Indane or dihydroindole derivatives

专利摘要:
The present invention relates to substituted indane or dihydroindole compounds of formula (I), wherein A is indole. This compound has a high affinity for the D 4 receptor. Formula I
公开号:KR20000069621A
申请号:KR1019997005622
申请日:1997-12-19
公开日:2000-11-25
发明作者:젠스 크리스티안 페레가아르트；베니 뱅-안데르젠；헨리크 페더젠；이반 미켈젠；로버트 댄서
申请人:피터슨 존 메이달；하. 룬트벡 아크티에 셀스카브；
IPC主号:

专利说明:

Indane or dihydroindole derivatives {INDANE OR DIHYDROINDOLE DERIVATIVES}
Compounds related to the compounds of the present invention are described in DE patent application No. 4, which describes 4- (indol-3-yl) -1- (indol-3-yl-alkylene) -piperidine. Known from 4414113. Patented herein is a compound that shows serotonin antagonist and facilitation activity and has a DOPA-accumulating action in striatum. No biological data given.
GB patent application no. It describes particular 1- (indol-3-yl-alkylene) -piperidine derivatives wherein 2 044 254 is substituted at the 3 or 4 position of the piperidine ring or isoquinoline ring with isoindole. These compounds have been patented which have 5-HT reuptake inhibitory activity and are useful as antidepressants.
Moreover, WO Patent Publication No. In WO 9421627, WO 9421630 and WO 9421626 various series of indolyl- or indazolylmethyl piperidine or piperazine derivatives are described as selective dopamine D ₄ antagonists. No data given. It is only described that the compound provides a Ki value of less than 1.5 μM in a test for the substitution of ³ H Spiferon from the human dopamine D4 receptor subtype in clone cell lines.
WO Patent Publication No. 95/33721 relates to 1- (indanemethyl, dihydrobenzofuranylmethyl, or dihydrobenzothiophenylmethyl) piperidine, -tetrahydropyridine, or piperazine derivatives. The 1-indanemethyl compound disclosed herein is substituted at position 6 with an amino containing group. The compound interacts with major 5-HT receptors, specifically 5-HT _1A and 5-HT _2A receptors. Some compounds are said to have a 5-HT reuptake inhibitory effect.
Dopamine D ₄ receptors belong to the dopamine D ₂ receptor family which is believed to be responsible for the antipsychotic action of neuroleptics. Dopamine D ₄ receptors are primarily located closer to the brain than the striatum (Van Tol, et al. Nature, 1991, 350, 610). Low levels of the D ₄ receptor present in the striatum suggest that the compound is selective for the dopamine D4 receptor and will not have extrapyramidal activity, which has a high affinity for the dopamine D ₄ receptor in the striatum and envelope pyramid. Proven by antipsychotic clozapine with no adverse side effects (Van Tol, et al. Nature, 1991, 350, 610). Dopamine D ₄ receptor levels have also been reported to be elevated in schizophrenic patients (Seeman et al., Nature, 1993, 365, 441).
Various actions are known for compounds that are ligands in other serotonin receptor subtypes. Already to relative to the 5-HT _2A receptors referred to as 5-HT ₂ receptors it has been reported action.
Treatment with classic neuroleptics in patients with schizophrenia has shown antidepressant action and improved sleep quality (Meert, TF; Janssen, PAJ Drug. Dev. Res. 1989, 18, 119), negative symptoms and extrapyramidal schizophrenia. Causing side effects reduction (Gelders, YG, British J. Psychiatry, 1989, 155 (suppl. 5, 33). Finally, selective 5-HT _2A is effective in the prevention and treatment of migraine headaches (Scrip Report; "Migraine"). -Current trends in research and treatment "; PJB Publications Ltd .; May 1991).
Clinical studies are useful for the treatment of anxiety disorders, such as generalized anxiety disorders, panic and obsessive compulsive agonists of 5-HT _1A (Glitz, DA, Pohl, R., Drugs 1991, 41, 11). Pre-symptom studies suggest that all agonists are useful for the treatment of the anxiety-related disorders mentioned above (Schipper, Human Psychopharmacol., 1991, 6, S53).
There is evidence of both clinical and pre-symptomatic support for the beneficial effects of partial agonists of 5-HT _1A in the treatment of depression, impulse suppression disorders and alcohol abuse (van Hest, Psychopharmacol., 1992, 107, 474; Schipper et. al, Human Psychopharmacol., 1991, 6, S53; Cervo et al, Eur. J. Pharm., 1988, 158, 53; Glitz and Poh, Drugs 1991, 41, 11; Grof et al., Int. Clin. 1993, 8,167-172; Ansseau et al., Human Psychopharmacol. 1993, 8,279-283).
5-HT _1A agonists and partial agonists inhibit aggression due to sequestration in male mice, suggesting that these compounds are useful for aggressive treatment (Sanchez et al., Psychopharmacology, 1993, 110, 53-59). .
Moreover, 5-HT _1A ligands have been reported to exhibit antipsychotic activity in animal models (Wadenberg and Ahlenius, J. Neural. Transm., 1991, 83, 43; Ahlenius, Pharmacol. & Toxicol., 1989, 64, 3). Lowe et al., J. Med. Chem., 1991, 34, 1860; New et al., J. Med. Chem., 1989, 32, 1147; and Martin et al., J. Med. Chem., 1989,32,1052).
Recent studies have also shown that the 5-HT _1A agonist is useful for the treatment of extrapyramidal side effects induced by conventional antipsychotic drugs such as haloperidol, while the 5-HT _1A receptor is haloperidol-induced schizophrenia. Implied in regulation (Hicks, Life Science 1990, 47, 1609, Wadenberg et al. Prarmacol. Biochem. & Behav. 1994, 47,509-513).
5-HT _1A agonists have been shown to be neuroprotective in rodent models of local and global cerebral ischemia and are useful in the treatment of ischemic disease states (Prehn, Eur. J. Pharm. 1995, 203, 213).
Pharmacological studies have been suggested suggesting that 5-HT _1A antagonists are useful for the treatment of senile dementia (Bowen et al, Trends Neur. Sci. 1992, 15, 84).
5-HT reuptake inhibitors are well known antidepressants.
Thus, dopamine D ₄ receptor ligands are potential agents for positive symptoms of psychosis and schizophrenia, and compounds with a combined action on dopamine D ₄ and 5-HT receptors and / or 5-HT transporters are associated with depression and anxiety. In patients with schizophrenia, such as symptoms, it is more beneficial because it has an improved effect on other psychiatric symptoms. 5-HT _1A and 5-HT _2A receptor ligands and 5-HT reuptake inhibitors are described in other animal models where anti-anxiety and anti-aggressive activity is expected (Perregaard et al., Recent Developments in Anxiolytics.Current Opinion in Therapeutic Patents 1993, 1,101-128) and / or having such a combined serotonin action is considered to be extremely beneficial as it has different activity in the model in which the action on other psychiatric diseases is anticipated.
Neurological and psychiatric chemical comprising a functional combination with the dopamine D ₄ receptor with the active compound and 5-HT reuptake inhibitory activity in combination with a dopamine D ₄ are compounds with the receptor activity specifically psychosis in the 5-HT receptor It is considered a new therapeutic approach in the treatment of disease.
The present invention relates to a new class of substituted indane or dihydroindole compounds that act on the dopamine D ₄ receptor. The compound is a selective dopamine D ₄ ligand or acts in combination with dopamine D ₄ , a 5-HT receptor and / or a 5-HT transporter. Therefore these compounds are useful for the treatment of certain psychiatric and neurological diseases, including psychosis, depression and anxiety.
It is an object of the present invention to provide compounds having a combined action on dopamine D ₄ activity or dopamine D ₄ receptor, 5-HT receptor and / or 5-HT transporter.
It has now been found that certain substituted indane or dihydroindole compounds act on the dopamine D ₄ receptor. Additionally many of the compounds interact with major serotonin receptors, specifically 5-HT _1A and / or 5-HT _2A receptors and / or act as 5-HT reuptake inhibitors.
The present invention therefore relates to novel formula (I) and pharmaceutically acceptable salts thereof.
Where A is the next group.

Y is a hydrocarbon group that completes the indane ring, a group that completes the dihydroindole ring NR ¹ or a group that completes the dihydroindole ring linked via position 1.
* W is a bond and n + m is 1,2,3,4,5 or 6;
W is CO, SO or SO ₂ , n is 2,3,4 or 5, m is 0,1,2 or 3 and n + m is 6 or less; or
* W is O, S, n is 2,3,4 or 5, m is 0,1,2 or 3 and n + m is 6 or less, and N completes the dihydroindole ring linked through 1 position If m is 2 or 3; M is 1,2 or 3 if Y is NR ^1, which completes the dihydroindole ring linked through the 2-position;
Dashed lines from X indicate additional bonds; If not a bond, X is N, CH or COH; If bound, X represents C.
R ¹ is
Hydrogen, C _1-6 -alk (en / yn) yl, C _3-8 -cycloalk (en) yl, C _3-8 -cycloalk (en) yl-C _1-6 -alk (en / yne) yl Yl, aryl, heteroaryl, aryl-C _1-6 alkyl, heteroaryl-C _1-6 -alkyl, acyl, thioacyl, C _1-6 alkylsulfonyl, trifluoromethylsulfonyl, arylsulfonyl or Heteroarylsulfonyl, or
R ¹⁵ VCO- where V is O or S and R ¹⁵ is C _1-6 -alk (en / yn) yl, C _3-8 -cycloalk (en) yl, C _3-8 -cycloalk (en / Yn) yl-C _1-6 -alk (en / yn) yl, aryl or heteroaryl; or
* A group R ¹⁶ R ¹⁷ NCO- or R ¹⁶ R ¹⁷ NCS- wherein R ¹⁶ and R ¹⁷ are independently hydrogen, C _1-6 -alk (en / yn) yl, C _3-8 -cycloalk (en ), C _3-8 -cycloalk (en) yl-C _1-6 -alk (en / yn) yl, heteroaryl or aryl or pyrrolidinyl with the N atom R ¹⁶ and R ¹⁷ linked thereto , Piperidinyl or perhydroazepine groups.
R ² -R ⁵ are independently hydrogen, halogen, cyano, nitro, C _1-6 -alk (en / yn) yl, C _1-6 alkoxy, C _1-6 -alkylthio, hydroxy, C _{3- 8} -cycloalk (en) yl, C _3-8 -cycloalk (en) yl-C _1-6 -alk (en / yn) yl, C _1-6 -alkylcarbonyl, phenylcarbonyl, halogen substituted Phenylcarbonyl, trifluoromethyl, trifluoromethylsulfonyloxy and C _1-6 alkylsulfonyl, otherwise -NR ¹³ R ¹⁴ , where R ¹³ is as defined for R ¹ and R ¹⁴ is Hydrogen, C _1-6 -alk (en / yn) yl, C _3-8 -cycloalk (en) yl, C _3-8 -cycloalk (en) yl-C _1-6 -alk (en / yn) Or one, aryl, heteroaryl, aryl-C _1-6 -alkyl or heteroaryl-C _1-6 -alkyl, or R ¹³ and R ¹⁴ are linked with an N atom to form the following groups.

