratios of acid halides and amines are used. The reaction can be carried out in various inert aprotic solvents such as pyridine, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran and the like. The reaction is preferably carried out at about 0 ° C. to about 60 ° C. until the completion of the reaction achieved within 1 to about 12 hours. After completion of the reaction, the product can be isolated and purified by methods well known in the art such as filtration, extraction, evaporation, trituration, chromatography and recrystallization.
[99] Alternatively, for example, acid halides can be used for the reaction under Schotten-Baumann conditions. Typically, 1 to 10 molar equivalents of amine are used under these conditions. Such coupling generally employs suitable bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like to remove the acid generated during the reaction. The reaction can be carried out in various mixed solvent systems and water such as dichloromethane, chloroform, ethyl acetate, tetrahydrofuran and the like. The reaction is preferably carried out at about 0 ° C. to about 80 ° C. until the completion of the reaction achieved within 1 to about 6 hours. After completion of the reaction, the product can be isolated and purified by techniques well known in the art, such as filtration, extraction, evaporation, trituration, chromatography and recrystallization.
[100] Alternatively, anhydrides (symmetric or mixed) can be used for the reaction, for example. Such anhydrides are formed by various methods known in the art. Typically, about 1 to 1.5 molar equivalents of anhydride and amine are used. It may be advantageous to use a suitable base to remove the acid that occurs during the reaction. Suitable bases include, for example, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, sodium carbonate, potassium carbonate, sodium bicarbonate and the like. The reaction can be carried out in various solvents. The reaction is preferably carried out at about 0 ° C. to about 60 ° C. until the completion of the reaction achieved within 1 to about 12 hours. After completion of the reaction, the product can be isolated and purified by techniques well known in the art such as filtration, extraction, evaporation, trituration, chromatography and recrystallization.
[101] Step b in Scheme B depicts reducing the compound of formula (6) or (8) to produce the compound of formula (I).
[102] For example, the compound of formula (6) or (8) is contacted with a suitable reducing agent to produce the compound of formula (I). Suitable reducing agents are those capable of reducing the amide to amines and include borane agents such as borane dimethyl sulfide complexes, hydride delivery agents such as aluminum hydride and lithium aluminum hydride, and the like. The reaction is typically carried out in a solvent such as tetrahydrofuran or diethyl ether, using 1 to 10 equivalents of reducing agent. The reaction is generally carried out at about 0 ° C. to the reflux temperature of the selected solvent, and typically takes 1 to about 48 hours. The product can be isolated and purified by techniques well known in the art such as quenching, filtration, extraction, evaporation, trituration, chromatography and recrystallization.
[103] As an optional step of Scheme B not shown, pharmaceutically acceptable acids are used to form acid addition salts of compounds of formula (I). The formation of acid addition salts is well known and known in the art.
[104] In Scheme A and B, as an optional step not shown, it is possible to those skilled in the art to produce compounds other than hydrogen the R _2, and R ₂ is hydrogen the alkylation of compounds of formula I, as read. Methods of alkylating such secondary amines are well known in the art and are discussed in step c of Scheme C below.
[105] In Schemes A and B, as will be appreciated by those skilled in the art, compounds of formula II may also be prepared by the methods described in schemes A and B using the compounds of formulas (9) and (10).
[106] And
[107] Suitable compounds of formula (9) are compounds wherein Y, R ₅ and R ₆ are required for the final product of formula II, and suitable compounds of formula (10) are those in which A is an active group as described above, Y, R ₅ and R ₆ are those required for the final product of Formula II.
[108] Starting materials for Schemes A and B are prepared by the following schemes. In the following reactions, all substituents are as defined above, unless otherwise indicated, and all starting materials and agents are well known and known in the art.
[109] Scheme C describes methods for the preparation of compounds of formula (1).
[110]
[111] Step a in Scheme C depicts the reaction of a suitable aldehyde of formula (24) and nitromethane to produce a compound of formula (25). Suitable aldehydes of formula (24) are aldehydes in which R ₁ is required for the final product of formula (I). The reaction of the aldehydes with the anions of natromethane to produce nitro olefins is well known and known in the art [Modern Synthetic Reactions, HO House (2nd ed. The Benjamin / Cummings Publishing Company 1972)].
[112] For example, an appropriate aldehyde of formula (24) is condensed with nitromethane to produce a compound of formula (25). Typically, the reaction is carried out in the presence of excess nitromethane. The reaction is carried out in suitable solvents such as tetrahydrofuran, nitromethane and dimethyl sulfoxide. The reaction is about 1.1. To about 3 molar equivalents of a suitable base such as sodium bis (trimethylsilyl) amide, potassium t-butoxide, sodium hydride, sodium acetate, triethylamine, N, N-diisopropylethylamine, ammonium salts, eg For example using ammonium acetate. The reaction is carried out at about -20 [deg.] C. to the reflux temperature of the selected solvent and generally takes 6 to 48 hours. The products of the coupling reaction can be isolated and purified using techniques well known in the art, such as extraction, evaporation, chromatography and recrystallization.
[113] Step b of Scheme C depicts the reduction of the compound of formula (25), producing a compound of formula (1) wherein R ₂ is hydrogen.
[114] For example, a suitable compound of formula (25) is hydrogenated on a suitable catalyst such as Raney® nickel or palladium catalyst. If Raney nickel is used, the reaction is carried out in a suitable solvent such as ethanol, methanol, water and mixtures thereof. It may be advantageous to carry out the hydrogenation under acidic conditions, for example with hydrochloric acid or sulfuric acid. When using a palladium catalyst, palladium on carbon is preferred and the reaction is carried out in a suitable solvent such as ethanol, methanol, tetrahydrofuran, water and mixtures thereof. It may be advantageous to carry out the hydrogenation under acidic conditions, for example with hydrochloric acid, trifluoroacetic acid or sulfuric acid. The reaction is generally carried out at temperatures from room temperature to 70 ° C. The reaction is carried out using hydrogen at 15 psi to 120 psi pressure in a device designed to carry out the reaction under pressure, such as a Parr® hydrogenation device. The product can be isolated by carefully removing the catalyst by filtration and evaporation. The product can be purified by extraction, evaporation, trituration, chromatography and recrystallization.
[115] Alternatively, for example, a suitable compound of formula (25) is contacted with a suitable reducing agent. Suitable reducing agents include hydride delivery agents such as aluminum hydride and lithium aluminum hydride and the like. The reaction is typically carried out in a solvent such as tetrahydrofuran or diethyl ether, using 1 to 10 equivalents of reducing agent. The reaction is generally carried out at about 0 ° C. to the reflux temperature of the selected solvent and typically takes 1 to about 48 hours. The product can be isolated and purified by techniques well known in the art such as quenching, filtration, extraction, evaporation, trituration, chromatography and recrystallization.
[116] In addition, a suitable compound of formula (25) can be reduced in two steps with a compound of formula (1). For example, an agent such as sodium borohydride can be used to reduce the vinyl group of the compound of formula (25). The reaction is typically carried out using excess borohydride in a solvent such as methanol, ethanol, isopropanol, water and the like. Intermediate 2-nitroethyl compounds can be isolated and purified by techniques well known in the art such as quenching, filtration, extraction, grinding, chromatography and recrystallization. Thereafter, various methods such as hydrogenation and hydride delivery agents as discussed above can be used to reduce the intermediate 2-nitroethyl compound. In addition, an intermediate 2-nitroethyl compound can be reduced using a metal such as zinc to produce the required amine of formula (1) wherein R ₂ is hydrogen.
[117] Step c of Scheme C shows an optional alkylation of a compound of formula (1) in the compound R _2, R ₂ is hydrogen to produce a of formula (I) other than hydrogen.
[118] For example, a compound of formula (1) wherein R ₂ is hydrogen is contacted with a suitable alkylating agent. Suitable alkylating agents are alkylating agents which deliver the R ₂ required for the final product of formula (I). The reaction is carried out in a suitable solvent such as dioxane, tetrahydrofuran, tetrahydrofuran / water mixture or acetonitrile. The reaction is carried out in the presence of 1.0 to 6.0 molar equivalents of a suitable base such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, triethylamine or N, N-diisopropylethylamine. The reaction is generally carried out at -78 ° C to reflux temperature of the solvent. In general, the reaction takes 1 to 72 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography and recrystallization.
[119] Alternatively, for example, to produce a compound of formula (1) compounds of formula (I) R ₂ is hydrogen is an aldehyde or ketone and a reducing Oh causes a folk R ₂ is not hydrogen. Suitable aldehydes include formaldehyde, acetaldehyde, propionaldehyde and acetone. The reaction is carried out as described in step a of Scheme A.
[120] In another alternative, for example, a compound of formula (1) wherein R ₂ is hydrogen results in amide or carbamate formation followed by reduction to yield a compound of formula (1) in which R ₂ is not hydrogen. Suitable aldehydes include formaldehyde, acetaldehyde, propionaldehyde and acetone. The reaction is carried out as described in step a of Scheme A.
[121] Steps d and e of Scheme C form an amide of formula (27) via amide formation using an appropriate compound of formula (7) and an amine of formula (26), followed by reduction of the compound of formula (1) The production method of an alternative of the compound of General formula (1) to produce is shown. Suitable compounds of formula (7) are as described in Scheme B. Suitable amines of formula (26) are amines which provide the R ₂ required for the final compound of formula (I). Those skilled in the art will recognize that various amides of formula (27) are commercially available and available in the art.
[122] Amide formation and reduction in Scheme C is carried out as described in Scheme B.
[123] Scheme D describes a process for preparing formula (1) wherein R ₁ is optionally substituted indol-3-yl.
[124]
[125] Step a of Scheme D depicts a two step reaction in which the appropriate indole of formula (28) is reacted with oxalyl chloride followed by the appropriate amine R ₂ NH ₂ of formula (26) to produce the compound of formula (29) . Suitable indoles of formula (28) are indole wherein Z 'represents any substituent on indole 2- and 4- to 7-positions as required for the final product of formula (I). Suitable amines of formula (26) are as described in Scheme C above.
[126] For example, a suitable indole of formula (28) is contacted with about 1-2 molar equivalents of oxalyl chloride to produce the intermediate keto-acid chloride. The reaction is carried out in a suitable solvent such as diethyl ether or tetrahydrofuran. The reaction is generally carried out at a temperature of 0 ° C. to 40 ° C., and generally takes 6 to 48 hours. Intermediate keto-acid chloride products can be isolated and purified using techniques well known in the art, such as extraction, evaporation, chromatography and recrystallization. In general, intermediate keto-acid chloride products are used directly after isolation. The intermediate keto-acid chloride product is contacted with a suitable amine R ₂ NH ₂ as defined above using the procedure described above.
[127] Step b of Scheme D depicts the reduction of the compound of formula (29), yielding a compound of formula (1) wherein R ₁ is optionally substituted indol-3-yl.
[128] For example, a suitable reducing agent such as lithium aluminum hydride is used to reduce the compound of formula (29) to produce a compound of formula (1) wherein R ₁ is optionally substituted indol-3-yl. The reaction is carried out using typically 1 to 12 molar equivalents of reducing agent in a solvent such as tetrahydrofuran or diethyl ether. The reaction is generally carried out at about 0 ° C. to the reflux temperature of the selected solvent and typically takes 12 to about 48 hours. The product can be isolated and purified by techniques well known in the art such as quenching, filtration, extraction, evaporation, trituration, chromatography and recrystallization.
[129] In step c of Scheme D, the appropriate indole of formula (28) is formylated to give the compound of formula (30). Suitable indole of formula (28) is as described in step a above.
[130] For example, a suitable indole of formula (28) is reacted with a suitable formyl delivery agent, such as the Vilsmeier agent formed from dimethylformamide. Generally, about 1 molar equivalent of formyl delivery agent is used. The reaction is carried out in a suitable solvent such as benzene, dimethylformamide, tetrahydrofuran or diethyl ether. The reaction is carried out at a temperature of about -70 deg. C to about 20 deg. C, and generally takes 1 to 6 hours. The reaction product can be isolated and purified using techniques well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.
[131] In step d of Scheme D, the appropriate indole of formula (28) is contacted with (CH ₃ ) ₂ N—CH═CH—NO ₂ to form a compound of formula (30). Suitable indole of formula (28) is as described in step a above.
[132] For example, a suitable indole of formula (28) is reacted with 1-dimethylamino-2-nitroethylene. Generally, about 1 equimolar amount of the formulation is used. The reaction is carried out in a suitable solvent such as trifluoroacetic acid or dichloromethane containing about 2 to 15 equivalents of trifluoroacetic acid. The reaction takes place at a temperature of about -70 ° C to about 20 ° C and generally takes 1 to 24 hours. The reaction product can be isolated and purified using techniques well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.
[133] Steps e and f of Scheme D produce a reaction of an aldehyde of formula (30), which produces a nitro olefin of formula (31), and a compound of formula (1), wherein R ₁ is optionally substituted indol-3-yl. The reduction of olefins to natro is shown. These steps can be carried out using the method described in Scheme C.
[134] As will be appreciated by those skilled in the art, in steps not shown, if desired, a suitable amine protecting group can be used to substitute the indole nitrogen of the compound of formula (1) to produce a compound wherein R ₁ is 1-substituted indol-3-yl. Can be. As one skilled in the art will also appreciate, at the stage described in Scheme C, R ₂ groups other than hydrogen can be introduced in various ways.
[135] Scheme E describes a process for the preparation of compounds of formula (2) wherein X is -O- or -S-.
[136]
[137] Step a in Scheme E illustrates acetal formation of the appropriate compound of formula (11), yielding a compound of formula (12). Suitable compounds of formula (11) are those wherein X and R ₃ are required for the final compound of formula (I). Such acetal formation reactions can be readily accomplished by methods well known in the art [Protecting Groups in Organic Synthesis, Theodora Greene (Wiley-Interscience)].
[138] For example, the compound of formula (11) is contacted with a suitable alcohol HOR under acid catalyst. Suitable alcohols are alcohols which are stable in the reaction of step b and which form acetal which is removed in the reaction of step c to give the compound of formula (2). Suitable alcohols include methanol, ethanol, propanol, 1,3-propane diol, ethylene glycol and the like.
[139] In step b of Scheme E, a suitable compound of formula (11), (12) or (14) is reacted with a preferred R ₄ group delivery agent to produce a compound of formula (2), (13) or (15), respectively. . Suitable compounds of formula (11), (12) and (14) are those wherein X and R ₃ are required for the final product of formula (I). Various agents that deliver the required R ₄ in the final product are available and suitable for the reaction shown in Scheme E. Such agents include halopyridine, halopyridine N-oxides, allyl halides, C ₂ -C ₄ alkanols, C ₂ -C ₄ alkyl halides and sulfonates, fluorinated C ₂ -C ₄ alkanols, fluorinated C ₂ -C ₄ alkyl halides and sulfonates, optionally substituted phenyl having one or more fluoro or chloro atoms, optionally substituted phenylsulfonyl halides or anhydrides, and optionally substituted benzyl halides.
[140] For example, if the suitable R ₄ group delivery agent is a halide, sulfonate or anhydride, the appropriate compounds of formulas (11), (12) or (14) are coupled under basic conditions, respectively to formulas (2), (13) Or (15). The reaction is carried out in suitable solvents such as acetonitrile, dimethylformamide, dimethylacetamide, tetrahydrofuran, pyridine and dimethyl sulfoxide. The reaction is in the presence of about 1 to about 3 molar equivalents of a suitable base such as potassium hydride, sodium hydroxide, sodium hydride, sodium carbonate, potassium carbonate, cesium carbonate, N, N-diisopropylethylamine, triethylamine and the like. Conduct. The reaction is carried out at a temperature of about -30 ° C to about 100 ° C and generally takes 6 to 48 hours. The reaction product can be isolated and purified using techniques known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.
[141] Of course, when using halopyridine N-oxides, the N-oxides are removed by reduction to produce the R ₄ required for the final product of formula (I). Such reduction can be readily performed by one skilled in the art and includes catalytic reduction on a palladium catalyst using hydrogen or ammonium formate in a suitable solvent such as methanol, ethanol, water and mixtures thereof.
[142] Alternatively, for example, when the appropriate R ₄ group delivery agent is alkanol, the coupling can be carried out under Mitsunobu conditions well known in the art. The reaction is carried out in a suitable solvent such as tetrahydrofuran and diethyl ether, phosphines such as triphenylphosphine or resin bound phosphine, and diethyl azodicarboxylate, diisopropyl azodicarboxylate or di- This is done using dialkyl azodicarboxylates such as t-butyl azodicarboxylate. The reaction is carried out at a temperature of about room temperature to about 60 ℃. The reaction generally takes 1 to 12 hours. The product can be isolated by techniques well known in the art, such as extraction and evaporation. The product can then be purified by techniques well known in the art such as distillation, chromatography or recrystallization.
[143] Step c of Scheme E depicts the deprotection of acetal of formula (13), resulting in a compound of formula (2). Such deprotection can be readily performed by methods well known in the art [Protecting Groups in Organic Synthesis, Theodora Greene (Wiley-Interscience)].
[144] For example, the compound of formula (13) is contacted under acidic conditions under aqueous conditions to produce the compound of formula (2).
[145] In step d of Scheme E, the bromo compound of formula (15) is formylated to give the compound of formula (2).
[146] For example, compounds of formula (15) are metallized by treatment with metallization agents such as butyllithium. The reaction is carried out in a suitable solvent such as hexane, benzene, toluene, tetrahydrofuran or diethyl ether. The reaction is typically carried out in the presence of about 1 to about 1.5 molar equivalents of metallization agent. The metallization reaction is carried out at a temperature of about -70 ° C to about 20 ° C, and generally takes 1 to 6 hours. The metallized species are then treated with formyl delivery agents, such as dimethylformamide or alkyl chloroformates, to produce a compound of formula (2) or an alkoxycarbonyl compound, which may be prepared as the aldehyde described herein. The reaction product can be isolated and purified using techniques well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.
[147] Scheme F describes a process for the preparation of the compound of formula (2) from the multipurpose intermediate compound (17) which is readily prepared by acetal formation as described above.
[148]
[149] Step a of Scheme F yields a compound of formula (13) and a suitable alcohol (R ₄ OH), which yields a compound of formula (13) as defined in Scheme E above, wherein X is -O- or -S-. The aromatic exchange reaction of a suitable thiol (R ₄ SH) is shown. Suitable compounds of formula (17) are those wherein R ₃ is required for the final product of formula (I). In suitable alcohols (R ₄ OH) or suitable thiols (R ₄ SH), R ₄ is what is required for the final product of formula (I) and C ₂ -C ₄ alkyl alcohols and thiols, optionally substituted phenols and thiophenols, optionally substituted Benzyl alcohol and thiols.
[150] For example, a suitable compound of formula (17) and a suitable alcohol (R ₄ OH) or a suitable thiol (R ₄ SH) are coupled to form a compound of formula (13). The reaction is carried out in suitable solvents such as dimethylformamide, dimethylacetamide and dimethyl sulfoxide. The reaction is carried out using about 1.1 to 3 molar equivalents of a suitable alcohol or thiol. The reaction is carried out in the presence of about 1 to about 6 molar equivalents of a suitable base such as potassium hydride, sodium hydroxide, potassium carbonate, sodium carbonate or sodium hydride. Coupling is carried out using a suitable catalyst such as a copper salt. The reaction generally takes 6 to 48 hours. The product of the coupling reaction can be isolated and purified using techniques well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.
[151] Steps b through e of Scheme F illustrate various reactions of the appropriate compound of Formula (17) after metallization described in Step d of Scheme E, each producing a compound of Formulas (18) to (21). In these steps, suitable compounds of formula (17) are those in which R ₃ is required in the final product of formula (I) and is not negatively affected by the metallization conditions of the reaction. In general, these reactions are carried out in the solvent and temperature used to form the metallized species. The products of these reactions can be isolated and purified using techniques well known in the art, including quenching, extraction, evaporation, trituration, chromatography and recrystallization.
[152] For example, in step b of Scheme F, the metallized compound of formula (17) is contacted with a suitable disulfide (R ₄ S-) ₂ to produce a compound of formula (18). Suitable disulfides are disulfides which produce the R ₄ required in the final product of formula (I) and give rise to compounds wherein X is -S-. Suitable disulfides include C ₁ -C ₄ alkyl disulfides, optionally substituted phenyl disulfides, and optionally substituted benzyl disulfides. The reaction is carried out using about 1 to about 2 molar equivalents of a suitable disulfide. The reaction is typically carried out at a temperature of about -78 ° C to about 50 ° C in the same solvent used for metallization. The reaction generally takes 12 to 48 hours.
[153] For example, in step c of Scheme F, the metallized compound of formula (17) is contacted with a suitable sulfonyl fluoride (R ₄ SO ₂ F) to produce compound of formula (19). Suitable sulfonyl fluorides are sulfonyl fluorides which deliver the required R ₄ in the final product of formula (I) and give rise to compounds wherein X is —SO ₂ —. Suitable sulfonyl fluorides include optionally substituted phenyl sulfonyl fluorides. The reaction is carried out using about 1 to about 3 molar equivalents of a suitable sulfonyl fluoride. The reaction is typically carried out at a temperature of about -78 ° C to about 0 ° C in the same solvent used for metallization. The reaction generally takes 2 to 12 hours.
[154] For example, in step d of Scheme F, the metallized compound of formula (17) is contacted with a suitable acid chloride (R ₄ C (O) Cl) to produce compound of formula (20). Suitable acid chlorides are acid chlorides which deliver the required R ₄ in the final product of formula (I) and give rise to compounds in which X is —C (O) —. Suitable acid chlorides include C ₂ -C ₄ alkyl acid chlorides, fluorinated C ₂ -C ₄ alkyl acid chlorides, optionally substituted phenyl acid chlorides, optionally substituted benzyl acid chlorides, and optionally substituted 5- and 6-membered monocyclic Click aromatic heterocycle acid chlorides. The reaction is carried out using about 0.8 to about 1.2 molar equivalents of a suitable acid chloride. The reaction is typically carried out at a temperature of about -78 ° C to about 50 ° C in the same solvent used for the metallization. The reaction generally takes 1 to 12 hours.
[155] For example, in step e of Scheme F, the metallized compound of formula (17) is contacted with a suitable aldehyde (R ₄ C (O) H) to produce compound of formula (21). Suitable aldehydes are aldehydes which transfer the required R ₄ to the final product of formula (I) and give rise to compounds wherein X is —CH (OH) —. Suitable aldehydes include C ₂ -C ₄ alkyl aldehydes, fluorinated C ₂ -C ₄ alkyl aldehydes, optionally substituted phenyl aldehydes, optionally substituted benzyl aldehydes, and optionally substituted May and 6 membered monocyclic aromatic heterocycle aldehydes Included. The reaction is carried out using about 1 to about 3 molar equivalents of suitable aldehyde. The reaction is typically carried out at a temperature of about -50 ° C to about 50 ° C in the same solvent used for metallization. The reaction generally takes 4 to 24 hours.
[156] As will be appreciated by those skilled in the art, the compounds of formulas (18) to (21) may undergo various other modifications shown in steps f to i of Scheme F to finally produce compounds of formula I having various groups at X have. Such modifications are obvious and can be fully implemented by those skilled in the art. Such modifications include oxidation of sulfides (step f), which can be achieved with peroxides, peracids and other agents known in the art; Reduction of benzyl alcohol which can be achieved with various agents such as triethylsilane / trifluoroacetic acid (step g); Halogenation of benzyl alcohol to produce fluoro using agents such as DAST and fluorinated agents (step h); Reduction of ketones using various hydride delivery agents (step i) or oxidation of benzyl alcohol (step i) that can be achieved under manganese dioxide or Swern conditions.
[157] In step j of Scheme F, the compounds of formulas (13) and (18) to (23) are deprotected to produce an aldehyde of formula (2) as described in step c of scheme E.
[158] Scheme G describes a process for the preparation of compounds of formula (5).
[159]
[160] In step a of Scheme G, the bromo compound of formula (15) is carboxylated to produce a compound of formula (5) wherein A is -OH.
[161] For example, the compound of formula (15) is metallized as described in step d of Scheme E, and then the metalized species are treated with carbon dioxide to produce a compound of formula (5) wherein A is -OH. The reaction product can be isolated and purified using techniques well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.
[162] In step b of Scheme G, the bromo compound of formula (15) is alkoxyformylated using a suitable chloroformate or carbonate to produce a compound of formula (32). Suitable chloroformates or carbonates are chloroformates or carbonates that carry the RO (O) C- group wherein R is methyl, ethyl or benzyl.
[163] For example, the compound of formula (15) is metalized as described in step d of Scheme E, and then the metalized species is treated with about 1 to 3 molar equivalents of appropriate chloroformate or carbonate. The reaction is typically carried out at a temperature of about -78 ° C to about 50 ° C in the same solvent used for the metallization. The reaction typically takes 1 to 24 hours. The reaction product can be isolated and purified using techniques well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.
[164] In step c of Scheme G, a suitable compound of formula (33) is reacted with a preferred R ₄ group transfer agent to produce compound of formula (32). Suitable compounds of formula (33) are those wherein X and R ₃ are required for the final product of formula (I). Formulations delivering R ₄ are as described in Scheme E.
[165] For example, when the R ₄ group delivery agent is a halide or anhydride, the appropriate compound of formula (34) is coupled under basic conditions to produce the compound of formula (33). The reaction is carried out in a suitable solvent such as dimethylformamide, tetrahydrofuran or pyridine. The reaction is typically carried out in the presence of about 1 to about 3 molar equivalents of a suitable base such as sodium carbonate, potassium carbonate, cesium carbonate, N, N-diisopropylethylamine, triethylamine and the like. The reaction is carried out at a temperature of about −30 ° C. to about 100 ° C. and generally takes 6 to 48 hours. The reaction product can be isolated and purified using methods well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.
[166] Alternatively, for example, where the appropriate R ₄ group delivery agent is an alkanol, the coupling can be carried out under Mitsunobu conditions well known in the art and described in Scheme E.
[167] In step d of Scheme G, the ester of formula (32) is deprotected to produce a compound of formula (5) wherein A is -OH. Such deprotection can be readily accomplished by methods well known in the art [Protecting Groups in Organic Synthesis, Theodora Greene (Wiley-Interscience)].
[168] In step e of Scheme G, a compound of formula (5) wherein A is —OH is converted to a compound of formula (5) wherein A is an activating group such as an acid halide, activated ester, activated amide or anhydride. The formation of such activated intermediates is well known and known in the art.
[169] For example, acid halides include oxalyl chloride, oxalyl bromide, thionyl chloride, thionyl bromide, phosphorous acid oxychloride, phosphorous acid trichloride, and phosphorous acid pentachloride; Mixed anhydrides of substituted phosphoric acids such as dialkyl phosphoric acid, diphenyl phosphoric acid and halophosphoric acid; Mixed anhydrides of aliphatic carboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid and 2-ethylbutyric acid; Activated esters such as phenol esters, p-nitrophenol esters, N-hydroxysuccinimide esters, N-hydroxyphthalimide esters, 1-hydroxybenztriazole esters; Or various formulations such as activated amides such as imidazole, dimethylpyrazole, triazole, and the like, and are prepared by methods well known and known in the art. Such activated intermediates are used directly in the scheme after preparation, or isolated after preparation and used in the scheme.
[170] Scheme H describes a process for the preparation of compounds of formula (4).
[171]
[172] In step a of Scheme H, the bromo compound of formula (15) is converted to a nitrile of formula (35).
[173] For example, a compound of formula (15) is treated with copper (I) cyanide to produce a compound of formula (35). The reaction is carried out in a suitable solvent such as dimethylformamide. The reaction is typically carried out in the presence of about 1 mole to about 3 moles of copper (I) cyanide. The reaction is carried out at a temperature of approximately room temperature to about 100 ° C. and generally takes about 6 to 48 hours. The reaction product can be isolated and purified using techniques well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.
[174] In step b of Scheme H, the nitrile compound of formula (35) is reduced to produce a compound of formula (4) wherein R ₂ is hydrogen.
[175] For example, the nitrile compound of formula (35) is contacted with sodium borohydride in the presence of cobalt chloride. The reaction is carried out in a suitable solvent such as methanol or ethanol. The reaction is generally carried out at a temperature of 0 ° C to 50 ° C. In general, the reaction takes 1 to 72 hours. The reaction can be isolated and purified by techniques well known in the art such as extraction with an aqueous acid solution, evaporation, trituration, chromatograph and recrystallization.
[176] Alternatively, for example, the nitrile compound of formula (35) is hydrogenated on a suitable catalyst such as Raney® nickel. The reaction is carried out in a suitable solvent, and when Raney® nickel is used as a catalyst, suitable solvents will generally contain ammonia, such as ethanol / ammonium hydroxide. The reaction is generally carried out at temperatures from room temperature to 50 ° C. The reaction is carried out at a pressure of 15 psi (103 kPa) to 120 psi (827 kPa) in a device designed to carry out the reaction under pressure, such as a par hydrogenation device. The product can be isolated by carefully removing the catalyst by filtration and evaporation. The product can be purified by extraction, evaporation, trituration, chromatography and recrystallization.
[177] In step c of Scheme H, the nitrile compound of formula (35) is converted to an amide of formula (36).
[178] For example, compounds of formula (35) are treated with acids or bases under hydrolysis conditions to produce compounds of formula (36). The reaction is carried out in a suitable solvent such as ethanol, isopropanol, dimethyl sulfoxide, each comprising water. Hydrolysis of aromatic nitriles to amides is well known and known in the art. The reaction product can be isolated and purified using techniques well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.
[179] Step d of Scheme H depicts the formation of an amide of formula (37), wherein the compound of formula (5) and the appropriate amine of formula H ₂ NR ₂ are reacted in an amide forming reaction. Suitable amines of formula H ₂ NR ₂ are amines which provide the R ₂ required for the extremity product of formula (I). Suitable methods of forming the amide are well known in the art and are described in Scheme B, above.
[180] In step e of Scheme H, the amide compound of formula (36) or (37) is reduced to the compound of formula (4). Reduction of such amides is readily accomplished as described in Scheme B above and known in the art.
[181] In step f of Scheme H, a compound of formula (2) and a suitable amine of formula H ₂ NR ₂ undergo reductive amination to produce a compound of formula (4). Such reductive amination is readily carried out by the method described in step B above and other methods known in the art.
[182] As will be appreciated by those skilled in the art, the compounds of formula (II) are readily prepared in a similar manner as described above.
[183] The invention is further illustrated by the following examples and preparations. These examples and preparations are illustrative only and are not intended to limit the invention in any way.
[184] The terms used in the examples and preparations have the general meaning unless stated otherwise. For example, "° C" refers to degrees Celsius; "N" refers to normal concentration; "M" indicates molar concentration; "mmol" refers to millimoles; "g" refers to grams; "mL" refers to milliliters; "mp" indicates melting point; "Brine" refers to saturated aqueous sodium chloride solution. ^{In 1} H NMR, all chemical shifts are given by δ unless otherwise indicated.
[185] Example 1
[186] 2- (3- (4-fluorophenoxy) phenyl)-(1,3) dioxolane
[187] 4-fluorophenol (3.0 g, 227.8 mmol), 2- (3-bromophenyl) -1,3-dioxolane (5.0 mL, 33.3 mmol), potassium carbonate (anhydrous, 8.0 g, 55.6 mmol) and dried Pyridine (50 mL) was combined. Copper oxide (5.5 g, 69.5 mmol) was added by heating to 90 ° C. Heated to reflux. After 24 hours, cooled to room temperature, diluted with dichloromethane and filtered. The filtrate was concentrated in vacuo to yield a yellow oil. The oil was chromatographed on silica gel eluting with hexanes: EtOAc (95: 5) to afford the title compound.
[188] By the method of Example 1, the following compounds were prepared:
[189] a) 2- (3- (2-fluorophenoxy) phenyl)-(1,3) dioxolane;
[190] b) 2- (3- (3-fluorophenoxy) phenyl)-(1,3) dioxolane;
[191] c) 2- (3- (naphth-2-yloxy) phenyl)-(1,3) dioxolane;
[192] d) 2- (3- (naphth-1-yloxy) phenyl)-(1,3) dioxolane;
[193] e) 2- (3- (pyrid-3-yloxy) phenyl)-(1,3) dioxolane;
[194] f) 3- (pyridin-3-yloxy) benzaldehyde;
[195] g) 3- (pyrimidin-5-yloxy) benzaldehyde; And
[196] h) 3- (pyridin-4-yloxy) benzaldehyde.
[197] Example 2
[198] 3- [1,3] dioxolan-2-ylphenyl) phenylamine
[199] 2- (3-bromophenyl) -1,3-dioxolane (0.7 mL, 4.3 mmol), aniline (0.4 mL, 4.7 mmol), sodium t-butoxide (0.6 g, 6.0 mmol), BINAP (10.0 mg , 0.03 mol), Pd ₂ (dba) ₃ (30.0 mg, 0.01 mmol) and toluene (20 mL) were combined. Heated at 80 ° C. After 18 hours, cooled to room temperature, diluted with ether (40 mL), filtered and concentrated to give a residue. The residue was chromatographed on silica gel eluting with hexanes: EtOAc (95: 5) to afford the title compound.
[200] By the method of Example 2, the following compounds were prepared:
[201] a) benzyl- (3- [1,3] dioxolan-2-ylphenyl) -amine;
[202] b) (3- [1,3] dioxolan-2-ylphenyl) -pyridin-3-ylamine;
[203] c) (3- [1,3] dioxolan-2-ylphenyl) -pyridin-4-ylamine; And
[204] d) (3- [1,3] dioxolan-2-ylphenyl) -pyridin-2-ylamine.
[205] Example 3
[206] 2- (3-phenylsulfanylphenyl)-[1,3] -dioxolane
[207] 2- (3-bromophenyl) -1,3-dioxolane (3.0 mL, 20.0 mmol) and tetrahydrofuran (100 mL) were combined. Cooled to about -78 ° C. N-butyllithium solution (13.4 mL, 21.0 mmol), a 1.6 M solution in hexane, was added dropwise. After 10 minutes, phenyl disulfide (4.3 g, 20.0 mmol) was added as a solution in tetrahydrofuran (50 mL). After 1 hour, warmed to room temperature over 1 hour, then quenched with water (150 mL) and extracted with ether. The combined organic layers were extracted sequentially with distilled water and brine, then dried (Na ₂ SO ₄ ), filtered and concentrated to give a residue. Chromatography eluting the residue with hexanes: EtOAc (9: 1) afforded the title compound.
[208] By the method of Example 3, the following compounds were prepared:
[209] a) 2- (3-p-tolylsulfanylphenyl)-[1,3] -dioxolane.
[210] Example 4
[211] 2- (3-benzenesulfonylphenyl)-[1,3] -dioxolane
[212] 2- (3-phenylsulfanylphenyl)-[1,3] -dioxolane (1.0 g, 3.6 mmol) and dichloromethane (15 mL) were combined. Cooled to about -78 ° C. A slurry of m-chloroperbenzoic acid (2.3 g, 7.2 mmol) in dichloromethane (10 mL) was added. After 30 minutes, the organic layers were combined and washed sequentially with distilled water and brine, then dried (Na ₂ SO ₄ ), filtered and concentrated to give a residue. Chromatography eluting the residue with EtOAc afforded the title compound.
[213] By the method of Example 4, the following compounds were prepared:
[214] a) 2- (3- (toluene-4-sulfonyl) -phenyl)-[1,3] -dioxolane.
[215] Example 5
[216] (3- [1,3] dioxolan-2-ylphenyl) phenylmethanol
[217] 2- (3-bromophenyl) -1,3-dioxolane (10.0 mL, 66.0 mmol) and tetrahydrofuran (100 mL) were combined and cooled to about -78 ° C. N-butyllithium solution (44.0 mL, 66.0 mmol), a 1.6 M solution in hexane, was added dropwise. After 10 minutes, a benzaldehyde (7.6 mL, 66.0 mmol) solution in tetrahydrofuran (50 mL) was added via cannula. After extraction with dichloromethane, the organic layers were combined and washed sequentially with distilled water and brine, then dried (Na ₂ SO ₄ ), filtered and concentrated to give a residue. Chromatography eluting the residue with hexanes: EtOAc (7: 3) gave the title compound.
[218] Example 6
[219] (3- [1,3] dioxolan-2-ylphenyl) phenylmethanone
[220] (3- [1,3] dioxolan-2-ylphenyl) -phenyl-methanol (5.0 g, 18.5 mmol) and 18-crown-6 (160 mg, 0.6 mmol) in dichloromethane were combined. Potassium permanganate (8.8 g, 55.5 mmol) was added. Heated to about 40 ° C. After 4 hours, cooled to room temperature and added water and sodium bisulfite (6.0 g). Basified with 1 N sodium hydroxide solution (about 60 mL) and extracted with dichloromethane. The organic layers were combined and washed sequentially with distilled and brine, then dried (Na ₂ SO ₄ ), filtered and concentrated to give a residue. Chromatography eluting the residue with EtOAc afforded the title compound.
[221] Example 7
[222] 3-benzylbenzaldehyde
[223] (3- [1,3] dioxolan-2-ylphenyl) -phenyl-methanol (2.3 g, 8.7 mmol) and sodium iodide (5.3 g, 35.0 mmol) in acetonitrile (25 mL) were combined. Dichloromethylsilane (2.1 mL, 17.4 mmol) was added to the syringe. After 10 minutes, diluted with EtOAc, washed with water, saturated sodium bicarbonate, 10% sodium thiosulfate and brine. The organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated to give a residue. Chromatography eluting the residue with hexanes: EtOAc (9: 1) afforded the title compound.
[224] Example 8
[225] 2- (3- (α-fluorobenzyl) phenyl)-[1,3] -dioxolane
[226] (3- [1,3] -dioxolan-2-ylphenyl) phenylmethanol (2.3 g, 8.9 mmol) and dichloromethane (50 mL) were combined. A solution of (diethylamino) sulfur trifluoride (1.7 mL, 12.9 mmol) was added dropwise and extracted with dichloromethane. The organic layers were combined and washed sequentially with distilled water and brine, then dried (Na ₂ SO ₄ ), filtered and concentrated to give a residue. Chromatography eluting the residue with hexanes: EtOAc (7: 3) gave the title compound.
[227] Example 9
[228] 3-nitrodibenzofuran
[229] Dibenzofuran (20.0 g, 0.11 mol) and acetic acid (80 mL) were combined. Heated to 65 ° C. 98% nitric acid (20.0 g, 11.8 mol) was added. After 3 hours, cooling to room temperature gave a solid. The solid was collected by filtration, washed with water and dried to afford the title compound.
[230] Example 10
[231] N-dibenzofuran-3-ylamine
[232] 3-nitrodibenzofuran (22.0 g, 0.1 mol) and Raney nickel (2.75 g) and ethanol (365 mL) were combined and hydrogenated at room temperature and 40 psi (276 kPa). After 18 hours, the filtrate was concentrated to the residue. Chromatography eluting the residue with hexanes: EtOAc (9: 1) afforded the title compound.
[233] Example 11
[234] 3-bromodibenzofuran
[235] N-dibenzofuran-3-ylamine (2.0 g, 10.8 mmol), water (20 mL) and concentrated hydrobromic acid (6 mL) were combined. Cool to 0 ° C. A solution of sodium nitrite (0.7 g, 10.8 mmol) in water (16 mL) was added. After 15 minutes, the mixture was added to a mixture of copper bromide (1.7 g, 12.3 mmol) and hydrobromic acid (4 mL) in water (9.2 mL). Warmed to room temperature. After 18 hours, water was added and extracted with dichloromethane. The organic layers were combined and washed sequentially with distilled water and brine, then dried (Na ₂ SO ₄ ), filtered and concentrated to give a residue. Chromatography eluting the residue with hexanes: EtOAc (8: 2) gave the title compound.
[236] Example 12
[237] Dibenzofuran-3-carbaldehyde
[238] 3-bromodibenzofuran (0.5 g, 2.0 mmol) and tetrahydrofuran (30 mL) were combined. Cooled to about -78 ° C. A t-butyllithium solution (2.2 mL, 3.0 mmol), a 1.6 M solution in hexane, was added and then warmed to about 0 ° C. for 10 minutes. Cool to about -78 ° C and add dimethylformamide (0.5 mL, 5.9 mmol). Warm to room temperature, quench with water and extract with dichloromethane. The organic layers were combined and washed sequentially with distilled water and brine, then dried (Na ₂ SO ₄ ), filtered and concentrated to give a residue. Chromatography eluting the residue with hexanes: EtOAc (8: 2) gave the title compound.
[239] Example 13
[240] 3- (azol-2-yloxy) benzaldehyde
[241] In a closed tube, 2-bromo-thiazole (2.0 mL, 22.2 mmol), 3-hydroxy-benzaldehyde (1.8 g, 15.0 mmol) and potassium carbonate (2.1 g, 15.0 mmol) in dimethylformamide (20 mL) ) Combined. Heated to 100 ° C. After 48 h, cooled, poured into water (150 mL) and extracted with ether. The organic layers were combined and washed sequentially with distilled water and brine, then dried (Na ₂ SO ₄ ), filtered and concentrated to give a residue. Chromatography eluting the residue with hexanes: EtOAc (9: 1) afforded the title compound.
[242] Example 14
[243] 6-bromo-1H-indole
[244] 4-Bromo-2-nitrotoluene (5.0 g, 23.1 mmol), dimethylformamide (50 mL), DMF-dimethylacetal (9.0 mL, 69.4 mmol) and pyrrolidine (2.0 mL, 23.1 mmol) were combined. . Heated to 110 ° C. After 3 h, cooled to rt, diluted with ether and washed with water. The organic layers were combined and concentrated to give a residue. The residue and 80% acetic acid aqueous solution (120 mL) were combined and heated at 75 ° C. Zinc dust (13.1 g, 200.5 mmol) was added in portions. Heated to 85 ° C. After 2 hours, it was cooled and filtered. The filtrate was diluted with ether, washed with water, dried (Na ₂ SO ₄ ) and concentrated to give a residue. Chromatography eluting the residue with hexanes: EtOAc (9: 1) afforded the title compound.
[245] According to the method of Example 14, the following compounds were prepared: 4-bromo-1H-indole.
[246] Example 15
[247] 1H-indole-6-carbaldehyde
[248] Hexane washed potassium hydride (1.3 g, 10.7 mmol) and ether (20 mL) were combined. Cool to about 0 ° C. and add 6-bromo-1H-indole solution (2.1 g, 10.7 mmol) in ether (5 mL). After 15 minutes, it was cooled to about -78 ° C and a solution of t-butyllithium (14.0 mL, 10.7 mmol), a 1.4 M solution in hexane, was added. After 10 minutes dimethylformamide (1.7 mL, 20.0 mmol) in ether (5 mL) was added. After slowly warming to room temperature, it was poured into an ice cold solution of 1 M phosphoric acid and extracted with EtOAc. The organic layers were combined and washed sequentially with distilled water and brine, then dried (Na ₂ SO ₄ ), filtered and concentrated to give a residue. Chromatography eluting the residue with hexanes: EtOAc (9: 1) afforded the title compound.
[249] According to the method of Example 15, the following compound was prepared: 1H-indole-4-carbaldehyde.
[250] Example 16
[251] 1-phenyl-1H-indole-6-carbaldehyde
[252] 1H-indole-6-carbaldehyde (0.9 g, 6.2 mmol), copper (I) trifluoromethanesulfate-complex (0.2 g, 0.3 mmol), phenanthroline in xylene (40 mL) in a closed tube (1.3 g, 6.2 mmol), transdibenzylideneacetone (0.1 g, 0.3 mmol), cesium carbonate (2.6 g, 7.9 mmol) and iodobenzene (1.6 mL, 14.3 mmol) were combined. Heated at about 110 ° C. After 24 hours, cooled to room temperature and diluted with dichloromethane and saturated ammonium chloride. The layers were separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed sequentially with distilled water and brine, dried (Na ₂ SO ₄ ), filtered and concentrated to give a residue. Chromatography eluting the residue with hexanes: EtOAc (8: 2) gave the title compound.
[253] According to the method of Example 16, the following compound was prepared: 1-phenyl-1H-indole-4-carbaldehyde.
[254] Example 17
[255] 3-phenylsulfanylbenzaldehyde
[256] 2- (3-phenylsulfanylphenyl)-[1,3] -dioxolane (0.3 g, 1.1 mmol) and acetonitrile (8.0 mL) were combined and hydrochloric acid solution (1 N, 2.0 mL) was added. After 18 hours, most of the acetonitrile was removed by concentration in vacuo, diluted with water and extracted with ether. The organic extracts were combined, washed once with saturated sodium bicarbonate and then brine. The organics were dried (Na ₂ SO ₄ ), filtered and concentrated to afford the title compound.
[257] According to the method of Example 17, the following compounds were prepared:
[258] a) 3-benzenesulfonylbenzaldehyde;
[259] b) 3-p-tolylsulfanylbenzaldehyde;
[260] c) 3- (p-tosyl) benzaldehyde;
[261] d) 3-benzylaminobenzaldehyde;
[262] e) 3-phenylaminobenzaldehyde;
[263] f) 3-benzoylbenzaldehyde;
[264] g) 3- (α-fluorobenzyl) benzaldehyde;
[265] h) 3- (4-fluorophenoxy) benzaldehyde;
[266] i) 3- (2-fluorophenoxy) benzaldehyde;
[267] j) 3- (3-fluorophenoxy) benzaldehyde;
[268] k) 3- (naphth-2-yloxy) benzaldehyde;
[269] l) 3- (naphth-1-yloxy) benzaldehyde;
[270] m) 3- (pyridin-3-ylamino) benzaldehyde;
[271] n) 3- (pyridin-4-ylamino) benzaldehyde;
[272] o) 3- (pyridin-2-ylamino) benzaldehyde; And
[273] p) 3- (pyridin-2-yloxy) benzaldehyde.
[274] Example 18
[275] 2-naphth-2-ylethylamine
[276] Naphth-2-ylacetonitrile (1.0 g, 6.0 mmol) and nickel (II) chloride hexahydrate (0.7 g, 3.0 mmol) and tetrahydrofuran (30 mL) were combined. Borane-tetrahydrofuran complex (24.0 mL, 24.0 mmol), a 1 M solution in tetrahydrofuran, was added dropwise. After 1 hour, evaporation gave a residue. Chromatography on silica gel eluting with EtOAc: (MeOH + 2% NH ₄ OH) (8: 2) afforded the title compound.
[277] According to the method of Example 18, the following compound was prepared: 2-naphth-1-ylethylamine.
[278] Example 19
[279] 5-methanesulfonyltrytamine
[280] 2- (3-chloropropyl)-(1,3) -dioxolane (6.69 g, 44.5 mmol), (4-methanesulfonylphenyl) hydrazine hydrochloride (9.92 g, in 300 ml methanol / water (1: 1), 44.5 mmol) and Na ₂ HPO ₄ (1.58 g, 11.1 mmol) were combined. Heated to reflux. After 4.5 hours it was cooled to room temperature and then evaporated to the residue. The residue was dissolved in 1 N NaOH and extracted with dichloromethane. Organic extracts were combined, washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated to residue. The residue was chromatographed on silica gel eluting with dichloromethane / 2N NH ₃ (methanol) (84/16) to afford the title compound as a light brown solid: mp 134-138 ° C., MS (ACPI): m / e 239.1 (M + 1). Anal for C ₁₁ H ₁₄ N ₂ O ₂ S: calc .: C, 55.44; H, 5.92; N, 11.76; Found: C, 55.33; H, 5.97; N, 11.48.
