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    • 专利摘要:
    The present invention relates to novel pyrrolopyridinone derivatives of formula (I) or (II), pharmaceutical compounds containing them and their use for the treatment of sexual dysfunction. Formula I Formula II
    公开号:KR20030031483A
    申请号:KR1020027015582
    申请日:2001-05-03
    公开日:2003-04-21
    发明作者:쑤이즈화；맥시랙마크제이；관지화；장웨이친；랜터제임스씨
    申请人:오르토-맥네일 파마슈티칼, 인코퍼레이티드；
    IPC主号:
    专利说明:

    Substituted pyrrolopyridinone derivatives useful as phosphodiesterase inhibitors}
    [1] Cross-Reference to Related Applications
    [2] This application claims the priority of US Provisional Application No. 60 / 204,646, filed May 17, 2000, which is incorporated herein by reference.
    [4] Erectile dysfunction (ED) defines that a hard enough erection is not achieved or maintained for satisfactory intercourse. It is now estimated that about 7-8% of the male population suffers from some ED, which is equivalent to at least 20 million men in the United States alone. Since the likelihood of ED increases with age, it is anticipated that cases of this disorder will increase in the future as the average age of the population increases.
    [5] Male erectile dysfunction may be the result of psychological and / or organic factors. Although ED occurs according to a number of factors, certain subgroups in the male group seem to appear with disease symptoms. In particular, patients with diabetes, hypertension, heart disease and multiple sclerosis show particularly high ED development. In addition, patients taking certain classes of drugs, such as hypotensives, antidepressants, sedatives and anxiolytics, are more likely to suffer from ED.
    [6] Treatment for ED includes a variety of pharmacological agents, vacuum devices and penile implants. Among the pharmacological preparations, papaverine, fentolamine and alprostadil are currently used in practice. These agents are effective only after direct intracavernosal or urethral injections and are associated with side effects such as erection persistence, fibrosis, penile pain and hematoma at the injection site. The vacuum device is a noninvasive selective treatment for ED. These devices create an erection by creating negative pressure around the penis axis, increasing blood flow into the penile cavernous body through passive artery dilation. Although this form of therapy is frequently successful in ED of organic origin, there have been complaints of difficulty and discomfort in the lack of spontaneity and time and assessment associated with the use of mechanical devices. Many semi-rigid or swelling penile prostheses have been used successfully in part, particularly in diabetic men. These devices are generally considered when other therapeutic options fail and are associated with an increased risk of infection and ischemia.
    [7] Recently, sildenafil (Viagra ® ), a phosphodiesterase V (PDEV) inhibitor, has received FDA approval as an orally effective medicament for ED treatment. Sildenafil, i.e. 5- [2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl] -1-methyl-3-n-propyl-6,7-dihydro-1H-pyrazolo [ Their use as 4,3-d] pyrimidin-7-ones and many related homologues and antianginases are described in US Pat. Nos. 5,250,534 and 5,346,901. The use of sildenafil and related homologs to treat male erectile dysfunction is described in PCT WO 94/28902, published December 22, 1994. In clinical studies, the drug improved sexual function in about 70% of men with ED with psychological or organic etiology. However, the drug was less dramatic in patients undergoing prostatectomy, with improved erection in 43% of patients taking sildenafil versus 15% of those receiving placebo. In addition, the use of sildenafil has accompanied some undesirable side effects, including headache, flushing and color identification disruption resulting from nonspecific effects on various tissues. Despite these drawbacks, the drug is considered to be preferred by the patient over the introduction of the drug directly into the penis via injection or other therapeutic means associated with external devices or surgical operations.
    [8] In US Pat. Nos. 5,859,009 and EP 0740668 B1, Dougan et.al. describes the synthesis and synthesis of a family of tetracyclic derivatives as inhibitors of cyclic guanosine 3 ', 5' monophosphates, specifically phosphodiesterases. Its use is described in the treatment of cardiovascular diseases. Dougan et al. Teach the use of these tetracyclic derivatives in WO 97/03675 for the treatment of dyspareunia.
    [9] In Garnetux, J.-F. et al., Tetrahedron Letters 38 (17), (1997), pp 2997-3000, 1,2,3,4-tetrahydro-β- It describes the synthesis of tricyclic quinolone derivatives through the oxidation of carbolines.
    [10] Penninger, E., in DE 2803541 and US Pat. No. 4,235,907, describes substituted 9H-pyrrolo- [3,4-b] quinolin-9-one and its use in treating allergic asthma. have.
    [11] Sexually stimulated penile erection results from the complex interaction of physiological processes involving the central nervous system, peripheral nervous system, and smooth muscle. Specifically, the release of nitric oxide from non-adrenergic, non-cholinergic nerves and endothelium activates guanylyl cyclase and increases intracellular cGMP levels in the corpus cavernosum. Increasing intracellular cGMP reduces intracellular calcium levels, resulting in trabecular smooth muscle relaxation, which in turn enlarges the corpus cavernosum and squeezes the lower capsular lavage, resulting in penile erection.
    [12] PDEV has been found in human platelets and vascular smooth muscle, suggesting the role of this enzyme in the regulation of intracellular concentrations of cGMP in cardiovascular tissues. In fact, PDEV inhibitors have been shown to potentiate the increase in intracellular cGMP induced by nitric oxide, resulting in endothelial-dependent vasorelaxation. Moreover, PDEV inhibitors selectively lower pulmonary artery pressure in animal models of congestive heart failure and pulmonary hypertension. Thus, in addition to their utility in ED, PDEV inhibitors are likely to have therapeutic advantages in conditions such as heart failure, pulmonary hypertension and angina.
    [13] Through increased release of cGMP or reduced degradation thereof, agents that increase cGMP levels in penile tissue are expected as effective treatments for ED. Intracellular levels of cGMP are regulated by enzymes involved in their production and degradation, namely guanylate cyclase and cyclic nucleotide phosphodiesterase (PDE). To date, at least nine families of mammalian PDEs have been described, of which five can hydrolyze active cGMP to inactive GMP under physiological conditions (PDE I, II, V, VI and IX). PDE V is a major isoform of human penile cavernos, and therefore inhibitors of PDEV are expected to increase the concentration of cGMP in the penile corpus cavernosum, improving the duration and frequency of penile erection.
    [14] In addition, specific PDE inhibitors are associated with various diseases and pathologies, such as male erectile dysfunction (ED), female sexual dysfunction, female sexual dysfunction associated with blood flow and nitric oxide production in the tissues of the vagina and clitoris, premature delivery For the treatment of pain, dysmenorrhea, cardiovascular disease, atherosclerosis, arterial obstruction, thrombosis, coronary restenosis, angina pectoris, myocardial infarction, heart failure, ischemic heart disease, hypertension, pulmonary hypertension, asthma, intermittent claudication and diabetic complications It is known to be useful.
    [15] Accordingly, it is an object of the present invention to identify compounds that increase the concentration of cGMP in penis tissue through inhibition of phosphodiesterases, specifically PDEV. It is a further object of the present invention to identify compounds useful for the treatment of sexual dysfunction, in particular erectile dysfunction and / or impotence in male animals, and sexual dysfunction in female animals. Another object of the invention is to identify a method for treating sexual dysfunction, in particular erectile dysfunction, using the compounds of the invention.
    [16] Another object of the present invention is to provide a pathology of a disease mediated by PDEV, such as male erectile dysfunction, female sexual dysfunction, cardiovascular disease, atherosclerosis, arterial obstruction, thrombosis, coronary artery stenosis, angina pectoris, myocardial myocardium. To identify compounds useful for the treatment of infarction, heart failure, ischemic heart disease, hypertension, pulmonary hypertension, asthma, intermittent claudication and diabetic complications.
    [17] We now describe a series of pyrrolopyridine derivatives with the ability to inhibit phosphodiesterase type V in an enzyme assay.
    [18] Summary of the Invention
    [19] The present invention provides novel pyrrolopyridine derivatives useful as phosphodiesterase inhibitors. More specifically, the present invention relates to compounds of formula (I) or (II) and pharmaceutically acceptable salts thereof.
    [20]
    [21]
    [22] In the above formulas (I) and (II),
    [23] R 1 is hydrogen, carboxy, -C (O) -C 1 -C 6 alkyl, -C (O) -C 1 -C 6 alkoxy, -C (O) -NH-C 1 -C 6 alkyl-NH 2 , -C (O) -NH-C 1 -C 6 alkyl-NHR A , -C (O) -NH-C 1 -C 6 alkyl-N (R A ) 2 , -C (O) -NH 2 , -C (O) -NHR A , -C (O) -N (R A ) 2 , -C 1 -C 6 alkyl-NH 2 , -C 1 -C 6 alkyl-NHR A , -C 1 -C 6 Alkyl-N (R A ) 2 and -NH-C 1 -C 6 alkyl-N (R A ) 2 wherein R A is each independently C 1 -C 6 alkyl, aryl, C 1 -C 6 aralkyl And heteroaryl; Aryl, aralkyl or heteroaryl may be optionally substituted by one to three R B ; R B are each independently halogen, nitro, cyano, C 1 -c 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylcarbonyl, carboxyC 1 -C 6 alkyl, C 1 -C 6 alkyl Sulfonyl, trifluoromethyl, amino, di (C 1 -C 6 alkyl) amino, acetylamino, carboxy C 1 -C 6 alkylcarbonylamino, hydroxyC 1 -C 6 alkylamino NMR A and N (R A ) is selected from the group consisting of 2 ;
    [24] R 2 is C 5 -C 10 alkyl (optionally substituted with one to three substituents independently selected from halogen, hydroxy, nitro, amino, NMR A or N (R A ) 2 ), independently selected from R C Aryl optionally substituted with one to three substituents, cycloalkyl (optionally substituted with one or three substituents independently selected from R A ), hetero (optionally substituted with one or three substituents independently selected from R C ) Aryl and heterocycloalkyl (optionally substituted with one to three substituents independently selected from R C ), wherein R C is halogen, nitro, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, tri Fluoromethyl, trifluoromethoxy, NH 2 , NH (C 1 -C 6 alkyl) and N (C 1 -C 6 alkyl) 2 );
    [25] R 3 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 2 -C 6 alkenylcarbonyl and C 2 -C 6 alkynylcarbonyl,
    [26] b is an integer from 0 to 4,
    [27] R 4 is independently halogen, hydroxy, carboxy, oxo, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, trifluoromethyl, (independently from R D Phenyl, phenylsulfonyl, naphthyl, C 1 -C 6 aralkyl (which may be optionally substituted with one to three substituents selected), optionally substituted with one to three substituents independently selected from R D R D, which may be independently optionally substituted with one to three selected in the substituent may be optionally substituted) -O- aralkyl, (one to three substituents independently selected from R D from) heteroaryl, heterocycloalkyl, NH 2 , NHR A , N (R A ) 2 , , , , , , And Wherein each R D is independently halogen, hydroxy, carboxy, oxo, C 1 -C 4 alkyl, C 1 -C 4 alkylthio, hydroxyC 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbonyl, trifluoromethyl, trifluoromethoxy, NH 2 , NHR A , N (R A ) 2 , C (O) N (R A ) 2 , SO 2 N (R A ) 2 , acetylamino, nitro, cyano, formyl, C 1 -C 6 alkylsulfonyl, carboxyC 1 -C 6 alkyl and aralkyl) Selected from
    [28] c is an integer from 0 to 4,
    [29] R 5 is independently halogen, nitro, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NH 2 , -NHR A , -N (R A ) 2 , OR A , -C (O) NH 2 , -C (O) NHR A , -C (O) N (R A ) 2 , -NHC (O) R A , -SO 2 NHR A , -SO 2 N (R A ) 2 , where R A are as defined above), (R B independently optionally substituted with one to three substituents selected) from the phenyl, (optionally substituted) heteroaryl, and (with one to three substituents independently selected from R B R Is selected from the group consisting of heterocycloalkyl, optionally substituted with one to three substituents independently selected from B ,
    [30] a is an integer from 0 to 1,
    [31] Y is -C 1 -C 6 -alkyl, -C (O),-(C 1 -C 6 alkyl) carbonyl-,-(C 2 -C 6 alkenyl) carbonyl-, -C 2 -C 6 (Alkynyl) carbonyl-, carbonyl (C 1 -C 6 alkyl)-, carbonyl (C 2 -C 6 alkenyl)-, -C (O) O- (C 1 -C 6 alkyl)-, -C (S)-, -SO 2 -,-(C 1 -C 6 alkyl) sulfonyl, -sulfonyl (C 1 -C 6 alkyl)-, -C (O) NH-, -C (O) NH- (C 1 -C 6 alkyl)-, C (O) (C 3 -C 7 cycloalkyl-) and-(C 3 -C 7 cycloalkyl) -C (O)-,
    [32] Is selected from the group consisting of phenyl, furyl, thienyl and pyrrolyl;
    [33] Is selected from the group consisting of aryl, heteroaryl, cycloalkyl and heterocycloalkyl,
    [34] Provided that R 1 is hydrogen, R 3 is hydrogen, b is 0, c is 0, a is 1, Y is -CH 2- , Is phenyl, When is phenyl, R 2 is not trimethoxyphenyl (ie the compound is 1,2,3,4-tetrahydro-2- (phenylmethyl) -3- (3,4,5-trimethoxy Phenyl) -9H-pyrrolo [3,4-b] quinolin-9-one).
    [35] An exemplary embodiment of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compounds described above. An exemplary embodiment of the present invention is a pharmaceutical composition prepared by mixing any of the compounds described above and a pharmaceutically acceptable carrier. An exemplary form of the present invention is a method of preparing a pharmaceutical composition comprising mixing any of the compounds described above and a pharmaceutically acceptable carrier.
    [36] Exemplary embodiments of the present invention include administering a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above to a subject in need thereof, including male erectile dysfunction (ED), impotence, female sexual function in the subject. Disorders, female sexual arousal disorders, female sexual dysfunction associated with blood flow and nitric oxide production in the vagina and clitoris tissues, preterm labor pain, dysmenorrhea, cardiovascular disease, atherosclerosis, arterial occlusion disease, thrombosis, coronary restenosis , Angina, myocardial infarction, heart failure, ischemic heart disease, hypertension, pulmonary hypertension, asthma, intermittent claudication and diabetic complications.
    [37] Another example of the invention comprises administering any of the compounds or pharmaceutical compositions described above to a male subject in need thereof, thereby inhibiting phosphodiesterases, particularly PDEV, in the penile tissues in the male patient. It is a way to increase the concentration of cGMP.
    [38] Another example of the invention involves administering any of the compounds or pharmaceutical compositions described above to a subject in need thereof, thereby enhancing endothelial dependency by enhancing an increase in intracellular cGMP induced by nitric oxide in the patient. It is a method of causing vascular relaxation.
    [39] Embodiments of the present invention provide for (a) treatment of sexual dysfunction, especially male erectile dysfunction, (b) impotence treatment, (c) increased cGMP, especially PDEV concentration, in penis tissue through inhibition of phosphodiesterase, And / or (d) preterm labor, menstrual irregularities, cardiovascular disease, atherosclerosis, arterial obstruction, thrombosis, coronary restenosis, angina pectoris, myocardial infarction, heart failure, ischemic heart disease, hypertension, pulmonary hypertension, asthma, intermittent claudication and The use of any of the compounds described above in the manufacture of a medicament for treating a subject selected from the group consisting of diabetic complications to a subject in need thereof.
    [3] The present invention relates to novel pyrrolopyridinone derivatives, intermediates used in the compounds, synthesis methods, pharmaceutical compositions containing them and their use for the treatment of sexual dysfunction. The compounds of the present invention are phosphodiesterase inhibitors useful for the treatment of sexual dysfunction, especially male erectile dysfunction.
    [40] The present invention provides novel pyrrolopyridinone derivatives useful for the treatment of sexual dysfunction, especially male erectile dysfunction (ED). The compounds of the present invention are mainly useful for the treatment of male sexual dysfunction or erectile dysfunction, but female sexual dysfunction, such as female sexual arousal disorder, female sexual dysfunction associated with blood flow and nitric oxide products in vaginal and clitoris tissues, and premature delivery It may also be useful in the treatment of analgesia and dysmenorrhea.
    [41] More particularly, the compounds of the present invention are of formula (I) or formula (II) and pharmaceutically acceptable salts thereof.
    [42] Formula I
    [43]
    [44] Formula II
    [45]
    [46] In the above formulas (I) and (II),
    [47] All symbols are as defined above.
    [48] Preferably, R 1 is hydrogen.
    [49] In one embodiment of the invention, R 2 is phenyl (halogen, nitro, cyano, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, trifluoromethoxy, NH 2 , NH (C 1 -C 3 alkyl) or N (C 1 -C 3 alkyl) 2 may be optionally substituted with one to two substituents), heteroaryl and heterocycloalkyl. Preferably, R 2 is 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 5- (2,3-dihydrobenzofuryl), 3,4-dihydrobenzo- [1,4] -Dioxin-6-yl, 5-benzofuryl, 5-indanyl and 3-thienyl. More preferably, R 2 is 3,4-methylenedioxyphenyl, 5- (2,3-dihydrobenzofuryl), 3,4-dihydrobenzo- [1,4] -dioxin-6-yl , 3-thienyl, 5-indanyl and 5-benzofuryl. Most preferably, R 2 is selected from the group consisting of 3,4-methylenedioxyphenyl, and 5- (2,3-dihydrobenzofuryl).
    [50] Preferably, R 3 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl. More preferably, R 3 is selected from the group consisting of hydrogen and methyl. Most preferably, R 3 is hydrogen.
    [51] Preferably, b is an integer from 0 to 4. More preferably, b is an integer of 0-1.
    [52] In one embodiment of the invention, R 4 is halogen, hydroxy, carboxy, oxo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkoxycarbonyl, phenyl, wherein phenyl is hydroxy , Carboxy, C 1 -C 4 alkyl, C 1 -C 4 alkylthio, hydroxyC 1-4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyloxycarbonyl, C (O) N (R A ) 1 to 2 substituents selected from 2 , trifluoromethyl, trifluoromethoxy, amino, (C 1-4 alkyl) amino, di (C 1-4 alkyl) amino, nitro, cyano or formyl May be optionally substituted with], O-aralkyl, heteroaryl, wherein heteroaryl is hydroxy, carboxy, oxo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkoxycarbonyl , C (O) N (R a) 2, trifluoromethyl, trifluoromethoxy, amino, nitro, C 1 -C 3 alkylcarbonyl or C 1 - to 4 1 to 2 substituents selected from aralkyl May be optionally substituted], hetero Cycloalkyl, , , , , , And It is selected from the group consisting of.
    [53] Preferably, R 4 is bromo, hydroxy, carboxy, oxo, methyl, phenyl, 4-hydroxyphenyl, 3-hydroxymethylphenyl, 4-hydroxymethylphenyl, 4-carboxyphenyl, 4-methylphenyl, 4- Methoxyphenyl, 3,4-dimethoxyphenyl, 4-methoxycarbonyl, 4-methoxycarbonylphenyl, 3-trifluoromethylphenyl, 4-cyanophenyl, 4-aminophenyl, 4-dimethylaminophenyl 3-nitrophenyl, 4-nitrophenyl, 4-formylphenyl, 4-methylthiophenyl, benzyloxy, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, N-oxy-2-pyridinyl, 3-thienyl, 2-furyl, 1-imidazolyl, 5- (1-benzyl-2-methylimidazolyl), 5- (1,2-dimethylimidazolyl), 5- (1-methyldi Midazolyl), 5- (1-benzylimidazolyl), 3,4-methylenedioxyphenyl, , , , , And It is selected from the group consisting of. More preferably, R 4 is 5-bromo, 2-hydroxy, 6-hydroxy, 4-carboxy, phenyl, 4-hydroxyphenyl, 3-hydroxymethylphenyl, 4-hydroxymethylphenyl, 4-carboxy Phenyl, 4-methylphenyl, 4-methylthiophenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-methoxycarbonyl, 4-methoxycarbonylphenyl, 3-trifluoromethylphenyl, 4- Aminophenyl, 4-dimethylaminophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-cyanophenyl, 4-formylphenyl, benzyloxy, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2 -Furyl, 3-thienyl, N-oxo-2-pyridinyl, 1-imidazolyl, 5- (1-benzyl-2-methylimidazolyl), 5-1,2-dimethylimidazolyl, 3 , 4-methylenedioxyphenyl, , , , And It is selected from the group consisting of. More preferably, R 4 is 5-bromo, 2-hydroxy, 6-hydroxy, 4-carboxy, phenyl, 4-hydroxyphenyl, 3-hydroxymethylphenyl, 4-hydroxymethylphenyl, 4-carboxy Phenyl, 4-methylphenyl, 4-methylthiophenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-methoxycarbonyl, 4-methoxycarbonylphenyl, 3-trifluoromethylphenyl, 4- Aminophenyl, 4-dimethylaminophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-cyanophenyl, 4-formylphenyl, benzyloxy, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, N Oxo-2-pyridinyl, 3-thienyl, 2-furyl, 1-imidazolyl, 5- (1-benzyl-2-methylimidazolyl), 5- (1,2-dimethylimidazolyl) , 3,4-methylenedioxyphenyl, , , And It is selected from the group consisting of. More preferably, R 4 is 6-hydroxy, 4-carboxy, phenyl, 4-hydroxyphenyl, 3-hydroxymethylphenyl, 4-methylphenyl, 4-methylthiophenyl, 4-methoxyphenyl, 3,4 -Dimethoxyphenyl, 4-methoxycarbonyl, 3-trifluoromethylphenyl, 3-nitrophenyl, 4-nitrophenyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, N-oxo-2- Pyridinyl, 3-thienyl, 5- (1-benzyl-2-methylimidazolyl), 5- (1,2-dimethylimidazolyl), And It is selected from the group consisting of. Most preferably, R 4 is hydroxy, 4-methylphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-methoxycarbonyl, 3-trifluoromethylphenyl, 4-nitrophenyl, 2- Pyridinyl, 3-pyridinyl, And It is selected from the group consisting of.
    [54] In a preferred embodiment, c is zero. In another preferred embodiment a is an integer from 0 to 1.
    [55] In an embodiment of the invention, Y is -C 1 -C 4 alkyl-, -C (S)-, -C (O)-, -C (O) O- (C 1 -C 4 alkyl)-, -C (O) - (C 1 -C 4 alkyl) -, -C (O) - (C 2 -C 4 alkenyl) -, C (O) - (C 3 -C 7 cycloalkyl) - and -C ( O) NH- (C 1 -C 3 alkyl)-. Preferably, Y is —CH 2 —, —C (S) —, —C (O) —, —C (O) O—CH 2 —, —C (O) —CH 2 CH 2 —, —C (O) —CH═CH—, —C (O) NH—CH 2 —, —C (O) -cyclopropyl, and —C (O) CH 2 —. More preferably, Y is -C (O)-, -C (O) O-CH 2- , -C (O) -CH 2 CH 2- , -C (O) -CH = CH-, and- It is selected from the group consisting of C (O) -cyclopropyl. More preferably, Y is selected from the group consisting of -C (O)-and -C (O) O-CH 2 .