Wherein Q is C═O, C═S or CH ₂ ; T is NH, N-alkyl, S, O or CH ₂ ; p is 1-4; or
Two adjacent groups employed from R ² -R ⁵ are joined to represent — (CH ₂ ) ₃ —, or —CH═CH—NH, thereby forming a fused five-membered ring;
R ⁶ -R ⁹ and R ¹¹ -R ¹² are independently hydrogen, halogen, cyano, nitro, C _1-6 -alk (en / yn) yl, C _1-6 -alkoxy, C _1-6 -alkylthio , Hydroxy, C _3-8 -cycloalk (en) yl, C _3-8 -cycloalk (en) yl-C _1-6 -alk (en / yn) yl, aryl, heteroaryl, phenylcarbonyl, Two adjacent groups employed from halogen substituted phenylcarbonyl, trifluoromethyl, or C _1-6 -alkylsulfonyl, or R ⁶ -R ⁹ together form a methylenedioxy group;
R ¹⁰ is as defined for R ¹ above;
Provided that the substituent R ³ or R ⁴ at position 6 cannot be —NR ¹³ R ¹⁴ if Y is CH ₂ , W is a bond, n + m is 1 and the ring is linked via position 1.
It has been found that the compounds of the present invention show high affinity for the dopamine D ₄ receptor and some of the compounds also show affinity for the serotonin receptor, including the 5-HT _1A receptor and / or the 5-HT _2A receptor. . The main group of compounds according to the invention are compounds which act on the dopamine D ₄ receptor in combination with 5-HT reuptake inhibitory action.
Thus, the compounds of the present invention are directed to the positive and negative symptoms of schizophrenia, other psychiatric disorders, generalized anxiety disorders, panic, anxiety disorders such as OCD, depression, alcohol abuse, impulse suppression disorders, aggression, and conventional antipsychotics. It is thought to be useful for the treatment and improvement of sleep caused by side effects caused by ischemia, migraine, migraine, senile dementia and cardiovascular disease.
In another aspect the present invention provides a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof as defined above in combination with one or more pharmaceutically acceptable carriers or diluents It provides a pharmaceutical composition comprising a.
In another aspect the present invention provides the use of a compound of formula (I) or an acid addition salt thereof as defined above for the production of pharmaceutical preparations for the treatment of the abovementioned diseases.
Some compounds of formula (I) exist as their optical isomers, which are also included in the present invention.
The expression C _1-6 -alk (en / yn) yl refers to a C _1-6 -alkyl, C _2-6 -alkenyl, or C _2-6 -alkenyl group.
It means a cycloalkenyl-expression C _3-8 - cycloalkyl alk (en) What C _3-8 - cycloalkyl group, or C _3-8.
The term C _1-6 alkyl refers to _1-6 including such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl and 2-methyl-1-propyl Refers to a branched or branched alkyl group having 3 carbon atoms.
Similarly, C _2-6 alkenyl and C _2-6 alkynyl, each having 2-6 carbon atoms, each containing a double bond and a triple bond, ethenyl, propenyl, butenyl, ethynyl, propynyl, And groups such as butynyl.
The terms C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylsulfonyl, C _1-6 alkylamino, C _1-6 alkylcarbonyl, and the like, as defined above, indicate that the alkyl group is C _1-6 alkyl. It represents a phosphorus group.
The term C _3-8 cycloalkyl refers to a monocyclic or bicyclic ring hydrocarbon having 3-8 carbon atoms such as cyclopropyl, cyclopentyl, cyclohexyl and the like.
The term C _3-8 cycloalkenyl refers to a monocyclic or bicyclic ring hydrocarbon having 3-8 carbon atoms and containing one double bond.
The term aryl refers to the aromatics of ring hydrocarbons such as phenyl, naphthyl, specifically methyl substituted naphthyl or phenyl, including phenyl.
The term heteroaryl is indole, thienyl, pyrimidyl, oxazolyl, isoxazole, thiazolyl, isothiazolyl, imidazolyl, benzofuranyl, benzothienyl, pyridyl and furanyl, specifically pyrimidyl, It refers to a single or double ring heterocyclic group such as indolyl and thienyl.
Halogen means fluoro, chlorine, bromine or iodine.
The term acyl as used herein is formyl, C _1-6 alk (en / yn) ylcarbonyl, arylcarbonyl, aryl-C _1-6 alk (en / yn) ylcarbonyl, C _3-8 Refers to a cycloalk (en) ylcarbonyl or C _3-8 -cycloalk (en) yl-C _1-6 alk (en / yn) ylcarbonyl group wherein the term thioacyl refers to a carbonyl group substituted with a thiocarbonyl group Having an acyl group.
One group of compounds according to the invention are those compounds in which Y completes the indan ring.
Another group of compounds according to the invention is a group of compounds wherein Y is NR ¹ or N to complete the dihydroindole ring.
Thus one group of compounds is a compound wherein Y is CH ₂ and A is group a), or group b), specifically group a), linked to X via positions 2 or 3.
Another group of compounds are compounds wherein Y is CH ₂ and A is a group c) linked to X via positions 4,5,6 or 7.
The third and fourth groups of compounds are groups a), or group b), specifically group a), wherein Y is NR ¹ or N and A is linked to X via positions 2,3.
The fifth and sixth group of compounds is the group c) where Y is NR ¹ or N and A is linked to X via positions 4,5,6 or 7.
Embodiments of the present invention
Y is a hydrocarbon group that completes the indane ring
A compound connected through a 2-position and A is a) via a position 3;
A compound connected through a 2-position and A is a group connected via position 2;
Linked through the 2-position and A is the group b);
A compound c) linked via the 2-position and A is the group c) linked via positions 4,5,6 or 7;
A compound linked through 1-position and A is group a) linked via position 3;
A compound linked through 1-position and A is group a) linked via position 2;
Linked through the 1-position and A is the group b); or
Is a group c) linked via 1-position and A is linked via position 4,5,6 or 7.
Another embodiment of the invention
Y is NR ¹ to complete the dihydroindole ring
A compound linked through 3-position and group A) in which A is linked via position 3;
A compound linked through 3-position and A is a group linked via position 2;
Linked via the 3-position and A is the group b);
A compound c) linked through the 3-position and A is the group c) linked via positions 4,5,6 or 7;
A compound connected through a 2-position and A is a) via a position 3;
A compound connected through a 2-position and A is a group connected via position 2;
Linked through the 2-position and A is the group b); or
And a group c) linked via the 2-position and A is linked via the position 4,5,6 or 7.
Another embodiment of the invention
Y is N to complete the dihydroindole
A compound wherein A is group a) linked via position 3;
A compound wherein A is group a) linked via position 2;
A is a group b); or
A is a group c) linked via position 4,5,6 or 7.
One group of compounds is selected from W is a bond and n + m is 1-4 or n + m is 1 and / or 2.
In other groups of compounds, W is a bond and n + m is 2-6, 2-5, 2-4, 3-6, 3-5 or 3-4
Phosphorus compound.
If W is not a bond, it is O or CO.
Another three groups of compounds are compounds wherein X is CH, X is C, and X is N, respectively.
In one embodiment R ¹ is selected from hydrogen, C _1-6 -alkyl, formyl, C _1-6 -alkylcarbonyl, C _1-6 -alkoxycarbonyl or C _1-6 -alkylaminocarbonyl.
In one embodiment of the invention R ² -R ⁵ is independently hydrogen, halogen, cyano, nitro, C _1-6 -alkyl, C _1-6 alkoxy, C _1-6 -alkylthio, hydroxy, C _{3 -8} -cycloalkyl C _3-8 -cycloalkyl-C _1-6 -alkyl, C _1-6 -alkylcarbonyl, trifluoromethyl, trifluoromethylsulfonyloxy and C _1-6 alkylsulfonyl ,
Otherwise a -NR ¹³ R ¹⁴ group, where R ¹³ is hydrogen, C _1-6 -alkyl, acyl, C _1-2 -alkylsulfonyl or R ¹⁶ is hydrogen, C _1-6 -alkyl, C _{3- 8} -cycloalkyl or C _3-8 -cycloalkyl-C _1-6 -alkyl and R ¹⁷ is hydrogen or C _1-6 -alkyl or R ¹⁶ and R ¹⁷ are linked with an N atom and together pyrrolidinyl, piperi A -R ¹⁶ R ¹⁷ NCO group that forms a dinyl or perhydroazepine group, R ¹⁴ is hydrogen or C _1-6 -alkyl, or R ¹³ and R ¹⁴ are linked to each other to form pyrrolidinyl, piperidinyl, perhydro Forms an azepine or a 5-7 membered unsubstituted lactam ring, specifically R ² -R ⁵ is hydrogen, halogen, cyano, nitro, C _1-6 -alkyl, C _1-6 -alkoxy, trifluor Romethyl and trifluoromethylsulfonyloxy.
Not any airway group NR ¹³ R ¹⁴ in R ² -R ⁵ in one group of compounds according to the invention, another group of compounds according to the invention in that at least one inde NR ¹³ R ¹⁴ where in R ² -R ⁵ R ¹³ is preferably methyl, formyl, acetyl, methylaminocarbonyl, dimethylaminocarbonyl, methylsulfonyl, aminocarbonyl, cyclopropylcarbonyl, pyrrolidinylcarbonyl or 4-fluorophenylaminocarbonyl And R ¹⁴ is preferably selected from hydrogen or C _1-6 -alkyl.
Another specific group of compounds according to the present invention combine two adjacent groups employed from R ² -R ⁵ to represent —CH═CH—NH—, thereby forming a fused five-membered ring.
In one embodiment of the invention R ⁶ -R ⁹ is independently hydrogen, halogen, cyano, nitro, C _1-6 -alkyl, C _1-6 -alkoxy, C _1-6 -alkylthio, hydroxy, C _3-8 - cycloalkyl, C _3-8 - cycloalkyl, -C _1-6 alkyl, selected from methyl and C _1-6 alkylsulfonyl, trifluoromethyl and R ⁶ of two adjacent groups are employed in the United from -R ⁹ A methylenedioxy group, specifically two adjacent groups wherein R ⁶ -R ⁹ are independently hydrogen, halogen, C _1-6 -alkyl, C _1-6 -alkoxy or R ⁶ -R ⁹ are combined to form methylenedi Represents an oxy group.
A subgroup of compounds are compounds wherein at least one of R ⁸ and R ⁹ is hydrogen and R ⁶ -R ⁷ are independently hydrogen or halogen, specifically chlorine.
Particular examples of R ¹¹ and R ¹² are hydrogen or C _1-6 -alkyl and R ¹⁰ is hydrogen, C _1-6 -alkyl or acyl.
Preferred compounds are those compounds selected from or pharmaceutically acceptable acid addition salts thereof.
6-chloro-3- [1- (6-bromo-1-yndanylmethyl) -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
3- [1- (1-indanylmethyl) -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
3- [1- (1-indanylmethyl) piperidin-4-yl] -1 H-indole,
6-chloro-3- [1- (7-methoxyindan-1-yl) methyl-1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
3- [1- (6-methoxyindan-1-yl) methyl-1,2,3,6-tetrahydropyridin-4-yl] -1H-indole, oxalate,
6-chloro-3- [1- (6-cyano-1-indanylmethyl) -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
6-chloro-3- [1- (6-cyano-1-yndanylmethyl) piperidin-4-yl] -1H-indole,
6-chloro-3- [1- (4-acetylamino-1-indanylmethyl) -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
6-chloro-3- [1- (5-acetylamino-1-indanylmethyl) -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
6-chloro-3- [1- (6-bromo-1-yndanylmethyl) -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
6-chloro-3- [1- [2- (indan-1-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
5-fluoro-3- [1- [2- (indan-1-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
5-fluoro-3- [1- [2- (indan-1-yl) ethyl] -piperidin-4-yl] -1 H-indole,
5-fluoro-3- [1- [4- (indan-1-yl) butan-1-yl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
5-fluoro-3- [1- [4- (indan-1-yl) butan-1-yl] -piperidin-4-yl] -1H-indole,
6-chloro-3- [1- [4- (indan-1-yl) butan-1-yl] -piperidin-4-yl] -1H-indole,
6-chloro-3- [1- [3- (indan-1-yl) propan-1-yl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
6-chloro-3- [1- [4- (indan-1-yl) butan-1-yl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
6-chloro-3- [1- (indan-2-yl) methyl-1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
3- [1- (indan-2-yl) methyl-1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
7-chloro-3- [1- (indan-2-yl) methyl-1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
6,7-dichloro-3- [1- (indan-2-yl) methyl-1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
3- [1- (indan-2-yl) methyl-1,2,3,6-tetrahydropyridin-4-yl] -5,6-methylenedioxy-1H-indole,
5- [4- (indan-2-yl) methylpiperazin-1-yl] -1H-indole,
6-chloro-3- [1- [2- (indan-2-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
6-chloro-3- [1- [3- (indan-2-yl) propan-1-yl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
6-chloro-3- [1- [4- (indan-2-yl) butan-1-yl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
3- [1-[(4- (2-propyl) oxyindan-2-yl) methyl] piperidin-4-yl] -6-chloro-1H-indole,
4- [4- (6-chloro-1H-indol-3-yl) -1,2,3,6-tetrahydropyridin-1-ylmethyl] -1,4,5,6-tetrahydrocyclopent [ e] indol,
6-chloro-3- [1- (4-acetylaminoindan-2-yl) methyl-1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
6-chloro-3- [1- (4-acetylaminoindan-2-yl) methylpiperidin-4-yl] -1H-indole,
6-chloro-3- [1- [2- (6-acetylaminoindan-1-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
6-chloro-3- [1- [3- (6-acetylaminoindan-1-yl) propan-1-yl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole ,
6-chloro-3- [1- [4- (6-acetylaminoindan-1-yl) butan-1-yl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole ,
3- [1- (5-acetylaminoindan-2-yl) methyl-1,2,3,6-tetrahydropyridin-4-yl] -6-chloro-1H-indole,
3- [1- (5-acetylaminoindan-2-yl) methylpiperid-4-yl] -6-chloro-1H-indole,
3- [1- [2- (1-acetyl-2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -6- Chloro-1H-indole,
3- [1- [2- (1-acetyl-2,3-dihydro-1H-indol-3-yl) ethyl] piperidin-4-yl] -6-chloro-1H-indole,
6-chloro-3- [1- [2- (1-formyl-2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridine-4- Japanese] -1H-indole,
6-chloro-3- [1- [2- (1-formyl-2,3-dihydro-1H-indol-3-yl) ethyl] piperidin-4-yl] -1H-indole,
3- [1- [2- (1-acetyl-5-bromo-2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridine-4- General] -6-chloro-1H-indole,
3- [1- [2- (1-acetyl-2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -7- Chloro-1H-indole,
3- [1- [2- (1-acetyl-2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -6, 7-dichloro-1H-indole,
3- [1- [2- (1-acetyl-2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -5, 6-methylenedioxy-1H-indole,
3- [1- [2- (1-tert-butoxycarbonyl-2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridine-4- General] -6-chloro-1H-indole,
5- [4- [2- (1-acetyl-2,3-dihydro-1H-indol-3-yl) ethyl] piperazin-1-yl] -1H-indole,
3- [1- [3- (1-acetyl-2,3-dihydro-1H-indol-3-yl) propan-1-yl] -1,2,3,6-tetrahydropyridin-4-yl ] -6-chloro-1H-indole,
3- [1- [2- (1-acetyl-5-fluoro-2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridine-4- General] -6-chloro-1H-indole,
3- [1- [2- (1-acetyl-5-methyl-2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl ] -6-chloro-1H-indole,
6-chloro-3- [1- (indan-2-ylmethyl) piperidin-4-yl] -1H-indole,
3- [1- (indan-2-ylmethyl) piperidin-4-yl] -1H-indole,
7-chloro-3- [1- (indan-2-ylmethyl) piperidin-4-yl] -1H-indole,
6,7-dichloro-3- [1- (indan-2-ylmethyl) piperidin-4-yl] -1H-indole,
3- [1- (indan-2-ylmethyl) piperidin-4-yl] -5,6-methylenedioxy-1H-indole,
6-chloro-3- [1- [2- (indan-2-yl) ethyl] piperidin-4-yl] -1H-indole,
6-chloro-3- [1- [3- (indan-2-yl) propan-3-yl] piperidin-4-yl] -1H-indole,
6-chloro-3- [1- [4- (indan-2-yl) butan-4-yl] piperidin-4-yl] -1H-indole,
4- [4- [2- (indan-2-yl) ethyl] piperazin-1-yl] -1H-indole,
5- [4- [2- (indan-2-yl) ethyl] piperazin-1-yl] -1H-indole,
5-chloro-1- [1- [2- (indan-2-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
1- [1- [2- (indan-2-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
2- [1- [2- (indanden-2-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
5-chloro-1- [1- [2- (indan-2-yl) ethyl] -piperidin-4-yl] -1H-indole,
1- [1- [2- (indan-2-yl) ethyl] -piperidin-4-yl] -1H-indole,
6-chloro-3- [1- [2- (2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H- Indol,
6-chloro-3- [1- [4- (2,3-dihydro-1H-indol-3-yl) butyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H- Indol,
6-chloro-3- [1- [2- (2,3-dihydro-1-methylaminocarbonyl-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridine- 4-day] -1H-indole,
(+)-(3- [1- [2- (1-acetyl-2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridine-4- General] -6-chloro-1H-indole,
(-)-(3- [1- [2- (1-acetyl-2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridine-4- General] -6-chloro-1H-indole,
3- [1- [4- (1-acetyl-2,3-dihydro-1H-indol-3-yl) butyl] -1,2,3,6-tetrahydropyridin-4-yl] -6- Chloro-1H-indole,
6-chloro-3- [1- [6-chloro-1-indanylmethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
6-chloro-3- [1- [6-nitro-1-indanylmethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
6-chloro-3- [1- [6-fluoro-l-indanylmethyl] -l, 2,3,6-tetrahydropyridin-4-yl] -lH-indole,
6-chloro-3- [1- [5-chloro-1-indanylmethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
6-chloro-3- [1- [6-methyl-1-indanylmethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
6-chloro-3- [1- (1-indanylmethyl) -1,2,3,6-tetrahydropyridin-4-yl] -1-methyl-1H-indole,
6-chloro-3- [1- (1-indanylmethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1- (2-propyl-1H-indole,
5-fluoro-3- [1- [6- (trifluoromethyl) -1-indanylmethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
5-fluoro-3- [1- [5- (trifluoromethylsulfonyloxy) -1-indanylmethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole ,
6-chloro-3- [1- [1-indanylmethyloxyethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
5-fluoro-3- [1- [6- (indan-1-yl) hexane-1-yl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
3- [1- [2- (1-acetyl-5-fluoro-2,3-dihydro-1H-indol-3-yl) ethyl] piperidin-4-yl] -6-chloro-1H- Indol,
6-chloro-3- [1- [2- (1-formyl-5-fluoro-2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetra Hydropyridin-4-yl] -1 H-indole,
6-chloro-3- [1- [2- (5-fluoro-2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridine-4- Japanese] -1H-indole,
6-chloro-3- [1- [2- (5-fluoro-2,3-dihydro-1-methylaminocarbonyl-1H-indol-3-yl) ethyl] -1,2,3,6 -Tetrahydropyridin-4-yl] -1 H-indole,
6-chloro-3- [1- [2- (2,3-dihydro-1-mesylaminocarbonyl-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridine- 4-day] -1H-indole,
6-chloro-3- [1- [2- (5-fluoro-2,3-dihydro-1-mesylaminocarbonyl-1H-indol-3-yl) ethyl] -1,2,3,6 -Tetrahydropyridin-4-yl] -1 H-indole,
3- [1-[(1-acetyl-2,3-dihydro-1H-indol-2-yl) methyl] -1,2,3,6-tetrahydropyridin-4-yl] -6-chloro- 1H-Indole,
3- [1-[(1-acetyl-5-fluoro-2,3-dihydro-1H-indol-2-yl) methyl] -1,2,3,6-tetrahydropyridin-4-yl] -6-chloro-1H-indole,
3- [1-[(1-acetyl-2,3-dihydro-1H-indol-2-yl) methyl] piperidin-4-yl] -6-chloro-1H-indole,
3- [1- [2- (1-acetyl-2,3-dihydro-1H-indol-2-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -6- Chloro-1H-indole,
3- [1- [2- (1-acetyl-5-fluoro-2,3-dihydro-1H-indol-2-yl) ethyl] -1,2,3,6-tetrahydropyridine-4- General] -6-chloro-1H-indole,
3- [1- [2- (1-acetyl-2,3-dihydro-1H-indol-2-yl) ethyl] piperidin-4-yl] -6-chloro-1H-indole,
6-chloro-3- [1- [2- (2,3-dihydro-1H-indol-2-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H- Indol,
6-chloro-3- [1- [2- (5-fluoro-2,3-dihydro-1H-indol-2-yl) ethyl] -1,2,3,6-tetrahydropyridine-4- Japanese] -1H-indole,
6-chloro-2- [4-[(indan-2-yl) methyl] piperazin-1-yl] -1H-indole,
6-chloro-2- [4- [2- (indan-2-yl) ethyl] piperazin-1-yl] -1H-indole,
2- [4- [2- (1-acetyl-2,3-dihydro-1H-indol-3-yl) ethyl] piperazin-1-yl] -6-chloro-1H-indole,
2- [4- [2- (1-acetyl-5fluoro-2,3-dihydro-1H-indol-3-yl) ethyl] piperazin-1-yl] -6-chloro-1H-indole,
6-chloro-3- [4-[(indan-2-yl) methyl] piperazin-1-yl] -1H-indole,
6-chloro-3- [4- [2- (indan-2-yl) ethyl] piperazin-1-yl] -1H-indole,
3- [4- [2- (1-acetyl-2,3-dihydro-1H-indol-3-yl) ethyl] piperazin-1-yl] -6-chloro-1H-indole,
3- [4- [2- (1-acetyl-5-fluoro-2,3-dihydro-1H-indol-3-yl) ethyl] piperazin-1-yl] -6-chloro-1H-indole ,
4- [4-[(indan-2-yl) methyl] piperazin-1-yl] -1H-indole,
4- [4- [2- (1-acetyl-2,3-dihydro-1H-indol-3-yl) ethyl] piperazin-1-yl] -1H-indole,
4- [4- [2- (1-acetyl-5-fluoro-2,3-dihydro-1H-indol-3-yl) ethyl] piperazin-1-yl] -1H-indole,
7- [4-[(indan-2-yl) methyl] piperazin-1-yl] -1H-indole,
7- [4- [2- (indan-2-yl) ethyl] piperazin-1-yl] -1H-indole,
7- [4- [2- (1-acetyl-2,3-dihydro-1H-indol-3-yl) ethyl] piperazin-1-yl] -1H-indole,
7- [4- [2- (1-acetyl-5-fluoro-2,3-dihydro-1H-indol-3-yl) ethyl] piperazin-1-yl] -1H-indole,
2- [1- [2- (1-acetyl-2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H- Indol,
2- [1- [2- (1-acetyl-2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -5- Chloro-1H-indole,
2- [1- [2- (1-acetyl-2,3-dihydro-1H-indol-3-yl) ethyl] piperidin-4-yl] -1H-indole,
2- [1- [2- (1-acetyl-2,3-dihydro-1H-indol-3-yl) ethyl] piperidin-4-yl] -5-chloro-1H-indole,
2- [1- (indan-2-yl) methyl-1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
5-chloro-2- [1- (indan-2-yl) methyl-1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
5-chloro-2- [1- [2- (indan-2-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
2- [1- (indan-2-yl) methylpiperidin-4-yl] -1H-indole,
5-chloro-2- [1- (indan-2-yl) methylpiperidin-4-yl] -1H-indole,
2- [1- [2- (indan-2-yl) ethyl] piperidin-4-yl] -1H-indole,
5-chloro-2- [1- [2- (indan-2-yl) ethyl] piperidin-4-yl] -1H-indole,
7- [4-[(6-chloro-1H-indol-3-yl) -1,2,3,6-tetrahydropyrid-1-yl] methyl] -3,6,7,8-tetrahydro Cyclopent [e] indole,
7- [4-[(6-chloro-1H-indol-3-yl) -1,2,3,6-tetrahydropyrid-1-yl] methyl] -1,5,6,7-tetrahydro Cyclopent [f] indole,
6- [4-[(6-chloro-1H-indol-3-yl) -1,2,3,6-tetrahydropyrid-1-yl] methyl] -1,6,7,8-tetrahydro Cyclopent [g] indole,
7- [4-[(6-chloro-1H-indol-3-yl) -1,2,3,6-tetrahydropyrid-1-yl] methyl] -1,6,7,8-tetrahydro Cyclopent [g] indole,
(+) 6-chloro-3- [1- [2- (2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole,
6-chloro-3- [1- [2- (2,3-dihydro-1H-indol-1-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H- Indol,
6-chloro-3- [1- [2- (2,3-dihydro-1H-indol-1-yl) ethyl] piperidin-4-yl] -1H-indole,
6-chloro-3- [1- [3- (2,3-dihydro-1H-indol-1-yl) propan-1-yl] -1,2,3,6-tetrahydropyridin-4-yl ] -1H-indole,
6-chloro-3- [1- [4- (2,3-dihydro-1H-indol-1-yl) butan-1-yl] -1,2,3,6-tetrahydropyridin-4-yl ] -1H-indole,
6-chloro-3- [1- [3- (2,3-dihydro-1H-indol-1-yl) -3-oxopropan-1-yl] -1,2,3,6-tetrahydropy Lead-4-yl] -1H-indole,
3- [1-[(5- (2-propyl) oxyindan-2-yl) methyl] piperidin-4-yl] -6-chloro-1H-indole,
3- [1-[(5,6-dimethoxyindan-2-yl) methyl] piperidin-4-yl] -6-chloro-1H-indole,
3- [1-[(4- (2-propyl) oxyindan-1-yl) methyl] piperidin-4-yl] -6-chloro-1H-indole,
3- [1-[(5- (2-propyl) oxyindan-1-yl) methyl] piperidin-4-yl] -6-chloro-1H-indole,
3- [1-[(7-methoxyindan-1-yl) methyl] piperidin-4-yl] -6-chloro-1H-indole,
3- [1-[(5,6-dimethoxyindan-1-yl) methyl] piperidin-4-yl] -6-chloro-1H-indole,
3- [1-[(4- (2-propyl) oxyindan-2-yl) methyl] -1,2,3,6-tetrahydropyridin-4-yl] -6-chloro-1H-indole,
3- [1-[(5- (2-propyl) oxyindan-2-yl) methyl] -1,2,3,6-tetrahydropyridin-4-yl] -6-chloro-1H-indole,
3- [1-[(5,6-dimethoxyindan-2-yl) methyl] -1,2,3,6-tetrahydropyridin-4-yl] -6-chloro-1H-indole,
3- [1-[(4- (2-propyl) oxyindan-1-yl) methyl] -1,2,3,6-tetrahydropyridin-4-yl] -6-chloro-1H-indole,
3- [1-[(5- (2-propyl) oxyindan-1-yl) methyl] -1,2,3,6-tetrahydropyridin-4-yl] -6-chloro-1H-indole,
3- [1-[(7-methoxyindan-1-yl) methyl] -1,2,3,6-tetrahydropyridin-4-yl] -6-chloro-1H-indole,
3- [1-[(5,6-dimethoxyindan-1-yl) methyl] -1,2,3,6-tetrahydropyridin-4-yl] -6-chloro-1H-indole, or
3- [4-[(5,6-dimethoxyindan-1-yl) methyl] -piperazin-1-yl] -6-chloro-1H-indole,
Acid addition salts of the compounds of the present invention are pharmaceutically acceptable salts formed with non-toxic acids. Examples of such organic salts are maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bis-methylenesalicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid Theophylline acetic acid, as well as 8-haloteophylline such as cinnamonic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid and 8-bromoteophylline for example Is added. Examples of inorganic salts are the addition of hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid.
The pharmaceutical compositions of the present invention or those produced according to the present invention can be administered orally in the form of tablets, capsules, powders, syrups or the like or parenterally in the form of injection solutions. Methods known in the art are used for the preparation of such compositions and pharmaceutically acceptable carriers, diluents, excipients or other additives commonly used in the art are used.
Conveniently, the compound of the present invention is administered in unit dosage form containing the compound in an amount of about 0.01-100 mg.
The total daily dose is generally in the range of about 0.05-500 mg, most preferably about 0.1-50 mg of the active compound of the present invention.
The compounds of the present invention can be prepared as follows.
1) alkylating piperazine, piperidine or tetrahydropyridine of formula II with an alkylated derivative of formula III:
Wherein R ² -R ⁵ , X, Y, A, n, m, W and the dotted line are as defined above and L is a leaving group such as for example halogen, mesylate or tosylate.
2) reducing the amidated carbonyl in the compound of formula IV:
Wherein R ² -R ⁵ , X, Y, A, m, W and the dotted line are as defined above, r is n-1 and n is as defined above.
3) reaction reagents such as halogens, halogenating agents, sulfonating agents, nitroating agents or reaction reagents that produce carbonium ions (RCO ⁺ , R ⁺ ) wherein R is alkyl alkynyl, aryl cycloalkyl or cycloalk (en / yn) yl Introducing substituents R ^{2 '} , R ^3' , R ^{4 '} , R ^5' by reacting a compound of formula