[281] Example 20
[282] N-t-butoxycarbonyl-2- (6-chloro-1H-indol-3-yl) ethylamine
[283] Di-tert-butyl dicarbonate (1.2 g, 5.34 mmol), 6-chlorotryptamine (866.4 mg, 4.45 mmol) and NaHCO ₃ (598.2 mg) were combined in dioxane (50 mL). Stir at room temperature. After 15 hours, the residue was evaporated and the residue partitioned between water and dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane. The organic extracts were combined, washed with brine, dried (Na ₂ SO ₄ ) filtered and evaporated to afford the title compound as a light yellow oil.
[284] Example 21A
[285] N-methyl-2- (6-chloro-1H-indol-3-yl) ethylamine
[286] Combine Nt-butoxycarbonyl-2- (6-chloro-1H-indol-3-yl) ethylamine (1.3 g, 4.41 mmol) and dry THF (20 mL) and dry THF (30 mL) cooled in an ice bath. ) Is added dropwise to a suspension of LiAlH ₄ (1.0 g, 26.5 mmol). Heated to reflux. After 2 hours, the mixture was cooled to room temperature and stirred. After 15 hours, it was quenched with saturated NaSO ₄ (100 mL / mol), stirred at room temperature for 1 hour and filtered under vacuum. The precipitate was washed with THF and the filtrate was evaporated and washed to give a residue. The residue was chromatographed on silica gel eluting with dichloromethane / 2N NH ₃ (methanol) (84/16) to afford the title compound: MS (ACPI): m / e 209.0 (M + 1).
[287] Example 21B
[288] 5- (4-fluorophenyl) -1H-indole
[289] 5-bromoindole (5.00 g, 25.50 mmol) and Pd (Ph ₃ P) ₄ (1.47 g, 1.28 mmol) in toluene (510 mL) were combined. After 30 minutes, a solution of 4-fluorobenzeneboronic acid (5.35 g, 38.26 mmol) in ethanol (153 mL) was added followed by saturated NaHCO ₃ (255 mL). Heated to reflux. After 4 hours, cooled to room temperature, poured into saturated NaCl (250 mL) and the organic layers were separated. The aqueous layer was extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried and evaporated to residue. The residue was chromatographed on silica gel eluting with ethyl acetate / hexanes (10/90) to afford the title compound: mp 84-89 ° C. MS (ACPI): m / e 212.0 (M + 1). Anal for C ₁₄ H ₁₀ FN: Calcd: C, 79.60; H, 4.77; N, 6.63; Found: C, 79.33; H, 4.92; N, 6.64.
[290] According to the method of Example 21, the following compounds were prepared:
[291] a) 5-phenyl-1H-indole: mp 71-74 ° C. MS (ACPI): m / e 194.0 (M + l). Anal for C ₁₄ H ₁₁ N: Calcd: C, 87.01; H, 5. 74; N, 7.25; Found: C, 86.67; H, 5. 82; N, 7.31.
[292] b) 4-phenylphenethylamine hydrochloride: (Exception-dichloromethane / 2N NH ₃ (methanol) (90/10) and the residue was chromatographed on silica gel to give the final product. Prepared in Acetate: MS (ACPI): m / e 198.1 (M + l) Anal for C ₁₄ H ₁₆ ClN: Cal .: C, 71.94; H, 6.90; N, 5.99; Determination: C, 71.66; H , 6.90; N, 5.94.
[293] Example 22
[294] 7-cyano-1H-indole
[295] 7-bromoindole (4.72 g, 24.0 mmol) and copper cyanide (4.30 g, 48.1 mmol) were combined in 1-methyl-2-pyrrolidine (40 mL). Heated to 200 ° C. After 2.5 hours, cooled to room temperature and added water-ethyl acetate (200 mL, 1/1) to give a solid. Filter through celite and extract the filtrate with ethyl acetate and combine the organic layers, wash with brine, dry over Na ₂ SO _4, filter and evaporate in vacuo to afford a residue. The residue was chromatographed on silica gel eluting with hexanes: ethyl acetate (10: 1) to give the title compound (1.87 g) as a yellow solid: ¹ H NMR (300 MHz, DMSO- d ₆ )) 6.64-6.66 (m, 1H), 7.17 (t, 1H, J = 7.6 Hz), 7.51-7.53 (m, 1H), 7.60-7.62 (m, 1H), 7.94 (d, 1H, J = 8.0 H), 12.03 ( br, 1H).
[296] Example 23
[297] 3-formyl-5-cyano-1H-indole
[298] Phosphorous oxychloride (11.76 g, 76.67 mmol) was added dropwise to DMF (24.3 mL) while maintaining a temperature below 10 ° C. Warm to room temperature and stir for 15 minutes at room temperature. 5-cyanoindole (10.00 g, 70.34 mmol) was added dropwise as a solution in DMF (30 mL) while maintaining at a temperature below 35 ° C. After 1 hour, the reaction mixture was poured into ice / water (300 mL) and stirred with the addition of 5 N NaOH (54 mL). An additional amount of 5 N NaOH (19.7 mL) was added slowly, then heated to 90 ° C. for 1 minute and then cooled to room temperature to give a precipitate. The precipitate was filtered off, washed with water and dried to afford the title compound: mp 248-250 ° C. MS (ACPI): m / e 171.0 (M + 1). Anal for C ₁₀ H ₆ N ₂ O: calc .: C, 70.58; H, 3.55; N, 16.46; Found: C, 70.41; H, 3.53; N, 16.33.
[299] According to the method of Example 23, the following compounds were prepared:
[300] a) 3-formyl-5- (4-fluorophenyl) -1H-indole; mp 215-217 ° C. MS (ACPI): m / e239.1 (M + 1). Anal for C ₁₅ H ₁₀ FNO: Calcd: C, 75.30; H, 4. 21; N, 5.85; Found: C, 74.94; H, 4. 17; N, 5.84;
[301] b) 3-formyl-5-phenyl-1H-indole; mp> 250 ° C. MS (ACPI): m / e 222.1 (M + 1). Anal for C ₁₅ H ₁₁ NO: calc .: C, 81.43; H, 5.01; N, 6.33; Found: C, 81.04; H, 5.05; N, 6.36;
[302] c) 3-formyl-6-methyl-1H-indole; mp 178-180 ° C. MS (ACPI): m / e 159.9 (M + 1). Anal for C ₁₀ H ₉ NO: calc .: C, 75.45; H, 5. 70; N, 8.80; Found: C, 75.60; H, 5.78; N, 8.97;
[303] d) 3-formyl-6-cyano-1H-indole; mp 246 ° C. MS (ACPI): m / e 171.0 (M + 1). Anal for C ₁₀ H ₆ N ₂ O: calc .: C, 70.58; H, 3.55; N, 16.46; Found: C, 70.51; H, 3.59; N, 16.40; And
[304] e) 3-formyl-6-trifluoromethoxy-1H-indole; mp 189-192 ° C. MS (ACPI): m / e 230.0 (M + l). Anal for C ₁₀ H ₆ F ₃ NO ₂ : Calcd: C, 52.41; H, 2. 64; N, 6.11; Found: C, 52.31; H, 2.61; N, 6.09.
[305] f) 3-formyl-7-cyano-1H-indole; ^OneH NMR (300 MHz, DMSO-d₆d 7.41 (t, 1H,J= 7.6 Hz), 7.80-7.82 (m, 1H), 8.42-8.50 (m, 2H), 10.02 (s 1H), 13.06 (br, 1H).
[306] g) 3-formyl-6-bromo-1H-indole; mp 197-200 ° C. Anal for C ₉ H ₆ BrNO: Calcd: C, 48.25; H, 2. 70; N, 6.25; Found: C, 47.87; H, 2.68; N, 6.17.
[307] h) 3-formyl-7-fluoro-1 H-indole; mp 211-214 ° C. MS (ACPI): m / e 163.9 (M + 1). Anal for C ₉ H ₆ FNO: Calcd: C, 66.26; H, 3.71; N, 8.59; Found: C, 66.12; H, 3.67; N, 8.56.
[308] Example 25
[309] 3- (2-nitrovinyl) -5-cyano-1H-indole
[310] 3-formyl-5-cyano-1H-indole (10.60 g, 63.32 mmol) and ammonium acetate solution (10.60 g) in nitromethane (660 mL) were combined. Heated to 90 ° C. After 2 hours, the mixture was cooled to room temperature to obtain a precipitate. The precipitate was collected by filtration, washed with MeOH / water (1: 1) (500 mL) and dried to give the title compound: mp 247-251 ° C. MS (ACPI): m / e 214.0 (M + l).
[311] According to the method of Example 25, the following compounds were prepared:
[312] a) 3- (2-nitrovinyl) -5- (4-fluorophenyl) -1H-indole; mp 217-220 ° C. MS (ACPI): m / e 282.2 (M + l). Anal for C ₁₅ H ₁₀ FN ₂ O ₂ : Calcd: C, 68.08; H, 3.93; N, 9.92; Found: C, 67.73; H, 3.92; N, 9.73;
[313] b) 3- (2-nitrovinyl) -5-phenyl-1 H-indole; MS (ACPI): m / e 265.1 (M + 1);
[314] c) 3- (2-nitrovinyl) -6-methyl-1H-indole; MS (ACPI): m / e 203.1 (M + l);
[315] d) 3- (2-nitrovinyl) -6-cyano-1H-indole; mp> 250 ° C. MS (ACPI): m / e 212.0 (M-1). Anal for C ₁₁ H ₇ N ₃ O ₂ : Calcd: C, 61.97; H, 3.31; N, 19.71; Found: C, 62.09; H, 3. 34; N, 20.06; And
[316] e) 3- (2-nitrovinyl) -6-trifluoro methoxy-1 H-indole; mp 139-143 ° C. MS (ACPI): m / e 273.0 (M + l).
[317] f) 3- (2-nitrovinyl) -6-phenoxy-1H-indole: ^l H NMR (DMSO d ₆ ) 12.1 (s, 1H), 8.38-8.34 (d, 1H), 8.20-8.19 (m, 1H), 8.01-7.97 (m, 2H), 7.39-7.35 (m, 2H), 7.14-7.07 (m, 2H), 7.02-7.00 (m, 2H), 6.95-6.92 (m, 1H).
[318] g) 3- (2-nitro-vinyl) -5- (pyridin-3-yloxy) -1H-indole: ISMS 282 (M + 1); _{^{l H NMR (DMSO-d 6}} ) 9.5 (bs, 1H), 8.36-8.32 (m, 2H), 8.26-8.24 (m, 2H), 7.98-7.95 (m, 1H), 7.79-7.78 (m, 1H ), 7.55-7.53 (m, 1H), 7.34-7.31 (m, 1H), 7.27-7.24 (m, 1H), 7.02-7.00 (m, 1H).
[319] h) 3- (2-nitro-vinyl) -7-cyano-1H-indole: ^OneH NMR (300 MHz, CDCl₃) d 7.36 (t, 1 H,J= 7.7 Hz), 7.76 (d, 1 H,J= 7.2 Hz), 8.09-8.14 (m, 1 H), 8.36-8.46 (m, 3H); MS (electrospray), m / e: 212.1 (M-1)
[320] i) 3- (2-nitrovinyl) -6-bromo-1H-indole; mp 210 ° C., dec. Anal for C ₁₀ H ₇ BrN ₂ O ₂ : Calcd: C, 44.97; H, 2. 64; N, 10.49; Found: C, 44.62; H, 2. 70; N, 10.49.
[321] j) 3- (2-nitrovinyl) -7-fluoro-1 H-indole; mp 176-180 ° C. MS (ACPI): m / e 207.1 (M + l). Anal for C ₁₀ H ₇ FN ₂ O ₂ : Calcd: C, 58.26; H, 3. 42; N, 13.59; Found: C, 58.01; H, 3.31; N, 13.26.
[322] Example 26
[323] 3- (2-nitroethyl) -5-cyano-1H-indole
[324] Sodium borohydride (25.65 g, 678 mmol) in 3- (2-nitrovinyl) -5-cyano-1H-indole (12.68 g, 59.5) in MeOH / DMF (1: 1) (600 mL) cooled in an ice bath mmol) was added to the solution. After 1.5 h, the pH was adjusted to approximately 7 with 5 N HCl after brine (600 mL) was added. Evaporate under reduced pressure to remove methanol and then extract with dichloromethane. Organic extracts were combined, washed with brine, dried (Na ₂ SO ₄ ) and evaporated to the residue. After evaporation, the residue was chromatographed on silica gel eluting with dichloromethane to afford the title compound as a colorless prismatic column: mp 132-136 ° C. MS (ACPI): m / e 215.0 (M + l). Anal for C ₁₁ H ₉ N ₃ O ₂ : Calcd: C, 61.39; H, 4. 22; N, 19.52; Found: C, 61.09; H, 4.10; N, 19.16.
[325] According to the method of Example 26, the following compounds were prepared:
[326] a) 3- (2-nitro-ethyl) -7-cyano-1H-indole;^OneH NMR (300 MHz, DMSO-d ₆ ) 3.39 (t, 2H,J= 6.9 Hz), 4.87 (t, 2H,J= 7.0 Hz), 7.17 (t, 1 H,J= 7.4 Hz), 7.38 (m, 1 H), 7.63 (d, 1 H,J= 7.4 Hz), 7.99 (d, 1H,J= 7.9 Hz), 11.96 (br, 1H). MS (Electrospray), m / e: 214.1 (M-1).
[327] Example 27
[328] 5-cyanotryptamine
[329] Zinc powder (16.22 g, 248.1 mmol) was added four times to 2 N HCl (300.0 mL). 3- (2-nitroethyl) -5-cyano-1H-indole (2.25 g, 10.5 mmol) was added dropwise as a solution in methanol (300.0 mL). Heated to reflux. After 2.5 hours, the mixture was cooled to room temperature, the pH was adjusted to 11 using 5 N NaOH, filtered through celite, washed with water, and the filtrate was extracted with dichloromethane. Organic extracts were combined, washed with brine, dried (Na ₂ SO ₄ ) and evaporated to afford the title compound: mp 102-105 ° C., MS (ACPI): m / e 186.1 (M + 1). Anal for C ₁₁ H ₁₁ N ₃ : Calcd: C, 71.33; H, 5.99; N, 22.69; Found: C, 71.03; H, 5.91; N, 22.64.
[330] According to the method of Example 27, the following compounds were prepared:
[331] a) 3- (2-aminoethyl) -7-cyano-1H-indole; ¹ H NMR (300 MHz, DMSO- d ₆ ) 2.76-2.82 (m, 4H), 7.15 (t, 1H, J = 7.6 Hz), 7.31 (s, 1H), 7.58 (d, 1H, J = 7.4 Hz ), 7.91-7.94 (m, 1 H), 11.80 (br, 1 H); MS (electrospray), m / e: 186.1 (M + 1), 184.1 (m-1).
[332] According to the method of Example 27, the following compounds were prepared:
[333] a) 6-bromotryptamine; mp 114-116 ° C. Anal for C ₁₀ H ₁₁ BrN ₂ : Calcd: C, 50.23; H, 4. 64; N, 11.72; Found: C, 49.96; H, 4. 49; N, 11.47.
[334] Example 28
[335] N-t-butoxycarbonyl-2- (5-cyano-1H-indol-3-yl) ethylamine
[336] A solution of di-tert-butyl dicarbonate and 5-cyanotryptamine (1.33 g, 7.15 mmol) and 2 N NaOH (4.2 mL) in THF (60 mL) was combined. After 3 hours at room temperature, the residue was evaporated. The residue was dissolved in water and extracted with dichloromethane. Organic extracts were combined, washed with brine, dried (Na ₂ SO ₄ ) and evaporated to residue. The residue was chromatographed on silica gel eluting with dichloromethane / 2N NH ₃ (methanol) (97/3) to afford the title compound: mp 129-132 ° C. MS (ACPI): m / e 286.2 (M + l). Anal for C ₁₆ H ₁₉ N ₃ O ₂ : Calcd: C, 67.35; H, 6.71; N, 14.73; Found: C, 67.16; H, 6.68; N, 14.46.
[337] According to the method of Example 28, the following compounds were prepared:
[338] a) N-t-butoxycarbonyl-2- (6-cyano-1H-indol-3-yl) ethylamine.
[339] Example 29
[340] N-t-butoxycarbonyl-2- (5-amido-1H-indol-3-yl) ethylamine
[341] Water (64.0 mL) and NaOH (8.53 g) were combined and cooled to about 5 ° C. in an ice bath. A solution of Nt-butoxycarbonyl-2- (5-cyano-1H-indol-3-yl) ethylamine (1.85 g, 6.50 mmol) in ethanol (128.0 mL) was added followed by addition to the cooled solution. . 30% peroxide (6.4 mL) was added dropwise while maintaining at a temperature below 5 ° C. After 30 minutes, warmed to room temperature. After 22 hours, excess peroxide was decomposed by stirring with the addition of 20% sodium bisulfite solution (45.0 mL). After 30 minutes, ethanol was removed by evaporation under reduced pressure and the resulting aqueous solution was extracted with ethyl acetate. Organic extracts were combined, washed with brine, dried (Na ₂ SO ₄ ) and evaporated to the residue. The residue was evaporated by chromatography on silica gel eluting with dichloromethane / 2N NH ₃ (methanol) (96/4) to afford the title compound: mp 65-68 ° C. MS (ACPI): m / e 304.2 (M + l). Anal for C ₁₆ H ₂₁ N ₃ O ₃ : Calcd: C, 63.35; H, 6.98; N, 13.85; Found: C, 63.26; H, 6. 99; N, 13.71.
[342] According to the method of Example 28, the following compounds were prepared:
[343] a) N-t-butoxycarbonyl-2- (6-amido-1H-indol-3-yl) ethylamine: MS (ACPI): m / e 302.3 (M-1).
[344] Example 30
[345] 5-amidotryptamine
[346] N-t-butoxycarbonyl-2- (5-amido-1H-indol-3-yl) ethylamine (1.83 g, 6.04 mmol) was dissolved in dioxane (25.0 mL). 4 M HCl in dioxane (7.5 mL) was added dropwise. After 18 hours, the solids were collected by filtration, washed with diethyl ether and dried to give the title compound as hydrochloride: mp 192-195 ° C. MS (ACPI): m / e 202.0 (M + l).
[347] According to the method of Example 30, the following compounds were prepared:
[348] a) 6-amidotriptamine: mp 169-173 ° C. MS (ACPI): m / e 204.1 (M + l).
[349] Example 32
[350] 5- (4-fluorophenyl) tryptamine
[351] LiAlH ₄ (2.66 g, 70.17 mmol) and dry THF (70.0 mL) were combined and the suspension cooled in an ice bath. A solution of 5- (4-fluorophenyl) -3- (2-nitrovinyl) -1H-indole (3.30 g, 11.69 mmol) in dry THF (30.0 mL) was added dropwise. Heated to reflux. After 1 hour, the mixture was cooled to room temperature and stirred. After 15 h, quenched with saturated Na ₂ S0 ₄ (100 mL / mol) and stirred at room temperature. After 1 h, filtered, the precipitate was washed with THF and the filtrate was evaporated to a residue. The residue was chromatographed on silica gel eluting with dichloromethane / 2N NH ₃ (methanol) (80/20) to afford the title compound. HCl salt in diethyl ether was prepared: mp> 250 ° C. MS (ACPI): m / e 255.0 (M + l). Anal for C ₁₆ H ₁₆ ClFN ₂ : Calcd: C, 66.09; H, 5.55; N, 9.63; Found: C, 65.78; H, 5. 48; N, 9.58.
[352] According to the method of Example 32, the following compounds were prepared:
[353] a) 5-phenyltryptamine; mp 244-246 ° C. MS (ACPI): m / e 237.1 (M + l). Anal for C ₁₆ H ₁₇ ClN ₂ : Calcd: C, 70.45; H, 6. 28; N, 10.27; Found: C, 70.75; H, 6. 33; N, 10.27. (Isolated as hydrochloride);
[354] b) 6-methyltryptamine; mp 139-141 ° C. MS (ACPI): m / e 175.0 (M + 1). Anal for C ₁₁ H ₁₄ N ₂ : Calcd: C, 75.82; H, 8. 10; N, 16.08; Found: C, 76.05; H, 8. 26; N, 16.12.
[355] c) 6-trifluoromethoxytrytamine; MS (ACPI): m / e 245.0 (M + l). Anal for C ₁₁ H ₁₁ F ₃ N ₂ O: calc .: C, 54.10; H, 4.54; N, 11.47; Found: C, 53.92; H, 4.50; N, 11.06.
[356] d) 7-fluorotrytamine; MS (ACPI): m / e 179.0 (M + l). Anal for C ₁₀ H ₁₁ FN ₂ : Calcd: C, 67.40; H, 6. 22; N, 15.72; Found: C, 67.06; H, 6. 11; N, 15.48.
[357] Example 33
[358] 6-ethoxycarbonyl-1H-indole
[359] 6-carboxy-1H-indole and ethanol (110 mL) were combined and cooled to 5 ° C. Concentrated H ₂ SO ₄ (96%, 11.08 mL) was added dropwise while maintaining at a temperature below 10 ° C. Heated to reflux. After 4 hours, it was cooled, poured into ice / water, the pH was adjusted to about pH 9 and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried (Na ₂ SO ₄ ) and concentrated to the residue. The residue was evaporated by chromatography on silica gel eluting with chloroform to afford the title compound: mp 72-75 ° C. MS (ACPI): m / e 189.9 (M + 1).
[360] Example 34
[361] 3- (2-nitrovinyl) -6-ethoxycarbonyl-1H-indole
[362] 1-dimethylamino-2-nitroethylene (1.93 g, 16.58 mmol) and TFA (10.0 mL) were combined and stirred until dissolved. 6-ethoxycarbonyl-1H-indole (3.14 g, 16.58 mmol) was added and stirred at room temperature. After 1 hour, the reaction mixture was poured into ice / water, extracted with ethyl acetate and evaporated to the residue. The residue was stirred in warm ethanol, cooled to room temperature, filtered and dried to afford the title compound as a dark yellow powder: mp 241 ° C. MS (ACPI): m / e 261.1 (M + 1). Anal for C ₁₃ H ₁₂ N ₂ O ₄ : Calcd: C, 60.00; H, 4.65; N, 10.76; Found: C, 59.99; H, 4.63; N, 10.59.
[363] Example 35
[364] 3- (2-nitroethyl) -6-ethoxycarbonyl-1H-indole
[365] Combine 3- (2-nitrovinyl) -6-ethoxycarbonyl-1H-indole (4.0 g, 15.37 mmol) and NaBH ₄ (726.7 mg, 19.21 mmol) in 100 mL of THF / methanol (9: 1) at room temperature Stirred at. After 1.5 h, concentrated to residue. The residue was partitioned between brine and ethyl acetate and washed with brine, the organic layers combined and dried (Na ₂ SO ₄ ) and then evaporated to afford the title compound as a yellow powder: mp 124-127 ° C. MS (ACPI): m / e 263.0 (M + 1). Anal for C ₁₃ H ₁₄ N ₂ O ₄ : Calcd: C, 59.54; H, 5. 38; N, 10.68; Found: C, 59.40; H, 5. 36; N, 10.53.
[366] According to the method of Example 35, the following compounds were prepared:
[367] a) 3- (2-nitroethyl) -6-cyano-1H-indole: m / e 214.1 (M-1). C₁₁H₉N₃O₂Analysis for: calcd .: C, 61.39; H, 4. 22; N, 19.52; Found: C, 61.05; H, 4.09; N, 19.19.
[368] b) 3- (2-nitroethyl) -6-bromo-1H-indole;
[369] c) 3- (2-nitroethyl) -6-methanesulfonyl-1H-indole; mp 162-164 ° C. MS (ACPI): m / e 269.1 (M + 1).
[370] d) 3- (2-nitroethyl) -6-benzenesulfonyl-1H-indole (exception: using 75 mL THF).
[371] Example 36
[372] 6-ethoxycarbonyltrytamine
[373] A solution of 3- (2-nitroethyl) -6-ethoxycarbonyl-1H-indole (3.55 g, 13.54 mmol) in Pt ₂ O (440 mg) and ethyl acetate (100 mL) was combined. Hydrogenated at 60 psi (410 kPa) and room temperature. After 4 h, filtered through celite and the filtrate was concentrated to the residue. The residue was evaporated by chromatography on silica gel eluting with dichloromethane / 2N NH ₃ (methanol) (85/15) to afford the title compound as an off-white powder: mp 127-131 ° C. MS (ACPI): m / e 233.0 (M + l). Anal for C ₁₃ H ₁₆ N ₂ O ₂ : Calcd: C, 67.22; H, 6.94; N, 12.06; Found: C, 66.87; H, 6. 86; N, 11.86.
[374] According to the method of Example 36, the following compounds were prepared:
[375] a) 6-cyanotryptamine: mp 144-147 ° C. MS (ACPI): m / e 186.0 (M + l). Anal for C ₁₁ H ₁₁ N ₃ : Calcd: C, 71.33; H, 5.99; N, 22.69; Found: C, 71.10; H, 5.89; N, 22.38.
[376] b) 6-methanesulfonyltrytamine: mp 149-153 ° C. MS (ACPI): m / e 239.1 (M + 1). Anal for C ₁₁ H ₁₄ N ₂ O ₂ S: calc .: C, 55.44; H, 5.92; N, 11.76; Found: C, 55.12; H, 5. 82; N, 11.97.
[377] c) 6-benzenesulfonyltrytamine: mp 169-172 ° C. MS (ACPI): m / e 301.0 (M + l).
[378] Example 38
[379] 6-trifluoromethoxy-1H-indole
[380] 1-methyl-4-trifluoromethoxybenzene (5.44 g, 30.87 mmol) and H ₂ SO ₄ (96%, 30.9 mL) were combined. Cool to about 0 ° C. Fuming HNO ₃ (2.06 g, 32.72 mmol) was added dropwise while maintaining at a temperature below 10 ° C. When the addition was complete, it was allowed to warm to room temperature. After 2.5 h, the mixture was poured into ice / water and extracted with dichloromethane. The organic extracts were combined, washed with brine, dried (Na ₂ SO ₄ ) and concentrated to the residue. The residue was evaporated by chromatography on silica gel eluting with hexanes / ethyl acetate (75/25) to give 1-methyl-2-nitro-4-trifluoromethoxybenzene: MS (ACPI): m / e 220.1 (M-1).
[381] 1-methyl-2-nitro-4-trifluoromethoxybenzene (3.73 g, 16.86 mmol), pyrrolidine (1.32 g, 18.55 mmol), N, N-dimethylformamidedimethyl acetal (6.03 g, 50.58 mmol) And dry DMF (35 mL). Heated to about 105 ° C. After 19 hours, the DMF was removed under reduced pressure to give an oily residue. The residue and ethyl acetate were combined, washed with brine, dried (Na ₂ SO ₄ ) and concentrated to afford N, N-dimethyl-2- (2-nitro-4-trifluoromethoxyphenyl) vinylamine.
[382] N, N-dimethyl-2- (2-nitro-4-trifluoromethoxyphenyl) vinylamine (4.64 g, 16.8 mmol) and Raney® Nickel (900 mg) in ethanol (100 mL) were combined. . Hydrogenated at 60 psi (410 kPa) and room temperature. After 18 h, filtered through celite and the filtrate was concentrated by residue and evaporated by chromatography on silica gel eluting with hexanes / ethyl acetate (30/70) to afford the title compound as an off-white powder: mp 59. ℃. MS (ACPI): m / e 200.0 (M-1).
[383] Example 39
[384] 2-phenylphenethylamine
[385] 2-phenylphenylacetonitrile (4.69 g, 24.26 mmol) and diethyl ether (10 mL) were combined and added dropwise to a LiAlH ₄ solution (2.76 g, 72.81 mmol) in cooled (-10 ° C.) diethyl ether (100 mL). It was. Warmed to room temperature. After 2 hours, it was quenched with saturated sodium sulfate (100 mL / mol). The precipitate was removed by filtration, the filtrate was dried (Na ₂ SO ₄ ), filtered and concentrated to residue. The residue was chromatographed on silica gel eluting with dichloromethane / 2N NH ₃ (methanol) (95/5) to afford the title compound as a yellow oil. HCl salt in diethyl ether was prepared: mp 197-199 ° C. MS (ACPI): m / e 198.1 (M + 1). Anal for C ₁₄ H ₁₆ ClN: Calcd: C, 71.94; H, 6. 90; N, 5.99; Found: C, 72.15; H, 6. 84; N, 6.09.
[386] Example 40
[387] 7-chloro-1H-indole
[388] J. Med. Chem. 1990, 33, 2777], 2-chloroaniline (5.8 g, 45.45 mmol) in anhydrous toluene (80 mL) was added dropwise to a solution of BCl ₃ 1 M in dichloromethane (50 mL). After addition, the reaction was stirred at 0 ° C. for 10 minutes. After 10 minutes at 0 ° C., chloroacetonitrile (13.72 g, 11.53 mL, 181.8 mmol, 4 equiv) and trichloride (6.67 g, 50 mmol, 1.1 equiv) were added in equal portions five times over 45 minutes. Heated to reflux (˜65 ° C.). After 6 hours, it was cooled to room temperature. After 16 hours, the reaction was cooled in an ice bath and the reaction was heated to reflux after addition of 2N HCl (61.4 mL). After 45 minutes, the acid was neutralized with 2N NaOH until the pH was about 5 while cooling in an ice bath and maintaining the reactant temperature below 15 ° C. The reaction was transferred to a separatory funnel and the organic layers removed. The aqueous layer was extracted with dichloromethane (2 x 200 mL). The organic layers were combined, dried over MgSO _4, filtered and the solvent removed in vacuo to yield 1- (2-amino-3-chlorophenyl) -2-chloroethanone which could be used without further purification.
[389] 1- (2-amino-3-chlorophenyl) -2-chloroethanone (7.0 g, 34.30 mmol) was dissolved in 10% aqueous 1,4-dioxane (75 mL). NaBH ₄ (2.6 g, 68.6 mmol, 2 equiv) was carefully added as a solid. Heated to reflux. After 4 h, cooled to rt, diluted with water (300 mL) and extracted with dichloromethane (2 x 200 mL). The organic layers were combined, dried over MgSO ₄ , filtered and the solvent removed in vacuo leaving a light brown oil in the flask. Purification of the oil by HPLC (silica gel mobile phase: from 100% hexanes to 50% EtOAc in hexanes for 50 minutes) gave the title compound as brown oil: ¹ H NMR (300 MHz, d6-DMSO-d6): 5.16 (m , 1H), 5.39 (d, 1H), 5.70 (bs, 1H), 6.59 (t, 1H), 7.09 (m, 2H); MS (ES &lt; ⁺ &gt;): m / z 154, 152 (M + H) ⁺ .
[390] According to the method of Example 40, the following compounds were prepared:
[391] a) 5-Bromo-7-ethyl-1H-indole: ¹ H NMR (300 MHz, d6-DMSO-d6): 1.25 (t, 3H), 2.85 (m, 2H), 6.41 (m, 1H), 7.02 (M, 1 H), 7.36 (m, 1 H), 7.55 (m, 1 H), 11.28 (bs, 1 H); MS (ES &lt; ⁺ &gt;): m / z 224, 226 (M + H) ⁺ ; Analysis for C ₁₀ H ₁₀ BrN: calculated; C, 53.60; H, 4.50; N, 6.25; ; C, 53.50; H, 4. 34; N, 6.22.
[392] Example 42
[393] 6-trifluoromethyl-1H-indole
[394] 2-bromo-5-trifluoromethylphenylamine (27.06 g, 112.74 mmol) and 200 mL of pyridine were combined. Cool in an ice bath and add ethyl chloroformate (18.35 g, 169.11 mL, 1.5 equiv). After the addition was complete, the reaction gradually warmed to room temperature. After 18 hours, the residue was evaporated in vacuo to give a residue. The residue was dissolved in Et ₂ O / water and transferred to a separatory funnel. The layers were separated and the aqueous layer was extracted with Et ₂ O (2 × 300 mL) and the organic layers combined, dried over MgSO ₄ , filtered and evaporated in vacuo to be used without further purification N- (2-bromo-5- Trifluoromethylphenyl) carbamic acid ethyl ester was obtained.
[395] J. Org. Chem. 1997, 62, 6507, according to the procedure described in N- (2-bromo-5-trifluoromethylphenyl) carbamic acid ethyl ester (34.33 g, 110 mmol), triethylamine (300 mL), dichlorobis ( Triphenylphosphine) palladium (II) (5.4 g, 7.7 mmol) and copper iodide (I) (1.47 g, 7.7 mmol) were combined. The dark solution was removed and N ₂ was fed twice, followed by vigorous stirring with rapid addition of (trimethylsilyl) acetylene (16.21 g, 165 mmol, 23.32 mL). Heated to 80 ° C. When TLC confirmed that no starting material was present, water and Et ₂ O were added, filtered through celite and the filtrate was evaporated in vacuo to give a residue. The residue was diluted with water, extracted with Et ₂ O, the organic layers combined and the evaporate removed to give a dark brown oil. The oil was absorbed into silica gel and loaded onto a short column of silica gel equilibrated with 100% hexanes. Wash with 100% hexanes (2 L) and elute the product with 1% EtOAc in hexanes. Fractions containing the product were combined and the solvent was removed under vacuum to give 5-trifluoromethyl-2-trimethylsilanylethynyl phenylamine as a red / brown oil; MS (IS): m / z 330 (M + H) ⁺ .
[396] NaH (10.83 g, 60% in oil, 270.8 mmol, 4 equiv) was carefully added to EtOH (200 mL). When cooled, a solution of 5-trifluoromethyl-2-trimethylsilanylethynylphenylamine (22.3 g, 67.7 mmol) in EtOH (400 mL) was added and stirred vigorously. After 2 hours, it was heated to reflux. After 4 hours, the EtOH was removed by evaporation in vacuo and the residue obtained was diluted with water and extracted with Et ₂ O. The organic layers were combined, washed with brine, dried over MgSO _4, filtered and evaporated to give a dark oil. The oil was absorbed into silica gel and loaded onto a short column of silica gel. Eluted with 20% EtOAc in hexanes. The fractions containing the product were collected and the solvent was removed leaving a dark brown oil. The oil from hexane to 1% Et ₂ O in a HPLC (silica column) using a gradient to 15% Et ₂ O in hexane to further purification. Fractions containing the product were combined and the solvent was removed to give the title compound as an orange solid: ¹ H NMR (300 MHz, d 6 -DMSO-d 6): 6.58 (m, 1H), 7.28 (m, 1H), 7.61 (t , 1H), 7.74 (m, 2H), 11.51 (bs, 1H); MS (EI +): m / z 185 (M &lt; + &gt;).
[397] According to the method of Example 42, the following compounds were prepared:
[398] a) 5-isopropyl-1H-indole: MS (ES +): m / z 160 (M + H) ⁺ ; (ES)-: m / z 158 (M ⁻ H) ⁻ .
[399] Example 44
[400] 6-fluoro-5-methoxy-1H-indole
[401] Fuming nitric acid (24 mL) was dissolved in concentrated H ₂ SO ₄ in a round bottom flask. 3,4-difluorobromobenzene (20 g, 104 mmol) was vigorously stirred with a pipette dropwise. After addition, the reaction was stirred for 2 hours at room temperature and the reaction was poured into ice water and extracted with Et ₂ O (2 × 250 mL). The organic layers were collected, combined, dried over MgSO ₄ , filtered and the solvent removed to give 1-bromo-4,5-difluoro-2-nitrobenzene as a light yellow oil.
[402] 1-Bromo-4,5-difluoro-2-nitrobenzene (24 g, 100 mmol) was added to a solution of sodium methoxide (1.2 equiv) in MeOH. After addition, the reaction was stirred at rt for 2.5 h. The solvent was removed in vacuo and the residue was diluted with water and extracted with Et ₂ O (2 × 250 mL). The organic layers were combined, dried over MgSO _4, filtered and the solvent removed in vacuo to give 1-bromo-4-fluoro-5-methoxy-2-nitrobenzene as a yellow solid: ¹ H NMR (300 MHz, CDCl). ₃ ): 3.99 (s, 3 H), 7.26 (m, 1 H), 7.83 (d, 1 H); MS (FD &lt; + &gt;): m / z 249, 251 (M &lt; + &gt;); Anal for C ₇ H ₅ BrFNO ₃ : Calcd: C, 33.63; H, 2.02; N, 5.60; Found: C, 33.79; H, 1.98; N, 5.62.
[403] Combine 1-bromo-4-fluoro-5-methoxy-2-nitrobenzene (20.5 g, 82 mmol) and carbon / platinum (sulphide) in THF (600 mL) and 4 hours at 60 psi (414 kPa) Hydrogenated. The reaction was filtered through celite to remove the catalyst and the solvent to afford 2-bromo-5-fluoro-4-methoxyaniline that could be taken without further purification as a brown solid.
[404] Brown N- (2-bromo-5-fluoro-4-methoxyphenyl) carbamic acid ethyl ester by the method of Example 42 using 2-bromo-5-fluoro-4-methoxyaniline Obtained as a solid: ¹ H NMR (300 MHz, CDCl ₃ ): 1.33 (t, 3H), 3.85 (s, 3H), 4.23 (q, 2H), 7.09 (d, 1H), 7.97 (bd, 1H) ; MS (FD &lt; + &gt;): m / z 291, 293 (M &lt; + &gt;); N- (5-fluoro-4-methoxy-2-trimethylsilanylethynylphenyl) carbamic acid ethyl ester was obtained as a yellow solid: MS (ES +): m / z 310 (M + H) ⁺ ; (ES-): m / z 308 (M ⁻ H) ⁻ ; The title compound was obtained as a solid: ¹ H NMR (300 MHz, CDCl ₃ ): 3.93 (s, 3H), 6.48 (m, 1H), 7.15 (m, 3H), 8.11 (bs, 1H); MS (ES &lt; ⁺ &gt;): m / z 166 (M + H) ⁺ ; (ES-): m / z 164 (M ⁻ H) ⁻ ; Anal for C ₉ H ₈ FNO: Calcd: C, 65.45; H, 4.88; N, 8.48; Found: C, 65.17; H, 4.97; N, 8.70.
[405] Example 45
[406] 5,6-difluoro-1H-indole
[407] Using the method of Example 42, 2-bromo-4,5-difluoroaniline was obtained, and N- (2-bromo-4,5-difluorophenyl) carbamic acid ethyl ester was obtained, N- (4,5-difluoro-2-trimethylsilanylethynylphenyl) carbamic acid ethyl ester was obtained and the title compound was obtained as an orange solid: ¹ H NMR (300 MHz, d6-DMSO-d 6): 6.43 (m, 1 H), 7.38 (m, 2 H), 7.50 (m, 1 H), 11.25 (bs, 1 H); MS (ES−): m / z 152 (M ⁻ H) ⁻ ; Anal for C ₈ H ₅ F ₂ N: calc .: C, 62.75; H, 3. 29; N, 9.15; Found: C, 62.41; H, 3.12; N, 8.98.
[408] Example 46
[409] 5-trifluoromethoxy-1H-indole
[410] N- (2-bromo-4-trifluoromethoxyphenyl) carbamic acid ethyl ester was obtained using 2-bromo-4- (trifluoromethoxy) aniline according to the method of Example 42: ¹ H NMR (300 MHz, CDCl ₃ ): 1.34 (t, 3H), 4.25 (m, 2H), 7.19 (m, 1H), 7.41 (m, 1H), 8.20 (d, 1H); MS (ES−): m / z 326, 328 (M ⁻ H) ⁻ ; Analysis for C ₁₀ H ₉ BrF ₃ NO ₃ : calculated; C, 36.6096; H, 2.7 650; N, 4.2692; Measurements; C, 36.50; H, 2.67; N, 3.97; This gave N- (4-trifluoromethoxy-2-trimethylsilanylethynylphenyl) carbamic acid ethyl ester and the title compound as yellow oil: MS (ES-): m / z 200 (MH ) ^- .
[411] Example 47
[412] 4-phenyl-1H-indole
[413] Synlett. 1994, 93-94, using the method of Carrera and Shepard, gave the title compound from 4-bromoindole: ¹ H NMR (300 MHz, d6-DMSO-d 6): 6.56 (m, 1 H), 7.08 (m, 1 H), 7.17 (m, 1 H), 7.43 (m, 5 H), 7.67 (m, 2 H), 11.27 (bs, 1 H); MS (ES &lt; ⁺ &gt;): m / z 194 (M + H) ⁺ ; (ES-): m / z 192 (M ⁻ H) ⁻ .
[414] Example 48
[415] (2-nitro-5-trifluoromethylphenyl) -acetonitrile
[416] Liebigs Ann. Chem. 1988, 203-208, using 4-nitrobenzotrifluoride (15 g, 78.49 mmol) to give the title compound: MS (ES-): m / z 229 (MH) ⁻ .
[417] Example 49
[418] 5-trifluoromethyl-1H-indole
[419] Liebigs Ann. Chem. 1988, 203-208], using (2-nitro-5-trifluoromethylphenyl) acetonitrile to give the title compound as a white solid: ¹ H NMR (300 MHz, d6-DMSO-d6): 6.60 ( m, 1H), 7.36 (m, 1H), 7.53 (m, 1H), 7.57 (m, 1H), 7.94 (m, 1H), 11.51 (bs, 1H); MS (ES−): m / z 184 (M ⁻ H) ⁻ .
[420] Example 50
[421] 3-formyl-4-methoxy-1H-indole
[422] It was vigorously stirred with DMF (cooled in ice bath) with addition of phosphorus oxychloride (1.1 equiv). After the addition was complete, the mixture was stirred for ˜ 10 minutes in an ice bath, followed by vigorous stirring with the addition of a solution of 4-methoxy-1H-indole (5 g) in anhydrous DMF. Stir at 0 ° C. After 1 hour, warmed to room temperature. After 16 h, 2 N NaOH 4 equivalents were stirred vigorously with careful addition. After heating to about 80 ° C., it was cooled. The reaction mixture was vigorously stirred while poured into cooled water to give a solid. The solid was collected by filtration at room temperature and dried in a vacuum oven to afford the title compound. The filtrate was acidified and extracted with EtOAc. The organic layers were combined and washed with 50% brine. The organic layers were collected, dried (MgSO ₄ ), filtered and the solvent removed to afford the title compound as a light purple solid. Total yield of the title compound was 5.44 g: MS (ES +): m / z 175 (M + H) ⁺ , 160 (M-CH ₃ ) ⁺ ; (ES-): m / z 174 (M ⁻ H) ⁻ .
[423] According to the method of Example 50, the following compounds were prepared:
[424] a) 3-formyl-6-methoxy-1H-indole, ¹ H NMR (300 MHz, d6-DMSO): 3.79 (s, 3H); 6.85 (dd, 1 H); 6.98 (m, 1 H); 7.92 (d, 1 H); 8.15 (s, 1 H); 9.86 (s, 1 H); 11.92 (bs, 1 H); MS (ES +): m / z 176 (M + H) ⁺ ; (ES−): m / z 174 (MH) ⁻ ;
[425] b) 3-formyl-7-methoxy-1H-indole;
[426] c) 3-formyl-4-chloro-1H-indole;
[427] d) 3-formyl-6-chloro-1H-indole, ¹ H NMR (300 MHz, d6-DMSO-d6): 7.24 (dd, 1H), 7.56 (d, 1H), 8.06 (d, 1H), 8.33 (s, 1 H), 9.93 (s, 1 H), 12.21 (bs, 1 H); MS (ES +): m / z 182, 180 (M + H) ⁺ ; (ES-): m / z 180, 178 (M ⁻ H) ⁻ ;
[428] e) 3-formyl-7-chloro-1H-indole, ¹ H NMR (300 MHz, d6-DMSO): 7.23 (t, 1H), 7.35 (d, 1H), 8.05 (d, 1H), 8.38 (bs , 1H), 9.95 (s, 1 H), 12.54 (bs, 1 H); MS (ES +): m / z 182, 180 (M + H) ⁺ ; (ES-): m / z 180, 178 (M ⁻ H) ⁻ ;
[429] f) 3-formyl-4-fluoro-1H-indole, ¹ H NMR (300 MHz, d6-DMSO): 7.01 (m, 1H), 7.24 (m, 1H), 7.36 (d, 1H), 8.30 ( s, 1 H), 10.03 (d, 1 H), 12.48 (bs, 1 H); MS (ES +): m / z 164 (M + H) ⁺ ; (ES-): m / z 162 (M ⁻ H) ⁻ ;
[430] g) 3-formyl-5-methoxy-6-trifluoromethyl-1H-indole, ¹ H NMR (300 MHz, d6-DMSO): 3.91 (s, 3H), 7.77 (dd, 1H), 7.95 ( bs, 1H), 8.42 (s, 1H), 9.96 (s, 1H), 12.29 (bs, 1H); MS (ES +): m / z 244 (M + H) ⁺ ; (ES-): m / z 242 (M ⁻ H) ⁻ ;
[431] h) 3-formyl-6-chloro-5-methoxy-1H-indole, ¹ H NMR (300 MHz, d6-DMSO): 3.88 (s, 3H), 7.58 (s, 1H), 7.71 (s, 1H ), 8.26 (s, 1 H), 9.91 (s, 1 H), 12.08 (bs, 1 H); MS (ES +): m / z 210, 212 (M + H) ⁺ ; (ES-): m / z 208, 210 (M ⁻ H) ⁻ ;
[432] i) 3-formyl-4-chloro-5-methoxy-1H-indole, ¹ H NMR (300 MHz, d6-DMSO): 3.89 (s, 3H), 7.13 m (dd, 1H), 7.47 (dd, 1H), 8.23 (s, 1H), 10.5 (s, 1H), 12.39 (bs, 1H); MS (ES +): m / z 210, 212 (M + H) ⁺ (ES−): m / z 208, 210 (MH) ⁻ ;
[433] j) 3-formyl-6-trifluoromethyl-1H-indole, ¹ H NMR (300 MHz, d6-DMSO): 7.52 (d, 1H), 8.27 (d, 1H), 8.51 (m, 1H), 9.99 (s, 1 H), 12.47 (bs, 1 H). MS (ES &lt; ⁺ &gt;): m / z 214 (M + H) ⁺ ; (ES-): m / z 212 (M ⁻ H) ⁻ ;
[434] k) 3-formyl-5-methoxy-2-methyl-1H-indole, ¹ H (300 MHz, d6-DMSO): 2.65 (s, 3H), 3.76 (s, 3H), 6.78 (dd, 1H) , 7.27 (d, 1 H), 7.56 (m, 1 H), 10.00 (s, 1 H), 11.85 (bs, 1 H); MS (ES &lt; ⁺ &gt;): m / z 190 (M + H) ⁺ ; (ES-): m / z 188 (MH) ^- ;
[435] l) 3-formyl-6-fluoro-5-methoxy-1H-indole, ¹ H NMR (300 MHz, d6-DMSO): 3.87 (s, 3H), 7.35 (d, 1H), 7.71 (d, 1H), 8.21 (s, 1H), 9.89 (s, 1H), 12.03 (bs, 1h); MS (ES &lt; ⁺ &gt;): m / z 194 (M + H) ⁺ ; (ES-): m / z 192 (M ⁻ H) ⁻ ;
[436] m) 3-formyl-5,6-difluoro-1H-indole, ¹ H NMR (300 MHz, d6-DMSO): 7.56 (m, 1 H), 7.92 (m, 1 H), 8.36 (s, 1 H) , 9.92 (s, 1 H), 12.25 (bs, 1 H); MS (ES &lt; ⁺ &gt;): m / z 182 (M + H) ⁺ (ES &lt; ⁺ &gt;): m / z 180 (MH) ^- ;
[437] n) 3-formyl-6-chloro-5-fluoro-1H-indole, ¹ H NMR (300 MHz, d6-DMSO): 7.72 (d, 1H), 7.91 (d, 1H), 8.40 (s, 1H ), 9.93 (s, 1 H), 12.29 (bs, 1 H); MS (ES &lt; ⁺ &gt;): m / z 198 (M + H) ⁺ ; (ES-): m / z 196 (M ⁻ H) ⁻ ;
[438] o) 3-formyl-5-trifluoromethoxy-1H-indole, ¹ H NMR (300 MHz, d6-DMSO): 7.24 (m, 1H), 7.61 (m, 1H), 7.97 (bs, 1H), 8.42 (d, 1 H), 9.95 (s, 1 H), 12.35 (bs, 1 H); MS (ES &lt; ⁺ &gt;): m / z 230 (M + H) ⁺ ; (ES-): m / z 228 (M ⁻ H) ⁻ ; Analysis for C ₁₀ H ₆ F ₃ NO ₂ : calcd. C, 52.4138; H, 2.6391; N, 6.1122; Measurements; C, 52.70; H, 2.73; N, 6.13;
[439] p) 3-formyl-4,6-difluoro-5-methoxy-1H-indole, MS (ES +): 212 (M + H) ⁺ ; (ES−): 210 (M ⁻ H) ⁻ ;
[440] q) 3-formyl-4-phenyl-1H-indole, ¹ H NMR (300 MHz, d6-DMSO): 7.07 (m, 1 H), 7.30 (m, 1 H), 7.46 (m, 6H), 7.53 (m , 1H), 8.20 (bs, 1H), 9.37 (s, 1H), 12.40 (bs, 1H). MS (ES &lt; ⁺ &gt;): m / z 222 (M + H) ⁺ ; (ES-): m / z 220 (M ⁻ H) ⁻ ;
[441] r) 3-formyl-6-phenyl-1H-indole, ¹ H NMR (300 MHz, d6-DMSO): 7.35 (m, 1H), 7.49 (m, 3H), 7.71 (m, 3H), 8.15 (m , 1H), 8.33 (d, 1H), 9.96 (s, 1H), 12.20 (bs, 1H). MS (EI +): m / z 221 (M) ⁺ ;
[442] s) 3-formyl-5-isopropyl-1H-indole, ¹ H NMR (300 MHz, d6-DMSO): 1.24 (d, 6H), 2.99 (m, 1H), 7.15 (m, 1H), 7.41 ( m, 1H), 7.94 (m, 1H), 8.22 (m, 1H), 9.90 (s, 1H), 12.02 (bs, 1H); MS (ES &lt; ⁺ &gt;): 188 (M + H) ⁺ ; (ES-): m / z 186 (M ⁻ H) ⁻ ;
[443] t) 3-formyl-4,6-difluoro-5-methoxy-1-methyl-1H-indole: ¹ H NMR (300 MHz, CDCl ₃ ): 3.81 (s, 3H), 4.02 (s, 3H ), 6.92 (m, 1 H), 7.77 (s, 1 H), 10.14 (d, 1 H); MS (ES &lt; ⁺ &gt;): m / z 226 (M + H) ⁺ ; And
[444] u) 3-formyl-4,6-difluoro-1-methyl-1H-indole: ¹ H NMR (300 MHz, d6-DMSO): 3.87 (s, 3H), 7.10 (m, 1H), 7.41 ( m, 1H), 8.32 (s, 1H), 9.93 (d, 1H); MS (ES &lt; ⁺ &gt;): 196 (M + H) ⁺ .
[445] Example 51
[446] 3- (2-nitrovinyl) -4-methoxy-1 H-indole
[447] Ammonium acetate as a solid (treated with toluene and dried from detoluene under vacuum) (0.75 equiv), nitromethane (20 equiv) and 4-methoxy-1H-indole-3-carbaldehyde (5.4 g, 30.82 mmol) were combined. Heated to about 65 ° C. After determining that the reaction was almost complete (performed by TLC), silica gel was added and evaporated under vacuum to remove nitromethane. Silica gel was loaded from the reaction mixture onto a short column of silica gel, eluted with 25% acetone in hexanes and evaporated to afford the title compound that could be used in the next step without further purification.
[448] According to the method of Example 51, the following compounds were prepared:
[449] a) 3- (2-nitrovinyl) -6-methoxy-1H-indole;
[450] b) 3- (2-nitrovinyl) -7-methoxy-1H-indole, ¹ H NMR (300 MHz; d6-DMSO): 3.95 (s, 3H), 5.02 (m, 1H), 6.86 (d, 1H), 7.17 (t, 1H), 7.50 (d, 1H), 8.38 (d, 1H), 12.40 (bs, 1H); MS (ES +): m / z 219 (M + H) ⁺ ; (ES-): m / z 217 (M ⁻ H) ⁻ ;
[451] c) 3- (2-nitrovinyl) -4-chloro-1H-indole, ¹ H NMR (300 MHz, d6-DMSO): 5.08 (m, 1H), 7.24 (m, 2H), 7.51 (dd, 1H) ), 8.12 (d, 1 H), 8.92 (d, 1 H), 12.6 (bs, 1 H); MS (ES−): m / z 221, 223 (M ⁻ H) ⁻ ;
[452] d) 3- (2-nitrovinyl) -6-chloro-1H-indole, ¹ H NMR (300 MHz, d6-DMSO): 5.03 (m, 1H), 7.22 (dd, 1H), 7.58 (d, 1H) , 8.03 (m, 2 H), 8.38 (d, 1 H), 12.23 (bs, 1 H); MS (ES-): m / z 223, 221 (M ⁻ H) ⁻ ;
[453] e) 3- (2-nitrovinyl) -7-chloro-1H-indole, ¹ H NMR (300 MHz, d6-DMSO): 7.23 (t, 1H), 7.36 (d, 1H), 7.97 (d, 1H) , 8.06 (d, 1 H), 8.33 (bs, 1 H), 8.40 (d, 1 H), 12.58 (bs, 1 H); MS (ES +): m / z 225, 223 (M + H) ⁺ ; (ES-): m / z 223, 221 (M ⁻ H) ⁻ ;
[454] f) 3- (2-nitrovinyl) -4-fluoro-1 H-indole,
[455] g) 3- (2-nitrovinyl) -5-methoxy-6-trifluoromethyl-1H-indole, MS (ES +): m / z 286 (M &lt; + &gt;); (ES-): m / z 285 (M-H)^-;
[456] h) 3- (2-nitrovinyl) -6-chloro-5-methoxy-1H-indole,
[457] i) 3- (2-nitrovinyl) -4-chloro-5-methoxy-1H-indole, ¹ H NMR (300 MHz, d6-DMSO): 3.88 (s, 3H), 5.03 (m, 2H), 7.13 (d, 1 H), 7.46 (d, 1 H), 8.08 (d, 1 H), 12.42 (bs, 1 H); MS (ES−): m / z 151, 153 (M ⁻ H) ⁻ ;
[458] j) 3- (2-nitrovinyl) -6-trifluoromethyl-1H-indole, MS (ES +): m / z 257 (M + H) ⁺ ; (ES-): m / z 255 (M ⁻ H) ⁻ ;
[459] k) 3- (2-nitrovinyl) -5-methoxy-2-methyl-1H-indole, ¹ H NMR (300 MHz, d6-DMSO): 2.58 (s, 3H), 3.84 (s, 3H), 6.82 (m, 1 H), 7.28 (m, 2 H), 7.89 (d, 1 H), 8.29 (d, 1 H), 12.14 (bs, 1 H); MS (ES &lt; ⁺ &gt;): m / z 233 (M + H) ⁺ ; (ES-): m / z 231 (M ⁻ H) ⁻ ;
[460] l) 3- (2-nitrovinyl) -6-fluoro-5-methoxy-1 H-indole;
[461] m) 3- (2-nitrovinyl) -5,6-difluoro-1 H-indole;
[462] n) 3- (2-nitrovinyl) -6-chloro-5-fluoro-1 H-indole;
[463] o) 3- (2-nitrovinyl) -5-trifluoromethoxy-1H-indole;
[464] p) 3- (2-nitrovinyl) -4,6-difluoro-5-methoxy-1 H-indole;
[465] q) 3- (2-nitrovinyl) -4-phenyl-1H-indole;
[466] r) 3- (2-nitrovinyl) -6-phenyl-1H-indole;
[467] s) 3- (2-nitrovinyl) -5-isopropyl-1H-indole;
[468] t) 3- (2-nitrovinyl) -4,6-difluoro-5-methoxy-1-methyl-1H-indole: ¹ H NMR (300 MHz, d6-DMSO): 3.82 (t, 3H), 3.92 (s, 3 H), 7.53 (m, 1 H), 7.84 (m, 1 H), 8.30 (m, 2 H); MS (ES &lt; ⁺ &gt;): m / z 269 (M + H) ⁺ ; And
[469] u) 3- (2-nitrovinyl) -4,6-difluoro-1-methyl-1H-indole.
[470] Example 52
[471] 4-methoxytryptamine
[472] LiAlH ₄ (6.78 g; 178.74 mmol; 6 equiv) and anhydrous THF were combined. 3- (2-nitrovinyl) -4-methoxy-1H-indole (6.5 g; 29.79 mmol) was dissolved in anhydrous THF and stirred vigorously with dropwise addition to LiAlH ₄ solution. After the addition was complete, it was heated to reflux. After 1 hour, the mixture was cooled to room temperature and stirred. After 16 hours, J. Med. Chem . Excess LiAlH ₄ was quenched as described in 1995, 38, 2050. The gray suspension was filtered through celite and the celite was washed with ethyl acetate. The filtrate was evaporated to residue under vacuum. Chromatography on silica gel eluting the residue with 1 L of CHCl ₃ / MeOH / NH ₄ OH (95: 10: 1) as mobile phase, followed by 1 L of CHCl ₃ / MeOH / NH ₄ OH (90: 10: 1) Was done. Fractions containing the product were combined and evaporated to afford the title compound as a tan solid: ¹ H NMR (300 MHz, d ₆ -DMSO): 2.96 (t, 2H); 3.42 (t, 2 H); 3.83 (s, 3 H); 6.42 (dd, 1 H); 6.93 (m, 3 H); 10.7 (s, 1 H); MS (ES +): m / z 191 (M + H) ⁺ ; 174 (M-NH ₂ ) ⁺ ; 159 (M- ° C H ₃ ) ⁺ ; (ES-): m / z 189 (M ⁻ H) ⁻ .
[473] According to the method of Example 52, the following compounds were prepared:
[474] a) 6-methoxytrytamine, ¹ H NMR (300 MHz; d6-DMSO): 2.86 (t, 2H); 3.42 (t, 2 H); 3.75 (s, 3 H); 6.62 (dd, 1 H); 6.83 (m, 1 H); 6.97 (bs, 1 H); 7.37 (m, 1 H); 10.55 (s, 1 H); MS (ES +): m / z 191 (M + H) ⁺ ; 174 (M-NH ₂ ) ⁺ ; (ES-): m / z 189 (M ⁻ H) ⁻ ;
[475] b) 7-methoxytrytamine, ¹ H NMR (300 MHz, d6-DMSO): 2.88 (t, 2H), 3.42 (t, 2H), 3.89 (s, 3H), 6.61 (d, 1H), 6.89 (t, 1 H), 7.02 (m, 1 H), 7.10 (d, 1 H), 10.85 (bs, 1 H); MS (ES &lt; ⁺ &gt;): m / z 191 (M + H) ⁺ , 174 (M-NH ₂ ) ⁺ ; (ES-): m / z 189 (MH) ^- ;
[476] c) 4-chlorotrytamine, ¹ H NMR (300 MHz, d6-DMSO): 3.11 (t, 2H), 3.44 (t, 2H), 6.99 (m, 2H), 7.22 (m, 1H), 7.30 ( d, 1 H), 11.19 (bs, 1 H); MS (ES &lt; ⁺ &gt;): m / z 178, 180 (M + H) ⁺ ; (ES-): m / z 193 (M ⁻ H) ⁻ ;
[477] d) 6-chlorotrytamine, ¹ H NMR (300 MHz, d6-DMSO): 2.89 (t, 2H), 3.42 (t, 2H), 6.96 (dd, 1H), 7.17 (bs, 1H), 7.35 ( m, 1H), 7.52 (d, 1H), 10.91 (bs, 1H); MS (ES &lt; ⁺ &gt;): m / z 197, 195 (M + H) ⁺ , 180, 178 (M-NH ₂ ) ⁺ ; (ES-): m / z 195, 193 (M ⁻ H) ⁻ ;
[478] e) 7-chlorotrytamine, ¹ H NMR (300 MHz, d6-DMSO): 2.91 (t, 2H), 3.43 (t, 2H), 6.98 (t, 1H), 7.13 (d, 1H), 7.20 ( bs, 1H), 7.51 (d, 1H), 11.15 (bs, 1H); MS (ES &lt; ⁺ &gt;): m / z 197, 195 (M + H) ⁺ , 180, 178 (M-NH2) ⁺ ; (ES-): m / z 195, 193 (MH) ^- ;
[479] f) 4-fluorotriptamine,
[480] g) 5-methoxy-6-trifluoromethyltryptamine,
[481] h) 6-chloro-5-methoxytrytamine, ¹ H NMR (300 MHz, d6-DMSO): 2.89 (t, 2H), 3.42 (t, 2H), 3.84 (s, 3H), 7.12 (bs, 1H), 7.19 (s, 1 H), 7.36 (s, 1 H), 8.01 (bs, 1 H); MS (ES +): m / z 225, 227 (M + H) ⁺ , 208, 210 (M-NH 2) ⁺ ; (ES-): m / z 223, 225 (M ⁻ H) ⁻ ;
[482] i) 4-chloro-5-methoxytrytamine, ¹ H NMR (300 MHz, d6-DMSO): 3.10 (t, 2H), 3.43 (t, 2H), 3.81 (s, 3H), 6.95 (d, 1H), 7.18 (m, 1H), 7.25 (dd, 1H), 10.93 (bs, 1H); MS (ES &lt; + &gt;): m / z 208, 210 (M-NH ₂ ) ⁺ (ES-): m / z 223, 225 (MH) ^- ;
[483] j) 6-trifluoromethyltryptamine,
[484] k) 5-methoxy-2-methyltryptamine, ¹ H NMR (300 MHz, d6-DMSO): 2.28 (s, 3H), 2.80 (t, 2H), 3.31 (bt, 2H), 6.59 (dd, 1H), 6.88 (d, 1H), 7.09 (d, 1H); MS (ES &lt; + &gt;): m / z 188 (M-NH ₂ ) ⁺ (ES-): m / z 203 (MH) ^- ;
[485] l) 6-fluoro-5-methoxytrytamine;
[486] m) 5,6-difluorotrytamine;
[487] n) 6-chloro-5-fluorotrytamine;
[488] o) 5-trifluoromethoxytrytamine;
[489] p) 4,6-difluoro-5-methoxytrytamine;
[490] q) 4-phenyltryptamine;
[491] r) 6-phenyltryptamine;
[492] s) 5-isopropyltryptamine;
[493] t) 4,6-difluoro-5-methoxy-1-methyltrytamine: ¹ H NMR (300 MHz, CDCl ₃ ): 3.0 (m, 4H), 3.67 (s, 3H), 3.98 (s, 3H), 6.85 (m, 2H); And
[494] u) 4,6-difluoro-5-methoxy-1-methyltrytamine: ¹ H NMR (300 MHz, d6-DMSO): 2.92 (t, 2H), 3.39 (t, 2H), 3.69 (s , 3H), 6.75 (m, 1 H), 7.13 (m, 2 H); MS (ES &lt; + &gt;): m / z 211; (M + H) ⁺ 194 (M-NH ₂ ) ⁺ .
[495] Example 53
[496] 4-methoxytryptamine hydrochloride
[497] 4-methoxytryptamine (1 g, 5.26 mmol) was dissolved in MeOH and NH ₄ Cl (0.97 equiv, 0.27 g, 5.10 mmol) was added. After 30 minutes, the MeOH was removed by evaporation in vacuo leaving a dark orange oil. The oil was dissolved in MeOH and stirred vigorously with dropwise addition to Et ₂ O (200 mL) to give a gummy white precipitate. Stirring with heating gave the title compound as a solid: ¹ H NMR (d ₆ -DMSO, 300 MHz): 3.06 (bs, 4 H); 3.86 (s, 3 H); 6.46 (dd, 1 H); 7.06-6.9 (m, 3 H); 7.93 (bs, 1 H); 10.9 (s, 1 H); MS (ES +): m / z 191 (M + H) ⁺ ; 175 (M-CH ₃ ) ⁺ ; 174 (M-NH ₂ ) ⁺ ; (ES-): 189 (M ⁻ H) ⁻ ; Anal for C ₁₁ H ₁₅ ClN ₂ O: Calcd: C, 58.2788; H, 6. 6692; N, 12.3566; Measurements; C, 58.18; H, 6.73; N, 12.15.
[498] Example 54
[499] 5,6-difluorotrytamine hydrochloride
[500] Prepared according to the method of example 53 to give the title compound: ¹ H NMR (300 MHz, d6-DMSO): 2.97 (m, 4H), 7.27 (m, 1H), 7.36 (m, 1H), 7.53 (m , 1H), 11.20 (bs, 1H); MS (ES &lt; ⁺ &gt;): m / z 197 (M + H) ⁺ , 180 (M-NH ₂ ) ⁺ ; (ES-): m / z 195 (M ⁻ H) ⁻ .
[501] Example 55
[502] 4-phenyltryptamine hydrochloride
[503] HCl solution (4.6 mL of 4 M HCl in 1,4-dioxane) was added dropwise to a solution of 4-phenyltryptamine (3.33 g, 14.09 mmol) in EtOAc / Et ₂ O to give a solid. The solid was collected by filtration at room temperature and dried in a vacuum oven overnight to yield the title compound as off-white solid: ¹ H NMR (300 MHz, d6-DMSO): 2.54 (m, 4H), 6.82 (m, 1H), 7.14 (t, 1H), 7.27 (m, 1H), 7.41 (m, 5H), 7.68 (bs, 2H), 11.28 (bs, 1H); MS (ES &lt; ⁺ &gt;): m / z 237 (M + H) ⁺ , 220 (M-NH 2) ⁺ ; (ES-): m / z 235 (M ⁻ H) ⁻ ; Analysis for C ₁₆ H ₁₇ ClN ₂ ; Calculated value; C, 70.4517; H, 6.2818; N, 10.2696; Measurements; C, 70.26; H, 6. 16; N, 10.20.
[504] Example 56
[505] 5-chloro-6-fluorotrytamine hydrochloride
[506] Prepared according to the method of example 55 to obtain the title compound: ¹ H NMR (300 MHz, d6-DMSO): 3.00 (m, 4H), 7.37 (m, 1H), 7.53 (d, 1H), 7.59 (d , 1H), 11.28 (bs, 1H); MS (ES &lt; ⁺ &gt;): m / z 213 (M + H) ⁺ , 196, 198 (M-NH ₂ ) ⁺ ; (ES-): m / z 211, 213 (M ⁻ H) ⁻ .
[507] Example 57
[508] 4-chlorotriptamine oxalate
[509] Oxalic acid (1.32 g, 1.3 equiv) in MeOH was vigorously stirred with dropwise addition of a solution of 4-chlorotryptamine (2.2 g, 11.3 mmol) in EtOAc. When the addition was complete, Et ₂ O was added to the cloud point and the flask placed in the refrigerator to give a solid. The solid was collected via filtration and washed with ether. Drying in a vacuum oven at room temperature gave the title compound as off-white solid: ¹ H NMR (300 MHz, d6-DMSO): 3.11 (m, 2H), 3.2 (m, 2H), 7.04 (m, 2H), 7.34 ( m, 2H), 11.44 (bs, 1H); MS (ES &lt; ⁺ &gt;): m / z 195 (M + H) ⁺ , 178 (M-NH ₂ ) ⁺ ; (ES-): m / z 193 (M ⁻ H) ⁻ ; Anal for C ₁₂ H ₁₃ ClN ₂ O ₄ : Calcd: C, 50.6263; H, 4. 6026; N, 9.8396; Found: C, 50.56; H, 4.57; N, 9.66.
[510] The following compound was obtained using the method of Example 57:
[511] a) 6-phenyltrytamine oxalate: 3.05 (m, 4H), 7.31 (m, 3H), 7.45 (t, 2H), 7.65 (m, 4H), 11.10 (bs, 1H). MS (ES &lt; + &gt;): m / z 237 (M + H) &lt; + &gt;, 220 (M-NH2) &lt; + &gt;; (ES-): m / z 235 (M-H);
[512] b) 4,6-difluoro-5-methoxytrytamine oxalate: 1 H NMR (300 MHz, d6-DMSO): 3.04 (m, 4H), 3.85 (s, 3H), 7.10 (m, 1H) , 7.22 (m, 1 H), 11.29 (bs, 1 H); MS (ES &lt; ⁺ &gt;): m / z 227 (M + H) ⁺ ; (ES-): m / z 225 (M ⁻ H) ⁻ .; Analysis for C ₁₃ H ₁₄ F ₂ N ₂ O ₅ : calculated; C, 49.3718; H, 4.4 620; N, 8.8576; Measurements; C, 49.68; H, 4.57; N, 8. 60; And
[513] c) 5-isopropyltrytamine oxalate: ¹ H NMR (300 MHz, d6-DMSO): 1.25 (d, 6H), 3.01 (m, 4H), 6.99 (m, 1H), 7.17 (m, 1H) , 7.27 (m, 1 H), 7.36 (bs, 1 H), 10.85 (bs, 1 H); MS (ES +): m / z 203 (M + H) ⁺ , 186 (M-NH 2) +; (ES-): m / z 201 (M ⁻ H) ⁻ .
[514] Example 58
[515] 5-trifluoromethoxy-trip bit amine oxalate oxalic acid (1.3 eq) in acetone was added in a 5-trifluoromethoxy-trip bit amine solution in acetone. After warming and addition of Et ₂ O to the cloud point, placed in the refrigerator overnight to give the title compound as a white crystalline solid: ¹ H NMR (300 MHz, d 6 -DMSO): 3.02 (m, 4H), 7.06 (m, 1H) , 7.39 (m, 1 H), 7.45 (d, 1 H), 7.55 (m, 1 H), 11.30 (bs, 1 H). MS (ES &lt; ⁺ &gt;): m / z 245 (M + H) ⁺ , 228 (M-NH ₂ ) ⁺ ; (ES-): m / z 243 (M ⁻ H) ⁻ ; Analysis for C ₁₁ H ₁₁ F ₃ N ₂ O: calcd. C, 46.7144; H, 3.9203; N, 8.3809; Measurements; C, 46.55; H, 3.62; N, 8.27.
[516] The following compound was obtained using the method of Example 58:
[517] a) 4,6-difluoro-5-methoxytrytamine oxalate: ¹ H NMR (300 MHz, d6-DMSO): 3.04 (m, 4H), 3.85 (s, 3H), 7.10 (m, 1H ), 7.22 (m, 1 H), 11.29 (bs, 1 H); MS (ES &lt; ⁺ &gt;): m / z 227 (M + H) ⁺ ; (ES-): m / z 225 (M ⁻ H) ⁻ .; Analysis for C ₁₃ H ₁₄ F ₂ N ₂ O ₅ : calculated; C, 49.3718; H, 4.4 620; N, 8.8576; Measurements; C, 49.68; H, 4.57; N, 8.60.
[518] Example 60
[519] 4-fluorotrytamine oxalate
[520] Oxalic acid (1.44 g, 1.2 equiv) in acetonitrile was stirred vigorously with dropwise addition to an acetonitrile solution of 4-fluorotryptamine. The solution was prepared by warming and adding MeOH. Et ₂ O was added to the cloud point and the solution was cooled in a refrigerator to give a solid. The solid was collected by filtration and dried overnight in a vacuum oven at 45 ° C. to give the title compound as a tan solid: ¹ H NMR (300 MHz, d 6 -DMSO): 3.07 (m, 4H), 6.73 (m, 1H), 7.04 (m, 1 H), 7.22 (m, 2 H), 11.30 (bs, 1 H); MS (ES +): m / z 179 (M + H) ⁺ ; (ES−): m / z 177 (MH) ⁻ .
[521] Example 61
[522] 6-fluoro-5-methoxytrytamine oxalate
[523] Oxalic acid in MeOH (3.91 g, 1.2 equiv) was stirred vigorously with dropwise addition to EtOAc / MeOH solution of 6-fluoro-5-methoxytrytamine. Et ₂ O was added to give a solid which was collected by filtration and dried overnight in a vacuum oven at 60 ° C. to give the title compound: ¹ H NMR (300 MHz, d 6 -DMSO): 3.0 (m, 4H), 3.85 (s, 3 H), 7.21 (m, 3 H), 10.89 (bs, 1 H); MS (ES &lt; ⁺ &gt;): m / z 209 (M + H) ⁺ ; Anal for C ₁₃ H ₁₅ FN ₂ O ₅ : Calcd: C, 52.3496; H, 5.0 690; N, 9.3919; Found: C, 52.06; H, 4.91; N, 9.20.