    [56] Preferably, Is phenyl.
    [57] In an aspect of the invention, Is selected from the group consisting of phenyl, heteroaryl and heterocycloalkyl. Preferably, Is phenyl, 2-furyl, 2-benzo (b) furyl, 2-pyrimidinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 1-imidazolyl, 2-imidazolyl, 2- Thiazolyl, and 2-oxo-bicyclo [2.2.1] heptanyl. More preferably, Is selected from the group consisting of phenyl, 2-furyl, 2-benzo (b) furyl, 2-pyrimidinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl and 2-thiazolyl. Most preferably, Is selected from the group consisting of 2-furyl, 2-benzo (b) furyl, 4-pyridinyl, 2-pyrimidinyl and 2-thiazolyl.
    [58] The term "halogen" may include iodine, bromine, chlorine and fluorine.
    [59] The term "alkyl", whether used alone or as part of a substitution group, refers to straight or branched chain alkanes having 1 to 10 carbon atoms or any carbon number in this range. For example, alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary-butyl, t-butyl, n-butyl, 3- (2-methyl) butyl, 2- Pentyl, 2-methylbutyl, neopentyl, n-hexyl and 2-methylpentyl. Similarly, alkenyl and alkynyl groups include straight and branched chain alkenes and alkynes having 2 to 10 carbon atoms or any carbon number in this range.
    [60] The term "alkoxy" means oxygen ether radicals of the aforementioned straight or branched alkyl groups. For example, alkoxy radicals include methoxy, ethoxy, n-propoxy, n-butoxy, secondary-butoxy, tert-butoxy and the like.
    [61] The term "aryl" refers to an aromatic group such as phenyl, naphthyl and the like.
    [62] The term "aralkyl" refers to an alkyl group substituted with an aryl group. For example, benzyl phenylethyl etc. are meant. Similarly, the term "aralkenyl" refers to an alkenyl group substituted with an aryl group, for example phenylethylenyl.
    [63] As used herein, the term “heteroaryl” refers to a stable 5- or 6-membered monocyclic aromatic ring system containing 1 to 3 heteroatoms independently selected from N, O or S or a carbon atom and N, O or S And any 9 or 10 membered bicyclic aromatic ring system containing 1 to 4 heteroatoms independently selected from the group. Heteroaryl groups can be attached to any hetero atom or carbon atom to produce a stable structure. Examples of heteroaryl groups are pyridyl, pyrimidyl, thienyl, furyl, amidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, benzimida Including zolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, indazolyl, indolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, furinyl However, the present invention is not limited thereto. Preferred heteroaryl groups include pyrimidinyl, pyridinyl, furyl, imidazolyl, benzofuryl and thiazolyl.
    [64] As used herein, the term "cycloalkyl" refers to a stable three to eight membered monocyclic ring structure consisting of saturated carbon atoms. Suitable examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
    [65] The term "heterocycloalkyl" refers to a stable saturated or partially saturated three to eight membered monocyclic containing carbon atoms and hetero atoms independently selected from 1 to 4, preferably 1 or 2 N, O or S. Ring structure; And any stable, saturated, partially saturated or partially aromatic 9 or 10 membered bicyclic ring system containing carbon atoms and 1 to 4 hetero atoms independently selected from n, o or S. Heterocycloalkyl can be attached to any carbon atom or hetero atom to produce a stable structure. Suitable examples of heterocycloalkyl groups include pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, ditianyl, tritianyl, dioxolanyl, dioxanyl, thiomorpholinyl, 3, 4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzo- [1,4] -dioxin-6-yl, 2,3-dihydro-furo [2,3- b] pyridinyl, 1,2- (methylenedioxy) cyclohexane, indanyl, 2-oxa-bicyclo [2,2,1] heptanyl and the like. Preferred heterocycloalkyl groups are piperidinyl, pyrrolidinyl, morpholinyl, indanyl, 2-oxa-bicyclo [2,2,1] -heptanyl, 3,4-methylenedioxyphenyl, 2,3 -Dihydrobenzofuryl and 2,3-dihydrobenzo- [1,4] -dioxin-6-yl.
    [66] As used herein, "*" indicates that the center of the stereoisomer is present.
    [67] The definition of any substituent or variant at a particular position is in accordance with its definition anywhere in the molecule. Substituents and substitution patterns in the compounds of the present invention are understood by those skilled in the art to provide compounds that are chemically stable and can be readily synthesized by techniques known in the art and the methods set forth herein. It is also understood that when b or c is> 1, the corresponding R 4 or R 5 substituents may be the same or different.
    [68] If the compounds according to the invention have one or more chiral centers, they may correspondingly exist as enantiomers. If the compounds have two or more chiral centers, they may also exist as stereoisomers. All such isomers and mixtures thereof are to be understood as included within the scope of the present invention. In addition, the crystalline forms of the compounds may exist in polymorphic form and are intended to be included in the present invention by themselves. In addition, some of the compounds may form solvates (ie hydrates) or common organic solvents with water, which solvates are intended to be included within the scope of the present invention.
    [69] Under the standard nomenclature used throughout this technology, the terminal sites of designated side chains first involve adjacent functionality towards the point of attachment. That is, for example, "phenylC 1 -C 6 alkylaminocarbonylC 1 -C 6 alkyl" substituents means a group of the formula:
    [70]
    [71] As used herein, the term “sexual dysfunction” refers to male sexual dysfunction, male dilated dysfunction, erectile dysfunction, female sexual dysfunction, female sexual stimulatory dysfunction, and female sex associated with nitric oxide production in blood flow and vaginal vestibular and clitoris tissue Includes dysfunction.
    [72] As used herein, the term “patient” refers to an animal, preferably a mammal, most preferably a human, for therapeutic, observational or experimental purposes.
    [73] As used herein, the term “therapeutically effective amount” refers to a biological or medical condition in a tissue system, animal or human as considered by an observer, veterinarian, medical doctor or other clinician, including alleviation of the symptoms of the disease or condition being treated. The amount of the active compound or pharmaceutical agent that elicits a response.
    [74] As used herein, the term “composition” is intended to include any product that produces a particular amount of a particular component and any product that directly or indirectly produces a combination of a particular amount of a particular component.
    [75] When used in medicine, salts of the compounds of the present invention refer to non-toxic "pharmaceutically acceptable salts". However, other salts may also be useful in the preparation of the compounds according to the invention or in the preparation of pharmaceutically acceptable salts thereof. Suitable pharmaceutically acceptable salts of the present compounds are, for example, solutions of the compounds and pharmaceutically acceptable acids such as hydrochloric acid, sulfuric acid, fumaric acid, malic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carboxylic acid or And a solution of phosphoric acid). In addition, when a compound of the present invention carries an acidic moiety, suitable pharmaceutically acceptable salts thereof include alkali metal salts, such as sodium or potassium salts; Alkaline earth metal salts, such as calcium or magnesium salts; And salts formed with suitable organic ligands, ie quaternary ammonium salts. That is, representative pharmaceutically acceptable salts include:
    [76] Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate, Bromine, Calcium Edetate, Chamlate, Carbonate, Chloride, Claburanate, Citrate, Dihydrochloride, Edetate, Idi Silates, Estoleates, Esylates, Fumarates, Gluceptates, Gluconates, Glutamate, Glycolyl arnate, Hexylsorbinate, Hydrabamine, Hydrobromide, Hydrochloride, Lahydroxynaphthoate , Iodide, isethionate, lactate, lactobionate, laurate, maleate, maleate, mandelate, mesylate, methyl bromide, methylnitrate, methyl sulfate, no catenate, lead sillate, nitrate, N-methyl-llucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantote Yates, Phosphates / Diphosphates, Polygalalturonates, Salicylates, Stearates, Sulfates, Subacetates, Succinates, Tannates, Tartrates, Theoclates, Tosylates, Triethoxides and Valerates .
    [77] Compounds of the invention are included within the prodrug domain of the compounds of the invention. In general, such prodrugs will be functional derivatives of the compounds that can be readily converted in vivo to the desired compound. That is, in the methods of treatment of the present invention, the term "administration" refers to treating a variety of diseases described using a specifically described compound or a compound that is not specifically described but is converted to a specific compound in vivo after administration to a patient It will include a box. Conventional processes for the selection and preparation of suitable prodrug derivatives are described in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
    [78] Abbreviations used in the present specification, particularly in the schemes and examples are as follows.
    [79] BINAP = (R)-(+)-2,2'-bis (diphenylphosphino) -1,1'-binafyl Cmpd = compound DBU = 2,3,4,6,7,8,9,10-oxahydro-pyrimido [1,2-a] azepine DCC = 1,3-dicyclohexylcarbodiimide DCM = Dichloromethane DEAD = Diethyl diagendicarboxylate DIPEA = Diisopropylethylamine DMAP = N, N'-dimethyl-4-pyridinamine DMF = N, N'-dimethylformamide DMSO = Dimethyl sulfoxide dppp = 1,3-bis (diphenylphosphino) propane EDTA = Ethylenedinitrotetraacetic Acid EtOAc = Ethyl acetate EtOH = ethanol Et 3 N = Triethylamine Fmoc-NCS = [(9H-Fluoren-9-ylmethoxy) carbonyl] -thiocyanate HEPES = 2- [4- (2-hydroxyethyl) -piperazinyl] -ethanesulfonic acid HPLC = High pressure liquid chromatography ID # = Compound definition number KOt-Bu = Potassium t-butoxide MeOH = Methanol mCPBA = 3-chloroperoxybenzoic acid NaOt-Bu = Sodium t-butoxide n-Bu = n-butyl NMP = N-methyl-2-pyrrolidinone Pd 2 dba 3 = Tris (dibenzylidene acetone) dipalladium (0) Pd (dppf) (OAc) 2 = 1,1'-bis (diphenylphosphino) ferrocene palladium diacetate Pd (OAc) 2 = Palladium (II) Acetate Pd (dppf) Cl 2 = 1,1'-bis (diphenylphosphino) ferrocene palladium (II) dichloride Pd (PPh 3 ) 4 or Pd (Ph 3 P) 4 = Palladium tetrakis (triphenyl phosphine) Ph = Phenyl PMSF = Phenylmethanesulfonyl Fluoride PPh 3 = Triphenyl phosphine PyBrOP = Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate TEA = Triethylamine TFA = Trifluoroacetic acid THF = Tetrahydrofuran TLC = Thin layer chromatography TsOH = p-toluenesulfonic acid SNP = Sodium nitroprusside
    [80] Compounds of formula (I) wherein R 3 is hydrogen can be prepared according to two separate methods from suitably substituted compounds of formula (III) selected and used as initiators.
    [81]
    [82] In Formula III above,
    [83] R 1 , R 2 , R 5 and c are as previously defined.
    [84] The compound of formula III is a known compound or a compound prepared by a known method, for example the method shown in Scheme 1 below.
    [85]
    [86] Thus, the aldehydes of formula V, which are known compounds or compounds prepared by known methods, are suitably substituted in organic solvents such as DCM, THF and toluene in the presence of acid catalysts such as TFA and tosic acid, etc. And the corresponding compounds of formula III are prepared.
    [87] In general, in the first of two separate methods, compounds of formula (I) can be prepared by reacting suitably substituted compounds of formula (III) to produce the corresponding substituted pyrrolopyridinone derivatives. In a second of two separate processes, the compound of formula I can be prepared by reacting a compound of formula III, which is first suitably substituted, to form a tricyclic pyrrolopyridinone moiety, followed by the introduction of additional substituents. This second method is particularly preferred for preparing compounds of formula I, wherein Y is -C (S), -C (O) OR 4 or -C (O) R A.
    [88] More particularly, compounds of formula I, wherein R 3 is hydrogen, can be prepared from compounds of formula III that are suitably substituted according to the method specified in Scheme 2.
    [89]
    [90] In a first process, a suitably substituted compound of formula (III) is substituted with a suitably substituted compound of formula (VI) in an organic solvent such as DMF, THF, DCM and toluene, wherein X is halogen, hydroxy, tosylate, mesylate or p- Nitrophenoxide and the like, preferably halogen, hydroxy or p-nitrophenoxide) to produce the corresponding compound of formula (VII). (Y) For compounds of formula I wherein a is (Y) 0 (ie Y is absent when a is 0), the reaction mixture is preferably heated to a temperature of at least about 100 ° C. (Y) a is (Y) 0 (i.e. Y is absent when a is 0) and For compounds of formula I, wherein is pyridinyl, the reaction mixture is preferably Pd (OAc) 2 in organic solvents such as 1,4-dioxane, THF, DMF, DCF and toluene, in the temperature range of about 30 to 120 ° C Catalyst with a catalyst such as Pd 2 dba 3 and Pd (dppf) Cl 2 or the like to give the corresponding compound of formula VII.
    [91] The compound of formula VII is then reacted with an oxidant such as NalO 4 , KO 2 , monovalent oxygen, oxygen gas and ozone, preferably oxygen gas applied at atmospheric pressure, to produce the corresponding pyrrolopyridinone derivative of formula Ia. When the oxidant is oxygen gas, the reaction is carried out in the presence of a base such as sodium hydride, potassium-t-butoxide and the like.
    [92] In another process specified in Scheme 2, the appropriately substituted compound of formula III is first reacted with an oxidizing agent such as NalO 4 , KO 2 , monovalent oxygen, oxygen gas and ozone, preferably oxygen gas applied at atmospheric pressure to To prepare a compound of formula VIII. When the oxidant is oxygen gas, the reaction is carried out in the presence of a base such as sodium hydride, potassium-t-butoxide and the like.
    [93] The compound of formula (VI) is then suitably substituted in an organic solvent such as DMF, THF, DCM and toluene, optionally in the presence of a catalyst such as DMAP, wherein X is halogen, hydroxy, tosylate, mesylate , p-nitrophenoxide and the like, preferably X is halogen, hydroxy or p-nitrophenoxide) to produce the corresponding substituted pyrrolopyridinone of formula (la). (Y) For compounds of formula I in which a is (Y) 0 (ie Y is absent when a is 0), the reaction mixture is preferably heated to a temperature of at least about 50 ° C. (Y) a is (Y) 0 (i.e. Y is absent when a is 0) and For compounds of formula VIII wherein is pyridinyl, the reaction mixture is preferably Pd (OAc) 2 in organic solvents such as 1,4-dioxane, THF, DMF, DCF and toluene at temperatures ranging from about 30 to 120 ° C. Catalyzed by a catalyst such as Pd 2 dba 3 and Pd (dppf) Cl 2 and the like to obtain the corresponding compound of formula la.
    [94] Further, (Y) a is CH 2 For compounds of formula I wherein is an unsubstituted or substituted aryl or an unsubstituted or substituted heteroaryl, about 80 p in the presence of a catalyst such as Pd, Pt, palladium on carbon, etc. in organic solvents such as methanol, ethanol and ethyl acetate Compounds of formula (VIII) may be prepared by reacting a compound of formula (Ia) with a hydrogen gas applied at a pressure in the atmospheric pressure range of .si. The compound of formula VIII may then be functionalized as further described above.
    [95] b is equal to 1 The compounds of formula I are groups, one of R 4 is substituted with a substituent) may be prepared from the appropriately substituted compound of formula (III) according to three separate ways indicated by.
    [96] In the first process, a suitably substituted compound of formula III is first converted to pyrrolopyridinone by following the process specified in Scheme 2 followed by two steps on pyrrole nitrogen as specified in Scheme 3.
    [97]
    [98] In particular, reacting a compound of formula (IX) with a suitably substituted compound of formula (IX) wherein X is halogen in the presence of a base such as TEA and DIPEA in an organic solvent such as DMF, DCM and THF, preferably in the temperature range of about 20 to 150 ° C. To give the corresponding compound of formula (X).
    [99] The compound of formula X is reacted with a suitably substituted boronic acid of formula XI or tributyl-stanan of suitably substituted formula XII to give the corresponding compound of formula Ib. When the reagent selected is boronic acid of formula (XI), preferably DMF, THF, dioxane, etc. in the presence of a catalyst such as Pd (Ph 3 P) 4 , Pd (dppf) (OAc) 2 , etc. The reaction is carried out in an organic solvent such as If the reagent selected is tributyl-stanan of formula XII, the compound of formula X is reacted in a solvent such as DMF in the presence of a catalyst such as Pd (dppf) (OAc) 2 .
    [100] In a second process, the compound of formula III is initially bromo substituted And then converted to the corresponding pyrrolopyridinone and then further as shown in Scheme 4. Substitute in
    [101]
    [102] More particularly, in an organic solvent such as DMF and toluene, preferably in the presence of a base such as TEA and DIPEA in the temperature range of about 100 to 150 ° C. The compound is reacted to give the corresponding compound of formula XIV.
    [103] The compound of formula XIV is reacted with an oxidant such as NaIO 4 , KO 2 , monovalent oxygen, oxygen gas and ozone, preferably oxygen gas applied at atmospheric pressure, to produce the corresponding compound of formula XV.
    [104] The compound of formula XV is reacted with a suitably substituted boronic acid of formula XI or tributyl-stanan of suitably substituted formula XII to give the corresponding compound of formula Ic. If the reagent selected is boronic acid of formula XI, preferably DMF, dioxane and water in the presence of a catalyst such as Pd (Ph 3 P) 4 and Pd (dppf) (OAc) 2 and the like at a temperature range of about 80 to about 160 ° The compound of formula XV is reacted in an organic solvent such as If the reagent selected is tributyl-stanan of formula XII, the compound of formula XV is reacted in a solvent such as DMF and TEA in the presence of a catalyst such as Pd (dppf) (OAc) 2 .
    [105] In a third process, the compound of formula III is initially bromo-substituted as shown in Scheme 5. And add Is substituted with an R 4 substituent followed by conversion to the corresponding pyrrolopyridinone.
    [106]
    [107] More particularly, compounds of formula (XIV) are reacted with suitably substituted boronic acids of formula (XI) or suitably substituted tributyl-stanan of formula (XII) to afford the corresponding compounds of formula (XVI). If the reagent selected is boronic acid of formula XI, the compound of formula XIV is preferably subjected to a catalyst such as Pd (Ph 3 P) 4 , Pd (dppf) (OAc) 2, etc., in an organic solvent such as DMF, dioxane, water, Reacts at a temperature in the range from about 80 to about 120 ° C. If the reagent selected is tributyl-stannan of formula XII, the compound of formula XIV is reacted in the presence of a catalyst such as Pd (dppf) (OAc) 2 in a solvent such as DMF, dioxane and the like.
    [108] The compound of formula XVI is reacted with an oxidizing agent such as NaIO 4 , KO 2 , single oxygen, oxygen gas, ozone and the like, preferably oxygen gas applied at atmospheric pressure. To yield the corresponding compound of formula (Ic).
    [109] b is an integer selected from 2, 3 and 4 (ie, where Is substituted with 2, 3 or R 4 groups) Containing reagents According to the process outlined in Schemes 3, 4, and 5, suitably replacing with corresponding reagents substituted with these 2, 3 or 4 bromine groups and subsequently reacting the bromine groups to incorporate the desired R 4 groups It can manufacture.
    [110] Compounds of formula (I) wherein (Y) a is C (O) can be prepared according to two optional processes. In the first process, the pyrrolopyridinone compound of formula VII is first substituted with a suitably selected carboxylic acid or acid chloride, Is further substituted with an R 4 substituent as outlined in Scheme 6.
    [111]
    [112] More particularly, a suitably substituted pyrrolopyridine compound of formula (VIII) may be prepared by a suitably substituted carboxylic acid or an acid chloride of formula (XVIII) wherein W is OH or Cl and a catalyst such as PyBrop, DCC, etc. when W is OH. In the presence of a base such as TEA, DIPEA and the like when W is Cl to give the corresponding compound of formula XVIII.
    [113] The compound of formula XVIII is prepared in the presence of a suitably substituted boronic acid of formula XI and a catalyst such as Pd (Ph 3 P) 4 and the like in an organic solvent such as DMF, dioxane, water and the like, preferably in the range of about Reaction at temperature gives the corresponding compound of formula Id.
    [114] In the second process, a suitably substituted compound of formula III is first converted to the corresponding pyrrolopyridinone, followed by suitably substituted carboxylic acid as outlined in Scheme 7, followed by boronic acid or stannan 2 step substitution.
    [115]
    [116] More particularly, suitably substituted compounds of formula III are selected from suitably substituted carboxylic acids of formula XVII, wherein W is halogen or hydroxy, and organic solvents such as TEA, DIPEA and the like, preferably from about 80 to about 130 ° C. Reaction at temperatures in the range affords the corresponding compound of formula XIX.
    [117] The compound of formula XIX is reacted with a suitably substituted boronic acid of formula XI or a suitably substituted tributyl-stanan of formula XII to give the corresponding compound of formula XX. If the reagent selected is boronic acid of formula (XI), the compound of formula (XIX) is prepared in the presence of a catalyst such as Pd (Ph 3 P) 4 , Pd (dppf) (OAc) 2, etc. And preferably at a temperature in the range from about 80 to about 120 ° C. If the reagent selected is tributyl-stannan of formula XII, the compound of formula XIX is reacted in the presence of a catalyst such as Pd (dppf) (OAc) 2 in a solvent such as DMF, dioxane and the like.
    [118] The compound of formula XX is reacted with an oxidizing agent such as NaIO 4 , KO 2 , single oxygen, oxygen gas, ozone and the like, preferably KO 2 , to give the corresponding compound of formula Id.
    [119] Compounds of formula I and compounds of formula II wherein R 3 is not hydrogen can be prepared according to the process outlined in Scheme 8.
    [120]
    [121] More specifically, compounds of formula (Ia) may be selected from suitable substituted compounds of formula (XXI) wherein X is halogen, hydroxy, tosylate, mesylate and other, preferably X is halogen, and THF, DMF, dichloromethane, toluene and the like. , Preferably in an organic solvent such as THF or DMF, to obtain a mixture of the corresponding substituted compound of formula (Ie) and the corresponding substituted compound of formula (II). When X is halogen in the compound of formula XXI, the reaction is preferably carried out in the presence of an organic or inorganic base such as traethylamine, diisopropylethylamine, potassium carbonate, sodium hydride, sodium hydroxide and the like.
    [122] Compounds of formula (Ie) and compounds of formula (II) are preferably separated by known methods such as recrystallization, column chromatography, HPLC and the like.
    [123] Y a is Y 0 (that is, Y is not present), Is a 2- (4-substituted) thiazolyl can be prepared according to the process outlined in Scheme 9.