Wherein one of R ^{2 ′} -R ^{5 ′} is hydrogen and the other are corresponding R ² , R ³ , R ⁴ or R ^{5 as defined above} and X, Y, A, m, n, W and the dotted line are defined above Same as one.
4) Reduction of Double Bonds in Indole Compounds of Formula VI
Wherein R ² -R ⁵ , R ¹ , X, n, m, W and A are as defined above.
5) Reduction of Tetrahydropyridinyl Double Bonds in Derivatives of Formula (VII)
Wherein R ² -R ⁵ , Y, n, m, W and A are as defined above.
6) L is a leaving group such as halogen, mesylate or tosylate and R ¹ is a reagent of formula R ¹ -L as defined above, or hal is halogen, R ^{1 ′} is acyl, thioacyl, R ¹⁵ , V , R ^16, and R ¹⁷ is R ¹⁶ and R ¹⁷ groups, except when both are other than hydrogen as described above only R ¹⁵ VCO-, or group R ¹⁶ R ¹⁷ NCO- or R ¹⁶ R ¹⁷ NCS- the formula R ¹ reagents of ^' -hal or R ^1' -OCOR, or lower halogenated alkylsulfonyl, halogenated trifluoromethylsulfonyl, or R ¹⁶ , as defined above: R ¹⁶ -N = C═O or R ¹⁶ -N = Reacting a dihydroindole derivative of formula VIII with an isocyanate or thiisocyanate of C = S:
Wherein R ² -R ⁵ , X, A, n, m, W and the dotted line are as defined above.
7) L is a leaving group such as halogen, mesylate or tosylate and R ¹³ is a reagent of formula R ¹³ -L as defined above or hal is halogen and R ^{13 ′} is acyl, thioacyl, R ¹⁵ , V, R ¹⁶ and R ¹⁷ is R ¹⁶ and R ¹⁷ groups are, unless both other than hydrogen as described above only R ¹⁵ VCO-, or group R ¹⁶ R ¹⁷ NCO- or R ¹⁶ R ¹⁷ NCS- of the formula R ^{13 '} formula -hal or R ¹³ or R ¹⁶ as methylsulfonyl ^'-OCOR reagents, or halogenated lower alkylsulfonyl, halogenated trifluoromethyl is one as defined above R ¹⁶ -N = C = O or R ¹⁶ -N = C Reacting an aniline derivative of formula IX with an isocyanate or thiisocyanate of = S:
Wherein R ² -R ⁵ is NHR ¹⁴ and R ¹⁴ is as defined above and other R ² -R ⁵ , X, Y, A, n, m, W and the dotted lines are as defined above.
8) alkylating a dihydroindole derivative of formula X with an alkylated derivative of formula XI:
Wherein R ² -R ⁵ , X, A, n, m, W and the dotted line are as defined above and L is a leaving group such as halogen, mesylate, tosylate; Also
9) reducing the amidated carbonyl compound of formula XII:
Wherein R ² -R ⁵ , X, A, n, W and the dotted line are as defined above, s is m-1 and m is as defined above.
As a result, the compound of formula I is separated as an organic base or a pharmaceutically acceptable acid addition salt thereof.
The reactions of methods 6) and 7) are low temperature (eg below room temperature) in an inert solvent such as acetone, dichloromethane, tetrahydrofuran or dimethoxyethane when reactive carboxylic acid chloride, isocyanate or isothiocyanate is used Is conveniently done in. Formated amines are prepared from the corresponding amines by reacting with formic acid esters of formic acid or by reacting with the prepared formic anhydride. Generally the reaction temperature is between 0 ° C. and the boiling point of the formyl precursor compound.
The alkylation according to methods 1) and 8) is generally carried out at reflux in a suitable solvent such as acetone, methyl isobutyl ketone, tetrahydrofuran, dioxane, ethanol or 2-propanol in the presence of a base such as triethylamine or potassium carbonate. Is performed by.
Reduction of the double bonds according to methods 4) and 5) is generally carried out by catalytic hydrogenation under low pressure (<3 atm) in the Parr apparatus or in trifluoroacetic acid in an inert solvent such as tetrahydrofuran, dioxane or diethyl ether. Is carried out using a reducing agent such as diborane or hydrobolic derivatives produced from NaBH ₄ .
Reduction according to methods 2) and 9) is generally carried out by the use of LiAlH ₄ , AlH ₃ or diborane in an inert solvent such as tetrahydrofuran, dioxane or diethyl ether at room temperature or slightly increased temperature.
Halogenation according to method 3) is generally conveniently carried out by the use of chlorine, bromine or N-chlorosuccinate, N-bromosuccinate or another halogen precursor molecule in the presence of a catalyst such as Fe ions or inorganic acids. Can be.
Indols such as 7-chloro-1H-indole and 6,7-dichloro-1H-indole are described in G. Bartoli et al., Tetrahedron Lett. It was prepared according to the procedure of 1989,30,2129-2132. Two piperazinyl indole 4- (piperazin-1-yl) -1H-indole and 5- (piperazin-1-yl) -1H-indole literature, WO Patent Publication No. 95/33743 and US Patent No. Described in .5576319.
Synthesis of 3- (piperidin-4-yl) -1H-indole and 3- (1,2,3,6-tetrahydropyridin-4-yl) -1H-idol are described in document EP-A1-465398 It is.
1-indanecarboxylic acids (V.Asham and WHLinnell, J. Chem. Soc. 1954,4691-4693, Hansen et al. Helv. Chim. Acta 1982,33,325-343) and 6-nitro-1-indanecar Core intermediates, such as acids (G.Kirsch et al. Just.Lieb.Ann. Chem. 1976, 10,1914), were prepared according to well known procedures. (Indan-2-yl) acetic acid, 3- (indan-2-yl) propionic acid, 4- (indan-2-yl) butyric acid and 2- (indan-2-yl) ethanol are described in Y. Tanaka et al. J. Med. Chem. 1994, 37,2071-2078.
Experiment section
Melting points were determined on the Buchi SMP-20 apparatus and did not change. Mass spectra were obtained on a Quattro MS-MS system from VG Biotech, Fisons Instruments. The MS-MS system was connected to the HPLC system of the HP 1050 module. A volume of 20-50 μl sample (10 μg / ml) dissolved in a mixture of 1% acetic acid in a 1: 1 ratio of acetonitrile to water was introduced into the Electrospray Source via a autosampler at a flow rate of 30 μl / min. Spectra were obtained from two standard sets of operating conditions. One set is for obtaining molecular weight information (MH +) (21 eV) and the other set is for inducing fracture patterns (70 eV). The background was removed. Relative concentrations of ions were obtained from the fracture patterns. If concentrations do not appear for Molecular Ion (MH +) these ions were only present under the first set of operating conditions. ¹ H NMR spectra of all new compounds were recorded at 250 MHz on Bruker AC 250 or 500 MHz on Bruker Avance DRX 500 machine. Deuterated chloroform (99,8% D) or dimethylsulfoxide (99,9% D) was used as the solvent. TMS was used as internal reference standard. Chemical change values are expressed in ppm-values. The following abbreviations were used for the diversity of the NMR signal: s = singlet, d = doublet, t = triplet, q = quartet, qui = quintet , h = heptet, dd = double doublet, dt = double triplet, dq = double quartet, tt = triplet of triplets, m = Multiplet. NMR signals corresponding to acidic protons are generally omitted. The volume of water in the crystalline compound is determined by Karl Fischer titration. Standard finishing procedures are referred to as extraction from an appropriate aqueous solution with an organic solvent, drying of the combined organic extracts (anhydrous MgSO ₄ or Na ₂ SO ₄ ), filtration and evaporation of the solvent in vacuo. Kieselgel 60 type silica gel, 230-400 mesh ASTM, was used for column chromatography.
Example 1
1-indanylmethanol, 1a.
(Intermediate)
To a LiAlH ₄ (4.7 g) suspension on diethyl ether (200 ml) was added dropwise a solution of AlCl ₃ on diethyl ether (200 ml). A solution of 1-indanecarboxylic acid (10 g) (prepared according to the method of Hansen et al. Helv. Chim. Acta 1982, 33, 325-343) on dry tetrahydrofuran (200 ml) was added dropwise at 10-15 ° C. Added. The mixture was finally stirred at room temperature for 1.5 hours. Excess AlH ₃ was destroyed by addition of concentrated aqueous NaOH (25 ml) solution at 0 ° C. The precipitated inorganic salts were filtered off and the solvent was evaporated in vacuo to yield 6.8 g of the title compound 1a as a viscous oil which was used without further purification.
The following 1-indanylmethanol was prepared in a similar manner:
The 6-bromo-1-yndanylmethanol is separated as a viscous oil from the alan reduction of the corresponding methyl 6-bromo-1-indancarboxylic acid ester. 1b.
Example 2
6-cyano-indanylmethanol 2a
(Intermediate)
CuCN (79 g) was added to a 6-bromo-1-yndanylmethanol (20 g) solution on N-methyl-2-pyrrolidone (NMP) (380 ml). The mixture was heated at 160 ° C. for 6 hours. After cooling to 80-90 ° C. the mixture was poured into an aqueous solution of NaCN (4 g) (500 ml). After stirring for 20 minutes, excess CuCN was filtered off. Ethyl acetate (300 ml) is added and the organic phase is separated off and finished. The remaining oil was dissolved in diethyl ether (300 ml) and washed with saturated brine (2 × 100 ml). The organic phase was separated and finished according to the general procedure to give 14.6 g of natural title compound 2a as a viscous oil. Column chromatography on silica gel (eluent: ethyl acetate / heptane 6: 4) gave pure 2a (8.7 g) which was used without further purification.
Example 3
6-cyano-1-indanylmethanol methanesulfonate, 3a.
(Intermediate)
A drop of a solution of methanesulfonyl chloride (1.5 ml) on dichloromethane (25 ml) to a solution of 6-cyano-1-yndanylmethanol 2a (3 g) and triethylamine (2.8 ml) on dichloromethane (50 ml) Thickly added at 0 ° C. The mixture was stirred at rt for 1 h. Water was added (200 ml) and then the organic phase was separated and finished according to the above standard procedure. The remaining crystal product was stirred with diethyl ether and filtered off. Yield 2.7 g. Mp 62-63 ° C.
The following methanesulfonates were prepared in a similar manner.
1-indanylmethanol methanesulfonate, 3b. Isolated as viscous oil
6-bromo-1-yndanylmethanol methanesulfonate, 3c.
6-nitro-1-yndanylmethanol methanesulfonate, 3d.
6-chloro-1-yndanylmethanol methanesulfonate, 3e.
Example 4
3- [1- (1-Indanylcarbonyl) -1,2,3,6-tetrahydropyridin-4-yl] -1 H-indole, 4a.
International Patent Application No. 3- (1,2,3,6-tetrahydro), dropwise at 0-5 ° C., of 1-indancarboxylic acid chloride (4.5 g) on dichloromethane (25 ml) prepared as described in WO 9533721-A1. Pyridin-4-yl) -1H-indole (5 g) (see general preparation method described in Guillaume et al. Eur. J. Med. Chem. 1987, 22, 33-43) and triethylamine on THF (50 ml) ( 3.8 ml) was added to the mixture. The resulting mixture was stirred at rt overnight. The mixture was poured into diluted aqueous NH ₄ OH (500 ml) and extracted several times with dichloromethane (4 × 100 ml). The combined organic phases were finished according to the general procedure above. Column chromatography of the natural product (eluting with 70/30 of ethyl acetate / heptane) gives the title compound 4a as a viscous oil (4.7 g) used without further purification.
The following amides were prepared in a similar manner:
3- [1- (1-Indanylcarbonyl) piperidin-4-yl] -1 H-indole 4b was isolated as an oil.
6-chloro-3- [1- (7-methoxy-1-indancarbonyl) 1,2,3,6-tetrahydropyridin-4-yl] -1H-indole, 4c.
Prepared from compound 23a and 6-chloro-3- (1,2,3,6-tetrahydropyridin-4-yl) -1H-indole.
3- [1- (6-methoxy-1-yndanylcarbonyl) -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole, 4d.
Prepared from compound 23b and 3- (1,2,3,6-tetrahydropyridin-4-yl) -1H-indole.
Example 5
3- [1- (1-Indanylmethyl) -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole, 5a.
Drop-by-drop in LiAlH ₄ (1.6 g) solution on dry THF (100 ml) maintained at 0 ° C. on 3- [1- (1-indanylcarbonyl) -1,2,3,6 on dry THF (200 ml) Tetrahydropyridin-4-yl] -1 H-indole 4a (4.7 g) solution was added. The mixture was kept stirring at rt overnight. Excess LiAlH ₄ was destroyed by carefully adding 10% water on THF. Precipitated inorganic salts were removed by filtration. The solvent was evaporated to give the natural title compound (5.2 g). Recrystallization from 2-propanol gave 2.8 g of pure 5a. Melting point 168-170 ° C. ¹ H NMR (CDCl ₃ ): δ 1.85-2.00 (m, 1H); 2.30-2.45 (m, 1 H); 2.60 (dd, 1 H); 2.60-2.70 (m, 2 H); 2.70-3.00 (m, 5H); 3.30 (broad t, 2H); 3.45 (quin, 1 H); 6.25 (broad t, 1 H); 7.10-7.25 (m, 6H); 7.30-7.40 (m, 2H); 7.90 (d, 1 H); 8.10 (broad s, 1 H). MS m / z (%): 329 (MH <+>, 2%), 160 (10%), 131 (100%), 91 (19%).
In a similar manner the following indanmethylamines were prepared:
3- [1- (1-indenmethyl) piperidin-4-yl] -1H-indole fumarate, 5b. Prepared from compound 4b. Melting point 216-218 ° C. ¹ H NMR (DMSO-d ₆ ): δ 1.70-2.00 (m, 5H); 2.20-2.35 (m, 1 H); 2.40-2.50 (m, 2 H); 2.65 (dd, 1 H); 2.80-3.00 (m, 4 H); 3.20 (broad t, 2H); 3.45 (quin, 1 H); 6.60 (s, 2 H); 6.95 (t, 1 H); 7.05 (t, 1 H); 7.15-7.30 (m, 4H); 7.30-7.40 (m, 2H); 7.60 (d, 1 H); 10.80 (s, 1 H). MS m / z (%): 331 (MH <+>, 15%), 214 (18%), 131 (100%).
6-chloro-3- [1- (7-methoxyindan-1-yl) methyl-1,2,3,6-tetrahydropyridin-4-yl] -1H-indole, 5c. Prepared from compound 4c. Melting point 177-178 ° C. ¹ H NMR (CDCl ₃ ) δ 2.15-2.30 (m, 2H); 2.45 (t, H); 2.55 (broad s, 2 H); 2.65-2.70 (m, 1 H); 2.75-2.90 (m, 2 H); 2.90-3.00 (m, 1 H); 3.00-3.10 (m, 1 H); 3.25 (d, 1 H); 3.40 (d, 1 H); 3.60-3.65 (m, 1 H); 3.85 (s, 3 H); 6.20 (broad s, 1 H); 6.70 (d, 1 H); 6.85 (d, 1 H); 7.05-7.20 (m, 3 H); 7.30 (s, 1 H); 7.80 (d, 1 H); 8.25 (broad s, 1 H). MS m / z (%): 393 (MH &lt; + &gt;) 190 (25%), 161 (100%).
3- [1- (6-methoxyinden-1-yl) methyl-1,2,3,6-tetrahydropyridin-4-yl] -1H-indole oxalate, 5d. Prepared from compound 4d. Melting point 118-120 ° C. ¹ H NMR (DMSO-d ₆ ): δ 1.90-2.00 (m, 1H); 2.35-2.45 (m, 1 H); 2.70-2.95 (m, 4 H); 3.15 (t, 1 H); 3.45 (broad s, 2 H); 3.50-3.65 (m, 2 H); 3.75 (s, 3 H); 3.95 (broad s, 2 H); 6.20 (broad s, 1 H); 6.75 (d, 1 H); 6.95 (s, 1 H); 7.10 (t, 1 H); 7.10-7.20 (m, 2H); 7.45 (d, 1 H); 7.55 (s, 1 H); 7.85 (d, 1 H); 11.35 (broad s, 1 H). MS m / z (%): 359 (MH &lt; + &gt;, 6%) 190 (15%), 161 (100%), 147 (74%).
Example 6
6-chloro-3- [1- (6-cyano-1-yndanylmethyl) -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole, 6a.
6-cyano-1-yndanylmethanol methanesulfonate on NMP (50 ml), 3a (1.3 g), 6-chloro-3- (1,2,3,6-tetrahydropyridin-4-yl) -1H A mixture of indole (2.5 g) and potassium carbonate (1.9 g) was heated at 110 ° C. for 5 hours. After cooling to room temperature the mixture was poured into water (500 ml) and ethyl acetate (100 ml) was added. Finishing according to the above general procedure yielded 4.7 g of impure product. Column chromatography (ethyl acetate / heptane / ethanol / triethylamine eluted with 30/60/10/4) afforded 1.5 g of pure compound. The crystal product was stirred with diethyl ether and then filtered. Melting point 175-177 ° C. ¹ H NMR (CDCl ₃ ): δ 1.85-2.00 (m, 1H); 2.35-2.45 (m, 1 H); 2.50-3.00 (m, 8H); 3.30 (broad t, 2H); 3.45 (quin, 1 H); 6.15 (broad t, 1 H); 7.05 (dd, 1 H); 7.20-7.50 (m, 4H); 7.70-7.85 (m, 2H); 10.60 (broad s, 1 H). MS m / z (%): 388 (MH <+>, 4%), 185 (40%), 156 (100%), 129 (53%).
In a similar manner the following indanylmethylamines were prepared:
6-Chloro-3- [1- (6-cyano-1-ynylmethyl) piperidin-4-yl] -1 H-indole, hemifumarate, 6b. Prepared from compound 3a. Melting point 175-177 ° C. ¹ H NMR (DMSO-d ₆ ): δ 1.65-2.00 (m, 5H); 2.20-2.30 (m, 3 H); 2.40-2.50 (m, 2 H); 2.65 (dd, 1 H); 2.70-3.15 (m, 4 H); 3.45 (quin, 1 H); 6.60 (s, 1 H); 6.95 (dd, 1 H); 7.15 (d, 1 H); 7.35 (d, 1 H); 7.45 (d, 1 H); 7.55-7.65 (m, 2H); 7.80 (s, 1 H); 10.95 (s, 1 H). MS m / z (%): 392 (17%), 390 (MH <+>, 47%), 239 (100%), 156 (69%).
6-chloro-3- [1- (4-acetylamino-1-indanylmethyl) -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole, 6c. Melting point 189-190 ° C. ¹ H NMR (DMSO-d ₆ ): δ 1.65-1.90 (m, 1H); 2.05 (s, 3 H); 2.10-2.30 (m, 1 H); 2.40-2.95 (m, 8H); 3.20 (broad s, 2H); 3.45 (quin, 1 H); 6.15 (broad t, 1 H); 7.00-7.15 (m, 3 H); 7.40-7.50 (m, 3H); 7.85 (d, 1 H); 9.25 (s, 1 H); 11.25 (s, 1 H). MS m / z (%): 420 (MH <+>, 16%), 217 (65%), 188 (100%), 146 (57%).
The last mentioned compound was again prepared from 4-acetylamino-1-indanemethanol methanesulfonate obtained from 4-amino-1-indanemethanol as follows.
4-amino-1-indanemethanol
G. Kirsch et al. Just. Lieb. Ann. Chem. A mixture of 4-nitro-1-indancarboxylic acid and 6-nitro-1-indancarboxylic acid was obtained according to the nitration procedure of 1-indancarboxylic acid according to 1976, 10, 1914. The mixture was reduced to alan according to the method described in Example 1. The resulting mixture of 4-nitro- and 6-nitroindan-1-methanol (21.9 g) was dissolved in glacial acetic acid (600 ml) and carbon black (11 g) 5% Pd was added. The mixture was hydrogenated at 2 atm or lower for 2.5 hours in a Parr apparatus. The catalyst was filtered off and the solvent was evaporated under vacuum. Water (500 ml) and ethyl acetate (200 ml) kept at 0 ° C. were added. The pH was made 10 or more by adding NaOH aqueous solution. The organic phase was separated and finished according to the general procedure above. 4- and 6-aniline isomers were separated by column chromatography on silica gel (eluted with ethyl acetate / heptane 60/40). The yield of 4-amino-1-indanemethanol as viscous oil is 3.6 g.
4-acetylamino-1-indanemethanol methanesulfonate
To a mixture of 4-amino-1-indanemethanol (3.4 g) and triethylamine (8.1 ml) on dichloromethane (150 ml), acetyl chloride (1.4 ml) on dichloromethane (20 ml) was added dropwise at −30 ° C. . The mixture was stirred while raising the temperature to 0 ° C. A solution of methanesulfonylchloride (1.7 ml) on dichloromethane (20 ml) was added slowly below 0 ° C. Finally the mixture was heated to room temperature. Water (200 ml) and dichloromethane (50 ml) were added. The organic phase was separated and finished as above to give the title methanesulfonate as an oil (6.7 g as natural product).
6-chloro-3- [1- (5-acetylamino-1-ynedylmethyl) 1,2,3,6-tetrahydropyridin-4-yl] -1H-indole hemifumarate, 6d. Melting point 241-242 ° C. ¹ H NMR (DMSO-d ₆ ) d 1.70-1.90 (1H, m); 2.00 (3H, s), 2.11-2.30 (1H, m); 2.40-2.60 (2H, m); 2.60-2.95 (5H, m); 3.20 (2H, bs); 3.25-3.40 (2H, m); 6.10 (1 H, s); 7.05 (1 H, d); 7.25 (2H, s); 7.40 (1 H, s); 7.45 (1 H, d); 7.55 (1 H, s); 7.85 (2, d); 9.80 (1 H, bs); 11.25 (1 H, bs). MS m / z (%): 420 (MH <+>, 5%), 188 (100%), 146 (100%), 217 (31%), 147 (27%).
The last mentioned compound is 5-acetylamino-1-prepared from 6-chloro-5-nitro-1-indanecarboxylic acid (G.Kirch et al, Lieb. Ann. Chem., 1976, 10, 1914). It was prepared by a method analogous to the synthesis of 4-acetylamino-1-indanemethanol methanesulfonate described above from indanmethanol methanesulfonate.
6-chloro-3- [1- (6-bromo-1-indenylmethyl) -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole, 6e. Prepared from compound 3c. Melting point 153-155 ° C. ¹ H NMR (CDCl ₃ ) d 1.85-1.95 (m, 1H); 2.30-2.40 (m, 1 H); 2.50-2.65 (m, 3 H); 2.65-2.90 (m, 5 H); 3.25 (broad s, 2 H); 3.45 (p, 1 H); 6.20 (broad s, 1 H); 7.00-7.20 (m, 3 H); 7.25 (s, 1 H); 7.30 (d, 1 H); 7.50 (s, 1 H); 7.80 (d, 1 H); 8.15 (broad s, 1 H). MS m / z (%): 443 (MH +, 7%), 441 (MH +, 7%), 240 (50%), 238 (49%), 211 (59%), 209 (62%), 130 ( 100%).
5-Fluoro-3- [1- (6-nitro-1-yndanylmethyl) -1,2,3,6-tetrahydropyridin-4-yl] -1 H-indole hemifumarate, 6f. Prepared from compound 3d. Melting point〉 300 ℃. ¹ H NMR (DMSOd ₆ ) d 1.85-1.95 (m, 1H); 2.30-2.40 (m, 1 H); 2.50-2.60 (m, 3 H); 2.70-3.05 (m, 5 H); 3.25 (broad dd, 2 H); 3.50 (p, 1 H); 6.10 (broad s, 1 H); 6.60 (s, 1 H); 6.95 (t, 1 H); 7.35 (dd, 1 H); 7.45-7.50 (m, 2H); 7.55 (d, 1 H); 8.05 (d, 1 H); 8.25 (s, 1 H); 11.25 (s, 1 H). MS m / z (%): 392 (MH <+>, 5%), 205 (29%), 176 (46%), 130 (100%).
6 g of 5-fluoro-3- [1- (6-nitro-1-yndanylmethyl) -piperidin-4-yl] -1 H-indole. Melting point〉 300 ℃. ¹ H NMR (CDCl ₃ ) d 1.75-1.95 (m, 3H); 2.00-2.10 (m, 2 H); 2.25 (t, 2 H); 2.30-2.40 (m, 1 H); 2.45-2.65 (m, 2 H); 2.75 (tt, 1 H); 2.85-3.15 (m, 4 H); 3.45 (p, 1 H); 6.95 (dt, 1 H); 7.15 (d, 1 H); 7.20-7.30 (m, 3H); 7.95 (broad s, 1 H); 8.05 (dd, 1 H); 8.30 (s, 1 H). MS m / z (%): 394 (MH <+>, 58%), 259 (95%), 176 (58%), 130 (57%), 98 (51%), 84 (100%).
3- [1- (6-Chloro-1-indanylmethyl) -1,2,3,6-tetrahydropyridin-4-yl] -5-fluoro-1 H-indole hemifumarate, 6 h. Prepared from compound 3e. Melting point 211-213 ° C. ¹ H NMR (DMSO-d ₆ ) d 1.75-1.85 (m, 1H); 2.20-2.30 (m, 1 H); 2.55-2.65 (m, 3 H); 2.75-2.90 (m, 5 H); 3.25 (broad s, 2 H); 3.45 (p, 1 H); 6.10 (broad s, 1 H); 6.60 (s, 1 H); 6.95 (t, 1 H); 7.20 (d, 1 H); 7.25 (d, 1 H); 7.35 (dd, 1 H); 7.40 (s, 1 H); 7.45 (s, 1 H); 7.55 (D, 1 H); 11.25 (S, 1 H). MS m / z (%): 381 (MH <+>, 5%), 167 (32%), 165 (100%), 130 (53%).
3- [1- (6-Chloro-1-indanylmethyl) -piperidin-4-yl] -5-fluoro-1 H-indole fumarate, 6i. Melting point 214-216 ° C. ¹ H NMR (DMSO-d ₆ ) d 1.75-1.85 (m, 3H); 2.00 (d, 2 H); 2.25-2.30 (m, 1 H); 2.40 (t, 2 H); 2.60 (t, 1 H); 2.75-2.90 (m, 4 H); 3.20 (broad t, 2H); 3.45 (p, 1 H); 6.60 (s, 2 H); 6.90 (t, 1 H); 7.15-7.25 (m, 3H); 7.30-7.35 (m, 2H); 7.45 (s, 1 H); 10.90 (s, 1 H); MS m / z (%): 383 (MH <+>, 16%), 248 (19%), 167 (31%), 165 (100%).
Example 7
6-chloro-3- [1- [2- (indan-1-yl) methylcarbonyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole, 7a.
Indan-1-acetic acid on CH ₂ Cl ₂ (250 ml) (Anderson, AG et al; J. Org. Chem. 1989, 38 (8), 1439-1444) (7.0 g, 39.7 mmol), DMF (3 ml) and A solution of SOCl ₂ (17.5 g, 147 mmol) was refluxed for 4 hours. The mixture was evaporated and evaporated again from toluene to give the corresponding acid chloride. 6-chloro-3- (1,2,3,6-tetrahydropyridin-4-yl) -1H-indole (EP Patent Publication No. 465398-A1) (9.2 g, 39.7 mmol) on THF (120 ml) and To the solution of TEA (10 ml) was added dropwise an acid chloride solution on THF (120 ml) over 20 minutes. The mixture was stirred for 1.5 hours and evaporated. H ₂ O (50 ml) was added to the residue and the mixture was extracted with CH ₂ Cl ₂ (2 × 150 ml). After washing with H ₂ O (20 ml) and brine (20 ml), the combined organic phases were dried over MgSO ₄ and evaporated. The product was purified by column chromatography (EtOAc: heptane = 1: 1) to give the title compound 7a (7.8 g, 50%): ¹ H NMR (DMSO-d ₆ ) δ 1.55-1.72 (1H, m); 2.20-2.60 (3H, m), 2.69-2.95 (4H, m); 3.48-3.58 (1 H, m); 3.61-3. 81 (2H, m); 4.18 (2H, bs); 6.12 (1 H, d); 7.05 (1H, doublet); 7.08-7. 16 (2H, m); 7.17-7.31 (2H, m); 7.42 (1 H, d); 7.49 (1 H, dd); 7.81 (1 H, dd); 11.31 (1 H, bs).
Example 8
6-chloro-3- [1- [2- (indan-1-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole 8a.
To a suspension of LiAlH ₄ (2.3 g, 60.0 mmol) on THF (150 ml) 6-chloro-3- [1- [2- (indan-1-yl) methylcarbonyl] -1,2, on THF (150 ml) A solution of 3,6-tetrahydropyridin-4-yl] -1H-indole, 7a (7.8 g, 20.0 mmol) was added dropwise over 20 minutes. The mixture was refluxed for 1.5 hours and cooled to 10-15 ° C. H ₂ O (3 ml), aqueous (15%) NaOH (3 ml) and H ₂ O (12 ml) were added dropwise, then the solution was filtered and evaporated to near dryness. The residue was dissolved in CH ₂ Cl ₂ , dried over MgSO ₄ and the solution was evaporated to give the title compound 8a (5.7 g, 77%): Melting point 181-183 ° C., ¹ H NMR (DMSO-d ₆ ) δ 1.45-1.70 (2H, m); 1.95-2.15 (1 H, m); 2.20-2.35 (1 H, m); 2.45-2.60 (4H, m); 2.60-2.95 (4H, m); 3.00-3.20 (3H, m); 6.10-6.15 (1 H, m); 7.00 (1 H, dd); 7.10-7.25 (4H, m); 7.40 (2H, d); 7.80 (1 H, d); 11.25 (1 H, bs). MS m / z (%): 377 (MH &lt; + &gt;, 38%), 131 (100%).
The following compounds were similarly prepared following the procedure described in Examples 7 and 8.
5-fluoro-3- [1- [2- (indan-1-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole, 8b. Melting point 172-176 ° C. ¹ H NMR (CDCl ₃ ) d 1.75-1.80 (m, 2H); 2.15-2.25 (m, 1 H); 2.30-2.40 (m, 1 H); 2.60-2.70 (m, 4 H); 2.75-2.85 (m, 2 H); 2.85-2.90 (m, 1 H); 2.90-3.00 (m, 1 H); 3.20-3.30 (m, 3 H); 6.10 (broad s, 1 H); 6.95 (t, 1 H); 7.15-7.30 (m, 6H); 7.50 (d, 1 H); 8.15 (broad s, 1 H). MS m / z (%): 361 (MH <+>, 67%), 174 (74%), 131 (100%).
The following compounds were obtained by hydrogenation of compound 8b at 3 atmospheres in acetic acid using PtO ₂ as catalyst in the Parr apparatus.
5-Fluoro-3- [1- [2- (indan-1-yl) ethyl] -piperidin-4-yl] -1 H-indole, oxalate 8c. Melting point 107-115 ° C., ¹ H NMR (DMSO-d ₆ ) d 1.55-1.85 (m, 2H); 1.90-2.00 (m, 2H); 2.10 (broad d, 2 H); 2.20-2.30 (m, 2 H); 2.75-2.85 (m, 1 H); 2.85-2.95 (m, 1 H); 3.00-3.20 (m, 6 H); 3.55 (broad s, 2 H); 6.90 (t, 1 H); 7.15-7.20 (m, 2H); 7.20-7.25 (m, 2H); 7.25 (d, 1 H); 7.30-7.40 (m, 1H); 7.35 (d, 1 H); 11.00 (s, 1 H). MS m / z (%): 363 (MH <+>, 9%), 117 (10%), 98 (100%).
5-fluoro-3- [1- [4- (indan-1-yl) butan-1-yl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole, 8d. Melting point 172-176 ° C. ¹ H NMR (CDCl ₃ ) d 1.40-1.70 (m, 6H); 1.85-1.95 (m, 1 H); 2.25-2.35 (m, 1 H); 2.50 (t, 2 H); 2.60 (broad s, 2 H); 2.70 (t, 2 H); 2.80-2.90 (m, 1 H); 2.90-3.00 (m, 1 H); 3.05-3.15 (m, 1 H); 3.25 (broad s, 2 H); 6.10 (broad s, 1 H); 6.95 (t, 1 H); 7.10-7.30 (m, 6H); 7.50 (d, 1 H); 8.10 (s, 1 H). MS m / z (%): 389 (MH <+>, 9%), 202 (100%), 171 (44%), 129 (73%).
The following compounds were obtained by hydrogenation of compound 8d at 3 atmospheres in acetic acid using PtO ₂ as catalyst in the Parr apparatus.
5-fluoro-3- [1- [4- (indan-1-yl) butan-1-yl] -piperidin-4-yl] -1H-indole, 8e. Melting point 83-86 ° C. ¹ H NMR (CDCl ₃ ) d 1.25-1.90 (m, 9H); 1.95-2.10 (m, 4 H); 2.20-2.30 (m, 1 H); 2.35-2.45 (m, 2 H); 2.70-2.90 (m, 3 H); 3.05-3.15 (m, 3 H); 6.90 (t, 1 H); 6.95 (s, 1 H); 7.10-7.30 (m, 6H); 8.15 (s, 1 H). MS m / z (%): 391 (MH <+>, 61%), 256 (78%), 98 (100%).