[524] Example 62
[525] 2- (2- (7-fluoro-1H-indol-3-yl) ethyl) isoindole-1,3-dione
[526] 2-fluorohydrazine hydrochloride (3.25 g, 20 mmol) and 2- (4,4-diethoxy-butyl) -isoindole-1,3-dione (6.99 g, 24 mmol) were combined and 4% H ₂ SO ₄ It was dissolved in an aqueous solution. The reaction was heated to reflux. After 2 hours, the mixture was cooled to room temperature. The reaction mixture was basified with 30% NH ₄ OH aqueous solution to a pH of about 11. Extracted with dichloromethane (2 x 100 mL). The organic phases were combined, dried over MgSO _4, filtered and the solvent removed leaving an orange oil. The oil was absorbed into silica gel and loaded onto a short column of silica gel equilibrated with 15% EtOAc in hexanes. After evaporation by elution with 15% EtOAc in hexanes (1500 mL) and then 30% EtOAc in hexanes (2000 mL), the title compound is obtained as a yellow solid: ¹ H NMR (300 MHz, d6-DMSO): 3.03 (t , 2H), 3.85 (t, 2H), 6.91 (m, 2H), 7.25 (m, 1H), 7.36 (d, 1H), 7.83 (m, 4H), 11.32 (bs, 1H); MS (FD): m / z 308 (M &lt; + &gt;).
[527] Example 63
[528] 7-fluorotrytamine oxalate
[529] 2- (2- (7-fluoro-1H-indol-3-yl) ethyl) isoindole-1,3-dione was dissolved in 25 mL THF. Ethanolamine (63.4 g, 62.65 mL, 1038 mmol, 100 equiv) was vigorously stirred and heated to 70 ° C. After 1.5 hours, it was cooled to room temperature. After 18 hours, the reaction mixture was poured into water (250 mL) containing 5 N NaOH (3 mL) and extracted with Et ₂ O (2 × 200 mL). The organic layers were combined and washed with 0.1N NaOH. The organic layers were collected, dried over MgSO ₄ , filtered and the solvent removed in vacuo to yield the title compound as a yellow oil.
[530] Oxalic acid (0.62 g, 1.2 equiv) in MeOH was stirred vigorously with dropwise addition of EtOAc solution of base (1.02 g, 5.72 mmol). The cloudy suspension was heated to reflux for 30 minutes and then cooled to give a solid. The solid was collected via filtration and dried overnight in a vacuum oven at 60 ° C. to afford the title compound as an off-white solid: ¹ H NMR (300 MHz, d 6 -DMSO): 3.04 (m, 4H), 6.96 (m, 2H), 7.30 (m, 1 H), 7.38 (d, 1 H), 11.51 (bs, 1 H); MS (ES &lt; ⁺ &gt;): m / z 179 (M + H) ⁺ , 162 (M-NH ₂ ) ⁺ ; (ES-): m / z 177 (M ⁻ H) ⁻ ; Anal for C ₁₂ H ₁₃ FN ₂ O ₄ : Calcd: C 53.7318; H 4.8849; N 10.4431; Found: C, 53.50; H, 4.86; N, 10.32.
[531] Example 64
[532] 6-trifluoromethyltryptamine oxalate
[533] 6-trifluoromethyltryptamine was added to acetone / Et ₂ O (1: 1). Oxalic acid (1.2 equiv) in acetone was added dropwise to give a solid. The solid was collected via filtration and dried overnight in a vacuum oven to afford the title compound: MS (ES +): m / z 212 (M-NH ₂ ) ⁺ ; (ES-): m / z 227 (M ⁻ H) ⁻ .
[534] Example 65
[535] 4,6-difluoro-5-methoxy-1H-indole
[536] 2,6-difluoro-4-nitrophenol (J. Heterocyclic. Chem. 1976, 13, 1253; 10 g, 57.11 mmol) was dissolved in 300 ml of benzene. A solution of 1-methyl-3-p-tolyltriagen (9.37 g, 62.82 mmol, 1.1 equiv) in benzene (150 mL) was added dropwise. After TLC confirmed that no starting material was present, the reaction mixture was transferred to a separatory funnel and washed with 1N HCl followed by saturated NaHCO ₃ and then water. The organic layers were dried over MgSO _4, filtered and the solvent removed to give a residue. The residue was crystallized from MeOH / water to give 1,3-difluoro-2-methoxy-5-nitrobenzene as white needles: ¹ H NMR (30 MHz, CDCl ₃ ): 4.25 (t, 3H), 7.80 (d, 2 H).
[537] Combine 1,3-difluoro-2-methoxy-5-nitrobenzene (10.12 g, 53.51 mmol) and 4-chlorophenoxyacetonitrile (11.21 g, 66.89 mmol, 1.25 equiv) in DMSO (150 mL) It was. To the suspension of solid NaOH (powder, 10.70 g, 267.55 mmol, 5 equiv) was added dropwise over 5 hours. After 18 hours, the reaction mixture was poured into cooled aqueous HCl solution and extracted with Et ₂ O (2 × 150 mL). The organic layers were combined, washed with brine and evaporated to give a residue. The residue was chromatographed on silica gel and evaporated by elution with 20% EtOAc in hexanes to give (2,4-difluoro-3-methoxy-6-nitrophenyl) acetonitrile as a yellow oil: MS (ES−): m / z 227 (M ⁻ H) ⁻ .
[538] Israel J. Chem. 1966, 4, 155-159 to obtain an oil using (2,4-difluoro-3-methoxy-6-nitrophenyl) acetonitrile in cyclization as described. After evaporation of the oil by chromatography on silica gel eluting with 20% EtOAc in hexanes, the title compound is obtained as a purple solid; ¹ H NMR (300 MHz, d6-DMSO): 3.85 (bs, 3H), 6.46 (m, 1H), 7.12 (d, 1H), 7.36 (m, 1H), 11.35 (bs, 1H); MS (ES−): m / z 182 (M ⁻ H) ⁻ .
[539] The following compound was obtained using the method of Example 65:
[540] a) 4,6-difluoro-1H-indole: ¹ H NMR (300 MHz, CDCl ₃ ): 4.68 (d, 2H), 6.14 (m, 2H), 6.57 (bs, 2H); MS (ES &lt; ⁺ &gt;): m / z 205, 207 (M + H) ⁺ from which the title compound was obtained.
[541] Example 66
[542] 4,6-difluoro-5-methoxy-1-methyl-1H-indole
[543] Combine 4,6-difluoro-5-methoxy-1H-indole (7.5 g, 40.95 mmol) and cooled DMF (100 mL) and stir vigorously while treating with NaH (1.8 g, 45.05 mmol, 1.1 equiv) It was. After about 10 minutes, iodomethane (11.62 g, 81.90 mmol, 2 equiv) was added dropwise. After the addition was complete, the reaction was stirred for several hours at room temperature until TLC confirmed that no starting material was present. The reaction was diluted with water and extracted with Et ₂ O (2 × 150 mL). The organic layers were combined, dried over MgSO _4, filtered and the solvent removed leaving oil. After evaporation of the oil by chromatography on silica gel eluting with 10% EtOAc in hexanes, the title compound was obtained as light yellow oil; ¹ H NMR (300 MHz, CDCl ₃ ): 3.72 (s, 3H), 3.97 (s, 3H), 6.50 (d, 1H), 6.84 (d, 1H), 6.98 (d, 1H); MS (ES &lt; ⁺ &gt;): m / z 198 (M + H) ⁺ ; Anal for C ₁₀ H ₉ F ₂ NO: Calcd: C, 60.91; H, 4. 60; N, 7.10; Found: C, 60.93; H, 4.63; N, 7.25.
[544] The following compound was obtained using the method of Example 66:
[545] a) 4,6-difluoro-1-methyl-1H-indole.
[546] Example 67
[547] N- (2- (5-methoxy-1H-indol-3-yl) ethyl) -3-phenoxybenzylamine
[548]
[549] Combine 3-phenoxybenzaldehyde (5.6 mL, 26.7 mmol), 5-methoxytrytamine (5.0 g, 26.7 mmol) and 3 ′ molecular sieve (1.0 g) in methanol (50 mL) under argon and reflux for 4 h. Heated. After removal of the molecular sieve by filtration, sodium borohydride (3.0 g, 60.0 mmol) was slowly added in portions. Stirred at rt for 1 h and concentrated under reduced pressure, the concentrated reaction mixture was dissolved in sodium hydroxide 1 N (100 mL) and extracted with dichloromethane (3 × 50 mL). The organic layers were combined and washed sequentially with distilled water (50 mL) and brine (50 mL), the organic layers were dried (Na ₂ SO ₄ ) and concentrated to give a residue. The residue was chromatographed on silica gel eluting with 2% NH ₄ OH and EtOAc: MeOH (9: 1) to afford the title compound.
[550] Formation of oxalate salt: Free base (8.7 g, 23.5 mmol) in EtOAc (50 mL) was added to a solution of oxalic acid (2.1 g, 23.5 mmol) in EtOAc (5 mL) to give a precipitate. The precipitate was collected and recrystallized from methanol / diethyl ether to give a solid. The solid was collected via filtration, washed with diethyl ether and dried overnight in a vacuum oven at 50 ° C. to afford the title compound as oxalate; mp 188-190 ° C., RMN agreement, mass: m / z 373.2 (M +), Analytical Calcd for C ₂₆ H ₂₆ N ₂ O ₆ : C, 67.52; H, 5.67; N, 6.06. Found: C, 67.38; H, 5. 46; N, 6.04.
[551] The following compounds were prepared according to the method of Example 67 and isolated as oxalate except as noted:
[552]
[553]
[554]
[555]
[556]
[557]
[558]
[559]
[560]
[561] The following compounds were prepared according to the method of Example 67 and isolated as oxalate except as noted:
[562]
[563]
[564]
[565]
[566]
[567]
[568]
[569]
[570] The following compounds were prepared according to the method of Example 67 and isolated as oxalate except as noted:
[571]
[572] The following compounds were prepared according to the method of Example 67 and isolated as oxalate except as noted:
[573]
[574] The following compounds were prepared according to the method of Example 67 and isolated as oxalate except as noted:
[575]
[576] The following compounds were prepared according to the method of Example 67 and isolated as oxalate except as noted:
[577]
[578] Example 220
[579] N- (2- (3-chlorophenyl) ethyl) -3-benzoylbenzylamine
[580]
[581] 3-benzoylbenzaldehyde (0.45 g, 2.1 mmol) and (3-chlorophenyl) ethylamine (0.3 mL, 2.1 mmol) and 3 ′ molecular sieve (1.0 g) in MeOH (30 mL) were combined. Heated to reflux. After 3 h, cooled, filtered and concentrated to give a residue. The residue was dissolved in dichloroethane (20 mL) and acetic acid (0.12 mL, 2.1 mmol) and sodium triacetoxy borohydride (0.6 g, 2.94 mmol). Was added and stirred at room temperature. After 2 hours, the reaction mixture was concentrated and dichloromethane (90 mL) was added and extracted sequentially with distilled water (50 mL), then brine (50 mL). The organic layers were dried over Na ₂ SO ₄ and a residue was obtained. The residue was chromatographed on silica gel eluting with EtOAc to afford the title compound as base.
[582] The title compound was obtained from oxalate using the method of example 67: mp 196-198 ° C., mass: m / z 350.4 (M +), analysis for C ₂₄ H ₂₂ ClNO ₅ ; Calc .: C, 65.53; H, 5.04; N, 3.18. Found: C, 65.27; H, 5.20; N, 3.13.
[583] Example 221
[584] N- (2- (3-chlorophenyl) ethyl) -3-ethoxybenzylamine
[585]
[586] In ethanol (230 ml) 3-ethoxybenzaldehyde (3.38 g, 22.5 mmol), 2- (3-chlorophenyl) ethylamine (2.33 g, 15.0 mol) and 3 ′ molecular sieve (2.88 g) were combined. The reaction mixture was stirred at reflux for 4 hours. After filtration to remove the molecular sieve, sodium borohydride (1.70 g, 45.0 mmol) was slowly added to the filtrate and stirred at room temperature. After 15 hours, the reaction mixture was concentrated to a residue, which was dissolved in 1 N NaOH and extracted with dichloromethane. Combine organic extracts, wash with brine, Na₂SO₄Dried over and concentrated to residue. The residue was chromatographed on silica gel eluting with ethyl acetate to afford the title compound. HCl salt was prepared in ethyl acetate to afford the title compound: mp 178-180 ° C .; MS (ACPI): m / e 290.1 (M + l); C₁₇H₂₁Cl₂Analysis for NO: calcd .: C, 62.58; H, 6. 49; N, 4.29; Found: C, 62.65; H, 6.53; N, 4.32.
[587] The following compounds were prepared according to the method of Example 221 and isolated as maleate except as noted:
[588]
[589] The following compounds were prepared according to the method of Example 221 and isolated as maleate except as noted:
[590]
[591]
[592]
[593]
[594] Example 261
[595] N- (2- (7-fluoro-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine hydrochloride
[596] Acetyl chloride (2.4 mL, 33.8 mmol) was added dropwise to anhydrous ethanol (50 mL) and the solution stirred at room temperature for 10 minutes, and N- (2- (7-fluoro-1H-indol-3-yl) in ethyl acetate ) Ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine (12.0 g, 30.1 mmol) solution was added. The resulting solution was concentrated under reduced pressure to give a yellow solid. The yellow solid was recrystallized from ethyl acetate / ethanol / diethyl ether to afford the title compound: mp 142-143 ° C. MS (m / e): 399 (M + 1), 397 (M-1). Calcd for C ₂₀ H ₁₉ F ₅ N ₂ 0-HCl: Calcd: C, 55.24; H, 4. 64; N, 6.44. Found: C, 55.44; H, 4. 66; N, 6.46.
[597] Example 262
[598] (N- (2- (7-fluoro-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine hydrochloride L (+) tartrate
[599] L-(+)-tartaric acid (49 mg, 0.33 mmol) and methanol in (N- (2- (7-fluoro-1H-indol-3-yl) ethyl) -3- (2,2, Was added to a solution of 3,3-tetrafluoropropoxy) benzylamine (130 mg, 0.33 mmol) The solvent was evaporated to give a rubber Crystallized from diethyl ether / ethyl acetate to give the title compound: mp 192-194 ° C.
[600] Example 263
[601] N- (2- (7-fluoro-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine hydrochloride
[602] Acetyl chloride (2.3 mL, 32.4 mmol) was added dropwise to anhydrous ethanol (50 mL) and the solution was stirred at room temperature for 10 minutes and N- (2- (7-fluoro-1H-indol-3-yl in diethyl ether). ) Ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine (10.7 g, 29.2 mmol) was added to the solution. The resulting solution was concentrated under reduced pressure to give a yellow solid. Recrystallization of the above yellow solid from ethyl acetate / methanol gave the title compound: mp 163-164 ° C .; MS (m / e): 367 (M + l), 365 (M-1); Calc'd for C ₁₉ H ₁₈ F ₄ N ₂ OHCl: calcd: C, 56.65; H, 4.75; N, 6.95. Found: C, 56.45; H, 4.54; N, 6.90.
[603] Example 264
[604] N- (2- (7-fluoro-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine L (+) tartrate
[605] L-(+)-tartaric acid (295 mg, 1.96 mmol) in methanol was diluted with N- (2- (7-fluoro-1H-indol-3-yl) ethyl) -3- (2,2,2 in ethyl acetate. -Trifluoroethoxy) benzylamine (720 mg, 1.96 mmol) solution. The resulting solution was concentrated under reduced pressure to give a clear colorless oil. The oil was crystallized from diethyl ether to afford the title compound: mp 118-119 ° C. MS (m / e): 367 (M + 1), 365 (M-1). Calcd for Ci ₉ H ₁₈ F ₄ N ₂ 0C ₄ H ₆ 0 ₆ : Calculated: C, 53.49; H, 4.68; N, 5.42. Found: C, 53.21; H, 4.55; N, 5.41.
[606] Example 270
[607] N- (2- (5-fluoro-1H-indol-3-yl) ethyl) -3-propoxybenzylamine hydrochloride
[608]
[609] In ethanol (200 mL) 3-propoxybenzaldehyde (2.96 g, 18.0 mmol), 5-fluorotryptamine hydrochloride (2.58 g, 12.0 mol), triethylamine (1.15 g), and 3 ′ molecular sieve (2.27 g) were combined. The reaction mixture was stirred at reflux for 4 hours. After filtration to remove the molecular sieve, sodium borohydride (1.36 g, 36.0 mmol) was slowly added to the filtrate and stirred at room temperature. After 15 h, the reaction mixture was concentrated to a residue and the residue was dissolved in 1 N NaOH and extracted with dichloromethane. Combine organic extracts, wash with brine, Na₂SO₄Dried over and concentrated to residue. The residue was chromatographed on silica gel eluting with ethyl acetate to give 3.31 g of oil. HCl salt was prepared in diethyl ether: mp 197-199 ° C .; MS (ACPI): m / e 327.2 (M + 1); C₂₀H₂₄ClFN₂Anal for O: Calcd: C, 66.20; H, 6.67; N, 7.72; Found: C, 66.06; H, 6.63; N, 7.76.
[610] The following compounds were prepared according to the method of Example 270 and isolated as maleate except as noted:
[611]
[612]
[613] Example 301
[614] N- (2- (6-chloro-1H-indol-3-yl) ethyl) -N-methyl-3- (2,2,3,3-tetrafluoropropoxy) benzylamine maleate
[615]
[616] 3- (2,2,3,3-tetrafluoropropoxy) benzaldehyde (232.6 mg, 0.98 mmol) was added N- (2- (6-chloro-1H-indol-3-yl in dichloroethane (50 mL). ) Ethyl) -N-methylamine (205.6 mg, 0.98 mmol) and sodium triacetoxy borohydride (305.3 mg, 1.37 mmol) were added to the solution. Stir at room temperature. After 24 hours, the residue was evaporated and the residue was dissolved in 1 N NaOH and then extracted with dichloromethane. Organic extracts were combined, washed with brine, dried (Na ₂ SO ₄ ), filtered and evaporated to residue. The residue was chromatographed on silica gel eluting with ethyl acetate to afford the title compound. Maleate salt was prepared in diethyl ether: mp 125-128 ° C. MS (ACPI): m / e 429.3 (M + l). Anal for C ₂₅ H ₂₅ ClF ₄ N ₂ O ₅ : Calcd: C, 55.10; H, 4. 62; N, 5.14; Found: C, 55.13; H, 4.59; N, 5.09.
[617] According to the method of Example 301, the following compounds were prepared:
[618]
[619]
[620] Example 306
[621] N- (2- (6-carboxy-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine
[622]
[623] N- (2- (6-ethoxycarbonyl-1H-indol-3-yl) ethyl) -N- (2,2,3,3-tetrafluoropropoxybenzyl) amine (in ethanol (4.8 mL) 1.09 g, 2.4 mmol) and 2 N NaOH (4.8 mL) were combined. Heated to reflux. After 2 h, cooled to room temperature, evaporated in vacuo to remove ethanol and neutralized with 5 N HCl (1.92 mL) to give a solid. The solid was collected by filtration and dried under vacuum to afford the title compound as a white powder: mp 186 ° C., dec, MS (ACPI): m / e 425.1 (M + 1).
[624] Example 307
[625] N- (2- (6-carboxy-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine
[626]
[627] The title compound was obtained by the method of Example 306: mp 232-235 ° C. MS (ACPI): m / e 393.2 (M + l).
[628] Example 310
[629] 5-phenoxy-1H-indole
[630] Potassium hydroxide (3 g, 0.054 mol) and phenol (15 g, 0.16 mol) were combined and heated to 110 ° C. until potassium hydroxide dissolved. The mixture was cooled to rt and 5-fluoro-2-nitrotoluene (7.75 g, 0.05 mol) was added in one portion. The reaction mixture was heated to 130 ° C. for 30 minutes and cooled to room temperature, then poured into 10% NaOH (200 mL). The aqueous solution was extracted with ether (2 x 100 mL) and the organic layers combined and washed with 10% NaOH (2 x 100 mL), water (2 x 100 mL), dried over Na ₂ S0 ₄ and concentrated in vacuo. Chromatography on silica gel eluting with hexanes / ethyl acetate gave 2-nitro-5-phenoxytoluene as a solid: ¹ H NMR (300 MHz, CDCl ₃ ) 2.59 (s, 3H), 6.81- 6.85 (m, 2H), 7.06-7.09 (m, 2H), 7.22-7.26 (m, 1H), 7.40-7.45 (m, 2H), 8.03-8.06 (m, 1H).
[631] 2-nitro-5-phenoxytoluene (1.15 g, 5.0 mmol) and tris (dimethylamino) methane (0.87 g, 6.0 mmol) in 10 ml of dry toluene were combined and heated to reflux under nitrogen. After 2 hours, the reaction mixture was cooled to room temperature and toluene was evaporated under reduced pressure to form a residue. The residue was dissolved in 15 mL EtOAc and mixed with Pd / C (10%, 100 mg) and stirred for 1.5 days at room temperature under 1 atmosphere of hydrogen. The catalyst was filtered off and the filtrate was concentrated. Chromatography on silica gel eluting with hexane / EtOAc gave the title compound as a solid: ¹ H NMR (300 MHz, CDCl ₃ ) 6.49-6.50 (m, 1H), 6.93-7.03 (m, 4H), 7.22-7.27 ( m, 5H), 8.15 (br, 1H).
[632] According to the method of Example 310, the following compounds were prepared:
[633] a) 4- (p-tolyloxy) -2-methylnitrobenzene: ¹ H NMR (300 MHz, CDCl ₃ ) 2.35 (s, 3H), 2.57 (s, 3H), 6.77-6.80 (m, 2H), 6.93-7.03 (m, 2 H), 7.18-7.24 (m, 2 H), 8.00-8.03 (m, 1 H);
[634] b) 5-p-tolyloxy-1H-indole: ¹ H NMR (300 MHz, CDCl ₃ ) 2.31 (s, 3H), 6.48-6.49 (m, 1H), 6.87-6.96 (m, 3H), 7.07- 7.10 (m, 2 H), 7.20-7.35 (m, 3 H), 8.15 (br, 1 H);
[635] c) 4- (o-tolyloxy) -2-methylnitrobenzene: ¹ H NMR (400 MHz, CDCl ₃ ) 2.16 (s, 3H), 2.57 (s, 3H), 6.50-6.78 (m, 2H), 6.93-7.03 (m, 3 H), 7.18-7.35 (m, 1 H), 8.00-8.03 (m, 1 H);
[636] d) 5-o-tolyloxy-1H-indole: ¹ H NMR (400 MHz, CDCl ₃ ) 2.31 (s, 3H), 6.45-6.46 (m, 1H), 6.78-6.80 (m, 1H), 6.90- 6.00 (m, 2H), 7.01-7.10 (m, 2H), 7.13-7.24 (m, 2H), 7.32-7.34 (m, 1H), 8.11 (br, 1H);
[637] e) 4- (m-tolyloxy) -2-methylnitrobenzene: ¹ H NMR (300 MHz, CDCl ₃ ) 2.37 (s, 3H), 2.60 (s, 3H), 6.80-6.88 (m, 4H), 7.03-7.06 (m, 1 H), 7.27-7.32 (m, 1 H), 8.03-8.06 (m, 1 H);
[638] f) 5-m-tolyloxy-1H-indole: 6.0 g (54%) were obtained (red oil). ¹ H NMR (300 MHz, CDCl ₃ ) 2.25 (s, 3H), 6.51-6.52 (m, 1H), 6.76-6.98 (m, 4H), 7.14-7.39 (m, 4H), 8.17 (br, 1H) ;
[639] g) 4- (4-fluorophenoxy) -2-methylnitrobenzene: ¹ H NMR (300 MHz, CDCl ₃ ) 2.60 (s, 3H), 6.80-6.82 (m, 2H), 7.03-7.12 (m , 4H), 8.03-8.06 (m, 1 H); And
[640] h) 5- (4-fluorophenoxy) -1 H-indole: 2.68 g (26%) were obtained (red oil). ¹ H NMR (300 MHz, CDCl ₃ ) 6.50-6.52 (m, 1H), 6.91-7.01 (m, 5H), 7.24-7.38 (m, 3H), 8.18 (br, 1H) .a) 5-p- Tolyloxy-1H-indole.
[641] Example 311
[642] 2-oxo- (5-phenoxy-1 H-indol-3-yl) acetyl chloride
[643] 5-phenoxy-indole (1.57 g, 7.5 mmol) and anhydrous ether (35 mL) were combined in 8 mL of ether and oxalyl chloride (1.07 g, 8.25 mmol) was added. A precipitate formed. The reaction was stirred overnight. The precipitate was collected and dried in vacuo to afford the title compound:^OneH NMR (300 MHz, DMSO-d6) 6.99-7.15 (m, 4H), 7.37-7.42 (m, 2H), 7.60 (d, 1H,J= 8.7 Hz), 7.75 (d, 1 H,J= 2.4 Hz), 8.47 (d, 1H,J= 3.2 Hz), 12.49, (br, 1H).
[644] According to the method of Example 311, the following compounds were prepared:
[645] a) 2-oxo- (5-p-tolyloxy-1H-indol-3-yl) acetyl chloride;
[646] b) 2-oxo- (5-o-tolyloxy-1 H-indol-3-yl) acetyl chloride:^OneH NMR (300 MHz, CDCl₃) 2.83 (s, 3H), 6.86-6.89 (m, 1H), 7.03-7.16 (m, 5H), 7.26-7.27 (m, 1H). 7.40-7.44 (m, 1 H), 7.87 (m, 1 H), 8.20-8.32 (m, 2 H), 8.90 (br, 1 H);
[647] c) 2-oxo- (5-m-tolyloxy-1H-indol-3-yl) acetyl chloride; And
[648] d) 2-oxo-((4-fluorophenoxy) -1 H-indol-3-yl) acetyl chloride.
[649] Example 312
[650] 2-oxo-2- (5-phenoxy-1 H-indol-3-yl) acetamide
[651] 2-oxo- (5-phenoxy-1H-indol-3-yl) acetyl chloride (2.15 g, 7.18 mmol) and ammonium hydroxide (28-30%, 32 mL, 680 mmol) were combined and stirred for 2 hours. The reaction mixture is poured into 10% HCl (aq) and extracted with dichloromethane, the organic layers combined and Na₂SO₄Dry over and evaporate solvent in vacuo to give 1.94 g (96%) of the title compound:^OneH NMR (300 MHz, CDCl₃) 4.87 (s, 2H), 7.51-7.91 (m, 7H), 8.13-8.24 (m, 3H).
[652] According to the method of Example 312, the following compounds were prepared:
[653] a) 2-oxo-2- (5-p-tolyloxy-1H-indol-3-yl) acetamide;
[654] b) 2-oxo-2- (5-o-tolyloxy-1H-indol-3-yl) acetamide; And
[655] c) 2-oxo-2- (5-m-tolyloxy-1 H-indol-3-yl) acetamide.
[656] Example 314
[657] 5-phenoxycitamine oxalate
[658] 2-oxo-2- (5-phenoxy-1H-indol-3-yl) acetamide (1.9 g, 6.86 mmol) in THF (60 mL) was diluted with LiAlH ₄ -THF (1.0 M, 41 mL) in THF. , 41.0 mmol) dropwise to the solution. The reaction mixture was heated to reflux for 4 hours and cooled to room temperature. The reaction mixture was quenched with water (6 mL) followed by NaOH (2 N, 3 mL). The precipitate was collected by filtration and washed with ether (3 x 50 mL). The filtrate was dried over Na ₂ SO ₄ and concentrated in vacuo and the residue was purified by flash chromatography (dichloromethane / MeOH / NH ₄ OH) to give 1.0 g (59%) of the free amine of the title compound. Oxalate of the title compound was obtained: mp 156-157 ° C .; ¹ H NMR (300 MHz, DMSO-d6) 2.94 (t, 2H, J = 7.3 Hz), 3.00 (t, 2H, J = 7.3 Hz), 5.00 (br, 2H), 6.83-7.04 (m, 4H) , 7.26-7.41 (m, 5 H), 11.05 (br, 1 H); MS (electrospray), m / e: 341.1 (M-1); Analytical Calcd C ₁₈ H ₁₈ N ₂ O ₅ : C, 63.15; H, 5. 30; N, 8.18. Found: C, 62.97; H, 5. 25; N, 8.20.
[659] The following compounds were prepared according to the method of Example 314 and isolated as oxalate unless stated otherwise:
[660] a) 5-p-tolyloxytryptamine: ¹ H NMR (300 MHz, CDCl ₃ ) 2.31 (s, 3H), 2.83 (t, 2H, J = 6.4 Hz), 2.98 (t, 2H, J = 6.3 Hz), 6.86-6.96 (m, 3H), 7.07-7.10 (m, 3H), 7.24-7.33 (m, 2H), 8.02 (br, 1H) (isolated as base);
[661] b) 5-o-tolyloxytryptamine: m.p. 187-188 ° C.^OneH NMR (300 MHz, DMSO-d6) 2.27 (s, 3H), 2.90-3.05 (m, 4H), 6.66-6.68 (m, 1H), 6.76-6.79 (m, 1H), 6.93-6.98 (m, 1H) , 7.06-7.16 (m, 2H), 7.24-7.39 (m, 3H), 7.66 (br, 2H), 11.05 (br, 1H); MS (electrospray) m / e: 265.1 (M-1-C₂H₂O₄); C₁₉H₂₂N₂O₅Analytical calculation for: C, 64.04; H, 5. 66; N, 7.86. Found: C, 63.90; H, 5.72; N, 7.83; And
[662] c) 5-m-tolyloxytryptamine: mp 164-165 ° C .; ¹ H NMR (250 MHz, DMSO-d6) 2.26 (s, 3H), 2.89-3.07 (m, 4H), 4.52 (br, 2H), 6.68-6.72 (m, 2H), 6.82-6.86 (m, 2H ), 7.17-7.42 (m, 4 H), 11.06 (br, 1 H); MS (electrospray) m / e: 265.1 (M-1-C ₂ H ₂ O ₄ ).
[663] Example 315
[664] 6-chloro-7-fluoro-1H-indole
[665] Boron trichloride (36.0 mL, 1.0 M solution in heptane, 36 mmol) and 1,2-dichloroethane (40 mL) were combined and cooled to 5 ° C. A solution of 2-fluoro-3-chloroaniline (4.36 g, 30.0 mmol) was added dropwise in 20 mL of 1.2-dichloroethane. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. To the reaction mixture was added chloroacetonitrile (2.71 g, 36.0 mmol), followed by TiCl ₄ (6.83 g, 3.84 mL, 36.0 mmol). The reaction mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature and 55.0 mL 2.5 N HCl was added and heated to 85 ° C. for 30 minutes. Cool to room temperature, extract with dichloromethane (3 x 25 mL), combine the organic layers, wash with brine, dry over Na ₂ S0 ₄ and concentrate in vacuo to give 1- (2-amino-2-fluoro-3-chlorophenyl 5.1 g))-2-chloroethanone was obtained: ¹ H NMR (300 MHz, CDCl ₃ ) 4.63 (s, 2H), 6.49 (br, 2H), 6,62-6.69 (m, 1H), 7.36- 7.39 (m, 1 H).
[666] 1- (2-amino-2-fluoro-3-chlorophenyl) -2-chloroethanone is dissolved in 50 ml of 10% water (v / v) in 1,4-dioxane and NaBH ₄ (0.86 g, 22.8 mmol) was added carefully at room temperature. The reaction mixture was refluxed for about 4 hours and cooled to room temperature. 35 mL of 1 N HCl was added and stirred at room temperature for 30 minutes, extracted with dichloromethane (20 mL × 3), the organic layers combined and H ₂ O and brine. Washed, dried over Na ₂ S0 ₄ and concentrated in vacuo. Chromatography on silica gel eluting with EtOAc / hexanes gave 0.94 g (24%) of the title compound: ¹ H NMR (300 MHz, CDCl ₃ ) 6.55-6.58 (m, 1H), 7.04-7.10 (m, 1H) , 7.22-7.33 (m, 2 H), 8.38 (br, 1 H).
[667] According to the method of Example 315, the following compounds were prepared:
[668] a) 5,7-difluoro-1H-indole: ¹ H NMR (300 MHz, CDCl ₃ ) 6.55-6.56 (m, 1H), 6.71-6.78 (m, 1H), 7.01-7.11 (m, 1H) , 7.26-7.28 (m, 1 H), 8.34 (br, 1 H);
[669] b) 6,7-difluoro-1H-indole: ¹ H NMR (300 MHz, CDCl ₃ ) 6.53-6.56 (m, 1H), 6.90-6.99 (m, 1H), 7.22-7.31 (m, 2H) , 8.39 (br, 1 H);
[670] c) 5,6,7-trifluoro-1H-indole: ¹ H NMR (300 MHz, CDCl ₃ ) 6.52-6.55 (m, 1H), 7.13-7.20 (m, 1H), 7.26-7.27 (m, 1H), 8.35 (br, 1H); And
[671] d) 4,5,7-trifluoro-1H-indole: ¹ H NMR (300 MHz, DMSO-d ₆ ) 6.68-6.71 (m, 1H), 7.20-7.29 (m, 1H), 7.57-7.59 ( m, 1 H), 12.07 (br, 1 H); MS (electrospray) m / e: 170.0 (M-1).
[672] e) 4,7-difluoro-1H-indole: ¹ H NMR (400 MHz, dmso-d ₆ ): 11.91 (br s, 1H), 7.44 (t, 1H, J = 2.8 Hz), 6.84-6.90 (m, 1 H), 6.69-6.74 (m, 1 H), 6.54-6.56 (m, 1 H); MS (ES-): m / e 152.0 (M-1).
[673] Example 316
[674] 3-formyl-6-chloro-7-fluoro-1H-indole
[675] Phosphorus oxychloride (0.94 g, 6.16 mmol) was stirred vigorously with addition to DMF (12 mL, cooled in ice bath). After about 10 minutes, 6-chloro-7-fluoro indole (0.93 g, 5.6 mmol) in anhydrous DMF (4 mL) was added and stirred at 0 ° C. for 1 hour, warmed to room temperature and overnight at room temperature (˜16 hours ) Was stirred. Stir vigorously while treating with 14.0 mL 2N NaOH (4 equiv). The reaction was heated to 80 ° C. for 30 minutes and then cooled. The reaction was poured into cooled water and stirred vigorously to yield a solid. The solid was collected via filtration and dried overnight in a vacuum oven at room temperature to give the title compound: ¹ H NMR (300 MHz, CD ₃ COD ₃ / CDCl ₃ ) 7.09 (t, 1H, J = 7.7 Hz), 7.83- 7.86 (m, 2 H), 9.89 (s, 1 H). According to the method of Example 316, the following compounds were prepared:
[676] a) 3-formyl-5,7-difluoro-1H-indole: ¹ H NMR (300 MHz, CD ₃ COCD ₃ ) 6.98-7.06 (m, 1H), 7.71-7.75 (m, 1H), 8.35 (s, 1 H), 10.04 (s, 1 H);
[677] b) 3-formyl-6,7-difluoro-1H-indole: ¹ H NMR (300 MHz, CDCl ₃ ) 7.10-7.19 (m, 1H), 7.86-7.88 (m, 1H), 7.98-8.03 (m, 1 H), 8.95 (br, 1 H), 10.06 (s, 1 H);
[678] c) 3-formyl-5,6,7-trifluoro-1H-indole: ¹ H NMR (300 MHz, CD ₃ COCD ₃ ) 7.87-7.93 (m, 1H), 8.42 (s, 1H), 10.07 (s, 1 H); And
[679] d) 3-formyl-4,5,7-trifluoro-1H-indole: ¹ H NMR (300 MHz, DMSO- d ₆ ) 7.46-7.55 (m, 1H), 8.49 (s, 1H), 10.02 (d, 1H, J = 3.7 Hz), 13.19 (br, 1H).
[680] e) 3-formyl-4,7-difluoro-1H-indole: ¹ H NMR (400 MHz, dmso-d ₆ ): d 13.03 (br s, 1H), 10.00 (d, 1H, J = 3.2 Hz), 8.36 (s, 1 H), 7.07-7.13 (m, 1 H), 6.94-7.00 (m, 1 H); MS (APCI): m / e 182.0 (M + 1).
[681] f) 3-formyl-4,5,6,7-tetrafluoro-1H-indole: ¹ H NMR (400 MHz, dmso-d ₆ ): d 13.33 (br s, 1H), 9.94 (d, 1H , J = 4.4 Hz), 8.49 (s, 1 H); MS (ES-): m / e 216.0 (M-1).
[682] Example 317
[683] 3- (2-nitrovinyl) -6-chloro-7-fluoro-1 H-indole
[684] 3-formyl-6-chloro-7-fluoro-1H-indole (1.00 g, 5.06 mmol), ammonium acetate (292 mg, 3.8 mmol, 0.75 equiv) (treated with toluene, dried to remove toluene under vacuum) And nitromethane (6.17 g, 101.2 mmol, 20 equiv) were combined. Warmed to 65 ° C. After completion of the reaction (check by TLC), silica gel was added and nitromethane was removed under vacuum. Silica gel was loaded on top of a short column of silica gel and eluted with 25% acetone in hexane to evaporate to afford the title compound.
[685] According to the method of Example 317, the following compounds were prepared:
[686] a) 3- (2-nitrovinyl) -5,7-difluoro-1H-indole: ¹ H NMR (300 MHz, CDCl ₃ ) 6.68-6.81 (m, 1H), 7.16-7.21 (m, 1H) , 7.60 (d, 1H, J = 13.5 Hz), 7.73 (d, 1H, J = 2.7 Hz), 8.18 (d, 1H, J = 13.5 Hz), 10.95 (br, 1H);
[687] b) 3- (2-nitrovinyl) -6,7-difluoro-1 H-indole:^OneH NMR (300 MHz, CDCl₃) 6.93-7.00 (m, 1H), 7.30-7.35 (m, 1H), 7.58 (d, 1H,J= 13.5 Hz), 7.69 (d, 1 H,J= 2.9 Hz), 8.10 (d, 1 H,J= 13.5 Hz), 11.18 (br, 1 H): MS (Electrospray) m / e: 225 (M + l), 223 (M-1);
[688] c) 3- (2-nitrovinyl) -5,6,7-trifluoro-1 H-indole.
[689] d) 3- (2-nitrovinyl) -4,5,7-trifluoro-1 H-indole.
[690] e) 3- (2-nitrovinyl) -4,7-difluoro-1 H-indole: MS (ES-): m / e 223.0 (M-1).
[691] f) 3- (2-nitrovinyl) -4,5,6,7-tetrafluoro-1H-indole: MS (ES-): m / e 259.0 (M-1).
[692] Example 318
[693] 6-chloro-7-fluorotrytamine
[694] A solution of 3- (2-nitrovinyl) -6-chloro-7-fluoro-1H-indole (1.20 g, 5.06 mmol) in anhydrous THF with lithium aluminum hydride (30.0 mL, 30.0 mmol, 1.0 M solution in THF) Dropped in It was heated to reflux for 2 hours and then cooled to room temperature. 1 N NaOH was added carefully and quenched to give a suspension. The suspension was filtered through celite and washed repeatedly with ether. The filtrate was evaporated in vacuo to give a residue. The residue was evaporated by chromatography on silica gel eluting with dichloromethane, methanol and ammonium hydroxide (10: 1: 01) to give the title compound: ¹ H NMR (300 MHz, CDCl ₃ ) 2.87 (t, 2H, J = 6.6 Hz), 3.02 (t, 2H, J = 6.7 Hz), 7.03-7.08 (m, 2H), 7.26-7.29 (m, 1H), 8.51 (br, 1H).
[695] According to the method of Example 318, the following compounds were prepared:
[696] a) 5,7-difluorotrytamine: ¹ H NMR (300 MHz, CDCl ₃ ) 2.46 (t, 2H, J = 6.5 Hz), 3.01 (t, 2H, J = 6.4 Hz), 6.69-6.77 (m, 1 H), 7.03-7.11 (m, 2 H), 8.29 (br, 1 H);
[697] b) 6,7-difluorotrytamine: ¹ H NMR (300 MHz, CDCl ₃ ) 2.87 (t, 2H, J = 6.6 Hz), 3.02 (t, 2H, J = 6.7 Hz), 6.88-6.97 (m, 1 H), 7.04 (m, 1 H), 7.20-7.25 (m, 1 H), 8.64 (br, 1 H);
[698] c) 5,6,7-trifluorotrytamine:^OneH NMR (300 MHz, CDCl₃) 2.83 (t, 2H,J= 6.6 Hz), 3.00 (t, 2H,J= 6.7 Hz), 7.08-7.14 (m, 2H), 8.71 (br, 1H); MS (Electrospray), m / e: 215.0 (M + l); And
[699] d) 4,5,7-trifluorotrytamine:^OneH NMR (300 MHz, CDCl₃) 2.93 (t, 2H,J= 6.6 Hz), 3.03 (t, 2H,J= 6.4 Hz), 6.73-6.82 (m, 1 H), 7.02 (s, 1 H), 8.58 (br, 1 H); MS (Electrospray), m / e: 215.0 (M + l), 213.0 (M-1).
[700] f) 4,7-difluorotrytamine: ^OneH NMR (400 MHz, dmso-d₆): 11.57 (br s, 1 H), 7.19 (s, 1 H), 6.80-6.85 (m, 1 H), 6.61-6.67 (m, 1 H), 2.79 (s, 4 H). MS (ES +): m / e 197.0 (M + l) 180.0 (M-NH₂).
[701] g) 4,5,6,7-tetrafluorotrytamine: ¹ H NMR (400 MHz, dmso-d ₆ ): d 7.31 (s, 1 H), 2.78 (s, 4H); MS (ES +): m / e 233.0 (M + l) 216.0 (M-16).
[702] Example 319
[703] N- (2- (5-phenoxy-1H-indol-3-yl) ethyl) -3-phenoxybenzylamine
[704]
[705] 5-phenoxycittriptamine (0.400 g, 1,59 mmol), 3-phenoxybenzaldehyde (0.377 g, 1.90 mmol) and molecular sieve 4x (0.40 g) in methanol (15 mL) were combined and stirred for 4 hours. . Filter and wash the molecular sieve several times with MeOH. NaBH ₄ (61.5 mg, 1.59 mmol) was added portionwise to the filtrate and stirred at room temperature for 1 hour. MeOH was removed in vacuo to give a residue, the residue diluted with dichloromethane / water and the layers separated and the aqueous layer extracted with dichloromethane, the organic layers combined and dried over Na ₂ SO ₄ . The title compound was concentrated in vacuo and chromatographed on silica gel eluting with dichloromethane / MeOH. An oxalate salt of the title compound was formed: mp 196-198 ° C .; ¹ H NMR (300 MHz, DMSO-d 6) 2.95-3.15 (m, 4H), 4.15 (s, 2H), 6.85-7.46 (m, 18H), 11.06 (br, 1H); MS (electrospray) m / e: 435.3 (M + l); _{HRMS (ES +) C 29 H} 27 N 2 O 2 Calcd for (M + H); 435.2084 measurement; 435.2073.
[706] The following compounds were prepared according to the method of Example 319 and isolated as oxalate except as noted:
[707]
[708]
[709]
[710]
[711] Example 335
[712] 2-fluoro-3-phenoxybenzaldehyde
[713] A solution of 2,2,6,6-tetramethylpiperidine (5.1 mL, 30.0 mmol) in THF (40 mL) was cooled to -78 ° C. n-butyllithium (18.7 mL, 30.0 mmol, 1.6 M in hexane) was added dropwise and stirred at −78 ° C. for 10 minutes. 2-fluorophenyl phenyl ether (4.7 g, 25.0 mmol) was added dropwise and stirred at -78 ° C for 2 hours. N, N-dimethylformamide (2.3 mL, 30.0 mmol) was added dropwise over 15 minutes. The resulting mixture was stirred at −78 ° C. for 3 hours and warmed to room temperature for 16 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give an oil. The oil was crystallized from hexane to give a solid, collected and recrystallized from hexane / ethyl acetate / methylene chloride to give the title compound: mp 75-77 ° C .; MS (m / e): 216 (M ⁺ ); Calculation for C ₁₃ H ₉ FO ₂ : Calcd: C, 72.22; H, 4.20. Found: C, 72.41; H, 4.23. The mother liquor was purified by silica gel chromatography (2-3% ethyl acetate / hexanes) to afford additional title compound: MS (m / e): 216 (M ⁺ ).
[714] According to the method of Example 335, the following compounds were prepared:
[715] a) 6-fluoro-3-phenoxybenzaldehyde: MS (m / e): 216 (M ⁺ ).
[716] Example 336
[717] 3-ethoxybenzaldehyde
[718] 3-hydroxybenzaldehyde (5.6 g, 46 mmol) and 1-iodoethane (10.7 g, 69 mmol) in DMSO (25 mL) were combined and warmed to 80 ° C. Treated with cesium carbonate (22.4 g, 69 mmol) in portions. The bath was removed by starting to increase the temperature during the addition. The reaction was stirred at 80 ° C. for 1 h, poured into 200 mL brine and extracted twice with 150 mL diethyl ether. The combined extracts were washed twice with 200 ml brine, dried over MgSO ₄ and concentrated in vacuo to afford an oil. Purification by chromatography (SiO ₂ ; 2.5% EtOAc in hexanes) gave 5.73 g (38 mmol; 83%) of the title compound as an oil: ^l H NMR (CDCl 3) 9.94 (s, 1H), 7.42-7.41 (m , 2H), 7.36-7.35 (m, 1 H), 7.16-7.13 (m, 1 H), 4.10-4.04 (q, 2H), 1.64-1.40 (t, 3H).
[719] According to the method of Example 336, the following compounds were prepared:
[720] a) 3-propoxybenzaldehyde: ^l H NMR (CDCl ₃ ) 9.95 (s, 1H), 7.43-7.41 (m, 2H), 7.37-7.36 (m, 1H), 7.17-7.14 (m, 1H), 9.98 -3.95 (t, 2H), 1.84-1.79 (m, 2H), 1.05-1.02 (t, 3H).
[721] Example 337
[722] p-toluene-3- (2,2,3,3-tetrafluoropropoxy) tosylate
[723] Pyridine (1.9 L) (dried over molecular sieve 4) in an inert atmosphere is added to a round bottom flask (5 L) equipped with a mechanical stirrer and 2,2,3,3-tetrafluoro-1-propanol (604.5 g, 4.58 mol) was added. The mixture was cooled to 0 ° C. with an ice bath. p - toluenesulfonyl chloride (960 g, 5.04 mol) was added to the reaction mixture four times for 20 minutes and stirred. A precipitate formed 20 minutes after cooling in the ice bath. The reaction mixture was stirred at 0 ° C. for 1 hour and at 20 ° C. for 2 hours. The reaction mixture was poured into an ice-water mixture (1.44 L) with stirring and left at 20 ° C. overnight (18 hours). The crude tosylate derivative was separated from the aqueous mixture as an oily substance (1.34 kg) containing 1.15 kg of tosylate (87.8%) and the corresponding 14% w / w pyridine. The crude material was transferred to the next reaction step without further purification: ¹ H-RMN coincided.
[724] Example 338
[725] 3- (2,2,3,3,3-pentafluoropropoxy) benzaldehyde
[726] 3-hydroxybenzaldehyde (137.6 g, 1.127 mol), p-toluene-3- (2,2,3,3,3-pentafluoropropoxy) in a double walled 4 μL reactor equipped with reflux condenser and mechanical stirrer Tosylate (243 g, 0.799 mol), potassium carbonate (220 1.5g, 1.597 mol) and dimethylformamide (2451 mL) were combined and heated at 110 ° C. under argon for 46.5 hours. The reaction mixture was cooled to room temperature and filtered through a bed of 400 g silica gel. The silica gel bed was eluted with 2.451 ml of ethyl acetate. The combined organic layers were poured into 7.3 L of ice water. 10 N sodium hydroxide (500 mL) was added to the mixture and stirred for 1 hour. The aqueous phase was separated and extracted with ethyl acetate (1000 mL). The organic phases were combined and washed with water (1000 mL) and brine (750 mL). Brown oily material containing the crude title compound by evaporation of the organic solvent under reduced pressure 159.79 g was obtained. Purification by fractional distillation (2 serial cycles) under reduced pressure (2 mm Hg) using a distillation apparatus equipped with a 30 cm length adiabatic column yielded a fraction of the expected product of 52.4 μg (96.2% area by HPLC). .
[727] Example 339
[728] 3- (3,3,3-trifluoropropoxy) benzaldehyde
[729] 3-hydroxybenzaldehyde (130.2 g, 1.066 mol), 3,3,3-trifluoropropoxy tosylate (143 g, 0.533 mol), potassium carbonate (147.35 g, 1,066 mol) and anhydrous ethanol (1430 mL) Were combined in a three-neck round bottom flask equipped with a reflux condenser and magnetic stir and refluxed under argon for 4 hours. The reaction mixture was concentrated under reduced pressure. The concentrated mixture was poured into 1N sodium hydroxide (2145 mL), stirred for 30 minutes and extracted with dichloromethane (2145 mL). The organic layers were decanted and washed with 1 N sodium hydroxide (2145 mL). After separation, the organic layers were washed twice in succession with 1 μL water (pH aqueous phase = 7), dried over 30 μg magnesium sulfate and the dichloromethane organic layers were evaporated under reduced pressure to dryness to give 55.4 μg (0.254 μmol, 47.6% yield) was obtained as a slightly yellow oily material.
[730] Example 340
[731] N- (2- (6-Fluoro-1H-indol-3-yl) ethyl) -2-fluoro-3-phenoxy-benzylamine
[732]
[733] 6-fluorotrytamine (419 mg, 2.35 mmol) and 2-fluoro-3-phenoxybenzaldehyde (610 mg, 2.82 mmol) in anhydrous ethanol (6 mL) were combined. The mixture was heated to 65 ° C. to obtain a homogeneous solution. 3mm molecular sieve (400 mg) was added to the mixture and heated to reflux for 5 hours. The reaction mixture was cooled to room temperature and sodium borohydride (267 mg, 7.1 mmol) was added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was cooled in a water bath, quenched with acetone, diluted with ethanol and acetone and the molecular sieve filtered. The filtrate was concentrated under reduced pressure, diluted with 1 N NaOH, extracted with ethyl acetate, washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give 1.0 g of oil. Chromatography on silica gel eluting with 1%, 4% 2 N ammonia / methylene chloride in methanol gave a clear colorless oil. Hydrochloride in ethyl acetate / methanol was formed to give the hydrochloride of the title compound: mp 173-174.5 ° C .; MS (m / e): 379 (M + 1), 377 (M-1); Calcd for C ₂₃ H ₂₀ F ₂ N ₂ O.HCl: Calcd: C, 66.59; H, 5. 10; N, 6.75. Found: C, 66.50; H, 5.09; N, 6.73.
[734] Example 341
[735] N- (2- (6-Fluoro-1H-indol-3-yl) ethyl) -6-fluoro-3-phenoxy-benzylamine
[736]
[737] The method of Example 340 gave the hydrochloride of the title compound: mp 183.5-185.5 ° C; MS (m / e): 379 (M + 1), 377 (M-1); Calcd for C ₂₃ H ₂₀ F ₂ N ₂ O.HCl: Calcd: C, 66.59; H, 5. 10; N, 6.75. Found: C, 66.54; H, 5.11; N, 6.68.
[738] The following compounds were prepared according to the method of Example 340 and isolated as hydrochloride except as noted:
[739]
[740]
[741] The following compounds were prepared according to the method of Example 340 and isolated as hydrochloride except as noted:
[742]
[743] Example 370
[744] N- (2- (6-fluoro-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine
[745]
[746] 6-fluorotrytamine oxalate (350 mg, 1.3 mmol), N, N-diisopropylethylamine (506 mg, 3.9 mmol), 3- (2,2,2-tri in EtOH (30 mL) Fluoroethoxy) benzaldehyde (266 mg, 1.3 mmol) and 4 ′ molecular sieve (4 g) were combined and refluxed for 7 hours. The liquid was decanted into a separate flask and treated with NaBH ₄ (148 mg, 3.9 mmol). Stirred for 1 hour and the mixture was concentrated in vacuo to give a residue. The residue was partitioned between 25 mL 5 N NaOH and 25 mL dichloromethane. The aqueous layer was extracted with 25 ml of dichloromethane, the organic layers combined, dried over MgSO ₄ and concentrated to approximately 20 ml volume. Chromatography on silica gel eluting with 1% MeOH in CHCl ₃ mixed with concentrated NH ₄ OH gave the title compound. EtOAc solution of the title compound was combined with EtOAc solution of 1 equivalent of oxalic acid to give a solid, filtered and dried in vacuo to give the oxalate salt of the title compound: ISMS 367 (M + 1); Anal for C ₁₉ H ₁₉ ClF ₄ N ₂ O: Calcd: C, 55.27; H, 4. 42; N, 6.14; Found: C, 55.17; H, 4.38; N, 6.09.
[747] The following compounds were prepared according to the method of Example 370 and isolated as hydrochloride except as noted:
[748]
[749] Example 381
[750] N-t-butoxycarbonyl-2- (5-m-tolyloxy-1H-indol-3-yl) ethylamine
[751] The title compound was obtained by the method of Example 20:^OneH NMR (300 MHz, CDCl₃) 1.41 (s, 9H), 2.30 (s, 3H), 2.89 (t, 2H,J= 6.7 Hz), 3.41 (m, 2H), 6.74-6.85 (m, 3H), 6.93-6.99 (m, 1H), 7.07-7.35 (m, 4H), 8.05 (br, 1H).
[752] Example 382
[753] N-methyl-2- (5-m-tolyl) tryptamine
[754] The method of Example 21 gave the title compound and produced an oxalate salt: mp 182-183 ° C; ¹ H NMR (250 MHz, DMSO-d6) 2.26 (s, 3H), 2.59 (s, 3H), 2.98-3.18 (m, 4H), 6.68-6.72 (m, 2H), 6.82-6.86 (m, 2H ), 7.17-7.22 (m, 1 H), 7.29-7.42 (m, 3 H), 11.06 (br, 1 H); MS (electrospray) m / e: 281.2 (M + 1-C ₂ H ₂ O ₄ ); C ₂₀ H ₂₂ N ₂ O ₅ Analytical Calcd: C, 64.85; H, 5.99; N, 7.56. Found: C, 65.01; H, 5. 74; N, 7.71.
[755] Example 383
[756] N-methyl-N- (2- (5-m-tolyloxy-1H-indol-3-yl) ethyl) -3-phenoxybenzylamine
[757]
[758] The method of Example 301 gave the title compound and produced the oxalate salt: mp 142-144 ° C .; ¹ H NMR (250 MHz, DMSO-d6) 2.24 (s, 3H), 2.634 (s, 3H), 3.01-3.12 (m, 4H), 3.92 (br, 2H)), 4.16 (s, 2H), 6.65 -6.70 (m, 2H), 6.81-6.84 (m, 2H), 6.99-7.03 (m, 3H), 7.12-7.26 (m, 6H), 7.34-7.43 (m, 4H), 11.00 (br, 1H) ; MS (electrospray) m / e: 463.4 (M + 1-C ₂ H ₂ O ₄ ); C ₃₃ H ₃₂ N ₂ O ₆ anal. Calcd .: C, 71.72; H, 5. 84; N, 5.07. Found: C, 71.44; H, 5.89; N, 4.99.
[759] Example 384
[760] 5-nitrotryptamine
[761] A mixture of 5-nitroindole (10 g, 62 mmol) and 200 ml of glacial acetic acid was warmed to 70 ° C. and treated with Eschenmoser salt (12 g, 65 mmol). After 1 hour, the reaction was concentrated to dryness in vacuo. The residue was mixed with 200 mL of toluene, concentrated again to dryness, and partitioned between 200 mL of concentrated ammonium hydroxide and 200 mL of EtOAc. When all solids were dissolved, the layers were separated and the aqueous layer was extracted with 200 mL of EtOAc. The combined organic layers were dried over MgSO ₄ and concentrated to give N, N-dimethyl-5-nitrotryptamine as a solid.
[762] The obtained N, N-dimethyl-5-nitrotryptamine was dissolved in 200 mL of dry DMSO, treated with iodomethane (7.7 mL, 17.5 g, 124 mmol) and stirred at room temperature for 1 hour. KCN (40 g, 621 mmol) and 18-crown-6 (0.5 g) were added. The reaction was warmed to 110 ° C. for 45 minutes, cooled, poured onto ice and saturated with NaCl. The quenched reaction mixture was extracted with EtOAc and the extracts were combined and washed three times with brine. Dry over MgSO ₄ and concentrate in vacuo. Chromatography on silica gel eluting with 1% MeOH in CHCl ₃ gave (5-nitro-1H-indol-3-yl) acetonitrile as a solid: FDMS 201 (M +); Anal for C ₁₀ H ₇ N ₃ O ₂ : Calcd: C, 59.70; H, 3.51; N, 20.89; Found: C, 59.32; H, 3.52; N, 20.56.
[763] (5-nitro-1H-indol-3-yl) -acetonitrile (9 g, 44.7 mmol) was dissolved in 250 mL of dry THF and treated with 90 mL of 1 M BH ₃ in THF at room temperature. The reaction was carefully quenched by stirring overnight and dropwise adding 10 ml of water. Concentrated to dryness in vacuo and the residue was partitioned between 5N HCl and EtOAc. The aqueous layer was extracted with EtOAc and combined with the original EtOAc layer. The aqueous layer was treated with 5 N NaOH and extracted three times with 10% MeOH in EtOAc. The extract was purified by flushing the extract through a pad of 100 g SCX ion exchange resin, washed with 2 L of discarded MeOH, eluted with 2 M NH ₃ in MeOH and concentrated to afford the title compound as a dark solid: ISMS 206 (M + 1); C ₂₀ H ₁₈ F ₆ N ₂ 0 ₂ 0.3H ₂ 0 0.1 C ₇ H ₈ Analytical analysis: Calcd: C, 57.34; H, 5. 74; N, 19.29; Found: C, 57.30; H, 5. 38; N, 19.08; ^{l H NMR (DMSO-d6)} 11.9-11.2 (bs, 1H), 8.50-8.49 (d, 1H), 7.95-7.92 (m, 1H), 7.47-7.45 (m, 1H), 7.38 (s, 1H) , 2.79 (s, 4H), 2.2-1.3 (bs, 2H).
[764] Example 385
[765] 6-nitrotryptamine
[766] The method of Example 384 gave (6-nitro-1H-indol-3-yl) -acetonitrile: ISMS 200 (M-1); Analysis for C ₁₀ H ₇ N ₃ O ₂ 0.1H ₂ O: calc .: C, 59.17; H, 3.58; N, 20.70; Found: C, 59.04; H, 3. 28; N, 20.39. This gave the title compound: ISMS 206 (M + 1); ^{l H NMR (DMSO-d6)} 11.5 (bs, 2H), 8.26 (s, 1H), 7.84-7.81 (m, 1H), 7.68-7.66 (m, 1H), 7.57 (s, 1H), 2.80-74 (m, 4H) (indole NH not observed).
[767] Example 390
[768] N- (2- (5-nitro-1H-indol-3-yl) ethyl) -3-phenoxybenzylamine
[769]
[770] The method of Example 340 gave the title compound, produced a salt in 10 mL of EtOH and 40 mL of toluene containing 0.25 mL of 5 N HCl, and then concentrated to a solid to give the hydrochloride of the title compound: C ₂₃ H ₂₁ Anal for N ₃ O ₃ HCl 0.2EtOH: Calcd: C, 64.62; H, 5. 17; N, 9.75; Found: C, 64.89; H, 5.40; N, 9.75; ISMS 388 (M + 1).
[771] The following compounds were prepared according to the method of Example 390 and isolated as hydrochloride except as noted:
[772]
[773] Example 396
[774] N- (2- (5-amino-1 H-indol-3-yl) ethyl) -3-phenoxybenzylamine
[775]
[776] MeOH 30 ㎖ from N- (2- (5- nitro -1H- indol-3-yl) ethyl) -3-phenoxy benzylamine hydrochloride (250 mg, 0.64 mmol) and _{NiCl 2 -6H 2 O (460 mg} , 1.9 mmol) were combined and treated with NaBH ₄ (73 mg, 1.9 mmol). After 1 h concentrated to dryness and partitioned between EtOAc and concentrated NH ₄ OH. The aqueous layer was extracted with EtOAc and the organic layers combined, dried over MgSO ₄ and concentrated to dryness. Chromatography on silica gel eluting with a gradient of THF / hexanes / Et ₃ N (20/75/5) followed by THF / hexanes / Et ₃ N (40/55/5) gave the title compound as an oil. In addition, chromatography on silica gel eluting with 1% MeOH in CHCl ₃ mixed with concentrated NH ₄ OH gave the title compound as an oil. Treatment with 10 mL of EtOH containing 0.25 mL of 5 N HCl and 40 mL of toluene, followed by concentration afforded the title compound as the hydrochloride: C ₂₃ H ₂₃ N ₃ O 2.6 HCl 0.6 EtOH: calcd: C, 59.66 ; H, 5.83; N, 9.07; Found: C, 59.30; H, 5. 48; N, 8.82; ISMS 358 (M + 1).
[777] The following compounds were prepared according to the method of Example 396 and isolated as hydrochloride except as noted:
[778]
[779] Example 401
[780] 6-fluorotrytamine
[781] 6-fluoroindole (108 g, 0.8 mol) and dichloromethane (324 mL) were combined. Cool in an ice bath. Trifluoroacetic acid (308 mL) was added for several minutes (exothermic). While maintaining at a temperature of about 0 ° C. to 5 ° C., a solution of Z-1-dimethylamino-2-nitroethylene (94.7 μg, 0.816 mol) in dichloromethane (600 mL) was added for 40 minutes. After 45 minutes, warmed to about 20 ° C. After 2 hours, it was poured into 1.2 ml of ice water and stirred with seeding overnight to obtain a solid. The solid was collected by filtration and washed first with 100 mL of dichloromethane-cyclohexane (1/1) mixture, then with 750 mL of water and dried at 40 ° C. to give 3- (2-nitrovinyl) -6-fluoroindole. Obtained.
[782] LiAlH ₄ (48.8 g, 1.286 mole, 5 equiv) and THF (848 mL) were combined and cooled to about 6 ° C. in an ice water bath while maintaining at a temperature below 32 ° C. A solution of 3- (2-nitrovinyl) -6-fluoroindole (53 g, 0.257 mol, 1 equiv) in THF (694 mL) was added while maintaining at a temperature below about 31 ° C. Stir at room temperature. After 2.5 hours, it was quenched with a mixture of 49 mL of water and 49 mL of THF, followed by 49 mL of 15% NaOH and finally quenched with 49 mL of water. The temperature was kept below ˜32 ° C. during quenching. Stir for 1.5 h, filter through celite bed and wash with THF. Evaporate the residue, dissolve in 750 ml of diethyl ether and cool in an ice water bath. HCl / diethyl ether solution was added to give a solid. Stir for 1 hour, collect the solid through filtration, wash with diethyl ether and dry under reduced pressure at 45 ° C. to give the hydrochloride of the title compound.
[783] Example 402
[784] N- (2- (6-fluoro-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine
[785]
[786] 6-fluorotrytamine hydrochloride (90 g, 0.419 mol) and water (900 mL) were combined. NaOH (2 N, 230 mL) aqueous solution and dichloromethane (900 mL) were added. After 1 h, the organic layers were separated and the aqueous layer was extracted with dichloromethane, the organic layers combined, washed with water, dried over MgSO ₄ and evaporated to the residue. The residue and toluene (200 mL) were combined and evaporated to give 78.45 g of brown oil. 78.45 g of the material was combined with 41.4 g of another batch to give 6-fluorotrytamine. 6-fluorotrytamine (119.85) and ethanol (3.325 L) were combined and 2,2,3,3-tetrafluoropropylbenzaldehyde (176 g, 0.745 mole, 1.2 equiv) and 3 μg of molecular sieve were added. Heated to reflux. After 2 hours, cooled to room temperature and NaBH ₄ (35.2 g, 0.93 mol, 1.5 equiv) was added. After 1 h, filtered through celite and washed with 500 mL of ethanol. The filtrate was evaporated under reduced pressure to give an oily residue. The residue was partitioned between water and dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane and the organic layers combined, washed with brine and dried over MgSO ₄ . Filtration and evaporation under reduced pressure gave the title compound.