    [124]
    [125] Thus, suitably substituted compounds of formula III are reacted with Fmoc-NCS in organic solvents such as DCM, DMF, THF and the like, preferably at room temperature, to yield the corresponding compounds of formula XXII.
    [126] The compound of formula XXII is reacted with 20% piperidine in alcohol such as methanol, ethanol and the like to produce the corresponding amine of formula XXIII.
    [127] The amine of formula XXIII is reacted at a temperature of about 70 ° C. in the presence of a base such as TEA, DIPEA, etc., in the presence of a suitably substituted α-halo methyl ketone of formula XXIV with an organic solvent such as DMF, ethanol: dioxane, and the like, To yield the corresponding compound of formula VIIa.
    [128] Specific diastereomers of compounds of formula (I) wherein R 1 is hydrogen and in which R-coordination at the chiral center of the R 2 bond to pyrrolopyridinone are preferred are prepared according to the process outlined in Scheme 10 can do.
    [129]
    [130] Thus, a suitably substituted compound of formula XXV, wherein R 1 is hydrogen, Ar is an aryl group, preferably naphthyl, more preferably 1-naphthyl, a known compound or a compound prepared by known methods. Is reacted under aprotic or protic conditions at a temperature within the range of about 25 to 270 ° C. in a suitably substituted aldehyde compound of formula XXVI with organic solvents such as p-xylene, o-xylene, toluene, DCM and the like. A diastereomer, ie a mixture of compounds of the formulas XXVII and XXVIII, is obtained.
    [131] R-diastereomers, ie compounds of formula (XXVII), are separated from compounds of formula (XXVIII) by recrystallization or silica gel chromatography.
    [132] The desired R-diastereomer is obtained by stirring a compound of formula XXVII (S-diastereomer) in the presence of an organic solvent such as CH 2 Cl 2 , DCM, 1,4-dioxane, etc. in an acid such as TFA, HCl, TsOH or the like. Conversion to isomers, ie compounds of formula XXVIII, affords the desired R-diastereomers, ie compounds of formula XXVIII.
    [133] The compound of formula XXVIII is reacted at about atmospheric pressure with an oxidant such as oxygen gas, single oxygen, KO 2 , NaIO 4 , ozone, etc., preferably oxygen gas, to give the corresponding compound of formula XXIX. When the oxidant is oxygen gas, the reaction is carried out in organic solvents such as DMF, DMSO, NMP and the like in the presence of a base such as sodium hydride, potassium-t-butoxide and the like.
    [134] The compound of formula XXIX is reacted with a reducing agent such as hydrogen gas in the presence of a catalyst such as palladium on carbon in a polar solvent such as methanol and ethanol to give the corresponding compound of formula VIIIa.
    [135] The compound of formula (VIIIa) may be further reacted to yield the corresponding compound of formula (I) according to the method described in Scheme 3 above.
    [136] For compounds of formula I in which R 1 is not hydrogen, the second chiral center may be present in the group of pyrrolopyridinone of the R 1 group. If a particular orientation of the R 1 group is present in the starting reagent, which is a compound of Formula XXV in Scheme 10 above, its orientation may affect the conversion of the diastereomers.
    [137] If the process for the preparation of the compounds according to the invention produces a mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, individual enantiomers may be prepared by enantioselective synthesis or degradation, or may be prepared from enantiomerically rich reagents. The compounds are for example used for salt formation with optically active acids, such as (-)-di-p-toluyl-d-tartic acid and / or (+)-di-p-toluyl-tartic acid. Formation of diastereomeric pairs followed by standard techniques such as fractional crystallization and regeneration of the free salts can be broken down into its component enantiomers. The compounds may also be decomposed by forming diastereomeric esters, amides or amines, followed by separation and removal of the chiral auxiliaries by chromatography. In addition, the compounds can be degraded using chiral HPLC columns.
    [138] During any method of preparing a compound of the invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any relevant molecule. This is described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmi, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991].
    [139] The use of this compound for treating sexual dysfunction can be determined according to the methods described in Examples 95, 96 and 97 herein.
    [140] Accordingly, the present invention relates to a patient in need of treatment of sexual dysfunction, more preferably erectile dysfunction, including administering one of the compounds as defined herein in an amount effective to treat erectile dysfunction (ED). In the sexual dysfunction, more preferably erectile dysfunction. The compound may be administered to the patient by any conventional route of administration, including intravenous, oral, subcutaneous, intramuscular, transdermal and parenteral administration. The amount of compound effective to treat ED is from 0.01 mg to 20 mg per kg body weight of the patient.
    [141] The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier with one or more compounds of the invention. Preferably, these compositions are intended for oral administration, nasal, sublingual or rectal administration, or administration by inhalation or aeration, tablets, pills, capsules, pills, steric, sterile parenteral solutions or suspensions, metered aerosols. Or in a single dosage form such as a liquid spray, drop, ampoule, autoinjector or suppository. In addition, the compositions may be present in a form suitable for once-weekly or once-monthly administration, and insoluble salts of the active compounds, such as, for example, decanoate salts, may be employed to provide an intramuscular depot preparation. . To prepare solid compositions, such as tablets, the main active ingredient is a pharmaceutical carrier such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or rubber. It is mixed with a tableting component and other pharmaceutical diluents such as water to form a solid preformulation composition containing a homogeneous mixture of a compound of the invention or a pharmaceutically acceptable salt thereof. When the preformulation composition is described as homogeneous, it means that the active ingredient is distributed evenly throughout the composition so that the composition can be immediately divided into equally effective dosage forms such as tablets, pills and capsules. The solid preformulation composition is then divided into unit dosage forms of the type described above containing 1 mg to about 1000 mg of the active ingredient of the invention. Tablets or pills of the novel compositions may be coated or otherwise synthesized to provide dosage forms that provide the benefit of prolonged activity. For example, a tablet or pill may include an internal dosage component and an external dosage component, the latter being in a form enclosed in the former stomach. The two components can be separated by an enteric layer that disrupts disintegration in the stomach and allows the internal components to be delivered to the duodenum intact or delayed release. Various materials can be used for such enteric layers or coatings, which include a number of polymeric acids with materials such as shellac, acetyl alcohol and cellulose acetate.
    [142] Liquid forms for oral or inhalation administration, in which the novel compositions of the present invention may be incorporated, include aqueous solutions, suitably flavored syrups, aqueous or oil suspending agents, and cottonseed oil, sesame oil, coconut oil or peanut oil. Emulsions flavored with the same edible oil, as well as elixirs and similar pharmaceutical vehicles. Dispersants or suspending agents suitable for aqueous suspensions include synthetic and natural rubbers such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin do.
    [143] In addition, the methods of treating sexual dysfunction, more particularly male erectile dysfunction described herein, can be carried out using a pharmaceutical composition comprising any one of the compounds described herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain about 1 to 1000 mg, preferably about 1 to 200 mg, of the compound and may be configured in any form suitable for the mode of administration chosen. Carriers include essential inert pharmaceutical excipients, including but not limited to binders, suspending agents, lubricants, flavoring agents, sweetening agents, preservatives, dyes and coatings. Compositions suitable for oral administration include solid forms and solvents such as pills, tablets, caplets, capsules (including intermediate and extended release and sustained release formulations), granules and powders, syrups, elixirs, emulsions and Liquid forms such as suspending agents. Forms useful for parenteral administration include sterile solvents, emulsions and suspensions.
    [144] Advantageously, the compounds of the present invention may be administered in a single daily dose, or the entire daily dose may be administered in two, three or four doses daily. In addition, the compounds of the invention may be administered in intranasal form via topical use of a suitable intranasal vehicle or may be administered via a transdermal patch. For administration in the form of a transdermal delivery system, the dosage will of course be continuous rather than intermittent throughout the dosage regimen.
    [145] For example, for oral administration in the form of tablets or capsules, the active drug component can be combined with an oral non-toxic pharmaceutically acceptable inert carrier such as ethanol and glycerol, water, and the like. In addition, suitable binders, lubricants, disintegrating agents and coloring agents may be incorporated into the mixture, if desired or necessary. Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic rubbers such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate Laterate, sodium benzoate, sodium acetate and sodium chloride. Disintegrants include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
    [146] Liquid forms may include suitably flavored suspending or dispersing agents such as synthetic and natural rubbers such as tragacanth, acacia and methyl-cellulose, and the like. For parenteral administration, sterile suspending agents and solvents are preferred. If intravenous administration is desired, isotonic agents containing suitable preservatives are generally used.
    [147] The compounds of the present invention can also be administered in the form of liposome delivery systems such as small single membrane vesicles, large single membrane vesicles, and multiple membrane vesicles. Liposomes can be formed from various phospholipids such as cholesterol, stearylamine or phosphatidylcholine.
    [148] Compounds of the invention can also be delivered using monoclonal antibodies as individual carriers to which the compound molecules are cuffed. In addition, the compounds of the present invention can be coupled to soluble polymers as targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamidephenols, polyhydroxyethyl aspartamide phenols, or polyethylene oxide polylysine substituted with palmitoyl moieties. In addition, the compounds of the present invention may be useful in the biodegradable polymers useful for achieving controlled release of drugs, such as polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro It can be coupled to a crosslinked or amphoteric block copolymer of pyran, polycyanoacrylate and hydrogel.
    [149] The compounds of the present invention may be administered in the form of the compositions described above, in accordance with dosage regimens established in the field of treatment of sexual dysfunction, more particularly male erectile dysfunction.
    [150] The daily dosage of the product can vary widely from 1 to 1,000 mg per adult per day. For oral administration, the composition is preferably provided to the patient to be treated as a tablet form containing the active ingredient 1.0, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg for symptom control of the dosage. An effective amount of drug is typically provided at a dosage level of about 0.01 to about 20 mg / kg body weight per day. Preferably, the range is about 0.1 to about 10 mg / kg body weight per day and in particular about 0.1 to 3 mg / kg body weight per day.
    [151] The optimal dosage to be administered can be readily determined by one skilled in the art and can vary depending on the particular compound used, the mode of administration, the strength of the formulation, the mode of administration and the progression of the disease state. In addition, factors associated with the particular patient being treated, including patient age, weight and diet, and time of administration, may create a need for dose control.
    [152] The following examples are presented to aid the understanding of the present invention and are not intended to limit in any way the present invention set forth in the claims that follow. Unless otherwise specified, 1 H NMR was performed on a Bruker instrument.
    [153] Example 1
    [154] 1- (3,4-methylenedioxyphenyl) -2-benzyl-2,3,4,9-tetrahydro-1H-β-carboline
    [155] 1- (3,4-methylenedioxyphenyl) -2,3,4,9-tetrahydro-1H-β-carboline in anhydrous DMF (25 mL) [WO97 / 43287, intermediate 7, page Triethylamine (3.52 mL, 25 mmol) and benzel bromide (3.00 mL, 25 mmol) are added to the solution of [0024]. The mixture is stirred overnight at ambient temperature and added dropwise to sodium hydroxide solution (25 mmol) in water (200 mL). A precipitate is formed, collected by vacuum filtration, washed with water (2 × 50 mL) and dried under vacuum overnight to afford the product as a free flowing pale yellow powder.
    [156]
    [157] Example 1A
    [158] (R) -1- (3,4-methylenedioxyphenyl) -2-benzyl-2,3,4,9-tetrahydro-1H-β-carboline
    [159] The procedure as described in Example 1 was carried out to react (R)-(3,4-methylenedioxyphenyl) -2,3,4,9-tetrahydro-1H-β-carboline to give the title compound. do.
    [160]
    [161] Example 2
    [162] 1- (2,3-dihydrobenzofuran-5-yl) -2-benzyl-2,3,4,9-tetrahydro-1H-β-carboline
    [163] The title compound was subjected to the procedure described in Example 1 using 1- (2,3-dihydrobenzofuran-5-yl) -2,3,4,9-tetrahydro-1H-β-carboline as starting material. To produce accordingly.
    [164]
    [165] Example 2A
    [166] (R) -1- (2,3, -dihydrobenzofuran-5-yl) -2-benzyl-2,3,4,9-tetrahydro-1H-β-carboline
    [167] Following the procedure as described in Example 2, (R) -1- (2,3, -dihydrobenzofuran-5-yl) -2,3,4,9-tetrahydro-1H-β-carboline Reaction to give the title compound.
    [168]
    [169] Example 3
    [170] 1,2,3,4-tetrahydro-2-benzyl-3- (3,4-methylenedioxyphenyl) -9H-pyrrolo- [3,4-b] quinolin-9-one) (# 54)
    [171] 1- (3,4-methylenedioxyphenyl) -2-benzyl-2,3,4,9-tetrahydro-1H-β-carboline (0.79 g, 2.0 mmol) (prepared as in Example 1) ) Is dissolved in anhydrous DMF (15 mL). Potassium tert-butoxide (0.56 g, 5.0 mmol) is added and bubbled through the syringe needle with oxygen. The mixture is kept at room temperature for 1 hour and poured into a mixture of 1N HCl (5 mL), water (35 mL) and ethyl acetate (35 mL). The downy yellow precipitate is collected, the organic layer is removed and the aqueous solution is extracted with ethyl acetate (15 mL). Shake the extracted worms and set overnight. The next day an additional amount of product (as a precipitate) is collected. The combined solids are dried to give the product as a yellow powder.
    [172]
    [173] Example 3A
    [174] (R) -1,2,3,4-tetrahydro-2-benzyl-3- (3,4, -methylenedioxyphenyl) -9H-pyrrolo- [3,4-b] quinolin-9-one (# 67)
    [175] Following the procedure as described in Example 3, (R) -1- (3,4-methylenedioxyphenyl) -2-benzyl-2,3,4,9-tetrahydro-1H-β-carboline Reaction yields the title compound.
    [176]
    [177] Example 4
    [178] 1,2,3,4-tetrahydro-2-benzyl-3- (2,3-dihydrobenzofuran-5-yl) -9H-pyrrolo- [3,4-b] quinolin-9-one ( # 60)
    [179] 1- (2,3-dihydrobenzofuran-5-yl) -benzyl-2,3,4,9-tetrahydro-1H-β-carboline (prepared as in Example 2) (3.10 g, 8.15 mmol) is dissolved in anhydrous DMF (20 mL). Potassium tert-butoxide (2.29 g, 20.38 mmol) is added and bubbled through the syringe needle with oxygen. The solution is stirred for 1.5 hours. The reaction mixture is added a solution of HCl in ether (10 mL, 2M) and the solution is dropped into water with rapid stirring. The resulting suspension is stirred overnight. The brown solid is filtered off and washed with water. The filtrate is neutralized with 1N NaOH and a pale yellow precipitate is formed. The solid is filtered off, washed with water, then simply dried and partially dissolved in THF / methanol. The precipitate solid is filtered off and washed with ether to give the product as a pale yellow solid.
    [180]
    [181] Example 4A
    [182] (R) -1,2,3,4-tetrahydro-2-benzyl-3- (2,3-dihydrobenzofuran-5-yl) -9H-pyrrolo- [3,4-b] quinoline- 9-on) (# 77)
    [183] According to the procedure described in Example 4, (R) -1- (2,3-dihydrobenzofuran-5-yl) -2-benzyl-2,3,4,9-tetrahydro-1H-β-car Reaction of boline gives the title compound.
    [184]
    [185] Example 5
    [186] 1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -9H-pyrrolo- [3,4-b] quinolin-9-one, hydrochloride salt (# 4)
    [187] Method A: HCl Salt
    [188] 1,2,3,4-tetrahydro-2-benzyl-3- (3,4-methylenedioxyphenyl) -9H-pyrrolo- [3, in methanol (50 mL) and 10% Pd / C (500 mg) To a suspension of 4-b] quinolin-9-one (prepared as in Example 3) (1.12 g, 2.82 mmol) was added HCl in ether solution (1.41 mL, 2N). The reaction mixture is shaken under a hydrogen atmosphere (45 psi) for 6 hours in a Parr apparatus. The resulting solution is filtered through celite and concentrated in vacuo to afford the product as a green solid.
    [189]
    [190] Method B: free base
    [191] Known compound 1- (3,4-methylenedioxyphenyl) -2,3,4,0-tetrahydro-1H-β-carboline (WO97 / 43287, Intermediate 7, page 24 Prepared according to the method as described in (15.35 g, 52.5 mmol) is dissolved in anhydrous DMF (90 mL). Potassium tert-butoxide (10.02 g, 89.3 mmol) is introduced in portions and the suspension is stirred until a clear solution is obtained. Oxygen gas is passed through the syringe needle into the solution for 50 minutes. The reaction was quenched by addition of glacial acetic acid (5.11 mL, 89.3 mmol), poured into diethyl ether (1 L), and the precipitate was collected by filtration. The product is purified by flash chromatography (0-50% EtOH / THF) to afford the product as a yellow powder.
    [192]
    [193] Example 5A
    [194] (R) -1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -9H-pyrrolo- [3,4-b] quinolin-9-one, hydrochloride salt ( # 48)
    [195] (R) -1,2,3,4-tetrahydro-2-benzyl-3- (3,4-methylenedioxyphenyl) -9H-pyrrolo according to the procedure as described in Example 5, Method A -[3,4-b] quinolin-9-one is reacted to give the title compound.
    [196]
    [197] Example 6
    [198] 1.2,3,4-tetrahydro-3- (2,3-dihydrobenzofuran-5-yl) -9H-pyrrolo- [3,4-b] quinolin-9-one, hydrochloride salt
    [199] Method A: HCl Salt
    [200] The title compound is prepared according to the method described in Example 4 by substituting the appropriate reactants.
    [201]
    [202] Method B: free base
    [203] 1- (2,3-dihydro-5-benzofuranyl) -2,3,4,9-tetrahydro-1H-β-carboline (1.06 g, 3.64 mmol), which is a known compound Prepared according to the method as described in WO97 / 43287, Intermediate 10, pafe 25), is dissolved in anhydrous DMF (8 mL). Potassium tert-butoxide (829 mg, 7.38 mmol) is dissolved in small portions and the suspension is stirred until a clear solution is obtained. The oxygen valence is passed through the syringe needle into the solution for 50 minutes. The reaction was quenched by addition of glacial acetic acid (0.42 mL, 7.34 mmol), poured into diethyl ether (50 mL), and the precipitate was collected by filtration. The product is purified by flash chromatography (0-50% MeOH / THF) to afford the product as a pale yellow powder.
    [204]
    [205] Example 6A
    [206] (R) -1,2,3,4-tetrahydro-3- (2,3-dihydrobenzofuran-5-yl) -9H-pyrrolo- [3,4-b] quinolin-9-one, Hydrochloride salt
    [207] Example 6, 1,2,3,4-tetrahydro-2-benzyl-3- (2,3-dihydrobenzofuran-5-yl) -9H-pyrrolo- [ 3,4-b] quinolin-9-one is reacted to give the title compound.
    [208]
    [209] Example 7
    [210] (4-pyridinyl) methyl-4-nitrophenylcarboxylic acid ester
    [211] To a solution of 4-pyridinylcarbinol (50 mmol) and triethylamine (50 mmol) in anhydrous dichloromethane (100 mL) was added a solution of 4-nitrophenylchloroformate (50 mmol). The reaction mixture is stirred at ambient temperature overnight and filtered to yield a yellow precipitate which is removed which is concentrated. The semisolid residue is treated with THF (50 mL) to form a white precipitate. The precipitate is collected by filtration, concentrated and purified by flash chromatography (20% THF / CHCl 3 ) to afford the product as an orange solid.
    [212]
    [213] Example 8
    [214] 6- [2- (1-morpholino) epoxy] -2-benzofurancarboxylic acid
    [215] A solution of 6-methoxy-2-benzofurancarboxylate methyl ester (868 mg, 4.52 mmol) in anhydrous benzene was converted to triphenylphosphine (1.18 g, 4.52 mmol) and 1- (2-hydroxyethyl)-under an argon atmosphere. Treated with morpholine (0.72 mL, 4.57 mmol). DEAD (0.55 mL, 4.5 mmol) is added dropwise to the reaction mixture at room temperature. The solution is stirred overnight, concentrated in vacuo, and the residue is purified by flash chromatography (0-10%, MeOH / CHCl 3 ).
    [216] The purified product is saponified in a 1: 1 mixture of methanol and aqueous 1N NaOH (80 mL) at reflux for 3 hours. The reaction mixture is neutralized with concentrated HCl and concentrated to afford a residue triturated with methanol (20 mL). The resulting salt is filtered off and concentrated to yield a second residue, similarly ground with THF. The third residue is dried under vacuum to give the product as a yellow powder.
    [217]
    [218] Example 9
    [219] 1- (3,4-methylenedioxyphenyl) -2- (tert-butoxycarbonyl) -2,3,4,9-tetrahydro-1H-β-carboline
    [220] 1- (3,4-methylenedioxyphenyl) -2,3,4,9-tetrahydro-1H-β-carboline (27.7 g, 94.8 mmol) (WO97 / 43287, Intermediate 7 tertiary butylpyrocarbonate (25.0 g, 114 mmol) is added to a suspension of the same). Immediately after addition of the pyrocarbonate, a clear solution is formed. The solution is stirred at ambient temperature for 1 hour to form a white precipitate. The solid is collected by filtration, washed with a 1: 1 mixture of diethyl ether: pentane and then dried under vacuum to afford the product as a white solid.
    [221]
    [222] Example 10
    [223] 1- (3,4-methylenedioxyphenyl) -2- (benzyloxycarbonyl) -2,3,4,9-tetrahydro-1H-β-carboline
    [224] 1- (3,4-methylenedioxyphenyl) -2,3,4,9-tetrahydro-1H-β-carboline (9.11 g, 31.1 mmol) in anhydrous dichloromethane (100 mL) (International Patent Publication) To a solution of WO97 / 43287, prepared according to the method described in Intermediate 7, page 24, triethylamine (8.80 mL, 63.1 mmol) and diethylaminopyridine (5 mg) were added and benzylchloroformate (4.60 mL, 30.6 mmol) is added dropwise over 30 minutes. The reaction mixture is stirred for 16 h, transferred to a separate funnel, washed with 2N HCl and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Flash chromatography yields the product as a white solid.
    [225]
    [226] Example 11
    [227] 1- (3,4-dimethoxyphenyl) -2,3,4,9-tetrahydro-1H-β-carboline
    [228] To a solution of tryptamine (5.0 g, 0.0312 mol) and 3,4-dimethoxybenzaldehyde (5.7 g, 0.0312 mol) in CH 2 Cl 2 (220 mL) is added TFA (4.5 mL, 0.0584 mol). The dark blue solution is stirred at room temperature for 20 hours. The reaction mixture is neutralized with NaHCO 3 (4.9 g, 0.0584 mol) in H 2 O (50 mL) and the organic layer is washed with brine (2 × 100 mL). The reaction mixture is dried over MgSO 4 and the solvent is evaporated. The product is separated by column chromatography as a yellow oil (silica gel; CH 3 OH: EtOAc = 1: 9) and it is slowly solidified while standing at room temperature.