6-chloro-3- [1- [4- (indan-1-yl) butan-1-yl] -piperidin-4-yl] -1H-indole, oxalate 8f. Melting point 206-208 ° C., ¹ H NMR (DMSO-d ₆ ) d 1.40-1.50 (m, 3H); 1.60-1.65 (m, 1 H); 1.65-1.70 (m, 2 H); 1.80-1.90 (m, 1 H); 1.95-2.10 (m, 4 H); 2.20-2.30 (m, 1 H); 2.70-2.80 (m, 1 H); 2.80-2.90 (m, 1 H); 2.95-3.10 (m, 6 H); 3.55 (broad d, 2 H); 6.95 (d, 1 H); 7.10-7.30 (m, 5H); 7.40 (s, 1 H); 7.65 (d, 1 H); 11.10 (s, 1 H). MS m / z (%): 407 (MH <+>, 69%), 256 (100%), 117 (39%), 98 (51%).
6-chloro-3- [1- [3- (indan-1-yl) propan-1-yl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole, oxalate 8 g . Melting point 198-200 ° C. ¹ H NMR (CHCl ₃ -d) 1.40-1.55 (1H, m); 1.60-1.80 (3H, m); 1.75-1.95 (1 H, m); 2.20-2.40 (1 H, m); 2.45-2.60 (4H, m); 2.70 (2H, t); 2.80-3.00 (2H, m); 3.10-3.15 (1 H, m); 3.20-3.25 (2H, m); 6.15 (1 H, s); 7.05-7.30 (6H, m); 7.30 (1 H, d); 7.80 (1 H, d); 8.25 (1 H, bs). MS m / z (%): 391 (MH <+>, 5%), 157 (100%), 129 (76%), 188 (56%).
6-chloro-3- [1- [4- (indan-1-yl) butan-1-yl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole, oxalate 8h . Melting point 191-192 ° C., ¹ H NMR (DMSO-d ₆ ) d 1.40-1.50 (3H, m); 1.60-1.65 (1 H, m); 1.70-1.80 (2H, m); 1.80-1.90 (1 H, m); 2.30-2.25 (1 H, m); 2.25-2.30 (3H, m); 2.30-2.90 (1 H, m); 3.05-3.20 (3H, m); 3.35 (2H, bs); 3.80 (2H, bs); 6.10 (1 H, s); 7.10 (1 H, d); 7.10 (2 H, m); 7.20 (2 H, m); 7.45 (1 H, s); 7.55 (1 H, s); 7.80 (1 H, d). MS m / z (%): 405 (MH <+>, 6%), 202 (100%), 129 (54%), 171 (36%).
Synthesis of 3- (indan-1-yl) propanoic acid and 4- (indan-1-yl) butanoic acid is described by A.Mukhopadhyay et al. J. Indian Chem. Soc. 1985, 62 (9), 690-2.
Example 9
Indan-2-carboxylic acid 9a.
(Intermediate)
A solution of indan-2,2-dicarboxylic acid (17 g, Baeyer and Perkin, Ber. 1884, 17, 122) on NMP (200 ml) was heated to 150 ° C. for one hour. After cooling to 20 ° C., the solution is poured into water (300 ml) and the pH is adjusted to 1 by addition of concentrated hydrochloric acid. The conventional finishing procedure with ether afforded the title compound (4.7 g). Melting point 132-33 ° C (from ether).
Example 10
6-chloro-3- [1-{(indan-2-yl) carbonyl} -1,2,3,6-tetrahydropyrid-4-yl] -1H-indole, 10a.
To a 9a (2.1 g) solution on dichloromethane (200 ml) was added thionyl chloride (1.4 ml) and DMF (2 ml). After 2.5 hours of reflux the mixture was concentrated in vacuo and dissolved in DMF (50 ml). The solution was transferred to 6-chloro-3- (1,2,3,6-tetrahydropyridin-4-yl) -1H-indole (EP patent application No 465398-A1 on DMF (200 ml) and triethylamine (9 ml). (3.0 g) was added dropwise to an ice cold solution. The reaction mixture is stirred at rt for 16 h and then poured into a saturated solution of sodium chloride (500 ml). Conventional finishing with ethyl acetate gave the title compound (4.7 g) pure enough for further reaction. In a similar manner the following compounds were prepared:
3- [1-[(indan-2-yl) carbonyl] -1,2,3,6-tetrahydropyrid-4-yl] -1H-indole, 10b.
Prepared from compound 9a and 3- (1,2,3,6-tetrahydropyridin-4-yl) -1H-indole.
7-chloro-3- [1-[(indan-2-yl) carbonyl] -1,2,3,6-tetrahydropyrid-4-yl] -1H-indole, 10c.
Prepared from compound 9a and 7-chloro-3- (1,2,3,6-tetrahydropyridin-4-yl) -1H-indole.
6,7-dichloro-3- [1-[(indan-2-yl) carbonyl] -1,2,3,6-tetrahydropyrid-4-yl] -1H-indole, 10d.
Prepared from compound 9a and 6,7-dichloro-3- (1,2,3,6-tetrahydropyridin-4-yl) -1H-indole.
3- [1-[(indan-2-yl) carbonyl] -1,2,3,6-tetrahydropyrid-4-yl] -5,6-methylenedioxy-1H-indole, 10e.
Prepared from compound 9a and 5,6-methylenedioxy-3- (1,2,3,6-tetrahydropyridin-4-yl) -1H-indole.
5- [4-[(indan-2-yl) carbonyl] piperazin-1-yl] -1H-indole, 10f.
Prepared from compound 9a and 5- (piperazinyl) -1H-indole.
6-chloro-3- [1- [2- (indan-2-yl) methylcarbonyl] -1,2,3,6-tetrahydropyrid-4-yl] -1H-indole, 10 g.
Prepared from 2- (indan-2-yl) acetic acid and 6-chloro-3- (1,2,3,6-tetrahydropyridin-4-yl) -1H-indole.
6-chloro-3- [1- [3- (indan-2-yl) ethylcarbonyl] -1,2,3,6-tetrahydropyrid-4-yl] -1H-indole, 10h.
Prepared from 3- (indan-2-yl) propionic acid and 6-chloro-3- (1,2,3,6-tetrahydropyridin-4-yl) -1H-indole.
6-chloro-3- [1- [4- (indan-2-yl) propylcarbonyl] -1,2,3,6-tetrahydropyrid-4-yl] -1H-indole, 10i.
Prepared from 4- (indan-2-yl) butyric acid and 6-chloro-3- (1,2,3,6-tetrahydropyridin-4-yl) -1H-indole.
Example 11
6-chloro-3- [1- (indan-2-yl) methyl-1,2,3,6-tetrahydropyridin-4-yl] -1H-indole, oxalate 11a.
A 10a (3.2 g) solution on THF (100 ml) was added at 5 ° C. to a cooled suspension of LiAlH ₄ (0.9 g) on THF (150 ml). The mixture was stirred at rt for 4 h. The mixture was cooled with ice and water (1.5 ml), 15% NaOH (1 ml) and water (3.5 ml) were added dropwise, then it was filtered and evaporated in vacuo. The residue was dissolved in CH ₂ Cl ₂ and finished by the conventional method to give yellow crystals (3.2 g) which was recrystallized from acetone to give 1.1 g, a melting point of 161-63 ° C. Title oxalate crystallized from acetone. Yield 0.45 g, Melting point 203-5 占 폚. ¹ H NMR (DMSO-d ₆ ) d 2.65-2.80 (m, 5H); 2.80-2.95 (m, 1 H); 2.95-3.30 (m, 5 H); 3.65 (s, 2 H); 6.15 (s, 1 H); 7.05 (dd, 1 H); 7.10-7.15 (m, 2H); 7.15-7.25 (m, 2H); 7.45 (d, 1 H); 7.55 (d, 1 H); 7.85 (d, 1 H); 11.45 (s, 1 H). MS m / z (%): 363 (MH <+>, 100%), 245 (17%), 230 (20%).
In a similar manner the following compounds were prepared:
3- [1- (indan-2-yl) methyl-1,2,3,6-tetrahydropyridin-4-yl] -1H-indole, 11b.
Manufactured from 10b. Melting point 156-157 ° C. ¹ H NMR (DMSO-d ₆ ) δ 2.40 (d, 2H); 2.45-2.85 (m, 7 H); 2.90-3.10 (m, 2 H); 3.15 (d, 2 H); 6.15 (s, 1 H); 6.95-7. 25 (m, 6H); 7.30-7.40 (m, 2H); 7.80 (d, 1 H); 11.10 (s, 1 H). MS m / z (%): 329 (MH <+>, 84%), 160 (87%), 131 (100%).
7-chloro-3- [1- (indan-2-yl) methyl-1,2,3,6-tetrahydropyridin-4-yl] -1H-indole, oxalate 11c.
Manufactured from 10c. Melting point 135-136 ° C. ¹ H NMR (DMSO-d ₆ ) δ 2.70-3.05 (m, 5H); 3.05-3.20 (m, 2 H); 3.30 (d, 2 H); 3.40 (t, 2 H); 3.90 (s, 2 H); 6.20 (s, 1 H); 7.05-7.30 (m, 6 H); 7.60 (d, 1 H); 7.85 (d, 1 H); 11.75 (s, 1 H). MS m / z (%): 365,363 (MH <+>, 46%, 81%), 160 (100%), 131 (53%) 98 (81%).
6,7-dichloro-3- [1- (indan-2-yl) methyl-1,2,3,6-tetrahydropyridin-4-yl] -1H-indole, 11d.
Manufactured from 10d. Melting point 151-152 ° C. ¹ H NMR (CDCl ₃ ) δ 2.45-2.65 (m, 4H); 2.65-2.90 (m, 5 H); 3.00-3.20 (m, 2 H); 3.20-3.30 (m, 2 H); 6.15 (broad s, 1 H); 7.05-7.30 (m, 6 H); 7.70 (d, 1 H); 8.35 (broad s, 1 H). MS m / z (%): 399, 397 (MH <+>, 33%, 53%), 160 (100%), 131 (24%).
3- [1- (indan-2-yl) methyl-1,2,3,6-tetrahydropyridin-4-yl] -5,6-methylenedioxy-1H-indole, 11e.
Manufactured from 10e. Melting point 192-193 ° C. ¹ H NMR (DMSO-d ₆ ) δ 2.40 (d, 2H); 2.45-2.55 (m, 2 H); 2.55-2.80 (m, 5 H); 2.95-3.05 (m, 2 H); 3.15 (s, 2 H); 5.95 (s, 2 H); 6.00 (s, 1 H); 6.90 (s, 1 H); 7.05-7.15 (m, 2H); 7.15-7.20 (m, 3 H); 7.25 (s, 1 H); 11.90 (s, 1 H). MS m / z (%): 373 (MH <+>, 100%), 160 (100%), 131 (73%) 114 (80%).
5- [4- (indan-2-yl) methylpiperazin-1-yl] -1H-indole, dihydrochloride 11f.
Manufactured from 10f. Melting point 263-265 ° C. ¹ H NMR (DMSO-d ₆ ) δ 2.80-2.90 (m, 2H); 2.90-3.05 (m, 1 H); 3.05-3.25 (m, 2H); 3.40 (d, 2 H); 3.45-3.95 (m, 8H); 6.45 (s, 1 H); 7.05-7.25 (m, 5H); 7.35-7.65 (m, 3 H); 11.25 (s, 1 H). MS m / z (%): 332 (MH <+>, 31%), 159 (100%), 131 (72%).
6-chloro-3- [1- [2- (indan-2-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole, 11 g.
Manufactured from 10 g. Melting point 217-218 ° C. ¹ H NMR (DMSO-d ₆ ) δ 1.70 (q, 2H); 2.35-2.70 (m, 9 H); 2.90-3.20 (m, 4 H); 6.10 (broad s, 1 H); 6.95-7.25 (m, 5H); 7.40 (d, 2 H); 7.80 (d, 1 H); 11.25 (broad s, 1 H). MS m / z (%): 379, 377 (MH <+>, 7%, 16%), 174 (93%), 143 (100%).
6-chloro-3- [1- [3- (indan-2-yl) propan-1-yl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole, 11h.
Prepared from 10 h. Melting point 176-177 ° C. ¹ H NMR (DMSO-d ₆ ) δ 1.40-1.70 (m, 4H); 2.30-2.70 (m, 9H); 2.90-3.15 (m, 4 H); 6.10 (broad s, 1 H); 6.95-7.25 (m, 5H); 7.40 (d, 2 H); 7.80 (d, 1 H); 11.25 (broad s, 1 H). MS m / z (%): 391 (MH <+>, 6%), 188 (100%), 129 (47%).
6-chloro-3- [1- [4- (indan-2-yl) butan-1-yl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole, 11i.
Manufactured from 10i. Melting point 211-214 ° C. ¹ H NMR (DMSO-d ₆ ) δ 1.30-1.65 (m, 6H); 2.25-2.70 (m, 9 H); 2.90-3.15 (m, 4 H); 6.10 (broad s, 1 H); 6.95-7.25 (m, 5H); 7.40 (d, 2 H); 7.80 (d, 1 H); 11.25 (broad s, 1 H). MS m / z (%): 407, 405 (MH <+>, 4%, 10%), 202 (100%), 129 (93%).
The following compounds were prepared using Compound 40a as a starting material according to the procedures of Examples 10 and 11.
6-chloro-3- [1-[(4- (2-propyl) oxyindan-2-yl) methyl] -piperidin-4-yl] -1H-indole, oxalate 11j. Melting point 119-126 ° C. ¹ H NMR (DMSO-d ₆ ) d 1.26 (3H, d); 1.27 (3H, d); 1.95-2.2 (4H, m); 2.60 (1 H, dd); 2.74 (1H, doublet); 2.91 (1 H, quin); 3.0-3.2 (5H, m); 3.2-3.3 (2H, m); 3.5-3.7 (2H, m); 4.57 (1 H, h); 6.77 (2H, t); 7.0 (1H, dd); 7.09 (1 H, t); 7.20 (1 H, s); 7.41 (1 H, s); 7.66 (1 H, d). MS m / z (%): 423 (MH <+>, 59%), 249 (21%), 147 (20%), 98 (100%).
5-fluoro-3- [1-[(4- (2-propyl) oxyindan-2-yl) methyl] -piperid-4-yl] -1H-indole, oxalate 11k. Melting point 181-189 ° C. ¹ H NMR (DMSO-d ₆ ) d 1.26 (3H, d); 1.26 (3 H, d); 2.61 (1 H, dd); 2.74 (1H, doublet); 2.7-2.8 (2H, m); 2.92 (1 H, h); 3.0-3.2 (2H, m); 3.15-3.3 (2H, m); 3.3-3.45 (2H, m); 3.7-3.9 (2H, m); 4.57 (1 H, h); 6.11 (1 H, s); 6.76 (1 H, d); 6.79 (1 H, d); 6.99 (1 H, dt); 7.42 (1 H, dd); 7.5-7.65 (2H, m). MS m / z (%): 405 (MH <+>, 7%), 231 (4%), 147 (5%), 98 (9%), 44 (100%).
The following compounds were prepared using Compound 40b as a starting material according to the procedures of Examples 10 and 11:
6-chloro-3- [1-[(5,6-dimethoxyindan-2-yl) methyl] -piperid-4-yl] -1H-indole, 11 l.
Melting point 68-79 ° C. ¹ H NMR (DMSO-d ₆ ) d 1.68 (2H, dq); 1.91 (2H, doublet); 2.06 (2H, dt); 2.31 (2H, d); 2.58 (2H, doublet); 2.65-2.77 (2H, m); 2.91 (1H, doublet); 3.70 (6H, s); 6.80 (2H, s); 6.96 (1 H, dd); 7.15 (1 H, d); 7.36 (1 H, d); 7.54 (1 H, d); 10.91 (1 H, s). MS m / z (%): 425 (MH <+>, 7%), 249 (11%), 191 (16%), 98 (100%).
Example 12
4-Methyl-1-indanone-3-carboxylic acid, 12a.
(Intermediate)
Piperidine (16 ml) was added to a mixture of o-tolualdehyde (500 g), ethyl cyanoacetate (445 g) and ethanol (500 ml). After constant boiling mixture distillation (200 ml) more ethanol (200 ml) was added and the mixture was refluxed for 2 hours. The solution was cooled to 40 ° C. and a NaCN (225 g) solution on water (300 ml) was added over 20 minutes. The mixture was stirred for 1 hour and left at room temperature for 16 hours. Concentrated HCl (5 L) is added slowly and water / ethanol is removed by distillation until the temperature reaches 100 ° C. The mixture was then refluxed for 4 hours and then stirred at room temperature for 16 hours. The mixture was filtered and the crystals washed with water. The crystals were dissolved in 4M NaOH (3 1) and filtered. The pH was adjusted to 1 with concentrated hydrochloric acid and the crystals were filtered off and dried to give 610 g which was dissolved in thionyl chloride (2 L). DMF (10 ml) was added and the solution was refluxed for 2.5 hours and evaporated in vacuo. The residue was dissolved in CH ₂ Cl ₂ (1.2l) was added to AlCl ₃ (600g) A mixture of CH ₂ Cl ₂ (4l) cooled at 0-5 ℃ for one hour. The mixture was stirred at rt for 16 h and poured into ice / water (5 l) and concentrated hydrochloric acid (500 ml). The conventional finish gave the natural title product (605 g) which was purified by silica gel column chromatography eluted with CH ₂ Cl ₂ -ether-acetic acid (50: 50: 2) to give 236 g of the title product.
Example 13
7-methyl-dan--1-carboxylic acid, 13a.
(Intermediate)
Triethylsilane (141 g) was added to a 12a (100 g) solution on trifluoroacetic acid. The mixture was stirred at rt for 72 h and evaporated in vacuo to dissolve the residue in ethyl acetate and extracted with dilute NaOH solution. The aqueous phase was washed with ethyl acetate and acidified with concentrated hydrochloric acid. A conventional finish using ethyl acetate yielded 80.4 g of natural product. Purification on silica gel eluted with ethyl acetate-heptane-acetic acid gave the title compound (76.6 g).
Example 14
3,6,7,8-tetrahydrocyclopent [e] indole-8-carboxylic acid, 14a.
(Intermediate)
A 13a (61.2 g) solution on CH ₂ Cl ₂ (100 ml) was added to a mixture of concentrated nitric acid (150 ml) and CH ₂ Cl ₂ (40 ml) with stirring at −50 ° C. for 20 minutes. After 30 min stirring at -52 ° C. the mixture was poured into ice and saturated NaCl solution. A conventional finish with ethyl acetate gave 58.2 g of natural product which was purified on silica gel eluted with heptane-ethyl acetate (2: 1) to 45.6 g of product containing 32% of 5-nitro compound along with other nitro compounds. Got. This product was dissolved in DMF (200 ml) and heated to 88 ° C. Tris- (dimethylamino) methane (34.5 g) was added and the temperature was raised to 123 ° C. and the mixture was stirred for 2 hours. The mixture was cooled to 27 ° C. and a solution of semicarbazide, HCl (19 g) in water (200 ml) was added over 8 minutes. The mixture was stirred at room temperature for 70 minutes. Ethanol (500 ml) was added and iron powder (30 g) and acetic acid (120 ml) were added in portions at 50 ° C. After reflux for 45 minutes the mixture was filtered and concentrated to 500 ml in vacuo. Water was added and the mixture was examined with ethyl acetate. The residue was purified on silica gel eluted with ethyl acetate to give 5.7 g of the title product. Melting point 166-7 ° C.
Example 15
8- [4- (6-chloro-1H-indol-3-yl) -1,2,3,6-tetrahydropyridin-1-ylcarbonyl] -3,6,7,8-tetrahydrocyclopent [e] indoles, 15a.
14a (1.4 g), 6-chloro-3- (1,2,3,6-tetrahydropyridin-4-yl) -1H-indole (1.6 g) on THF (100 ml), dicyclohexylcarbodiimide ( 1.9 g) and 4-dimethylaminopyridine (0.1 g) were stirred at room temperature for 24 hours. The mixture was filtered and evaporated in vacuo. The residue was purified on silica gel eluted with ethyl acetate-heptane (3: 2) to afford 1.1 g of the title compound as an amorphous powder.
Example 16
8- [4- (6-chloro-1H-indol-3-yl) -1,2,3,6-tetrahydropyridin-1-ylmethyl] -3,6,7,8-tetrahydrocyclopent [ e] indole, oxalate 16a.
The title product was prepared from 15a (1.05 g) as described in Example 3.
Yield 0.59 g, Melting point 155-7 占 폚. ¹ H NMR (DMSO-d ₆ ) δ 2.10-2.40 (m, 2H); 2.75-2.95 (m, 3 H); 2.95-3.25 (m, 2 H); 3.35-3.65 (m, 3 H); 3.85-4.10 (m, 3 H); 6.15 (s, 1 H); 6.50 (s, 1 H); 6.95 (d, 1 H); 7.10 (dd, 1 H); 7.25 (d, 1 H); 7.35 (t, 1 H); 7.45 (d, 1 H); 7.55 (d, 1 H); 7.85 (d, 1 H); 11.15 (s, 1 H); 11.55 (s, 1 H). MS m / z (%): 402 (MH &lt; + &gt;, 6%), 170 (96%), 156 (100%).
(Example 17)
Carboxylic acid 4-nitroindan-2-chloride, 17a.
(Intermediate)
A mixture of 3-nitro-o-xylene (100 g), N-bromosuccinimide, and dibenzoyl peroxide (2 g) was heated to reflux for 14 hours. The mixture was filtered and evaporated in vacuo to give an oil (202 g) which was purified on silica gel eluted with heptane-ether (10: 1) to give 86.4 g bromine compound which was dissolved in NMP (850 ml) and dissolved in NMP (1 l). ) Was added to a mixture of diethyl malonate (38 g) and 30% Na-methanol salt on methanol (105 ml). After stirring for 30 minutes at 60 ° C., the mixture was cooled, poured into cold water and finished with a mixture of ether and ethyl acetate. The residue was purified on silica gel eluted with toluene-ethyl acetate (6: 1). The product (25.1 g) was dissolved in ethanol (250 ml) and THF (50 ml). KOH (27 g) present in water (150 ml) was added and the mixture was stirred at rt for 16 h. The mixture was concentrated to 100 ml in vacuo and filtered through activated carbon. The filtrate was acidified with concentrated hydrochloric acid and finished with a mixture of ether and ethyl acetate. The residue (16.46 g) was dissolved in NMP (150 ml) and heated to 145 ° C. for 10 minutes. The solution was cooled to room temperature and poured into saturated NaCl solution. Finished with ether / ethyl acetate in the usual way to give 10.7 g of solid which was dissolved 6.0 g of CH ₂ Cl ₂ (100 ml) and DMF (1 ml). Thionyl chloride (8.4 ml) was added and the solution was refluxed for 16 h. Evaporation in vacuo gave the semi-crystal title compound (8.4 g).
5-nitroindan-2-carboxylic acid chloride, 17b.
A solution of indan-2-carboxylic acid 9a (18.8 g) on ether (250 ml) was added to concentrated sulfuric acid (300 ml) (temperature = 3-13 ° C.). To this mixture was added concentrated nitric acid (4.4 ml) and concentrated sulfuric acid (100 ml) (temperature = -1 ° C). The mixture was stirred at 2-8 ° C. for 1 hour, poured onto ice and the aqueous phase was extracted with ether. The combined organic extracts were washed with brine, dried (MgSO ₄ ) and evaporated to dryness in vacuo. The residue was crystallized from ether to give 5-nitroindan-2-carboxylic acid (6.0 g). The solid was dissolved in CH ₂ Cl ₂ (100 ml) and DMF (1 ml). Thionyl chloride (8.4 ml) was added and the solution was boiled under reflux for 5 hours. Evaporation in vacuo gave the title compound (8.6 g).
(Example 18)
6-chloro-3- [1- (4-acetylaminoindan-2-yl) methyl-1,2,3,6-tetrahydropyridin-4-yl] -1H-indole, oxalate 18a.
DMF (50 ml) to a solution of 6-chloro-3- (1,2,3,6-tetrahydropyridin-4-yl) -1-H-indole (6.4 g) on DMF (250 ml) and triethylamine (14 g) A 17a (8.4 g) solution on) was added at 3-5 ° C. for 25 minutes. The mixture was stirred at room temperature for 45 minutes and then poured into water. The precipitate was removed by filtration, washed with water and dried to give 9.11 g of solid, which was slurried at 90% ethanol (450 ml) reflux. Iron powder (9 g) and concentrated hydrochloric acid (1.8 ml) were added in portions for 15 minutes and the mixture was refluxed. The mixture was concentrated in vacuo and ice and concentrated ammonium hydroxide were added. A conventional finish using ethyl acetate gave 4.67 g which was treated with LiAlH ₄ as described in Example 11 to give 3.2 g of solid which was dissolved in 2 g of THF (50 ml) and triethylamine (3.5 ml). I was. An ice cold acetyl chloride (0.43 g) solution on THF (15 ml) was added at 1-4 ° C. After warming to room temperature, the mixture was filtered and evaporated in vacuo and the residue was purified on silica gel eluted with ethyl acetate-ethanol-triethylamine (100: 4: 4) to give 1.51 g of the title compound as 2-propanol Crystallized as an oxalic acid salt. Yield 1.29 g, melting point 143-4 ° C. ¹ H NMR (DMSO-d ₆ ) δ 2.0 (s, 3H); 2.55-3.00 (m, 5H); 3.00-3.15 (m, 4 H); 3.25 (broad s, 2 H); 3.70 (s, 2 H); 6.15 (s, 1 H); 7.0 (d, 1 H); 7.05-7.15 (m, 2H); 7.35 (d, 1 H); 7.45 (d, 1 H); 7.55 (d, 1 H); 7.85 (d, 1 H); 9.40 (s, 1 H); 11.45 (s, 1 H). MS m / z (%): 420 (MH &lt; + &gt;, 11%), 217 (87%), 174 (100%).
In a similar manner the following compounds were prepared.
6-chloro-3- [1- (4-acetylaminoindan-2-yl) methylpiperidin-4-yl] -1H-indole, oxalate, 18b. Prepared from 6-chloro-3- (piperidin-4-yl) -1H-indole and 17a.
Melting point 153-5 ° C. ¹ H NMR (DMSO-d ₆ ) δ 1.80-2.10 (m, 7H); 2.55-3.15 (m, 10 H); 3.40 (broad d, 2 H); 6.95-7.05 (m, 2 H); 7.10 (t, 1 H); 7.20 (d, 1 H); 7.35-7.40 (m, 2H); 7.60 (d, 1 H); 9.35 (s, 1 H); 11.05 (s, 1 H). MS m / z (%): 422 (MH &lt; + &gt;, 100%), 249 (2%), 98 (16%).
Suitable w- (6-acetylamino-1-indanyl) -alkanoic acid is converted to the corresponding acid chloride as described in Example 17 and 6-chloro-3- (1, Reaction with 2,3,6-tetrahydropyridin-4-yl) -1H-indole afforded the following compounds.
6-chloro-3- [1- [2- (6-acetylaminoindan-1-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole oxalate, 18c .
Melting point 153-155 ° C. ¹ H NMR (DMSO-d ₆ ) d 1.60-1.90 (2H, m); 2.00 (3H, s); 2.10-2.35 (2H, m); 2.65-2.90 (4H, m); 3.05-3.30 (3H, m); 3.30-3.50 (2H, m); 3.90 (2H, bs); 6.10 (1 H, s); 7.05-7.15 (2H, m); 7.25 (2H, d); 7.45 (1 H, s); 7.60 (2 H, m); 7.85 (1 H, d); 9.90 (1 H, bs); 11.50 (1 H, bs). MS m / z (%): 434 (MH <+>, 3%), 188 (100%), 231 (14%), 174 (12%).
6-chloro-3- [1- [3- (6-acetylaminoindan-1-yl) propan1-yl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole oxalic acid Salt, 18d.
Melting point 110-115 ° C. ¹ H NMR (DMSOd ₆ ) d 1.35-1.50 (1H, m); 1.60-1.70 (1 H, m); 1.80 (3 H, bs); 2.00 (3H, s); 2.20-2.39 (1 H, m); 2.65-2.90 (4H, m); 3.05-3.20 (3H, m); 3.90 (2H, bs); 3.80 (2H, bs); 6.10 (1 H, s); 7.05-7.10 (2H, m); 7.25 (2H, d); 7.45 (1 H, s); 7.55 (1 H, d); 7.80 (1 H, d); 9.80 (1 H, bs); 11.50 (1 H, bs). MS m / z (%): 448 (MH <+>, 5%), 245 (100%), 214 (35%), 246 (16%).
6-chloro-3- [1- [4- (6-acetylaminoindan-1-yl) butan-1-yl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole Oxalate, 18e.
Melting point 125-128 ° C. ¹ H NMR (DMSO-d ₆ ) d 1.25-1.50 (3H, m); 1.50-1.90 (4H, m); 2.00 (3H, s); 2.10-2.30 (1 H, m); 2.60-2.90 (4H, m); 2.90-3.15 (3H, m); 3.40 (2H, bs); 3.80 (2H, bs); 6.10 (1 H, s); 7.00-7.10 (2H, m); 7.25 (1 H, d); 7.45 (1 H, s); 7.55 (1 H, d); 7.80 (1 H, d); 9.85 (1 H, bs); 11.50 (1 H, bs). MS m / z (%): 462 (MH <+>, 4%), 259 (100%), 186 (43%), 228 (17%).
2- (6-acetylaminoindan-1-yl) acetic acid, 3- (6-acetylaminoindan-1-yl) propanoic acid and 4- (6-acetylaminoindan-1-yl) butanoic acid in KCN or Mal Prepared from 6-nitro-1-indanecarboxylic acid by classical chain extension using diethyl lonate. The methodology is described by R. Gruber et al. Tetrahedron 1974, 30, 3605-10, for homologous incidence rows. Alanes are used for the reduction of intermediate carboxylic acids.
3- [1- (5-acetylaminoindan-2-yl) methyl-1,2,3,6-tetrahydropyridin-4-yl] -6-chloro-1H-indole, oxalate, 18f. Manufactured from 17b. Melting point 201-203 ° C. ¹ H NMR (DMSO-d ₆ ) δ 2.00 (s, 3H); 2.55-3.20 (m, 11 H); 3.55 (broad s, 2 H); 6.15 (broad s, 1 H); 7.00-7.15 (m, 2H); 7.25 (d, 1 H); 7.45 (d, 1 H); 7.50 (broad s, 2 H); 7.85 (d, 1 H); 9.80 (s, 1 H); 11.40 (broad s, 1 H). MS m / z (%): 420 (MH &lt; + &gt;, 5%), 217 (12%), 174 (100%).
3- [1- (5-acetylaminoindan-2-yl) methylpiperidin-4-yl] -6-chloro-1H-indole, hemifumarate, 18 g. Manufactured from 17b. Melting point 151-152 ° C. ¹ H NMR (DMSOd ₆ ) d 1.65-2.05 (m, 7H); 2.30 (t, 2 H); 2.45-2.90 (m, 6 H); 2.90-3.20 (m, 4 H); 6.55 (s, 1 H); 6.95 (dd, 1 H); 7.10 (d, 1 H); 7.15 (d, 1 H); 7.25 (dd, 1 H); 7.40 (d, 1 H); 7.50 (s, 1 H); 7.60 (d, 1 H); 9.80 (s, 1 H); 10.95 (broad s, 1 H). MS m / z (%): 424, 422 (MH &lt; + &gt;, 19%, 54%), 249 (13%), 98 (100%).
Example 19
1-acetyl-2,3-dihydro-3- [2- (methanesulfonyl) ethyl] -1 H-indole, 19a.
(Intermediate)
To a solution of indole-3-acetic acid (100 g) in methanol (1 l) was added ether saturated with HCl (200 ml) and the solution was left at room temperature for 3 hours. The solution was evaporated in vacuo and the residue was slowly added to a stirred suspension of LiAlH ₄ (28.6 g) on THF (1 l) with cooling and cooling. After stirring for 2 hours at room temperature the mixture was cooled to a cold bath and water (57 ml), 15% NaOH (29 ml), and water (143 ml) were added. The mixture was filtered and evaporated in vacuo and the residue (84.9 g) was dissolved in dioxane (1.5 l). Borane trimethylamine complex (200 g) was added and concentrated hydrochloric acid (150 ml) was added to the stirred mixture for one hour. The mixture was heated to 40 ° C. for 30 minutes and then refluxed for 2.5 hours. 6M hydrochloric acid (460ml) was added and reflux was continued for 30 minutes. The solution was concentrated in vacuo and the residue poured on ice. The solution was washed with ether, basified with concentrated NaOH and extracted with ether. The organic phase was dried over MgSO ₄ and evaporated in vacuo. The residue was dissolved in CH ₂ Cl ₂ (680 ml) and triethylamine (68 ml). Acetyl chloride (36 ml) was added at 5 ° C. for one hour. After one more hour of stirring at room temperature the mixture was washed with dilute hydrochloric acid and NaHCO ₃ solution. After drying over MgSO ₄ and evaporation in vacuo the residue was dissolved in methanol (500 ml) and 30% NaCl (10 ml) was added. The mixture was stirred at rt for 4 h and then evaporated in vacuo, dissolved in CH ₂ Cl ₂ , washed with saturated NaCl solution, dried over MgSO ₄ and evaporated in vacuo. The residue (75.4 g) was dissolved in CH ₂ Cl ₂ (1 L) and triethylamine (100 ml). While cooling, a solution of methanesulfone chloride (27 ml) on CH ₂ Cl ₂ (175 ml) was added at 10 ° C. After stirring for 30 minutes at 0 ° C. and 1 hour at room temperature, the mixture was evaporated in vacuo and purified on silica gel eluted with ethyl acetate to afford the title compound as an oil (74 g).
In a similar manner the following compounds were prepared:
1-formyl-2,3-dihydro-3- [2- (methanesulfonyl) ethyl] -1H-indole, 19b. Formylation was carried out with a mixture of formic acid and acetic anhydride. The compound was an oil.
1-acetyl-2,3-bromo-2,3-dihydro-3- [2- (methanesulfonyl) ethyl] -1 H-indole, 19c. Bromination was done by treating 19a with bromine in a mixture of acetic acid and dichloromethane. The compound was an oil.