[787] HCl salts were formed as follows: N- (2- (6-fluoro-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropyl) benzyl at room temperature Amine (387 g, 0.97 mole) and diethyl ether (3.95 L) were combined. Solid was obtained by dropwise addition of HCl / Et ₂ O (298 mL) solution for 15 minutes until the pH was about 3. Stir for 1 hour, collect the solid, wash with ether and dry under reduced pressure at 40 ° C. to afford the title compound as hydrochloride.
[788] Example 410
[789] (5-Bromo-1H-indol-3-yl) acetonitrile
[790] The title compound was obtained by the method of Example 384 using 5-bromoindole: ISMS 234 (M-1); Analysis for _{C 10 H 7 BrN 2 0.1H 2} O: calcd: C, 50.70; H, 3.06; N, 11.83; Found: C, 50.69; H, 2. 90; N, 11.64; _{^{l H NMR (CDCl 3) 8.22}} (s, 1H), 7.70-7.69 (m, 1H), 7.33-7.31 (m, 1H), 7.24 (s, 1H), 7.23-7.22 (m, 1H), 3.78- 3.77 (m, 4 H).
[791] Example 411
[792] 5-bromotryptamine
[793] 5-Bromo-1H-indole-3-carbonitrile (9.5 g, 40.4 mmol) was dissolved in 200 mL of dry THF and treated with 80 mL of 1 M BH ₃ in THF at room temperature. The reaction was stirred overnight and carefully quenched by dropwise addition of 5 ml of water. Concentrate to dry residue under vacuum. Partitioned between 1 N HCl and EtOAc. The organic layers were extracted with 1 N HCl combined with the original aqueous layer. The aqueous layer was treated with 5 N NaOH and extracted with EtOAc. Saturated with NaCl and extracted again with EtOAc. The extracts were combined, dried over MgSO ₄ and concentrated to dryness to give 4.72 g (19.7 mmol, 49%) of crystallized oil.
[794] The EtOAc solution of the compound was treated with a solution of 1 equivalent of oxalic acid to convert the oxalate salt. The resulting solid was filtered and dried under vacuum: analysis for C ₁₀ H ₁₁ BrN ₂ C ₂ H ₂ O ₂ H ₂ O: calculated: C, 43.08; H, 4.10; N, 8.37; Found: C, 43.26; H, 3.91; N, 8.20; ISMS 240 (M + 1).
[795] Example 413
[796] 5-methoxycarbonyl-1H-indole
[797] 5-carboxyindole (7.2 g, 44.7 mmol) and 100 ml of MeOH were combined in 400 ml of dichloromethane and 35 ml of 2 M TMS diazomethane in hexane was added dropwise. Stir overnight at room temperature. Concentration in vacuo gave the title compound as a solid: analysis for C ₁₀ H ₉ NO ₂ 0.1H ₂ O: calcd: C, 67.86; H, 5. 24; N, 7.91; Found: C, 68.03; H, 5. 15; N, 7.98; _{^{l H NMR (CDCl 3) 8.44}} (bs, 1H), 8.412-8.409 (m, 1H), 7.91-7.88 (m, 1H), 7.46-7.38 (m, 1H), 7.26-7.24 (m, 1H), 6.64-6.63 (m, 1 H), 3.92 (s, 3 H); ISMS 176 (M + 1).
[798] Example 414
[799] 3-formyl-5-methoxycarbonyl-1H-indole
[800] Anhydrous DMF (25 mL) was added to the flask under nitrogen atmosphere, cooled to 10 ° C, and treated dropwise with POCl ₃ (8.22 g, 54 mmol) while maintaining the temperature below 15 ° C. While maintaining at a temperature below 20 ° C., a 5-methoxycarbonyl-1H-indole solution in 30 ml of DMF was added in portions. The cooling bath was removed and the mixture was stirred at room temperature for 1 hour and then poured into ice. 50 mL of 5 N NaOH was added to precipitate the solid, filtered and washed with water and EtOAc to afford the title compound: ^l H NMR (DMSO-d 6) 9.95 (s, 1H), 8.76 (s, 1H), 8.4 (s, 1H), 7.9-7.8 (m, 1H), 7.5-7.7 (d, 1H), 3.85 (s, 3H), 1.7 (s, 1H); ISMS 204 (M + 1).
[801] Example 415
[802] 3- (2-nitroethyl) -5-methoxycarbonyl-1H-indole
[803] The method of example 317 gave the title compound: ^l H NMR (DMSO-d 6) 12.5 (bs, 1H), 8.38-8.37 (m, 1H), 8.37-8.34 (m, 1H), 8.23 (s, 1H ), 7.87-7.84 (m, 1 H), 7.80-7.77 (m, 1 H), 7.57-7.55 (d, 1 H), 3.85 (s, 3H); ISMS 246 (M + 1).
[804] Example 416
[805] 3- (2-nitroethyl) -5-methoxycarbonyl-1H-indole
[806] A solution of 3- (2-nitrovinyl) -5-methoxycarbonyl-1H-indole (57 mg, 0.23 mmol) in 9 mL THF and 2 mL MeOH was treated with NaBH ₄ (26 mg, 0.69 mmol). Stirred overnight at room temperature, concentrated to dryness and partitioned between concentrated NH ₄ OH (10 mL) and dichloromethane. The aqueous layer was extracted with dichloromethane, acidified with concentrated HCl and extracted twice with dichloromethane. The organic layers were combined, concentrated and chromatographed on silica gel eluting with 1% MeOH in CHCl ₃ to afford the title compound as a solid: ^l H NMR (CDCl ₃ ) 8.35 (bs, 1H), 8.32 (s, 1H), 7.92- 7.90 (m, 1 H), 7.38-7.36 (d, 1 H), 7.12-7.11 (m, 1 H), 4.69-4.65 (t, 2H), 3.93 (s, 3H), 3.51-3.48 (t, 2H); ISMS 248 (M +).
[807] Example 417
[808] 5-methoxycarbonyltrytamine
[809] 3- (2-nitroethyl) -5-methoxycarbonyl-1H-indole (280 mg, 1.1 mmol), PtO ₂ (200 mg) and 15 mL of MeOH were combined and hydrogenated overnight at ambient pressure. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated and chromatographed on silica gel eluting with 5% MeOH in CHCl ₃ mixed with concentrated NH ₄ OH to give the title compound as an oil: ISMS 219 (M + 1 ); ^l N NMR (CDCl ₃ ) 9.01 (s, 1H), 8.36 (s, 1H), 7.88-7.85 (m, 1H), 7.32-7.24 (m, 1H), 7.05 (s, 1H), 3.91 (s, 3H), 3.05-3.01 (m, 2H), 2.93-2.89 (m, 2H), 1.22 (bs, 2H).
[810] Example 418
[811] 2- (2- (5-benzyloxy-1H-indol-3-yl) ethyl) isoindole-1,3-dione
[812] 5-benzyloxytrytamine hydrochloride (1 g, 3.3 mmol), phthalic anhydride (.56 g, 4.0 mmol) and N, N-diisopropylethylamine (0.86 g, 6.6 mmol) were combined in 25 mL of anhydrous pyridine. , Refluxed for 1 hour, cooled to room temperature and treated with 4 g of a 3mm molecular sieve. After reflux continued for 60 hours, the mixture was filtered. Concentration in vacuo gave a residue mixed with 25 mL CHCl ₃ , which was filtered to give a solid. The filtrate was purified by chromatography on silica gel eluting with 1% MeOH in CHCl ₃ to afford additional title compound: ISMS 397 (M + 1); Anal for C ₂₅ H ₂₀ N ₂ O ₃ 0.3H ₂ OC ₇ H ₈ : Calcd: C, 75.09; H, 5. 25; N, 6.82; Found: C, 75.00; H, 5. 22; N, 6.96.
[813] According to the method of Example 418, the following compounds were prepared:
[814] a) 2- (2- (5-hydroxy-1H-indol-3-yl) ethyl) isoindole-1,3-dione: (4.5 mmol, 95%); ^{l H NMR (DMSO-d6)} 10.47 (s, 1H), 8.59 (bs, 1 H), 7.84-7.78 (m, 4H), 7.09-7.06 (d, 1H), 7.03-7.02 (d, 1H), 6.85-6.84 (d, 1 H), 6.56-6.54 (m, 1 H), 3.79-3.75 (t, 2 H), 2.91-2.87 (m, 2H).
[815] Example 419
[816] 2- (2- (5-hydroxy-1-triisopropylsilanyl-1H-indol-3-yl) ethyl) isoindole-1,3-dione
[817] Oil dispersion of KH (40%, 1 g) in 30 mL of dry THF and 2- (2- (5-benzyloxy-1H-indol-3-yl) ethyl) isoindole-1,3-dione in 30 mL of THF A mixture of (1.2 g, 3 mmol) of suspension was combined little by little. Stirred at room temperature for 1 hour and cooled to 0 ° C., triisopropylsilyltrifluoromethanesulfonate (1.85 g, 6 mmol) was added and the additive was stirred at room temperature for 1 hour. The reaction was poured into a rapidly stirred solution of saturated NaHCO ₃ and extracted with 2 × 50 mL of EtOAc. The organic layers were combined, dried over MgSO ₄ , concentrated to dryness and chromatographed on silica gel eluting with 1% MeOH in CHCl ₃ to give 2- (2- (5-benzyloxy-1-triisopropylsilanyl-1H-indole). -3-yl) ethyl) isoindole-1,3-dione was obtained as an oil.
[818] 2- (2- (5-benzyloxy-1-triisopropylsilanyl-1H-indol-3-yl) ethyl) isoindole-1,3-dione and EtOAc (40 mL) were combined and 5 at ambient pressure Hydrogenated overnight at 1 g of% Pd / C. Filtration through celite, concentrated to dryness and chromatography on silica gel eluting stepwise with a gradient from 10% EtOAc in hexanes to 30% EtOAc in hexanes gave the title compound as a solid: FDMS 462 (M + 1 ) For C ₂₇ H ₂₄ N ₂ O ₃ Si H ₂ O: calcd: C, 69.55; H, 7. 44; N, 6.01; Found: C, 69.44; H, 7. 17; N, 6.00.
[819] Example 420
[820] 2- (2- (5-propoxy-1-triisopropylsilanyl-1H-indol-3-yl) ethyl) isoindole-1,3-dione
[821] 2- (2- (5-hydroxy-1-triisopropylsilanyl-1H-indol-3-yl) ethyl) isoindole-1,3-dione (0.7 g, 1.5 mmol) in DMF (25 mL) Cesium carbonate (1 g, 3 mmol) and 1-iodopropane (0.4 g, 2.3 mmol) were combined and stirred at room temperature overnight. The reaction mixture was poured into 50% EtOAc in hexanes and washed three times with brine. The organic layers were dried over MgSO ₄ and concentrated in vacuo to afford an oil. Chromatography on silica gel eluting with 5% EtOAc in hexanes afforded the title compound: ISMS 505 (M + 1); _{^{l H NMR (CDCl 3) 7.80-7.78}} (m, 2H), 7.67-7.65 (m, 2H), 7.30-7.27 (d, 1H), 7.12-7.11 (d, 1H), 7.02 (s, 1H), 6.77-6.74 (m, 1H), 4.01-3.96 (m, 4H), 3.12-3.08 (m, 2H), 1.86-1.81 (m 2H), 1.64-1.57 (m, 3H), 1.08-1.04 (m, 21H).
[822] Example 421
[823] 5-propoxy-1-triisopropylsilanyltrytamine
[824] 2- (2- (5-propoxy-1-triisopropylsilanyl-1H-indol-3-yl) ethyl) isoindole-1,3-dione (416 mg, 0.8 mmol) and hydrazine in 20 ml of EtOH 1 ml of hydrate was combined. It was refluxed for 3 hours, filtered through celite and concentrated to the residue. The residue was dissolved in 10 mL MeOH, loaded into a 12 g SCX ion exchange cartridge and washed sequentially with MeOH, DMF, MeOH. The product was eluted with 2 M NH ₃ in MeOH to afford the title compound as an oil: ISMS 375 (M + 1); _{^{l H NMR (CDCl 3) 7.34-7.32}} (d, 1H), 7.02 (s, 1H), 7.00-6.99 (d, 1H), 6.80-6.77 (m, 1H), 3.97-3.94 (m, 2H), 3.01-2.98 (m, 2H), 2.86-2.83 (m, 2H), 1.88-1.76 (m 2H), 1.70-1.58 (m, 3H), 1.3 (bs, 2H), 1.14-1.08 (m, 18H) , 1.06-1.02 (t, 3 H).
[825] Example 422
[826] 6-benzyloxytryptamine
[827] A mixture of LAH (6.2 g, 163.1 mmol) in 300 mL of dry THF solution and 3- (2-nitrovinyl) -6-benzyloxy-1H-indole (9 g, 30.6 mmol) in 200 mL of THF were added. The mixture was refluxed overnight and then cooled to 0 ° C. and quenched sequentially with 6.2 ml water, 6.2 ml 15% NaOH aqueous solution and 18.6 ml water. After stirring for 2 hours, filtration through celite and concentration gave 7.9 g (96%) of the title compound as an oil: ^l H NMR (CDCl ₃ ) 8.06 (bs, 1H), 7.47-7.43 (m, 3H ), 7.38-7.35 (m, 2H), 7.32-7.28 (m, 1H), 6.88-6.84 (m, 3H), 5.08 (s, 2H), 3.01-2.97 (m, 2H), 2.87-2.83 (m , 2H), 1.6 (bs, 2H).
[828] Example 423
[829] N-t-butoxycarbonyl-2- (6-benzyloxy-1H-indol-3-yl) ethylamine
[830] The method of example 20 gave the title compound: ^l H NMR (CDCl ₃ ) 7.84 (bs, 1H), 9.36 (s, 2H), 8.91 (s, 1H), 7.38-7.33 (m, 2H), 7.28 -7.26 (m, 1H), 7.20-7.18 (m, 1H), 7.09-7.07 (m, 1H), 6.94-6.93 (m, 1H), 6.68-6.67 (m, 1H), 6.50-6.47 (m, 1H), 4.79-4.72 (m, 2H), 4.13 (s, 2H), 3.05-3.02 (m, 4H).
[831] Example 425
[832] N-t-butoxycarbonyl-2- (6-hydroxy-1H-indol-3-yl) ethylamine
[833] The title compound was obtained by the method of Example 471.
[834] Example 428
[835] 2- (2- (5-ethoxy-1H-indol-3-yl) ethyl) isoindole-1,3-dione
[836] 2- (2- (5-hydroxy-1H-indol-3-yl) ethyl) isoindole-1,3-dione (900 mg, 2.9 mmol) in cesium carbonate in N-methylpyrrolidinone (5 mL) (960 mg, 2.9 mmol) and 1-iodoethane (920 mg, 5.9 mmol) were combined and stirred at room temperature for 4 hours, poured into brine and extracted twice with EtOAc. The combined extracts were washed three times with brine, dried over MgSO ₄ and concentrated in vacuo to afford an oil. Chromatography on silica gel eluting with 20% EtOAc in hexanes gave the title compound as a white solid: ISMS 335 (M + 1); Anal for C ₂₀ H ₁₈ N ₂ O ₃ : Calcd: C, 71.84; H, 5. 43; N, 8.38; Found: C, 71.97; H, 5.47; N, 8.36.
[837] According to the method of Example 428, the following compounds were prepared:
[838] a) 2- (2- (5-isopropoxy-1H-indol-3-yl) ethyl) isoindole-1,3-dione: ISMS 348 (M +) ^l H NMR (CDCl ₃ ) 7.94 (bs, 1H ), 7.82-7.80 (m, 2H), 7.70-7.67 (m, 2H), 7.21-7.19 (d, 1H), 7.18 (s, 1H), 7.05-7.04 (d, 1H), 6.82-6.79 ( m, 1H), 4.55-4.49 (m, 1H), 3.99-3.95 (m, 2H), 3.11-3.07 (m, 2H), 1.64-1.33 (d, 6H);
[839] b) 2- (2- (5- (2,2,2-trifluoroethoxy) -1H-indol-3-yl) ethyl) isoindole-1,3-dione: ISMS 389 (M + 1) ; Anal for C ₂₀ H ₁₅ F ₃ N ₂ O ₃ : Calcd: C, 61.86; H, 3.89; N, 7.21; Found: C, 61.77; H, 3.83; N, 7.20;
[840] c) 2- (2- (5-butoxy-1H-indol-3-yl) ethyl) isoindole-1,3-dione: ISMS 363 (M + 1); Anal for C ₂₂ H ₂₂ N ₂ O ₃ : Calcd: C, 72.91; H, 6. 11; N, 7.73; Found: C, 72.76; H, 6.09; N, 7. 42; _{^{l H NMR (CDCl 3) 7.86-7.81}} (m, 3H), 7.72-7.68 (m, 2 H), 7.23-7.20 (m, 1H), 7.16-7.15 (m, 1H), 7.08-7.07 (m, 1H), 6.85-6.84 (m, 1H), 6.4.02-3.98 (m, 4H), 3.13-3.09 (m, 2H), 1.83-1.76 (m, 2H), 1.56-148 (m, 2H), 1.01-0.98 (t, 3 H);
[841] d) 2- (2- (5-nitro-1H-indol-3-yl) ethyl) isoindole-1,3-dione: ISMS 334 (M-1); Anal for C ₁₈ H ₁₃ N ₃ O ₄ 0.1H ₂ O: Calcd: C, 64.13; H, 3.95; N, 12.47; Found: C, 64.05; H, 3. 82; N, 12.27.
[842] According to the method of Example 421, the following compounds were prepared:
[843] a) 5-ethoxytryptamine: ISMS 205 (M + 1); Anal for C ₁₂ H ₁₆ N ₂ OH ₂ O: Calcd: C, 69.33; H, 7.95; N, 13.48; Found: C, 69.62; H, 7.75; N, 13.30;
[844] b) 5-isopropoxycitfatamine: ISMS 219 (M + 1); _{^{l H NMR (CDCl 3) 8.57}} (bs, 1H), 7.20-7.18 (d, 1 H), 7.08-7.07 (d, 1H), 6.95 (s, 1H), 6.84-6.82 (m, 1H), 4.54 -4.48 (m, 1H), 3.01-2.98 (m, 2H), 2.86-2.83 (m, 2H), 1.38 (bs, 2H), 1.35-1.33 (d, 6H);
[845] c) 5- (2,2,2-trifluoroethoxy) trytamine: ISMS 258 (M +); _{^{l H NMR (CDCl 3) 8.33}} (bs, 1H), 7.26-7.24 (d, 1 H), 7.09-7.08 (d, 1H), 7.03-7.02 (m, 1H), 6.90-6.87 (m, 1H) , 4.40-4.34 (m, 2H), 3.03-3.00 (m, 2H), 2.87-2.84 (m, 2H), 1.44 (bs, 2H);
[846] d) 5-butyloxytryptamine: ^l H NMR (CDCl ₃ ) 8.08 (bs, 1H), 7.23-7.21 (d, 1H), 7.03-7.02 (d, 1H), 7.03-7.02 (m, 1H ), 6.98-6.83 (m, 1H), 4.01-3.98 (m, 2H), 3.02-2.99 (m, 2H), 2.87-2.84 (m, 2H), 1.82-1.74 (m, 2H), 1.56-1.50 (m, 2H), 1.32 (bs, 2H), 1.00-0.96 (t, 3H);
[847] Example 429
[848] 5-benzenesulfonyl-1H-indole
[849] A 35% oil dispersion of KH (6 g) was added to a flask under nitrogen, washed with 50 ml of hexane and dried under vacuum. The solid suspension in 100 mL of anhydrous DMF was cooled to 0 ° C. A solution of 5-bromoindole (10.3 g, 52.5 mmol) in 25 mL DMF was added dropwise for 10 minutes. The mixture was stirred at 0 ° C. for 1 h and then treated with triisopropylsilyltrifluoromethane sulfonate (32.2 g, 105.1 mmol). The cold bath was removed and the reaction stirred for 72 h, then poured into 500 mL of water and extracted with EtOAc. The combined extracts were diluted with hexanes, washed with brine and dried over MgSO ₄ . Concentration in vacuo and chromatography on silica gel eluting with 1% EtOAc in hexanes gave 5-bromo-1-triisopropylsilanyl-1H-indole as colorless oil: ^l H NMR (CDCl ₃ ) 7.73- 7.72 (d, 1H), 7.36-7.34 (d, 1H), 7.24-7.23 (d, 1H), 7.21-7.19 (m, 1H), 6.55-6.54 (m, 1H), 1.72-1.61 (m, 3H), 1.13-1.10 (m, 18H).
[850] A solution of 5-bromo-1-triisopropylsilanyl-1H-indole (9 g, 25.5 mmol) in 550 mL of dry THF was cooled to -75 ° C under argon and maintained at a temperature below -60 ° C while maintaining 1.7 M Treated with t-butyl lithium (33 mL, 56.2 mmol). After addition, the reaction mixture was recooled to about −73 ° C. and then a solution of phenylsulfonyl fluoride (4.6 g, 28.7 mmol) in 30 mL of THF was added. The reaction was stirred at -78 ° C for 1 h and then quenched with saturated NaHCO ₃ followed by brine. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were treated with 1M tetrabutylammonium fluoride (35 mL) in THF at room temperature for 1 hour and then concentrated to dryness. The residue was combined with EtOAc and washed twice with 1 N HCl, dried over MgSO ₄ and concentrated to an oil. The oil was chromatographed on silica gel eluting stepwise with 50% CHCl ₃ in hexanes and then 50% CHCl ₃ in MeOH to give an oily solid. The oily solid was triturated with CHCl ₃ to afford the title compound as a solid: C ₁₄ H ₁₁ NO ₂ SH ₂ O. Assay: calcd: C, 64.89; H, 4. 36; N, 5.41; Found: C, 64.76; H, 4. 45; N, 5.33; ISMS 257 (M +).
[851] Example 430
[852] 2- (2- (5-amino-1 H-indol-3-yl) ethyl) isoindole-1,3-dione
[853] 2- (2- (5-nitro-1H-indol-3-yl) ethyl) isoindole-1,3-dione (1.8 g, 5.4 mmol), PtO ₂ (500 mg), 100 mL of MeOH and 100 mL of THF Mixtures were combined and hydrogenated overnight at ambient pressure. The reaction was filtered through a pad of celite and concentrated to dryness. The residue was redissolved in chloroform / dichloromethane (50/50) and refiltered through a pad of celite. Concentration in vacuo gave the title compound as a dark solid: ISMS 306 (M + 1); C ₁₈ H ₁₃ N ₃ O ₄ 0.1C ₇ H ₈ 0.2 Anal for dichloromethane: Calcd: C, 68.70; H, 4.89; N, 12.58; Found: C, 69.08; H, 4.75; N, 12.69; _{^{l H NMR (CDCl 3) 7.9-7.8}} (m, 3H), 7.75-7.65 (m, 2 H), 7.2-7.1 (m, 1H), 7.05-7.0 (m, 2H), 6.7-6.6 (m, 1H), 4.0-3.9 (m, 2H), 3.4 (bs, 2H), 3.1-3.0 (m, 2H).
[854] Example 431
[855] 2- (2- (5-benzoylamino-1H-indol-3-yl) ethyl) isoindole-1,3-dione
[856] 2- (2- (5-amino-1 H-indol-3-yl) ethyl) isoindole-1,3-dione (0.5 g, 1.64 mmol) and 4-dimethylaminopyridine (0.3 g, 2.5 mmol) were combined It was dissolved in 30 ml of dichloromethane and cooled to 0 ° C. The reaction mixture was treated with benzoyl chloride (276 mg, 1.96 mmol) and stirred overnight while warming to room temperature. Concentration to residue and chromatography on silica gel eluting with 0.5% MeOH in CHCl ₃ gave the title compound as a solid: ISMS 410 (M + 1); _{^{l H NMR (CDCl 3) 7.86-7.85}} (m, 2H), 7.79 (s, 1 H), 7.72-7.68 (m, 2H), 7.60-7.57 (m, 2H), 7.46-7.42 (m, 1H) , 7.4-7.36 (m, 3H), 7.1 3-7.11 (d, 1H), 6.89-6.88 (m, 1H), 3.88-3.84 (t, 2H), 3.00-2.97 (t, 2H).
[857] According to the method of Example 431, the following compounds were prepared:
[858] a) 2- (2- (5-methanesulfonylamino-1H-indol-3-yl) ethyl) isoindole-1,3-dione: ISMS 384 (M + 1); ^l H NMR (CDCl ₃ ) 10.84 (s, 1H), 9.21 (s, 1H), 7.83-7.76 (m, 4H), 7.39-7.38 (m, 1H), 7.27-7.24 (m, 1H), 7.17 -7.16 (m, 1H), 6.96-6.93 (m, 1H), 3.83-3.80 (m, 2H), 2.98-2.94 (m, 2H), 2.79 (s, 3H), 3.88-3.84 (t, 2H) , 3.00-2.97 (t, 2 H).
[859] According to the method of Example 421, the following compounds were prepared:
[860] a) 5-benzoylaminotrytamine: ^l H NMR (CD ₃ OD) 7.94-7.92 (m, 2H), 7.85 (s, 1H), 7.54-7.47 (m, 3H), 7.34-7.29 (m, 2 H), 7.08 (s, 1 H), 4.86 (s, 2 H), 3.33 (s, 2 H), 2.95-2.86 (m, 4 H); And
[861] b) 5-methanesulfonylaminotrytamine: ISMS 253 (M +); _{^{l H NMR (CD 3 OD)}} 7.46-7.45 (d, 1H), 7.31-7.28 (d, 1H), 7.08 (s, 1 H), 7.04-7.01 (m, 1H), 4.86 (s, 4H), 2.89-2.83 (m, 7 H).
[862] Example 432
[863] 5-ethoxycarbonyl-1H-indole
[864] 5-carboxyindole (4.8 g, 29.8 mmol) and carbonyldiimidazole (9.7 g, 59.6 mmol) were combined in 150 mL THF and stirred overnight at room temperature. The reaction mixture was treated with 25 ml EtOH and 1.2 g (29.8 mmol) of a 60% oil dispersion of NaH and stirred for 2 hours. Concentration in vacuo gave a residue. The residue was partitioned between 150 mL EtOAc and 100 mL brine. The layers were separated and the organic layers were dried over MgSO _4, filtered and concentrated to an oil. Chromatography on silica gel eluting with 1% MeOH in CHCl ₃ gave 7.2 g of oil. The oil was crystallized from toluene to give the title compound: analysis for C ₁₁ H ₁₁ NO ₂ : calcd: C, 69.83; H, 5.86; N, 7.40; Found: C, 69.82; H, 5. 90; N, 7.38; ISMS 190 (M + 1).
[865] Example 433
[866] 5- (N-butylamido) -1H-indole
[867] A mixture of 5-carboxyindole (5 g, 31 mmol) was dissolved in 150 mL THF, treated with carbonyldiimidazole (5 g, 31 mmol) and stirred at room temperature overnight. The reaction mixture was treated with 4.5 g (62 mmol) of n-butylamine and refluxed for 1 hour. Concentration in vacuo gave a residue dissolved in EtOAc. Washed sequentially with 5N HCl, 5N NaOH and brine. The organic layers were dried over MgSO ₄ and concentrated to afford the title compound as an oil: ^l H NMR (CDCl ₃ ) 8.54 (bs, 1H), 8.07-8.06 (m, 1H), 7.63-7.61 (m, 1H), 7.39 -7.37 (m, 1H), 7.26-7.24 (m, 1H), 6.60-6.59 (m, 1H), 6.14 (bs, 1H), 3.5-3.45 (m, 2H), 1.64-1.57 (m, 2H) , 1.47-1.37 (m, 2H), .97-0.93 (m, 3H); EIMS 217 (M + 1).
[868] Example 434
[869] 5- (N-propylamido) -1H-indole
[870] The title compound was obtained by the method of Example 433: ^l H NMR (CDCl ₃ ) 8.07 (bs, 1H), 8.07 (s, 1H), 7.63-7.60 (m, 1H), 7.38-7.36 (m, 1H) , 7.25-7.24 (m, 1H), 6.59-6.58 (m, 1H), 6.21 (bs, 1H), 3.46-3.41 (m, 2H), 1.69-1.60 (m, 2H), 1.00-0.96 (m, 3H); EIMS 203 (M + 1).
[871] According to the method of Example 414, the following compounds were prepared:
[872] a) 3-formyl-5-benzenesulfonyl-1H-indole: ISMS 286 (M + 1); ^{l H NMR (DMSO-d6)} 9.83 (s, 1H), 8.55 (s, 1 H), 7.89-7.86 (m, 2H), 7.61 (s, 2H), 7.59-7.52 (m, 3H), 1.70 ( s, 3H).
[873] b) 3-formyl-5-ethoxycarbonyl-1H-indole: for C ₁₂ H ₁₁ NO ₃ : calcd. for C, 66.35; H, 5. 10; N, 6.45; Found: C, 65.97; H, 5. 17; N, 6.46; ISMS 218 (M + 1);
[874] c) 3-formyl-N-butylamido-1H-indole: C ₁₄ H ₁₆ N ₂ O ₂ Anal for 0.1H ₂ O: Calcd: C, 68.33; H, 6. 64; N, 11.38; Found: C, 68.35; H, 6. 24; N, 11.30; ISMS 245 (M + 1);
[875] d) 3-formyl-5- (N-propylamido) -1 H-indole: for C ₁₃ H ₁₄ N ₂ O ₂ : calculated: C, 67.81; H, 6. 13; N, 12.16; Found: C, 67.42; H, 6.04; N, 12.10; ^{l H NMR (DMSO-d6)} 9.95 (s, 1H), 8.6 (s, 1H), 8.48-8.45 (t, 1H), 8.36-8.35 (m, 1H), 7.76-7.73 (m, 1H), 7.52 -7.50 (d, 1H), 3.32 (bs, 1H), 3.24-3.19 (m, 2H), 1.58-1.48 (m, 2H), 0.90-0.86 (m, 3H); EIMS 230 (M +);
[876] e) 3-formyl-6-benzyloxy-1H-indole: ^l H NMR (DMSO-d6) 11.93 (s, 1H), 9.83 (s, 1H), 8.12-8.11 (m, 1H), 7.92-7.90 (m, 1H), 7.45-7.27 (m, 5H), 7.04-7.03 (m, 1H), 6.92-6.89 (m, 1H), 5.11 (s, 2H).
[877] According to the method of Example 415, the following compounds were prepared:
[878] a) 5-Benzenesulfonyl-3- (2-nitrovinyl) -1 H-indole: C ₁₆ H ₁₂ N ₂ O ₄ S 0.1H ₂ O Assay: calcd: C, 58.42; H, 3.83; N, 8.31; Found: C, 58.63; H, 3.52; N, 8.02; ISMS 229 (M + 1);
[879] b) 3- (2-nitrovinyl) -5-ethoxycarbonyl-1H-indole: for C ₁₆ H ₁₂ N ₂ O ₄ S 0.1H ₂ O: calcd: C, 58.42; H, 3.83; N, 8.31; Found: C, 58.63; H, 3.52; N, 8.02; ISMS 229 (M + 1);
[880] c) Assay for 3- (2-nitro-vinyl) -N-butylamido-1H-indole: C ₁₅ H ₁₇ N ₃ O ₃ : calcd: C, 62.71; H, 5.96; N, 14.62; Found: C, 62.46; H, 5.81; N, 14.38; ISMS 288 (M + 1);
[881] d) 3- (2-nitro-vinyl) -N-propylamido-1H-indole: ISMS 273 M (+1); ^{l H NMR (DMSO-d6)} 12.38 (s, 1H), 8.62-8.59 (t, 1H), 8.43-8.39 (d, 1H), 8.37 (s, 1H), 8.31-8.30 (d, 1H), 8.18 -8.15 (d, 1H), 7.84-7.82 (m, 1H), 7.55-7.53 (d, 1H), 3.31-3.24 (m, 2H), 1.61-1.52 (m, 2H), 0.92-0.89 (t, 3H); Anal for C ₁₄ H ₁₅ N ₃ O ₃ 0.1H ₂ O: Calcd: C, 61.12; H, 5.57; N, 15.28; Found: C, 61.06; H, 5. 38; N, 15.05;
[882] e) 3- (2-nitro-vinyl) -6-benzyloxy-1H-indole: ^l H NMR (DMSO-d6) 11.85 (bs, 1H), 8.32-8.29 (m, 1H), 8.09 (s, 1H ), 7.94-7.91 (m, 1H), 7.83-7.81 (m, 1H), 7.45-7.43 (m, 2H), 7.38-7.31 (m, 2H), 7.29-7.27 (m, 1H), 7.05-7.04 (m, 1 H), 6.92-6.89 (m, 1 H), 5.13 (s, 2 H).
[883] According to the method of Example 416, the following compounds were prepared:
[884] a) 5-Benzenesulfonyl-3- (2-nitroethyl) -1H-indole: C ₁₆ H ₁₄ N ₂ O ₄ S 0.1H ₂ O Assay: calcd C, 57.85; H, 4.31; N, 8.43; Found: C, 57.72; H, 4. 22; N, 8.25; ISMS 329 (M-1);
[885] b) 3- (2-nitroethyl) -5-ethoxycarbonyl-1H-indole: for C ₁₃ H ₁₄ N ₂ O ₄ : calculated: C, 59.54; H, 5. 38; N, 10.68; Found: C, 59.23; H, 5. 25; N, 10.53; ISMS 263 (M + 1);
[886] c) Assay for 3- (2-nitroethyl) -N-butylamido-1H-indole: C ₁₅ H ₁₉ N ₃ O ₃ : calcd: C, 62.27; H, 6. 62; N, 14.52; Found: C, 61.98; H, 6.39; N, 14.42: ISMS 290 (M + l); And
[887] d) 3- (2-nitroethyl) -N-propylamido-1H-indole: ^l H NMR (CDCl ₃ ) 8.52 (bs, 1H), 8.06 (s, 1H), 7.58-7.55 (m, 1H) , 7.35-7.33 (m, 1H), 7.10-7.09 (m, 1H), 6.23 (bs, 1H), 4.65-4.61 (t, 2H), 3.48-3.43 (m, 4H), 1.71-1.62 (m, 2H), 1.01-0.98 (t, 3H); Anal for C ₁₄ H ₁₇ N ₃ O ₃ 0.1H ₂ O: Calcd: C, 60.68; H, 6. 26; N, 15.16; Found: C, 60.88; H, 6.05; N, 15.07.
[888] According to the method of Example 421, the following compounds were prepared:
[889] a) 5-benzenesulfonyltrytamine: ISMS 301 (M + 1); l N NMR (HCl-DMSO-d 6) (s, 1H), 8.3 (s, 1 H), 8.2 (bs, 2H), 8.0-8.9 (m, 2H), 7.4-7.2 (m, 5H), 7.1- 7.0 (m, 1 H), 3.2-3.0 (s, 4 H);
[890] b) 5-ethoxycarbonyltrytamine (isolated as oxalate salt): for C ₁₃ H ₁₆ N ₂ O ₂ C ₂ H ₂ O ₄ : calcd: C, 55.90; H, 5.63; N, 8.69; Found: C, 56.07; H, 5.54; N, 8. 29; ISMS 233 (M + 1); And
[891] c) 5-N-butylamidotryptamine: Anal for C ₁₅ H ₂₁ N ₃ O 0.3H ₂ O: Calcd: C, 68.05; H, 8.22; N, 15.87; Found: C, 68.36; H, 8.11; N, 15.49; ISMS 260 (M + 1); And
[892] d) 5-N-propylamidotriptamine: (isolated as oxalate salt): C ₁₄ H ₁₉ N ₃ OC ₂ H ₂ O ₄ Assay for 0.1EtOAc: calcd: C, 57.23; H, 6. 38; N, 12.21; Found: C, 57.48; H, 6.53; N, 12.12; ^{l H NMR (DMSO-d6)} 11.2 (s, 1H), 8.4 (t, 1H), 8.2 (s, 1H), 7.75-7.65 (m, 1H), 7.6 (bs, 4H), 7.4-7.35 (m , 1H), 7.3-7.25 (d, 1H), 3.3-3.2 (m, 2H), 3.15-3.0 (m, 4H), 1.6-1.45 (m, 2H), 0.9-0.8 (t, 3H); ISMS 246 (M + 1).
[893] Example 435
[894] N-t-butoxycarbonyl-2- (6-butoxy-1H-indol-3-yl) ethylamine
[895] Nt-butoxycarbonyl-2- (6-hydroxy-1H-indol-3-yl) ethylamine (250 mg, 0.9 mmol), cesium carbonate (295 mg, 0.9 mmol) and 1-iodobutane (200 mg, 1.1 mmol) and N-methylpyrrolidinone (10 mL) were combined, stirred at room temperature for 2 hours and poured into 75 mL brine. The mixture was extracted twice with 25 mL of EtOAc. The combined extracts were washed with 2 x 50 mL of brine, dried over MgSO ₄ and concentrated in vacuo to afford an oil. Chromatography on silica gel eluting with 30% EtOAc in hexanes gave the title compound as a solid: ISMS 333 (M + 1); Anal for C ₁₉ H ₂₈ N ₂ O ₃ : Calcd: C, 68.65; H, 8.49; N, 8.43; Found: C, 68.83; H, 8. 18; N, 8.33.
[896] According to the method of Example 435, the following compounds were prepared:
[897] a) Nt-butoxycarbonyl-2- (6-ethoxy-1H-indol-3-yl) ethylamine: ISMS 305 (M + 1); Anal for C ₁₇ H ₂₄ N ₂ O ₃ : Calcd: C, 67.08; H, 7.95; N, 9.20; Found: C, 66.85; H, 7.79; N, 9.14.
[898] Example 436
[899] 6-butoxytrytamine
[900] Combine Nt-butoxycarbonyl-2- (6-butoxy-1H-indol-3-yl) ethylamine (430 mg, 1.3 mmol), 1 mL of anisole and 5 mL of trifluoroacetic acid, and add 2 at room temperature. Stir for hours. The reaction was concentrated to dryness in vacuo, mixed with 10 mL of concentrated NH ₄ OH and extracted with 20 mL of dichloromethane. The extract was dried over MgSO ₄ and concentrated to 300 mg oil (1.3 mmol, 100%).
[901] According to the method of Example 436, the following compounds were prepared:
[902] a) 6-ethoxytryptamine: ISMS 305 (M + 1); Anal for C ₁₇ H ₂₄ N ₂ O ₃ : Calcd: C, 67.08; H, 7.95; N, 9.20; Found: C, 66.85; H, 7.79; N, 9.14
[903] Example 437
[904] N-t-butoxycarbonyl-2- (6-phenylsulfonate-1H-indol-3-yl) ethylamine
[905] Combine Nt-butoxycarbonyl-2- (6-hydroxy-1H-indol-3-yl) ethylamine (750 mg, 2.7 mmol) and pyridine (430 mg, 5.4 mmol) in dichloromethane (30 mL) Cooled to 0 ° C. and treated with benzene sulfonyl chloride (480 mg, 2.7 mmol). The reaction was allowed to warm to rt and stirred overnight. The mixture was concentrated in vacuo to dryness, mixed with dichloromethane and chromatographed on silica gel eluting with 30% EtOAc in hexane to give Nt-butoxycarbonyl-2- (6-phenylsulfonate-1H-indole-3- Il) ethylamine was obtained as an oil: ISMS 415 (M-1); _{^{l H NMR (CDCl 3) 8.14}} (bs, 1H), 7.66-7.62 (m, 2H), 7.51-7.47 (m, 1H), 7.40-7.38 (m, 2H), 7.10 (s, 1H), 7.04- 7.03 (m, 2H), 6.59-6.57 (m, 1H), 4.57 (bs, 1H), 3.40-3.80 (m, 2H), 2.89-2.86 (m, 2H), 1.41 (s, 9H).
[906] Nt-butoxycarbonyl-2- (6-phenylsulfonate-1H-indol-3-yl) ethylamine (0.5 g, 1.2 mmol) was placed in a flask passed through N ₂ vapor and heated to 200 ° C. overnight. Cool to room temperature. The residue was dissolved in dichloromethane and chromatographed on silica gel eluting with 2% MeOH in CHCl ₃ —NH ₄ OH to afford the title compound as an oil.
[907] The following compounds were prepared according to the method of Example 425 and isolated as hydrochloride except as noted:
[908]
[909] Example 440
[910] N- (2- (5-propoxy-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine
[911]
[912] 2- (5-propoxy-1-triisopropylsilanyltrytamine (138 mg, 0.37 mmol), 3- (2,2,3,3-tetrafluoropropoxy) benzaldehyde (87 in 25 mL EtOH) mg, 1.8 mmol) and 1 g of 3 'molecular sieves were combined and refluxed overnight The liquid was decanted into a separate flask and cooled to 0 ° C. and treated with 42 mg (1.1 mmol) of NaBH ₄ for 1 hour at room temperature. Stirred, treated with 0.74 mmol of tetrabutylammonium fluoride and stirred for an additional hour Concentrated in vacuo to give a residue The residue was chromatographed on silica gel eluting with 10% MeOH in CHCl ₃ to give the title compound. The title compound was treated with 10 mL EtOH, 0.25 mL 5 N HCl and 40 mL toluene, then concentrated to give the hydrochloride of the title compound: ISMS 439 (M + 1); ¹ H NMR (free base- CDCl ₃ ) 7.89 (bs, 1H), 7.23-7.21 (m, 1H), 7.03-7.02 (d, 1H), 6. 99-6.98 (d, 1H), 6.94-6.92 (m, 1H), 6.89-6.83 (m, 2H), 6.78-6.75 (m, 1H), 6.18-5.90 (m, 1H), 4.29-4.23 (m , 2H), 3.95-3.91 (m, 2H), 3.78 (s, 2H), 2.95 (s, 4H), 1.85-1.75 (m, 2H), 1.51 (bs, 1H), 1.06-1.03 (t, 3H ).
[913] The following compounds were prepared according to the method of Example 440 and isolated as hydrochloride except as noted:
[914]
[915]
[916]
[917] Example 471
[918] N- (2- (5-hydroxy-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine
[919]
[920] N- (2- (5-benzyloxy-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine hydrochloride (295 mg, 0.6 mmol) and EtOH 25 The mls were combined, treated with 0.3 ml 5 N HCl and 300 mg 5% Pd / C and hydrogenated overnight at ambient pressure. The reaction was filtered through a pad of celite and concentrated to dryness and then chromatographed on silica gel to afford the title compound: ISMS 365 (M + 1); ^{l H NMR (DMSO-d6)} 10.6 (bs, 1H), 9.4 (bs, 2H), 8.75 (s, 1H), 7.45-6.6 (m, 7H), 4.9-4.7 (m, 2H), 4.2 (bs , 2H), 3.2-2.9 (m, 4H).
[921] The following compounds were prepared according to the method of Example 471 and isolated as hydrochloride except as noted:
[922]
[923] Example 475
[924] N- (2- (5-carboxy-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine
[925]
[926] N- (2- (5-methoxycarbonyl-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine (200 mg, 0.5 in 50 mL THF) mmol) and 1 ml of 3 N NaOH. The mixture was refluxed overnight, treated with 0.7 mL 5 N HCl and concentrated to dryness. Chromatography gave the title compound: ISMS 393 (M + 1); C ₂₀ H ₁₉ F ₃ N ₂ O ₃ CF ₃ COOH 1.2C ₇ H ₈ Anal for 2.1H ₂ O: Calcd: C, 55.76; H, 5.20; N, 4.28; Found: C, 55.51; H, 5.47; N, 4.50.
[927] Example 480
[928] 3- (3-fluoropropoxy) benzaldehyde
[929] 1-Bromo-3-fluoropropane (10.0 g, 77.1 mmol) and 3-hydroxybenzaldehyde (10.4 g, 92.5 mmol) in dimethylformamide (220 mL) were combined and stirred at room temperature. Treated with potassium carbonate (21.3 g, 144.2 mmol) in portions. The reaction mixture was heated to 100 ° C. for 36 h and then poured into a 1: 1 mixture of ice water and dichloromethane. The phases were separated and the aqueous layer was extracted with additional dichloromethane. The combined organic extracts were washed sequentially with 1.0 N sodium hydroxide, saturated sodium bicarbonate, brine and then dried over sodium sulfate. Filtration and the solvent provided under vacuum gave a residue. The residue was chromatographed on silica gel eluting with 40% ethyl acetate in hexanes to give the title compound as a yellow oil:^OneH NMR (400 MHz, CDCl₃) 9.98 (s, 1H), 7.50-7.42 (m, 2H), 7.42-7.38 (m, 1H), 7.22-7.16 (m, 1H), 4.66 (dt, 2H, J = 46.8, 5.8 Hz), 4.17 (t, 2H, J = 6.0 Hz), 2.19 (d quintet, 2H, J = 26.0, 6.0 Hz); MS (APCI): m / e 183.1 (M + l).
[930] Example 481
[931] 2,2-difluoroethyltosylate
[932] P-toluenesulfonyl chloride (12.9 g, 67.4 mmol) in pyridine (15 mL) was combined at room temperature and treated dropwise with 2,2-difluoroethanol (5.0 g, 60.9 mmol) via syringe. The reaction mixture was stirred for 72 h under nitrogen and partitioned between water (20 mL) and dichloromethane (20 mL). The aqueous phase was separated and extracted with additional dichloromethane (2 x 40 mL). The organic extracts were combined and washed sequentially with 1 N hydrochloric acid (2 x 50 mL), sodium bicarbonate (2 x 50 mL) and brine (2 x 50 mL). The organic layers were dried over sodium sulfate and concentrated in vacuo to afford the title compound as a yellowish oil:^OneH NMR (300 MHz, CDCl₃): 7.82 (d, 2 H,J= 9.0 Hz), 7.40 (d, 2H,J= 9.0 Hz), 5.92 (tt, 1H,J= 55.0, 0.4 Hz), 4.19 (td, 2H,J= 12.6, 4.0 Hz), 2.48 (s, 3H).
[933] Example 482
[934] 3- (2,2-difluoroethoxy) benzaldehyde
[935] The method of Example 480 gave the title compound as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ): 9.97 (s, 1H), 7.56-7.44 (m, 2H), 7.41-7.37 (m, 1H), 7.21 (ddd, 1H, J = 8.0, 2.8, 1.2 Hz ), 6.11 (tt, 1H, J = 55.0, 4.0 Hz), 4.24 (td, 2H, J = 12.6, 4.0 Hz).
[936] Example 483
[937] N- (2- (6-chloro-1H-indol-3-yl) ethyl) -3- (3-fluoropropoxy) benzylamine
[938]
[939] 6-Chlorotriptamine (1.4 g, 7.2 mmol), 3- (3-fluoropropoxy) benzaldehyde (1.3 g, 7.2 mmol) and molecular sieves in ethanol (150 mL) were combined and heated at 78 ° C. overnight. . The reaction mixture was filtered through a plug of celite and the resulting filtrate was treated with sodium borohydride (817 mg, 21.6 mmol) and stirred overnight at room temperature. The solvent was evaporated in vacuo to give a residue. The residue was chromatographed on silica gel eluting with a 9: 1 mixture of dichloromethane and 1 N ammonia in methanol to give a residue. The residue was chromatographed on a 10 g SCX column (the column was washed with methanol and then eluted with 1 N ammonia in methanol) and concentrated in vacuo to give a light yellow oil. The oil was dissolved in methanol and treated with a methanolic solution of ammonium chloride (112 mg, 2.1 mmol). The resulting mixture was sonicated for 10 minutes and the solvent was removed in vacuo and the resulting residue was triturated with ether containing a few drops of acetonitrile to give a solid. The solid was collected via filtration to give the title compound as hydrochloride: mp 177.8-178.9 ° C.^OneH NMR (400 MHz, dmso-d₆): 11.15 (br s, 1 H), 9.41 (br s, 2 H), 7.57 (d, 1 H,J= 8.0 Hz), 7.39 (d, 1H,J= 2.0 Hz), 7.32 (t, 1 H,J= 7.8 Hz), 7.26 (d, 1H,J= 2.4 Hz), 7.25-7.21 (m, 1H), 7.11 (d, 1H,J= 8.0 Hz), 7.01 (dd, 1H,J= 8.8, 2.0 Hz), 6.97 (dd, 1H,J= 8.0, 2.0 Hz), 4.60 (dt, 2H,J= 47.6, 6.0 Hz), 4.13 (br s, 2H), 4.08 (t, 2H,J= 6.4 Hz), 3.10 (br s, 4H), 2.11 (d quintet, 2H,J= 26.0, 6.0 Hz); MS (ES &lt; + &gt;): m / e 361.3 (M + l); CHN (C₂₀H₂₂ClFN₂O.HCl) calc .: C 60.46, H 5.83, N 7.05; Found: C 60.48, H 5.86, N 7.16.
[940] The following compounds were prepared according to the method of Example 483 and isolated as hydrochloride except as noted:
[941]
[942]
[943] Example 490
[944] N- (2- (6-chloro-1H-indol-3-yl) ethyl) -N-methyl-3- (2,2-difluoroethoxy) benzylamine
[945]
[946] N- (2- (6-chloro-1H-indol-3-yl) ethyl) -3- (2,2-difluoroethoxy) benzylamine (276 mg, 0.76 mmol) in dichloroethane (15 mL) And formaldehyde (55.5 mL of 38% aqueous solution, 0.76 mmol) were combined and stirred at room temperature for 10 minutes. Sodium triacetoxy borohydride (321 mg, 1.51 mmol) was added twice in 10 minutes. The reaction mixture was stirred at rt overnight, diluted with methanol (10 mL) and quenched with 1 drop of glacial acetic acid. The solvent was removed in vacuo to give a residue, the crude residue was redissolved in methanol and loaded directly onto a 10 g SCX column. The column was washed thoroughly with methanol and then eluted with 2 N ammonia in methanol. Concentration in vacuo gave the title compound as an oil. The oil (239 mg, 0.64 mmol) was dissolved in methanol (20 mL) and treated with a solution of ammonium chloride (36 mg, 0.67 mmol) in methanol (5 mL). After the mixture was sonicated for 10 minutes, the solvent was removed in vacuo to yield the title compound as hydrochloride. The salt was dissolved in 10 ml of acetonitrile-water (1: 1) and lyophilized overnight to give a fluffy white solid. The solid was triturated with diethyl ether (10 mL) and acetonitrile (2 drops), filtered and dried to give the title compound as hydrochloride: mp: 63.8-65.8 ° C .;^OneH NMR (400 MHz, dmso-d₆): 11.10 (br s, 1 H), 7.52 (d, 1 H,J= 8.4 Hz) 7.36 (d, 1H,J= 2.0 Hz), 7.40-7.26 (m, 2H), 7.22 (d, 1H,J= 2.4 Hz), 7.20-7.11 (m, 1H), 7.04 (br d, 1H,J= 7.6 Hz), 6.96 (dd, 1H,J= 8.6, 1.4 Hz), 6.38 (tt, 1H,J= 54.4, 3.6, Hz), 4.50-4.02 (br m, 2H), 4.30 (td, 2H,J= 14.4, 3.2 Hz), 3.15 (br s, 4H), 2.68 (br s, 3H); MS (ES &lt; + &gt;): m / e 378.9 (M + l).
[947] The following compounds were prepared according to the method of Example 490 and isolated as hydrochloride except as noted:
[948]
[949] Example 495
[950] N- (2- (6-chloro-1H-indol-3-yl) ethyl) -N-isopropyl-3- (2,2,3,3,3-pentafluoropropoxy) benzylamine
[951]
[952] N- (2- (6-chloro-1H-indol-3-yl) ethyl) -3- (2,2,3,3,3-pentafluoropropoxy in 20 ml of methanol-acetic acid (95: 5) Benzylamine (254 mg, 0.59 mmol) was combined and treated with acetone (441 mL, 5.9 mmol) and then treated with sodium cyanoborohydride (148 mg, 2.3 mmol) in portions. The reaction mixture was stirred overnight at 50 ° C. and then for another 2 days at room temperature. The solvent was removed in vacuo to give a residue. The residue was chromatographed on silica gel eluting with 4% methanol in dichloromethane to afford the title compound as a colorless oil. Oil (237 mg, 0.49 mmol) was dissolved in methanol (15 mL) and treated with a solution of ammonium chloride (27 mg, 0.49 mmol) in methanol (5 mL). The mixture was sonicated for 10 minutes and then concentrated to a tacky white solid. The sticky solid was dissolved in 10 ml of acetonitrile-water (1: 1) and lyophilized to give 241 mg (96%) of the title compound as hydrochloride: mp: 77.0-80.2 ° C .; ¹ H NMR (400 MHz, Methanol-d ₄ ): 7.31 (br t, 1H, J = 7.8 Hz), 7.26-7.21 (m, 1H), 7.16 (br d, 1H, J = 8.4 Hz), 7.15- 7.07 (m, 2H), 7.05-6.95 (m, 2H), 6.83 (dd, 1H, J = 8.0, 2.0 Hz), 4.52 (t, 2H, J = 12.8 Hz), 4.12 (br s, 2H), 3.53 (br s, 1 H), 3.11 (br s, 2 H), 2.89 (br s, 2 H), 1.27 (br s, 6 H); MS (APCI): m / e 475.1 (M + l).
[953] According to the method of Example 495, the following compounds were prepared and isolated as maleate:
[954]
[955] Example 500
[956] N- (2- (6-chloro-5-methoxy-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxybenzylamine
[957]
[958] 5-methoxy-6-chlorotrytamine (0.2 mmol) in dichloromethane (1 mL) and 3- (2,2,3,3-tetrapropylfluoropropoxy) benzaldehyde (in dichloromethane (1 mL) 0.32 mmol) were combined and spun. After 2 hours, sodium borohydride (37.83 mg, 1.0 mmol) was added as a stock solution in dichloromethane (1 mL). After spinning overnight, the reaction mixture was diluted with 1 ml of methanol and the resulting solution was applied directly to a 2 g SCX column. The column was washed thoroughly with methanol, eluted with 2 M ammonia-methanol and concentrated to the residue. TLC of the eluate confirmed that the reaction was not completed. The residue was diluted with dichloromethane (1 mL) and a second stock of sodium borohydride (37.83 mg, 1.0 mmol) in 1-methyl-2-pyrrolidinone (1 mL) was added. After spinning for 2 hours, the reaction mixture was diluted with 1 ml of methanol and the resulting solution was applied directly to a 2 g SCX column. The column was washed thoroughly with methanol, eluted with 2 M ammonia-methanol and concentrated to the residue. Further purification on SI column. Eluted with straight ethyl acetate. Compounds were characterized using LC method 1 or 2. LCMS R _t 2.749 min at 254 nm, 2.800 min at 220 nm; m / e 445 (M + l).
[959] Common LC Method:
[960] Method 1: (Shimadzu QP8000) 10 to 90 in 4.5 minutes. Solvent A: 0.1% trifluoroacetic acid in water, Solvent B: acetonitrile 0.1% trifluoroacetic acid. Column: C18 Metachem, monochrom 3 micron, 2.5 × 25.
[961] Method 2: (Shimazu) 10 to 80 in 9 minutes. Solvent A: 0.1% trifluoroacetic acid in water, Solvent B: acetonitrile 0.08% trifluoroacetic acid. Column: C18 metachem, monochrome 5 micron, 4.6 × 50.
[962] The following compounds were prepared in a similar manner as in Example 500 and isolated as base unless otherwise noted:
[963]
[964]
[965] Example 523
[966] N- (2- (6-trifluoromethyl-1H-indol-3-yl) ethyl) -3-phenoxybenzylamine
[967]
[968] 5-trifluoromethyltryptamine (0.1 mmol) in methanol (1 mL) and 3-phenoxybenzaldehyde (0.2 mmol) in methanol (1 mL) were combined and spun. After 3 hours, sodium borohydride (18 mg, 0.5 mmol) was added as a stock solution in 1-methyl-2-pyrrolidinone (0.5 mL). After spinning overnight, the reaction mixture was diluted with 1 ml of methanol and the resulting solution was applied directly to a 2 g SCX column. The column was washed thoroughly with methanol, eluted with 2 M ammonia-methanol and the eluate was concentrated. Further purification on an SI column and eluting with ethyl acetate gave the desired compound. Method 1 was used to characterize the compound. LCMS R _f 2.954 min at 254 nm, 2.954 min at 220 nm, m / e 411 (M + 1).
[969] LC method:
[970] Method 1: (Shimazu QP8000) 10 to 90 in 4.5 minutes. Solvent A: 0.1% trifluoroacetic acid in water, Solvent B: acetonitrile 0.1% trifluoroacetic acid. Column: C18 metachem, monochrome 3 micron, 2.5 × 25.
[971] The following compounds were prepared following a procedure similar to Example 523 and isolated as a base unless otherwise noted:
[972]
[973] Example 531
[974] N- (2- (4-sulfonamidophenyl) ethyl) -3- (2,2,3,3,3-pentafluoropropoxy) benzylamine
[975]
[976] 4-sulfonamidophenylethylamine (0.2 mmol) in methanol (1 mL) and 3- (2,2,3,3,3-pentapropylfluoropropoxy) benzaldehyde (0.32 mmol) in methanol (1 mL) Were combined and rotated. After 1 hour, sodium borohydride (18 mg, 1.0 mmol) was added as a stock solution in 1-methyl-2-pyrrolidinone (1 mL). After spinning overnight, the reaction mixture was diluted with 1 ml of methanol and the resulting solution was applied directly to a 2 g SCX column. After washing thoroughly with methanol, the column was eluted with 2 M ammonia-methanol and the eluate was concentrated to the residue. Further purification with the Gilson UV preparation system afforded the desired compound, and Method 1 was used to characterize the compound. LCMS R _f 2.345 min at 254 nm, 2.347 min at 220 nm, m / e 439 (M + l) 461 (M + 22).
[977] LC method:
[978] Method 1: (Shimazu QP8000) 10 to 90 in 4.5 minutes. Solvent A: 0.1% trifluoroacetic acid in water, Solvent B: acetonitrile 0.1% trifluoroacetic acid. Column: C18 metachem, monochrome 3 micron, 2.5 × 25.
[979] The following compounds were prepared using a procedure similar to Example 531 and isolated as a base unless otherwise noted:
[980]
[981] Example 545
[982] N- (2- (6-methoxy-1H-indol-3-yl) ethyl) -3- (2,2,3,3,3-pentafluoropropoxy) benzylamine
[983]
[984] In 1-methyl-2-pyrrolidinone (1 mL) Amine (0.2 mmol) and aldehyde (0.32 mmol) in dichloromethane (1 mL) were combined and spun. After 1 hour, sodium borohydride (18 mg, 1.0 mmol) was added as a stock solution in 1-methyl-2-pyrrolidinone (1 mL). After spinning overnight, the reaction mixture was diluted with 1 ml 10% acetic acid / methanol and the resulting solution applied directly to a 2 g SCX column. Washed thoroughly with methanol and the column was eluted with 2 M ammonia-methanol and the eluate was concentrated to residue, which was further purified by Gilson UV preparation system. Method 1 was used to characterize the compound. LCMS Rf 3.752 min at 254 nm, 3.753 min at 220 nm, m / e 429 (M + 1).
[985] LC method:
[986] Method 1: (Shimazu QP8000) 10 to 90 in 4.5 minutes. Solvent A: 0.1% trifluoroacetic acid in water, Solvent B: acetonitrile 0.1% trifluoroacetic acid. Column: C18 metachem, monochrome 3 micron, 2.5 × 25.
[987] Following the same procedure as in Example 545, the following compounds were prepared:
[988]
[989]
[990]
[991]
[992] Following the same procedure as in Example 545, the following compounds were prepared:
[993]
[994] Example 620
[995] N- (2- (5-methoxy-1H-indol-3-yl) ethyl) -3- (2,2,3,3,3-pentafluoropropoxy) benzylamine
[996]
[997] Amine (0.2 mmol) in dichloromethane (0.5 mL) and aldehyde (0.4 mmol) in dichloromethane (1 mL) were combined and spun. After 1 hour, sodium triacetoxy borohydride (82 mg, 0.8 mmol) was added as a stock solution in 1-methyl-2-pyrrolidinone (1 mL) and spun. After spinning overnight, the reaction mixture was diluted with 1 ml of methanol and applied directly to a 2 g SCX column. After washing thoroughly with methanol, the column was eluted with 2 M ammonia-methanol and the eluate was concentrated to the residue, which was further purified by Gilson UV preparation system. Method 3 was used to characterize the compound. LCMS R _f 4.823 min at 254 nm, 4.823 min at 220 nm, m / e 443 (M + 1).
[998] LC method:
[999] Method 3: (Shimazu QP8000) 5-90 in 4.5 min. Solvent A: 0.1% trifluoroacetic acid in water, Solvent B: acetonitrile 0.1% trifluoroacetic acid. Column: C18 metachem, monochrome 3 micron, 2.5 × 25.
[1000] Using the same procedure as in Example 620, the following compounds were prepared:
[1001]
[1002] Example 624
[1003] N- (2- (6-fluoro-1-methyl-1H-indol-3-yl) ethyl) -N-methyl-3-propoxybenzylamine
[1004]
[1005] N-methyl-N- (2- (6-fluoro-1-methyl-1H-indol-3-yl) ethylamine (0.2 mmol) and dichloromethane in 1-methyl-2-pyrrolidinone (0.5 mL) 3-propyloxybenzaldehyde (0.32 mmol) in (1 mL) was combined and spun, after spinning overnight, sodium borohydride (1.0 mmol) was added as a stock solution in 1-methyl-2-pyrrolidinone (0.5 mL) and After spinning for 3 hours, the reaction mixture was diluted with 1 ml of 10% acetic acid / methanol and the resulting solution was applied directly to a 2 g SCX column After washing thoroughly with methanol, the column was washed with 2 M ammonia-methanol. Was eluted and the eluate was concentrated to a residue, which was further purified by a Gilson UV preparation system.
[1006] LC method:
[1007] Method 1: (Shimazu QP8000) 10 to 90 in 4.5 minutes. Solvent A: 0.1% trifluoroacetic acid in water, Solvent B: acetonitrile 0.1% trifluoroacetic acid. Column: C18 metachem, monochrome 3 micron, 2.5 × 25.
[1008] Following the procedure similar to that found in Example 624, the following compounds were prepared:
[1009]
[1010]
[1011]
[1012]
[1013] Example 650
[1014] N-2- (3-chlorophenyl) ethyl-3-hydroxybenzylamine
[1015]
[1016] 2- (3-chlorophenyl) ethylamine (1.866 gm; 15.28 mmol) and 3-hydroxybenzaldehyde (1.567 gm; 10.07 mmol) in 40 ml of methanol were combined, stirred for 20 minutes at room temperature and sodium borohydride (0.950 gm) 25.1 mmol) at one time. The mixture was stirred at room temperature. After 15 h, water (10 mL) was added and methanol was removed by rotary evaporation. Water (25 mL) and dichloromethane (50 mL) were added to the slurry, the layers were separated and the aqueous layer was extracted with dichloromethane (50 mL). The combined organic layers were washed with saturated brine (3 times), dried over MgSO ₄ and concentrated to give the title compound.
[1017] Example 650A
[1018] N-t-butoxycarbonyl-N-2- (3-chlorophenyl) ethyl-3-hydroxybenzylamine
[1019] N-2- (3-chlorophenyl) ethyl-3-hydroxybenzylamine, dichloromethane (40 mL) and di-tert-butyl dicarbonate (1.556 gm; 7.131 mmol) and triethylamine (1.0 mL; 7.2 mmol) were combined. After 18 h, poured into water (50 mL) and the layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water, dried over MgSO ₄ and concentrated. Chromatography on silica gel eluting with 5% ethyl acetate in hexanes gave the title compound.
[1020] Example 651
[1021] N-t-butoxycarbonyl-N-2- (3-chlorophenyl) ethyl-3-propoxybenzylamine
[1022] A 50% sodium hydroxide solution in water (0.8 mL) was added Nt-butoxycarbonyl-N-2- (3-chlorophenyl) ethyl-3-hydroxybenzylamine (46.7 mg, 0.129 mmol) in toluene (1 mL). to n-propyl iodide (0.17 mg, 1.00 mmol) and tetrabutylammonium bromide (18 mg, 0.057 mmol) solution. The mixture was stirred at 1200 rpm and heated at 50-54 ° C. After 64.5 hours, the mixture was poured into 5 ml of water and the phases were separated and the aqueous phase was extracted twice with dichloromethane. The organic phases are combined and washed with saturated sodium bicarbonate solution followed by saturated brine and dried (MgSO₄) To give a residue. The residue was chromatographed on silica gel to give the title compound: MS (ES +): m / e (M + 1) 404. TLC (20% EtOAc in hexanes, R_f0.54).
[1023] Example 652
[1024] N- (2- (3-chlorophenyl) ethyl) -3-propoxybenzylamine
[1025]
[1026] Methanesulfonic acid (70 uL) is added to a solution of Nt-butoxycarbonyl-N-2- (3-chlorophenyl) ethyl-3-propoxybenzylamine in dichloromethane (4 mL) and the mixture is allowed to stand for 3 hours at room temperature. Stirred at. 10% Na₂CO₃Aqueous solution (2 mL) was added and the layers were separated and the organic layers were concentrated in nitrogen stream to give a residue. The residue was dissolved in 4 mL 5% acetic acid in methanol and passed through a 1 gm SCX column and eluted with 1 M ammonia in methanol to afford the title compound: MS (ES +): m / e (M + 1). HPLC (Over 7.5 minutes 10 to 90% water / acetonitrile, Tr=4.490 minutes).
[1027] Following the procedure similar to Examples 651 and 652, the following compounds were prepared:
[1028]
[1029] Example 665
[1030] N- (2- (5-methoxy-1-ethyl-1 H-indol-3-yl) ethyl) -N-ethyl-3-phenyloxybenzylamine
[1031]
[1032] Acetaldehyde (0.080 mL; 0.77 mmol) was dissolved in N- (2- (5-methoxy-1H-indol-3-yl) ethyl) -3-phenyloxybenzylamine (free base, 55.5 in dichloromethane (1 mL). mg, 0.149 mmol) in solution, followed by a suspension of sodium triacetoxy borohydride (64 mg; 0.30 mmol) in dichloromethane (1 mL). After 44 h, methanol (0.5 mL) was added to quench and concentrated in a nitrogen stream to afford a residue. The residue was dissolved in 4 ml of 5% acetic acid in methanol, partially purified by passage through a 1 gm SCX column and eluted with 1 M ammonia in methanol to give a residue. The residue was chromatographed with preparative HPLC (C-18 column, flow rate 20 mL / min, 5 to 90% water / acetonitrile for 12 minutes) to afford the title compound: MS (ES +): m / e (M +1); HPLC: (10 to 90% water / acetonitrile over 10 minutes, Tr=5.25 minutes).
[1033] Following a procedure similar to Example 665, the following compounds were prepared:
[1034]
[1035] Example 670
[1036] 3-propoxybenzaldehyde
[1037] 3-hydroxybenzaldehyde (7.50 gm; 61.4 mmol), n-propyl iodide (17.3 gm; 102 mmol) and potassium carbonate (16.90 gm; 122 mmol) in 2-butanone (100 mL) were combined and refluxed. After 17 h the mixture was cooled to rt, the solution was decanted and concentrated by rotary evaporation. The residue was partitioned between diethyl ether (150 mL) and water (150 mL), the layers separated and the aqueous layer extracted with diethyl ether (2 x 100 mL). The organic layers were combined and washed with water, 1 N NaOH, then water, dried over MgSO ₄ and concentrated to give a residue. The residue was distilled off to give the title compound: bp: 122-125 ° C. (15 mm); TLC (10% Et ₂ O / hexanes; R _f 0.35).
