Derivatives of substituted pyrrolopyridinone useful as phosphodiesterase inhibitors

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes a compound of the general formula (I) or (II) wherein R1 represents hydrogen atom; R2 is taken among the group consisting of aryl and heteroaryl; R3 is taken among the group consisting of halogen atom, nitro-, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, trifluoromethyl, trifluoromethoxy-group, -NH2, -NH-(C1-C6)-alkyl and -N-(C1-C6)-alkyl)2; b is a whole number from 0 to 4; R4 is taken independently among the group consisting of halogen atom, hydroxy-, carboxy-, oxo-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkoxycarbonyl, phenyl (wherein phenyl group can be substituted optionally with one-three substitutes taken independently among RD), phenylsulfonyl, heteroaryl (wherein heteroaryl can be substituted optionally with one-three substitutes taken independently among RD), heterocycloalkyl, -NH2, -NHRA, -N-(RA)2,

wherein each RD is taken independently among halogen atom, hydroxy-, carboxy-, oxo-group, (C1-C4)-alkyl, (C1-C4)-alkylthio, hydroxy-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkylcarbonyl, trifluoromethyl, trifluoromethoxy-group, -NH2. -NHRA, -N-(RA)2, -C(O)N(RA)2, -SO2N(RA)2, acetylamino-, nitro-, cyano-group, formyl, (C1-C6)-alkylsulfonyl, carboxy-(C1-C6)-alkyl and aralkyl; c = 0; a means a whole number from 0 to 1; Y is taken among the group consisting of a residue -(C1-C)-alkyl, -C(O)-, -(C2-C6)-alkenyl)-carbonyl, -carbonyl-(C1-C6)-alkyl)-, -C(S)-, -C(O)NH-(C1-C6)_alkyl), -C(O)-(C3-C7)-cycloalkyl)- and (C3-C7)-cycloalkyl)-C(O)-; represents phenyl;

is taken among the group consisting of phenyl, heteroaryl and cycloalkyl under condition that when R1 represents hydrogen atom, R3 represents hydrogen atom, b = 0, c = 1, Y represents -CH2-, represents phenyl and represents phenyl then R2 is not trimethoxyphenyl, and its pharmaceutically acceptable salts. Also, invention describes a pharmaceutical composition designated for inhibition of activity of phosphodiesterase comprising a pharmaceutically acceptable vehicle and compound by cl. 1, method for preparing pharmaceutical composition, methods for treatment of sexual dysfunction by using compound by cl. 1 or pharmaceutical composition, method for increasing the concentration of cGMP in penis tissue and method for treatment of state when inhibition of activity of phosphodiesterase shows the favorable effect. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal and biochemical properties of compounds and composition.

17 cl, 7 tbl, 98 ex

 

CROSS-REFERENCE TO RELATED APPLICATION

In this application claims priority based on provisional application of the United States, registration No. 60/204646, filed may 17, 2000, the contents of which are thereby incorporated by reference.

The SCOPE of the INVENTION

The invention relates to new derivatives of pyrrolopyridine, intermediate products used in the synthesis, and pharmaceutical compositions containing the compounds, and their use for the treatment of sexual dysfunction. Compounds of the present invention are inhibitors of phosphodiesterase suitable for the treatment of sexual dysfunction, more specifically, men's erectile dysfunction.

BACKGROUND of INVENTION

Erectile dysfunction (ED) is defined as the inability to achieve or maintain an erection firm enough for satisfactory sexual intercourse. Currently, it is estimated that approximately 7-8% of the male population suffers from some degree of ED, which is equivalent to at least 20 million men in the United States. Because the probability of ED increases with age, predicted that the prevalence of this condition will grow in the future as the average age of the population increases.

Male erectile dysfunction can be due to psychogenic and/or organic the factors. Although ED is multifactorial, it is more likely that some sub-groups within the male population have symptoms of disorders. In particular, patients with diabetes, hypertension, heart disease and multiple sclerosis are of a particularly high proliferation ED. In addition, patients who are taking certain classes of drugs, such as antihypertensives, antidepressants, sedatives and anxiolytics are more prone to ED.

Treatment of ED include various pharmacological agents, vacuum devices and penile prosthesis. Among pharmacological agents in practice currently use papaverine, phentolamine and alprostadil. These agents are effective only after direct intracavernous or intraurethral injections and are associated with side effects such as priapism, fibrosis, pain in the penis and hematoma at the injection site. Vacuum devices are devices for non-invasive alternative treatment for ED. These devices cause an erection by creating a vacuum around the body of the penis, which leads to increased blood flow in the bulk of the cavernous body through passive arterial dilatation. Although this form of therapy is often successful in the treatment of ED of organic origin, complaints include a lack of spontaneity and time is EIW, required when using the device, and the difficulty and discomfort during ejaculation. With some success used different semi-solid or inflatable penile prosthesis, especially in men with diabetes. These devices are usually considered when other treatment options have failed and are associated with an increased risk of infection and ischemia.