1-tert-butoxycarbonyl-2,3-dihydro-3- [2- (methanesulfonyl) ethyl] -1H-indole, 19d. tert-butoxycarbonylation was carried out with di-tert-butyl bicarbonate. The compound was an oil.
1-tert-butoxycarbonyl-2,3-dihydro-3- [4- (methanesulfonyl) butan-1-yl] -1H-indole, 19e. Prepared from 4- (1H-indol-3-yl) butyric acid.
1-acetyl-5-fluoro-2,3-dihydro-3- (2-bromoethyl) -1H-indole, 19f.
5-Fluoro-indole (15.0 g, 135.2 mmol) was dissolved in dry Et ₂ O (450 mL), cooled to 0 ° C., and oxalyl chloride solution on dry Et ₂ O (50 mL) was added over 15 minutes. The mixture was stirred at 0 ° C. for 30 minutes and at room temperature for 3 hours. The crystals were collected by filtration and washed with Et ₂ O to afford 19.5 g of solid which was dissolved in EtOH (140 ml) and cooled to 0 ° C. and triethylamine (9.6 g) was added dropwise. The mixture was refluxed for 3 hours and stirred at room temperature for 24 hours. The crystals were collected by filtration and washed with H ₂ O and Et ₂ O to afford 18.0 g of solid which was dried in a vacuum oven and then dissolved in dry THF (150 ml) and cooling of LiAlH ₄ (16.1 g) on dry THF (350 ml). Dropwise to the prepared suspension (5-15 ° C.). The mixture was refluxed for 4 hours and cooled to 10 ° C. Water (16 ml), aqueous (15%) NaOH (16 ml) and water (80 ml) were added dropwise, then the solution was filtered and evaporated to near dryness. The residue was dissolved in EtOAc and dried over MgSO ₄ . Evaporation of the solvent gave 2- (5-fluoroindol-3-yl) ethanol (15.2 g) as an oil which was treated as described in Example 19 to acylate after borane triethylamine reduction to mesyl of the title compound. An acid salt was obtained which was refluxed with LiBr (8.0 g) in acetone (200 ml) for 2 hours. The mixture was purified by cooling, filtration, evaporation and column chromatography using EtOAc: heptane = 1: 2 as eluent to afford the title compound (9.0 g).
1-acetyl-5-methyl-2,3-dihydro-3- (2-bromoethyl) -1H-indole, 19 g.
Manufactured in a similar manner to 19f.
Example 20
3- [1- [2- (1-acetyl-2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -6- Chloro-1H-indole, 20a.
6-chloro-3- (1,2,3,6-tetrahydropyridin-4-yl) -1H-indole (1.6 g), 19a (2.0 g), K ₂ CO ₃ (4.0 g), and methyliso The mixture of butyl ketone (20 ml) was refluxed for 16 hours. The mixture was filtered and evaporated in vacuo and the residue was purified on silica gel eluted with ethyl acetate-methanol-triethylamine (90: 5: 5). Tableting from ethanol gave the title product (0.3 g). Melting point 172-4 ° C. ¹ H NMR (DMSOd ₆ ) d 1.75-1.95 (m, 1H); 2.05-2.20 (m, 1 H); 2.25 (s, 3 H); 2.50-2.65 (m, 4 H); 2.75 (t, 2 H); 3.25 (broad s, 2 H); 3.45-3. 60 (m, 1 H); 3.80 (dd, 1 H); 4.20 (t, 1 H); 6.15 (broad s, 1 H); 7.00-7.15 (m, 3 H); 7.25 (d, 1 H); 7.45 (d, 2 H); 7.80 (d, 1 H); 8.15 (s, 1 H); 8.25 (d, 1 H). MS m / z (%): 420 (MH &lt; + &gt;, 7%), 174 (100%), 144 (55%).
In a similar manner the following compounds were prepared.
3- [1- [2- (1-acetyl-2,3-dihydro-1H-indol-3-yl) ethyl] piperidin-4-yl] -6-chloro-1H-indole, 20b. Prepared from 19a and 6-chloro-3- (piperidin-4-yl) -1H-indole (EP Patent Publication No 465398-A1). Melting point 188-90 ° C. ¹ H NMR (DMSO-d ₆ ) d 1.70-1.90 (m, 3H); 1.95-2.20 (m, 5 H); 2.25 (s, 3 H); 2.40-2.55 (m, 2 H); 2.80 (tt, 1 H); 3.00-3.10 (m, 2 H); 3.40-3.55 (m, 1 H); 3.75 (dd, 1 H); 4.20 (t, 1 H); 6.95 (d, 1 H); 7.05 (ddd, 1 H); 7.25 (dt, 1 H); 7.35 (d, 1 H); 7.55 (d, 1 H); 8.00 (s, 1 H); 8.25 (d, 1 H). MS m / z (%): 422 (MH &lt; + &gt;, 100%), 249 (15%), 146 (19%).
6-chloro-3- [1- [2- (1-formyl-2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridine-4- General] -1 H-indole, 20c. Prepared from 19b and 6-chloro-3- (1,2,3,6-tetrahydropyridin-4-yl) -1H-indole. Melting point 183-5 ° C. (from acetone). ¹ H NMR (DMSO-d _6, shows disturbed rotation in which spectrum is removed by heating above 100 ° C.) δ 1.60-1.80 (m, 1H); 1.95-2.10 (m, 1 H); 2.35-2.55 (m, 4 H); 2.70 (t, 2 H); 3.15 (s, 2 H); 3.35-3.55 (m, 1 H); 3.65 (dd, 0.76 H); 3.90 (dd, 0.24 H); 4.10 (t, 0.76 H); 4.30 (t, 0.24 H); 6.15 (s, 1 H); 6.95-7. 15 (m, 2H); 7.25 (t, 1 H); 7.35 (d, 1 H); 7.40-7.50 (m, 3H); 7.80 (d, 0.76 H); 7.90 (d, 0.24 H); 8.50 (s, 0.24 H); 9.05 (s, 0.76 H); 11.20 (s, 1 H). MS m / z (%): 406 (MH &lt; + &gt;, 100%), 377 (5%), 244 (15%).
6-chloro-3- [1- [2- (1-formyl-2,3-dihydro-1H-indol-3-yl) ethyl] piperidin-4-yl] -1H-indole, oxalate , 20d. Prepared from 19b and 6-chloro-3- (piperidin-4-yl) -1H-indole. Melting point 143-145 ° C. ¹ H NMR (DMSO-d _{6, which} indicates the spectrum is disturbed) δ 1.75-2.30 (m, 6H); 2.65-3.10 (m, 5 H); 3.30-3.55 (m, 3 H); 3.65 (dd, 0.8 H); 3.90 (dd, 0.2 H); 4.10 (t, 0.8 H); 4.25 (t, 0.2 H); 6.95 (dd, 1 H); 7.00-7.40 (m, 5H); 7.45 (d, 0.8 H); 7.60 (d, 1 H); 7.95 (d, 0.2 H); 8.50 (s, 0.2 H); 9.05 (s, 0.8 H); 11.10 (s, 1 H). MS m / z (%): 410,408 (MH &lt; + &gt;, 9%, 25%), 146 (11%), 98 (100%).
3- [1- [2- (1-acetyl-5-bromo-2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridine-4- Il] -6-chloro-1H-indole, oxalate, 20e. Prepared from 19c and 6-chloro- (1,2,3,6-tetrahydropyridin-4-yl) -1H-indole. Melting point 157-159 ° C. ¹ H NMR (DMSOd ₆ ) δ 1.80-2.00 (m, 1H); 2.10-2.40 (m, 1 H); 2.20 (s, 3 H); 2.70 (broad s, 2 H); 2.90-3.15 (m, 2 H); 3.20 (broad s, 2 H); 3.45-3. 60 (m, 1 H); 3.65 (broad s, 2 H); 3.85 (dd, 1 H); 4.25 (t, 1 H); 6.15 (broad s, 1 H); 7.10 (dd, 1 H); 7.35 (dd, 1 H); 7.45 (d, 1 H); 7.55 (s, 2 H); 7.85 (d, 1 H); 8.00 (d, 1 H); 11.45 (broad s, 1 H). MS m / z (%): 502,500,498 (MH <+>, 8%, 27%, 22%), 297 (95%), 295 (100%).
3- [1- [2- (1-acetyl-2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -7- Chloro-1H-indole, oxalate, 20f. Prepared from 19a and 7-chloro- (1,2,3,6-tetrahydropyridin-4-yl) -1H-indole. Melting point 171-173 ° C. ¹ H NMR (DMSO-d ₆ ) δ 1.90-2.00 (m, 1H); 2.20 (s, 3 H); 2.20-2.30 (m, 1 H); 2.80 (broad s, 2 H); 3.10-3.30 (m, 2 H); 3.40 (broad s, 2 H); 3.50 (t, 1 H); 3.80-3.95 (m, 3 H); 4.25 (t, 1 H); 6.15 (broad s, 1 H); 6.95-7. 15 (m, 2H); 7.15-7.25 (m, 2H); 7.35 (d, 1 H); 7.60 (s, 1 H); 7.80 (d, 1 H); 8.05 (d, 1 H); 11.65 (broad s, 1 H). MS m / z (%): 422,420 (MH &lt; + &gt;, 3%, 7%), 174 (100%), 144 (43%).
3- [1- [2- (1-acetyl-2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -6, 7-dichloro-1H-indole, oxalate, 20 g. Prepared from 19a and 6,7-dichloro- (1,2,3,6-tetrahydropyridin-4-yl) -1H-indole. Melting point 115-117 ° C. ¹ H NMR (DMSO-d ₆ ) δ 1.90-2.05 (m, 1H); 2.20 (s, 3 H); 2.20-2.35 (m, 1 H); 2.80 (broad s, 2 H); 3.10-3.30 (m, 2 H); 3.40 (broad s, 2 H); 3.50 (broad s, 1 H); 3.80-3.95 (m, 3 H); 4.25 (t, 1 H); 6.15 (broad s, 1 H); 7.05 (t, 1 H); 7.20 (t, 1 H); 7.25 (d, 1 H); 7.35 (d, 1 H); 7.65 (s, 1 H); 7.80 (d, 1 H); 8.05 (d, 1 H); 11.90 (broad s, 1 H). MS m / z (%): 456,454 (MH <+>, 4%, 6%), 217 (36%), 174 (100%), 144 (36%).
3- [1- [2- (1-acetyl-2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -5, 6-methylenedioxy-1H-indole, oxalate, 20 h. Prepared from 19a and 5,6-methylenedioxy- (1,2,3,6-tetrahydropyridin-4-yl) -1H-indole. Melting point 182-183 ° C. ¹ H NMR (DMSO-d ₆ ) δ 1.90-2.00 (m, 1H); 2.20 (s, 3 H); 2.20-2.30 (m, 1 H); 2.75 (broad s, 2 H); 3.10-3.30 (m, 2 H); 3.40 (broad s, 2 H); 3.50 (broad s, 1 H); 3.80-3.90 (m, 3 H); 4.20 (t, 1 H); 5.95 (s, 2 H); 6.05 (broad s, 1 H); 6.95 (s, 1 H); 7.05 (t, 1 H); 7.20 (t, 1 H); 7.25-7.40 (m, 3 H); 8.05 (d, 1 H); 11.15 (broad s, 1 H). MS m / z (%): 430 (MH &lt; + &gt;, 6%), 217 (26%), 174 (100%), 144 (62%).
3- [1- [2- (1-tert-butoxycarbonyl-2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridine-4- Il] -6-chloro-1H-indole, oxalate, 20i. Prepared from 19d and 6-chloro- (1,2,3,6-tetrahydropyridin-4-yl) -1H-indole. Melting point 132-135 ° C. ¹ H NMR (DMSO-d ₆ ) δ 1.55 (s, 9H); 1.90-2.00 (m, 1 H); 2.20-2.30 (m, 1 H); 2.80 (broad s, 2 H); 3.10-3.25 (m, 2 H); 3.40 (broad s, 3 H); 3.65 (dd, 1 H); 3.85 (broad s, 2 H); 4.10 (t, 1 H); 6.15 (broad s, 1 H); 6.95 (t, 1 H); 7.10 (d, 1 H); 7.20 (t, 1 H); 7.30 (d, 1 H); 7.50 (s, 1 H); 7.55 (s, 1 H); 7.60-7.80 (broad s, 1 H); 7.85 (d, 1 H); 11.60 (broad s, 1 H). MS m / z (%): 478 (MH &lt; + &gt;, 10%), 219 (100%), 144 (27%).
5- [4- [2- (1-acetyl-2,3-dihydro-1H-indol-3-yl) ethyl] piperazin-1-yl] -1H-indole,
Hydrochloride, 20j. Prepared from 19a and 5-piperazinyl-1H-indole. Melting point 241-243 ° C. ¹ H NMR (DMSOd ₆ ) δ 1.95-2.15 (m, 1H); 2.20 (s, 3 H); 2.25-2.35 (m, 1 H); 3.15-3.50 (m, 6H); 3.55 (broad s, 1 H); 3.70 (d, 4 H); 3.90 (dd, 1 H); 4.25 (t, 1 H); 6.40 (s, 1 H); 6.95-7. 10 (m, 2H); 7.20 (t, 1 H); 7.25-7.45 (m, 4 H); 8.05 (d, 1 H); 11.10 (s, 1 H). MS m / z (%): 389 (MH &lt; + &gt;, 71%), 159 (71%), 118 (100%).
3- [1- [3- (1-acetyl-2,3-dihydro-1H-indol-3-yl) propyl] -1,2,3,6-tetrahydropyridin-4-yl] -6- Chloro-1H-indole, oxalate, 20k. Prepared from Compound 22a. Melting point 112-115 ° C. ¹ H NMR (DMSO-d ₆ ) δ 1.45-1.60 (m, 1H); 1.70-1.90 (m, 3 H); 2.20 (s, 3 H); 2.80 (broad s, 2 H); 3.15 (broad s, 2 H); 3.30-3.50 (m, 3 H); 3.70-3.90 (m, 3 H); 4.25 (t, 1 H); 6.15 (broad s, 1 H); 7.00 (t, 1 H); 7.10 (d, 1 H); 7.20 (t, 1 H); 7.30 (d, 1 H); 7.45 (s, 1 H); 7.55 (s, 1 H); 7.85 (d, 1 H); 8.05 (d, 1 H); 11.60 (broad s, 1 H). MS m / z (%): 436.434 (MH <+>, 2%, 5%), 231 (100%), 189 (36%), 158 (70%).
3- [1- [2- (1-acetyl-5-fluoro-2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridine-4- Il] -6-chloro-1H-indole, 20 l. Prepared from compound 19f and 6-chloro- (1,2,3,6-tetrahydropyridin-4-yl) -1H-indole. Melting point 183-185 ° C. ¹ H NMR (DMSO-d ₆ ) d 1.65-1.75 (m, 1H); 2.00-2.10 (m, 1 H); 2.15 (s, 3 H); 2.40-2.55 (m, 4 H); 2.60-2.75 (m, 2 H); 3.05-3.25 (dd, 2H); 3.45 (bs, 1 H); 3.80-3.90 (m, 1 H); 4.25 (t, 1 H); 6.10 (bs, 1 H); 6.95 (t, 1 H); 7.05 (d, 1 H); 7.15 (d, 1 H); 7.40 (s, 2 H); 7.80 (d, 1 H); 8.05 (m, 1 H); 11.20 (bs, 1 H). MS m / z (%): 438 (MH &lt; + &gt;, 7%), 162 (100%), 192 (63%), 235 (58%).
3- [1- [2- (1-acetyl-5-methyl-2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl ] -6-chloro-1H-indole, 20 m. Prepared from 19 g of compound and 6-chloro- (1,2,3,6-tetrahydropyridin-4-yl) -1H-indole. Melting point 179-181 ° C. ¹ H NMR (DMSO-d ₆ ) d 1.60-1.70 (m, 1 H); 1.95-2.05 (m, 1 H); 2.15 (s, 3 H); 2.25 (s, 3 H); 2.40-2.60 (m, 4 H); 2.65 (bs, 2 H); 3.05-3.20 (dd, 2H); 3.40 (bs, 1 H); 3.75-3.85 (m, 1 H); 4.20 (t, 1 H); 6.10 (bs, 1 H); 6.90 (d, 1 H); 7.00 (d, 1 H); 7.05 (s, 1 H); 7.40 (s, 2 H); 7.80 (d, 1 H); 7.90 (d, 1 H); 11.25 (bs, 1 H). MS m / z (%): 434 (MH &lt; + &gt;, 3%), 188 (100%), 158 (31%), 231 (21%).
Example 21
6-chloro-3- [1- (indan-2-ylmethyl) piperidin-4-yl] -1H-indole oxalate, 21a.
Platinum oxide (0.12 g) was added to a 11a (0.51 g) solution on ethanol (40 ml) and acetic acid (10 ml). The mixture was vibrated for 4.5 hours under hydrogen pressure of 3 atmospheres. The mixture was filtered and evaporated in vacuo. The residue was dissolved in CH ₂ Cl ₂ and the organic phase was vibrated with dilute ammonium hydroxide and finished with conventional procedures to yield 0.46 g of natural product from which the title product crystallized from acetone to oxalate. Yield 0.36 g, Melting point 229-30 ° C. ¹ H NMR (DMSO-d ₆ ) d 1.85-2.10 (m, 4H); 2.65-3.15 (m, 10 H); 3.50 (d, 2 H); 7.00 (dd, 1 H); 7.10-7.20 (m, 2H); 7.20-7.30 (m, 3H); 7.40 (d, 1 H); 7.65 (d, 1 H); 11.05 (s, 1 H). MS m / z (%): 365 (MH &lt; + &gt;, 100%), 249 (17%), 131 (20%).
In a similar manner the following compounds were prepared:
3- [1- (indan-2-ylmethyl) piperidin-4-yl] -1H-indole 21b. Manufactured from 11b. Melting point 146-147 ° C. ¹ H NMR (CDCl ₃ ) δ 1.85 (q, 2H); 2.05 (d, 2H); 2.20 (t, 2 H); 2.45 (d, 2 H); 2.65-2.90 (m, 4 H); 3.00-3.20 (m, 4 H); 6.95 (s, 1 H); 7.05-7.30 (m, 6 H); 7.35 (d, 1 H); 7.65 (d, 1 H); 7.95 (broad s, 1 H). MS m / z (%): 331 (MH &lt; + &gt;, 11%), 131 (11%), 98 (100%).
7-chloro-3- [1- (indan-2-ylmethyl) piperidin-4-yl] -1H-indole, oxalic acid 21c. Manufactured from 11c. Melting point 218-219 ° C. ¹ H NMR (DMSO-d ₆ ) δ 2.00-2.25 (m, 4H); 2.70-2.85 (m, 2 H); 2.85-3.35 (m, 8 H); 3.55 (d, 2 H); 7.00 (t, 1 H); 7.10-7.30 (m, 6H); 7.65 (d, 1 H); 11.30 (broad s, 1 H). MS m / z (%): 367, 365 (MH <+>, 9%, 25%), 131 (14%), 98 (100%).
6,7-dichloro-3- [1- (indan-2-ylmethyl) piperidin-4-yl] -1H-indole, 21d. Manufactured from 11d. Melting point 141-142 ° C. ¹ H NMR (CDCl ₃ ) δ 1.75-1.90 (m, 2H); 2.00 (d, 2 H); 2.15 (t, 2 H); 2.45 (d, 2 H); 2.65-2.85 (m, 4 H); 3.00-3.15 (m, 4 H); 7.00 (s, 1 H); 7.10-7.25 (m, 5H); 7.45 (d, 1 H); 8.20 (broad s, 1 H). MS m / z (%): 401, 399 (MH <+>, 17%, 26%), 131 (19%), 98 (100%).
3- [1- (Indan-2-ylmethyl) piperidin-4-yl] -5,6-methylenedioxy-1H-indole, 21e. Manufactured from 11e. Melting point 187-188 ° C. ¹ H NMR (DMSO-d ₆ ) δ 1.55-1.70 (m, 2H); 1.90 (d, 2 H); 2.05 (t, 2H); 2.30 (d, 2 H); 2.60-2.75 (m, 4 H); 2.85-3.05 (m, 4 H); 5.90 (s, 2 H); 6.85 (s, 1 H); 6.90 (s, 1 H); 7.00 (s, 1 H); 7.05-7.15 (m, 2H); 7.15-7.25 (m, 2H); 10.55 (broad s, 1 H). MS m / z (%): 375 (MH &lt; + &gt;, 10%), 131 (9%), 98 (100%).
6-chloro-3- [1- [2- (indan-2-yl) ethyl] piperidin-4-yl] -1H-indole, 21f. Manufactured from 11 g. Melting point 155-156 ° C. ¹ H NMR (DMSO-d ₆ ) δ 1.60-1.75 (m, 4H); 1.90 (d, 2 H); 2.05 (t, 2H); 2.35-2.45 (m, 3 H); 2.45-2.60 (m, 2 H); 2.70 (t, 1 H); 2.90-3.05 (m, 4 H); 6.95 (d, 1 H); 7.05-7.20 (m, 5H); 7.35 (s, 1 H); 7.55 (d, 1 H); 10.90 (broad s, 1 H). MS m / z (%): 381, 379 (MH <+>, 33%, 89%), 228 (45%), 145 (44%), 98 (100%).
21 g of 6-chloro-3- [1- [3- (indan-2-yl) propan-1-yl] piperidin-4-yl] -1H-indole. Manufactured from 11h. Melting point 134-135 ° C. ¹ H NMR (CDCl ₃ ) δ 1.45-1.60 (m, 2H); 1.60-1.75 (m, 2 H); 1.75-1.90 (m, 2 H); 2.05 (d, 2H); 2.10 (t, 2 H); 2.35-2.55 (m, 3 H); 2.55-2.65 (m, 2 H); 2.80 (t, 1 H); 2.95-3.15 (m, 4 H); 6.95 (s, 1 H); 7.00-7.25 (m, 5H); 7.30 (s, 1 H); 7.55 (d, 1 H); 8.10 (broad s, 1 H). MS m / z (%): 395, 393 (MH <+>, 8%, 21%), 242 (53%), 117 (52%), 98 (100%).
6-chloro-3- [1- [4- (indan-2-yl) butan-1-yl] piperidin-4-yl] -1H-indole, 21h. Manufactured from 11i. Melting point 139-140 ° C. ¹ H NMR (CDCl ₃ ) δ 1.30-1.70 (m, 6H); 1.70-1.95 (m, 2H); 1.95-2.20 (m, 4 H); 2.35-2.65 (m, 5 H); 2.70-2.90 (m, 1 H); 2.95-3.15 (m, 4 H); 6.95 (d, 1 H); 7.00-7.25 (m, 5H); 7.35 (d, 1 H); 7.55 (d, 1 H); 8.05 (broad s, 1 H). MS m / z (%): 409, 407 (MH &lt; + &gt;, 32%, 90%), 256 (96%), 98 (100%).
Example 22
1-acetyl-3- (3-bromopropan-1-yl) -2,3-dihydro-1H-indole, 22a.
(Intermediate)
A mixture of 3- (1H-indol-3-yl) propionic acid (10 g), methanol (200 ml), and saturated HCl solution on ether (75 ml) was stirred for 4 days at room temperature. The solvent was removed in vacuo and the residue was finished by conventional methods using dilute ammonium hydroxide and ethyl acetate to give an oil (10.6 g). The oil was dissolved in acetic acid (200 ml) and NaCNBH ₄ (12 g) was added in portions 1 g. The mixture was stirred for 48 hours at room temperature and poured into ice cold water. The pH of the solution was set to 8 with sodium hydroxide (25%) and the aqueous phase was extracted with ether. The combined organic phases were extracted with 1M HCl solution. The pH of the aqueous phase was adjusted to 8 with sodium hydroxide and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO ₄ and the solvent was removed in vacuo. The residue was purified on silica gel eluted with ethyl acetate-heptane (1: 1) to give an oil (6.1 g). The residue was dissolved in THF (50 ml) and added to a LiAlH ₄ (2.0 g) suspension on THF (100 ml) at about 30 ° C. The mixture was stirred at room temperature for 15 minutes and cooled to 5 ° C. Water (4.0 ml), 15% NaOH solution (2.0 ml), and water (10 ml) were added by dropwise addition. The mixture was dried (MgSO ₄ ) and concentrated in vacuo. The oil was dissolved in THF (200 ml) and triethylamine (11 ml) added and cooled to -20 ° C. To this mixture was added a solution of acetyl chloride (2.1 ml) on THF (50 ml) and the mixture was warmed to 5 ° C. To this mixture was added a solution of methanesulfonyl chloride (2.1 ml) on THF (50 ml). Ether (200 ml) was added and the mixture was filtered. The liquid was concentrated in vacuo and purified on silica gel eluted with ethyl acetate-heptane (4: 1) to give crystalline compound (7.3 g). The compound was dissolved in acetone (500 ml) and lithium bromide (10.3 g) was added and the mixture was boiled under reflux for 1 hour. The mixture was cooled, filtered and evaporated to dryness in vacuo to afford the title compound.
The following compounds were prepared in a similar manner.
1-acetyl-2,3-dihydro-3- (2-iodineethyl) -1H-indole, 22b. Manufactured from 19a and lithium iodide.
2-iodinemethylindane, 22c. Prepared from 2-indanemethanol methanesulfonate prepared from 9a as described in Example 3.
Example 23
7-methoxy-1-indanecarboxylic acid, 23a.
(Intermediate)
J. Am. On toluene (300 ml). Chem. Soc. To the mixture of 7-methoxy-1-indanone (25 g), ZnI ₂ (0.5 g) prepared according to 1948, 70, 1386, trimethylsilyl cyanide (added 25 ml and 15 ml after 3 hours) And the reaction mixture was stirred at 60 ° C. for 5 hours. Water was added and the mixture was stirred at rt for 1 h. The phases were separated and the organic phase was dried (MgSO ₄ ) and evaporated to dryness in vacuo. The residue was purified on silica gel eluted with dichloromethane (25 g). The residue was dissolved in acetic acid (100 ml) and 6M HCl solution (100 ml) and the mixture was heated at 100 ° C. for 7 hours. Acetic acid was removed in vacuo and the aqueous phase was extracted with ether. The combined organic phases were dried (MgSO ₄ ), evaporated to dryness in vacuo and purified on silica gel eluted with dichloromethane (5 g). The residue was dissolved in ethanol (200 ml) and palladium on carbon (5%) (2 g) was added to the solution and the mixture was vibrated for 3 hours under 3 atmospheres of hydrogen pressure. The mixture is filtered and evaporated in vacuo (5 g). The residue was dissolved in acetic acid (10 ml), concentrated sulfuric acid (5 ml), water (5 ml) and the mixture was heated at 110 ° C. for 3 hours. The mixture was cooled and extracted with ethyl acetate. The organic phase was washed with water, ether added and extracted with 2M NaOH solution. The pH of the aqueous phase was adjusted to 1 with hydrochloric acid and extracted with ether. The combined organic phases were dried (MgSO ₄ ) and evaporated to dryness in vacuo to afford the title compound (2 g).
In a similar manner the following compounds were prepared.
6-methoxy-1-indanecarboxylic acid, 23b. Prepared from 6-methoxy-1-indanone.
Example 24
2- (2-iodineethyl) ind; 24a.
(Intermediate)
A mixture of 2- (indan-2-yl) ethanol (19.3 g), imidazole (12.1 g), triphenylphosphine (34.3 g) and toluene (250 ml) was heated to 90 ° C. Iodide (33.2 g) was added to this mixture and the resulting mixture was stirred at 90 ° C. for 20 minutes. The mixture was cooled to rt, filtered and concentrated in vacuo. The residue was purified on silica gel eluted with ethyl acetate-heptane (1: 4) to give an oil (28.4 g, 87%).
(Example 25)
4- [4- [2- (indan-2-yl) ethyl] piperazin-1-yl] -1H-indole, 25a.
4- (piperazin-1-yl) -1H-indole (1.5 g), 2- (2-iodineethyl) indane (2.0 g), K ₂ CO ₃ , methyl isobutyl ketone (150 ml), and N-methyl The mixture of pyrrolidone (10 ml) was boiled under reflux for 3 hours. The mixture was cooled to rt, filtered and concentrated in vacuo. The residue was purified on silica gel eluted with ethyl acetate-heptane (1: 2) to give a crystal compound which was recrystallized (ethyl acetate) to give the title compound (1.2 g, 47%).
Melting point 146-147 ° C. ¹ H NMR (CDCl ₃ ) δ 1.70-1.85 (m, 2H); 2.40-2.70 (m, 5 H); 2.75 (broad s, 4H); 3.00-3.15 (m, 2 H); 3.30 (broad s, 4H); 6.55 (s, 1 H); 6.60 (d, 1 H); 7.00-7.30 (m, 7 H); 8.20 (broad s, 1 H). MS m / z (%): 346 (MH &lt; + &gt;, 34%), 159 (88%), 145 (100%).
In a similar manner the following compounds were prepared.
5- [4- [2- (indan-2-yl) ethyl] piperazin-1-yl] -1H-indole, hydrochloride 25b. Prepared from 24a and 5- (piperazin-1-yl) -1H-indole. Melting point 251-253 ° C. ¹ H NMR (DMSO-d ₆ ) δ 1.90-
* 2.05 (m, 2 H); 2.40-2.55 (m, 1 H); 2.55-2.70 (m, 2 H); 3.00-3.15 (m, 2 H); 3.25 (broad s, 2 H); 3.50 (broad s, 2 H); 3.75 (broad s, 6H); 6.45 (s, 1 H); 7.05-7.30 (m, 5H); 7.40 (s, 1 H); 7.45 (d, 1 H); 7.55 (broad s, 1 H); 11.30 (broad s, 1 H). MS m / z (%): 346 (MH &lt; + &gt;, 44%), 159 (87%), 145 (100%).
Example 26
5-chloro-1- (pyridin-4-yl) -1H-indole, 26a.
(Intermediate)
A mixture of 5-chloro-1H-indole (20 g), 4-bromopyridine, HCl (45 g), K ₂ CO ₃ (55 g), CuBr (5 g), and Cu (2 g) was heated at 150 ° C. for 24 hours. It was. The reaction mixture was cooled down and poured into water (700 ml) and the natural product was collected by filtration. The natural compound was dissolved in ethyl acetate (1000 ml) and the organic phase was washed with dilute ammonium hydroxide and saturated NaCl solution. The organic phase is dried (MgSO ₄ ) and concentrated in vacuo (150 ml). Crystalline 5-chloro-1- (pyrid-4-yl) -1H-indole was collected by filtration (18.0 g, 60%).
In a similar manner the following compounds were prepared.
1- (pyridin-4-yl) -1H-indole, 26b.
Example 27
2- (pyridin-4-yl) -1H-indole, 27a.
(Intermediate)
A mixture of isnicotinic acid (7.1 g) and thionyl chloride (150 ml) was boiled under reflux for 2 hours and evaporated to dryness in vacuo. The residue was dissolved in DMF (100 ml) and added to a suspension of 2-aminobenzyltriphenylphosphonium bromide (L. Capuano et al, Chem. Ber. 1986, 119, 2069-2074) on dichloromethane. The resulting clear solution was stirred at room temperature for 2 hours and concentrated in vacuo. The natural product was recrystallized (ethanol) to give 21.3 g of crystals. 1.0 g of compound was suspended in toluene (25 ml) and the mixture was heated to reflux. tert-butoxylated potassium (0.44 g) is added in one portion and the reaction mixture is boiled under reflux for 15 minutes, filtered and concentrated in vacuo. Purification on silica gel eluted with ethyl acetate-heptane-TEA (80: 20: 5) afforded the title compound.
Example 28
5-chloro-1- [1- [2- (indan-2-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole, 28a.
A mixture of 5-chloro-1- (pyridin-4-yl) -1H-indole 26a (4.0 g), 2- (2-iodineethyl) indane 24a (4.8 g), and methyl isobutyl ketone (100 ml) was added to 20 Boil under reflux for hours. The mixture was cooled and the crystalline compound was collected by filtration (6.5 g). 5.5 g of the compound was suspended in methanol (100 ml) and NaBH ₄ (1.5 g) was added in portions of 0.5 g. The resulting mixture was stirred at rt for 1 h and the solvent was removed in vacuo. Purification on silica gel eluted with ethyl acetate-heptane (1: 1) after conventional finishing with acetic acid and water gave a natural product which was crystallized (ethyl acetate) to give the title compound (1.1 g, 27%).
Melting point 93-94 ° C. ¹ H NMR (CDCl ₃ ) δ 1.75-1.90 (m, 2H); 2.45-2.55 (m, 1 H); 2.55-2.70 (m, 6 H); 2.75-2.90 (m, 2 H); 3.05-3.15 (m, 2 H); 3.25 (d, 2 H); 5.90 (broad s, 1 H); 6,45 (s, 1 H); 7.05-7.25 (m, 6H); 7.45 (d, 1 H); 7.60 (s, 1 H). MS m / z (%): 377 (MH &lt; + &gt;, 6%), 143 (100%). 128 (50%).
In a similar manner the following compounds were prepared:
1- [1- [2- (Indan-2-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole, oxalate 28b. Manufactured from 24a and 26b. Melting point 176-178 ° C. ¹ H NMR (DMSO-d ₆ ) δ 1.85-1.95 (m, 2H); 2.40-2.55 (m, 1 H); 2.55-2.70 (m, 2 H); 2.85 (broad s, 2 H); 3.00-3.10 (m, 2 H); 3.15 (t, 2 H); 3.40 (broad s, 2 H); 3.85 (broad s, 2 H); 5.95 (broad s, 1 H); 6.60 (d, 1 H); 7.05-7.25 (m, 6H); 7.55 (d, 1 H); 7.60-7.70 (m, 2H). MS m / z (%): 343 (MH &lt; + &gt;), 143 (100%), 128 (80%).
2- [1- [2- (indan-2-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole, 28c. Manufactured from 27a and 24a. Melting point 175-176 ° C. ¹ H NMR (CDCl ₃ ) δ 1.75-1.85 (m, 2H); 2.45-2.55 (m, 1 H); 2.55-2.60 (m, 2 H); 2.60-2.70 (m, 4 H); 2.70-2.80 (m, 2 H); 3.05-3.15 (m, 2 H); 3.25 (broad s, 2 H); 6.05 (broad s, 1 H); 6.45 (s, 1 H); 7.05 (t, 1 H); 7.10-7.25 (m, 5H); 7.35 (d, 1 H); 7.55 (d, 1 H); 8.10 (broad s, 1 H). MS m / z (%): 343 (MH &lt; + &gt;, 8%), 174 (32%), 143 (100%).
2- [1- (indan-2-yl) methyl-1,2,3,6-tetrahydropyridin-4-yl] -1H-indole, 28d. Prepared from 22c and 27a. ¹ H NMR (CDCl ₃ ) d 2.50-2.55 (m, 2H); 2.65 (broad s, 2 H); 2.70-2.85 (m, 5 H); 3.00-3.15 (m, 2 H); 3.25 (d, 2 H); 6.05 (broad s, 1 H); 6.45 (s, 1 H); 7.05 (t, 1 H); 7.10-7.25 (m, 5H); 7.30 (d, 1 H); 7.55 (d, 1 H); 8.10 (broad s, 1 H). MS m / z (%): 329 (MH &lt; + &gt;, 5%), 160 (4%), 131 (4%), 91 (6%), 44 (100%).
2- [1- [2- (1-acetyl-2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H- Indole, 28e. Prepared from 22b and 27a. ¹ H NMR (DMSO-d ₆ ) d 1.65-1.80 (m, 1 H); 1.95-2.10 (m, 1 H); 2.15 (s, 3 H); 2.45-2.60 (m, 4 H); 2.65 (broad s, 2 H); 3.10-3.20 (m, 2 H); 3.40-3.50 (m, 1 H); 3.75-3.85 (m, 1 H); 4.20 (t, 1 H); 6.30 (s, 1 H); 6.40 (s, 1 H); 6.90 (t, 1 H); 6.95-7. 10 (m, 2H); 7.15 (t, 1 H); 7.25-7.35 (m, 2 H); 7.45 (d, 1 H); 8.05 (d, 1 H); 11.05 (broad s, 1 H). MS m / z (%): 386 (MH &lt; + &gt;, 13%), 217 (20%), 174 (10%), 144 (87%), 132 (45%), 44 (100%).
(Example 29)
5-chloro-1- [1- [2- (indan-2-yl) ethyl] piperidin-4-yl] -1H-indole, 29a.