[1038] Example 671
[1039] 3- (3,3,3-trifluoropropoxy) benzaldehyde
[1040] The mixture of toluenesulfonyl chloride (7.43 gm; 39.0 mmol) and pyridine (50 mL) was cooled to 0 ° C. and 3,3,3-3,3,3-trifluoropropanol (2.23 gm; 19.5 mmol) was added. And the mixture was stored at 3 ° C. After 48 hours, the reaction mixture was poured into 350 mL of ice water and extracted with diethyl ether (3 x 125 mL). The organic layers were combined and washed with 5 N HCl, water, saturated sodium bicarbonate solution and brine, dried over MgSO ₄ and concentrated to give 3,3,3-trifluoropropyl tosylate. The material was transferred to the next step without purification.
[1041] 3,3,3-trifluoropropyl tosylate (4.057 gm; 15.12 mmol), 3-hydroxybenzaldehyde (1.85 gm; 15.12 mmol) and K ₂ CO ₃ (4.15 gm; 30.0 mmol) in DMF (80 mL) Were combined and heated at 100 ° C. After 18 h, cooled to rt, diluted with water (200 mL) and extracted with dichloromethane (2 x 200 mL). The organic extracts were combined and washed sequentially with water (100 mL), 0.1 M NaOH (2 × 100 mL), saturated sodium bicarbonate (100 mL) and saturated brine (100 mL), dried (MgSO ₄ ) and concentrated. Chromatography on silica gel (0-20% ethyl acetate in hexanes) gave the title product.
[1042] Example 672
[1043] 3- (2-fluoroethoxy) benzaldehyde
[1044] 1-bromo-2-fluoroethane (4.575 g; 36.0 mmol), 3-hydroxybenzaldehyde (4.103 gm; 33.60 mmol) and K ₂ CO ₃ (7.05 gm; 51.0 mmol in 2-butanone (100 mL) ) Were combined and refluxed. After 18 hours, the mixture was cooled to room temperature, concentrated and partitioned between 100 ml of water and 100 ml of dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 75 mL). The organic layers were combined and washed sequentially with brine (2 x 150 mL), 1 M NaOH (2 x 100 mL), NaHCO ₃ (saturated, 100 mL) and brine (150 mL), dried (MgSO ₄ ) and concentrated and silica Gel phase chromatography (0-25% diethyl ether in hexanes) afforded the title compound.
[1045] Example 673
[1046] N- (2- (5-fluoro-1H-indol-3-yl) ethyl) -3-propoxybenzylamine
[1047]
[1048] 3-propoxybenzaldehyde (29.6 mg; 0.18 mmol) and 5-fluorotryptamine (14.2 mg; 0.080 mmol) in methanol (2 mL) were combined. Sodium borohydride solution (1 mL of 0.5 M solution; 0.50 mmol) in diglyme was added and stirred. After 63 hours, concentrated at room temperature in a nitrogen stream. The residue was dissolved in methanol and added to a 1 gm SCX column which was previously washed with 5% acetic acid in methanol. The product was eluted from SCX column with 1 M ammonia in methanol to give the title compound: MS (ES +): m / e (M + 1); HPLC (10 to 90% water / acetonitrile over 10 minutes), Tr=4.08 minutes.
[1049] Common LC Method:
[1050] Method 1: (Shimachu Class VP HPLC and Micromass Platform LC on HP 1100 LC System) 10 to 90 in 7.5 min. Solvent A: 0.1% trifluoroacetic acid in water, Solvent B: acetonitrile 0.1% tri Fluoroacetic acid. Column: C18 metachem, monochrome 3 micron, 2.5 × 25.
[1051] Method 2: (Shimachu Class VP HPLC and Micromass Platform LC on HP 1100 LC system) 10 to 90 in 10 minutes. Solvent A: 0.1% trifluoroacetic acid in water, Solvent B: Acetonitrile 0.1% trifluoroacetic acid. Column: C18 metachem, monochrome 3 micron, 2.5 × 25.
[1052] Method 3: (Waters Millennium HPLC and Micromass Platform LC on HP 1100 LC System) 10 to 10 minutes 10. Solvent A: 0.1% trifluoroacetic acid, Solvent B: Acetonitrile 0.08% trifluoroacetic acid . Column: YMC, 5 micron, 2.5 × 25.
[1053] Method 4: (Shimachu QP8000) 10 to 90 in 4.5 minutes. Solvent A: 0.1% trifluoroacetic acid in water, Solvent B: acetonitrile 0.1% trifluoroacetic acid. Column: C18 metachem, monochrome 3 micron, 2.5 × 25.
[1054] Following the procedure according to example 673, the following compounds were prepared:
[1055]
[1056] Following the procedure according to example 673, the following compounds were prepared:
[1057]
[1058]
[1059] Following the procedure according to example 673, the following compounds were prepared:
[1060]
[1061] Following the procedure according to example 673, the following compounds were prepared:
[1062]
[1063]
[1064] Following the procedure according to example 673, the following compounds were prepared:
[1065]
[1066] Example 760
[1067] 3-trifluoromethoxyphenethylamine
[1068] Nitromethane (1.8 g, 30 mmol), ethanol (4 mL) and 10 N NaOH (0.1 mL) were combined. 3-trifluoromethoxybenzaldehyde (5.0 g, 28.6 mmol) was added and stirred. After 20 h, poured into ethyl acetate, washed with water, dried over Na ₂ S0 ₄ , filtered and concentrated to give a residue. The residue was chromatographed on silica gel to give 2-nitro-1- (3-trifluoroethoxyphenyl) ethanol: MS (M-1) 250; ¹ H NMR (CDCl ₃ ) 7.45 (1 H, t, J = 8.4 Hz), 7.36-7.30 (2 h, m), 7.24-7.20 (1 h, m), 5.51 (1 h, dt, J = 8.8 And 4.0 Hz), 4.62-4.51 (2 H, m).
[1069] 2-nitro-1- (3-trifluoroethoxyphenyl) ethanol (6.1 g, 24.2 mmol) and methanesulfonyl chloride (2.02 mL) in dichloromethane (50 mL) were combined and cooled in an ice bath. Triethylamine (7.28 mL) was added dropwise while maintaining at a temperature near 0 ° C. After 2 h, poured into ethyl acetate, washed with water, dried over Na ₂ SO ₄ , filtered and concentrated to residue. The residue was chromatographed on silica gel to give 3- (2-nitrovinyl) -1-trifluoroethoxybenzene: MS (MH ⁺ ) 234; ¹ H NMR (CDCl ₃ ) 7.97 (1 H, d, J = 13.6 Hz), 7.57 (1 H, d, J = 13.6 Hz), 7.53-7.48 (2 H, m), 7.40-7.35 (2 H, m).
[1070] 3- (2-nitrovinyl) -1-trifluoroethoxybenzene (3.0 g, 12.88 mmol) and methanol (50 mL) and concentrated HCl (5 mL) were combined and at room temperature in the presence of PtO ₂ (0.6 g) And hydrogenated at 50 psi (340 kPa). After 5 h, filtered with catalyst and the filtrate was diluted with 1 N HCl (50 mL) and washed with ethyl acetate. The aqueous layer was separated, neutralized with 2N NaOH (100 mL), extracted with ether, dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound which could be used without further purification. MS (MH &lt; + &gt;)206; ¹ HNMR (CDCl ₃ ) 7.32 (1 H, t, J = 7.6 Hz), 7.18-7.06 (3 H, m), 2.98 (2 H, t, J = 7.2 Hz), 2.77 (2 H, t, J = 7.2 Hz).
[1071] Example 761
[1072] N- (2- (3-trifluoromethoxyphenyl) ethyl) -3- (2,2,2-trifluoroethyl) benzylamine
[1073]
[1074] Combine trifluoromethoxyphenethylamine (400 mg, 1.95 mmol) and 3- (2-trifluoroethoxy) benzaldehyde (596 mg, 2.92 mmol) and 4 'molecular sieve (4.0 g) in ethanol (30 mL) It was refluxed. After 4.5 h, decanted and treated with NaBH ₄ (221 mg, 5.85 mmol). After 1 h, evaporated and partitioned between 5 N NaOH and dichloromethane. The organic layers were separated, dried over Na ₂ SO _4, filtered and concentrated to give a residue. The residue was chromatographed by HPLC to afford the title compound. HCl salt of the title compound was obtained as a white solid: MS (MH ⁺ ) 394; ¹ H (DMSO-d6) 9.48 (2 H, br s), 7.48 (1 H, t, J = 7.6 Hz), 7.40 (1 H, t, J = 8.0 Hz), 7.34 (1 H, s), 7.32-7.21 (4 H, m), 7.11 (1 H, dd, J = 8.4 and 2.8 Hz), 4.79 (2 H, q, J = 8.8 Hz), 4.15 (2 H, s), 3.22-3.12 ( 2 H, m), 3.11-3.04 (2 H, m).
[1075] Example 762
[1076] N- (2- (3-trifluoromethoxyphenyl) ethyl) -3- (2,2,3,3-tetrafluoropropyl) benzylamine
[1077]
[1078] The title compound was obtained by the method of Example 761. HCl salt of the title compound was obtained as a white solid: MS (MH ⁺ ) 426; ¹ H (DMSO-d6) 9.42 (2 H, br s), 7.48 (1 H, t, J = 7.6 Hz), 7.40 (1 H, t, J = 7.6 Hz), 7.32-7.26 (3 H, m ), 7.20 (1 H, d, J = 7.2 Hz), 7.11 (1 H, dd, J = 8.4 and 2.8 Hz), 6.70 (1 H, tt, J = 52 and 5.2 Hz), 4.62 (2 H, t, J = 13.6 Hz), 4.15 (2H, s), 3.22-3.12 (2H, m), 3.10-3.02 (2H, M).
[1079] Example 763
[1080] N- (2- (4,7-difluoro-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine
[1081]
[1082] 2- (4,7-difluoro-1H-indol-3-yl) ethylamine (483 mg, 2.46 mmol) and ethanol (45 mL) were combined and stirred. After 10 minutes, it was treated with 3- (2,2,2-trifluoroethoxy) benzaldehyde (502 mg, 2.46 mmol) and anhydrous sodium sulfate (3.5 g), stirred under nitrogen and heated to 70 ° C. After 2 hours, the reaction was cooled with a vacuum filter, sodium sulfate removed and treated with sodium borohydride (279 mg, 7.38 mmol) in a 500 ml round bottom flask equipped with a magnetic stirrer. The solution was stirred at room temperature for 2 hours and then carefully treated with 3 drops of glacial acetic acid to quench excess hydride. The solvent was removed in vacuo and the crude material redissolved in methanol. Purification with a 10 g SCX column by complete washing with methanol, eluting with 2 N ammonia in methanol and concentration in vacuo gave the title compound as a straw colored oil. Hydrochloride was prepared by dissolving free base (800 mg, 2.08 mmol) in methanol (15 mL) and treating with a solution of ammonium chloride (111 mg, 2.08 mmol) in methanol (5 mL). The mixture was sonicated for 10 minutes and then concentrated in vacuo to yield a white solid. Recrystallization from ethyl acetate gave the hydrochloride of the title compound: mp 208.5-210.0 ° C .; ¹ H NMR (400 MHz, dmso-d ₆ ): 11.79 (br s, 1H), 9.21 (br s, 2H), 7.39 (t, 1H, J = 7.8 Hz), 7.32 (d, 1H, J = 2.0 Hz) 7.30 (s, 1H), 7.18 (d, 1H, J = 8.0 Hz), 7.11 (dd, 1H, J = 2.6, 8.2 Hz), 6.85-6.91 (m, 1H), 6.67-6.73 (m, 1H), 4.77 (q, 2H, J = 8.8 Hz), 4.16 (s, 4H), 3.12-3.16 (m, 4H); MS (APCI): m / e 385.1 (M + l); CHN (C ₁₉ H ₁₇ F ₅ N ₂ O.HCl) calc .: C 54.23, H 4.31, N 6.66; Found: C 54.20, H 4.30, N 6.66.
[1083] Example 764
[1084] N- (2- (4,5,6,7-tetrafluoro-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine
[1085]
[1086] In a similar manner to Example 763, 2- (4,5,6,7-tetrafluoro-1H-indol-3-yl) ethylamine (484 mg, 2.08 mmol), ethanol (45 mL), 3- ( The free base of the title compound was straw colored using 2,2,2-trifluoroethoxy) benzaldehyde (425 mg, 2.08 mmol), anhydrous sodium sulfate (3.5 g), sodium borohydride (236 mg, 6.24 mmol). Obtained as a solid. Recrystallization from methylene chloride gave the title compound: mp 107.2-108.2 ° C. ¹ H NMR (400 MHz, dmso-d ₆ ): 11.92 (br s, 1H), 7.32 (s, 2H), 6.95-6.99 (m, 2H), 6.87 (dd, 1H, J = 2.4, 8.0 Hz) 4.68 (q, 2H, J = 8.8 Hz), 3.70 (s, 2H), 2.88 (t, 2H, J = 7.2 Hz) 2.75 (t, 2H, J = 7.2 Hz). MS (ES &lt; + &gt;): m / e 421.1 (M + l). CHN (C ₁₉ H ₁₅ F ₇ N ₂ O.1HCl.0.20H ₂ O) calc .: C 53.83, H 3.66, N 6.61; Found: C 53.75, H 3.33, N 6.
[1087] Example 765
[1088] 5-trifluoromethyltryptamine
[1089] 4-trifluoromethylaniline (32.2 g, 199.8 mmol) and dichloromethane (600 mL) were combined in a 2 L round bottom flask under nitrogen and cooled to 0 ° C. Tert-Butylhypochlorite (protected from light) (22.8 μg, 210 mmol) in dichloromethane (150 mL) was added and stirred at about −65 to −70 ° C. for a total of 45 minutes. At 35 minutes, a solution of methylthioacetaldehyde dimethylacetal (30 g, 220.2 mmol) in dichloromethane (150 mL) was added. At 45 minutes, a solution of triethylamine (31.2 mL, 22.78 μg, 225.1 mmol) in dichloromethane (80 mL) was added at −70 ° C. The reaction mixture was brought to room temperature. Washed with water and evaporated to dryness to yield 72 kg of oil.
[1090] The oil was dissolved in toluene (600 mL) and triethylamine (60 mL) was added. Heated to reflux. After 24 hours, the solvent was evaporated and the residue dried in vacuo to give a 7a residue. The residue, diethyl ether (600 mL) and 2 N HCl (500 mL) were combined and stirred at rt for 24 h. The aqueous layer was separated and the organic layers were washed successively with water and saturated NaHCO ₃ , dried over MgSO ₄ , filtered and evaporated to give a residue. Chromatography on silica gel eluting with cyclohexane-ethyl acetate (8/2, v / v), fractions containing the expected substance are collected and evaporated to 33.8 g of 2-methylthio-5-trifluoromethyl-1H-indole Obtained.
[1091] Wet Raney Nickel (330 g), 2-methylthio-5-trifluoromethyl-1H-indole (33.8 g, 146.2 mmol) and anhydrous ethanol (850 mL) were combined and stirred. After 1.5 h, the mixture was filtered through celite and the celite was washed with ethanol (500 mL). The filtrate was evaporated to dryness, toluene (20 mL) was added, evaporated and dried to afford 5-trifluoromethylindole: mp = 55-60 ° C.
[1092] 5-trifluoromethylindole (24 g, 130 mmol) was dissolved in anhydrous diethyl ether (288 mL), cooled to 10 ° C. and oxalyl chloride (12 mL) was added dropwise for 10 minutes (exothermic reaction) at room temperature Stir for 4 hours. An additional amount of oxalyl chloride (3 mL) was added and stirred overnight at room temperature to give a solid. The solid was collected, washed with anhydrous diethyl ether (20 mL) and dried to give 2- (5- (trifluoromethyl-1H-indol-3-yl) -2-oxo-acetyl chloride.
[1093] 2- (5- (trifluoromethyl-1H-indol-3-yl) -2-oxo-acetyl chloride and NH ₄ OH 1 N (700 mL) were combined and the suspension was stirred vigorously. After 3 hours, 2 -(5- (trifluoromethyl) -1H-indol-3-yl) -2-oxo-acetamide was collected.
[1094] LiAlH ₄ (37.95 g, 1.00 mol) was added to THF (650 mL) under a cooled ice bath. A solution of AlCl ₃ (50 g, 375 mmol) in THF (600 mL) was prepared and added dropwise to LiAlH ₄ solution at 5-10 ° C. for 45 minutes. Solution of 2- (5- (trifluoromethyl) -1H-indol-3-yl) -2-oxo-acetamide (21.4 g, 83.5 mmol) in THF (600 mL) while maintaining at a temperature of about 5 ° C. Was added and stirred overnight while warming to room temperature. The mixture was cooled with ice water and treated with 30% NaOH (100 mL) while maintaining the temperature below about 30 ° C. After stirring for about 30 minutes, it is filtered, washed with THF (2 L) and the filtrate is evaporated to afford the title compound. The HCl salt was formed (until acidic) by dissolving the title compound in diethyl ether and adding HCl solution in diethylether. The solid was collected by filtration, washed with diethyl ether and dried under reduced pressure to give the hydrochloride of the title compound.
[1095] The hydrochloride salt can be further purified by basic extraction with ethyl acetate, dried over MgSO _4, filtered and evaporated to dryness to form the hydrochloride salt in diethyl ether.
[1096] Example 766
[1097] 3-propoxybenzaldehyde
[1098] 3-hydroxybenzaldehyde (790 g), K₂CO₃, (1627 g) and DMF (8 L) were combined. 1-iodopropane (1000 g) was added and heated to 105 ° C. and stirred for 4 hours. Cool to about 50 ° C. and add water (15 L), continue to cool to room temperature and add toluene (10 L). The organic layers were separated and the aqueous phase was extracted with toluene (2 × 10 L), the organic phases were combined, washed with NaOH 1 N (2 × 5.8 L) and the combined organic layers were concentrated in vacuo to afford the title compound.
[1099] Example 777
[1100] N- (2- (5-methoxy-1H-indol-3-yl) ethyl) -3-propoxybenzylamine
[1101] 3-propoxybenzaldehyde (14.05 g, 0.0856 mole) and 5-methoxytryptamine (13.64 g, 0.0717 mole) were combined in 390 mL of dry EtOH. Molecular sieves (19.2 g) were added and the suspension heated to reflux. After 4 hours, cooled to room temperature and NaBH ₄ (37.32 g, 0.2146 mole) was added three times. The mixture was stirred at rt for 1 h and filtered, the filtrate was evaporated to a mass of about 100 g and water and dichloromethane were added. After separation, the aqueous phase was washed with dichloromethane and the organic layers combined and dried over MgSO ₄ , filtered and the solvent was evaporated in vacuo to afford the title compound.
[1102] The title compound and isopropanol (250 mL) were combined and a solution of HCl in EtOH (33 mL, 2.5 N) was added slowly. Heated to reflux and stirred for 30 minutes. Cool to room temperature and stir for 2 hours to give a solid. The solids were collected by filtration and the isopropanol was washed and dried to give the hydrochloride of the title compound.
[1103] Example 778
[1104] 2,2,3,3,3-pentafluoropropyl tosylate
[1105] 2,2,3,3,3-pentafluoropropan-1-ol (9.7 mL) and pyridine were combined. Cool to 0-10 [deg.] C. and p-toluenesulfonylchloride (6.2 g) was added portionwise and stirred with warming to room temperature. After 3 hours at room temperature, the reaction mixture was poured into ice water and stirred for 30 minutes to give a solid. The solid was filtered off, washed with water and dried to afford the title compound.
[1106] Example 779
[1107] 3,3,3-trifluoro-propyl tosylate
[1108] 3,3,3-trifluoropropan-1-ol (61.8 mL) and pyridine (224 mL) were added. Cool to 0-10 [deg.] C. and p-toluenesulfonylchloride (147 g) was added in portions. Warm to room temperature and stir overnight. 0.5 N HCl (1.6 L) was added and extracted with ethyl acetate and the organic layers combined, dried over MgSO ₄ , filtered and evaporated to afford the title compound.
[1109] Example 780
[1110] 6-fluorotrytamine
[1111] 422 mL of glacial acetic acid was added dropwise to 40% aqueous dimethylamine solution (408 mL) over 40 minutes while maintaining the temperature below about 15 ° C. Cool to 0 ° C. After stirring at 0 ° C. for 20 minutes, 37% aqueous formaldehyde solution (289 mL, 1.3 equiv) was slowly added over about 15 minutes. 6-fluoroindole (400 g, 2.96 mol, 1 equiv) was added four times for about 15 minutes. After 30 minutes, the reaction mixture was divided into two portions. In one portion, 1149 g (75% of total mass) was added slowly to 3 L of 10% NaOH for 30 minutes and stirred at room temperature. After 18 hours, the resulting solids were collected, washed three times with 200 ml of water and dried by suction to give 3- (N, N-dimethylaminomethyl) -6-fluoroindole in the wet state.
[1112] Another portion of the reaction mixture (383 g, 25% of total mass) was diluted with aqueous NaOH solution until pH was 12-13 to give a solid. After 30 minutes, the solid was collected by filtration, washed with water and dried at 50 ° C. overnight to yield 3- (N, N-dimethylaminomethyl) -6-fluoroindole.
[1113] KCN (50.8 g, 0.78 mol), 3- (N, N-dimethylaminomethyl) -6-fluoroindole (100 g, 0.52 mol), DMF (400 mL) and water (200 mL) were combined. Heated to reflux. At about 70 ° C. gas was released. Reflux was maintained for 4 hours. The reaction mixture was cooled to room temperature, diluted with water and toluene and stirred for 10 minutes. The organic layers were decanted and washed successively with saturated aqueous sodium bicarbonate solution and 2 M aqueous hydrochloric acid solution. The organic layers were concentrated to dryness to afford 2- (6-fluoro-1H-indol-3-yl) acetonitrile.
[1114] 2- (6-Fluoro-1H-indol-3-yl) acetonitrile (165 g, 0.925 mol) and THF (1.32 L) were combined. BH ₃ 1 M solution in THF (2.042 L, 1832 Kg, 0.131 mol) was added slowly over about 40 minutes. When the addition was complete, it was heated to reflux within 1 hour. After refluxing for 1 hour, the reaction mixture was cooled to room temperature for about 25 minutes and added to a well stirred 15% aqueous NaOH solution (1.9 L, 9.5 mol). After addition, it was gradually heated to 50 ° C. gradually. After 1 hour, it was heated to 60 ° C. After 30 minutes, it was heated to reflux for 1 hour. Cool to room temperature, stir overnight, decanted the alkaline aqueous layer and replace with water. THF was distilled off by heating to 30 ° C. under a pressure of 200 mbar until about 2.5 kg of distillate was removed. The mixture was extracted with dichloromethane. To the combined organic layers a mixture of 37% aqueous HCl solution (143 g) and water (220 g) was added slowly over 25 minutes and stirred to give a solid. After 1 h, the solids were collected by filtration, washed with dichloromethane and dried overnight to give the hydrochloride of the title compound.
[1115] 6-fluorotryptamine hydrochloride (100 g, 0.437 mol), 2% w / w NaOH (2.5 kg) and dichloromethane (1.5 L) were combined and stirred. After 15 minutes, the organic layers were decanted off, the aqueous layer extracted with dichloromethane, and the organic layers combined and concentrated to give a residue. The residue and isopropanol were combined and evaporated in vacuo to afford the title compound.
[1116] Example 782
[1117] N- (2- (6-fluoro-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropyl) benzylamine
[1118]
[1119] Isopropanol (500 g), 2,2,3,3-tetrafluoropropylbenzaldehyde (116.8 g) and 6-fluorotryptamine (1.15 equiv) were combined. Heated to reflux over about 1.5 hours. After reflux for 30 minutes, it was distilled over 30 minutes and about 380 g of distillate was collected. The reaction mixture was cooled to 50 ° C. and NaBH ₄ (19.71 g) was added all at once. After 1 hour at 50 ° C., water was added slowly over 15 minutes and the resulting solution was cooled to room temperature overnight. Isopropanol was distilled off under reduced pressure to obtain a residue, which was extracted with dichloromethane, and the organic layers were combined and treated with 1N HCl aqueous solution (650 mL) to give a solid. The dark suspension was stirred at 20-25 ° C. for 2 hours. The solid was collected by filtration, washed with dichloromethane and dried overnight under vacuum at 50 ° C. to afford the title compound.
[1120] Example 783A
[1121] 3- (2,2,2-trifluoroethoxy) benzaldehyde
[1122] 3-hydroxybenzaldehyde (134.3 g), potassium carbonate (304.0 g), 2,2,2-trifluoroethyl p-toluenesulfonate (293.6 g) and dimethylformamide (2 L) were combined. The mixture was heated at 90 ° C. After 15 hours, cooled to room temperature, poured into ice water and extracted with dichloromethane. The organic layers were combined and washed with 1 N sodium hydroxide and then with water. The organic phase was dried over magnesium sulphate, filtered and concentrated to the residue. The residue was dissolved in toluene (200 mL) and chromatographed on silica gel eluted sequentially with toluene and then ethyl acetate to give a residue. The residue was distilled under reduced pressure using a Claisen flask equipped with a Vigreux column to give the title compound: bp 0.8 mmHg, 84-85 ° C. A portion of the fractions were re-distilled using a Krysen flask equipped with a non-lux column followed by an adiabatic column filled with a Rasching ring to give the title compound: bp 0.9-1.0 mmHg, 74-76 ° C.
[1123] Example 783B
[1124] 3- (2,2,3,3-tetrafluoropropoxy) benzaldehyde
[1125] 3- (2,2,3,3-tetrafluoropropoxy) tosylate (200 μg, 0.664 μmol), 3-hydroxybenzaldehyde (101.7 μg, 0.833 μmol), dimethylformamide (1.5 μL) and powdered carbonic acid Potassium (192 μg) was combined. While stirring, it was heated at 92 ° C. for about 22 hours. The reaction mixture was cooled to 40 ° C., poured into ice water and extracted with ethyl acetate. The organic phases were combined and washed with 1 N sodium hydroxide (1 L and 0.5 L), then saturated sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered and evaporated to dryness to give an oily residue. The oily residue was distilled off under reduced pressure in the Klyssen flask to give the first fraction of the title compound: 108-110 ° C. at bp 0.4-0.5 mmHg and 110-111 ° C. at 0.4-0.5 mmHg.
[1126] Example 784
[1127] 3- (2,2,3,3-tetrafluoropropoxy) benzaldehyde
[1128] 3- (2,2,3,3-tetrafluoropropoxy) tosylate (5.72 g, 17.2 mmol), 3-hydroxybenzaldehyde (2.44 2g, 20.0 mmol), dimethylformamide (36 mL) and powdered carbonic acid Potassium (3.03 μg) was combined and heated at 110 ° C. for 10 hours. Cool to 20 ° C. An aluminum-oxide-90 bed (57.2 g, 70-230 mesh, Grade II-III, Brockmann: Merck # 1.01097) was passed through and eluted with toluene (120 mL). The eluted organic phase was washed with 1 N HCl (36 mL) and then water. The organic layers were evaporated under reduced pressure to afford the title compound.
[1129] Example 785
[1130] 2- (5-Chloro-1H-indol-3-yl) -2-oxo-acetyl chloride
[1131] 5-chloroindole (20 g, 0.13 mole) and dibutyl ether (230 mL) were combined and cooled to 5 ° C. and oxalyl chloride (20.08 g, 0.16 mole) was maintained for 15 minutes while maintaining a temperature of 5 ° C. to 10 ° C. Added slowly. Warm to room temperature and stir for 1 hour to give a solid. Cool to 5 ° C., stir for 15 minutes, collect the solid through filtration, wash with dibutyl ether and dry under vacuum to afford the title compound.
[1132] Example 786
[1133] (2- (5-chloro-1H-indol-3-yl) -2-oxoacetamide
[1134] 2- (5-chloro-lH-indol-3-yl) -oxo-acetyl chloride (28.9 g, 0.12 mole) and NH ₄ OH 1 N solution (720 mL) were combined to give a suspension. After 18 h, filtered, washed with water and dried in vacuo to afford the title compound.
[1135] Example 787
[1136] 5-chlorotryptamine
[1137] LiAlH ₄ (40.97 g) suspension in THF (700 mL) was cooled to 5 ° C. AlCl ₃ (53.9 g, 0.40 mole) solution was added to THF (645 mL) for about 30 minutes while maintaining at a temperature of about 5 ° C to 10 ° C. While maintaining at a temperature between 5 ° C. and 7.5 ° C., (2- (5-chloro-1H-indol-3-yl) -2-oxo-acetamide (20 g, 0.09 mole) in THF (900 mL) was added. When the addition was complete, it was allowed to warm to room temperature After stirring overnight, it was cooled to 7 ° C. and NaOH 50% (342 g, 4.28 mol) solution was added slowly, after stirring for about 1 hour, anhydrous Na ₂ SO ₄ (30 g) was added and the suspension was filtered on a celite bed The filtrate was evaporated to dryness to give an oil, combined with Et ₂ O (500 mL) and Et ₂ O / HCl 4.5 N (15 mL) at room temperature. Solution was added to give a solid, The suspension was stirred at room temperature for 1 hour, filtered, washed with 50 ml of Et ₂ O and dried at 50 ° C. under vacuum to give the hydrochloride of the title compound.
[1138] 5-Chlorotryptamine hydrochloride (15 g, 0.06 mole), water (150 mL), NaOH IN (75 mL) and dichloromethane (350 mL) were added. The mixture was stirred at rt for 30 min and the phases separated. The aqueous phase was washed with dichloromethane and the organic phases combined, dried over MgSO ₄ , filtered and evaporated to dryness in vacuo to afford the title compound.
[1139] Example 789
[1140] N- (5-chloro-lH-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoro-propoxy) benzylamine
[1141]
[1142] 5-Chlorotryptamine (12.1 g, 0.0621 mol) and 3- (2,2,3,3-tetrafluoropropoxy) benzaldehyde (17.6 g, 0.0621 mole) in EtOH (340 mL) were combined. Molecular sieves were added and heated to reflux and stirred for 4 hours. The mixture was cooled to rt and NaBH ₄ (7 g, 0.1876 mol) was added three times. Stir at room temperature for 1 hour. The solid was filtered off and the filtrate was evaporated to a weight of about 90 g, water was added and extracted with dichloromethane. The combined organic layers were dried over MgSO _4, filtered and the solvent removed under reduced pressure to afford the title compound.
[1143] The title compound (27.6 g) and isopropanol (300 mL) were combined. A solution of oxalic acid (6 g) in isopropanol (60 mL) was added to give a suspension. The suspension was heated to reflux and stirred for 30 minutes, then cooled to room temperature. Stir at room temperature for 1 hour. The solid was collected via filtration, washed with isopropanol and dried under vacuum to afford the oxalate of the title compound.
[1144] Example 790
[1145] N-2- (5-chloro-lH-indol-3-yl) ethyl) -3- (2,2,3,3, -tetrafluoro-propoxy) benzylamine L-tartaric acid salt
[1146] N-2- (5-chloro-lH-indol-3-yl) ethyl)-(3- (2,2,3,3-tetrafluoropropoxy) benzylamine oxalic acid salt and dichloromethane (700 mL) Combine and add NaOH IN (150 mL), water (450 mL) and MeOH (190 mL) The mixture was stirred for 1 h at rt The layers were separated Water (200 mL) was added to the aqueous phase Extracted with dichloromethane, the organic layers combined, dried over MgSO ₄ , filtered and evaporated in vacuo to N-2- (5-chloro-lH-indol-3-yl) ethyl) -3- (2,2,3 19.4 g of, 3-tetrafluoropropoxy) benzylamine were obtained.
[1147] N-2- (5-chloro-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine (19.4 g) in isopropanol (125 mL) Combine and warm to dissolve. A solution of L-tartaric acid (7.02 g) in isopropanol (70 mL) was added. Coagulation crystals were added and stirred to give a solid. After 2.5 h, the solids were collected by filtration, washed with isopropanol and dried under vacuum at 45 ° C. to afford the title compound.
[1148] The following compounds were prepared according to the method of Example 221 and isolated as maleate except as noted:
[1149]
[1150] Example 799
[1151] 6-methanesulfonyl-1H-indole
[1152] 6-Methanesulfonyl-indol-1-ol (5.0 g, 23.7 mmol) was dissolved in triethyl phosphite (35 mL) and heated at 160 ° C. for 5 hours. The solution was cooled to room temperature and diluted with diethyl ether. The ether solution was washed with brine and water, then dried (sodium sulfate) and reduced to the residue. Crystallization of the residue from warm ethyl acetate gave the title compound as a colorless cube: mp 149-152 ° C. MS (ACPI): m / e 196.0 (M + l). Anal for C ₉ H ₉ NO ₂ S: calc .: C, 55.37; H, 4.65; N, 7.17; Found: C, 55.14; H, 4.71; N, 7.20.
[1153] Example 800
[1154] 6-benzenesulfonyl-1H-indole
[1155] 6-bromoindole (6.0 g, 30.6 mmol) was dissolved in THF (100 mL), the mixture was cooled to −10 ° C. and 60% NaH in mineral oil (3.67 g) was added slowly. After 1 hour, triisopropylsilyltrifluoromethane sulfonate (9.9 mL, 36.7 mmol) was added slowly and the cooling bath was removed and stirred for 24 hours. Excess NaH was quenched with ice and THF was removed in vacuo. The remaining residue was diluted with water and extracted with dichloromethane. Combined, washed (brine), dried (sodium sulfate) and reduced the extract to residue. The residue was purified on silica gel using 60% hexanes / dichloromethane to give a yellow oil.
[1156] A solution of 6-bromo-1-triisopropylsilanyl-1H-indole (5.5 g, 15.7 mmol) in 100 mL of dry THF was cooled to -78 ° C under nitrogen and maintained at -78 ° C while maintaining 1.7 Mt. Treated with -butyl lithium (20.5 mL, 34.5 mmol). After addition, phenylsulfonyl fluoride (2.1 mL, 17.3 mmol) was added slowly and stirred at -78 ° C for 30 minutes. The mixture was warmed to room temperature and stirred for 1 hour. Excess t-butyl lithium was quenched with ice and the mixture was diluted with water and then extracted with ethyl acetate. Combined, washed (brine), dried (sodium sulfate) and reduced the extract to residue. The residue was purified on silica gel using 50% hexanes / dichloromethane to give the product as a white solid.
[1157] The resulting white solid was dissolved in THF (50 mL) and the solution was treated with 1 M tetrabutylammonium fluoride (18.1 mL) and 1 M boric acid (18.1 mL). After stirring at room temperature for 1.5 hours, the mixture was diluted with water and extracted with ethyl acetate. Combined, washed (brine), dried (sodium sulfate) and reduced the extract to residue. The residue was purified on silica gel using 1% methanol / dichloromethane to afford the title compound as a white solid: mp 141-144 ° C. MS (ACPI): m / e 258.0 (M + l). Anal for C ₁₄ H ₁₁ NO ₂ S: Calcd: C, 65.35; H, 4.31; N, 5.44; Found: C, 64.99; H, 4.31; N, 5.39.
[1158] The following compounds were prepared according to the method of Example 440 and isolated as hydrochloride except as noted:
[1159]
[1160] The following compounds were prepared according to the method of Example 270 and isolated as maleate except as noted:
[1161]
[1162] Example 811
[1163] N- (2- (5-methoxy-1H-indol-3-yl) -ethyl)-(3- (3,3,3-trifluoropropoxy) benzyl) amine
[1164]
[1165] 350 mg (1.8 mmol) of 5-methoxytrytamine, 401 mg of 3-trifluoropropoxybenzaldehyde (1.8 mmol) and 4 g of 4A molecular sieve were combined and refluxed overnight in 35 mL of EtOH. The liquid was decanted into a separate flask and treated with 209 mg (5.5 mmol) of NaBH ₄ . The reaction was stirred at room temperature for 1 hour. Concentrated in vacuo and partitioned between 50 ml of 1 N NaOH and 25 ml of dichloromethane. The aqueous layer was extracted with 25 mL of dichloromethane and the organic layers were combined and concentrated to dryness. The resulting oil was purified by radial chromatography (SiO ₂ ; 1% MeOH in CHCl ₃ mixed with concentrated NH ₄ OH) to afford 705 mg (1.8 mmol; 100%) of the desired compound as an oil. The solution of the compound in 50 mL of THF / EtOH (50/50) was stirred overnight with 1 g of polyvinyl pyridine hydrochloride to convert to its HCl salt, filtered and concentrated to a solid. The product was recrystallized from EtOAc: C ₂₁ H ₂₃ F ₃ N ₂ O ₂ ^. Analysis for HCl: Calcd: C, 58.81; H, 5. 64; N, 6.53; Found: C, 58.42; H, 5. 44; N, 6.51; ISMS 393 (M + 1).
[1166] The following compounds were prepared according to the method of Example 811 and isolated as hydrochloride except as noted:
[1167]
[1168] Example 825
[1169] N-2- (5-nitro-1H-indol-3-yl) -ethyl) -3-phenoxybenzylamine
[1170]
[1171] 5-nitrotryptamine (500 mg, 2.4 mmol), 3-phenoxybenzaldehyde (480 mg, 2.4 mmol) and 4 g of 4A molecular sieve in 30 mL EtOH were combined and refluxed overnight. The liquid was decanted into a separating flask and treated with NaBH ₄ (280 mg, 7.2 mmol) at room temperature. After 1 hour it was concentrated in vacuo and the residue was partitioned between 25 mL 1 N NaOH and 25 mL dichloromethane. The aqueous layer was extracted with 25 ml of dichloromethane and the combined organic layers were dried over MgSO ₄ and concentrated to dryness. The resulting oil was purified by radial chromatography (SiO ₂ ; 2% MeOH in CHCl ₃ ) to afford the desired compound as an oil. The compound solution in 10 ml of EtOH was converted to HCl salt by treatment with 0.25 ml of 5 N HCl and 40 ml of toluene and then concentrated to a solid. C ₂₃ H ₂₁ N ₃ O ₃ ^. HCl ^. Analysis for 0.2 EtOH: Calcd: C, 64.62; H, 5. 17; N, 9.75; Found: C, 64.89; H, 5.40; N, 9.75; ISMS 388 (M + 1).
[1172] The following compounds were prepared according to the method of Example 825 and isolated as hydrochloride except as noted:
[1173]
[1174]
[1175]
[1176]
[1177] Example 863
[1178] 6-phenoxycitfatamine
[1179] Using a method similar to Example 422, the title compound was prepared: ISMS 253 (M + 1); _{^{l H NMR (CDCl 3) 8.1}} (bs, 1H), 7.56-7.54 (m, 1H), 7.32-7.28 (m, 3H), 7.07-6.98 (m, 4H), 6.89-6.86 (m, 1H), 3.06-3.02 (m, 2H), 2.92-2.88 (m, 2H), 1.68 (bs, 2H).
[1180] Example 864
[1181] 2- (5- (pyridin-3-yloxy) -1H-indol-3-yl) -ethylamine
[1182] Using a method similar to Example 422, the title compound was prepared: ISMS 254 (M + 1); C ₁₅ H ₁₅ N ₃ O. 1.1 C ₂ H ₂ O _4. Assay for 0.2H ₂ O: Calcd: C, 58.04; H, 4.98; N, 11.81; Found: C, 58.17; H, 4. 62; N, 11.45.
[1183] Example 865
[1184] 6-phenoxy-1H-indole-3-carbaldehyde
[1185] Using a method similar to Example 414, the title compound was prepared: ISMS 238 (M + 1); ^l N NMR (CDCl ₃ ) 10.78 (bs, 1H), 9.95 (s, 1H), 8.20-8.18 (m, 1H), 7.76-7.75 (m, 1H), 7.30-7.26 (m, 2H), 7.06- 7.02 (m, 2 H), 7.00-6.95 (m, 3 H).
[1186] Example 866
[1187] 5- (pyridin-3-yloxy) -1H-indole-3-carbaldehyde
[1188] Using a method similar to Example 414, the title compound was prepared: ISMS 239 (M + 1); Anal for C ₁₄ H ₁₀ N ₂ O ₂ 0.3H ₂ O: Calculated: C, 69.01; H, 4. 39; N, 11.50; Found: C, 68.91; H, 4. 16; N, 11.39.
[1189] Example 867
[1190] 3- (3-methyl-4-nitrophenoxy) pyridine
[1191] A 35% oil dispersion of KH (12 g, 11 mmol) was washed twice with 100 mL of hexane and dried under vacuum and then cooled in an ice bath. 100 ml of dry DMF was added dropwise, followed by dropwise addition of a solution of 3-hydroxypyridine (10 g, 105 mmol) in 100 ml of DMF. The solution was treated with 5-fluoro-2-nitrotoluene (16.3 g, 105 mmol) in 50 mL DMF to give a dark solution. The mixture was stirred at room temperature for 1 hour and the mixture was poured into 1 L of brine and extracted twice with 200 mL of EtOAc. The extracts were combined and washed twice with 500 ml brine, dried over MgSO ₄ and concentrated to 24 g of dark oil. Purification by chromatography with 20% EtOAc in hexanes gave the title compound as an oil: ISMS 231 (M + 1); C ₁₂ H ₁₀ N ₂ O ₃ : Calcd: C, 62.61; H, 4.38; N, 12.17; Found: C, 62.63; H, 4.58; N, 12.06.
[1192] Example 869
[1193] 3-ethoxybenzaldehyde
[1194] 5.6 g of 3-hydroxybenzaldehyde (46 mmol) and 10.7 g of 1-iodoethane (69 mmol) in DMSO (25 mL) were combined, warmed to 80 ° C., treated slightly with 22.4 g of cesium carbonate (69 mmol) and stirred It was. After 1 hour, it was poured into 200 ml of brine and extracted twice with 150 ml of diethyl ether. The extracts were combined and washed twice with 200 ml brine, dried over MgSO ₄ and concentrated in vacuo to afford an oil. Purification by chromatography (SiO ₂ ; 2.5% EtOAc in hexanes) gave 5.73 g (38 mmol; 83%) of the desired compound as an oil: ^l H NMR (CDCl ₃ ) 9.94 (s, 1H), 7.42-7.41 ( m, 2H), 7.36-7.35 (m, 1H), 7.16-7.13 (m, 1H), 4.10-4.04 (q, 2H), 1.64-1.40 (t, 3H).
[1195] Example 870
[1196] 3-propoxybenzaldehyde
[1197] Using a method similar to Example 869, the title compound was prepared: ^l H NMR (CDCl ₃ ) 9.95 (s, 1 H), 7.43-7.41 (m, 2 H), 7.37-7.36 (m, 1 H), 7.17- 7.14 (m, 1 H), 9.98-3.95 (t, 2H), 1.84-1.79 (m, 2H), 1.05-1.02 (t, 3H).
[1198] Example 872
[1199] 4-phenoxy-1-methyl-2-nitrobenzene
[1200] Phenyl boronic acid (7.32 g, 60 mmol), 4-methyl-3-nitrophenol (4.5 g, 30 mmol) and Cu (oAC) ₂ -H ₂ O (6 g, 30 mmol) in 30 mL CH ₂ Cl ₂ . Were combined and treated with 6 g of 4A molecular sieve powder. Et ₃ N (15.18 g, 150 mmol) was added dropwise and the reaction stirred at room temperature for 8 days. Diluted with 100 mL of CH ₂ Cl ₂ , filtered through celite, and concentrated to dryness. Purification by chromatography using 2% EtOAc in hexanes gave the desired product as a yellow oil.
[1201] Example 873
[1202] 6-phenoxy-1H-indole
[1203] 4-phenoxy-1-methyl-2-nitro-benzene (6 g, 26.2 mmol) and DMF dimethylacetal (15.6 g, 131 mmol) in 60 mL dry DMF were combined and heated at 170 ° C. for 16 h. Cool to room temperature and concentrate to dryness. The residue was dissolved in 50 mL of EtOAc and hydrogenated with 2% 5% Pd / C and hydrogen for 3 h at ambient pressure. Filter through celite and concentrate to oil. Purification by chromatography using Hex / EtoAC gave a tan solid: ISMS 210 (M + 1)
[1204] _{^{l H NMR (CDCl 3) 8.08}} (bs, 1H), 7.61-7.59 (m, 1H), 7.34-7.29 (m, 2H), 7.18-7.17 (m, 1H), 7.18-7.0 (m, 4H), 6.92-6.89 (m, 1 H), 6.56-6.54 (m, 1 H).
[1205] Example 874
[1206] 5-pyridin-3-yl-1-methyl-2-nitro-benzene
[1207] In a similar manner to Example 872, the title compound was prepared.
[1208] Example 875
[1209] 5- (pyridin-3-yloxy) -1H-indole
[1210] In a similar manner to Example 873, the title compound was prepared: ISMS 211 (M + 1); Anal for C ₁₃ H ₁₀ N ₂ O.0.1H ₂ O: Calcd: C, 73.64; H, 4. 85; N, 13.21; Found: C, 73.76; H, 4.80; N, 13.09.
[1211] Example 877
[1212] N-2- (5-phenoxy-1H-indol-3-yl) -ethyl) -3-phenoxybenzylamine
[1213]
[1214] Combine 2- (5-phenoxy-1H-indol-3-yl) ethylamine (0.400 g, 1,59 mmol), 3-phenoxybenzaldehyde (0.377 g, 1.90 mmol) and molecular sieve 4A (0.40 g) And stirred in methanol (15 mL). After 4 hours, the molecular sieves were filtered and washed several times with MeOH. NaBH ₄ (61.5 mg, 1.59 mmol) was added portionwise to the MeOH solution, and the resulting mixture was stirred at room temperature for 1 hour. MeOH was removed in vacuo and the residue was diluted with CH ₂ Cl ₂ / water and extracted with CH ₂ Cl ₂ , the organic layers combined and dried over Na ₂ SO ₄ . The solvent was concentrated in vacuo and purified on silica gel (CH ₂ Cl ₂ / MeOH) to give the free base of the title compound. The free base was reacted with oxalic acid to form a salt: mp 196-198 ° C .; ¹ H NMR (300 MHz, DMSO-d 6) 2.95-3.15 (m, 4H), 4.15 (s, 2H), 6.85-7.46 (m, 18H), 11.06 (br, 1H); MS (electrospray) m / e: 435.3 (M + l); HRMS (ES &lt; + &gt;) Calcd for C ₂₉ H ₂₇ N ₂ 0 ₂ (M + H) 435.2084. Found 435.2073.
[1215] Example 878
[1216] (3-phenoxybenzyl)-(2- (5-phenoxy-1H-indol-3-yl) -ethyl) -carbamic acid tert butyl ester
[1217] (3-phenoxy-benzyl)-(2- (5-phenoxy-1H-indol-3-yl) -ethyl) -amine (0.96 g, 2.2 mmol) and NaOH (87.7 mg, 2.2 mmol) were combined, It was dissolved in THF (10 mL) and stirred at room temperature for 15 minutes. Di-tert-butyl dicarbonate (0.58 g, 2.64 mmol) in THF (10 mL) was added and stirred. After 2 h the reaction was diluted with water and extracted with EtOAc (3 × 15 mL) and Na₂SO₄Dried over. The organic solvent was concentrated in vacuo to afford the title compound as an oil: ^OneH NMR (300 MHz, CDCl₃) 1.36 (s, 9H), 2.85-2.91 (m, 2H), 3.89-3.65 (m, 2H), 4.26 (s, 1H), 4.39 (s, 1H) 6.83-7.13 (m, 10H), 7.21- 7.33 (m, 7 H), 8.00 (s, 1 H); MS (electrospray) m / e 534.9 (M + 1).
[1218] Example 879
[1219] N-methyl-N-2- (5-phenoxy-1H-indol-3-yl) -ethyl) -3-phenoxybenzylamine
[1220]
[1221] LiAlH ₄ -THF (5.5 mL, 5.5 mmol) 1.0 M solution was diluted with (3-phenoxy-benzyl)-(2- (5-phenoxy-1H-indol-3-yl) -ethyl)-in 10 mL of dry THF. To the solution of carbamic acid-tert-butyl ester (0.60 g, 1.12 mmol) was added slowly. After addition, the reaction mixture was heated to reflux. After 2 hours, the reaction was quenched by cooling to room temperature and adding 1.5 ml of water, then carefully adding 2N NaOH (1.0 ml). The suspension was filtered and washed repeatedly with ether and the organic solution was dried over Na ₂ S0 ₄ and concentrated in vacuo. Purification on silica gel using CH ₂ Cl ₂ / MeOH as eluent gave the free base of the title compound, which was further reacted with oxalic acid to form a salt: mp 174-175 ° C .; ¹ HNMR (250 MHz, DMSO-d6) 2.51 (s, 3H), 3.00-3.13 (m, 4H), 4.15 (s, 2H), 6.81-7.03 (m, 7H), 7.11-7.42 (m, 11H) , 11.05 (br, 1 H); MS (electrospray) m / e: 449.1 (M + 1-C ₂ H ₂ O ₄ ).
[1222] Example 880
[1223] N- (2- (6-chloro-1H-indol-3-yl) ethyl)-(3- (2,2-difluoroethoxy) benzyl) amine
[1224]
[1225] 2- (6-chloro-lH-indol-3-yl) ethylamine hydrochloride (1.0 g, 4.3 mmol) and ethyldiisopropylamine (900 mL, 5.2 mmol) in ethanol (150 mL) were combined and stirred at room temperature And treated with 3- (2,2-difluoroethoxy) benzaldehyde (856 mg, 4.6 mmol) and anhydrous sodium sulfate (12 g) and heated at 78 ° C. overnight. Cool to room temperature and filter. The resulting filtrate was treated with sodium borohydride (488 mg, 12.9 mmol) and the milky-white mixture was stirred at rt overnight. Purification of the bath on silica gel eluting the solvent under vacuum and eluting with 10% methanol in dichloromethane gave the free base of the title compound as a light yellow oil. A portion of the oil was dissolved in (651 mg, 1.78 mmol) methanol (15 mL) and treated with a homogeneous solution of ammonium chloride (95 mg, 1.78 mmol) in methanol (3 mL). The resulting solution was sonicated for 10 minutes and then the solvent was removed in vacuo to yield an off-white solid. It was triturated with diethyl ether containing several drops of acetonitrile. The precipitate was filtered and dried to give the title hydrochloride as a white solid: mp 131.6-133 ° C .; ¹ H NMR (400 MHz, dmso-d ₆ ): 11.15 (br s, 1H), 9.50 (br s, 2H), 7.57 (d, 1H, J = 8.8 Hz), 7.39 (d, 1H, J = 2.0 Hz), 7.36 (t, 1H, J = 8.2 Hz), 7.32 (br s, 1H), 7.26 (d, 1H, J = 2.0 Hz), 7.17 (d, 1H, J = 7.6 Hz), 7.04 (dd , 1H, J = 7.8, 2.2 Hz), 7.01 (dd, 1H, J = 8.4, 2.0 Hz), 6.41 (tt, 1H, J = 54.4, 3.4 Hz), 4.32 (td, 2H, J = 14.8, 3.6 Hz), 4.14 (br s, 2 H), 3.11 (br s, 4 H); MS (ES +): m / e 365.3 (M + l); _{CHN (C 19 H 19 F 2} ClN 2 O · HCl · 0.3H 2 0) calcd: C 56.11; H 5.11; N 6.89; Found: C 56.03; H 4.95; N 7.18.
[1226] Example 881
[1227] N-methyl-N- (2- (6-chloro-1H-indol-3-yl) ethyl) -3- (2,2-difluoroethoxy) benzylamine
[1228]
[1229] (2- (6-chloro-1H-indol-3-yl) ethyl)-(3- (2,2-difluoroethoxy) benzyl) amine (276 mg, 0.76 mmol) in dichloroethane (15 mL) And formaldehyde (55.5 μl 38% aqueous solution, 0.76 mmol) were combined and stirred at room temperature for 10 minutes. Sodium triacetoxy borohydride (321 mg, 1.51 mmol) was added twice over 10 minutes and stirred at room temperature overnight, then diluted with methanol (10 mL) and quenched with 1 drop of glacial acetic acid. The solvent was removed under vacuum and the crude residue was redissolved in methanol and loaded directly onto a 10 g SCX column. After washing thoroughly with methanol, the column was eluted with 2N ammonia in methanol. The eluate was concentrated in vacuo to give the free base of the title compound as a straw oil. The free base (239 mg, 0.64 mmol) was dissolved in methanol (20 mL) and treated with a solution of ammonium chloride (36 mg, 0.67 mmol) in methanol (5 mL). After the mixture was sonicated for 10 minutes, the solvent was removed in vacuo to give the hydrochloride as a sticky yellow oil. The oil was dissolved in 10 ml of acetonitrile-water (1: 1) and lyophilized overnight to give a downy white solid which was triturated with diethyl ether (10 ml) and acetonitrile (2 drops). The resulting precipitate was filtered and dried to afford the desired hydrochloride as a white amorphous solid: mp: 63.8-65.8 ° C .; ¹ H NMR (400 MHz, dmso-d ₆ ): 11.10 (br s, 1H), 7.52 (d, 1H, J = 8.4 Hz) 7.36 (d, 1H, J = 2.0 Hz), 7.40-7.26 (m, 2H), 7.22 (d, 1H, J = 2.4 Hz), 7.20-7.11 (m, 1H), 7.04 (br d, 1H, J = 7.6 Hz), 6.96 (dd, 1H, J = 8.6, 1.4 Hz) , 6.38 (tt, 1H, J = 54.4, 3.6, Hz), 4.50-4.02 (br m, 2H), 4.30 (td, 2H, J = 14.4, 3.2 Hz), 3.15 (br s, 4H), 2.68 ( br s, 3 H); MS (ES &lt; + &gt;): m / e 378.9 (M + l); CHN (C ₂₀ H ₂₁ ClF ₂ N ₂ O.HCl.0.7H ₂ 0) Calcd: C 56.14, H 5.51, N 6.55; Found: C 55.72, H 5.32, N 7.07.
[1230] The following compounds were prepared according to the method of Example 319 and isolated as oxalate except as noted:
[1231]
[1232]
[1233] Example 892
[1234] 2- (7-trifluoromethyl-1H-indol-3-yl) -ethylamine
[1235] In a 500 ml round bottom flask equipped with a magnetic stirrer, (2-trifluoromethyl-phenyl) -hydrazine (5.0 g, 28.4 mmol) and 4-aminobutyraldehyde dimethyl acetal (4.54 g, 34.1 mmol) were combined and stirred It was. After 5 minutes, 1 N HCl (200 mL) was added slowly and the reaction was heated to 85 ° C. for 2 hours to form an orange-red solution. The temperature was increased to 100 ° C. for 10 minutes and cooled to room temperature. The reaction mixture was poured into ice and stirred for 10 minutes, then adjusted to pH ˜10 with ammonium hydroxide. The mixture was extracted with methylene chloride and the organic phases were combined, dried over sodium sulfate and concentrated in vacuo to give a dark orange-brown oil. Purified on a prepackaged and HMDS treated silica column using a gradient of 9% methanol to 17% methanol in methylene chloride to give the pure title compound as an orange oil: ¹ H NMR (400 MHz, dmso-d ₆ ): 11.18 (br s, 1H), 7.82 (d, 1H, J = 7.6 Hz), 7.40 (d, 1H, J = 7.2 Hz), 7.24 (d, 1H, J = 2.0 Hz), 7.13 (t, 1H, J = 7.6 Hz) 2.76-2.83 (m, 4H). MS (APCI): m / e 229.0 (M + l), 212.0 (M-NH ₂ ).
[1236] Example 893
[1237] (7-nitro-1H-indol-3-yl) -acetonitrile
[1238] In a 500 mL round bottom flask equipped with a magnetic stirrer, 7-nitro indole (4.55 g, 28.1 mmol) was dissolved in 130 mL glacial acetic acid and heated to 70 ° C. Di-methyl-methylene ammonium iodide (essenmozer salt) was added and the mixture was stirred at 70 ° C. After 45 minutes, the reaction mixture was cooled and the solvent removed in vacuo to yield a crude yellow solid. The crude material was treated with 200 mL ammonium hydroxide and extracted with ethyl acetate. The organic phases are combined, dried over magnesium sulfate and concentrated in vacuo Amine intermediates were obtained as yellow crystalline solids. The intermediate was immediately dissolved in 200 ml of dimethyl sulfoxide, treated with methyl iodide (4.55 ml, 56.2 mmole) and stirred at rt overnight. Potassium cyanide (18.30 g, 281 mmol) and 18-crown-6 (226 mg) were added and the mixture was stirred at 50 ° C. for 25 minutes. The resulting brown-yellow suspension was poured on ice, stirred for 10 minutes, saturated with sodium chloride and extracted with ethyl acetate. The combined extracts were washed once with water, twice with brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound as a yellow-brown solid. No further purification was necessary.^OneH NMR (400 MHz, dmso-d₆): 11.92 (br s, 1 H) 8.14 (d, 1 H,J= 8.0 Hz), 8.12 (d, 1H,J= 8.0 Hz) 7.53 (d, 1 H,J= 2.0 Hz) 7.31 (t, 1H,J= 8.0 Hz), 4.16 (s, 2H), MS (ES−): m / e 200.0 (M−1).
[1239] Example 894
[1240] 2- (7-nitro-1H-indol-3-yl) ethylamine
[1241] In a 500 mL round bottom flask equipped with a magnetic stirrer and a nitrogen inlet, (7-nitro-1H-indol-3-yl) -acetonitrile (5.27 g, 26 mmol) was dissolved in dry tetrahydrofuran (150 mL). . The solution was treated with 1 M BH ₃ : THF (55 mL, 55 mmol) and stirred at room temperature. After 20 hours, water (9 mL) was added dropwise carefully to quench the reaction and stirred until foaming and gas evolution ceased. The mixture was concentrated to dryness in vacuo, redissolved in 1 N HCl (300 mL) and extracted with ethyl acetate. The aqueous phase was basified with 5 N NaOH and extracted with ethyl acetate. The ethyl acetate extracts were combined, dried over sodium sulfate and concentrated in vacuo to afford the title compound as an orange-brown solid: ¹ H NMR (400 MHz, dmso-d ₆ ): 11.66 (br s, 1H) 8.07 (t, 2H) , J = 7.6 Hz), 7.32 (s, 1H), 7.20 (t, 1H, J = 8.0 Hz) 2.79-2.83 (m, 4H), MS (APCI): m / e 189.0 (M-NH ₂ ).
[1242] Example 895
[1243] N- (2- (6-Fluoro-1H-indol-3-yl) ethyl) -4-fluoro-3-phenoxy-benzylamine
[1244]
[1245] The method of Example 340 gave the hydrochloride of the title compound: mp 173-175 ° C; MS (m / e): 379 (M + 1), 377 (M-1); Calcd for C ₂₃ H ₂₀ F ₂ N ₂ O.HCl: Calcd: C, 66.59; H, 5. 10; N, 6.75. Found: C, 66.39; H, 5.05; N, 6.57.
[1246] Example 896
[1247] N- (2- (6-fluoro-1H-indol-3-yl) ethyl) -3-phenoxybenzylamine
[1248]
[1249] The method of Example 340 gave the hydrochloride of the title compound: mp 196-199 ° C; MS (m / e): 361 (M + 1), 359 (M-1); Calcd for C ₂₃ H ₂₁ FN ₂ 0HCl: Calcd: C, 69.60; H, 5.59; N, 7.06. Found: C, 69.23; H, 5.58; N, 7.00.
[1250] Example 897
[1251] 4-fluoro-1-methyl-3-phenoxybenzene
[1252] Triethylamine (28.6 mL, 205 mmol) was added 2-fluoro-5-methylphenol (5.18 g, 41.1 mmol), copper (II) acetate (7.46 g, 41.1 mmol), phenylboronic acid (10.0 g, 82.1 mmol ), To a mixture of a powdered 4mm sieve (7 g) and methylene chloride (400 ml). Stir at room temperature. After 22 hours, the filtrate was concentrated. The residue was purified by silica gel chromatography (50% methylene chloride / hexane) and concentrated and purified again by silica gel chromatography (100% hexane) to give 2.4 g (29%) of the title compound: MS (m / e): 202 (M ⁺ ).