    [229]
    [230] Example 12
    [231] 1- (3,4-methylenedioxyphenyl) -2- [5- (4-methoxyphenyl) pyrimidin-2-yl] -2,3,4,9-tetrahydro-1H-β-carboline
    [232] 1- (3,4-methylenedioxyphenyl) -2,3,4,9-tetrahydro-1H-β-carboline (2.72 g, 9.6 mmol) (WO 97/43287, Intermediate 7, 24 Prepared according to the method described in the above) and 2-chloro-5- (4-methoxyphenyl) pyrimidine (1.04 g, 4.78 mmol) are stirred in DMF (20 mL, anhydrous) at 120 ° C. for 16 hours. . The resulting mixture is quenched with saturated NH 4 Cl and extracted with ethyl acetate and then dried using MgSO 4 . The reaction mixture solvent is evaporated and the residue is purified by column chromatography (silica gel, ethyl acetate: hexane = 1: 2) to give the product as a white solid.
    [233] Melting point: 200-202 ° C .; MS (m / z): 477 (MH + )
    [234]
    [235] Example 13
    [236] 1- (3,4-methylenedioxyphenyl) -2- [5- (3,4-dimethoxyphenyl) pyrimidin-2-yl] -2,3,4,9-tetrahydro-1H-β- Kaboline
    [237] In the same manner as summarized in Example 12, 1- (3,4-methylenedioxyphenyl) -2,3,4,9-tetrahydro-1H-β-carboline (3.73 g, 12.8 mmol) Prepared according to the method described in WO 97/43287, Intermediate 7, page 24) and 2-chloro-5- (3,4-dimethoxyphenyl) pyrimidine (1.60 g, 6.4 mmol) in DMF (50 mL). , Anhydrous) to give the product as a white solid.
    [238] Melting point: 173 to 175 ° C; MS (m / z): 507 (MH + )
    [239]
    [240] Example 14
    [241] 1- (3,4-methylenedioxyphenyl) -2- [5- (4-methylphenyl) -pyrimidin-2-yl] -2,3,4,9-tetrahydro-1H-β-carboline
    [242] In the same manner as summarized in Example 12, 1- (3,4-methylenedioxyphenyl) -2,3,4,9-tetrahydro-1H-β-carboline (2.19 g, 7.5 mmol) Prepared according to the method described in WO 97/43287, Intermediate 7, page 24) and 2-chloro-5- (4-methylphenyl) pyrimidine (1.03 g, 5 mmol) toluene (50 mL, anhydrous) and DBU (0.9 mL)) to afford the product as a white solid.
    [243]
    [244] Example 15
    [245] 1- (3,4-methylenedioxyphenyl) -2- (pyridin-4-yl) methyl-2,3,4,9-tetrahydro-1H-β-carboline
    [246] 1- (3,4-methylenedioxyphenyl) -2,3,4,9-tetrahydro-1H-β-carboline (2.92 g, 10 mmol) in DMF (50 mL) (WO 97/43287, A solution of intermediate 7, prepared according to the method described on page 24), 4-picolylchloride hydrochloride (1.64 g, 10 mmol) and DBU (3.1 g, 20 mmol) is stirred at room temperature for 16 hours. Water (100 mL) and ethyl acetate (100 mL) are added to the reaction mixture. The solute present in the organic phase is purified by column chromatography (silica gel, ethyl acetate) to yield the product as off-white solid.
    [247]
    [248] Example 16
    [249] 1- (3,4-methylenedioxyphenyl) -2- (pyrimidin-2-yl) -2,3,4,9-tetrahydro-1H-β-carboline
    [250] 1- (3,4-methylenedioxyphenyl) -2,3,4,9-tetrahydro-1H-β-carboline (2.3 g, 8.0 mmol) (WO 97/43287, Intermediate 7, 24 Prepared according to the method described in the above) and 2-chloropyrimidine (0.914 g, 8.0 mmol) are stirred in anhydrous DMF (15 mL) at 140 ° C. for 24 hours. The reaction mixture is diluted with ethyl acetate (100 mL) and then washed with saturated NH 4 Cl solution (100 mL). The aqueous layer is extracted with ethyl acetate (2 x 50 mL). The combined organic layers are washed with brine (2 x 80 mL) and dried using MgSO 4 . The solvent is evaporated and the column chromatography (silica gel, EtOAc: hexane = 1: 9) separates the product as a yellow solid.
    [251] Melting point: 176-177 ° C
    [252]
    [253] Example 17
    [254] 1- (3,4-methylenedioxyphenyl) -2- [5- (4-chlorophenyl) -pyrimidin-2-yl] -2,3,4,9-tetrahydro-1H-β-carboline
    [255] 1- (3,4-methylenedioxyphenyl) -2,3,4,9-tetrahydro-1H-β-carboline (295 mg, 1 mmol) in DMF (50 mL, anhydrous) (WO 97/43287) , Intermediate 7, prepared according to the method described on page 24) and 2-chloro-5- (4-chlorophenyl) pyrimidine (113 mg, 0.5 mmol) to give the product as a white solid.
    [256]
    [257] Example 18
    [258] [5- (3,4-Dimethoxyphenyl) -pyrimidin-2-yl] -1- (3,4-dimethoxyphenyl) -2,3,4,9-tetrahydro-1H-β-carboline
    [259] In the same manner as summarized in Example 16, 1- (3,4-methylenedioxyphenyl) -2,3,4,9-tetrahydro-1H-β-carboline (WO 97/43287, intermediate 7, prepared according to the method described on page 24) and 2-chloro-5- (3,5-dimethoxyphenyl) pyrimidine to give the product as a white solid.
    [260] Melting Point 184-186 ° C
    [261]
    [262] Example 19
    [263] 1,2,3,4-tetrahydro-3- (3,4-dimethoxyphenyl) -9H-pyrrolo- [3,4-b] quinolin-9-one (# 12)
    [264] 1- (3,4-methylenedioxyphenyl) -2,3,4,9-tetrahydro-1H-β-carboline (1.854 g, 6.04 mmol) (prepared as in Example 11) and KOt- Bu (1.14 g, 10.15 mmol) is stirred in DMF (60 mL) for 10 minutes at room temperature. Oxygen is bubbled through the solution for 1 hour. The reaction mixture is neutralized with 1N HCl solution (10.15 mL, 10.15 mmol) and water is removed in vacuo as an azeotropic mixture with toluene. Silica gel (about 5 g) was added to the residual DMF solution, followed by addition of diethyl ether (600 mL) to precipitate the product on the silica gel. The diethyl ether is decanted and the silica gel is washed with diethyl ether (2 x 100 mL). After decanting the solvent, any remaining traces are evaporated and the residue is purified by column chromatography (silica gel; EtOH: EtOAc = 1: 9) to afford the product as a pale yellow solid. The product is recrystallized from methanol.
    [265] Melting point 223-225 ° C
    [266]
    [267] Example 20
    [268] 1,2,3,4-tetrahydro-2- [5- (4-methoxyphenyl) -pyrimidin-2-yl] -3- (3,4-methylenedioxyphenyl) -9H-pyrrolo- [3,4-b] quinolin-9-one (# 2)
    [269] Sodium hydride (60% in mineral oil, 36 mg, 0.9 mmol) and 1- (3,4-methylenedioxyphenyl) -2- [5- (4-methoxyphenyl) -pyrimidine in DMF (10 mL, anhydrous) 2-yl] -2,3,4,9-tetrahydro-1H-β-carboline (186 mg, 0.39 mmol) (prepared as in Example 12) is stirred at room temperature for 30 minutes. Dry air is then bubbled through the solution for 16 hours. Ethyl acetate (100 mL) and saturated NaHCO 3 are added and the organic phase is washed with water, brine and then dried using MgSO 4 . The solvent is evaporated and the residue is triturated with ethyl acetate to give the product as a white solid.
    [270] Melting Point: 325-327 ° C
    [271]
    [272] Example 21
    [273] 1,2,3,4-tetrahydro-2- [5- (3,4-dimethoxyphenyl) -pyrimidin-2-yl] -3- (3,4-methylenedioxyphenyl) -9H-P Rolo- [3,4-b] quinolin-9-one (# 1)
    [274] Sodium hydride (60% in mineral oil, 40 mg, 1.0 mmol) and 1- (3,4-methylenedioxyphenyl) -2- [5- (3,4-dimethoxyphenyl)-in DMF (10 mL, anhydrous) Pyrimidin-2-yl] -2,3,4,9-tetrahydro-1H-β-carboline (218 mg, 0.43 mmol) (prepared as in Example 13) is stirred at room temperature for 30 minutes. Dry air is then bubbled through the solution for 16 hours. Ethyl acetate (100 mL) and saturated NaHCO 3 are added and the organic phase is washed with water, brine and then dried using MgSO 4 . The solvent is evaporated and the residue is purified by chromatography (silica gel, ethyl acetate) to give the product as a white solid.
    [275]
    [276] Example 21A
    [277] (S) -1,2,3,4-tetrahydro-2- [5- (3,4-dimethoxyphenyl) -pyrimidin-2-yl] -3- (3,4-methylenedioxyphenyl) -9H-pyrrolo- [3,4-b] quinolin-9-one (# 35)
    [278] (S) -1- (3,4-methylenedioxyphenyl) -2- [5- (3,4-dimethoxyphenyl) -pyrimidin-2-yl] -2, according to the method described in Example 21; 3,4,9-tetrahydro-1H-β-carboline is reacted to afford the title compound.
    [279] Example 21B
    [280] (R) -1,2,3,4-tetrahydro-2- [5- (3,4-dimethoxyphenyl) -pyrimidin-2-yl] -3- (3,4-methylenedioxyphenyl) -9H-pyrrolo- [3,4-b] quinolin-9-one (# 36)
    [281] (R) -1- (3,4-methylenedioxyphenyl) -2- [5- (3,4-dimethoxyphenyl) -pyrimidin-2-yl] -2, according to the method described in Example 21; 3,4,9-tetrahydro-1H-β-carboline is reacted to afford the title compound.
    [282] Example 22
    [283] 1,2,3,4-tetrahydro-2- [5- (4-methylphenyl) -pyrimidin-2-yl] -3- (3,4-methylenedioxyphenyl) -9H-pyrrolo- [3 , 4-b] quinolin-9-one (# 7)
    [284] Sodium hydride (60% in mineral oil, 43 mg, 1.09 mmol) and 1- (3,4-methylenedioxyphenyl) -2- [5- (in DMF (15 mL, anhydrous) according to the method summarized in Example 21 4-methylphenyl) -pyrimidin-2-yl] -2,3,4,9-tetrahydro-1H-β-carboline (278 mg, 0.60 mmol) (prepared as in Example 21) to react with white The product is obtained as a solid.
    [285]
    [286] Example 23
    [287] 1,2,3,4-tetrahydro- [5- (3,4-dimethoxyphenyl) -pyrimidin-2-yl] -3- (3,4-dimethoxyphenyl) -9H-pyrrolo [3 , 4-b] quinolin-9-one (# 15)
    [288] [5- (3,4-Dimethoxyphenyl) -pyrimidin-2-yl] -1- (3,4-methoxyphenyl) -2,3,4,9- according to the method outlined in Example 19 Tetrahydro-1H-β-carboline (prepared as in Example 18) is reacted to give the product as a white solid.
    [289]
    [290] Example 24
    [291] 1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -2- (pyridin-4-yl) methyl-9H-pyrrolo- [3,4-b] quinoline-9 -On (# 5)
    [292] Sodium hydride (60% in mineral oil, 40 mg, 1.0 mmol) and 1- (3,4-methylenedioxyphenyl) -2- (pyridine-4) in DMF (10 mL, anhydrous) according to the method summarized in Example 21 -Yl) methyl-2,3,4,9-tetrahydro-1H-β-carboline (192 mg, 0.50 mmol) (prepared as in Example 15) to give the product as a white solid.
    [293]
    [294] Example 25
    [295] 1,2,3,4-tetrahydro-2- (tert-butoxycarbonyl) -3- (3,4-methylenedioxyphenyl) -9H-pyrrolo- [3,4-b] quinoline- 9-on (# 3)
    [296] 2-3-butoxycarbonyl-1- (3,4-methylenedioxyphenyl) -2,3,4,9-tetrahydro-1H-β-carboline (4.09 g, 10.4 mmol) (Example (As prepared in 9) is dissolved in anhydrous DMF (100 mL). Potassium tert-butoxide (2.55 g, 22.7 mmol) is introduced into one fraction and the suspension is stirred to give a clear solution. The oxygen gas is then passed through the solution with a syringe for 16 hours. Glacial acetic acid (25 mmol) is added to quench the reaction and poured into a mixture of diethyl ether and water to form a precipitate which is collected by filtration. The product is purified by flash chromatography (0-10% MeOH / CHCl 3 ) to afford the product as a white solid.
    [297]
    [298] Example 26
    [299] 1,2,3,4-tetrahydro-2- (benzyloxycarbonyl) -3- (3,4-methylenedioxyphenyl) -9H-pyrrolo- [3,4-b] quinolin-9-one (# 27)
    [300] 2-benzyloxycarbonyl-1- (3,4-methylenedioxyphenyl) -2,3,4,9-tetrahydro-1H-β-carboline (3.63 g, 8.51 mmol) (as in Example 10 and Prepared together) is dissolved in anhydrous DMF (25 mL). Potassium tert-butoxide (2.40 g, 221.4 mol) is introduced into one fraction and the suspension is stirred to give a clear solution. The oxygen gas is then passed through the solution with a syringe for 16 hours. Glacial acetic acid (1.23 mL, 21.0 mmol) is added to quench the reaction and poured into water (250 mL) to form a precipitate which is collected by filtration. The product is purified by flash chromatography (2-10% MeOH / CHCl 3 ) to afford the product as a red powder.
    [301]
    [302] Example 27
    [303] (E) -4- [3-oxo-3- [1,2,3,4-tetrahydro-3- (2,3-dihydrobenzofuran-5-yl) -9H-pyrrolo- [3, 4-b] quinolin-9-one-2-yl] -1-propenyl] benzoic acid methyl ester (# 20)
    [304] A. (E) -4-carbomethoxycinnamic acid (5.09 g, 24.7 mmol) solution is dissolved in anhydrous THF (25 mL) and treated with oxalyl chloride (3.00 mL, 34.4 mmol) and anhydrous DMF slime under an argon atmosphere. . After heating at 50 ° C. for 2 hours, the reaction mixture is concentrated in vacuo to give the acid chloride of (E) -carboxymethyl cinnamic acid as a brown solid.
    [305] B. The product in Part A (78 mg, 0.35 mmol) was converted to 1,2,3,4-tetrahydro-3- (2,3-dihydrobenzofuran-5-yl) -9H-pyrrolo- [3, 4-b] quinolin-9-one (93.5 mg, 0.31 mmol) (prepared in Example 6), THF (3 mL), triethylamine (0.20 mL, 1.43 mmol) and DMAP (5 mg) . The mixture is stirred at rt for 16 h, diluted with 1N HCl (10 mL) and the white precipitate obtained is recovered by filtration. The solid is washed with water (three times) and ether (three times) and dried under vacuum to afford the product as a pale pink solid.
    [306] MS (m / z): 493 (MH + )
    [307]
    [308] Example 28
    [309] 1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -2- [5- (3-trifluoromethylphenyl) furoyl] -9H-pyrrolo- [3,4 -b] quinolin-9-one (# 13)
    [310] Oxalyl chloride (43.85 mg, 0.345 mmol) was added to a solution of 5- (3-trifluoromethylphenyl) -2-fumaric acid (80.44 mg, 0.314 mmol) in DCM: THF (1: 1) (5 mL, amorphous). Add 2 drops of DMF. The mixture is stirred at rt for 1 h. 1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -9H-pyrrolo [3,4-b] quinoline-9 in DCM: THF (1: 1) (5 mL) A suspension of -one (96.2 mg, 0.314 mmol) (prepared in Example 5), triethylamine (0.13 mL) and DMAP (trace) is added. The resulting mixture is stirred at rt for 16 h. Ethyl acetate (50 mL) is added and the solution is washed with aqueous NaHCO 3 , brine, 1N HCl, brine and then dried over MgSO 4 . The solvent is evaporated and the residue is titrated with ethyl acetate to give the product as a white solid.
    [311] Melting Point: 219-221 ° C
    [312] MS (m / z): 545 (MH + ), 567 (M + 23), 543 (MH)
    [313]
    [314] Example 29
    [315] 1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -2- (6-hydroxy-2-benzo-furoyl) -9H-pyrrolo- [3,4- b] quinolin-9-one (# 9)
    [316] Oxalyl chloride (0.046 g, 0.36 mmol) was added to a solution of 6-hydroxy-2-benzofuranoic acid (0.054 g, 0.3 mmol) in tetrahydrofuran (5 mL) at 0 ° C., followed by DMF (2 drops). Add. The mixture is warmed to 25 ° C. and stirred for 30 minutes and then concentrated in vacuo. The residue was dissolved in tetrahydrofuran (5 mL) and 1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -9H-pyrrolo [3,4- in THF (5 mL). b] Add a solution of quinoline-9-one (0.092 g, 0.3 mmol) (prepared as in Example 5), triethylamine (0.045 g, 0.45 mmol) and 4-dimethylaminopyridine (0.01 g) . The solution is stirred at 25 ° C. for 20 hours and then concentrated in vacuo. The obtained residue is purified by silica gel column chromatography eluting with 3% methanol in dichloromethane to give a clear oil as product.
    [317]
    [318] Example 30
    [319] (E) -4- [3-oxo-3- [1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -9H-pyrrolo- [3,4-b] Quinolin-9-one-2-yl] -1-propenyl] benzoic acid methyl ester (# 6)
    [320] 1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -9H-pyrrolo- [3,4-b] quinoline-9-, according to the process outlined in Example 20 Warm (398 mg, 1.30 mmol) (prepared as in Example 5) was dissolved in (E) -carboxymethyl cinnamic acid in the presence of triethylamine (0.54 mL, 3.87 mmol) in a 1: 1 mixture of dichloromethane: THF. 301 mg, 1.34 mmol) of acid chloride to give the product as a brown solid.
    [321] MS (m / z): 493 (M-1)
    [322]
    [323] Example 31
    [324] 1,2,3,4-tetrahydro-2- (imidazol-1-yl) thiocarbonyl-3- (3,4-methylenedioxyphenyl) -9H-pyrrolo- [3,4-b] Quinolin-9-one (# 18)
    [325] 1,2,3,4-tetrahydro-3- (3,4-methylenedi) in a suspension of 1,1'-thiocarbonyldiimidazole (0.192 g, 1.08 mmol) in DMF (5 mL, amorphous) at 0 ° C. Oxyphenyl) -9H-pyrrolo- [3,4-b] quinolin-9-one (0.30 g, 0.98 mmol) (prepared as in Example 5) is added. The mixture is warmed to room temperature and stirred for 20 hours. The solution is diluted with water and extracted with ethyl acetate. The organic layers are combined and washed with aqueous NaHCO 3 and brine, dried over MgSO 4 and concentrated in vacuo to afford the product as a light brown solid.
    [326] Melting Point: 211-215 ° C (Decomposition)
    [327] MS (m / z): 415 (M-1)
    [328]
    [329] Example 32
    [330] (E) -4- [3-oxo-3- [1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -9H-pyrrolo- [3,4-b] Quinolin-9-one-2-yl] -1-propenyl] benzoic acid (# 8)
    [331] (E) -4- [3-oxo-3- [1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -9H-pyrrolo- [3,4-b] Quinolin-9-one-2-yl] -1-propenyl] benzoic acid methyl ester (149 mg, 0.30 mmol) (prepared as in Example 30) was prepared with a 1: 1 mixture of 1N aqueous sodium hydroxide: methanol ( 10 mL), heated to reflux for 8 hours. The reaction mixture is treated with aqueous HCl to pH 1, yielding a white precipitate. The precipitate is recovered by filtration and washed with water (30 mL) and diethyl ether (160 mL) to afford the product as a white solid.
    [332] MS (m / z): 481 (MH + )
    [333]
    [334] Example 33
    [335] 1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -2- [5- (4-nitrophenyl) -furoyl] -9H-pyrrolo- [3,4- b] quinolin-9-one (# 16)
    [336] 1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -9H-pyrrolo- [3,4-b] quinolin-9-one (70.3 mg, 0.229 mmol) Prepared as in Example 5), 5- (4-nitrophenyl) -2-furoic acid (58.9 g, 0.25 mmol) and PyBrOP (0.118 g, 0.25 mmol) were added to DMF (3 mL) and DIPEA (0.088 mL, 0.50). mmol) for 16 h. The reaction mixture is poured into ethyl acetate (80 mL) and the organic layer obtained is washed with 1N aqueous HCl (3 x 50 mL), saturated aqueous Na 2 CO 3 solution (1 x 50 mL) and brine (1 x 50 mL). The organic layer is dried over MgSO 4 and the solvent is evaporated in vacuo. The residue is column chromatographed (silica gel, 5% CH 3 OH / CH 3 Cl) to give the product as a yellow powder.
    [337] MS (m / z): 522 (MH + ), 520 (M-1)
    [338]
    [339] Example 34
    [340] 1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) 2- [5- (4-aminophenyl) -furoyl] -9H-pyrrolo [3,4-b] Quinolin-9-one (# 26)
    [341] 1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -2-[(5- (4-nitrophenyl))-furoyl] -9H-pyrrolo [3,4 -b] quinolin-9-one (25 mg, 0.0479 mmol) (prepared as in Example 33) was stirred with 10% Pd on carbon (5.1 mg, 0.00479 mmol) for 14 hours under 1 atmosphere H 2 at room temperature do. The solvent is evaporated and the residue is isolated as a yellow powder by preparative TLC.
    [342] MS (m / z): 492 (MH + ); 490 (M-1)
    [343]
    [344] Example 35
    [345] 1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -2- [2-hydroxynicotinoyl) -9H-pyrrolo [3,4-b] quinoline-9 -On (# 25)
    [346] According to the process outlined in Example 33, the product is obtained as a pale yellow solid using a suitable substitute for the reagent.
    [347] MS (m / z): 428 (MH + ); 426 (M-1)
    [348]
    [349] Example 36
    [350] 1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -2- [5- (4-methoxyphenyl) -furoyl] -9H-pyrrolo [3,4- b] -quinolin-9-one (# 21)
    [351] According to the process outlined in Example 33, the product is obtained as a pale yellow solid using a suitable substitute for the reagent.
    [352] MS (m / z): 507 (MH + ); 505 (M-1)
    [353]
    [354] Example 37
    [355] 1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -2- [5- (4-hydroxyphenyl) -furoyl] -9H-pyrrolo [3,4- b] quinolin-9-one (# 22)
    [356] According to the process outlined in Example 33, the product is obtained as a pale yellow solid using a suitable substitute for the reagent.