5-chloro-1- [1- [2- (indan-2-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H-indole, 28a. (1.9 g), A mixture of acetic acid (50 ml) and platinum oxide (0.1 g) was vibrated for 3 hours under hydrogen pressure at 3 atmospheres. The mixture was filtered and evaporated in vacuo. The residue was dissolved in ethyl acetate and the organic phase was vibrated with dilute ammonium hydroxide and finished with conventional procedures. Further purification was carried out on silica gel eluted with ethyl acetate-heptane (1: 1) to give 2.0 g of natural product. The natural product was crystallized (ethyl acetate) and the title compound was collected by filtration (1.1 g, 58%).
Melting point 108-109 ° C. ¹ H NMR (CDCl ₃ ) δ 1.70-1.80 (m, 2H); 2.00-2.10 (m, 4 H); 2.10-2.25 (m, 2 H); 2.40-2.55 (m, 3 H); 2.55-2.70 (m, 2 H); 3.00-3.20 (m, 4 H); 4.10-4.25 (m, 1 H); 6.45 (d, 1 H); 7.05-7.35 (m, 7 H); 7.60 (s, 1 H). MS m / z (%): 379 (MH <+>, 3%), 228 (13%), 145 (29%), 143 (28%), 98 (100%).
The following compounds were prepared in a similar manner.
1- [1- [2- (indan-2-yl) ethyl] piperidin-4-yl] -1H-indole, 29b. Manufactured from 28b. Melting point 80-81 ° C. ¹ H NMR (CDCl ₃ ) δ 1.70-1.85 (m, 2H); 2.00-2.25 (m, 6H); 2.40-2.55 (m, 3 H); 2.55-2.70 (m, 2 H); 3.00-3.20 (m, 4 H); 4.15-4.30 (m, 1 H); 6.50 (d, 1 H); 7.05-7.30 (m, 7H); 7.40 (d, 1 H); 7.65 (d, 1 H). MS m / z (%): 345 (MH <+>, 4%), 228 (9%), 145 (30%), 143 (34%), 98 (100%).
(Example 30)
6-chloro-3- [1- [2- (2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl] -1H- Indole, oxalate 30a.
3- [1- [2- (1-tert-butoxycarbonyl-2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6 as free base (4.0 g) -Tetrahydropyridin-4-yl] -6-chloro-1H-indole, oxalate 20i, dichloromethane (50 ml), and THF (25 ml) were cooled in a cold bath and trifluoroacetic acid (40 ml) in the mixture. Was added. The reaction mixture was stirred for 16 hours at room temperature and poured into an ice cold solution of dilute ammonium hydroxide. The natural product was obtained by conventional finishing with ethyl acetate. 1.4 g of natural product was converted to oxalate and recrystallized (methanol-ether-heptane) to give the title compound (0.5 g).
Melting point 109-111 ° C. ¹ H NMR (DMSOd ₆ ) δ 1.80-2.00 (m, 1H); 2.10-2.30 (m, 1 H); 2.80 (broad s, 2 H); 3.05-3.35 (m, 4H); 3.35-3.65 (m, 3 H); 3.90 (broad s, 2 H); 6.15 (broad s, 1 H); 6.45-6.65 (m, 2 H); 6.95 (t, 1 H); 7.00-7.15 (m, 2H); 7.45 (d, 1 H); 7.60 (d, 1 H); 7.85 (d, 1 H); 11.55 (d, 1 H). MS m / z (%): 378 (MH &lt; + &gt;, 4%), 169 (19%), 168 (38%), 144 (100%).
The following compounds were prepared in a similar manner.
6-chloro-3- [1- [4- (2,3-dihydro-1H-indol-3-yl) butan-1-yl] -1,2,3,6-tetrahydropyridin-4-yl ] -1H-indole 30b. Manufactured from 19e.
(Example 31)
6-chloro-3- [1- [2- (2,3-dihydro-1-methylaminocarbonyl-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridine- 4-yl] -1H-indole, oxalate 31a.
6-chloro-3- [1- [2- (2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridine- as free base (3.6 g) To a solution of 4-yl] -1H-indole, oxalate 30a. On dichloromethane (100 ml) was added methylisocyanate (1.4 g) on dichloromethane (20 ml). The mixture was stirred at rt for 16 h and the solvent was removed in vacuo. The residue was purified on silica gel eluted with ethyl acetate-ethanol-triethylamine (90: 10: 5) to give the natural product which was recrystallized (methanol-ethyl acetate-ether) to give the title compound (1.8 g). . ¹ H NMR (DMSOd ₆ ) δ 1.60-1.70 (m, 1H); 1.95-2.05 (m, 1 H); 2.40-2.60 (m, 4 H); 2.60-2.75 (m, 5 H); 3.15 (q, 2 H); 3.35-3.50 (m, 1 H); 3.55-3.65 (m, 1 H); 4.00 (t, 1 H); 6.10 (broad s, 1 H); 6.55 (d, 1 H); 6.85 (t, 1 H); 7.05 (d, 1 H); 7.10 (t, 1 H); 7.20 (d, 1 H); 7.45 (s, 2 H); 7.80 (d, 1 H); 7.85 (d, 1 H); 11.25 (broad s, 1 H). MS m / z (%): 437,435 (MH &lt; + &gt;, 2%, 6%), 201 (54%), 189 (100%), 144 (64%).
(Example 32)
(+/-)-methyl (1-tert-butoxycarbonyl-2,3-dihydro-1H-indol-3-yl) acetate 32a.
(Intermediate)
A mixture of (1H-indol-3-yl) acetic acid (62 g), methanol (800 ml), and saturated HCl solution on ether (200 ml) was stirred at room temperature for 4 days. The solvent was removed in vacuo and the residue was finished by conventional methods using dilute ammonium hydroxide and ethyl acetate to give an oil (64 g). The oil was dissolved in acetic acid (600 ml) and NaCNBH ₄ (27.6 g) was added in portions 1 g. The mixture was stirred for 48 hours at room temperature and then poured into ice cold water. The pH of the solution was adjusted to 8 with ammonium hydroxide (25%) and the aqueous phase was extracted with ethyl acetate (3 × 1 L). The combined organic phases are washed with brine and dried (MgSO ₄ ) and the solvent is removed in vacuo (73 g). The residue was dissolved in THF (500 ml) and to this mixture was added a solution of di-tert-butyl bicarbonate (89 g) on THF (500 ml). The mixed reaction was stirred at rt for 24 h and the solvent was removed in vacuo. The natural product was purified on silica gel eluted with ethyl acetate-heptane (1: 4) to afford the title compound as an oil (92 g).
(Example 33)
(+)-(1-tert-butoxycarbonyl-2,3-dihydro-1H-indol-3-yl) acetic acid 33a.
(Intermediate)
Candida Antarctica Lipase (CAL, SP-435, Novo Nordisk, Denmark) (2.5 g) was added (+/-)-methyl (1-tert-butoxycarbonyl-2,3-dihydro-1H-indole-3- I) suspended in acetate 32a (50 g) and the mixture was further suspended in 0.1 M phosphate buffer (pH = 7.0) (3 L) under vigorous stirring. The reaction mixture was kept at 25 ° C. and the pH was maintained at 7 by addition of 0.5M NaOH solution. The reaction could be monitored by the amount of NaOH added and it was stopped after addition of about 0.45 equivalents of base (about 120 hours). The enzyme was filtered off and washed with ether (1 l). The pH on water was set to 8. The aqueous phase was extracted with ether (2 X 11). The combined organic extracts were dried (MgSO ₄ ) and evaporated to dryness in vacuo to give a single enantiomer-rich starting ester. The aqueous phase was cooled with ice and the pH was adjusted to 1.5 by addition of concentrated HCl. The aqueous phase was extracted with ether (3 × 1 l). The combined organic extracts were dried (MgSO ⁴ ) and the solvent was removed in vacuo to yield the title compound with excess enantiomer of about 80-85%. Recrystallization from diisopropyl ether gave the title compound with excess enantiomer of 96.5%. [α] D = + 12.8 (c = 0.45, methanol). Melting point 137-138 ° C.
(-)-(1-tert-butoxycarbonyl-2,3-dihydro-1H-indol-3-yl) acetic acid 33b.
The rich ester obtained from the synthesis of 33a was treated once more as described for racemate 32a and the reaction mixture was finished in a similar manner to 33a. 33.7 g of single enantiomer-rich esters were dissolved in ethanol (500 ml) and treated with 1M NaOH solution (500 ml). The mixture was stirred at room temperature for 30 minutes and the ethanol was removed in vacuo. The aqueous phase was washed with ether, cooled by the addition of ice and the pH adjusted to 1. The aqueous phase was extracted with ether (3 × 400 ml) and the combined organic extracts were washed with brine and dried (MgSO ₄ ) and the solvent removed in vacuo (31 g, 94.6% excess enantiomer). The residue was recrystallized from diisopropyl ether (50 ml) to give the title compound with excess enantiomer of 97.7%. [α] D = -12.6 (c = 0.47, methanol). Melting point 136-137 ° C. Chiral HPLC analysis was performed on a device equipped with a UV sensor (set at 230 nm). The analysis was carried out on a Ultron ES OVM 150 x 4.6 mm flow rate 1.0 ml / min, eluent 25 mM phosphate buffer (pH 4.6) / methanol / isopropanol / THF 90/5/5 / 0.5, temperature was carried out at 30 ° C. The purity of the enantiomer, expressed as an excess of enantiomer (ee), was calculated from the peak area.
Example 34
(+)-(3- [1- [2- (1-acetyl-2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridine-4- Il] -6-chloro-1H-indole, 34a.
Saturated HCl over (+)-(1-tert-butoxycarbonyl-2,3-dihydro-1H-indol-3-yl) acetic acid 33a. (5.0 g), methanol (200 ml), and ether (50 ml) The mixture of solutions was stirred at rt for 16 h. The solvent was removed in vacuo and the residue was dissolved in ice cold water. The aqueous phase was washed with ether and the pH was adjusted to 8 with saturated NaHCO ₃ solution. The aqueous phase was extracted with ethyl acetate (3 × 150 ml) and the combined organic extracts were washed with brine, dried (MgSO ₄ ) and evaporated to dryness in vacuo (3.4 g). The residue was dissolved in THF (50 ml) and added to LiAlH ₄ (1.6 g) suspension on THF (150 ml) at about 30 ° C. The mixture was stirred at rt for 30 min and cooled to 5 ° C. Dropwise addition of water (3.2 ml), 15% NaOH solution (1.6 ml), and water (8 ml) were added. The mixture was dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified on silica gel eluted with ethyl acetate-ethanol (200: 5) to give an oil (2.6 g). 80 ml) and triethylamine (2.7 ml) were added and cooled to −30 ° C. To this mixture was added a solution of acetyl chloride (1.1 ml) on dichloromethane (10 ml) and the mixture was warmed to 5 ° C. Triethylamine (2.7 ml) was added and to this mixture was added a solution of methanesulfonyl chloride (1.3 ml) on dichloromethane (10 ml) The reaction mixture on silica gel eluted with ethyl acetate-heptane (4: 1). Purification gave an oil (4.5 g) which was dissolved in methyl isobutyl ketone (100 ml) and 6-chloro-3- (1,2,3,6-tetrahydropyridin-4-yl) -1H under reflux. mixture of indole _{(5.5g), K 2 CO 3} (4.4g), methyl isobutyl ketone (100ml), and N- methylpyrrolidone (10ml) - The mixture was boiled under reflux for 6 h and evaporated to dryness in vacuo, purified on silica gel eluted with ethyl acetate-ethanol (10: 1) to give the natural product which was recrystallized (ethyl acetate) 97.4 The title compound (2.9 g) was obtained with an excess of enantiomers of%. [Α] D = + 35.9 (c = 0.25, methanol). Melting point 169-170 ° C. ¹ H NMR (DMSOd ₆ ) δ 1.65-1.80 (m, 1H); 2.00-2.10 (m, 1 H); 2.15 (s, 3 H); 2.45-2.60 (m, 4 H); 2.65 (broad s, 2 H); 3.05-3.20 (m, 2 H); 3.40-3.50 (m, 1 H); 3.80 (dd, 1 H); 4.25 (t, 1 H); 6.10 (broad s, 1 H); 6.95-7.05 (m, 2 H); 7.15 (t, 1 H); 7.30 (d, 1 H); 7.40-7.45 (m, 2H); 7.80 (d, 1 H); 8.05 (d, 1 H); 11.20 (broad s, 1 H). MS m / z (%): 422,420 (MH &lt; + &gt;, 3%, 8%), 217 (30%), 174 (100%), 144 (41%).
In a similar manner, the following compounds were prepared from 33b.
(-)-(3- [1- [2- (1-acetyl-2,3-dihydro-1H-indol-3-yl) ethyl] -1,2,3,6-tetrahydropyridine-4- General] -6-chloro-1H-indole, 34b.
Excess enantiomer of 98.4%. [α] D = -34.9 (c = 0.27, methanol). Melting point 168-169 ° C. Chiral HPLC analysis was performed on a device equipped with a UV sensor (set at 230 nm). The analysis was performed at Chiral AGP 100 × 4 mm flow rate 0.8 ml / min, eluent 25 mM phosphate buffer (pH = 6.0) / methanol / isopropanol / THF 90/5/5/1, temperature at 25 ° C. The purity of the enantiomer, expressed as an excess of enantiomer (ee), was calculated from the peak area.
Example 35
3- [1- [4- (1-acetyl-2,3-dihydro-1H-indol-3-yl) butan-1-yl] -1,2,3,6-tetrahydropyridin-4-yl ] -6-chloro-1H-indole, 35.
6-chloro-3- [1- [4- (2,3-dihydro-1H-indol-3-yl) butan-1-yl] -1,2,3,6-tetrahydropyridin-4-yl ] -1H-indole 30b (4.9 g), triethylamine (3.7 g), and a mixture of THF (200 ml) are cooled (5 ° C.) and to the mixture is added a solution of acetyl chloride (1.0 g) in THF (50 ml) It was. The reaction mixture was warmed to rt, filtered and concentrated in vacuo. The residue was purified on silica gel eluted with ethyl acetate-ethanol-triethylamine (90: 10: 5) to give the natural product which was recrystallized (methanol-ethyl acetate) to give the title compound (2.7 g).
¹ H NMR (DMSO-d ₆ ) δ 1.30-1.45 (m, 2H); 1.45-1.60 (m, 3 H); 1.75-1.85 (m, 1 H); 2.15 (s, 3 H); 2.40 (t, 2 H); 2.45-2.55 (m, 2 H); 2.55-2.65 (m, 2 H); 3.10 (broad s, 2H); 3.40 (broad s, 1 H); 3.70-3.80 (m, 1 H); 4.20 (t, 1 H); 6.10 (broad s, 1 H); 6.95 (t, 1 H); 7.05 (d, 1 H); 7.15 (t, 1 H); 7.25 (d, 1 H); 7.40 (s, 2 H); 7.80 (d, 1 H); 8.05 (d, 1 H); 11.20 (broad s, 1 H). MS m / z (%): 448 (MH &lt; + &gt;, 3%), 245 (17%), 172 (100%).
Example 36
2,3-dimethyl-1- (2-propyl) oxybenzene, 36a.
(Intermediate)
To a stirred solution / suspension of 2,3-dimethylphenol (10 g) and potassium carbonate (6.8 g) on acetone (150 ml) was added dropwise 2-bromopropane (46 ml) over 30 minutes under reflux. The solution was heated at reflux for 4 days. After cooling the solvent was evaporated and the residue was dissolved in ether and water. The ether phase was separated and finished according to the general procedure. A liquid, slightly brown, oil that is used without further purification by column chromatography on silica gel (eluent: ethyl acetate / heptane 1:19), pure 2,3-dimethyl-1- (2-propyl) oxybenzene (13.2 g )
(Example 37)
2,3-di (bromomethyl) -1- (2-propyl) oxybenzene, 37a.
(Intermediate)
To a stirred solution of 2,3-dimethyl-1- (2-propyl) oxybenzene (10 g) on carbon tetrachloride (150 ml) is added N-bromosuccinate (22 g) and dibenzoyl peroxide (370 mg) and the mixture is Heated under reflux for 1.5 hours. The solution was cooled to room temperature and filtered. The residue was washed with another carbon tetrachloride (100 ml) and the combined filtrates were evaporated to use 2,3-di (bromomethyl) -1- (2-propyl) oxybenzene (21.0 g) without further purification. Obtained as a yellow / orange oil.
1,2-dimethoxy-4,5-bis (chloromethyl) benzene, 37b
A stirred solution / suspension of veratrol (20 g), zinc chloride (3.2 g) and sodium chloride (420 mg) on ether (400 ml) is cooled to above 20 ° C. using a cold bath and the HCl gas is bubbled through the mixture for 10 minutes. Caused. The bubbling continued and the formaldehyde solution (26 ml, 12.3 M in water) was added dropwise over 20 minutes. Stirring / bubbling was continued for another 4 hours after which there was no further temperature increase. During this time the temperature was fixed between 20-30 ° C. by adding ice to the cold bath. Foaming of HCl was stopped, the flask was capped and the mixture was stirred overnight. The solution was evaporated and dissolved in ethyl acetate and water. The organic extract was successively washed with sodium bicarbonate solution, brine, dried over magnesium sulfate and evaporated to afford a white / yellow solid. This was purified by column chromatography on silica gel (eluent: ethyl acetate / heptane 1: 9-1: 4) to give 1,2-dimethoxy-4,5-bis (chloromethyl) benzene (19.98 g) as a white solid. Obtained as and used without further purification.
(Example 38)
Diethyl-4- (2-propyl) oxyindan-2,2-dicarboxylate, 38a.
(Intermediate)
Sodium hydroxide (7.7 g, 50-60% dispersion in oil) was washed with heptane (twice) to liberate from the oil. It was added to a 2,3-di (bromomethyl) -1- (2-propyl) oxybenzene (21 g) solution on THF (600 ml) and the solution was heated to reflux. A solution of diethyl malonic acid (10.4 g) on THF (150 ml) was added dropwise over 1 hour. After one more hour, the solution was cooled to room temperature and water (200 ml) was added dropwise to decompose excess sodium hydroxide. The mixture was poured into aqueous hydrochloric acid (500 ml, 3M) and extracted with ethyl acetate (3 x 300 ml). The general test procedure yielded a dark oil which was purified by silica gel (eluent: ethyl acetate / heptane 1: 9) column chromatography to give diethyl 4- (2-propyl) oxyindane-2,2-dicarboxylate (11.5). g) was obtained as a clear oil which was used without further purification.
Example 39
4- (2-propyl) oxyindan-2,2-dicarboxylic acid, 39a.
(Intermediate)
The solution / suspension of diethyl 4- (2-propyl) oxyindane-2,2-dicarboxylate (11.5 g) on potassium hydroxide solution (50 ml, 3M) was heated to reflux for 18 hours. The solution was cooled to rt and extracted with ether. The aqueous phase was acidified to pH <1 with aqueous hydrochloric acid (3M) and extracted with ethyl acetate. By standard finishing, 4- (2-propyl) oxyindane-2,2-dicarboxylic acid (8.5 g) was obtained as a brown solid which was used without further purification.
Example 40
4- (2-propyl) oxyindan-2-carboxylic acid, 40a.
(Intermediate)
The solution of 4- (2-propyl) oxyindane-2,2-dicarboxylic acid (11.5 g) on NMP (20 ml) was heated to 150 ° C. After a further 15 minutes, the solution was cooled to room temperature and poured into aqueous hydrochloric acid (1500 ml, 1M). This mixture was extracted with ethyl acetate (2 x 500 ml) and 4- (2-propyl) oxyindane-2-carboxylic acid (3.98 g) was obtained as a dark brown solid which was used as standard finish without further purification.
The following compounds were prepared using Compound 37b of Examples 38, 39 and 40 as starting material for the following procedure:
5,6-dimethoxyindan-2-carboxylic acid, 40b.
Example 41
6-chloro-3- [1- [3- (2,3-dihydro-1H-indol-1-yl) -3-oxopropan-1-yl] -1,2,3,6-tetrahydropyridine -4-yl] -1 H-indole 41a.
To a solution of indolin (6.0 g) and triethylamine (15.8 g) on THF (200 ml) was added a mixture of 3-chloropropionyl chloride (6.6 g) and THF (100 ml) at 5-9 ° C. The mixture was warmed to room temperature and evaporated to dryness in vacuo and purified on silica gel eluted with ethyl acetate-heptane (1: 2) to afford crystalline compound (5.6 g). The compound was dissolved in butanone (200 ml) and 6-chloro-3- (1,2,3,6-tetrahydropyridin-4-yl) -1H-indole (5.8 g), triethylamine (18.6 ml) , And butanone (400 ml) were added to the boiling mixture. The resulting mixture was boiled under reflux for 3 hours, evaporated in vacuo and the residue was purified on silica gel eluted with THF-triethylamine (95: 5) to give crystalline compound (5.4 g). The title compound was obtained after crystallization (THF-ethyl acetate-heptane).
¹ H NMR (DMSO-d ₆ ) d 2.50 (broad s, 3H); 2.65-2.85 (m, 5 H); 3.05-3.20 (m, 4 H); 4.15 (t, 2 H); 6.10 (broad s, 1 H); 6.95 (t, 1 H); 7.05 (d, 1 H); 7.15 (t, 1 H); 7.25 (d, 1 H); 7.40 (broad s, 2 H); 7.80 (d, 1 H); 8.10 (d, 1 H); 11.20 (broad s, 1 H).
In a similar manner the following compounds were prepared.
6-chloro-3- [1- [4- (2,3-dihydro-1H-indol-1-yl) -4-oxobutan-1-yl] -1,2,3,6-tetrahydropyridine -4-yl] -1 H-indole, 41b. ¹ H NMR (DMSOd ₆ ) d 1.85 (t, 2H); 2.40-2.55 (m, 6 H); 2.65 (t, 2 H); 3.10 (broad s, 4H); 4.10 (t, 2 H); 6.10 (broad s, 1 H); 6.95 (t, 1 H); 7.05 (d, 1 H); 7.15 (t, 1 H); 7.20 (d, 1 H); 7.35-7.45 (m, 2 H); 7.80 (d, 1 H); 8.10 (d, 1 H); 11.20 (broad s, 1 H).
Example 42
6-chloro-3- [1- [3- (2,3-dihydro-1H-indol-1-yl) -propan-1-yl] -1,2,3,6-tetrahydropyridine-4- General] -1 H-indole, 42a.
This compound was prepared from 41a described in Example 11 but used alan instead of LiAlH ₄ for reduction.
¹ H NMR (DMSO-d ₆ ) d 1.75 (q, 2H); 2.40-2.60 (m, 4 H); 2.65 (t, 2 H); 2.90 (t, 2 H); 3.00-3.20 (m, 4 H); 3.25-3.40 (m, 2 H); 6.10 (broad s, 1 H); 6.40-6.60 (m, 2H); 6.90-7.10 (m, 3 H); 7.40-7.50 (m, 2H); 7.80 (d, 1 H); 11.20 (broad s, 1 H).
Pharmacological test
The compounds of the present invention were tested in a well recognized and reliable manner. The test is as follows.
³ H-YM-09151-2-bond
It was determined in the laboratory that pharmaceuticals inhibited the binding of dopamine D ₄ antagonist ³ H-YM-09151-2 to the dopamine D ₄ receptor present on the human dopamine receptor subtype 4.2 membrane cloned by this method. Thus this is an affinity test for the dopamine D ₄ receptor. The test was cloned dopamine D ₄ cell membrane CRM-016 according to the product specification. , Dupharma A / S, Denmark. As a result, Table 1 was obtained with IC ₅₀ values.
Compound No. D ₄ -bond Compound no. D ₄ -bond Compound no. D ₄ -bond Compound no. D ₄ -bond 5a 3.5 11b 3.0 20d 3.0 25a 2.7 5b 5.0 11c 3.8 20e 21% 25b 5.3 5c 32.0 11 27.0 20f 3.2 28a 160. ^*5d 20.0 11e 16.0 20 g 16.0 28b 14.0 6a 6.8 11f 1.6 20h 30.0 28c 13.0 6b 3.3 11 g 12.0 20i 2.9 ^* 29a 6.9 6c 12.0 11h 24.0 20j 6.9 29b 2.2 6e 84.0 11i 37% 20k 10.0 30a 9.9 6d 30.0 11j nt. 20l nt. 30b nt. 8a 3.5 16a 6.2 20 m 8.4 31a nt. 8b 2.8 18a 7.5 21a 0.48 34a 4.0 8c 2.3 18b 4.3 21b 2.1 34b 24.0 8d 20.0 ^* 18c 41.0 21c 1.8 35 nt. 8e 8.3 18d 7.3 21d 3.9 8f 12.0 18e 66.0 21e 23.0 8 g 14.0 20a 3.1 21f 3.2 8h 34.0 20b 6.7 21 g 7.2 11a 2.8 20c 2.4 21h 14.0
Table 1: Binding Data (IC ₅₀ values nM or% inhibiting binding at 50 nM) (* means test results are preliminary and nt. Did not test)
³ H-8-OH-DPAT binding.
Drugs inhibit the binding of 5-HT _1A agonist ³ H-8-OH-DPAT (1 nM) to the 5-HT _1A receptor on the membrane of the cerebellar deficient brain of rat cloned by this method. Determined from This is therefore an affinity test for the 5-HT _1A receptor. This test is described in Hyttel et al., Drug. Dev. As described by Res., 1988, 15, 389-404.
³ H-Ketanserin combined.
It was determined in the laboratory that the binding of ³ H-Ketanserin (0.5 nM) to the 5-HT _2A receptor present on the rat's membrane by this method was inhibited by the pharmaceuticals. The method is described in Hyttel, Pharmacology & Toxicology, 61, 126-129, 1987.
³ H- spiro bond Perry stone for the test D ₂ receptor by Hyttel et al, J. Neurochem., 1985, 44, method 1615 in terms of affinity for the compounds of the invention on dopamine D ₂ receptor in addition to the It was tested by measuring its ability to inhibit. Furthermore, the compound was tested by measuring the ability of the whole rat brain to inhibit ³ H-serotonin uptake into synaptosomes in terms of 5-HT reuptake inhibition activity. This measurement was performed as described in Hyttel, J., Psychophrmacology, 1978, 60, 13.
In general, it has been found that the compounds of the present invention effectively inhibit the binding of YM-09151-2 to the dopamine D4 receptor. In addition, many compounds have been found to be effective 5-HT reuptake inhibitors and many compounds have been tested in the laboratory for the binding of 8-hydroxy-2-dipropylaminotetraline (8-OH-DPAT) to the 5-HT _1A receptor and And / or inhibit the binding of ³ H ketanserine to the 5-HT _2A receptor. Some compounds bind only one or two serotonin receptor subtypes, 5-HT _1A or 5-HT _2A . The compound is not essential or has only a weak affinity for the dopamine D2 receptor.
The VTA model is used to investigate the action on spontaneously active DA neurons in the ventral cortical region (VTA) due to repeated oral treatments. Inhibition of the number of active DA neurons in VTA suggests the antipsychotic action of the compounds. The VTA model is described in more detail on page 4 of EP-A2-392 959.
Some compounds of the present invention were tested and found to be effective in reducing the number of active DA neurons in VTA.
Thus, the compounds of the present invention are prepared by positive and negative symptoms of schizophrenia, other psychosis, generalized anxiety disorders, anxiety disorders such as panic and obsessive compulsive disorder, depression, alcohol abuse, impulse suppression disorders, aggressiveness, conventional antipsychotic agents It is believed to be useful in the treatment of induced side effects, ischemia, migraine, senile dementia and cardiovascular disease and in improving sleep. In particular, the compounds of the present invention are believed to be useful for the treatment of positive and negative symptoms of schizophrenia without extrapyramidal side effects.
Example of Formulation
The pharmaceutical preparations of the invention can be prepared by conventional methods in the art.
For example: Tablets are prepared by mixing the active ingredient with common adjuvants and / or diluents and then compressing the mixture in a conventional tableting machine.
Examples of auxiliaries and diluents include cornstarch, potato starch, talc, magnesium stearate, gelatin, lactose, rubber and the like. Other adjuvants or additives commonly used for purposes such as colorants, flavors, preservatives and the like are suitably used in the active ingredients.
Injection solutions are prepared by dissolving the active ingredient and possible additives in sterile water, preferably in a portion of the injection solvent, adjusting the solution to the desired volume, sterilizing the solution and filling it with an appropriate ampoule or vial. Other suitable additives such as tonics, preservatives, antioxidants and the like conventionally used in the art may be added. Typical examples of the formulation of the invention are as follows:
1) Tablet containing 5.0 mg of compound 4a calculated as free base
Compound 5a 5.0 mg
60 mg lactose
Corn Starch 30mg
Hydroxypropylcellulose 2.4mg
Microcrystalline Cellulose 19.2mg
Croscarmellose Sodium Type A 2.4mg
Magnesium Stearate 0.84mg
2) Tablet containing 0.5 mg of compound 21 calculated as free base
Compound 21 0.5mg
Lactose 46.9mg
Cornstarch 23.5mg
Povidone 1.8mg
Microcrystalline Cellulose 14.4mg
Croscarmellose Sodium Type A 1.8mg
Magnesium Stearate 0.63mg
3) syrup containing the following ingredients per milliliter:
Compound 21 25mg
Sorbitol 500mg
Hydroxypropylcellulose 15mg
Glycerol 50mg
1 mg of methyl-paraben
Propyl-paraben 0.1mg
Ethanol 0.005ml
Flavor 0.05mg
Saccharin Sodium 0.5mg
Water ad 1ml
4) Injection solution containing the following components per milliliter
Compound 4a 0.5mg
Sorbitol 5.1mg
Acetic acid 0.05mg
Saccharin Sodium 0.5mg
Water ad 1ml