[1253] Example 898
[1254] 4-fluoro-3-phenoxybenzaldehyde
[1255] 4-fluoro-1-methyl-3-phenoxybenzene (2.43 g, 12.0 mmol), N-bromosuccinimide (4.92 g, 27.6 mmol), benzoyl peroxide (408 mg, 1.68 mmol) and carbon tetrachloride (55 Ml) were combined. The mixture was heated at reflux for 6.5 h and cooled to 0 ° C. for 64 h. The solid was filtered off and the filtrate was concentrated. The residue was dissolved in chloroform and washed with ice cold sodium carbonate solution. The chloroform solution was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in acetonitrile (50 mL) and 4-methylmorpholine-4-oxide (4.6 g, 39.1 mmol) and a powder IX sieve (200 mg) were added. Stir at room temperature for 20 hours, filter and concentrate. Purification by silica gel chromatography (5%, 30% ethyl acetate / hexanes) gave 220 mg (8%) of the title compound: MS (m / e): 216 (M ⁺ ).
[1256] Example 899
[1257] 7-fluorotryptamine
[1258] Lithium aluminum hydride (12.8 g; 336.1 mmol) and 0 ° C. anhydrous tetrahydrofuran (160 mL) were combined. The resulting exothermic material was cooled to 0 ° C. 7-fluoro-3- (2-nitrovinyl) -1H-indole (11.55 g, 56.0 mmol) in anhydrous THF (200 mL) was added dropwise. After 30 minutes, warmed to room temperature. After 4 h, cooled to 0 ° C. and saturated sodium sulfate solution (35 mL) was added dropwise. The solid was filtered off and washed with THF and ethyl acetate. The filtrate was concentrated and the residue was dissolved in methylene chloride. The precipitate was filtered to give 1.26 g of the product as brown crystals. The filtrate was concentrated and chromatographed on silica gel eluting with 5%, 7%, 10% 2 N ammonia in methanol / methylene chloride to give the product: MS (m / e): 179 (M + 1), 177 (M -One); Calculation for C ₁₀ H ₁₁ FN ₂ : Calcd: C, 67.40; H, 6. 22; N, 15.72. Found: C, 67.06; H, 6. 11; N, 15.48.
[1259] Example 900
[1260] 3- (2-nitrovinyl) -6-methanesulfonyl-1H-indole
[1261] 1-dimethylamino-2-nitroethylene (892.1 mg, 7.68 mmol) and TFA (9.0 mL) were combined and stirred until dissolved. 6-methanesulfonyl-1H-indole (1.5 g, 7.68 mmol) was added and stirred at room temperature. After 24 hours, the reaction mixture was poured into ice / water and extracted with ethyl acetate, then ethyl acetate was washed with brine and saturated sodium bicarbonate. Filtration, washing and drying the precipitate gave the title compound as a yellow powder: mp> 250 ° C. MS (ACPI): m / e 267.0 (M + 1). Anal for C ₁₁ H ₁₀ N ₂ O ₄ S: calc .: C, 49.62; H, 3.79; N, 10.52; Found: C, 49.86; H, 3.97; N, 10.25.
[1262] Example 901
[1263] 3- (2-nitrovinyl) -6-benzenesulfonyl-1H-indole
[1264] 1-dimethylamino-2-nitroethylene (676.9 mg, 5.83 mmol) and TFA (9.0 mL) were combined and stirred until dissolved. 6-benzenesulfonyl-1H-indole (1.5 g, 5.83 mmol) was added and stirred at room temperature. After 24 hours, the reaction mixture was poured into ice / water and adjusted to pH 8. After stirring, the precipitate was filtered off, washed with water and dried to give the title compound as a yellow powder: mp 110 ° C., dec. MS (ACPI): m / e 329.0 (M + l). Anal for C ₁₆ H ₁₂ N ₂ O ₄ S: calc .: C, 58.53; H, 3.68; N, 8.53; Found: C, 58.54; H, 3.83; N, 7.85.
[1265] Example 902
[1266] (3-phenoxybenzyl)-(2-pyridin-2-yl-ethyl) amine oxalic acid salt
[1267] 2-pyridin-2-yl-ethylamine (Aldrich, 0.36 mL, 3.0 mmol), 3-phenoxybenzaldehyde (Aldrich, 0.58 mL, 3.66 mmol), 3A molecular sieve (0.5 g) and methanol (30 mL ) Were combined and heated to reflux for 4 hours. Molecular sieves were removed by filtration. Sodium borohydride (0.35 g, 9.0 mmol) was added slowly and the reaction was stirred at room temperature. After 1 hour, the reaction was concentrated, the residue was dissolved in a mixture of 1 N NaOH solution and methylene chloride and the mixture was extracted with methylene chloride. The organic extract was washed with water, dried (Na ₂ SO ₄ ) and concentrated to give a pale yellow oil. Salt formation with oxalic acid and crystallization from ethyl acetate gave a white solid: mp = 183-185 ° C; ms: ions at 305.2.
[1268] Example 903
[1269] (3- [1,3] dioxolan-2-yl-phenyl) -pyridin-2-ylamine
[1270] 2-aminopyridine (8.25 g, 95 mmol), 2- (3-bromo-phenyl)-[1,3] dioxolane (13.8 mL, 90 mmol), sodium t-butoxide (12.2 g, 126 mmol) , BINAP (210 mg, 0.62 mmol), Pd2 (dbu) 3 (630 mg, 0.21 mmol) and toluene (100 mL) were combined and heated to reflux for 48 hours. The reaction was cooled to rt, dissolved in ether, filtered and the resulting solution was concentrated. Purification by flash chromatography (hexane / EtOAc (8.5: 1.5), then hexanes / EtOAc (7: 3)) gave the title compound as a yellow oil.
[1271] Example 904
[1272] 3- (pyridin-2-ylamino) -benzaldehyde
[1273] (3- [1,3] dioxolan-2-yl-phenyl) -pyridin-2-yl-amine (10.32 g, 42.6 mmol) was dissolved in THF (150 mL). Concentrated HCl solution (37.5 mL) was added and the solution was stirred at rt overnight. The reaction was concentrated, treated with water and extracted with CH ₂ Cl ₂ . The organic extract was washed with water, dried (Na ₂ SO ₄ ) and concentrated to give crude product. Purification by flash chromatography (hexane / EtOAc (7: 3)) gave the title compound as a yellow solid.
[1274] Example 905
[1275] N- (3- (2- (6-chloro-1H-indol-3-yl) ethyl) -3- (pyrid-2-ylamino) benzylamine
[1276]
[1277] 6-chlorotryptamine (0.22 g, 1.1 mmol), 3- (pyridin-2-ylamino) benzaldehyde (0.22 g, 1.1 mmol), 3A molecular sieve (0.5 g) and methanol (25 mL) combined and 4 h Heated to reflux. Molecular sieves were removed by filtration. Sodium borohydride sodium was added slowly and the reaction stirred at room temperature. After 1 hour, the reaction was concentrated and the residue was dissolved in a mixture of 1 N NaOH solution and methylene chloride and the mixture was extracted with methylene chloride. The organic extract was washed with water, dried (Na ₂ SO ₄ ) and concentrated to give crude product. Purification by flash chromatography (concentrated NH ₄ OH solution and EtOAc / MeOH (9: 1)) gave the desired product as a colorless oil. Dihydrochloride was formed and crystallized from EtOAc to afford the desired product: mp = 164-166 ° C .; ms: ions at 377.1.
[1278] Following the procedure according to example 673, the following compounds were prepared:
[1279]
[1280] Following the procedure according to example 673, the following compounds were prepared:
[1281]
[1282] Following a procedure similar to Example 665, the following compounds were prepared:
[1283]
[1284] The following compounds were prepared according to the method of Example 221 and isolated as maleate except as noted:
[1285]
[1286] Example 914
[1287] 3-propoxybenzonitrile
[1288] 3-hydroxybenzonitrile (11.052 gm; 92.8 mmol), n-propyl bromide (24.4 gm; 198 mmol) and potassium carbonate (38.65 gm; 280 mmol) in 2-butanone (175 mL) were combined, heated and refluxed. . After 17 h, the mixture was cooled to rt, the solution was decanted and concentrated by rotary evaporation. The residue was partitioned between diethyl ether (150 mL) and water (150 mL), the layers separated and the aqueous layer extracted with diethyl ether (2 x 100 mL). The organic layers were combined and washed with water, 1 N NaOH and water, dried over MgSO ₄ and concentrated. The residue was distilled off to give the title compound.
[1289] Example 915
[1290] 3-propoxybenzylamine hydrochloride
[1291] 100 ml of lithium aluminum hydride (1M in THF) and 50 ml of THF were combined and sulfuric acid (100%) was added dropwise at 10 ° C. The mixture was warmed to room temperature and stirred. After a period of 1 hour, the solids were removed by filtration through diatomaceous earth using nitrogen pressure and a nitrile solution in 50 mL of THF was added dropwise at 0 ° C. to this clear solution. The reaction was stirred. After 1 hour at 0 ° C., warmed to room temperature and stirred for a period of 2.5 hours. The reaction was cooled to 0 ° C. and 16 mL of water / THF (1: 1) solution was added dropwise and 2 M NaOH (60 mL) was added dropwise. The resulting mixture was filtered and the solid was washed with THF (2 × 100 mL), the organic layers combined, dried over sodium sulfate and concentrated. The residue was dissolved in dry ether (250 mL) and acidified with HCl / dioxane solution (20 mL of 4 M solution). The resulting solid was washed with ether to give the title compound as a white solid.
[1292] Example 916
[1293] 2- (3-bromophenyl) -N- (3-propoxybenzyl) acetamide
[1294] Combine 3-propoxy-benzylamine in 50 ml of dichloromethane and mix a mixture of 3-bromophenylacetyl chloride (4.90 gm; 21.0 mmol) and triethylamine (3.60 gm; 35.9 mmol) in 250 ml dichloromethane at 0 ° C. Dropped at The reaction was warmed to rt and stirred for 18 h. The reaction was poured into 100 mL of saturated brine, the layers separated and the aqueous layer extracted with 100 mL of dichloromethane. The organic layers were combined, washed with brine, dried (MgSO ₄ ) and concentrated. Purification by chromatography on silica gel using 40% EtOAc in hexanes afforded the title compound.
[1295] Example 917
[1296] 2- (4'-fluorobiphenyl-3-yl) -N- (3-propoxybenzyl) acetamide
[1297] Bromoamide (0.365 gm; 1.008 mmol), 4-fluorophenylboronic acid (0.175 gm; 1.25 mmol), cesium fluoride (0.360 gm; 2.37 mmol) and dichloro (bistriphenylphosphine) in NMP (3 mL) Palladium (II) (0.062 gm; 0.088 mmol) was combined and heated at 104 ° C. After 13.3 hours, it was cooled to room temperature and diluted with 40 mL each of dichloromethane and water. The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 20 mL). The organic layers were combined and washed four times with 10 ml portions of saturated brine, dried (MgSO ₄ ) and concentrated. Purification by chromatography on silica gel using 40% EtOAc in hexanes afforded the title compound.
[1298] Example 918
[1299] N- (2- (3- (4-fluorophenyl) phenyl) ethyl) -3-propoxybenzylamine
[1300]
[1301] 2- (4'-fluorobiphenyl-3-yl) -N- (3-propoxybenzylacetamide) in 15 mL of THF was combined and BH ₃ -SMe ₂ (2 M in THF) solution was added dropwise at 0 ° C. . The reaction was warmed to room temperature and stirred. After 5 hours, ethanol (1 mL) was added carefully and the mixture was concentrated. The residue was dissolved in ethanol (2 mL), heated to reflux for 2 hours and concentrated. Purification gave the title compound as a tan solid. The amine was dissolved in 10 ml of dichloromethane / methanol (1: 1) and 600 mg of polyvinylpyridine hydrochloride was added. The mixture was shaken for 4 hours and the polymer was removed by filtration, the residue was concentrated and washed with ether to give the title compound as hydrochloride: MS (ES +): m / e 364 (M + 1).
[1302] Example 919
[1303] N- (2- (5-benzyloxy-1H-indol-3-yl) -ethyl) -3-phenoxybenzylamine
[1304]
[1305] 5-benzyloxy tryptamine (1.23 g, 4.6 mmol), 3-phenoxybenzaldehyde (97%, 1.09 g, 5.53 mmol) and molecular sieve 4A (1.0 g) were combined and in methanol (15 mL) for 4 h. Stirred. The molecular sieves were filtered and washed several times with MeOH. NaBH ₄ (174 mg, 4.60 mmol) was added portionwise to the MeOH solution and the resulting mixture was stirred at room temperature for 1 hour. MeOH was removed in vacuo and the residue was diluted with CH ₂ CL ₂ / water, extracted with CH ₂ Cl ₂ , the organic layers combined, dried over Na ₂ SO ₄ and the solvent was concentrated in vacuo. Purification by silica gel chromatography (CH ₂ Cl ₂ / MeOH) afforded the free base. The free base was combined with oxalic acid to form a salt: (300 MHz, DMSO-d ₆ ) 2.95-3.15 (m, 4H), 3.93 (s, 2H), 4.10 (br, 1H), 5.05 (s, 2H), 6.85-7.46 (m, 18 H), 10.67 (br, 1 H); ms (electrospray) m / e: 449.2 (M + l).
[1306] Example 921
[1307] N- (2- (5-benzyloxy-1H-indol-3-yl) ethyl) -N-methyl-3-phenoxy-benzylamine
[1308]
[1309] Combine N- (2- (5-benzyloxy-1H-indol-3-yl) ethyl) -3-phenoxy-benzylamine (1.61 g, 3.59 mmol) and NaOH (143.6 mg, 3.591.75 mmol) and THF (25 mL) and stirred at room temperature. After 15 minutes, di-tert-butyl dicarbonate (1.57 g, 7.18 mmol) was added in THF (20 mL) and heated to reflux for 4 hours. The solvent was removed and diluted with water, extracted with CH ₂ Cl ₂ (3 × 15 mL), dried over Na ₂ SO ₄ and concentrated in vacuo to give a brown oil. The crude product was used directly in the next step without purification.
[1310] LiAlH ₄ -THF (13.4 mL, 13.4 mmol) 1.0 M solution and (3-phenoxy-benzyl)-(2- (5-benzyloxy-1H-indol-3-yl) -ethyl) -carbamic acid tert-butyl The esters (1.83 g, 3.34 mmol) were combined and 15 mL of dry THF was added slowly. After addition, the reaction mixture was heated to reflux. After 4.5 hours, it was cooled to room temperature. The reaction was quenched by careful addition of water (1.5 mL) followed by 10% NaOH. The suspension was filtered off and washed repeatedly with ether. The organic solution was dried over Na ₂ S0 ₄ and the solvent was concentrated in vacuo. Purification by silica gel chromatography using CH ₂ Cl ₂ / MeOH as eluent gave a free base: ¹ H NMR (300 MHz, CDCl ₃ ) 2.35 (s, 3H), 2.69-2.74 (m, 2H), 2.91-2.96 9m, 2H), 3.65 (s, 2H), 5.07 (s, 2H), 6.90-7.53 (m, 18H), 7.80 (s, 1H). The compound was further reacted with oxalic acid to form salts.
[1311] Example 922
[1312] N- (2- (6,7-difluoro-1H-indol-3-yl) -ethyl) -3- (pyridin-4-yloxy) benzylamine
[1313]
[1314] 6,7-difluorotrytamine (0.285 g, 1.450 mmol), 3-pyridin-4-yloxybenzaldehyde (0.303 g, 1.52 mmol, 1.05 equiv) and molecular sieve 4A (0.30 g) were combined and methanol (12 Ml). After 4 hours, the molecular sieves were filtered and washed several times with MeOH. NaBH ₄ (55.0 mg, 1.45 mmol) was added portionwise to the MeOH solution and stirred at room temperature for 1 hour. MeOH was removed in vacuo and the residue was diluted with CH ₂ Cl ₂ / water and extracted with CH ₂ Cl ₂ , the organic layers combined, dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by flash chromatography on silica gel (CH ₂ Cl ₂ / MeOH) gave a free base that was converted to hydrochloride: ¹ H NMR (300 MHz, DMSO- d ₆ ) 3.13 (s, 4H), 4.20 (s, 2H ), 6.85-7.55 (m, 10H), 8.47-8.50 (m, 1H), 9.58 (br, 1H), 11.57 (br, 1H): MS (electrospray) m / e: 380.2 (M + 1- HCl), 378.3 (M-1-HCl).
[1315] The present invention also provides novel intermediates of the compounds of formula (I). The present invention provides intermediates of formula (III):
[1316]
[1317] Where
[1318] R ₃ is selected from the group consisting of hydrogen, fluoro and methyl,
[1319] R _{4 '} is fluorinated C ₂ -C ₄ alkyl.
[1320] The present invention also provides novel crystalline forms of the compound of formula (I). Thus, for example, N- (2- (6-fluoro-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine hydrochloride under controlled conditions It can be prepared by crystallization under to obtain a new crystalline form. Crystallization and slurrying techniques from solutions are considered to be within the scope of the process of the invention. Indeed, many factors have been obtained, including temperature and solvent composition (N- (2- (6-fluoro-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoro Propoxy) benzylamine hydrochloride may affect the form Crystals (N- (2- (6-fluoro-1H-indol-3-yl) ethyl) -3- (2,2,3,3- The exact conditions under which tetrafluoropropoxy) benzylamine hydrochloride is formed can be determined empirically, but it is only possible to provide a number of methods that have been found to be suitable in practice N- (2- (6-fluoro-1H-indole-). Preferred polymorphic forms of 3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine hydrochloride can be prepared by crystallization from diethyl ether or as a slurry. Other preferred polymorphic forms of-(6-fluoro-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine hydrochloride are aqueous dichloromethane, acetone aqueous solution Ethyl acetate, Ethyl acetate / cyclohexane, ethyl acetate / hexane, ethyl acetate / heptane, acetone / cyclohexane, isopropanol / hexane, acetonitrile, acetonitrile / toluene, n-propanol / isoamylacetate / hexane, isopropyl acetate / diethyl ether It can be prepared by crystallization from methyl t-butyl ether / acetone, water, water / acetone, water / diethyl ether.
[1321] Crystalline (N- (2- (6-fluoro-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine crystallized directly under controlled conditions In addition, the novel crystalline forms of the invention are (N- (2- (6-fluoro-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetra Fluoropropoxy) benzylamine can be prepared by dissolving in a solvent and then adding it to a solution containing hydrochloric acid to form hydrochloride to crystallize while controlling the temperature.
[1322] There are many ways to characterize the crystalline form of organic compounds. For example, the method includes differential scanning calorimetry, solid state NMR spectroscopy, infrared spectroscopy, and X-ray powder diffraction. Among them, X-ray powder diffraction and solid state NMR spectroscopy are very useful for identifying and distinguishing between crystalline forms.
[1323] X-ray powder diffraction analysis is performed by various methods known to those skilled in the art. These methods may be varied to increase sensitivity by using stronger radiation, fewer scan steps, and slower scan rates by sample preparation techniques. One method is as follows. The sample was loaded into the sample holder for X-ray powder diffraction measurement, with or without crushing the sample with agate mortar and pestle. The X-ray powder diffraction pattern is a Siemens equipped with a CuKα source (λ = 1.54056 μs) operating at 50 kV and 40 mA using a diverging slit of 1 mm, a receiving slit of 1 mm and a detection slit of 0.1 mm. ) Was measured using a D5000 X-ray powder diffractometer. Samples were scanned at 4 ° to 35 ° (2θ) with a step size of 0.02 ° and a maximum scan speed of 3 seconds per step. Data was collected using Kevex solid-state silicon lithium detection. In some cases, silicon detection was routinely performed to check instrument alignment.
[1324] It is known in the field of crystallography that for any given crystal form, the relative intensity and peak width of the diffraction peaks may vary depending on many factors, including the effect of the desired orientation and / or particle size. If there is an effect of the desired orientation and / or particle size, the peak intensity may change but the characteristic peak position of the polymorph does not change. See, eg, The United States Pharmacopoeia # 24, National Formulary # 19, pages 1843-1844, 2000.
[1325] Grinding can be used to minimize peak intensity. However, if the grinding significantly changes the diffractogram or the crystal state of the sample, then the diffraction pattern of the uncrushed sample should be used. Grinding is carried out in small agate mortars and mortars. The induction is maintained during grinding, and a mild pressure is applied to the pestle.
[1326] Thus, a compound of formula (I), which is a suitably prepared sample crystal, may be characterized by one or more 2θ values in the X-ray diffraction pattern obtained as described above.
[1327] In addition, the compounds of crystalline formula (I) can be characterized by solid state NMR spectroscopy. The solid state ¹³ C chemical shift reflects not only the molecular structure but also the electrical environment of the molecules in the crystal.
[1328] Solid state NMR ( ¹³ C) analysis can be performed using ¹³ C cross polarization / magic angle spinning (CP / MAS). NMR (solid-state NMR or SSNMR) spectra are obtained using a Varian Unity 400 MHz spectrometer equipped with a complete solid accessory and a Varian 7 mm VT CP / MAS probe operating at a carbon frequency of 100.580 MHz. . The acquisition parameters are easily determined and are typically 90 ° proton rf pulse width 4.0 Hz, contact time 1.0 ms, pulse repetition time 5 s, MAS frequency 7.0 kHz, spectral width 50 kHz and acquisition time 50 ms. Chemical shifts are generally reported to be related to the methyl group of the external hexamethylbenzene, ie the sample is replaced with hexamethylbenzene.
[1329] Thus, the crystalline compound of formula (I) may be characterized by one or more resonances in the solid state ¹³ C nuclear magnetic spectrum as described above.
[1330] The compounds of the present invention may be administered alone or in the form of pharmaceutical compositions, i.e., in combination with a pharmaceutically acceptable carrier or excipient. The compounds of the present invention are effective on their own but can be formulated and administered in the form of their pharmaceutically acceptable salts for the purpose of stability, convenience, solubility and the like. In practice, the compounds of formulas (I) and (II) are usually administered in the form of pharmaceutical compositions, ie in admixture with a pharmaceutically acceptable carrier or diluent.
[1331] Accordingly, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or (II) and a pharmaceutically acceptable diluent.
[1332] The compounds of formulas (I) and (II) can be administered by various routes. In carrying out the treatment of a patient suffering from the disorders described herein, the compounds of formulas (I) and (II) are administered in any form or manner which makes the compounds bioavailable in effective amounts, including oral and parenteral routes. can do. For example, the compounds of Formulas (I) and (II) may be orally, inhaled, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, intraocularly, topically, sublingually, orally Orally. Oral administration is generally preferred for the treatment of the disorders described herein.
[1333] Those skilled in the art of preparing the formulations will find appropriate forms, depending on the particular characteristics of the selected compound, the disorder or condition to be treated, the stage of the disorder or condition, the solubility and chemical nature of the selected compound, the route of administration chosen, and other relevant circumstances contemplated by the pharmaceutical implementation of the standard and The mode of administration can be easily chosen [Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co. (1990)].
[1334] Pharmaceutical compositions are prepared in a manner known in the pharmaceutical art. Carriers or excipients may be solids, semi-solids or liquid substances that serve as vehicles or media for the active ingredient. Suitable carriers or excipients are known in the art. Pharmaceutical compositions may be adapted for oral, inhalation, parenteral or topical use and may be administered to a patient in the form of tablets, capsules, aerosols, inhalants, suppositories, solutions, suspensions and the like.
[1335] The compounds of the present invention may be administered orally or compressed into tablets with an inert diluent or capsule or the like. For the purpose of therapeutic oral administration, the compounds may be incorporated with excipients or used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. Such preparations should contain at least 4% of the active compound of the present invention, which may vary depending on the particular form and may conveniently be from 4% to about 70% of the unit weight. The amount of the compound present in the composition is that amount that will yield a suitable dosage. Preferred compositions and preparations according to the invention can be determined by one skilled in the art.
[1336] Tablets, pills, capsules, troches and the like may also contain one or more of the following adjuvants: binders such as microcrystalline cellulose, rubber tragacanth or gelatin and the like; Excipients such as starch or lactose and the like, disintegrants such as alginic acid, Primogel, corn starch and the like; Lubricants such as magnesium stearate or sterotex and the like; Lubricants such as colloidal silicon dioxide and the like; And sweetening agents such as sucrose or saccharin or flavoring agents such as peppermint, methyl salicylate or orange scent. When the dosage unit form is a capsule, it may contain a liquid carrier such as polyethylene glycol or fatty oil in addition to the above types of substances. Other dosage unit forms may contain a variety of other materials that change the physical form of the dosage unit, for example, as a coating. Thus, tablets or pills can be coated with sugars, shellac or other coating agents. Syrups may contain, in addition to the compounds of the present invention, sucrose and certain preservatives, dyes and colorants and flavors as sweeteners. The materials used to prepare these various compositions should be pharmaceutically pure and nontoxic in the amounts used.
[1337] For the purpose of therapeutic parenteral administration, the compounds of the present invention may be incorporated into solutions or suspensions. Such preparations typically contain at least 0.1% of the compounds of the present invention but can vary from 0.1 to about 90% of their weight. The amount of compounds of formulas (I) and (II) present in such compositions is that amount that will yield a suitable dosage. In addition, the solution or suspension may comprise one or more of the following adjuvants: sterilized diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents, and the like; Antibacterial agents such as benzyl alcohol or methyl parabens; Antioxidants such as ascorbic acid or sodium bisulfite; Chelating agents such as ethylene diaminetetraacetic acid and the like; Buffers such as acetates, citrates or phosphates and tonicity modifiers such as sodium chloride or dextrose and the like. Parenteral preparation can be sealed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Preferred compositions and methods of preparation can be determined by one skilled in the art.
[1338] In addition, the compounds of the present invention may be administered topically, wherein the carrier may suitably comprise a solution, ointment or gel base. The substrate may comprise, for example, one or more of the following materials: diluents and emulsifiers and stabilizers, such as mineral oil, lanolin, polyethylene glycol, bees wax, mineral oil, water and alcohols and the like. Topical formulations may contain formulas (I) and (II) or pharmaceutical salts thereof at a concentration of about 0.1 to about 10% w / v (weight per unit volume).
[1339] Compounds of formula (I) and (II) are antagonists of the 5-HT ₆ receptor. Such antagonism can be confirmed by the following method.
[1340] Example A
[1341] 5HT ₆Analysis of the binding
[1342] Assay buffer used was 50 mM Tris-HCl pH 7.4, 120 mM NaCl, 5 mM KCl, 5 mM MgCl ₂ , 1 mM EDTA. Used radioligand New England Nuclear Cat. (New England Nuclear Cat.) # NET 638-75.9 ³ H-LSD at Ci / mmol. The membrane used is receptor biology, cat. (Receptor Biology, Cat.) RB-HS6. This was the membrane of HEK-293 cells expressing human 5HT ₆ receptor.
[1343] Test compounds were obtained as 10 mM stocks in 100% DMSO. Dilute to 1 mM in 100% DMSO by adding 180 μl DMSO to 20 μl of the stock solution in 96 well plates using multidrop. The 1 mM stock solution was then diluted using 10% DMSO as diluent to prepare 11 concentrations in the range from 125 μM to 1.25 nM in half log increments. This was done using a TECAN robot. The final DMSO at this stage was 21.25%.
[1344] The radioligand was diluted in assay buffer to prepare a 125 nM solution and each vial of the membrane was diluted to 92 ml in assay buffer. The final assay volume was 250 μl, including 210 μl of diluted membrane, 20 μl of compound or 21.25% DMSO for total binding and 20 μl of diluted radioligand. Compounds were transferred from drug dilution plates to corning 96 well assay plates using a 96 well Multimek pipettor. Radioligands and membranes were added to assay plates using a multiply pipette. Nonspecific binding was determined in wells containing a final serotonin concentration of 10 μM. The radioligand in the final assay volume was 10 nM and the membrane protein was approximately 25 μg per well. Final drug concentrations ranged from 10 μM to 0.1 nM in half log. Final DMSO in the analysis was 1.7%.
[1345] After addition of drug, membrane and ligand, plates were incubated for 1 hour at room temperature. During this time 96 well Millipore filter plates (MAFBNOB50) were immersed for at least 30 minutes at 200 μl per well of 0.5% polyethyleneimine.
[1346] 0.5% PEI was removed from the filter plate wells using a TiterTek MAP aspirator and after mixing 200 μl of the incubation mixture was transferred from the incubation plate to the filter plate. The transfer was performed using a 96 tip multimec pipette. After transfer to the filter plate, the filter plate was extracted and washed twice with 220 μl per well of buffer cooled in MAP aspirator. The bottom strip was removed from the filter plate and added per well using 100 μl per well of microscint 20 scintillation fluid. The plate was placed in a suitable holder and left for 3 hours at room temperature and counted ³ H with a Wallac Microbeta counter or Packard Topcount.
[1347] In one embodiment, the invention provides, 5-HT ₆ A method of treating disorders associated with the receptor, which comprises administering a compound of formula (I) in an effective amount to a patient in need of disorders associated with 5-HT ₆ receptor do. Accordingly, the present invention contemplates the various disorders described herein to be treated and other disorders that may be treated with other antagonists as assessed by those skilled in the art.
[1348] In particular, due to their nature of antagonizing the 5-HT ₆ receptor, it is recognized that the compounds of the present invention are useful for treating cognitive disorders, ie disorders associated with cognitive deficits. Many disorders that can be treated with 5-HT ₆ antagonists have been established and are known according to acceptable classification, but others are not.
[1349] Because cognition is a complex and sometimes poorly defined phenomenon, some disorders treated in accordance with the present invention are poorly categorized and classified. However, it is widely recognized that cognition includes various "domains." The domain includes short term memory, long term memory, working memory, performance functions and attention.
[1350] Although many disorders that can be treated according to the invention are not consistently described or classified in the art, the compounds of the invention are characterized in the treatment of disorders characterized by defects in any of the cognitive domains listed above or other aspects of cognition. Usefulness is understood. The term "cognitive impairment" is meant to include any disorder characterized by the combination of one or more cognitive domains, including but not limited to short-term memory, long-term memory, working memory, performance functions, and attention.
[1351] One cognitive impairment treated with the present invention is age related cognitive degeneration. Such disorders are not well defined but include degeneration in age-related cognitive domains, especially memory and attention domains. Another example is mild cognitive impairment. In addition, the disorder is not well defined in the art, but is believed to be present in the majority of patients with early Alzheimer's disease, including degeneration in the cognitive domain. In addition, various injuries, including stroke, ischemia, hypoxia, inflammatory and infectious processes, can lead to cognitive deficits, which can be treated according to the present invention.
[1352] Disorders that can be treated with 5-HT ₆ antagonists are currently established and are known according to accepted taxonomy, which can be found from a variety of sources. For example, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV ™) (1994, American Psychiatric Association, Washington, DC), It provides a diagnostic tool to identify many of them. In addition, the International Classification of Diseases, Tenth Revision (ICD-10) provides a taxonomy for many of the disorders described herein. Those skilled in the art will appreciate alternative nomenclature, hematology and taxonomy systems for the disorders described herein, including those not well characterized in the art and those described in DMS-IV and ICD-10. It will be recognized by medical and scientific methods.
[1353] In one embodiment, the present invention comprises administering an effective amount of a compound of formula (I) or (II) to a patient in need of treatment for the following disease: age related cognitive impairment, mild cognitive impairment, mood disorder (depression, mania , Including bipolar disorder), psychosis (particularly schizophrenia), anxiety (including generalized anxiety disorders, panic disorder, and obsessive compulsive disorder), idiopathic and drug-induced Parkinson's disease, epilepsy, cramps, migraine (migraine) Headaches), substance withdrawal (including substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, sleeping pills, etc.), sleep disorders (including narcolepsy), attention deficit / hyperactivity disorders , Conduction disorders, learning disorders, dementia (Alzheimer's disease and AIDS-induced dementia), Huntington's chorea, cognitive deficiency after heart bypass surgery and transplantation, seizures, cerebral infarction, spinal cord trauma, head trauma, prenatal hypoxia, Provided are methods for treating a disorder selected from the group consisting of cardiac arrest and hypoglycemic neuronal damage, vascular dementia, multiple infarction dementia, amyotrophic lateral sclerosis and multiple sclerosis. That is, the present invention provides the use of a compound of formula (I) and (II) or a pharmaceutical composition thereof for treating a disorder associated with 5-HT ₆ receptor.
[1354] It is recognized that the terms “treat” and “treat” are intended to include amelioration of cognitive deficiency associated with each of the disorders associated with the 5-HT ₆ receptor described herein. It is also recognized that those skilled in the art can overcome the disorder by treating a patient currently suffering from the disorder with an effective amount of a compound of formula (I) or prophylactically treating a patient deemed susceptible to the disorder. Thus, the terms "treatment" and "treat" are intended to relate to any method that can slow, hinder, arrest, control or stop the progression of the disorders described herein, but essentially complete all symptoms. It does not indicate elimination and is intended to include prophylactic treatment of such disorders. For example, the present invention specifically includes the treatment of cognitive deficiencies associated with schizophrenia, stroke, Alzheimer's disease and other disorders described herein. Accordingly, it is understood that the present invention encompasses adjuvant treatment of the disorders described herein. More specifically, the compounds of formula (I) and (II) are combined with various therapeutic agents, in particular AMPA adjuvant; Typical and atypical antipsychotics, including olanzapine; various agents such as mGluR agonists, NMDA antagonists, IL 1-6 inhibitors, and the like; Compounds that inhibit amyloid protein processing, including cholinergic agents and amyloid precursor protein processing inhibitors, such as cholinesterase inhibitors such as tacrine and donepezil and the like, and antibodies derived against amyloid proteins; Antidepressants, including SSRIs and the like; And anti-anxiety agents and the like, which are useful for the treatment of cognitive disorders. The combination is believed to be synergistically beneficial to provide efficacy at the small doses required to provide the same effect as using individual components.
[1355] As used herein, the term "patient" refers to a warm animal, such as a mammal, suffering from one or more disorders associated with the 5-HT ₆ receptor. Guinea pigs, dogs, cats, mice, mice, horses, cattle, sheep, pigs, and humans are understood to be examples of animals that fall within the meaning of the term.
[1356] As used herein, the term "effective amount" of a compound of formula (I) or (II) refers to an amount, ie dosage, effective for treating a disorder described herein.
[1357] Effective amounts can easily be determined by those skilled in the art using routine techniques and observing the results obtained under similar circumstances. In determining the effective dose of a compound of formula (I), the attending physician considers a number of factors, including the compounds of formula (I) or (II) to be administered; If other therapeutic agents are used, co-administration with other therapeutic agents; Species of mammal; The size, age and general health of the mammal; Specific disorders involved; Degree of association or severity of the disorder; Response of each patient; Mode of administration; Bioavailability characteristics of the administered preparation; Selected capacity plan; The use of other concomitant medications; And other related situations, but are not limited thereto.
[1358] Effective amounts of compounds of Formulas (I) and (II) are expected to vary from about 0.1 mg (0.1 mg / kg / day) to about 100 mg / kg / day per kg of body weight per day. Preferred amounts can be determined by one skilled in the art.
[1359] Many disorders treated according to the invention are particularly preferred.
[1360] In a preferred embodiment the invention provides a method of treating a cognitive disorder comprising administering an effective amount of a compound of claim 1 to a patient in need thereof.
[1361] In another preferred embodiment the invention provides a method of treating Alzheimer's disease comprising administering an effective amount of a compound of formula (I) to a patient in need thereof.
[1362] In a preferred embodiment the present invention provides a method of treating schizophrenia comprising administering an effective amount of a compound of formula (I) to a patient in need thereof.
[1363] Diagnostic and Statistical Manual of Mental Disorders (DSM-IV ™), 4th Edition (1994, American Psychiatric Association, Washington, DC) is a schizophrenia and related disorders, specifically all disorders understood to be included within the scope of the present invention. It provides a diagnostic tool comprising a.
[1364] In a preferred embodiment the invention provides a method of treating migraine, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) or (II) or a pharmaceutical composition thereof.
[1365] In one of the available sources of diagnostic tools, the Dorland's Medical Dictionary (23 ^rd Ed., 1982, WB Saunders Company, Philidelphia, PA), migraine headaches are often associated with irritability, nausea, vomiting, constipation or diarrhea and It is defined as a complex symptom with glare and usually a periodic headache in the temporal and lateral side. The term "migraine" as used herein includes such periodic headaches, both associated with hypersensitivity, nausea, vomiting, constipation or diarrhea, glare and other related symptoms in both temporal and lateral. Those skilled in the art will recognize that there are alternative nomenclature, disease taxonomy and taxonomy systems for neurological and psychiatric disorders, including migraines, and the like, that the systems have been developed in medical and scientific methods.
[1366] In a preferred embodiment the invention provides a method of treating anxiety disorders comprising administering an effective amount of a compound of formula (I) to a patient in need of treatment of anxiety disorders including generalized anxiety disorders, panic disorders, obsessive compulsive disorders, and the like. to provide.
[1367] Currently, the Fourth Edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV ™) (1994, American Psychiatric Association, Washington, D.C.) provides diagnostic tools including anxiety and related disorders. These include panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, social phobia, obsessive compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety due to general medical conditions Disorders, substance-induced anxiety disorders and other unspecified anxiety disorders. The term "anxiety" as used herein is intended to include the treatment of such anxiety disorders and related disorders as specifically described in DSM-IV, and the term "anxiety" is intended to include disorders and the like described in other diagnostic sources.
[1368] Numerous preclinical laboratory animal models describe the disorders described herein.
[1369] Example B
[1370] Fear-enhancing surprise paradigm
[1371] Harlan Sprague-Dawley, Inc., male Sprague-Dawley rats weighing 325-400 g. (Harlan Sprague-Dawley, Inc.) from Cumberland, IN and provided a one week compliance period prior to testing. The rats were fed with food and water at 6:00 A.M. and 6:00 P.M. A 12-hour light / dark cycle that shines in between allows individual habitation in the animal room. The compound of Example 16 was prepared in a suspension of 5% ethanol, 0.5% CMC, 0.5% Tween 80 and 99% water. 2S-2-amino-2- (1S, 2S-2-carboxycyclopropan-1-yl) -3- (xant-9-yl) propionic acid was prepared in sterile water. Each vehicle was obtained from control mice.
[1372] The fear-enhancing surprise paradigm was conducted for three consecutive days. All three days started with an adaptation period of 5 minutes before starting the experiment. On Day 1 (surprise baseline), after the acclimatization period, 30 experiments with 120 dB auditory noise were performed on animals. Animals were assigned to similar numbers of groups using the average surprise size (V _max ) prior to starting regulation. Day 2 consists of conditioning the animal. Each animal receives a 5 second light that lasts to prolong the impact, and then receives a shock of 0.5 mA for 500 msec. The light was lit 10 times and the shock was performed. Day 3 was a test experiment in which drug administration was performed before the test. 24 hours after the adjustment, a surprise test session was conducted. Ten auditory surprises (120 dB) with no light were present at the start of the session. Then, 20 random experiments with noise alone and 20 random experiments with noisy light were performed. With the exception of the first 10 experiments, the surprise response size for each type of experiment was averaged for each animal. Data were obtained as the difference between light + noise and noise-alone. Differences between surprise response sizes were analyzed with Jmp statistical software using One-way Anova (variance analysis, t-test). Differences between groups were considered significant when p <0.05.
[1373] A radial arm maze model could be used as a cognitive model and could be used to evaluate the compounds of the present invention.
[1374] Example C
[1375] Radiation Arm Maze
[1376] Effect of Drugs on Delayed Non-Matching Memory Retention on Sample Jobs [Pussinen, R. and Sirvio, J. J of Psychopharm 13: 171-179 (1999); Staubli, U., et al. Proc Natl Acad Sci 91: 777-781 (1994)] has been used in an eight-arm radial maze.
[1377] Well trained rats were asked to retrieve food rewards from a randomly selected arm of the maze (sampling step). After a few hours, the rats were exposed to eight published arms and tested for their ability to avoid arms that had previously entered and remembered to obtain food. Reentry of the food-fed palo during the sampling session was calculated as the reference error, but more than one entry into the same follow-up during the holding session was calculated as the operational error. The total number of errors (reference + operation) during the retention test increased with increasing delay period. For example, young male mice exhibited 0.66 (+ 0.4) error at 1 minute delay, 2 (+ 0.5) error at 1 hour delay and 3.95 (+ 0.2) error at 7 hour delay (as observed in the laboratory above).
[1378] Male Sprague-Dawley rats were individually incubated and maintained in a 12 hour light / dark cycle (lit at 6 am). Mice were allowed free access to water and maintained at 85% of free-feed weight by food supplementation of Purina Lab Chow.
[1379] Mice were initially trained to find food at the tips of each of the eight arms. Once the mice reached a scale of 2 or fewer errors for three consecutive days (ie, entering more than once on the same arm during the session), a 1 minute delay was placed between the fourth and fifth arm selections. The training ensured that the rats were fully familiar with the procedural aspects of the job prior to the administration of any drug. Once stable behavior was performed in the delayed job (ie there was no less than one error for three consecutive days), drug and vehicle testing was started using a 7 hour delay period. For each date and each rat, a new set of arms was placed on the food and the maze was completely cleared during the delay period.
[1380] During the sampling session, each rat was placed on a central platform that accessed the arms of all eight mazes blocked. Four of the eight arms were randomly selected and food was placed. The gate of the arm holding the food was raised and the rat was allowed to get food at the ends of each of the four arms for 5 minutes. As soon as the rats obtained the food, the food was removed, the vehicle or various doses of the compound was administered and returned to the habitat cage. After 7 hours (holding session), mice were placed back on the central platform approaching the arms of all eight mazes blocked. During the sampling session, food was placed on four arms that had been pre-cooked, and all eight arms were raised. Rats were allowed to obtain 4 pieces of food remaining for 5 minutes. Entry into an unattended palo or re-entry into a previously taken palo was calculated as an error. After using repeated measures ANOVA, a Dunnett test was performed for comparison with the control to determine significance (p <0.05).
[1381] To compare test compounds and standards, scopolamine and tacrine were administered subcutaneously immediately after the sampling step. The known forgetfulness, which is the effect of scopolamine after a 3 hour delay, was tested while the effect of tacrine, a cholinesterase inhibitor used in the treatment of Alzheimer's disease, after a 6 hour delay was tested. Scopolamine disrupted retention in a dose-related manner after a three hour delay. Tacrine significantly improved retention at 10 mg / kg after a 6 hour delay, but not at 3 mg / kg.
[1382] Example D
[1383] Learning in the Radial Maze (Learning the Radial Maze with 8 Arms)
[1384] A prominent early feature of Alzheimer's disease (AD) symptoms is a manifested deficit in descriptive memory [R.W. Parks, R. F. Zec & R.S. Wilson (Eds.), Neuropsychology of Alzheimer's disease and other dementias. NY: Oxford University Press pp. 3-80 (1993)].
[1385] As the disease progresses, other domains of cognition are also severely affected. The area of the brain that is initially affected by AD progression is the hippocampus, and the hippocampus is a critical neuronal substrate for descriptive memory [West M.J., Coleman P.D., Flood D.G. & Troncoso J.C .. Differences in the pattern of hippocampal neuronal loss in normal aging and Alzheimer's disease. Lancet, 344: 769-772 (1994). One behavioral test that is often used to access hippocampal function in animal models is a radial labyrinth with eight arms [Olton D.S. The radial arm maze as a tool in behavioral pharmacology. Physiology & Behavior, 40: 793-797 (1986)].
[1386] Disease or pharmaceutical blockage of the hippocampus interferes with the behavior of the task. Moreover, aged animals generally exhibit deficiencies in these duties [Porsolt R.D., Roux S. & Wettstein J.G. Animal models of dementia. Drug Development Research, 35: 214-229 (1995).
[1387] In this test of spatial learning and memory, hungry rats were placed in the center of the maze and traversed the maze to find food located at the end of each passage arm. In this version of the maze, the rat learned a win-move strategy that the arms he visited were not replaced. Therefore, the most efficient retrieval strategy is to visit each arm at a time. In addition, when mice were not experienced in the labyrinth on day 1 of the 4-day experiment, the version of the labyrinth uses the usual learning method.
[1388] Upon arrival, male Sprague-Dawley rats were individually inhabited in a standard light-circulating residence room and allowed to acclimate for at least 4 days prior to testing. Each rat was reduced and maintained to 85% of the target body weight throughout the experiment. Proper body weight was maintained by adjusting the allocation of lab chow based on a combination of age and daily weight values of rats.
[1389] After placing each mouse in the center of the maze, the session was started with all the small (guillotine) gates raised and the mice freely accessing all areas of the maze. A food bowl was placed at the end of each of the eight aisle arms and a single food pellet was placed in each food bowl. Each day session was terminated when the rats visited all eight food-bowls or when the rats exceeded the time (15 minutes on day 1: 5 minutes on days 2-4). The number of arms entered was recorded. Errors were calculated when arm entry was repeated during the session or when arm visits failed. The animals were excluded from the study if they failed to visit one or more arms on Day 1, two or more Arms on Day 2 and four or more Arms on Days 3 and 4.
[1390] Each rat was assigned a pseudo random number to the vehicle group or the drug group to perform the same treatment throughout the experiment. The vehicle consisted of 5% acacia in sterile water. Injections were administered subcutaneously for 20-30 minutes before each daily session.
[1391] In the acquisition task, the vehicle treated animals did not consistently exhibit significant acquisition of maze learning as compared to the number of errors done on day 1. Applicants have found that in compounds that facilitate the acquisition of maze learning, no effect is often observed until the fourth day of training. Therefore, the results consist of the total error of day 4, depending on the treatment group.
[1] The present invention relates to the field of pharmaceuticals and organic chemistry and relates to compounds that are antagonists of the 5-HT ₆ receptor.