Recently, a phosphodiesterase inhibitor V (PDEV), sildenafil (viagra) was approved by the FDA as orally effective drug therapies for the treatment of ED. Sildenafil, 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)phenyl]-1-methyl-3-n-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidine-7-he, and a number of related analogs and their use as agents against angina is described in U.S. patent 5250534 and 5346901. Use of sildenafil and related analogues for the treatment of male erectile dysfunction is described in published International patent application PCT WO 94/28902 published 22 December 1994. In clinical studies, the drug was improved sexual function in approximately 70% of men who suffer from ED psychogenic or organic etiology. However, the drug showed less effective in patients who had undergone radical prostatectomy, observed increased erections in 43% of patients who took si is denafil, compared to 15% of patients taking placebo. In addition, the use of sildenafil has been associated with several undesirable side effects, including headache, a rush of blood to the face and disturbed color perception, which are the result of non-selective actions on different tissues. Despite these shortcomings, the drug is considered by patients as preferred in comparison with other treatment methods, which consist in the introduction of drugs directly into the penis by injections, the use of external devices or surgery.

Daugan et al. in U.S. patent 5859009 and EP 0740668 B1 described the synthesis of a number of tetracyclic derivatives as inhibitors of cyclic guanosine-3',5'-monophosphate especially phosphodiesterase and their use in the treatment of cardiovascular diseases. Daugan et al. in WO 97/03675 reported use of tetracyclic derivatives for the treatment of impotence.

Garinaux, J.-F. et al. in Tetrahedron Letters 38(17), (1997), PP. 2997-3000 described the synthesis of tricyclic quinolone derivatives by oxidation of 1,2,3,4-tetrahydro-β-carbolines, which.

Pfenninger, E. in German patent 2803541 and U.S. patent 4235907 described substituted N-pyrrolo[3,4-b]quinoline-9-ones and their use in the treatment of allergic asthma.

Sexually stimulated erection sex is about a member is the result of a complex interaction of physiological processes, including the processes of the Central nervous system, peripheral nervous system and smooth muscle. In particular, the emission of nitric oxide from neadrenergicheskoy, neholinergichesky nerves and endothelium activates guanililcyclase and increases the levels of intracellular cGMP in volumetric cavernous body. Increased intracellular cGMP reduces the levels of intracellular calcium, which leads to relaxation of trabecular smooth muscle, which, in turn, leads to an increase in body volume and compression intrathecal venules, leading to penile erection.

PDE V found in platelets and vascular smooth muscle of a man that suggests the role of this enzyme in the regulation of intracellular concentrations of cGMP in cardiovascular tissue. Actually, it is shown that inhibitors PDEV cause endothelial-dependent vasodilatation potentiation increases levels of intracellular cGMP induced by nitric oxide. In addition, PDEV inhibitors selectively reduce pulmonary arterial pressure in animal models of congestive heart failure and pulmonary hypertension. Therefore, in addition to their usefulness in ED, PDEV inhibitors might be therapeutically useful in conditions like heart failure, pulmonary hypertension and angina.

It is assumed that the agents, which is haunted increase the concentration of cGMP in the tissue of the penis either through increased release any reduced decomposition of cGMP, are effective means to treat ED. Intracellular levels of cGMP regulate the enzymes involved in their formation and degradation, namely, guanylate cyclase and cyclooctatetraene (PDE). By now described, at least nine families of PDE mammals, five of which are able to hydrolyze active cGMP to inactive GMP under physiological conditions (PDEs I, II, V, VI and IX). PDE V is the predominant isoform in the bulk of the cavernous body. Therefore, we can assume that the PDEV inhibitors increase the concentration of cGMP in the bulk of the cavernous body and increase the duration and frequency of erections of the penis.

In addition, it is known that selective PDE inhibitors are suitable for the treatment of various disorders and conditions, including male erectile dysfunction (ED), female sexual dysfunction irritability, female sexual dysfunction related to blood flow and the production of nitric oxide in the tissues of the vagina and clitoris, premature labour, dysmenorrhoea, cardiovascular disorders, atherosclerosis, arterial occlusal disorders, thrombosis, coronary stenosis at rest, angina, myocardial infarction, heart failure, ischemic disorders, heart, hypertension, pulmonary hypertension, asthma, re iahushua claudication and diabetic complications.

In line with this, the aim of the invention is to identify compounds that increase the concentration of cGMP in the tissue of the penis by inhibiting phosphodiesterase, especially PDEV. Another aim of the invention is to identify compounds that are suitable for the treatment of sexual dysfunction, especially erectile dysfunction and/or impotence in male animals and sexual dysfunction in female animals.

Another aim of the invention is the determination of the methods of treatment of sexual dysfunction, especially erectile dysfunction, with the use of compounds of the present invention.