权利要求:
Claims (65)
[1" claim-type="Currently amended] Substituted indane or dihydroindole compounds of formula I or pharmaceutically acceptable acid addition salts thereof.
Formula I

Where A is the next group.

Y is a hydrocarbon group that completes the indane ring, a group that completes the dihydroindole ring linked via the group NR ¹ or 1-position that completes the dihydroindole ring,
* W is a bond and n + m is 1,2,3,4,5 or 6;
W is CO, SO or SO ₂ , n is 2,3,4 or 5, m is 0,1,2 or 3 and n + m is 6 or less; or
* W is O, S, n is 2,3,4 or 5, m is 0,1,2 or 3 and n + m is 6 or less and Y completes the dihydroindole ring linked through the 1-position If N then m is 2 or 3; M is 1,2 or 3 if Y is NR ¹ completing the dihydroindole ring linked via the 2-position;
Dashed lines from X indicate additional bonds; X is N, CH or COH if no bond is indicated; X represents C,
R ¹ is
Hydrogen, C _1-6 -alk (en / yn) yl, C _3-8 -cycloalk (en) yl, C _3-8 -cycloalk (en) yl-C _1-6 -alk (en / yne) yl Yl, aryl, heteroaryl, aryl-C _1-6 -alkyl, heteroaryl-C _1-6 -alkyl, acyl, thioacyl, C _1-6 alkylsulfonyl, trifluoromethylsulfonyl, arylsulfonyl Or heteroarylsulfonyl; or
R ¹⁵ VCO- where V is O or S and R ¹⁵ is C _1-6 -alk (en / yn) yl, C _3-8 -cycloalk (en) yl, C _3-8 -cycloalk (en / Yn) yl-C _1-6 -alk (en / yn) yl, aryl or heteroaryl; or
* A group R ¹⁶ R ¹⁷ NCO- or R ¹⁶ R ¹⁷ NCS- wherein R ¹⁶ and R ¹⁷ are independently hydrogen, C _1-6 -alk (en / yn) yl, C _3-8 -cycloalk (en ), C _3-8 -cycloalk (en) yl-C _1-6 -alk (en / yn) yl, heteroaryl or aryl or pyrrolidinyl with the N atom R ¹⁶ and R ¹⁷ linked thereto Form a piperidinyl or perhydroazepine group,
R ² -R ⁵ are independently hydrogen, halogen, cyano, nitro, C _1-6 -alk (en / yn) yl, C _1-6 alkoxy, C _1-6 -alkylthio, hydroxy, C _{3- 8} -cycloalk (en) yl, C _3-8 -cycloalk (en) yl-C _1-6 -alk (en / yn) yl, C _1-6 -alkylcarbonyl, phenylcarbonyl, halogen substituted Phenylcarbonyl, trifluoromethyl, trifluoromethylsulfonyloxy and C _1-6 alkylsulfonyl, otherwise one of R ² -R ⁵ is a group -NR ¹³ R ¹⁴ , wherein R ¹³ is Same as defined for R ¹ and R ¹⁴ is hydrogen, C _1-6 -alk (en / yn) yl, C _3-8 -cycloalk (en) yl, C _3-8 -cycloalk (en) yl- C _1-6 -alk (en / yn) yl, aryl, heteroaryl, aryl-C _1-6 -alkyl or heteroaryl-C _1-6 -alkyl, or an N atom to which R ¹³ and R ¹⁴ are linked thereto With the following groups,