权利要求:
Claims (49)
[1" claim-type="Currently amended] Compounds of formula (I) and pharmaceutically acceptable salts thereof.
<Formula I>

Where
X is selected from the group consisting of -O-, -NH-, -S-, -SO _2- , -CH _2- , -CH (F)-, -CH (OH)-and -C (O)- ;
R ₁ is an optionally substituted 5- and 6-membered monocyclic aromatic heterocyclo having one heteroatom selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, nitrogen, oxygen and sulfur and optionally benzofused Selected from the group consisting of;
R ₂ is selected from the group consisting of hydrogen and C ₁ -C ₃ alkyl;
R ₃ is selected from the group consisting of hydrogen, fluoro and methyl;
R ₄ is selected from the group consisting of hydrogen, allyl, C ₂ -C ₄ alkyl, fluorinated C ₂ -C ₄ alkyl, optionally substituted phenyl, optionally substituted phenylsulfonyl, optionally substituted benzyl, and nitrogen, oxygen and sulfur Optionally selected from the group consisting of optionally substituted 5- and 6-membered monocyclic aromatic heterocycles with one or two heteroatoms selected, wherein X is -SO _2- , -CH _2- , -CH (F)-, Or -CH (OH) or -C (O)-, it is not an optionally substituted phenylsulfonyl.
[2" claim-type="Currently amended] The compound of claim 1, wherein X is selected from the group consisting of —O— and —NH—.
[3" claim-type="Currently amended] The compound of claim 2, wherein X is —O—.
[4" claim-type="Currently amended] The compound of claim 3, wherein R ₃ is hydrogen.
[5" claim-type="Currently amended] The compound of claim 4, wherein R ₄ is selected from the group consisting of C ₂ -C ₄ fluorinated alkyl and optionally substituted phenyl.
[6" claim-type="Currently amended] 6. An optionally substituted 5- and 6-membered monocyclic aromatic hetero according to claim 5, wherein R ₁ is optionally substituted phenyl and one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and optionally benzofused. A compound selected from the group consisting of cycles.
[7" claim-type="Currently amended] The compound of claim 6, wherein R ₁ is optionally substituted phenyl.
[8" claim-type="Currently amended] 7. The compound of claim 6, wherein R ₁ is an optionally substituted 5- and 6-membered monocyclic aromatic heterocycle having one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur.
[9" claim-type="Currently amended] The compound of claim 8, wherein the benzofused 5- and 6-membered monocyclic aromatic heterocycles are optionally substituted indol-3-yl.
[10" claim-type="Currently amended] The compound of claim 7, wherein R ₄ is optionally substituted phenyl.
[11" claim-type="Currently amended] The compound of any one of claims 7-9 wherein R ₄ is C ₂ -C ₄ fluorinated alkyl.
[12" claim-type="Currently amended] The compound of claim 1, which is N- (2- (6-fluoro-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine.
[13" claim-type="Currently amended] The compound of claim 1, which is N- (2- (6-fluoro-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine hydrochloride .
[14" claim-type="Currently amended] The compound of claim 1, wherein N- (2- (5-methoxy-6-fluoro-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethylamino) benzylamine , N- (2- (5-methoxy-6-fluoro-1H-indol-3-yl) ethyl) -3- (2,2,3,3,3-pentafluoropropylamino) benzylamine, N- (2- (5-methoxy-6-fluoro-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- ( 2- (5-methoxy-6-fluoro-1H-indol-3-yl) ethyl) -3- (2,2, -trifluoroethoxy) benzylamine, N- (2- (5-chloro -1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (5-chloro-1H-indol-3-yl) ethyl) -3- (3-fluoropropoxy) benzylamine, N- (2- (5-chloro-lH-indol-3-yl) ethyl) -3- (2,2,3,3,3-pentafluoro Ropropoxy) benzylamine, N- (2- (5-chloro-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (5-methoxy-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (5-cyano-1H -Indol-3-yl) ethyl) -3- (2, 2,2-trifluoroethoxy benzylamine, N- (2- (5-methylsulfonyl-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) Benzylamine, N- (2- (5-cyano-1H-indol-3-yl) ethyl) -3- (3,3,3-trifluoropropoxy) benzylamine, N- (2- (5 -Methylsulfonyl-1H-indol-3-yl) ethyl) -3- (3,3,3-trifluoropropoxy) benzylamine, N- (2- (4-fluoro-1H-indole-3 -Yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (4-fluoro-1H-indol-3-yl) ethyl) -3- (2 , 2,3,3,3-pentafluoropropoxy) benzylamine, N- (2- (4-fluoro-1H-indol-3-yl) ethyl) -3- (2,2,3,3 -Tetrafluoropropoxy) benzylamine, N- (2- (7-fluoro-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (7-fluoro-1H-indol-3-yl) ethyl) -3- (2,2,3,3,3-pentafluoropropoxy) benzylamine, N- (2- ( 7-fluoro-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (5-amido-1H-indole -3-yl) ethyl) -3- (3,3,3- Trifluoropropoxy) benzylamine, N- (2- (5-amido-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N -(2- (6-phenyl-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (6-methyl-1H- Indol-3-yl) ethyl) -3- (2,2,3,3,3-pentafluoropropoxy) benzylamine, N- (2- (6-phenyl-1H-indol-3-yl) ethyl ) -3- (2,2,3,3,3-pentafluoropropoxy) benzylamine, N- (2- (6-phenyl-1H-indol-3-yl) ethyl) -3- (2, 2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (6-methyl-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy ) Benzylamine, N- (2- (6-methyl-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoro propoxy) benzylamine, N- (2- (6-ethoxycarbonyl-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (6-ethoxycarb Bonyl-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (6-cyano-1H-indol-3-yl) Ethyl) -3- (2,2,2-trifluoro Benzylamine, N- (2- (6-cyano-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- ( 2- (6-amido-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (6-amido-1H- Indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (6-trifluoromethoxy-1H-indol-3-yl) Ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (6-trifluoromethoxy-1H-indol-3-yl) ethyl) -3- ( 2,2,2-trifluoroethoxy) benzylamine, N- (2- (7-chloro-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoro Propoxy) benzylamine, N- (2- (7-chloro-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (5-trifluoromethyl-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (5-trifluoromethyl- 1H-indol-3-yl) ethyl) -3- (3,3,3-trifluoropropoxy) benzylamine, N- (2- (4-methoxy-1H-indol-3-yl) ethyl) - 3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (5-cyano-1H-indol-3-yl) ethyl) -3- (2,2,3 , 3-tetrafluoropropoxy) benzylamine, N- (2- (5-cyano-1H-indol-3-yl) ethyl) -3- (2,2,3,3,3-pentafluoro Propoxy) benzylamine, N- (2- (5- (4-fluorophenyl) -1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) Benzylamine, N- (2- (5- (4-fluorophenyl) -1H-indol-3-yl) ethyl) -3- (2,2,3,3,3-pentafluoropropoxy) benzyl Amine, N- (2- (5-phenyl-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (5 -Phenyl-1H-indol-3-yl) ethyl) -3- (2,2,3,3,3-pentafluoropropoxy) benzylamine, N- (2- (5- (4-fluorophenyl ) -1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (5-phenyl-1H-indol-3-yl) ethyl ) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (4-phenyl-1H-indol-3-yl) ethyl) -3- (2,2,3, 3,3-pentafluoropropoxy) benzylamine, N- (2- (4-phenyl-1H-indole- 3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (4-phenyl-1H-indol-3-yl) ethyl) -3- (2 , 2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (7-phenyl-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoro Methoxy) benzylamine, N- (2- (7-phenyl-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2 -(6-chloro-lH-indol-3-yl) ethyl) -N-methyl-3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (4-meth Oxy-1H-indol-3-yl) ethyl) -N-methyl-3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (4-fluoro-1H- Indol-3-yl) ethyl) -N-methyl-3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (6-phenyl-1H-indol-3-yl) ethyl ) -N-methyl-3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (6-carboxy-1H-indol-3-yl) ethyl) -3- ( 2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (6-carboxy-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoro Ethoxy) benzylamine, N- (2- (6-chloro -7-fluoro-1 H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (6-chloro-7-fluoro- 1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (5,7-difluoro-1H-indole-3 -Yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (5,7-difluoro-1H-indol-3-yl) ethyl) -3 -(2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (6,7-difluoro-1H-indol-3-yl) ethyl) -3- (2,2 , 2-trifluoroethoxy) benzylamine, N- (2- (6,7-difluoro-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoro Ropropoxy) benzylamine, N- (2- (5,6,7-trifluoro-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzyl Amine, N- (2- (5,6,7-trifluoro-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N -(2- (4,5,7-trifluoro-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- ( 4,5,7-trifluoro-1H-indol-3-yl) Ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (7-cyano-1H-indol-3-yl) ethyl) -3- (2, 2,2-trifluoroethoxy) benzylamine, N- (2- (7-cyano-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoroprop Foxy) benzylamine, N- (2- (5-fluoro-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (5-Fluoro-1H-indol-3-yl) ethyl) -3- (2,2,3,3,3-pentafluoropropoxy) benzylamine, N- (2- (5-methoxy- 1H-indol-3-yl) ethyl) -3- (2,2,3,3,3-pentafluoropropoxy) benzylamine, N- (2- (5-methoxy-1H-indole-3- Yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (5-methoxy-1H-indol-3-yl) ethyl) -3- ( 3,3,3-trifluoropropoxy) benzylamine, N- (2- (5-fluoro-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoro Lopropoxy) benzylamine, N- (2- (4-chloro-5-methoxy-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine , N- (2- (4-chloro-5-methoxy-1H- Dol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (4-chloro-5-methoxy-1H-indole-3- Yl) ethyl) -3- (3,3,3-trifluoropropoxy) benzylamine, N- (2- (6-fluoro-1H-indol-3-yl) ethyl) -3- (2, 2,2-trifluoroethoxy) benzylamine, N- (2- (6-fluoro-1H-indol-3-yl) ethyl) -3- (2,2,3,3,3-pentafluoro Ropropoxy) benzylamine, N- (2- (6-chloro-5-methoxy-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine , N- (2- (6-chloro-5-methoxy-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- ( 2- (6-Fluoro-1H-indol-3-yl) ethyl) -3- (3,3,3-trifluoropropoxy) benzylamine, N- (2- (5-trifluoromethoxy- 1H-indol-3-yl) ethyl) -3- (2,2,3,3,3-pentafluoropropoxy) benzylamine, N- (2- (5-trifluoromethoxy-1H-indole- 3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (5-trifluoromethoxy-1H-indol-3-yl) ethyl) - 3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (5-nitro-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoro Loethoxy) benzylamine, N- (2- (5-nitro-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (6-nitro-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (6-nitro-1H-indole -3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (6-nitro-1H-indol-3-yl) ethyl) -3 -(2,2,3,3,3-pentafluoropropoxy) benzylamine, N- (2- (5-amino-1H-indol-3-yl) ethyl) -3- (2,2,2 -Trifluoroethoxy) benzylamine, N- (2- (5-amino-1 H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine , N- (2- (6-amino-1 H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (6-amino- 1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (5-propoxy-1H-indol-3-yl) Ethyl) -3- (2,2,3,3-tetrafluor Lopropoxy) benzylamine, N- (2- (5-n-propyl amido-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (5-ethoxycarbonyl-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- ( 5-phenoxy-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (1H-indol-3-yl) Ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (1H-indol-3-yl) ethyl) -3- (2,2,3,3,3 -Pentafluoropropoxy) benzylamine, N- (2- (5-n-butylamido-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) Benzylamine, N- (2- (5-hydroxy-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (5 -Benzyloxy-1H-indol-3-yl) ethyl) -3- (2,2,3,3,3-pentafluoropropoxy) benzylamine, N- (2- (6-benzyloxy-1H- Indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (6-benzyloxy-1H-indol-3-yl) ethyl) -3 -(2,2,3,3-tetrafluoropropoxy Benzylamine, N- (2- (6-butyloxy-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (5-butyloxy-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (6-ethoxy-1H- Indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (6-phenylsulfonyloxy-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (6-phenylsulfonyloxy-1H-indol-3-yl) ethyl) -3- (2,2, 3,3-tetrafluoropropoxy) benzylamine, N- (2- (6-butyloxy-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoroprop Foxy) benzylamine, N- (2- (5-hydroxy-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (5-hydroxy-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (6-hydroxy-1H- Indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (6-hydroxy-1H-indol-3-yl) ethyl) -3 -(2,2,3,3-tetraflu Oropropoxy) benzylamine, N- (2- (5-carboxy-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2 -(6-Chloro-1H-indol-3-yl) ethyl) -3- (3-fluoropropoxy) benzylamine, N- (2- (6-fluoro-1H-indol-3-yl) ethyl ) -3- (3-fluoropropoxy) benzylamine, N- (2- (6-fluoro-1H-indol-3-yl) ethyl) -3- (2,2-difluoroethoxy) Benzylamine, N- (2- (6-chloro-1H-indol-3-yl) ethyl) -3- (2,2-difluoroethoxy) benzylamine, N- (2- (6-chloro- 1H-indol-3-yl) ethyl) -3- (2,2,3,3,3-pentafluoropropoxy) benzylamine, N- (2- (5-isopropyl-1H-indole-3- Yl) ethyl) -3- (2,2,3,3,3-pentafluoropropoxy) benzylamine, N- (2- (5-isopropyl-1H-indol-3-yl) ethyl) -3 -(2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (6-chloro-1H-indol-3-yl) ethyl) -N-methyl-3- (2,2 -Difluoroethoxy) benzylamine, N- (2- (6-fluoro-1H-indol-3-yl) ethyl) -N-methyl-3- (3-fluoropropoxy) benzylamine, N -(2- (6- Loro-1H-indol-3-yl) ethyl) -N-methyl-3- (3-fluoropropoxy) benzylamine, N- (2- (6-chloro-1H-indol-3-yl) ethyl) -N-isopropyl-3- (2,2,3,3,3-pentafluoropropoxy) benzylamine, N- (2- (6-chloro-1H-indol-3-yl) ethyl) -N -Propyl-3- (2,2,3,3,3-pentafluoropropoxy) benzylamine, N- (2- (6-chloro-lH-indol-3-yl) ethyl) -N-ethyl- 3- (2,2,3,3,3-pentafluoropropoxy) benzylamine, N- (2- (6-chloro-5-methoxy-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (6-chloro-5-methoxy-1H-indol-3-yl) ethyl) -3- (2,2 , 2-trifluoroethoxy) benzylamine, N- (2- (4-chloro-5-methoxy-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoro Ethoxy) benzylamine, N- (2- (4-chloro-5-methoxy-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzyl Amine, N- (2- (5-methoxy-1H-indol-3-yl) ethyl) -3- (2-fluoroethoxy) benzylamine, N- (2- (6-methoxy-1H- Indol-3-yl) ethyl) -3- (2,2,3,3,3- Tafluoropropoxy) benzylamine, N- (2- (4-chloro-1H-indol-3-yl) ethyl) -3- (2,2,3,3,3-pentafluoropropoxy) benzyl Amine, N- (2- (4-methoxy-1 H-indol-3-yl) ethyl) -3- (2,2,3,3,3-pentafluoropropoxy) benzylamine, N- (2 -(5-methoxy-2-methyl-1H-indol-3-yl) ethyl) -3- (2,2,3,3,3-pentafluoropropoxy) benzylamine, N- (2- ( 7-methoxy-1H-indol-3-yl) ethyl) -3- (2,2,3,3,3-pentafluoropropoxy) benzylamine, N- (2- (4-methoxy-1H -Indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (5-methoxy-2-methyl-1H-indole-3 -Yl) ethyl) -3- (2,2,3, -tetrafluoropropoxy) benzylamine, N- (2- (7-methoxy-1H-indol-3-yl) ethyl) -3- ( 2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (6-methoxy-1H-indol-3-yl) ethyl) -3- (2-fluoroethoxy) benzyl Amine, N- (2- (4-chloro-1H-indol-3-yl) ethyl) -3- (2-fluoroethoxy) benzylamine, N- (2- (4-methoxy-1H-indole -3-yl) ethyl) -3- (2-fluoroethoxy) Nitrile, N- (2- (5-methoxy-2-methyl-1H-indol-3-yl) ethyl) -3- (2-fluoroethoxy) benzylamine, N- (2- (7- Methoxy-1H-indol-3-yl) ethyl) -3- (2-fluoroethoxy) benzylamine, N- (2- (6-chloro-1H-indol-3-yl) ethyl) -3- (2-fluoroethoxy) benzylamine, N- (2- (6-methoxy-1H-indol-3-yl) ethyl) -3- (2,2-difluoroethoxy) benzylamine, N -(2- (6-Fluoro-1H-indol-3-yl) ethyl) -3- (2-fluoroethoxy) benzylamine, N- (2- (4,6-dichloro-5-methoxy -1H-indol-3-yl) ethyl) -3- (2,2-difluoroethoxy) benzylamine, N- (2- (4-chloro-1H-indol-3-yl) ethyl) -3 -(2,2-difluoroethoxy) benzylamine, N- (2- (4-methoxy-1H-indol-3-yl) ethyl) -3- (2,2-difluoroethoxy) Benzylamine, N- (2- (5-methoxy-2-methyl-1H-indol-3-yl) ethyl) -3- (2,2-difluoroethoxy) benzylamine, N- (2- (7-methoxy-1H-indol-3-yl) ethyl) -3- (2,2-difluoroethoxy) benzylamine, N- (2- (6-methoxy-1H-indole-3- Yl) ethyl) -3- (3-fluoropropoxy) benzylamine, N- ( 2- (4-chloro-1H-indol-3-yl) ethyl) -3- (3-fluoropropoxy) benzylamine, N- (2- (4-methoxy-1H-indol-3-yl) Ethyl) -3- (3-fluoropropoxy) benzylamine, N- (2- (5-methoxy-2-methyl-1H-indol-3-yl) ethyl) -3- (3-fluoroprop Foxy) benzylamine, N- (2- (7-methoxy-1H-indol-3-yl) ethyl) -3- (3-fluoropropoxy) benzylamine, N- (2- (6-chloro- 1H-indol-3-yl) ethyl) -3- (3-fluoropropoxy) benzylamine, N- (2- (6-methoxy1H-indol-3-yl) ethyl) -3- (2, 2,2-trifluoroethoxy) benzylamine, N- (2- (4-chloro-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzyl Amine, N- (2- (4-methoxy-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (5- Methoxy-2-methyl-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (7-methoxy-1H-indole -3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (6-chloro-lH-indol-3-yl) ethyl) -3- ( 2,2,2-trifluoroethoxy) benzylamine , N- (2- (6-methoxy-1-methyl-1H-indol-3-yl) ethyl) -3- (2,2-difluoroethoxy) benzylamine, N- (2- (5 -Methoxy-4,6-difluoro-1-methyl-1H-indol-3-yl) ethyl) -3- (3-fluoropropoxy) benzylamine, N- (2- (5-methoxy -4,6-difluoro-1-methyl-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (5- Methoxy-1-methyl-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (5-methoxy-1 -Methyl-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (6-trifluoromethyl-1H-indole-3 -Yl) ethyl) -3- (3,3,3-trifluoropropoxy) benzylamine, N- (2- (5-fluoro-6-chloro-1H-indol-3-yl) ethyl)- 3- (3,3,3-trifluoropropoxy) benzylamine, N- (2- (5,6-difluoro-1H-indol-3-yl) ethyl) -3- (3,3, 3-trifluoropropoxy) benzylamine, N- (2- (5-fluoro-6-chloro-1H-indol-3-yl) ethyl) -3- (2,2-difluoroethoxy) Benzylamine, N- (2- (5,6-difluoro) -1H-indol-3-yl) ethyl) -3- (2,2-difluoroethoxy) benzylamine, N- (2- (6-trifluoromethyl-1H-indol-3-yl) ethyl ) -3- (2,2-difluoroethoxy) benzylamine, N- (2- (6-trifluoromethyl-1H-indol-3-yl) ethyl) -3- (2,2,2 -Trifluoroethoxy) benzylamine, N- (2- (5-fluoro-6-chloro-1H-indol-3-yl) ethyl) -3- (2,2,3,3,3-penta Fluoropropoxy) benzylamine, N- (2- (5,6-difluoro-1H-indol-3-yl) ethyl) -3- (2,2,3,3,3-pentafluoroprop Foxy) benzylamine, N- (2- (6-trifluoromethyl-1H-indol-3-yl) ethyl) -3- (2,2,3,3,3-pentafluoropropoxy) benzylamine , N- (2- (5,6-difluoro-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- ( 5,6-difluoro-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (5,6-difluoro -1H-indol-3-yl) ethyl) -3- (3-fluoropropoxy) benzylamine, N- (2- (6-trifluoromethyl-1H-indol-3-yl) ethyl) -3 -(3-fluoropro Benzylamine, N- (2- (6-fluoro-1-methyl-1H-indol-3-yl) ethyl) -3- (3,3,3-trifluoropropoxy) benzylamine, N -(2- (6-Fluoro-1-methyl-1H-indol-3-yl) ethyl) -3- (2,2,3,3,3-pentafluoropropoxy) benzylamine, N- ( 2- (6-fluoro-1-methyl-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (5-methyl -1H-indol-3-yl) ethyl) -3- (2-fluoroethoxy) benzylamine, N- (2- (5-fluoro-1H-indol-3-yl) ethyl) -3- ( 2-fluoroethoxy) benzylamine, N- (2- (5-methyl-1H-indol-3-yl) ethyl) -3- (2,2-difluoroethoxy) benzylamine, N- ( 2- (5-fluoro-1H-indol-3-yl) ethyl) -3- (2,2-difluoroethoxy) benzylamine, N- (2- (5-chloro-1H-indole-3 -Yl) ethyl) -3- (2,2-difluoroethoxy) benzylamine, N- (2- (5-fluoro-1H-indol-3-yl) ethyl) -3- (4,4 , 4-trifluorobutoxy) benzylamine, N- (2- (5-fluoro-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzyl Amine, N- (2- (5-chloro-lH-indol-3-yl) Ethyl) -3- (4,4,4-trifluorobutoxy) benzylamine, N- (2- (5-fluoro-1H-indol-3-yl) ethyl) -3- (3-fluoro Propoxy) benzylamine, N- (2- (5-chloro-1H-indol-3-yl) ethyl) -3- (3-fluoropropoxy) benzylamine, N- (2- (5-methyl- 1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (5-methyl-1H-indol-3-yl) ethyl ) -3- (2,2,3,3,3-pentafluoropropoxy) benzylamine, N- (2- (5-methyl-1H-indol-3-yl) ethyl) -3- (3- Fluoropropoxy) benzylamine, N- (2- (5-methoxy-1H-indol-3-yl) ethyl) -3- (4,4,4-trifluorobutoxy) benzylamine, N- (2- (5-chloro-lH-indol-3-yl) ethyl) -3- (2-fluoroethoxy) benzylamine, N- (2- (4,7-difluoro-lH-indole- 3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (4,5,6,7-tetrafluoro-1H-indol-3-yl ) Ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (6-bromo-1H-indol-3-yl) ethyl) -3- (2,2 , 3,3-tetrafluoropropoxy) benzylamine, N- (2- (6-bromo-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethyl) benzylamine, N- (2- (6-methanesulfonyl -1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (6-methanesulfonyl-1H-indole-3- Yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (6-benzenesulfonyl-1H-indol-3-yl) ethyl) -3- (2 , 2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (6-benzenesulfonyl-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoro Loethoxy) benzylamine, N- (2- (6-methoxy-1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N -(2- (7-Fluoro-1H-indol-3-yl) ethyl) -3- (3,3,3-trifluoropropoxy) benzylamine, N- (2- (6-bromo- 1H-indol-3-yl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (6-bromo-1H-indol-3-yl) Ethyl) -3- (2,2,3,3,3-pentafluoropropoxy) benzylamine, N- (2- (6-methoxycarbonyl-1H-indol-3-yl) ethyl) -3 -(2,2,2-trifluoroethoxy) bene Amine, N-2- (5-benzamido-1H-indol-3-yl) -ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N-2- (5- Benzamido-1H-indol-3-yl) -ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N-2- (5-methylsulfonylamino-1H- Indol-3-yl) -ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N-2- (5-methylsulfonylamino-1H-indol-3-yl) -ethyl ) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N-2- (5-isopropyl-1H-indol-3-yl) -ethyl) -3- (2,2 , 2-trifluoroethoxy) benzylamine, N-2- (5-isopropyl-1H-indol-3-yl) -ethyl) -3- (2,2,3,3-tetrafluoropropoxy ) Benzylamine, N-2- (5-ethoxy-1H-indol-3-yl) -ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N-2- (5 -Ethoxy-1H-indol-3-yl) -ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N-2- (5- (2,2,2- Trifluoroethoxy) -1H-indol-3-yl) -ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N-2- (5- (2,2,2 Trifluoroethoxy) -1H-indol-3-yl) -ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N-2- (5-butoxy-1H-indol-3-yl ) -Ethyl) -3- (pyrid-2-yloxy) benzylamine, N-2- (5-benzenesulfonyl-1H-indol-3-yl) -ethyl) -3- (2,2,3 , 3-tetrafluoropropoxy) benzylamine, N-2- (5-benzenesulfonyl-1H-indol-3-yl) -ethyl) -3- (2,2,2-trifluoroethoxy) Benzylamine, N-2- (5-ethoxycarbonyl-1H-indol-3-yl) -ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N-2- ( 5- (N'-propylamido) -1H-indol-3-yl) -ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N-2- (5- (N'-propylamido) -1H-indol-3-yl) -ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N-2- (5- (N'- Butylamido) -1H-indol-3-yl) -ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N-2- (1H-indol-3-yl) -Ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N-2- (5-benzyloxy-1H-indol-3-yl) -ethyl) -3- (2 , 2,2-trifluoroethoxy) benzylamine, N-2- (5-benzyloxy-1H-indol-3-yl) -ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N-2- (5-phenoxy-1H- Indol-3-yl) -ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N-2- (5-phenoxy-1H-indol-3-yl) -ethyl ) -3- (2,2,2-trifluoroethoxy) benzylamine, N-2- (5- (pyrid-3-yloxy) -1H-indol-3-yl) -ethyl) -3 -(2,2,3,3-tetrafluoropropoxy) benzylamine, N-2- (5- (pyrid-3-yloxy) -1H-indol-3-yl) -ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N-methyl-N- (2- (6-chloro-1H-indol-3-yl) ethyl) -3- (2,2-difluoro Roethoxy) benzylamine, N-2- (4,7-difluoro-1H-indol-3-yl) -ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N-2- (4,5,6,7-tetrafluoro-1H-indol-3-yl) -ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N-2 -(4,7-difluoro-1 H-indol-3-yl) -ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N-2- (4,5 , 6,7-tetrafluoro-1H-indol-3-yl) -ethyl) -3- (2,2 , 3,3-tetrafluoropropoxy) benzylamine, N-2- (7-trifluoromethyl-1H-indol-3-yl) -ethyl) -3- (2,2,2-trifluoro Ethoxy) benzylamine, N-2- (7-trifluoromethyl-1H-indol-3-yl) -ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N-2- (7-nitro-1H-indol-3-yl) -ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine and N-2- (7-nitro-1H- Indol-3-yl) -ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine.
[15" claim-type="Currently amended] The compound of claim 1, wherein N- (2-phenylphenylethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (4-phenylphenylethyl) -3- (2,2 , 2-trifluoroethoxy) benzylamine, N- (2- (4-chlorophenyl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- ( 3-trifluoromethylphenyl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (3-chlorophenyl) ethyl) -3- (2,2,3 , 3,3-pentafluoropropoxy) benzylamine, N- (2- (3-trifluoromethylphenyl) ethyl) -3- (2,2,3,3,3-pentafluoropropoxy) benzyl Amine, N- (2- (3-chlorophenyl) ethyl) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (3-trifluoromethylphenyl) ethyl ) -3- (2,2,3,3-tetrafluoropropoxy) benzylamine, N- (2- (3-trifluoromethylphenyl) ethyl) -3- (3,3,3-trifluoro Propoxy) benzylamine, N- (2- (3-chlorophenyl) ethyl) -3- (3,3,3-trifluoropropoxy) benzylamine, N- (2- (3,5-dimethoxy Phenyl) ethyl) -3- (2,2,2-trifluoro Methoxy) benzylamine, N- (2- (3-chlorophenyl) ethyl) -3- (2-fluoroethoxy) benzylamine, N- (2- (3-trifluoromethylphenyl) ethyl) -3- (2-fluoroethoxy) benzylamine, N- (2- (3,5-dimethoxyphenyl) ethyl) -3- (2-fluoroethoxy) benzylamine, N- (2- (3-tri Fluoromethyl-4-fluorophenyl) ethyl) -3- (3,3,3-trifluoropropoxy) benzylamine, N- (2- (3-trifluoromethyl-4-fluorophenyl) Ethyl) -3- (2,2-difluoroethoxy) benzylamine, N- (2- (3-trifluoromethyl-4-fluorophenyl) ethyl) -3- (2,2,3, 3,3-pentafluoropropoxy) benzylamine, N- (2- (3-trifluoromethyl-4-fluorophenyl) ethyl) -3- (2,2,2-trifluoroethoxy) Benzylamine and N- (2- (3-trifluoromethyl-4-fluorophenyl) ethyl) -3- (3-fluoropropoxy) benzylamine.
[16" claim-type="Currently amended] The compound of claim 1, wherein N- (2- (5-methoxy-1H-indol-3-yl) ethyl) -3-phenoxybenzylamine, N- (2- (1H-indol-3-yl) ethyl ) -3-phenoxybenzylamine, N- (2- (5-methoxy-1H-indol-3-yl) ethyl) -3- (3-fluorophenoxy) benzylamine, N- (2- ( 1H-indol-3-yl) ethyl) -3- (3-fluorophenoxy) benzylamine, N- (2- (5-methoxy-1H-indol-3-yl) ethyl) -3- (2 -Fluorophenoxy) benzylamine, N- (2- (1H-indol-3-yl) ethyl) -3- (2-fluorophenoxy) benzylamine, N- (2- (5-methoxy- 1H-indol-3-yl) ethyl) -3- (4-fluorophenoxy) benzylamine, N- (2- (1H-indol-3-yl) ethyl) -3- (4-fluorophenoxy ) Benzylamine, N- (2- (5-hydroxy-1H-indol-3-yl) ethyl) -3-phenoxybenzylamine, N- (2- (5-phenoxy-1H-indole-3- Il) ethyl) -3-phenoxybenzylamine, N- (2- (5-p-tolyloxy-1H-indol-3-yl) ethyl) -3-phenoxybenzylamine, N- (2- (5 -o-tolyloxy-1H-indol-3-yl) ethyl) -3-phenoxy benzylamine, N- (2- (5-m-tolyloxy-1H-indol-3-yl) ethyl) -3- Phenoxybenzylamine, N- (2- (6-fluoro-1H-indol-3-yl) Tyl) -2-fluoro-3-phenoxy-benzylamine, N- (2- (6-fluoro-1H-indol-3-yl) ethyl) -6-fluoro-3-phenoxy-benzylamine , N-methyl-N- (2- (5-m-tolyloxy-1H-indol-3-yl) ethyl) -3-phenoxybenzylamine, N- (2- (5-nitro-1H-indole- 3-yl) ethyl) -3-phenoxybenzylamine, N- (2- (5-amino-1 H-indol-3-yl) ethyl) -3-phenoxybenzylamine, N- (2- (5- Propoxy-1H-indol-3-yl) ethyl) -3-phenoxybenzylamine, N- (2- (5-ethoxycarbonyl-1H-indol-3-yl) ethyl) -3-phenoxy benzyl Amine, N- (2- (5-phenyl-1H-indol-3-yl) ethyl) -3-phenoxybenzylamine, N- (2- (5- (4-fluorophenyl) -1H-indole- 3-yl) ethyl) -3-phenoxybenzylamine, N- (2- (6-phenyl-1H-indol-3-yl) ethyl) -3-phenoxybenzylamine, N- (2- (6- Trifluoromethyl-1H-indol-3-yl) ethyl) -3-phenoxybenzylamine, N- (2- (6-fluoro-1H-indol-3-yl) ethyl) -3-phenoxybenzyl Amine N- (2- (6-chloro-5-methoxy-1H-indol-3-yl) ethyl) -3-phenoxybenzylamine, N- (2- (4-chloro-5-methoxy-1H -Indol-3-yl) ethyl) -3-phenoxy Benzylamine, N- (2- (6-chloro-1H-indol-3-yl) ethyl) -3-phenoxybenzylamine, N- (2- (4,6-dichloro-5-methoxy-1H- Indol-3-yl) ethyl) -3-phenoxybenzylamine, N- (2- (6-methoxy-1H-indol-3-yl) ethyl) -3-phenoxybenzylamine, N- (2- (4-chloro-1H-indol-3-yl) ethyl) -3-phenoxybenzylamine, N- (2- (4-methoxy-1H-indol-3-yl) ethyl) -3-phenoxybenzyl Amine, N- (2- (5-methoxy-2-methyl-1H-indol-3-yl) ethyl) -3-phenoxybenzylamine, N- (2- (7-methoxy-1H-indole- 3-yl) ethyl) -3-phenoxybenzylamine, N- (2- (5-methoxy-4,6-difluoro-1-methyl-1H-indol-3-yl) ethyl) -3- (2,2,2-trifluoroethoxy) benzylamine, N- (2- (5-methyl-1H-indol-3-yl) ethyl) -3-phenoxybenzylamine, N- (2- ( 5-chloro-1H-indol-3-yl) ethyl) -3-phenoxybenzylamine, N- (2- (5- (4-fluorophenyl) -1H-indol-3-yl) ethyl) -3 -Phenoxybenzylamine, N- (2- (5-methanesulfonyl-1H-indol-3-yl) -ethyl) -3-phenoxy benzylamine, N- (2- (5-cyano-1H- Indol-3-yl) -ethyl) -3-phenoxybenzylamine, N- (2- (5-methoxy Cycarbonyl-1H-indol-3-yl) -ethyl) -3-phenoxybenzylamine, N- (2- (5-amido-1H-indol-3-yl) -ethyl) -3-phenoxy Benzylamine, N-2- (5-nitro-1H-indol-3-yl) -ethyl) -3-phenoxybenzylamine, N-2- (5-butoxy-1H-indol-3-yl)- Ethyl) -3-phenoxybenzylamine, N-2- (5-benzamido-1H-indol-3-yl) -ethyl) -3-phenoxybenzylamine, N-2- (5-methylsulfonyl Amino-1H-indol-3-yl) -ethyl) -3-phenoxybenzylamine, N-2- (5-isopropyl-1H-indol-3-yl) -ethyl) -3-phenoxybenzylamine, N-2- (5-ethoxy-1H-indol-3-yl) -ethyl) -3-phenoxybenzylamine, N-2- (5- (2,2,2-trifluoroethoxy)- 1H-indol-3-yl) -ethyl) -3-phenoxybenzylamine, N-2- (5-benzenesulfonyl-1H-indol-3-yl) -ethyl) -3-phenoxybenzylamine, N -2- (5- (N'-propylamido) -1 H-indol-3-yl) -ethyl) -3-phenoxybenzylamine, N-2- (5- (N'-butylamido)- 1H-indol-3-yl) -ethyl) -3-phenoxybenzylamine, N-2- (5-phenoxy-1H-indol-3-yl) -ethyl) -3-phenoxybenzylamine, N- Methyl-N-2- (5-phenoxy-1H-indol-3-yl)- Tyl) -3-phenoxybenzylamine, N- (2- (6-fluoro-1H-indol-3-yl) ethyl) -4-fluoro-3-phenoxybenzylamine, N- (2- ( 6-fluoro-1H-indol-3-yl) ethyl) -3-phenoxybenzylamine, N- (2- (5-benzyloxy-1H-indol-3-yl) -ethyl) -3-phenoxy Benzylamine and N- (2- (5-benzyloxy-1H-indol-3-yl) -ethyl) -N-methyl-3-phenoxybenzyl) benzylamine.
[17" claim-type="Currently amended] A compound according to claim 1, wherein N- (2- (3-chlorophenyl) ethyl) -3-phenoxybenzylamine, N- (2- (3-trifluoromethylphenyl) ethyl) -3-phenoxybenzylamine, N- (2- (4-methoxyphenyl) ethyl) -3-phenoxybenzylamine, N- (2- (3,4-dimethoxyphenyl) ethyl) -3-phenoxybenzylamine, N- (2 -(3-methoxyphenyl) ethyl) -3-phenoxybenzylamine, N- (2- (3,4-dichlorophenyl) ethyl) -3-phenoxybenzylamine, N- (2- (3-chloro Phenyl) ethyl) -3- (3-trifluoromethylphenoxy) benzylamine, N- (2- (3-chlorophenyl) ethyl) -3- (4-t-butylphenoxy) benzylamine, N- (2- (3-chlorophenyl) ethyl) -3- (4-chlorophenoxy) benzylamine, N- (2- (3-chlorophenyl) ethyl) -3- (4-methoxyphenoxy) benzylamine , N- (2- (3-chlorophenyl) ethyl) -3- (4-methylphenoxy) benzylamine, N- (2- (3-chlorophenyl) ethyl) -3- (3,5-dichlorophenoxy Benzylamine, N- (2- (3-chlorophenyl) ethyl) -3- (3,4-dichlorophenoxy) benzylamine, N- (2-phenylethyl) -3-phenoxybenzylamine, N -(2- (4-chlorophenyl) ethyl) -3-phenoxybenzylamine, N- (2- (3-chlorophenyl) ethyl) -3- (4-fluorophenoxy) benzylamine, N- (2- (3-trifluoromethylphenyl) ethyl) -3- (4-fluoro Phenoxy) benzylamine, N- (2- (3-chlorophenyl) ethyl) -3- (2-fluorophenoxy) benzylamine, N- (2- (3-trifluoromethylphenyl) ethyl) -3 -(2-fluorophenoxy) benzylamine, N- (2- (3-chlorophenyl) ethyl) -3- (3-fluorophenoxy) benzylamine, N- (2- (3-trifluoro Methylphenyl) ethyl) -3- (3-fluorophenoxy) benzylamine, N- (2- (2-chlorophenyl) ethyl) -3-phenyloxybenzylamine, N- (2- (3,4-dime Methoxyphenyl) ethyl) -3-phenoxyoxybenzylamine, N- (2- (3-chlorophenyl) ethyl) -N-methyl-3-phenoxybenzylamine, N- (2- (3-chlorophenyl) Ethyl) -N-ethyl-3-phenoxybenzylamine, N- (2- (2-fluorophenyl) ethyl) -3-phenoxybenzylamine, N- (2- (3-fluorophenyl) ethyl) -3-phenoxybenzylamine, N- (2- (4-chlorophenyl) ethyl) -3-phenoxybenzylamine, N- (2- (4-hydroxyphenyl) ethyl) -3-phenoxybenzylamine , N- (2- (2-methoxy Phenyl) ethyl) -3-phenoxybenzylamine, N- (2- (3-bromo-3-methoxyphenyl) ethyl) -3-phenoxybenzylamine, N- (2- (4-fluorophenyl ) Ethyl) -3-phenoxybenzylamine, N- (2- (2-chlorophenyl) ethyl) -3-phenoxybenzylamine, N- (2- (4-bromophenyl) ethyl) -3-phenoxy Cibenzylamine, N- (2- (4-methylphenyl) ethyl) -3-phenoxybenzylamine, N- (2- (3-methoxyphenyl) ethyl) -3-phenoxybenzylamine, N- (2 -(4-methoxyphenyl) ethyl) -3-phenoxybenzylamine, N- (2- (2-ethoxyphenyl) ethyl) -3-phenoxybenzylamine, N- (2- (4-ethoxy Phenyl) ethyl) -3-phenoxybenzylamine, N- (2- (4-phenoxyphenyl) ethyl) -3-phenoxybenzylamine, N- (2- (4-sulfonamidophenyl) ethyl)- 3-phenoxybenzylamine, N- (2- (3,4-dichlorophenyl) ethyl) -3-phenoxybenzylamine, N- (2- (2,5-dichlorophenyl) ethyl) -3-phenoxy Benzylamine, N- (2- (2,6-dichlorophenyl) ethyl) -3-phenoxybenzylamine, N- (2- (2,5-dimethoxyphenyl) ethyl) -3-phenoxybenzylamine, N- (2- (2,3-dimethoxyphenyl) ethyl) -3-phenoxybenzylamine, N- (2- (3,5-dimethoxyphenyl) ethyl) -3-phenoxybenzylamine and N- (2- (3-ethoxy-4-methoxyphenyl) ethyl) -3-phenoxybenzylamine compound.
[18" claim-type="Currently amended] The compound of claim 1, wherein N- (2-pyrid-4-ylethyl) -3-phenoxybenzylamine, N- (2-pyrid-3-ylethyl) -3-phenoxybenzylamine, N- (2- (pyrid-2-ylethyl) -3-phenoxybenzylamine, N- (2-imidazol-4-ylethyl) -3-phenoxybenzylamine, N- (2-naphth-2 -Ylethyl) -3-phenoxybenzylamine, N- (2-naphth-1-ylethyl) -3-phenoxybenzylamine and N- (2- (thien-2-ylethyl) -3-phenoxy A compound selected from the group consisting of cibenzylamine.
[19" claim-type="Currently amended] The compound of claim 1, wherein N- (2- (1H-indol-3-yl) ethyl) -3-thiophenoxybenzylamine, N- (2- (1H-indol-3-yl) ethyl) -3 -Phenylsulfonylbenzylamine, N- (2- (5-methoxy-1H-indol-3-yl) ethyl) -3-thiophenoxybenzylamine, N- (2- (5-methoxy-1H -Indol-3-yl) ethyl) -3-phenylsulfonylbenzylamine, N- (2- (1H-indol-3-yl) ethyl) -3- (4-methylthiophenoxy) benzylamine, N -(2- (1H-indol-3-yl) ethyl) -3- (4-methylphenylsulfonyl) benzylamine, N- (2- (5-methoxy-1H-indol-3-yl) ethyl)- 3- (α-fluorobenzyl) benzylamine, N- (2- (1H-indol-3-yl) ethyl) -3- (α-fluorobenzyl) benzylamine, N- (2- (5-meth Oxy-1H-indol-3-yl) ethyl) -3- (benzyl) benzylamine, N- (2- (1H-indol-3-yl) ethyl) -3- (benzyl) benzylamine, N- (2 -(5-methoxy-1H-indol-3-yl) ethyl) -3- (α-hydroxybenzyl) benzylamine, N- (2- (5-methoxy-1H-indol-3-yl) ethyl ) -3- (N-phenylamino) benzylamine, N- (2- (1H-indol-3-yl) ethyl) -3- (N-phenylamino) benzylamine, N- (2- (5-meth Oxy-1H-indol-3-yl) ethyl) -3- (N-benzylamino) benzylamine , N- (2- (1H-indol-3-yl) ethyl) -3- (N-benzylamino) benzylamine, N- (2- (5-methoxy-1H-indol-3-yl) ethyl) -3-hydroxybenzylamine, N- (2- (1H-indol-3-yl) ethyl) -3-hydroxybenzylamine, N- (2- (5-methoxy-1 H-indol-3-yl ) Ethyl) -3-naphth-1-yloxybenzylamine, N- (2- (1H-indol-3-yl) ethyl) -3-naphth-1-yloxybenzylamine, N- (2- (5-methoxy-1H-indol-3-yl) ethyl) -3-naphth-2-yloxybenzylamine, N- (2- (1H-indol-3-yl) ethyl) -3-naphth 2-yloxybenzylamine, N- (2- (5-methoxy-1H-indol-3-yl) ethyl) -3-benzyloxybenzylamine, N- (2- (1H-indol-3-yl ) Ethyl) -3-benzyloxybenzylamine, N- (2- (5-methoxy-1H-indol-3-yl) ethyl) -3-pyrimid-5-yloxy benzylamine, N- (2- (1H-Indol-3-yl) ethyl) -3-pyrimid-5-yloxybenzylamine, N- (2- (5-methoxy-1H-indol-3-yl) ethyl) -3-pyrid 4-yloxybenzylamine, N- (2- (1H-indol-3-yl) ethyl) -3-pyrid-4-yloxybenzylamine, N- (2- (6-chloro-1H-indole -3-yl) ethyl) -3-pyrid-4-yloxybenzylamine, N- (2- (5) -Methoxy-1H-indol-3-yl) ethyl) -3-pyrid-3-yloxybenzylamine, N- (2- (1H-indol-3-yl) ethyl) -3-pyrid-3 -Yloxybenzylamine, N- (2- (5-fluoro-1H-indol-3-yl) ethyl) -3-pyrid-3-yloxybenzylamine, N- (2- (6-chloro- 1H-indol-3-yl) ethyl) -3-pyrid-3-yloxy benzylamine, N- (2- (5-methoxy-1H-indol-3-yl) ethyl) -3-pyrid- 2-yloxybenzylamine, N- (2- (1H-indol-3-yl) ethyl) -3-pyrid-2-yloxybenzylamine, N- (2- (6-chloro-1H-indole- 3-yl) ethyl) -3-pyrid-2-yloxybenzylamine, N- (2- (5-methoxy-1H-indol-3-yl) ethyl) -3-thiazol-2-yloxy Benzylamine, N- (2- (1H-indol-3-yl) ethyl) -3-thiazol-2-yloxybenzylamine, N- (2- (5-methoxy-1H-indol-3-yl ) Ethyl) -3- (2,6-difluorosulfonyloxy) benzylamine, N- (2- (1H-indol-3-yl) ethyl) -3- (2,6-difluorosulfonyl Oxy) benzylamine, N- (2- (5-methoxy-1H-indol-3-yl) ethyl) -3- (pyrid-2-ylamino) benzylamine, N- (2- (1H-indole) -3-yl) ethyl) -3- (pyrid-2-ylamino) benzyl , N- (2- (6-chloro-1H-indol-3-yl) ethyl) -3- (pyrid-2-ylamino) benzylamine, N- (2- (5-methoxy-1H-indole -3-yl) ethyl) -3- (pyrid-3-yl amino) benzylamine, N- (2- (1H-indol-3-yl) ethyl) -3- (pyrid-3-ylamino) Benzylamine, N- (2- (6-chloro-1H-indol-3-yl) ethyl) -3- (pyrid-3-ylamino) benzylamine, N- (2- (5-methoxy-1H -Indol-3-yl) ethyl) -3- (pyrid-4-ylamino) benzylamine, N- (2- (1H-indol-3-yl) ethyl) -3- (pyrid-4-yl Amino) benzylamine, N- (2- (6-chloro-1H-indol-3-yl) ethyl) -3- (pyrid-4-ylamino) benzylamine, N- (2- (5-methoxy -1H-indol-3-yl) ethyl) -3-benzoylbenzylamine, N- (2- (1H-indol-3-yl) ethyl) -3-benzoylbenzylamine, N- (2- (6-fluoro Rho-1H-indol-3-yl) ethyl) -3- (pyrid-4-yloxy) benzylamine, N- (2- (6-fluoro-1H-indol-3-yl) ethyl) -3 -(Pyrid-3-yloxy) benzylamine, N- (2- (3-chlorophenyl) ethyl) -3-thiophenoxybenzylamine, N- (2- (3-chlorophenyl) ethyl)- 3-sulfonylphenylbenzylamine, N- (2-phenyl ) -3-thiophenoxybenzylamine, N- (2-phenylethyl) -3-sulfonylphenylbenzylamine, N- (2- (3-chlorophenyl) ethyl) -3- (4-methylthiope NOXY) Benzylamine, N- (2- (3-chlorophenyl) ethyl) -3-sulfonyl-4-methylphenylbenzylamine, N- (2- (3-chlorophenyl) ethyl) -3- (N- Benzylamino) benzylamine, N- (2- (3-chlorophenyl) ethyl) -3- (N-phenylamino) benzylamine, N- (2- (3-chlorophenyl) ethyl) -3- (α- Hydroxybenzyl) benzylamine, N- (2- (3-chlorophenyl) ethyl) -3-benzylbenzylamine, N- (2- (3-chlorophenyl) ethyl) -3- (α-fluorobenzyl) Benzylamine, N- (2- (3-chlorophenyl) ethyl) -3-naphth-2-yloxybenzylamine, N- (2- (3-trifluoromethylphenyl) ethyl) -3-naphth- 2-yloxybenzylamine, N- (2- (3-chlorophenyl) ethyl) -3-naphth-1-yloxybenzylamine, N- (2- (3-trifluoromethylphenyl) ethyl) -3 -Naphth-1-yloxybenzylamine, N- (2- (3-chlorophenyl) ethyl) -3-hydroxybenzylamine, N- (2- (3-trifluoromethylphenyl) ethyl) -3- Hydroxybenzylamine, N- (2- (3-trifluoromethylphenyl) ethyl) -3-benzyloxybenzylamine, N- (2- (3-chlorophenyl) ethyl) -3- (2,4-difluoro phenylsulfonyl Oxy) benzylamine, N- (2- (3-trifluoromethylphenyl) ethyl) -3- (2,4-difluoro phenylsulfonyloxy) benzylamine, N- (2- (3-chlorophenyl) Ethyl) -3-thiazol-2-yloxybenzylamine, N- (2- (3-trifluoromethylphenyl) ethyl) -3-thiazol-2-yloxy benzylamine, N- (2- (3 -Chlorophenyl) ethyl) -3-pyrid-3-yloxybenzylamine, N- (2- (3-trifluoromethylphenyl) ethyl) -3-pyrid-3-yloxybenzylamine, N- ( 2- (3-methoxyphenyl) ethyl) -3-pyrid-2-yloxybenzylamine, N- (2- (3-trifluoromethylphenyl) ethyl) -3-pyrid-4-yloxybenzyl Amine, N- (2- (3-chlorophenyl) ethyl) -3-pyrimid-5-yloxybenzylamine, N- (2- (3-trifluoromethylphenyl) ethyl) -3-pyrimid-5 -Yloxybenzylamine, N- (2- (3-trifluoromethylphenyl) ethyl) -3-pyrid-2-yloxybenzylamine, N- (2- (3-chlorophenyl) Ethyl) -3-pyrid-3-ylaminobenzylamine, N- (2- (3-trifluoromethylphenyl) ethyl) -3-pyrid-3-ylaminobenzylamine, N- (2- (3 -Chlorophenyl) ethyl) -3-pyrid-4-ylaminobenzylamine, N- (2- (3-trifluoromethylphenyl) ethyl) -3-pyrid-4-ylaminobenzylamine, N- ( 2- (3-chlorophenyl) ethyl) -3-pyrid-2-ylaminobenzylamine, N- (2- (3-trifluoromethylphenyl) ethyl) -3-pyrid-2-ylaminobenzylamine , N- (2- (3-chlorophenyl) ethyl) -3-benzyloxybenzylamine, N- (2- (3-trifluoromethylphenyl) ethyl) -3- (phenylamino) benzylamine, N- ( 2- (7-fluoro-1H-indol-3-yl) ethyl) -3- (pyrid-4-yloxy) benzylamine, N- (2- (7-fluoro-1H-indole-3- Yl) ethyl) -3- (pyrid-3-yloxy) benzylamine, N- (2- (3-chlorophenyl) ethyl) -3- (pyrid-2-ylmethoxy) benzylamine, N- ( 2- (3-chlorophenyl) ethyl) -3- (pyrid-3-ylmethoxy) benzylamine, N- (2- (3-chlorophenyl) ethyl) -3- (pyrid-4-ylmethoxy) Benzylamine, N-2- (5-butoxy -1H-indol-3-yl) -ethyl) -3- (pyrid-2-yloxy) benzylamine and N- (2- (6,7-difluoro-1H-indol-3-yl)- Ethyl) -3- (pyridin-4-yloxy) benzylamine.
[20" claim-type="Currently amended] The compound of claim 1, wherein N- (2- (3-chlorophenyl) ethyl) -3-ethoxybenzylamine, N- (2- (3-chlorophenyl) ethyl) -3-propoxybenzylamine, N- (2- (3-trifluoromethylphenyl) ethyl) -3-propoxybenzylamine, N- (2- (3-trifluoromethylphenyl) ethyl) -3-ethoxybenzylamine, N- (2- ( 5-chloro-1H-indol-3-yl) ethyl) -3-ethoxybenzylamine, N- (2- (5-chloro-1H-indol-3-yl) ethyl) -3-propoxybenzylamine, N- (2- (5-fluoro-1H-indol-3-yl) ethyl) -3-propoxybenzylamine, N- (2- (5-fluoro-1H-indol-3-yl) ethyl) 3-Ethoxybenzylamine, N- (2- (5-trifluoromethyl-1H-indol-3-yl) ethyl) -3-ethoxybenzylamine, N- (2- (5-trifluoro Methyl-1H-indol-3-yl) ethyl) -3-propoxybenzylamine, N- (2- (5-methoxy-1H-indol-3-yl) ethyl) -3-ethoxybenzylamine, N -(2- (5-methoxy-1H-indol-3-yl) ethyl) -3-propoxybenzylamine, N- (2- (4-chloro-1H-indol-3-yl) ethyl) -3 Propoxybenzylamine, N- (2- (4-methoxy-1 H-indol-3-yl) ethyl) -3-propoxybene Amine, N- (2- (5-methoxy-2-methyl-1H-indol-3-yl) ethyl) -3-propoxybenzylamine, N- (2- (7-methoxy-1H-indole- 3-yl) ethyl) -3-propoxybenzylamine, N- (2- (6-chloro-1H-indol-3-yl) ethyl) -3-propoxybenzylamine, N- (2- (6- Fluoro-1-methyl-1H-indol-3-yl) ethyl) -N-methyl-3-propoxybenzylamine, N- (2- (3-trifluoromethyl-4-fluorophenyl) ethyl) -3-propoxy-4-methylbenzylamine, N- (2- (5-fluoro-6-chloro-1 H-indol-3-yl) ethyl) -3-propoxy-4-methylbenzylamine, N -(2- (6-Fluoro-1-methyl-1H-indol-3-yl) ethyl) -3-propoxy-4-methylbenzylamine, N- (2- (3-chlorophenyl) ethyl)- 3-propoxybenzylamine, N- (2- (3-chlorophenyl) ethyl) -3-butoxybenzylamine, N- (2- (3-chlorophenyl) ethyl) -3-hexybenzylamine, N -(2- (2-fluorophenyl) ethyl) -3-propoxybenzylamine, N- (2- (3-fluorophenyl) ethyl) -3-propoxybenzylamine, N- (2- (4 -Fluorophenyl) ethyl) -3-propoxybenzylamine, N- (2- (2-chlorophenyl) ethyl) -3 -Propoxybenzylamine, N- (2- (4-chlorophenyl) ethyl) -3-propoxybenzylamine, N- (2- (4-bromophenyl) ethyl) -3-propoxybenzylamine, N -(2- (4-methylphenyl) ethyl) -3-propoxybenzylamine, N- (2- (4-hydroxyphenyl) ethyl) -3-propoxybenzylamine, N- (2- (2-meth Methoxyphenyl) ethyl) -3-propoxybenzylamine, N- (2- (3-methoxyphenyl) ethyl) -3-propoxybenzylamine, N- (2- (4-methoxyphenyl) ethyl)- 3-propoxybenzylamine, N- (2- (3-ethoxyphenyl) ethyl) -3-propoxybenzylamine, N- (2- (4-ethoxyphenyl) ethyl) -3-propoxybenzylamine , N- (2- (4-phenoxyphenyl) ethyl) -3-propoxybenzylamine, N- (2- (4-sulfonamidophenyl) ethyl) -3-propoxybenzylamine, N- (2 -(3,4-dichlorophenyl) ethyl) -3-propoxybenzylamine, N- (2- (2,5-dichlorophenyl) ethyl) -3-propoxybenzylamine, N- (2- (2, 6-dichlorophenyl) ethyl) -3-propoxybenzylamine, N- (2- (3,4-dimethoxyphenyl) ethyl) -3-propoxybenzylamine, N- (2- (2,5-dimeth Methoxyphenyl) ethyl) -3-pro Cibenzylamine, N- (2- (2,3-dimethoxyphenyl) ethyl) -3-propoxybenzylamine, N- (2- (3,5-dimethoxyphenyl) ethyl) -3-propoxybenzyl Amine, N- (2- (3-bromo-4-methoxyphenyl) ethyl) -3-propoxybenzylamine, N- (2- (3-methoxy-4-ethoxyphenyl) ethyl) -3 Propoxybenzylamine, N- (2- (3-ethoxy-4-methoxyphenyl) ethyl) -3-propoxybenzylamine, N- (2- (pyrid-2-yl) ethyl) -3 Propoxybenzylamine, N- (2- (pyrid-3-yl) ethyl) -3-propoxybenzylamine, N- (2- (pyrid-4-yl) ethyl) -3-propoxybenzyl Amine, N- (2- (7-methyl-1H-indol-3-yl) ethyl) -3-propoxybenzylamine, N- (2- (6-methoxy-1H-indol-3-yl) ethyl ) -3-propoxybenzylamine, N- (2- (thien-3-yl) ethyl) -3-propoxybenzylamine, N- (2- (5-methyl-1H-indol-3-yl) ethyl ) -3-propoxybenzylamine, N- (2- (5-methoxy-1H-indol-3-yl) ethyl) -3-propoxybenzylamine, N- (2- (3-bromophenyl) Ethyl) -3-propoxybenzylamine, N- (2- (3-methoxycarbonylphenyl) ethyl) -3-propoxybenzylamine N- (2- (3- (4- fluorophenyl) phenyl) ethyl) -3-propoxy-benzyl compound selected from the group consisting of amine.
[21" claim-type="Currently amended] A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable diluent.
[22" claim-type="Currently amended] The method of treating disorders associated with 5-HT ₆ receptor which comprises the treatment of disorders associated with the compound of claim 1 and a 5-HT ₆ receptor administered to a patient in need an effective amount.
[23" claim-type="Currently amended] The method of claim 22, comprising administering an effective amount of the compound of claim 1 to a patient in need of treatment for a disorder associated with the 5-HT ₆ receptor, wherein the disorder is selected from the group consisting of cognitive impairment, schizophrenia, anxiety and Alzheimer's disease. How.
[24" claim-type="Currently amended] A method of treating cognitive disorders comprising administering an effective amount of a compound of claim 1 to a patient in need thereof.
[25" claim-type="Currently amended] A method of treating memory disorders comprising administering an effective amount of a compound of claim 1 to a patient in need thereof.
[26" claim-type="Currently amended] A method of treating psychosis comprising administering an effective amount of a compound of claim 1 to a patient in need thereof.
[27" claim-type="Currently amended] A method of treating schizophrenia comprising administering an effective amount of the compound of claim 1 to a patient in need thereof.
[28" claim-type="Currently amended] A method of treating anxiety comprising administering an effective amount of a compound of claim 1 to a patient in need of treatment for a disorder associated with a 5-HT ₆ receptor.
<Claim 28>
Use as a pharmaceutical of claim 1.
[29" claim-type="Currently amended] Use of the compound of claim 1 for the manufacture of a medicament for treating a disorder associated with 5-HT ₆ receptor.
[30" claim-type="Currently amended] Use of a compound of claim 1 for the manufacture of a medicament for treating a cognitive disorder.
[31" claim-type="Currently amended] Use of a compound of claim 1 for the manufacture of a medicament for treating a memory disorder.
[32" claim-type="Currently amended] Use of a compound of claim 1 for the manufacture of a medicament for the treatment of psychosis.
[33" claim-type="Currently amended] Use of a compound of claim 1 for the manufacture of a medicament for treating schizophrenia.
[34" claim-type="Currently amended] Use of a compound of claim 1 for the manufacture of a medicament for treating anxiety.
[35" claim-type="Currently amended] Compounds of Formula II and pharmaceutically acceptable salts thereof.
<Formula II>