    [357] MS (m / z): 493 (MH + ); 491 (M-1)
    [358]
    [359] Example 38
    [360] 1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -2- [5- (4-hydroxycarbonylphenyl) -furoyl] -9H-pyrrolo [3, 4-b] quinolin-9-one (# 24)
    [361] According to the process outlined in Example 33, the product is obtained as a pale yellow solid using a suitable substitute for the reagent.
    [362]
    [363] Example 39
    [364] 1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -2- [5- (4-formylphenyl) -furoyl] -9H-pyrrolo [3,4-b ] -Quinolin-9-one (# 23)
    [365] According to the process outlined in Example 33, the product is obtained as a pale yellow solid using a suitable substitute for the reagent.
    [366] MS (m / z): 503 (M-1)
    [367]
    [368] Example 40
    [369] (E) -4- [3-oxo-3- [1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -4-methyl-9H-pyrrolo [3,4 -b] quinolin-9-one-2-yl] -1-propenyl] benzoic acid, methyl ester (# 63) and
    [370] (E) -4- [3-oxo-3- [1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -9-methoxy-9H-pyrrolo [3, 4-b] quinolin-2-yl] -1-propenyl] benzoic acid, methyl ester (# 64)
    [371] (E) -4- [3-oxo-3- [1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -9H-pyrrolo- [in anhydrous acetone (10 mL) 3,4-b] quinolin-9-one-2-yl] -1-propenyl] benzoic acid methyl ester (349 mg, 0.62 mmol) (prepared as in Example 30) and iodomethane (0.060 mL, 0.96 mmol) solution is treated with anhydrous potassium carbonate (241 mg, 1.74 mmol) and heated to reflux for 3 h under an argon atmosphere. The reaction mixture is concentrated in vacuo and the residue is purified by flash chromatography (0-10% methanol in dichloromethane) to afford a mixture of N-methylated moles and O-methylated products.
    [372] The mixture of molar N-methylated product and O-methylated product was separated by column chromatography (0-10% MeOH / DCM) to give N-methylated product (E) -4- [3-oxo-3- [1,2 , 3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -4-methyl-9H-pyrrolo- [3,4-b] quinolin-9-one-2-yl] -1- Propenyl] benzoic acid, methyl ester is obtained as a brown solid.
    [373] MS (m / z): 509 (M-1)
    [374]
    [375] O-methylated product (E) -4- [3-oxo-3- [1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -9-methoxy-9H-pi Rolo- [3,4-b] quinolin-2-yl] -1-propenyl] benzoic acid, methyl ester is obtained as a pink solid.
    [376] MS (m / z): 509 (M-1)
    [377]
    [378] Example 41
    [379] 1,2,3,4-tetrahydro-2- (pyrimidin-2-yl) -3- (3,4-methylenedioxyphenyl) -9H-pyrrolo- [3,4-b] quinoline-9 -On (# 11)
    [380] 1- (3,4-methylenedioxyphenyl) -2- (pyrimidin-2-yl) -2,3,4,9-tetrahydro-1H-β-carboline (0.153 in anhydrous DMF (4.1 mL) g, 0.415 mmol) (as prepared in Example 16) was added KOtBu (0.079 g, 0.70 mmol, 1.7 equiv). After 5 minutes, the oxygen gas is bubbled through the solution for 1 hour. Diethyl ether (45 mL) is added to the reaction mixture and the supernatant is decanted. Brine (2 mL) is added to the residue and the pH is adjusted to pH 7 by adding a few drops of 1N HCl. Water is removed in vacuo as a boil with toluene. The dark red residue obtained is dissolved in a minimum amount of THF and purified by column chromatography (silica gel; EtOH: CH 2 Cl 2 = 1: 9) to afford the product as a white solid.
    [381] MS (m / z): 383 (M-1); 385 (MH + )
    [382]
    [383] Example 42
    [384] 1,2,3,4-tetrahydro-2- (pyrimidin-2-yl) -3- (3,4-methylenedioxyphenyl) -9H-pyrrolo- [3,4-b] quinoline-9 -On (# 11)
    [385] 1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -9H-pyrrolo- [3,4-b] quinolin-9-one (100 mg, 0.3265 mmol) (Example Prepared as in 5) and 2-chloropyrimidine (38 mg, 0.3265 mmol) are stirred in DMF (2.5 mL) at 100 ° C. for 16 h. The solvent is removed in vacuo and the residue is purified by column chromatography (silica gel, 5% CH 3 OH / CH 3 Cl) to give a yellow oil. The oil is triturated with MeOH to give the product as a pale yellow solid.
    [386] MS (m / z): 383 (M-1); 385 (MH + )
    [387]
    [388] Example 43
    [389] 1,2,3,4-tetrahydro-2-[(4-pyridinyl) methyloxycarbonyl] -3- (3,4-methylenedioxyphenyl) -9H-pyrrolo- [3,4-b ] Quinolin-9-one, hydrochloride salt (# 37)
    [390] 1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -9H-pyrrolo- [3,4-b] quinolin-9-one, hydrochloride salt (101 mg, 0.33 mmol ) (Prepared as in Example 5), (4-pyridinyl) methyl-4-nitrophenylcarboxylic acid ester (106 mg, 0.38 mmol) (prepared as in Example 7) and triethylamine (2 equiv. ) Is heated to reflux for 1 hour. The reaction mixture is concentrated in vacuo and purified by flash chromatography (0-10% MeOH / CHCl 3 ). The corresponding salt is formed by precipitating a methanolic free base solution using HCl-ether solution.
    [391]
    [392] Example 44
    [393] 1,2,3,4-tetrahydro-2-[(4-pyridinyl) methyloxycarbonyl] -3- (2,3-dihydrobenzofuran-5-yl) -9H-pyrrolo- [3 , 4-b] quinolin-9-one (# 53)
    [394] Using the procedure outlined in Example 36, 1,2,3,4-tetrahydro-3- (2,3-dihydrobenzofuran-5-yl) -9H-pyrrolo- [3,4- b] quinolin-9-one, a hydrochloride salt (prepared as in Example 6) and (4-pyridinyl) methyl-4-nitrophenylcarboxylic acid ester (prepared in Example 7) to react The product is obtained as a pale pink solid.
    [395]
    [396] Example 45
    [397] 1,2,3,4-tetrahydro-2-[[5- [2- (4-morpholinyl) ethoxy] -2-benzofuryl] carbonyl] -3- (3,4-methylenedioxy Phenyl) -9H-pyrrolo- [3,4-b] quinolin-9-one, hydrochloride salt (# 49)
    [398] 1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -9H-pyrrolo- [3,4-b] quinolin-9-one, hydrochloride salt (222 mg, 0.65 mmol ) (Prepared as in Example 5) and 6- [2- (1-morpholino) ethoxy] -2-benzofurancarboxylic acid (209 mg, 0.72 mmol) (prepared as in Example 8) Suspension in anhydrous THF (10 mL). PyBrOP (358 mg, 0.77 mmol) and triethylamine (0.40 mL, 2.87 mmol) are added to the mixture. The mixture is stirred overnight under argon atmosphere and concentrated in vacuo. The residue is purified by flash chromatography (0-10% MeOH / CHCl 3 ) to give the free base. The corresponding salt is formed by precipitating a methanolic free base solution using HCl-ether solution.
    [399]
    [400] Example 46
    [401] 1- (2,3-dihydrobenzofuranyl) -2- [5- (4-methoxyphenyl) -pyrimidin-2-yl] -2,3,4,9-tetrahydro-1H-β- Kaboline
    [402] 1- (2,3-dihydrobenzo-5-furanyl) -2,3,4,9-tetrahydro-1H-β-carboline (as described in WO 97/43287). Prepared in the same manner, intermediate 10, p. 25) (3.35 g, 11.54 mmol), 5- (4-methoxyphenyl) -2-chloropyrimidine (2.55 g, 11.54 mmol) and N, N-diisopropylethylamine (3.5 mL) is stirred at 120 ° C. for 16 h in DMF (10 mL, anhydrous). The resulting mixture is quenched with 10% NaCl and extracted with ethyl acetate. The organic layer is washed with 10% NaCl and brine and then dried over MgSO 4 . The reaction mixture solution is evaporated and the resulting residue is triturated with CH 2 Cl 2 and then filtered. The filtrate is purified by column chromatography (silica gel, ethyl acetate: hexane = 4: 6) to give the product as a white solid.
    [403] Melting point: 242-243 ° C.
    [404]
    [405] Example 47
    [406] 1,2,3,4-tetrahydro-2- [5- (4-methoxyphenyl) -pyrimidin-2-yl] -3- (3,4-dihydrobenzofuranyl) -9H-pyrrolo -[3,4-b] quinolin-9-one (# 39)
    [407] Sodium hydroxide (60% in mineral oil, 87 mg, 2.18 mmol) and 1- (2,3-dihydro-5-benzofuranyl) -2,3,4,9-tetrahydro-2 in DMF (30 mL, anhydrous) -[5- (4-methoxyphenyl) -2-pyrimidinyl] -1H-β-carboline (450 mg, 0.95 mmol) (prepared as in Example 46) is stirred at room temperature for 30 minutes. Thereafter, dry air is bubbled through the solution for 16 hours. Thereafter, ethyl acetate (200 mL) is added to the solution. The resulting mixture is washed with 10% NaCl solution and brine and then dried over MgSO 4 . The solvent is evaporated and the residue is triturated with ethyl acetate to yield the product as a white solid.
    [408]
    [409] Example 47A
    [410] (R) -1,2,3,4-tetrahydro-2- [5- (4-methoxyphenyl) -pyrimidin-2-yl] -3- (3,4-dihydrobenzofuranyl)- 9H-pyrrolo- [3,4-b] quinolin-9-one (# 66)
    [411] (R) -1,2,3,4-tetrahydro-3- (2,3-dihydrobenzofuran-5-yl) -9H-pyrrolo- [3,4-b] quinolin-9-one ( 0.23 g, 0.678 mmol) (prepared as in Example 6A) and 5- (4-methoxyphenyl) -2-chloropyrimidine (0.167 g, 0.758 mmol) at 60 ° C. for 36 hours in DMF (5 mL). Stirred with diisopropyl ether amine (0.33 mL) and KF (44.8 mg, 0.758 mmol). The reaction mixture is diluted with CH 2 Cl 2 (75 mL) and EtOAc (75 mL). It is washed with 1N aqueous HCl (3 × 100 mL). After this, it is washed with brine (2 x 100 mL). After drying with MgSO 4 , it is concentrated to a yellow oil. The crude product is purified by silica gel column to give the product as a white solid.
    [412]
    [413] Example 48
    [414] (R) -1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -2- [5- (3-trifluoromethylphenyl) furo-2-yl] -9H- Pyrrolo- [3,4-b] quinolin-9-one (# 50)
    [415] 1: 1 1: 1 DCM: Oxalyl chloride (275 mg, 2.17 mmol) was added to a 5- (3-trifluoromethylphenyl) -2-furoic acid solution (504.4 mg, 1.97 mmol) in THF (10 mL, anhydrous). Add 2 drops of DMF. The reaction mixture is stirred at room temperature for 2 hours. To the reaction mixture was triethylamine (1.1 mL), DMAP (trace volume) and isomerically pure 1,2,3,4-tetrahydro-3- (3,4- in 1: 1 DCM: THF (10 mL). Methylenedioxyphenyl) -9H-pyrrolo- [3,4-b] quinolin-9-one suspension (603 mg, 1.97 mmol) (prepared as in Example 5A) is added. The resulting mixture is stirred at rt for 16 h. Ethyl acetate (100 mL) is added and the solution is washed with aqueous NaHCO 3 , brine 1N HCl and brine and then dried over MgSO 4 . The reaction mixture solution is evaporated and the residue is triturated with ethyl acetate to afford the product as a white solid.
    [416]
    [417] Example 49
    [418] 1- (2,3-dihydrobenzofuranyl) -2- [5- (2-pyridinyl) -pyrimidin-2-yl] -2,3,4,9-tetrahydro-1H-β-car Bolin
    [419] Prepared as described in 1- (2,3-dihydrobenzofuranyl) -2,3,4,9-tetrahydro-1H-β-carboline (WO 97/43287) , Intermediate 10, p. 25) (1.35 g, 4.66 mmol), 2-chloro-5- (2-pyridine) -pyrimidine (893 mg, 4.66 mmol) and N, N-diisopropylethylamine (1.4 mL) Stir in DMF (10 mL, anhydrous) at 120 ° C. for 16 h. The resulting mixture is quenched with 10% NaCl and extracted with ethyl acetate. The extracted organic layer is washed with 10% NaCl and brine and then dried over MgSO 4 . The reaction mixture solution is evaporated and the residue is purified by column chromatography (silica gel, ethyl acetate: hexane = 4: 6) to afford the product as a white solid.
    [420]
    [421] Example 50
    [422] 1,2,3,4-tetrahydro-2- [5- (2-pyrimidine) -pyrimidin-2-yl] -3- (3,4-dihydrobenzofuranyl) -9H-pyrrolo- [3,4-b] quinolin-9-one (# 61)
    [423] Sodium hydroxide (60% in mineral oil, 182 mg, 4.55 mmol) and 1- (2,3-dihydro-5-benzofuranyl) -2,3,4,9-tetrahydro-2 in DMF (30 mL, anhydrous) -[5- (2-pyridinyl) -2-pyrimidinyl] -1H-β-carboline (16176-23) (882 mg, 1.98 mmol) (prepared as in Example 49) at room temperature for 30 minutes Stir while. Thereafter, dry air is bubbled through the reaction mixture for 16 hours. Ethyl acetate (200 mL) is added and the resulting mixture is washed with 10% NaCl solution and brine and then dried over MgSO 4 . The reaction mixture solution is evaporated and the residue is triturated with ethyl acetate to afford the product as a white solid.
    [424]
    [425] Example 50 (A)
    [426] (R) -1,2,3,4-tetrahydro-2- [5- (2-pyrimidin) -2-yl] -3- (3,4-dihydrobenzofuranyl) -9H-pyrrolo -[3,4-b] quinolin-9-one (# 65)
    [427] A. 1-methyl-5- (2-pyridinyl) -2- (1H) pyrimidone
    [428] A mixture of 2- (2-pyridinyl) malondialdehyde (5 g, 0.0335 mol), methyl urea (4.72 g, 0.0637 mol) and toluenesulfonic acid (450 mg) was prepared with a Dean-Stark water separator. The device is refluxed in toluene (100 mL) for 4 hours. The mixture is cooled and the precipitate is filtered off. The solid is triturated with water and recrystallized from ethanol to give the product.
    [429]
    [430] B. 2-chloro-5- (2-pyridinyl) pyrimidine
    [431] A mixture of 1-methyl-5- (2-pyridinyl) -2 (1H) pyrimidone (8.994 g, 0.048 mol), phosphorus pentachloride (2.156 g, 0.0104 mol) and phosphorus oxychloride (24 ml) was added at 8 ° C. Reflux for time. POCl 3 is distilled under reduced pressure. The residue is cooled to room temperature and ice water is added. The mixture is extracted with EtOAc and the organic layer is washed with 15% NaCl solution and brine and dried over MgSO 4 . The solvent is distilled off under dark to give a solid. The aqueous layer is adjusted to pH 6-7 with saturated Na 2 CO 3 and then extracted with EtOAc. The organic layer is washed with 15% NaCl, brine and dried over MgSO 4 . The solvent is distilled lightly to give a solid. After grinding with MeOH, additional product is obtained.
    [432] MS m / z (M + H) 192
    [433]
    [434] C. (R) -1,2,3,4-tetrahydro-2 [5- (2-pyridinyl) -pyrimidin-2-yl] -3- (3,4-dihydrobenzofuranyl)- 9H-pyrrolo- [3,4-b] quinolin-9-one
    [435] (R) -1,2,3,4-tetrahydro-3- (2,3-dihydrobenzofuran-5-yl) -9H-pyrrolo- [3,4-b] quinoline in DMF (45 ml) -9-one, hydrochloride (1.273 g, 0.00373 mol) (prepared in Example 6A), 2-chloro-5- (2-pyridinyl) pyrimidine (0.714 g, 0.00373 mol), KF (0.216 g, 0.00373 mol) and diisopropylethylamine (2.27 ml) are heated at 55 ° C. for 4 hours. EtOAc is added and the mixture is washed with 0.5N citric acid, then 15% NaCl, brine and dried over MgSO 4 . The solvent is distilled off under reduced pressure to give a solid. The solid is dissolved in 10% methanol in dichloromethane and purified by column chromatography (10% CH 3 OH in EtOAc to EtOAc) to afford the title compound.
    [436] Melting Point 231-233 ° C
    [437] MS m / z (M + H) 460
    [438]
    [439] The title compound is dissolved in methanol and 1 equivalent of 0.02 M (in methanol) methanesulfonic acid
    [440] Add. The solvent is distilled under reduced pressure to give the methane sulfonic acid salt.
    [441] [α] = − 236.2 ° (c = 1.0333 g / dl, CH 3 OH).
    [442] Example 51
    [443] 2-chloro-5-bromopyrimidine
    [444] 2-chloro-5-bromopyrimidine is prepared in 2-hydroxypyrimidine (commercially available from Frontier Scientific Inc.) according to the method described in US Pat. No. 5,693,611 Formulation Example 6 column 17.
    [445] Example 52
    [446] 1- (3,4-methylenedioxyphenyl) -2- (5-bromopyrimidin-2-yl) -2,3,4,9-tetrahydro-1H-βcarboline
    [447] 1- (3,4-methylenedioxyphenyl) -2,3,4,9-tetrahydro-1H-βcarboline (4.38 g, 15.0 mmol) in anhydrous degassed DMF (30 ml) (WO 97/43287, N, N-diisopropylethyl in a solution of 2-chloro-5-bromopyrimidine (2.90 g, 15.0 mmol) (prepared in Example 51) Add amine (4.2 ml, 30 mmol). The mixture is stirred overnight at 120-130 ° C. The mixture is then cooled and diluted with ethyl acetate. The solution is washed with 0.5N citric acid, water and brine, then dried over Na 2 SO 4 and concentrated in vacuo. Purification by flash column (silica gel, hexane: ethyl acetate = 6: 1, v / v then hexanes: ethyl acetate = 4: 1, v / v) yields the product as a white solid.
    [448]
    [449] Example 53
    [450] 1,2,3,4-tetrahydro-2- (5-bromopyrimidin-2-yl) -3- (3,4-methylenedioxyphenyl ) -9H-pyrrole- [3,4-b] Quinolin-9-one (# 55)
    [451] Method A:
    [452] 1- (3,4-methylenedioxyphenyl) -2- (5-bromopyrimidin-2-yl) -2,3,4, in anhydrous DMF (40 ml) (prepared as in Example 52) The 9-tetrahydro-1H-β-carboline (1.0 g, 2.2 mmol) solution is cooled in an ice bath. NaH (60% in mineral oil, 0.18 g, 4,4 mmol) is added and the mixture is stirred at 0 ° C. for 45 minutes. Anhydrous air is bubbled into the solution and the mixture is allowed to warm to room temperature overnight. The reaction mixture is cooled with water and extracted with ethyl acetate. The organic phase is washed with brine and water and then dried over Na 2 SO 4 and purified by flash column (silica gel, hexanes: ethyl acetate = 1: 1, v / v then pure ethyl acetate) to give the product as a white solid.
    [453]
    [454] Method B:
    [455] 1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -9H-pyrrolo- in anhydrous degassed DMF (2 ml) (prepared as in Example 51) In a solution of [3.4-b] quinolin-9-one (31 mg, 0.1 mmol) and 2-chloro-bromopyrimidine (19 mg, 0.1 mmol), N, N-diisopropylethylamine (28 μL, 0.2 mmol) was added. Add. The mixture is heated at 120-130 ° C. overnight. The solution is then cooled and diluted with ethyl acetate, washed with 0.5N citric acid, water and brine, then dried over Na 2 SO 4 and concentrated in vacuo. Purification by flash column (silica gel, hexane: ethyl acetate = 1: 1, v / v then hexanes: ethyl acetate) affords the product as a white solid.
    [456]
    [457] Example 54
    [458] 1,2,3,4-tetrahydro-2- [5- (3-pyridinyl) pyrimidin-2-yl] -3- (3,4-methylenedioxyphenyl) -9H-pyrrolo- [3 , 4-b] quinolin-9-one (# 56)
    [459] Method A:
    [460] A stirred mixture of palladium (II) acetate (0.8 mg, 3.6 μmol) and 1,1′-bis (diphenylphosphino) ferrocene (dppf) (2.4 mg, 4.3 μmol) in anhydrous DMF (1.0 ml) was heated to 50 ° C. Warm for 15 minutes and then cool. 1,2,3,4-tetrahydro-2- (5-bromopyridin-2-yl) -3- (3,4-methylenedioxyphenyl) -9H-pyrrolo- [3,4-b] Quinolin-9-one (20 mg, 43 μmol) (prepared as in Example 53), pyridine-3-boric acid (6.0 mg, 43 μmol) and triethylamine (8 μl, 60 μmol) were added to the solution and the mixture was 90 ° C. Heated for 16 hours. The solution is diluted with ethyl acetate and filtered through filter paper. The organic phase is washed with brine and water and then dried over Na 2 SO 4 . A small amount of silica gel is added to the solution and the solution is dried in vacuo. Purification by flash column (silica gel, 10% ammonium hydroxide: acetonitrile in water = 1: 10 v / v) affords the product as a white solid.
    [461]
    [462] Method B:
    [463] 1- (3,4-methylenedioxyphenyl) -2- [5- (3-pyridyl) pyrimidin-2-yl] -2 (prepared as in Example 55) in anhydrous DMF (4.0 ml) A solution of 3,4,9-tetrahydro-1H-βcarboline (100 mg, 0.22 mmol) is cooled in an ice bath. NaH (60% in mineral oil, 3.1 mg, 0.78 mmol) is added and the mixture is stirred at 0 ° C. for 45 minutes. Anhydrous air is bubbled into the solution and the mixture is allowed to warm to room temperature overnight. The reaction mixture is cooled with water and extracted with ethyl acetate. The organic phase is washed with brine and water and then dried over Na 2 SO 4 and purified by flash column (silica gel, 10% ammonium hydroxide: acetonitrile = 1: 10, v / v in water) to give the product as a white solid.