Wherein Q is C═O, C═S or CH ₂ ; T is NH, N-alkyl, S, O or CH ₂ ; p is 1-4; or
Two adjacent groups employed from R ² -R ⁵ are joined to represent — (CH ₂ ) ₃ —, or —CH═CH—NH—, thereby forming a fused five-membered ring;
R ⁶ -R ⁹ and R ¹¹ -R ¹² are independently hydrogen, halogen, cyano, nitro, C _1-6 -alk (en / yn) yl, C _1-6 -alkoxy, C _1-6 -alkylthio , Hydroxy, C _3-8 -cycloalk (en) yl, C _3-8 -cycloalk (en) yl-C _1-6 -alk (en / yn) yl, aryl, heteroaryl, phenylcarbonyl, Two adjacent groups employed from halogen substituted phenylcarbonyl, trifluoromethyl, or C _1-6 -alkylsulfonyl, or R ⁶ -R ⁹ together form a methylenedioxy group;
R ¹⁰ is as defined for R ¹ above;
Provided that at position 6 the substituent R ³ or R ⁴ cannot be —NR ¹³ R ¹⁴ if Y is CH ₂ , W is a bond, n + m is 1 and the ring is linked through the 1-position.
[2" claim-type="Currently amended] The compound of claim 1, wherein Y is CH ₂ .
[3" claim-type="Currently amended] A compound according to claim 1, wherein Y is NR ¹ or N to complete the dihydroindole ring.
[4" claim-type="Currently amended] 4. A compound according to claim 3, wherein Y is NR ¹ and the resulting dihydroindole ring is linked to the (CH ₂ ) nW- (CH ₂ ) m group via the 2- or 3-position.
[5" claim-type="Currently amended] 4. The method of claim 3, Y is N and via a dihydro-indol-1-position results _{(CH 2) nW- (CH 2} ) compounds, characterized in that connected to m groups.
[6" claim-type="Currently amended] 3. A compound according to claim 2, wherein A is group a), or group b) linked to X via positions 2 or 3.
[7" claim-type="Currently amended] 7. A compound according to claim 6 wherein A is group a) linked to X via positions 2 or 3.
[8" claim-type="Currently amended] 3. A compound according to claim 2, wherein A is group c) linked to X via positions 4,5,6 or 7.
[9" claim-type="Currently amended] 6. The compound according to claim 3, wherein A is group a), or group b) linked to X via positions 2 or 3. 7.
[10" claim-type="Currently amended] 10. A compound according to claim 9, wherein A is group a) linked to X via positions 2 or 3.
[11" claim-type="Currently amended] 6. The compound of claim 3, wherein A is a group c) linked to X via positions 4,5,6 or 7. 7.
[12" claim-type="Currently amended] 12. A compound according to any one of claims 1 to 11, wherein X is CH.
[13" claim-type="Currently amended] 12. A compound according to any one of claims 1 to 11, wherein X is C.
[14" claim-type="Currently amended] 12. A compound according to any one of claims 1 to 11, wherein X is N.
[15" claim-type="Currently amended] 14. A compound according to claim 13, wherein Y is NR ¹ or N to complete the dihydroindole ring and A is group a) linked to X via positions 2 or 3.
[16" claim-type="Currently amended] 3. A compound according to claim 2, wherein indan is linked via 2-position and A is linked via position 3.
[17" claim-type="Currently amended] 3. A compound according to claim 2, wherein indan is linked via the 2-position and A is the group a) linked via position 2.
[18" claim-type="Currently amended] 3. A compound according to claim 2, wherein indan is linked via the 2-position and A is group b).
[19" claim-type="Currently amended] 3. A compound according to claim 2, wherein indan is linked via the 2-position and A is the group c) linked via positions 4,5,6 or 7.
[20" claim-type="Currently amended] 3. A compound according to claim 2, wherein indan is linked via 1-position and A is linked via position 3.
[21" claim-type="Currently amended] 3. A compound according to claim 2, wherein indan is linked via 1-position and A is linked via position 2.
[22" claim-type="Currently amended] 3. A compound according to claim 2, wherein indan is linked via the 1-position and A is the group b).
[23" claim-type="Currently amended] 3. A compound according to claim 2, wherein indan is linked via the 1-position and A is the group c) linked via positions 4,5,6 or 7.
[24" claim-type="Currently amended] 5. The compound of claim 4, wherein the dihydroindole ring is linked through the 3-position and A is the group a) linked through the position 3.
[25" claim-type="Currently amended] 5. The compound of claim 4, wherein the dihydroindole ring is linked via the 3-position and A is the group a) linked via position 2. 6.
[26" claim-type="Currently amended] The compound of claim 4, wherein the dihydroindole ring is linked through the 3-position and A is the group b).
[27" claim-type="Currently amended] 5. The compound of claim 4, wherein the dihydroindole ring is linked through the 3-position and A is the group c) linked through positions 4,5,6 or 7. 6.
[28" claim-type="Currently amended] 5. A compound according to claim 4, wherein the dihydroindole ring is linked via 2-position and A is a group linked via position 3.
[29" claim-type="Currently amended] 5. The compound of claim 4, wherein the dihydroindole ring is linked via the 2-position and A is the group a) linked through the position 2.
[30" claim-type="Currently amended] 5. A compound according to claim 4, wherein the dihydroindole ring is linked via the 2-position and A is the group b).
[31" claim-type="Currently amended] 5. The compound of claim 4, wherein the dihydroindole ring is linked via the 2-position and A is the group c) linked through the positions 4,5,6 or 7. 6.
[32" claim-type="Currently amended] 6. A compound according to claim 5, wherein A is group a) linked via position 3.
[33" claim-type="Currently amended] 6. A compound according to claim 5, wherein A is group a) linked via position 2.
[34" claim-type="Currently amended] A compound according to claim 5, wherein A is group b).
[35" claim-type="Currently amended] 6. A compound according to claim 5, wherein A is group c) linked via positions 4,5,6 or 7.
[36" claim-type="Currently amended] 36. The compound of any of claims 1-35, wherein W is a bond and m + n is 1-4.
[37" claim-type="Currently amended] 36. The compound of any of claims 1-35, wherein W is a bond and m + n is 1-2.
[38" claim-type="Currently amended] 36. The compound of any one of claims 1 to 35, wherein W is a bond and m + n is one.
[39" claim-type="Currently amended] 36. The compound of any of claims 1 to 35, wherein W is a bond and m + n is 2.
[40" claim-type="Currently amended] 36. The compound of any of claims 1-35, wherein W is a bond and m + n is 2-6.
[41" claim-type="Currently amended] 36. The compound of any of claims 1-35, wherein W is a bond and m + n is 2-5.
[42" claim-type="Currently amended] 36. The compound of any of claims 1-35, wherein W is a bond and m + n is 2-4.
[43" claim-type="Currently amended] 36. The compound of any of claims 1-35, wherein W is a bond and m + n is 3-6.
[44" claim-type="Currently amended] 36. The compound of any of claims 1-35, wherein W is a bond and m + n is 3-5.
[45" claim-type="Currently amended] 36. The compound of any of claims 1-35, wherein W is a bond and m + n is 3-4.
[46" claim-type="Currently amended] 36. The compound of any of claims 1-35, wherein W is O.
[47" claim-type="Currently amended] 36. The compound of any of claims 1 to 35, wherein W is CO.
[48" claim-type="Currently amended] 48. The compound of any one of claims 15-47, wherein X is CH.
[49" claim-type="Currently amended] 48. The compound of any one of claims 15-47, wherein X is C.
[50" claim-type="Currently amended] 48. The compound of any of claims 15-47, wherein X is N.
[51" claim-type="Currently amended] 51. The compound of any of claims 1 to 50, wherein R ¹ is hydrogen, C _1-6 -alkyl, formyl, C _1-6 -alkylcarbonyl, C _1-6 -alkoxycarbonyl or C _{1- 6} -alkylaminocarbonyl and R ² -R ⁵ are independently hydrogen, halogen, cyano, nitro, C _1-6 -alkyl, C _1-6 alkoxy, C _1-6 -alkylthio, hydroxy, C _{3 -8} -cycloalkyl, C _3-8 -cycloalkyl-C _1-6 -alkyl, C _1-6 -alkylcarbonyl, trifluoromethyl, trifluoromethylsulfonyloxy and C _1-6 alkylsulfonyl Is selected from,
Otherwise one of R ² -R ⁵ is a group —NR ¹³ R ¹⁴ wherein R ¹³ is hydrogen, C _1-6 -alkyl, acyl, C _1-2 -alkylsulfonyl or R ¹⁶ is hydrogen, C _1-6 -alkyl, C _3-8 -cycloalkyl or C _3-8 -cycloalkyl-C _1-6 -alkyl and R ¹⁷ is hydrogen or C _1-6 -alkyl or R ¹⁶ and R ¹⁷ are A -R ¹⁶ R ¹⁷ NCO group which forms a pyrrolidinyl, piperidinyl or perhydroazepine group with the linked N-atom, R ¹⁴ is hydrogen or C _1-6 -alkyl or R ¹³ and R ¹⁴ are linked to each other Thereby forming pyrrolidinyl, piperidinyl, perhydroazepine or a 5-7 membered unsubstituted lactam ring.
[52" claim-type="Currently amended] 53. The compound of claim 51, wherein R²-R⁵end Hydrogen, halogen, cyano, nitro, C_1-6Alkyl, C_1-6-Alkoxy, trifluoromethyl, and trifluoromethylsulfonyloxy.
[53" claim-type="Currently amended] The compound of any one of claims 1-51, wherein none of R ² -R ⁵ is a group NR ¹³ R ¹⁴ .
[54" claim-type="Currently amended] The compound of any one of claims 1-49, wherein at least one of R ² -R ⁵ is a group NR ¹³ R ¹⁴ .
[55" claim-type="Currently amended] 55. The compound of claim 54, wherein R ¹³ is methyl, formyl, acetyl, methylaminocarbonyl, dimethylaminocarbonyl, methylsulfonyl, aminocarbonyl, cyclopropylcarbonyl, pyrrolidinylcarbonyl or 4-fluorophenylamino And carbonyl and R ¹⁴ is hydrogen or C _1-6 -alkyl.
[56" claim-type="Currently amended] 51. The method of any one of claims 1 to 50, wherein two adjacent groups employed from R ² -R ⁵ are joined to represent -CH = CH-NH-, thereby forming a fused five-membered ring. Compound.
[57" claim-type="Currently amended] The compound of claim 51, wherein R ⁶ -R ⁹ is independently hydrogen, halogen, cyano, nitro, C _1-6 -alkyl, C _1-6 -alkoxy, C _1-6 -alkylthio, hydroxide Hydroxy, C _3-8 -cycloalkyl, C _3-8 -cycloalkyl-C _1-6 alkyl, trifluoromethyl or C _1-6 alkylsulfonyl, or two adjacent ones employed from R ⁶ -R ⁹ A group wherein the groups are combined to represent a methylenedioxy group, wherein R ¹¹ and R ¹² are hydrogen or C _1-6 -alkyl and R ¹⁰ is hydrogen, C _1-6 -alkyl or acyl.
[58" claim-type="Currently amended] 59. The compound of claim 57, wherein R ⁶ -R ⁹ is independently selected from hydrogen, halogen, C _1-6 -alkyl, C _1-6 -alkoxy or two adjacent groups employed from R ⁶ -R ⁹ are associated A compound characterized by representing a methylenedioxy group.
[59" claim-type="Currently amended] 59. The compound of claim 58, wherein R ⁹ is hydrogen.
[60" claim-type="Currently amended] 60. The compound of claim 59, wherein R ⁸ is hydrogen.
[61" claim-type="Currently amended] 61. The compound of claim 60, wherein R ⁶ -R ⁷ is independently hydrogen or halogen.
[62" claim-type="Currently amended] 62. The compound of claim 61, wherein R ⁶ -R ⁷ is independently hydrogen or chlorine.
[63" claim-type="Currently amended] 63. A pharmaceutical composition comprising a compound of any one of claims 1 to 62 in a therapeutically effective amount with one or more pharmaceutically acceptable carriers or diluents.
[64" claim-type="Currently amended] Positive and negative symptoms of schizophrenia, other psychiatric disorders, generalized anxiety disorders, anxiety disorders such as panic and obsessive compulsive disorder, depression, alcohol abuse, impulse suppression disorders, aggression, side effects caused by conventional antipsychotic drugs, local Use of the compound of any one of claims 1 to 62 for the manufacture of a medicament useful for the treatment of anemia, migraine, senile dementia and cardiovascular disease and for improving sleep.
[65" claim-type="Currently amended] 63. Anxiety, such as positive and negative symptoms of schizophrenia, other psychiatric disorders, generalized anxiety disorder, panic and obsessive compulsion, comprising the administration of a therapeutically acceptable amount of a compound according to any of claims 1-62 Methods of treating and improving sleep for disorders, depression, alcohol abuse, impulse suppression disorders, aggression, side effects caused by conventional antipsychotic drugs, ischemia, migraine, senile dementia and cardiovascular 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:
1996-12-20|Priority to DK151496

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1996-12-20|Priority to DK1514/96

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1997-12-19|Application filed by 피터슨 존 메이달, 하. 룬트벡 아크티에 셀스카브

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1997-12-19|Priority to PCT/DK1997/000587

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2000-11-25|Publication of KR20000069621A

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2004-05-20|Application granted

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2004-05-20|Publication of KR100432297B1

优先权:

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申请号 | 申请日 | 专利标题

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DK151496|1996-12-20|

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DK1514/96|1996-12-20|

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PCT/DK1997/000587|WO1998028293A1|1996-12-20|1997-12-19|Indane or dihydroindole derivatives|