Where
Y is selected from the group consisting of O, NH and NR ₉ , wherein R ₉ is selected from the group consisting of C ₁ -C ₄ alkyl and optionally substituted phenyl;
R ₅ and R ₆ are hydrogen, or combine with the atoms to which they are attached to form a benzo ring, but when Y is NR ₉ , it is hydrogen;
R ₇ is an optionally substituted 5- and 6-membered monocyclic aromatic heterocyclo having one heteroatom selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, nitrogen, oxygen and sulfur and optionally benzofused Selected from the group consisting of;
R ₈ is selected from the group consisting of hydrogen and C ₁ -C ₃ alkyl.
[36" claim-type="Currently amended] The method of claim 31, wherein Compounds having residues attached at 4- or 6-positions.
[37" claim-type="Currently amended] 37. The compound of claim 36, wherein Y is O.
[38" claim-type="Currently amended] The compound of claim 36, wherein Y is NH.
[39" claim-type="Currently amended] The compound of claim 36, wherein Y is NR ₉ .
[40" claim-type="Currently amended] The compound of claim 36, wherein R ₅ and R ₆ join together with the atoms to which they are attached to form a phenyl ring.
[41" claim-type="Currently amended] The compound of claim 36, wherein R ₅ and R ₆ are hydrogen.
[42" claim-type="Currently amended] 42. The optionally substituted 5 member of any one of claims 36 to 41, wherein R ₇ is optionally substituted phenyl and one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and optionally benzofused. And a 6 membered monocyclic aromatic heterocycle.
[43" claim-type="Currently amended] 43. The compound of claim 42, wherein the optionally benzofused 5- and 6-membered monocyclic aromatic heterocycle is optionally substituted indol-3-yl.
[44" claim-type="Currently amended] A pharmaceutical composition comprising the compound of claim 35 and a pharmaceutically acceptable diluent.
[45" claim-type="Currently amended] The compound of claim 35 for 5-HT ₆ A method of treating disorders associated with, 5-HT ₆ receptor which comprises the treatment of disorders associated with the receptor administered to a patient in need an effective amount.
[46" claim-type="Currently amended] 46. The method of claim 45, wherein said disorder is selected from the group consisting of cognitive impairment, schizophrenia, anxiety and Alzheimer's disease.
[47" claim-type="Currently amended] Use of the compound of claim 35 for the manufacture of a medicament.
[48" claim-type="Currently amended] Use of the compound of claim 35 for the manufacture of a medicament for the treatment of a disorder associated with 5-HT ₆ receptor.
[49" claim-type="Currently amended] 49. The use of claim 48, wherein the disorder is selected from the group consisting of cognitive impairment, schizophrenia, anxiety and Alzheimer's disease.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2001-03-29|Priority to US27992801P

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2001-03-29|Priority to US60/279,928

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2001-10-15|Priority to US32944901P

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2001-10-15|Priority to US60/329,449

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2002-03-15|Application filed by 일라이 릴리 앤드 캄파니

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2002-03-15|Priority to PCT/US2002/005115

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2003-11-28|Publication of KR20030090694A

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2009-04-22|Application granted

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2009-04-22|Publication of KR100894189B1

优先权:

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申请号 | 申请日 | 专利标题

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US27992801P| true| 2001-03-29|2001-03-29|

---

US60/279,928|2001-03-29|

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US32944901P| true| 2001-10-15|2001-10-15|

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US60/329,449|2001-10-15|

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PCT/US2002/005115|WO2002078693A2|2001-03-29|2002-03-15|N-benzylamines as antagonists of the 5-ht6 receptor|