    [464]
    [465] Example 55
    [466] 1- (3,4-methylenedioxyphenyl) -2- [5- (3-pyridinyl) -pyrimidin-2-yl) -2,3,4,9-tetrahydro-1H-βcarboline
    [467] A stirred mixture of palladium (II) acetate (27 mg, 0.12 mmol) and 1.1′-bis (diphenylphosphino) ferrocene (dppf) (83 mg, 0.15 mmol) in anhydrous DMF (20 ml) was warmed to 50 ° C. for 15 minutes. Then cooled. 1- (3,4-methylenedioxyphenyl) -2- (5-bromopyridin-2-yl) -2,3,4,9-tetrahydro-1H-βcarboline (674 mg, 1.5 mmol) ( Prepared as in Example 52), pyridine-3-boric acid (203 mg, 1,7 mmol) and triethylamine (0.3 ml, 2.1 mmol) are added to the solution and the mixture is heated to 90 ° C. for 16 h. The solution is diluted with ethyl acetate and filtered through filter paper. The organic phase is washed with brine and water and then dried over Na 2 SO 4 . A small amount of silica gel is added to the solution and the solution is dried in vacuo. Purification by flash column (silica gel, hexane: ethyl acetate = 1: 1, v / v then hexanes: ethyl acetate = 1: 2, v / v) affords the product as a white solid.
    [468]
    [469] Example 56
    [470] 1,2,3,4-tetrahydro-2- [5- (4-pyridinyl) -pyrimidin-2-yl] -3- (3,4-methylenedioxyphenyl) -9H-pyrrolo- [ 3,4-b] quinolin-9-one (# 57)
    [471] Method A:
    [472] 1,2,3,4-tetrahydro-2- (5-bromopyridin-2-yl) -3- (3,4-methylenedioxyphenyl) -9H-pyrrolo in anhydrous DMF (2.0 ml) [3,4-b] quinolin-9-one (46 mg, 0.1 mmol) (prepared as in Example 53), (PPh 3 ) 4 Pd (3.5 mg, 30 μmol) and 4-tri-n-butyls The stirred mixture of tanylpyridine (37 mg, 0.1 mmol) is heated to 140 ° C. for 12 h. Further catalyst (3.5 mg) is added and the mixture is refluxed for 4 hours and then cooled. The solution is diluted with ethyl acetate and filtered through filter paper. The organic phase is washed with brine and water and then dried over Na 2 SO 4 . A small amount of silica gel is added to the solution and the solution is dried in vacuo. Purification by flash column (silica gel, 10% ammonium hydroxide in water: acetonitrile = 1: 10, v / v) affords the product as a white solid.
    [473]
    [474] Example 57
    [475] 1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -2- (5- (2-bromo) -furoyl)-9H-pyrrolo- [3,4- β] quinolin-9-one (# 30)
    [476] 5-Bromo-2-furonic acid (1.44 g, 7.54 mmol) in THF (20 ml) is stirred with oxalyl chloride (1.06 ml, 7.54 mmol) at room temperature. Two drops of DMF are added to the mixture to induce a vigorous reaction with gas evolution. After gas evolution ceased, an additional amount of oxalyl chloride (0.1 ml, 0.71 mmol) was introduced into the syringe and the mixture was stirred at room temperature for 10 minutes and then at 90 ° C. for 10 minutes. The solvent and excess oxalyl chloride are removed in vacuo to yield a pale yellow crystalline solid. To this solid THF (20 ml) followed by 3- (2,3-dihydro-5-benzofuran) -1,2,3,4-tetrahydro-9H-pyrrolo [3,4- in THF (20 ml). b] Quinoline-9-one (2.1 g) (prepared as in Example 6), Et 3 N (4.55 mmol, 32.6 mmol) and a catalytic amount of DMAP (40 mg) are added to the reaction mixture. Droplets of DMF are added to give a clear reaction mixture. The reaction mixture is heated at room temperature for 4 hours. The reaction mixture solvent is evaporated to give a solid residue. The residue is redissolved in CHCl 3 (200 ml), washed with water (3 × 200 ml) and the organic layer is dried over MgSO 4 . Evaporation of the organic solvent gives the product as an off-white solid.
    [477]
    [478] Example 58
    [479] 4- (4-Methyl) -piperazinylcarbonyl benzeneboronic acid
    [480] 4-carboxybenzeneboronic acid (0.332 g, 2 mmol), 1-methylpiperazine (0.22 mL, 2 mmol) and PyBrOP (0.9334 g, 2 mmol) were added DIPEA (0.696 mL, 4 mmol) in DMF (7 mL) for 16 hours at room temperature. Was stirred. Preparative TLC (10% MeOH / CHCl 3 ) afforded the product as a white solid.
    [481]
    [482] Example 59
    [483] 1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -2- (5- (4- (1- (4-methyl) -piperazinylcarbonyl) -phenyl) -Furoyl) -9H-pyrrolo [3,4-b] quinolin-9-one (# 44)
    [484] 1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -2- (5- (2-bromo-furoyl) -9H-pyrrole [3,4-b] quinoline -9-one (59.6 mg, 0.12 mmol) (prepared as in Example 57) with Pd (PPh 3 ) 4 (7.37 mg, 0.0062 mmol) in dioxane (5.5 mL) with nitrogen bubbling for 10 minutes. Then, a solution of 4- (4-methyl) -piperazinylcarbonyl benzeneboronic acid (37.0 mg, 0.15 mmol) and K 2 CO 3 (51.5 mg, 0.37 mmol) in H 2 O (1.1 mL) was added. The reaction mixture was stirred for 1 h at 100 ° C. The solvent was evaporated and the residue was purified by preparative TLC (10% MeOH / CHCl 3 ) and then titrated with ether / MeOH (15 mL / 1 mL) as pale yellow powder. The product was obtained.
    [485]
    [486] Example 59A
    [487] ( R) -1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -2- (5- (4- (1- (4-methyl) -piperazinylcarbonyl ) -Phenyl) -furoyl) -9H-pyrrole [3,4-b] quinolin-9-one (# 69)
    [488] A 5- (4- (4-methyl) -piperazinylcarbonylphenyl) furonic acid, methyl ester
    [489] 4- (4-Methyl) -piperazinylcarbonyl benzeneboronic acid (prepared as in Example 58) (1.31 g, 5.28 mmol), methyl bromofuroic acid ester (5 in HCl / MeOH for 5 hours at room temperature) A mixture of 1.08 g, 5.28 mmol), prepared from bromofuroic acid, was degassed by nitrogen bubbling in dioxane (45 mL) and H 2 O (9 mL) for 10 minutes. Pd (PPh 3 ) 4 (0.627 g, 0.528 mmol) and K 2 CO 3 (2.185 g, 15.84 mmol) were added thereto. This solution was stirred at 100 ° C. for 3 hours. Solvent was evaporated and the residue was dissolved in CH 2 Cl 2 (100 mL). It was washed with brine (3 × 100 mL), dried over MgSO 4, concentrated in vacuo and the crude product was purified by a Silica gel column (5% CH 3 OH / CHCl 3 ) to afford the product as a yellow solid.
    [490]
    [491] B. 5- (4- (4-methyl) -piperazinylcarbonylphenyl) furonic acid
    [492] The product from step A, (5- (4- (4-methyl) -piperazinyricarbonylphenyl) furonic acid, dissolved in THF (98.7 mL), methyl ester (1.08 g, 3.29 mmol), was dissolved in LiOH ( 16.45 mL in H 2 O, 0.2 N) was added The solution was stirred at rt for 3.5 h and neutralized with HCl (3.29 mL in ether) After concentration, the crude product was used without further purification.
    [493]
    [494] C. (R) -1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -2- {5- [4- (1- (4-methyl) -piperazinyl Carbonyl) -phenyl] furoyl} -9H-pyrrolo [3,4-b] quinolin-9-one (# 69)
    [495] 1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -9H-pyrrolo- [3,4-b] quinolin-9-one, hydrochloride salt (1.12 g, 3.29 mmol) (prepared as in Example 5A) and the product resulting from step B (1.034 g, 3.29 mmol) was dissolved in PyBroP (1.535 g, 3.29 mmol) and diisopropyl ethyl amine (1.716 mL, 9.87 in DMF (30 mL). mmol) was stirred at rt for 12 h. The reaction mixture was diluted with CH 2 Cl 2 (75 ml) and EtOAc (75 mL). This was purified on a silica gel column (pure CH 2 Cl 2 , 2.5% CH 3 OH / CH 2 Cl 2 ) to afford the product as off white solid.
    [496]
    [497] Example 60
    [498] 1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -2- (5- (2- (4-hydroxy) phenyl) furoyl) -9H-pyrrolo [3 , 4-b] quinolin-9-one, sodium salt (Na salt of # 22)
    [499] Following the procedure described in Example 59, the reagents were replaced as appropriate to afford the product as an off-white solid.
    [500]
    [501] Example 61
    [502] (4- (2- (1-pyrrolidinyl) ethoxy) phenyl) boronic acid
    [503] (Prepared according to the procedure described in Hoye, T.R. and Chen, M. in J. Org. Chem. 1996, 61, 7940)
    [504] To a solution of 1- [2- (4-bromophenoxy) ethyl] -pyrrolidine (2.70 g, 10 mmol) in THF (40 mL) add n-butyl lithium (6.9 mL 1.6 M in hexanes, 11 mmol) -78 Add at ° C. The reaction mixture was stirred at −78 ° C. for 15 minutes and then at 0 ° C. for 15 minutes. Trimethyl borate (2.5 mL, 22 mmol) was then added to the reaction mixture at 0 ° C. The mixture was gradually warmed to room temperature overnight. Methyl borate in the reaction mixture was hydrolyzed by reaction with saturated aqueous NH 4 Cl solution (100 mL) at room temperature for 30 minutes. The upper organic layer was collected. The aqueous layer was extracted with CHCl 3 (2 × 100 mL). The organic layers were combined, washed with brine (2 × 100 mL) and dried over MgSO 4 . The solvent was evaporated and purified by column chromatography (10% MeOH / CHCl 3 and 1% Et 3 N) to give the product as a white solid.
    [505]
    [506] Example 62
    [507] 1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -2- (5- (4- (2- (1-pyrrolidinyl) ethoxy) phenyl) -furoyl ) -9H-pyrrolo [3,4-b] quinolin-9-one (# 45)
    [508] Following the procedure described in Example 59, the reagents were properly replaced to yield the product as an off-white solid.
    [509]
    [510] Example 63
    [511] 3- (2,3-dihydro-5-benzofuranyl) -1,2,3,4-tetrahydro-2- (benzyl) -9H-pyrrolo [3,4-b] quinolin-9-one (# 60)
    [512] 1- (2,3-dihydro-5-benzofuranyl) -2-benzyl-2,3,4,9-tetrahydro-1H-β-carboline (prepared as in Example 2) (5.25 g , 13.81 mmol), potassium dioxide (3.29 g, 55.24 mmol) and 18-crown-6 (3.65 g, 13.81 mmol) were mixed with DMF (100 mL) in a 200 mL flask. The reaction mixture was kept overnight at room temperature. The reaction mixture was slowly added to a separate 500 mL flask containing a mixture of EtOAc (172 mL), H 2 O (172 mL) and 1N aqueous HCl (50 mL). The mixture was observed to produce fine gas bubbles. The reaction mixture was stirred at 0 ° C. for 30 minutes and a precipitate formed on the surfaces of the two liquid layers. The precipitate was collected by filtration, washed with H 2 O (20 mL) and dried in a vacuum oven to afford the product as off white.
    [513]
    [514] Example 64
    [515] 3- (3,4-methylenedioxyphenyl) -1,2,3,4-tetrahydro-2- [5- (3-trifluoromethyl) phenyl-2-furoyl] -9H-pyrrolo [ 3,4-b] quinolin-9-one (# 13)
    [516] 1- (3,4-methylenedioxyphenyl) -2-benzyl-2,3,4,9-tetrahydro-1H-β-carboline, with appropriate replacement of the reagents, according to the procedure described in Example 63. (0.381 g, 0.719 mmol) was reacted to give the product as off white solid. For the overall formation of the precipitate, the two liquid reaction mixtures were kept at room temperature for 48 hours than overnight.
    [517]
    [518] Example 65
    [519] 1- (3,4-methylenedioxyphenyl) -2- [4- (4-methoxyphenyl) thiazol-2-yl] -2,3,4,9-tetrahydro-1H-β-carboline
    [520] A. 1- (3,4-Methylenedioxyphenyl) -2- [3- (fluorenylmethyloxycarbonyl) thiocarbamoyl] -2,3,4,9-tetrahydro-1H-β-car Bolin
    [521] 1- (3,4-methylenedioxyphenyl) -2,3,4,9-tetrahydro-1H-β-carboline (2.66 g, 9.08 mmol) (WO97 / 43287, Intermediate 7, page 24) Prepared according to the procedure described in) and Fmoc-isothiocyanate (2.82 g, 10.14 mmol) was dissolved in anhydrous dichloromethane (50 mL). The mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. Purification by flash chromatography (0-10% methanol in dichloromethane) afforded thiourea protected as a pale yellow solid.
    [522]
    [523] B. 1- (3,4-Methylenedioxyphenyl) -2- (thiocarbamoyl) -2,3,4,9-tetrahydro-1H-β-carboline
    [524] A solution of protected thiourea (4.78 g, 8.33 mmol) resulting from step A in 20% (v / v) piperidine in methanol was refluxed with heating for 5 hours. The mixture was concentrated in vacuo to afford a crude residue which was purified by flash chromatography (SiO 2 , 0-10% methanol in dichloromethane) to give a yellow solid.
    [525]
    [526] C. 1- (3,4-Methylenedioxyphenyl) -2- [4- (4-methoxyphenyl) thiazol-2-yl] -2,3,4,9-tetrahydro-1H-β- Kaboline
    [527] To a solution of thiourea (223 mg, 0.63 mmol) resulting from step B in a 1: 1 mixture of dioxane: ethanol (5 mL) 4-methoxyphenyl-2'-bromoacetophenone (175 mg, 0.76 mmol) and tri Ethylamine (0.40 mL) was added. The mixture was heated at 70 ° C. for 3 hours, cooled at room temperature and concentrated on a rotary evaporator. The residue was purified by flash chromatography (SiO 2 , 0-10% methanol in dichloromethane) to give as a colorless solid.
    [528]
    [529] Example 66
    [530] 1- (3,4-methylenedioxyphenyl) -2- [4-phenylthiazol-2-yl] -2,3,4,9-tetrahydro-1H-β-carboline
    [531] A. 1- (3,4-Methylenedioxyphenyl) -2- [3- (fluorenylmethyloxycarbonyl) thiocarbamoyl] -2,3,4,9-tetrahydro-1H-β-car Bolin
    [532] 1- (3,4-methylenedioxyphenyl) -2,3,4,9-tetrahydro-1H-β-carboline (2.66 g, 9.08 mmol) (WO97 / 43287, on page 24 intermediate 7 Prepared) and Fmoc-isothiocyanate (2.82 g, 10.14 mmol) were dissolved in anhydrous dichloromethane (50 mL). The mixture was stirred at ambient temperature for 16 hours and then concentrated in vacuo. Purification by flash chromatography (0-10% methanol in dichloromethane) gave a thiourea light yellow solid in protected form.
    [533]
    [534] B. 1- (3,4-Methylenedioxyphenyl) -2- (thiocarbamoyl) -2,3,4,9-tetrahydro-1H-β-carboline
    [535] The protected thiourea obtained from A, dissolved in 20% piperidine (v / v) in methanol, was heated to reflux for 5 hours. The mixture was concentrated in vacuo to afford a crude residue, which was then purified by flash chromatography (SiO 2 , 0-10% methanol in dichloromethane) to give a yellow solid.
    [536]
    [537] C. 1- (3,4-methylenedioxyphenyl) -2- [4-phenylthiazol-2-yl] -2,3,4,9-tetrahydro-1H-β-carboline
    [538] Β-bromoacetophenone (159 mg, 0.80 mmol) and triethylamine (0.40 mL) were added to the thiourea solution (227 mg, 0.65 mmol) obtained in B. The mixture was heated to 70 ° C. for 3 hours, then cooled to room temperature and concentrated on a rotary evaporator. The residue was purified by flash chromatography (SiO 2 , 0-10% methanol in dichloromethane) to give a pale yellow solid.
    [539]
    [540] Example 67
    [541] 3- (2,3-dihydro-benzofuran-5-yl) -1,2,3,4-tetrahydro-3R-9H-pyrrolo [3,4-b] quinolinone
    [542] [2- (1H-indol-3-yl) -ethyl according to the method described in A. Kawate et al. (Kawate, T .; Yamanaka, M .; Nakagawa, M. in Heterocycles, 1999, 50, 1033) ]-(1-naphthalen-1-yl-ethyl) -amine was prepared.
    [543] B. 1- (2,3-Dihydrobenzofuran-5-yl) -2- (1R-1-naphthalen-1-yl-ethyl) -2,3,4,9-tetrahydro-1H-β- R- and S-diastereomers of Carboline
    [544] [2- (1H-Indol-3-yl) -ethyl]-(1-naphthalen-1-yl-ethyl) -amine (1.0 g, 3.18 mmol) and 2,3-dihydrobenzofuran-5-carbaldehyde (2.356 g, 15.92 mmol) was stirred for 7 h at 165 ° C. in p-xylene (20 mL). Silica gel (10 g) and hexane (200 mL) were added to the reaction mixture. The reaction mixture was filtered to remove the colorless filtrate. Silica gel was washed with ethyl acetate (100 mL). Ethyl acetate solvent was evaporated and the crude product was concentrated and dissolved in a small amount of CH 2 Cl 2 and packed into a silica gel column. This column was developed with 5% ethyl acetate / hexanes to give diastereomers.
    [545] 1- (2,3-dihydro-benzofuran-5-yl) -2- (1R-1-naphthalen-1-yl-ethyl) -2,3,4,9-tetrahydro-1S-1H-β -Carboline (unpurpose diastereomer A) (Rf = 0.59 in 30% EtOAc / hexanes) was obtained as a yellow solid.
    [546]
    [547] 1- (2,3-dihydro-benzofuran-5-yl) -2- (1R-1-naphthalen-1-yl-ethyl) -2,3,4,9-tetrahydro-1R-1H-β -Carboline (the desired diastereomer B) (Rf = 0.51 in 30% EtOAc / hexanes) was obtained as a yellow solid.
    [548]
    [549] C. Conversion of S-diastereomers to R-diastereomers
    [550] 1- (2,3-dihydro-benzofuran-5-yl) -2- (1R-1-naphthalen-1-yl-ethyl) -2,3,4,9-tetrahydro-1S-1H-β -Carboline (unpurpose diastereomer A) (190 g, 0.428 mmol) was stirred overnight in room temperature in 1000 mL CH 2 Cl 2 and TFA (52 mL, 701 mol). The reaction was terminated with aqueous NaOH solution (35 g in 100 mL water, 0.875 mol). The reaction mixture was mixed well and left for 0.5 hours to allow precipitation to form. The precipitate was filtered off, the solid was washed with water and then dried under high pressure to give a solid product.
    [551] 1 H NMR data shows 1- (2,3-dihydro-benzofuran-5-yl) -2- (1R-1-naphthalen-1-yl-ethyl) -2,3,4,9-tetrahydro-1R 1H-β-carboline (target diastereomer B).
    [552] D. 3- (2,3-Dihydro-benzofuran-5-yl) -2- (1R-1-naphthalen-1-yl-ethyl) -1,2,3,4-tetrahydro-3R-9H -Pyrrole [3,4-b] quinolinone
    [553] 1- (2,3-dihydro-benzofuran-5-yl) -2- (1R-1-naphthalen-1-yl-ethyl) -2,3,4,9-tetrahydro-1R-1H-β Carboline (0.6469 g, 1.46 mmol) and potassium-t-butoxide (0.279 g, 2.48 mmol) were stirred at room temperature in DMF (14 mL). Oxygen gas was fed to the reaction mixture overnight. The reaction was terminated with HCl (2.48 mL, 1N aqueous solution). Ethyl acetate (50 mL) and H 2 O (50 mL) were added. The organic phase was separated. The aqueous phase was extracted with ethyl acetate (50 mL) and CH 2 Cl 2 (50 mL). The organic phase was washed with brine (3 × 50 mL) and then dried over MgSO 4 . The product was concentrated and purified by silica gel (2% methanol / CH 2 Cl 2 ) to give a yellow solid product.
    [554]
    [555] E. 3- (2,3-Dihydro-benzofuran-5-yl) -1,2,3,4-tetrahydro-3R-9H-pyrrolo [3,4-b] quinolinone
    [556] 3- (2,3-dihydro-benzofuran-5-yl) -2- (1R-1-naphthalen-1-yl-ethyl) -1,2,3,4-tetrahydro-3R-9H-pyrrole [3,4-b] -quinolinone (24 mg, 0.0524 mmol) was dissolved in 5 mL ethanol. To the reaction mixture was added 10% Pd / C (50 mg) and HCl (1.0 M in diethyl ether (0.05 mL, 0.05 mL)). The reaction mixture was stirred at room temperature under H 2 gas pressure (35 psi) for 3 hours. The catalyst was filtered off over a celite plug. The reaction mixture was concentrated to give the crude product. Purification by preparative TLC (5% MeOH / CH 2 Cl 2 ) gave the title yellow solid.
    [557]
    [558] Example 68
    [559] 3-benzo [1,3] dioxol [-5-yl-2- (5-bromo-furan-2-carbonyl) -1,2,3,4-tetrahydropyrrole [3,4-b] Quinolin-9-one
    [560] Oxalyl chloride (0.66 mL, 7.541 mmol) was added to a 5-bromo-2-furoic acid (2.1 g, 6.856 mmol) solution in THF (20 mL). Two drops of DMF were then added to the reaction mixture with vigorous CO gas droplets. Oxalyl chloride ((COCl) 2 , 0.1 mL) was then added. The reaction mixture was stirred at room temperature for 10 minutes and then at 90 ° C. for 10 minutes. Solvent and excess (COCl) 2 were removed in vacuo to afford 5-bromo-furan-2-carbonyl chloride pale yellow solid.
    [561] 5-Bromo-furan-2-carbonyl chloride was then dissolved in THF (20 mL). 3- (2,3-dihydro-benzofuran-5-yl) -1,2,3,4-tetrahydro-9H-pyrrole [3,4-b] quinolinone (2.1 g in THF (20 mL) , 6.865 mmol) was added. Triethylamine (4.55 mL, 32.64 mmol) and DMAP (40 mg, 0.327 mmol) were then added successively. A few drops of DMF were added to this reaction mixture to keep the solution clear. The reaction mixture was stirred at rt for 4 h and then concentrated in vacuo. The residue was dissolved in CHCl 3 (200 mL) and washed with H 2 O (3 × 200 mL). The organic phase was dried over magnesium sulfate to give the title compound as a non-white (grey or yellowish white) solid. No further purification was necessary.
    [562]
    [563] Examples 69-79
    [564] General course
    [565] 3-benzo [1,3] dioxol-5-yl-2 (5-bromo-furan-2-carbonyl) -1,2,3,4-tetrahydropyrrole [3,4-b] quinoline- 9-one (0.100 g, 0.2086 mmol), boronic acid (0.2296 mmol, 1.1 equiv), Pd (PPh 3 ) 4 (12.4), appropriately substituted in 1,4-dioxane (8 mL) and H 2 O (2 mL) mg, 0.01043 mmol) and K 2 CO 3 (86.4 mg, 0.6258 mmol) were stirred with the mixed mixture, and then degassed under N 2 , followed by stirring at 100 ° C. for 1.5 hours. The crude reaction mixture was placed on a silica gel preparative TLC plate and developed with 5% CH 3 OH / CH 2 Cl 2 to obtain a solid product.
    [566] Compound No. 110 (reacts with phenyl boronic acid)
    [567]
    [568] Compound number 111 (reacts with 4-methylthiophenyl boronic acid)
    [569]
    [570] Compound number 112 (reacts with 3-thienyl boronic acid)
    [571]
    [572] Compound number 116 (reacts with 4-methylphenyl boronic acid)
    [573]
    [574] Compound number 113 (reacts with 2-nitrophenyl boronic acid)
    [575]
    [576] Compound No. 117 (reacts with 2-thienyl boronic acid)
    [577]
    [578] Compound number 118 (reacts with 3,4-methylenedioxyphenyl boronic acid)
    [579]
    [580] Compound No. 119 (reacts with 4-cyanophenyl boronic acid)
    [581]
    [582] Compound number 120 (reacts with 4-hydroxymethylphenyl boronic acid)
    [583]
    [584] Compound number 121 (reacts with 3-hydroxymethylphenyl boronic acid)
    [585]
    [586] Compound No. 122 (reacts with 4-dimethylaminophenylboronic acid)
    [587]
    [588] Example 80
    [589] 3- (2,3-dihydro-benzofuran-5-yl) -2-pyrimidin-2-yl-1,2,3,4-tetrahydro-pyrrolo [3,4-b] quinoline-9 -On (# 123)
    [590] 3- (2,3-dihydro-benzofuran-5-yl) -1,2,3,4-tetrahydro-pyrrolo [3,4-b] quinolin-9-one-HCl salt (0.15 g, 0.440 mmol) was stirred with chloropyrimidine (60.5 mg, 0.528 mmol), KF (31 mg, 0.528 mmol) and DIEA (0.19 mL, 1.1 mmol) at 60 ° C. for 16 h. The reaction mixture was diluted with H 2 O (20 mL). This solid was filtered off and dried in vacuo with a suction funnel. Silicagel preparative TLC gave the title compound as a yellow solid.
    [591]
    [592] Example 81
    [593] 3-benzofuran-5yl-2- (5-pyridin-2-yl-pyrimidin-2-yl) -1,2,3,4-tetrahydro-
    [594] Pyrrole [3,4-b] quinolin-9-one (# 126)
    [595] A: Benzofuran-5-carbaldehyde was prepared according to the method described in Hiroya, K .; Hashimura, K .; Ogasawara, K. in Heterocycles, 1994, Vol. 38, No. 11, 2463-72. do.
    [596] B: 1-benzofuran-5-yl-2,3,4,9-tetrahydro-1H-β-carboline is prepared according to the method described in Example 12.
    [597]
    [598] Example C: 1-benzofuran-5-yl-2- (5-pyridin-2-yl-pyrimidin-2-yl) -2,3,4,9-tetrahydro-1H-β-carboline Prepared according to the method described in 12.
    [599]
    [600] D: 1- (5-benzofuryl) 2,3,4,9-tetrahydro-2- [5- (2-pyridinyl) -2-pyridinyl] -1H-β-carboline (30 mg, 0.06764 mmol) and KOtBu (12.9 mg, 0.115 mmol) are stirred in DMF (1 ml) under O 2 gas for 10 hours at room temperature. Preparative TLC (5% methanol in CH 2 Cl 2 ) affords the title product as a yellow solid.
    [601]
    [602] Example 82
    [603] 3- (2,3-dihydro-benzofuran-5yl) -2- [5- (1-oxy-pyridin-2-yl) -pyrimidin-2-yl] -1,2,3,4- Tetrahydro-pyrrolo [3,4-b] quinolin-9-one (# 125)
    [604] 3- (2,3-dihydro-5-benzofuranyl) -1,2,3,4-tetrahydro-2- [5- (2-pyridinyl) -2-pyrimidinyl]-(3R) -9H-pyrrolo [3,4-b] quinolin-9-one (4.5 mg, 0.010 mmol) and mCPBA (1.73 mg, 0.010 mmol) are stirred in THF (2 ml). Traces of DMF are added to make the solution clear. The reaction mixture is stirred at room temperature for 80 hours and then at 60 ° C. for 8 hours. The title product is obtained as a gray solid with some starting material recovered by preparative TLC (10% methanol in CH 2 Cl 2 ).
    [605]
    [606] Examples 83-86
    [607] 1- (2,3-Dihydro-benzofuran-5yl) -2- [5- (2,3-dimethyl-3H-imidazol-4-yl) -pyrimidin-2-yl] -2,3 , 4,9-tetrahydro-1H-β-carboline
    [608] 2- (5-Bromo-2-pyrimidyl) -1- (2,3-dihydro-5-benzofuranyl) -2,3,4,9-tetrahydro-1H-β-carboline (0.45 g, 1.00 mmol), 1,2-dimethyl-1H-imidazole (0.18 g, 1.87 mmol), Pd (OAc) 2 (12 mg, 0.05 mmol), PPh 3 (26 mg, 0.1 mmol) and K 2 CO 3 ( 0.28 g, 2 mmol) is stirred in 3.5 ml of DMF at 140 ° C. for 14 hours. The mixture is poured into 10% aqueous NaOH solution (50 ml). The resulting solution is extracted with CH 2 Cl 2 (3 × 50 ml) and dried over Na 2 SO 4 . Purification by preparative TLC affords the title product as a yellow powder.
    [609]
    [610] The following compounds are similarly prepared according to the methods described above by substituting the appropriate selection and appropriately substituted reagents.
    [611] 2- [5- (3-benzyl-2-methyl-3H-imidazol-4-yl) -pyrimidin-2-yl] -1- (2,3-dihydro-benzofuran-5-yl)- 2,3,4,9-tetrahydro-1H-β-carboline
    [612] MS (m / z) 539, (MH + ), 537 (MH − )
    [613] 3- (2,3-Dihydro-benzofuran-5yl) -2- [5- (2,3-dimethyl-3H-imidazol-4-yl) -pyrimidin-2-yl] -1,2 , 3,4-tetrahydro-pyrrolo [3,4-β] quinolin-9-one (# 128)
    [614]
    [615] 2- [5- (3-benzyl-2-methyl-3H-imidazol-4-yl) -pyrimidin-2-yl] -3- (2,3-dihydrobenzofuran-5-yl) -1 , 2,3,4-tetrahydro-pyrrolo [3,4-b] quinolin-9-one (# 127)
    [616]
    [617] Example 87
    [618] 3- (2,3-dihydro-benzofuran-5yl) -2-pyridin-2-yl-1,2,3,4-tetrahydro-pyrrolo [3,4-b] quinolin-9-one (# 129)
    [619] 3- (2,3-dihydro-5-benzofuranyl) -1,2,3,4-tetrahydro-9H-pyrrolo [3,4-b] quinolin-9-one HCl (0.30 g, 0.88 mmol) and 2-bromo-pyridine (2 ml), Pd 2 dba 3 (0.23 g, 0.25 mmol), BINAP (0.47 g, 0.75 mmol) and KaOtBu (0.66 g, 6.87 mmol) were added at 90 ° C. for 1 hour. Stir in, 4-dioxane (4 ml). The resulting mixture is concentrated and filtered over a plug of celite containing CH 2 Cl 2 . Purification by preparative TLC (5% CH 3 OH / CH 2 Cl 2 ) affords the title product as a yellow solid.
    [620]
    [621] Example 88
    [622] 3-benzo [1,3] dioxol-5yl-2- (4-imidazol-1-yl-phenyl) -1,2,3,4-tetrahydro-pyrrolo [3,4-b] quinoline -9-on (# 133)
    [623] 3- (1,3-benzodioxol-5yl) -1,2,3,4-tetrahydro-9H-pyrrolo [3,4-b] quinolin-9-one (30.6 mg, 0.1 mmol), 1- (4-bromo-phenyl) -1H-imidazole (22.3 mg, 0.1 mmol), Pd 2 dba 3 (4.6 mg, 0.005 mmol), biphenyl-2-yl-di-tert-butyl-force Plates (3.0 mg, 0.01 mmol) and KaOtBu (14 mg, 0.14 mmol) are stirred in 1,4-dioxane (0.6 ml) at 89 ° C. for 17 hours. Purification by preparative TLC (5% CH 3 OH / CH 2 Cl 2 ) affords the title product as a yellow powder.
    [624]
    [625] Example 89
    [626] 2- [2,3 '] bipyridinyl-6'-yl-3- (2,3-dihydro-benzofuran-5-yl) -1,2,3,4-tetrahydro-pyrrolo [3 , 4-b] quinolin-9-one (# 134)
    [627] A: 2- (5-Bromo-pyridin-2-yl) -1- (2,3-dihydro-benzofuran-5-yl) -2,3,4,9-tetrahydro-1H-β- Kaboline
    [628] 1- (2,3-dihydro-5-benzofuranyl) -2,3,4,9-tetrahydro-1H-β-carboline (11.6 g, 40 mmol), 2,5-dibromopyridine ( 10.42 g, 44 mmol), Pd 2 dba 3 (1.465 g, 1.6 mmol), dppp (1.32 g, 3.2 mmol) and KaOtBu (5.38 g, 56 mmol) are stirred in 60 ml of DMF at 80 ° C. for 3 days. The reaction mixture is filtered through a plug of celite containing CH 2 Cl 2 . The reaction mixture is then concentrated and then the crude mixture is loaded onto a foxy column (110 g silica gel) and eluted with ethyl acetate / hexanes (3: 7). The product is crystallized in test tube. The product is concentrated and then recrystallized from THF to give the product as yellow crystals.
    [629]
    [630] B: 2- [2,3 '] bipyridinyl-6'-yl-1- (2,3-dihydro-benzofuran-5yl) -2,3,4,9-tetrahydro-1H-β Caboline
    [631] The product from step A (0.4 g, 0.896 mmol), 2-tributylstannyl-pyridine (0.8 g, 2.17 mmol) and Pd (PPh 3 ) 4 (0.12 g, 0.104 mmol) were added at 88 ° C. for 24 hours. Stir in 1,4-dioxane (5 ml). The reaction mixture is filtered through a plug of celite with CH 2 Cl 2 and concentrated to a small volume. Preparative TLC (3: 7 ethylacetate / hexanes; then 5% CH 3 OH / CH 2 Cl 2 ) affords the title product as a yellow solid.
    [632]
    [633] C.2- [2,3 '] bipyridinyl-6'-yl-3- (2,3-dihydro-benzofuran-5-yl) -1,2,3,4-tetrahydro-pyrrolo [3,4-b] quinolin-9-one (# 134)
    [634] Subsequent selection and appropriate replacement of the reagents yield the title compound as a solid according to the method described in Example 19.
    [635]
    [636] Example 90
    [637] 3- (2,3-Dihydro-benzofuran-5-yl) -2- [5- (3-methyl-3H-imidazol-4-yl) -pyridin-2-yl] -1,2,3 , 4-tetrahydro-pyrrolo [3,4-b] quinolin-9-one (# 137)
    [638] A. 2-Chloro-5- (3-methyl-3H-imidazol-4-yl) -pyridine
    [639] 2-chloro-4-iodo-pyridine (0.239 g, 1 mmol), 1-methyl-1H-imidazole (0.41 g, 5 mmol), Pd (OAc) 2 (22.5 mg, 0.1 mmol), PPh 3 (53 mg, 0.2 mmol) and Cs 2 CO 3 (0.326 g, 1 mmol) are stirred in DMF (3 ml) at 120 ° C. for 6 hours. Purification by preparative TLC affords the product as an oil comprising 1-methyl-1H-imidazole. The product is used for next step without further purification.
    [640]
    [641] B.3- (2,3-Dihydro-benzofuran-5-yl) -2- [5- (3-methyl-3H-imidazol-4-yl) -pyridin-2-yl] -1,2 , 3,4-tetrahydro-pyrrolo [3,4-b] quinolin-9-one (# 137)
    [642] 3-2,3-dihydro-benzofuran-5-yl) -1,2,3,4-tetrahydro-pyrrolo [3,4-b] quinolin-9-one (0.127 g, 0.372 mmol), 2-Chloro-5- (3-methyl-3H-imidazol-4-yl) -pyridine (0.06 g, 0.31 mmol), Pd (OAc) 2 (3.5 mg, 0.0155 mmol), biphenyl-2-yl- Dicyclohexyl-phosphane (5.43 mg, 0.0155 mmol) and NaOtBu (0.104 g, 1.085 mmol) are stirred in 1,4-dioxane (0.6 ml) at 90 ° C. Purification by preparative TLC (5% CH 3 OH / CH 2 Cl 2 ) affords the product as a yellow solid.
    [643]
    [644] Example 91
    [645] 2- [5- (3-benzyl-3H-imidazol-4-yl) -pyridin-2yl] -3- (2,3-dihydro-benzofuran-5yl) -1,2,3,4 Tetrahydro-pyrrolo [3,4-b] quinolin-9-one (# 138)
    [646] A: 5- (3-benzyl-3H-imidazol-4-yl) -2-chloro-pyridine
    [647] Subsequent selection and appropriate replacement of the reagents yield the product as a solid according to the method described in Example 90, Step A.
    [648]
    [649] B: The product is obtained as a solid according to the method described in Example 90, Step B by replacing with a suitable selection and suitably replaced reagent.
    [650]
    [651] Example 92
    [652] 3- (2,3-dihydro-benzofuran-5-yl) -2-pyridin-2-yl-1,2,3,4-tetrahydro-pyrrolo [3,4-b] quinoline-9- ON (# 136)
    [653] 3- (2,3-dihydro-benzofuran-5-yl) -1,2,3,4-tetrahydro- (3R) -9H-pyrrolo [3,4-b] quinolin-9-one HCl (0.0341 g, 0.1 mmol), 2-iodo-pyridine (0.0341 g, 0.2 mmol), Pd 2 dba 3 (22.9 mg, 0.025 mmol), BINAP (46.7 mg, 0.075 mmol) and NaOtBu (58 mg, 0.6 mmol) Was stirred in 1,4-dioxane (0.8 ml) at 50 ° C. for 3 h. Purification by preparative TLC (5% methanol / CH 2 Cl 2 ) affords the product as a yellow solid.
    [654]
    [655] Example 93
    [656] 3- (2,3-dihydro-benzofuran-5-yl) -2- [5-3H-imidazol-4-yl) -pyridin-2-yl] -1,2,3,4-tetrahydro -Pyrrolo [3,4-b] quinolin-9-one
    [657] 2- [5- (3-benzyl-3H-imidazol-4-yl) -pyridin-2-yl] -3- (2,3 prepared in Example 91 in CH 3 OH (3 ml) at about 80 ° C. -Dihydro-benzofuran-5-yl) -1,2,3,4-tetrahydro-pyrrolo [3,4-b] quinolin-9-one (0.005 mmol, 1 equiv) and p-toluenesulfonyl Hydrazide (0.25 mmol, 50 equiv) is added to a solution of sodium acetate (0.5 mmol, 100 equiv) in H 2 O (2 mL) over about 2 hours. The mixture is stirred for an additional about 3 hours at about 80 ° C., then cooled to about 25 ° C. and the solvent is evaporated. The residue is dissolved in CH 2 Cl 2 (20 ml), washed with saturated aqueous NaCl (10 ml), dried (Na 2 SO 4 ) and concentrated to afford the title compound.
    [658] Example 94
    [659] 3- (2,3-dihydro-benzofuran-5-yl) -2- [5- (2-methyl-3H-imidazol-4-yl) -pyrimidin-2-yl] -1,2, 3,4-tetrahydro-pyrrolo [3,4-b] quinolin-9-one
    [660] 2- [5- (3-benzyl-2-methyl-3H-imidazol-4-yl) -pyrimidin-2-yl] -3- (2,3-dihydro-benzofuran prepared in Example 86 -5-yl) -1,2,3,4-tetrahydro-pyrrolo [3,4-b] quinolin-9-one is reacted according to the method described in Example 93 to afford the title compound.
    [661] Example 95
    [662] In vitro test
    [663] Cyclic Nucleotide Phosphodiesterase (PDE) Assay
    [664] PDEV is described in International Journal of Impotence Research 1996 8, 47-52, Boolell, M., Allen, MJ, Ballard, SA, Ge [o-Atte, S., Muirhead, GJ, Naylor, AM, Osterioh, IH, and the method described in Gingell, C), with a slight modification to isolate from rabbit and human tissue.
    [665] In summary, rabbit and human tissues are homogenized in ice-cold buffer containing 20 mM HEPES (pH 7.2), 0.25 M sucrose, 1 mM EDTA and 1 mM phenylmethylsulfonyl fluoride (PMSF). The homogenate is centrifuged at 100,000 g at 4 ° C. for 60 minutes. The supernatant is filtered through 0.2 μM and loaded onto a Pharmacia mono Q anion exchange column (1 ml bed volume) equilibrated with 20 mM HEPES, 1 mM EDTA and 0.5 mM PMSF. After washing the unbound protein, the enzyme is eluted with a 100-600 mM NaCl line gradient in the same buffer (30-50 ml total, depending on tissue, skeletal muscle, cavernous body, retina, heart and platelets, respectively, 35, 40, 45). , 50 and 55 ml). The column is run at a flow rate of 1 ml / min to collect 1 ml fractions. Different PDE activities are pooled for each of the fractions and used in subsequent studies.
    [666] Inhibition Measurement of PDEV
    [667] The PDE test was carried out with minor modifications to the method described by Thompson and Eppelman, Biochemistry 1971 10, 311-316, as described below.
    [668] This test was applied to the 96-well format. Enzyme in 5 mM MgCl 2 , 15 mM Tris HCl (pH 7.4), 0.5 mg / ml bovine serum albumin, 1 μM cGMP or cAMP, 0.1 μCi [ 3 H] -cGMP or [ 3 H] -cAMP and column eluate 2-10 μl Tested. The total volume of this test subject was 100 μl. The reaction mixture was incubated at 30 ° C. for 30 minutes. The reaction was stopped by boiling for 1 minute and then cooled on ice. In addition, the addition of 25㎕ 1mg / ml venom (OPA operational Hanna Gus) of the snake in the 5'-mono-nucleotide [3 H] which is generated by the following incubation at 30 ℃ for 10 minutes, a mono-nucleotide non-charged [3 H] Modified with -nucleotides. The reaction was stopped by adding 1 ml of Bio-Rad AG1-X2 resin slurry (1: 3). Unfilled nucleotides bordered with the resin, leaving only unfilled [ 3 H] -nucleotides supernatant after centrifugation. 200 μl of the separated solution was taken and measured by liquid scintillation. PDE activity was expressed in pmol / min / milliliter of hydrolyzed circular nucleotides of enzyme preparation.
    [669] Inhibitor studies were performed in test buffer with a final concentration of 10% DMSO. Under these conditions, the hydrolysis of the product proceeded in a linear curve fashion that increased with time and enzyme concentration.
    [670] Example 96
    [671] K of phosphodiesterase inhibitors in vitro iMeasure
    [672] This test was applied to the 96-well format. Phosphodiesterase was tested in 5 mM MgCl 2 , 15 mM Tris HCl (pH 7.4), 0.5 mg / ml bovine serum albumin, 30 nM 3 H-cGMP and various concentrations of test compounds. Enzymes were used in amounts until less than 15% of the initial substrate was modified during testing in each reaction. In all cases the test compound was dissolved and then diluted in 100% DMSO (2% DMSO in the test). The total volume of the test subject was 100 μl. The reaction mixture was incubated at 30 ° C. for 90 minutes. The reaction was stopped by boiling for 1 minute and then immediately transferred to an ice bath for cooling. To each well, 25 μl 1 mg / ml of snake venom (Opiopagus hannah) was added and then incubated at 30 ° C. for 10 minutes. The reaction was stopped by adding 1 ml of Bio-Rad AG1-X2 resin slurry (1: 3). 200 μl of the separated solution was taken and measured by liquid scintillation.
    [673] The percent inhibition of maximal substrate modification (by enzyme without inhibitor) was determined for each test compound concentration. IC 50 was determined by plotting the log of the percent inhibition and the test compound concentration using a nonlinear regression analysis of GraphPad Prism (S phase colon dose response). If the substrate concentration of the enzyme is much less than the Km of the enzyme (substrate concentration at half the maximum rate of the enzyme), K 1 is similar to the IC 50 value.
    [674] The compounds described in Tables 1-6 were prepared by the method described above. PDEV inhibitory activity of these compounds is expressed as percent inhibition, IC 50 (μM) at the indicated concentrations of the test compound, or as Ki values, as in the table below. Unless otherwise noted, PDEV inhibitory activity was measured using human tissue. The abbreviation "stereo" refers to stereoisomeric configuration and the abbreviation "Rac" refers to racemic mixtures.
    [675]
    [676]
    [677]
    [678]
    [679]
    [680]
    [681]
    [682]
    [683]
    [684]
    [685]
    [686]
    [687]
    [688]
    [689]
    [690] Example 97
    [691] In vitro experiment
    [692] Carter et al., Carter, A.J., Ballard, S.A., and Naylor, A.M .; According to the method described in Journal of Urology 1998, 160, 242-246, the in vitro efficacy of the compounds listed in Table 7 was measured and shown with the test results.
    [693] ID # efficacy 36 activation 37 activation 65 activation 66 activation
    [694] Example 98
    [695] As a specific example of the oral composition, 100 mg of the compound of Example 21 was formulated with sufficiently finely divided lactose and filled into a sized hard gel capsule to give a total weight of 580-590 mg.
    [696] The foregoing specification illustrates the principles of the invention, and the examples are provided for purposes of illustration, but the practice of the invention includes all modifications, applications and / or modifications in the general claims and the following claims and their equivalents. Will be understood.
    权利要求:
    Claims (18)
    [1" claim-type="Currently amended] A compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof.
    Formula I

    Formula II

    In the above formulas (I) and (II),
    R 1 is hydrogen, carboxy, -C (O) -C 1 -C 6 alkyl, -C (O) -C 1 -C 6 alkoxy, -C (O) -NH-C 1 -C 6 alkyl-NH 2 , -C (O) -NH-C 1 -C 6 alkyl-NHR A , -C (O) -NH-C 1 -C 6 alkyl-N (R A ) 2 , -C (O) -NH 2 , -C (O) -NHR A , -C (O) -N (R A ) 2 , -C 1 -C 6 alkyl-NH 2 , -C 1 -C 6 alkyl-NHR A , -C 1 -C 6 Alkyl-N (R A ) 2 and -NH-C 1 -C 6 alkyl-N (R A ) 2 wherein R A is each independently C 1 -C 6 alkyl, aryl, C 1 -C 6 aralkyl And heteroaryl; Aryl, aralkyl or heteroaryl may be optionally substituted by one to three R B ; R B are each independently halogen, nitro, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylcarbonyl, carboxyC 1 -C 6 alkyl, C 1 -C 6 alkyl Sulfonyl, trifluoromethyl, amino, di (C 1 -C 6 alkyl) amino, acetylamino, carboxy C 1 -C 6 alkylcarbonylamino, hydroxyC 1 -C 6 alkylamino, NHR A and N ( R A ) is selected from the group consisting of 2 ;
    R 2 is independently from (halogen, hydroxy, nitro, amino, NHR A or N (R A) 2 optionally substituted with one to three substituents independently selected from optionally substituted) C 5 -C 10 alkyl, (C R Aryl optionally substituted with one to three substituents selected, cycloalkyl (optionally substituted with one to three substituents independently selected from R A ), optionally substituted with one to three substituents independently selected from R C ) Heteroaryl and heterocycloalkyl (optionally substituted with one to three substituents independently selected from R C ), wherein R C is halogen, nitro, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, Trifluoromethyl, trifluoromethoxy, NH 2 , NH (C 1 -C 6 alkyl) and N (C 1 -C 6 alkyl) 2 );
    R 3 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 2 -C 6 alkenylcarbonyl and C 2 -C 6 alkynylcarbonyl,
    b is an integer from 0 to 4,
    R4Independently halogen, hydroxy, carboxy, oxo, nitro, COne-C6Alkyl, COne-C6Alkoxy, COne-C6Alkoxycarbonyl, trifluoromethyl, (RDPhenyl, optionally substituted with one to three substituents independently selected from phenyl, phenylsulfonyl, naphthyl, (RDC may be optionally substituted with one to three substituents independently selected fromOne-C6Aralkyl, (RD-O-aralkyl, which may be optionally substituted with one to three substituents independently selected fromDHeteroaryl, heterocycloalkyl, NH, which may be optionally substituted with one to three substituents independently selected from2, NHRA, N (RA)2, ,,,,,AndWhere RDAre each independently halogen, hydroxy, carboxy, oxo, COne-C4Alkyl, COne-C4Alkylthio, hydroxy COne-C4Alkyl, COne-C4Alkoxy, COne-C4Alkoxycarbonyl, COne-C4Alkylcarbonyl, trifluoromethyl, trifluoromethoxy, NH2, NHRA, N (RA)2, C (O) N (RA)2, SO2N (RA)2, Acetylamino, Nitro, Cyano, Formyl, COne-C6Alkylsulfonyl, carboxy COne-C6Selected from the group consisting of alkyl and aralkyl),
    c is an integer from 0 to 4,
    R 5 is independently halogen, nitro, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NH 2 , -NHR A , -N (R A ) 2 , OR A , -C (O) NH 2 , -C (O) NHR A , -C (O) N (R A ) 2 , -NHC (O) R A , -SO 2 NHR A , -SO 2 N (R A ) 2 , where R A are as defined above), (R B independently optionally substituted with one to three substituents selected) from the phenyl, (optionally substituted) heteroaryl, and (with one to three substituents independently selected from R B R Is selected from the group consisting of heterocycloalkyl, optionally substituted with one to three substituents independently selected from B ,
    a is an integer from 0 to 1,
    Y is -C 1 -C 6 alkyl-, -C (O),-(C 1 -C 6 alkyl) carbonyl-,-(C 2 -C 6 alkenyl) carbonyl-, -C 2 -C 6 (Alkynyl) carbonyl-, carbonyl (C 1 -C 6 alkyl)-, carbonyl (C 2 -C 6 alkenyl)-, -C (O) O- (C 1 -C 6 alkyl)-, -C (S)-, -SO 2 -,-(C 1 -C 6 alkyl) sulfonyl, -sulfonyl (C 1 -C 6 alkyl)-, -C (O) NH-, -C (O) NH- (C 1 -C 6 alkyl)-, C (O) (C 3 -C 7 cycloalkyl-) and-(C 3 -C 7 cycloalkyl) -C (O)-,
    Is selected from the group consisting of phenyl, furyl, thienyl and pyrrolyl,
    Is selected from the group consisting of aryl, heteroaryl, cycloalkyl and heterocycloalkyl,
    Provided that R 1 is hydrogen, R 3 is hydrogen, b is 0, c is 0, a is 1, Y is -CH 2- , Is phenyl, When is phenyl R 2 is not trimethoxyphenyl.
    [2" claim-type="Currently amended] The method of claim 1,
    R 1 is hydrogen,
    R 2 is (halogen, nitro, cyano, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, trifluoromethoxy, NH 2 , NH (C 1 -C 3 alkyl) and N ( Phenyl, heteroaryl and heterocycloalkyl, which may be optionally substituted with one or two substituents selected from C 1 -C 3 alkyl) 2 ,
    R 3 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl,
    b is an integer from 0 to 4,
    R 4 is halogen, hydroxy, carboxy, oxo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkoxycarbonyl, (hydroxy, carboxy, C 1 -C 4 alkyl, C 1 -C 4 alkylthio, hydroxy-C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxycarbonyl, C (O) N (R A ) 2 , trifluoromethyl, trifluoro Phenyl, optionally substituted with one or two substituents selected from methoxy, amino, (C 1 -C 4 alkyl) amino, di (C 1 -C 4 alkyl) amino, nitro, cyano or formyl) Aralkyl, (hydroxy, carboxy, oxo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkoxycarbonyl, C (O) N (R A ) 2 , trifluoromethyl, Heteroaryl, heterocycloalkyl, which may be optionally substituted with one or two substituents selected from trifluoromethoxy, amino, nitro, C 1 -C 3 alkylcarbonyl and C 1 -C 4 aralkyl, , , , , , And Is selected from the group consisting of
    c is 0,
    a is an integer of 0 to 1,
    Y is C 1 -C 4 alkyl, -C (S)-, -C (O)-, -C (O) O- (C 1 -C 4 alkyl)-, -C (O)-(C 1- C 4 alkyl)-, -C (O)-(C 2 -C 4 alkenyl)-, C (O)-(C 3 -C 7 cycloalkyl)-and -C (O) NH- (C 1- C 3 alkyl)-, and
    Is phenyl;
    Compounds selected from the group consisting of phenyl, heteroaryl and heterocycloalkyl and pharmaceutically acceptable salts thereof.
    [3" claim-type="Currently amended] The method of claim 2,
    R 2 is 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 5- (2,3-dihydrobenzofuryl), 3,4-dihydrobenzo- [1,4] -dioxin- 6-yl, 5-benzofuryl, 5-indanyl and 3-thienyl,
    R 3 is selected from the group consisting of hydrogen and methyl,
    R 4 is bromo, hydroxy, carboxy, oxo, methyl, phenyl, 4-hydroxyphenyl, 3-hydroxymethylphenyl, 4-hydroxymethylphenyl, 4-carboxyphenyl, 4-methylphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-methoxycarbonyl, 4-methoxycarbonylphenyl, 3-trifluoromethylphenyl, 4-cyanophenyl, 4-aminophenyl, 4-dimethylaminophenyl, 3-nitro Phenyl, 4-nitrophenyl, 4-formylphenyl, 4-methylthiophenyl, benzyloxy, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, N-oxy-2-pyridinyl, 3-thienyl, 2-furyl, 1-imidazolyl, 5- (1-benzyl-2-methylimidazolyl), 5- (1,2-dimethylimidazolyl), 5- (1-methylimidazolyl), 5 -(1-benzylimidazolyl), 3,4-methylenedioxyphenyl, , , , , And Is selected from the group consisting of
    Y is -CH 2- , -C (S)-, -C (O)-, -C (O) O-CH 2- , -C (O) -CH 2 CH 2- , -C (O)- CH = CH-, -C (O) NH-CH 2- (107), -C (O) -cyclopropyl and -C (O) CH 2 ,
    Divalent phenyl, 2-furyl, 2-benzo (b) furyl, 2-pyrimidinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 1-imidazolyl, 2-imidazolyl, 2- A compound selected from the group consisting of thiazolyl and 2-oxa-bicyclo [2.2.1] heptanyl and pharmaceutically acceptable salts thereof.
    [4" claim-type="Currently amended] The method of claim 3,
    R 2 is 3,4-methylenedioxyphenyl, 5- (2,3-dihydrobenzofuryl), 3,4-dihydrobenzo- [1,4] -dioxin-6-yl, 3-thienyl , 5-indanyl and 5-benzofuryl,
    R 3 is hydrogen,
    b is an integer from 0 to 1,
    R 4 is 5-bromo, 2-hydroxy, 6-hydroxy, 4-carboxy, phenyl, 4-hydroxyphenyl, 3-hydroxymethylphenyl, 4-hydroxymethylphenyl, 4-carboxyphenyl, 4-methylphenyl , 4-methylthiophenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-methoxycarbonyl, 4-methoxycarbonylphenyl, 3-trifluoromethylphenyl, 4-aminophenyl, 4- Dimethylaminophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-cyanophenyl, 4-formylphenyl, benzyloxy, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-furyl, 3-thier Nyl, N-oxo-2-pyridinyl, 1-imidazolyl, 5- (1-benzyl-2-methylimidazolyl), 5- (1,2-dimethylimidazolyl), 3,4-methylene Deoxyphenyl, , , , And Is selected from the group consisting of
    Y is -C (O)-, -C (O) O-CH 2- , -C (O) -CH 2 CH 2- , -C (O) -CH = CH- and -C (O) -cyclo From a group of profiles,
    And pharmaceuticals selected from the group consisting of phenyl, 2-furyl, 2-benzo (b) furyl, 2-pyrimidinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl and 2-thiazolyl Acceptable salts thereof.
    [5" claim-type="Currently amended] The method of claim 4, wherein
    R 2 is 3,4-methylenedioxyphenyl, 5- (2,3-dihydrobenzofuryl), 3,4-dihydrobenzo- [1,4] -dioxin-6-yl, 3-thienyl , 5-indanyl and 5-benzofuryl,
    R 4 is 5-bromo, 2-hydroxy, 6-hydroxy, 4-carboxy, phenyl, 4-hydroxyphenyl, 3-hydroxymethylphenyl, 4-hydroxymethylphenyl, 4-carboxyphenyl, 4-methylphenyl , 4-methylthiophenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-methoxycarbonyl, 4-methoxycarbonylphenyl, 3-trifluoromethylphenyl, 4-aminophenyl, 4- Dimethylaminophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-cyanophenyl, 4-formylphenyl, benzyloxy, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, N-oxo-2-pyri Diyl, 3-thienyl, 2-furyl, 1-imidazolyl, 5- (1-benzyl-2-methylimidazolyl), 5- (1,2-dimethylimidazolyl), 3,4-methylene Deoxyphenyl, , , And Is selected from the group consisting of
    And a pharmaceutically acceptable salt thereof, wherein Y is selected from the group consisting of -C (O)-, -C (O) O-CH 2-, and -C (O) -CH = CH-.
    [6" claim-type="Currently amended] The method of claim 5,
    R 4 is 6-hydroxy, 4-carboxy, phenyl, 4-hydroxyphenyl, 3-hydroxymethylphenyl, 4-methylphenyl, 4-methylthiophenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-methoxycarbonyl, 3-trifluoromethylphenyl, 3-nitrophenyl, 4-nitrophenyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, N-oxo-2-pyridinyl, 3- Thienyl, 5- (1-benzyl-2-methylimidazolyl), 5- (1,2-dimethylimidazolyl), And Compounds selected from the group consisting of: and pharmaceutically acceptable salts thereof.
    [7" claim-type="Currently amended] The method of claim 6,
    R 2 is selected from the group consisting of 3,4-methylenedioxyphenyl and 5- (2,3-dihydrobenzofuryl),
    R 4 is hydroxy, 4-methylphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-methoxycarbonyl, 3-trifluoromethylphenyl, 4-nitrophenyl, 2-pyridinyl, 3- Pyridinyl, And Is selected from the group consisting of
    Y is selected from the group consisting of -C (O)-and -C (O) O-CH 2 ,
    Silver is a compound selected from the group consisting of 2-furyl, 2-benzo (b) furyl, 4-pyridinyl, 2-pyrimidinyl and 2-thiazolyl and pharmaceutically acceptable salts thereof.
    [8" claim-type="Currently amended] The method of claim 7, wherein
    1,2,3,4-tetrahydro-2- [5- (3,4-dimethoxyphenyl) -pyrimidin-2-yl] -3- (3,4-methylenedioxyphenyl) -9H-P Rolo- [3,4-b] quinolin-9-one;
    1,2,3,4-tetrahydro-2-[(4-pyridinyl) methyloxycarbonyl] -3- (3,4-methylenedioxyphenyl) -9H-pyrrolo- [3,4-b ] Quinolin-9-one;
    1,2,3,4-tetrahydro-2- [5- (2-pyridinyl) -pyrimidin-2-yl] -3- (3,4-dihydrobenzofuranyl) -9H-pyrrolo- [3,4-b] quinolin-9-one;
    1,2,3,4-tetrahydro-2- [5- (4-methoxyphenyl) -pyrimidin-2-yl] -3- (3,4-dihydrobenzofuranyl) -9H-pyrrolo -[3,4-b] quinolin-9-one;
    1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -2- (5- (4- (1- (4-methyl) -piperazinylcarbonyl) -phenyl) -Furoyl) -9H-pyrrolo- [3,4-b] quinolin-9-one;
    1,2,3,4-tetrahydro-2- [2,3'-bipyridine] -6'-yl-3- (2,3-dihydro-5-benzofuranyl) -9H-pyrrolo- [3,4-b] quinolin-9-one;
    1,2,3,4-tetrahydro-2- (2-pyridinyl) -3- (2,3-dihydro-5-benzofuranyl) -9H-pyrrolo- [3,4-b] quinoline -9-one; And a pharmaceutically acceptable salt thereof.
    [9" claim-type="Currently amended] The method of claim 8,
    R-1,2,3,4-tetrahydro-2- [5- (3,4-dimethoxyphenyl) -pyrimidin-2-yl] -3- (3,4-methylenedioxyphenyl) -9H -Pyrrolo- [3,4-b] quinolin-9-one;
    R-1,2,3,4-tetrahydro-2-[(4-pyridinyl) methyloxycarbonyl] -3- (3,4-methylenedioxyphenyl) -9H-pyrrolo- [3,4 -b] quinolin-9-one;
    R-1,2,3,4-tetrahydro-2- [5- (2-pyridinyl) -pyrimidin-2-yl] -3- (3,4-dihydrobenzofuranyl) -9H-pi Rolo- [3,4-b] quinolin-9-one;
    R-1,2,3,4-tetrahydro-2- [5- (4-methoxyphenyl) -pyrimidin-2-yl] -3- (3,4-dihydrobenzofuranyl) -9H- Pyrrolo- [3,4-b] quinolin-9-one;
    R-1,2,3,4-tetrahydro-3- (3,4-methylenedioxyphenyl) -2- (5- (4- (1- (4-methyl) -piperazinylcarbonyl)- Phenyl) -furoyl) -9H-pyrrolo- [3,4-b] quinolin-9-one;
    R-1,2,3,4-tetrahydro-2- (2-pyridinyl) -3- (2,3-dihydro-5-benzofuranyl) -9H-pyrrolo- [3,4-b ] Quinolin-9-one; And a pharmaceutically acceptable salt thereof.
    [10" claim-type="Currently amended] Compounds of formula (I) or (II) and pharmaceutically acceptable salts thereof.
    Formula I

    Formula II

    In the above formulas (I) and (II),
    R 1 is hydrogen, carboxy, -C (O) -C 1 -C 6 alkyl, -C (O) -C 1 -C 6 alkoxy, -C (O) -NH-C 1 -C 6 alkyl-NH 2 , -C (O) -NH-C 1 -C 6 alkyl-NHR A , -C (O) -NH-C 1 -C 6 alkyl-N (R A ) 2 , -C (O) -NH 2 , -C (O) -NHR A , -C (O) -N (R A ) 2 , -C 1 -C 6 alkyl-NH 2 , -C 1 -C 6 alkyl-NHR A , -C 1 -C 6 Alkyl-N (R A ) 2 and -NH-C 1 -C 6 alkyl-N (R A ) 2 wherein R A is each independently C 1 -C 6 alkyl, aryl, C 1 -C 6 aralkyl And heteroaryl; Aryl, aralkyl or heteroaryl may be optionally substituted by one to three R B ; R B are each independently halogen, nitro, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylcarbonyl, carboxyC 1 -C 6 alkyl, C 1 -C 6 alkyl Sulfonyl, trifluoromethyl, amino, di (C 1 -C 6 alkyl) amino, acetylamino, carboxy C 1 -C 6 alkylcarbonylamino, hydroxyC 1 -C 6 alkylamino, NHR A and N ( R A ) is selected from the group consisting of 2 ;
    R 2 is independently from (halogen, hydroxy, nitro, amino, NHR A or N (R A) 2 optionally substituted with one to three substituents independently selected from optionally substituted) C 5 -C 10 alkyl, (C R Aryl optionally substituted with one to three substituents selected, cycloalkyl (optionally substituted with one to three substituents independently selected from R A ), optionally substituted with one to three substituents independently selected from R C ) Heteroaryl and heterocycloalkyl (optionally substituted with one to three substituents independently selected from R C ), wherein R C is halogen, nitro, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, Trifluoromethyl, trifluoromethoxy, NH 2 , NH (C 1 -C 6 alkyl) and N (C 1 -C 6 alkyl) 2 );
    R 3 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 2 -C 6 alkenylcarbonyl and C 2 -C 6 alkynylcarbonyl,
    b is an integer from 0 to 4,
    R4Independently halogen, hydroxy, carboxy, nitro, COne-C6Alkyl, COne-C6Alkoxy, COne-C6Alkoxycarbonyl, trifluoromethyl, (RDPhenyl, phenylsulfonyl, naphthyl, C, which may be optionally substituted with one to three substituents independently selected fromOne-C6Aralkyl, (RD-O-aralkyl, which may be optionally substituted with one to three substituents independently selected fromDHeteroaryl, optionally substituted with one to three substituents independently selected from2, NHRA, N (RA)2, ,,,,,AndWhere RDAre each independently halogen, hydroxy, carboxy, COne-C4Alkyl, COne-C4Alkoxy, COne-C4Alkoxycarbonyl, COne-C4Alkylcarbonyl, trifluoromethyl, trifluoromethoxy, NH2, NHRA, N (RA)2, C (O) N (RA)2, SO2N (RA)2, Acetylamino, Nitro, Cyano, Formyl, COne-C6Alkylsulfonyl and carboxy COne-C6Selected from the group consisting of alkyl),
    c is an integer from 0 to 4,
    R 5 is independently halogen, nitro, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NH 2 , -NHR A , -N (R A ) 2 , OR A , -C (O) NH 2 , -C (O) NHR A , -C (O) N (R A ) 2 , -NHC (O) R A , -SO 2 NHR A , -SO 2 N (R A ) 2 , where R A are as defined above), (R B independently optionally substituted with one to three substituents selected) from the phenyl, (optionally substituted) heteroaryl, and (with one to three substituents independently selected from R B R Is selected from the group consisting of heterocycloalkyl, optionally substituted with one to three substituents independently selected from B ,
    a is an integer from 0 to 1,
    Y is -C 1 -C 6 alkyl-, -C (O),-(C 1 -C 6 alkyl) carbonyl-,-(C 2 -C 6 alkenyl) carbonyl-, -C 2 -C 6 (Alkynyl) carbonyl-, carbonyl (C 1 -C 6 alkyl)-, carbonyl (C 2 -C 6 alkenyl)-, -C (O) O- (C 1 -C 6 alkyl)-, -C (S)-, -SO 2 -,-(C 1 -C 6 alkyl) sulfonyl, -sulfonyl (C 1 -C 6 alkyl)-, -C (O) NH-, -C (O) NH- (C 1 -C 6 alkyl)-, C (O) (C 3 -C 7 cycloalkyl-) and-(C 3 -C 7 cycloalkyl) -C (O)-,
    Is selected from the group consisting of phenyl, furyl, thienyl and pyrrolyl,
    Is selected from the group consisting of aryl, heteroaryl, cycloalkyl and heterocycloalkyl,
    Provided that R 1 is hydrogen, R 3 is hydrogen, b is 0, c is 0, a is 1, Y is -CH 2- , Is phenyl, When is phenyl R 2 is not trimethoxyphenyl.
    [11" claim-type="Currently amended] A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
    [12" claim-type="Currently amended] A pharmaceutical composition prepared by mixing the compound of claim 1 and a pharmaceutically acceptable carrier.
    [13" claim-type="Currently amended] A method of preparing a pharmaceutical composition comprising mixing the compound of claim 1 and a pharmaceutically acceptable carrier.
    [14" claim-type="Currently amended] A method of treating sexual dysfunction comprising administering a therapeutically effective amount of a compound of claim 1 to a subject in need thereof.
    [15" claim-type="Currently amended] A method of treating sexual dysfunction comprising administering to a subject in need thereof a therapeutically effective amount of the composition of claim 11.
    [16" claim-type="Currently amended] 15. The method of claim 14, wherein the sexual dysfunction is associated with male sexual dysfunction, male erectile dysfunction, impotence, female sexual dysfunction, female sexual dysfunction, and blood flow and nitric oxide production in vaginal and clitoris tissues.
    [17" claim-type="Currently amended] A method of increasing cGMP concentration in penile tissues of a male, comprising administering an effective amount of the compound of claim 1 to a male subject in need thereof.
    [18" claim-type="Currently amended] A method comprising administering a therapeutically effective amount of a compound of claim 1 to a subject in need thereof, comprising: male erectile dysfunction (ED), impotence, female sexual dysfunction, blood flow and nitric oxide production in vaginal and clitoris tissue Female sexual dysfunction, preterm labor, dysmenorrhea, cardiovascular disease, atherosclerosis, arterial obstruction, thrombosis, coronary resting stenosis, angina pectoris, myocardial infarction, heart failure, ischemic heart disease, hypertension, pulmonary hypertension, asthma, intermittent claudication and diabetes complications A method of treating a symptom selected from the group consisting of.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2000-05-17|Priority to US20464600P
    2000-05-17|Priority to US60/204,646
    2001-05-03|Application filed by 오르토-맥네일 파마슈티칼, 인코퍼레이티드
    2003-04-21|Publication of KR20030031483A
    优先权:
    申请号 | 申请日 | 专利标题
    US20464600P| true| 2000-05-17|2000-05-17|
    US60/204,646|2000-05-17|
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