Another aim of the invention is the determination of compounds that are suitable for treating conditions disorders mediated PDEV, such as male erectile dysfunction, female sexual dysfunction, cardiovascular disorders, atherosclerosis, arterial occlusal disorders, thrombosis, coronary stenosis at rest, angina, myocardial infarction, heart failure, ischemic disorders, heart, hypertension, pulmonary hypertension, asthma, intermittent claudication or diabetic complications.

Next, the authors described a number of derivatives of pyrrolopyridine with the ability to inhibit phosphodiesterase type V enzyme assays.

A SUMMARY IS SUBRAMANIA

The present invention relates to new derivatives of pyrrolopyridine, suitable as inhibitors of phosphodiesterase. More specifically, the present invention relates to compounds of General formula (I) or (II):

where R1selected from the group consisting of hydrogen, carboxy, -C(O)-C1-C6alkyl, -C(O)-C1-C6alkoxy, -C(O)-NH-C1-C6alkyl-NH2-C(O)-NH-C1-C6alkyl-otherA-C(O)-NH-C1-C6alkyl-N(RA)2-C(O)-NH2, -C(O)-otherA, -C(O)-N(RA)2- 1-C6alkyl-NH2- 1-C6alkyl-otherA- 1-C6alkyl-N(RA)2, -NH-C1-C6alkyl-N(RA)2;

where each RAindependently selected from the group consisting of C1-C6of alkyl, aryl, C1-C6aralkyl and heteroaryl, where aryl, aralkyl or heteroaryl may be optionally substituted by one to three RB;

where each RBindependently selected from the group consisting of halogen, nitro, cyano, C1-C6of alkyl, C1-C6alkoxy, C1-C6alkylcarboxylic, carboxy1-C6of alkyl, C1-C6alkylsulfonyl, trifloromethyl, amino, di(C1-C6alkyl)amino, acetylamino, carboxyl1-C6alkylcarboxylic, hydroxys 1-C6alkylamino, otherAand N(RA)2;

R2selected from the group consisting of C5-C10the alkyl (optionally substituted by one to three substituents, independently selected from halogen, hydroxy, nitro, amino, otherAor N(RA)2), aryl (optionally substituted by one to three substituents, independently selected from RC), cycloalkyl (optionally substituted by one to three substituents, independently selected from RA), heteroaryl (optionally substituted by one to three substituents, independently selected from RCand geterotsiklicheskie (optionally substituted by one to three substituents, independently selected from RC);

where RCselected from the group consisting of halogen, nitro, cyano, C1-C6of alkyl, C1-C6alkoxy, trifloromethyl, triptoreline, NH2, NH(C1-C6alkyl) and N(C1-Cb-alkyl)2;

R3selected from the group consisting of hydrogen, C1-C6of alkyl, C1-C6alkylcarboxylic,2-C6alkenylboronic and C2-C6alkynylaryl;

b is an integer from 0 to 4;

R4independently selected from the group consisting of halogen, hydroxy, carboxy, oxo, nitro, C1-C6of alkyl, C1-C6alkoxy, C1-C6alkoxycarbonyl the La, trifloromethyl, phenyl (where the phenyl group can be optionally substituted with one to three substituents, independently selected from RD), phenylsulfonyl, naphthyl, C1-C6aralkyl, -O-aralkyl (where kalkilya group can be optionally substituted with one to three substituents, independently selected from RD), heteroaryl (where heteroaryl may be optionally substituted with one to three substituents, independently selected from RD), geterotsiklicheskie, NH2, OtherAN(RA)2,

where each RDindependently selected from halogen, hydroxy, carboxy, oxo, C1-C4of alkyl, C1-C4alkylthio, hydroxys1-C4of alkyl, C1-C4alkoxy, C1-C4allyloxycarbonyl,1-C4alkylcarboxylic, trifloromethyl, triptoreline, NH2, OtherAN(RA)2C(O)N(RA)2, acetylamino, nitro, cyano, formyl, C1-C6alkylsulfonyl, carboxy1-C6the alkyl and aralkyl;

C is an integer from 0 to 4;

R5independently selected from the group consisting of halogen, nitro, hydroxy, C1-C6of alkyl, C1-C6alkoxy, -NH2-The otherA, -N(RA)2, -ORA, -The(o)NH 2, -C(O)otherA, -C(O)N(RA)2, -NHC(O)RA, -SO2OtherA, -SO2N(RA)2where RAhas the above values, phenyl (optionally substituted by one to three substituents, independently selected from RB), heteroaryl (optionally substituted by one to three substituents, independently selected from RBand geterotsiklicheskie (optionally substituted by one to three substituents, independently selected from RB);

and is an integer from 0 to 1;

Y is selected from the group consisting of the following: -C1-C6alkyl-, -C(O)-, -(C1-C6alkyl)carbonyl-, -(C2-C6alkenyl)carbonyl, -(C2-C6quinil)carbonyl-, carbonyl(C1-C6alkyl)-, -carbonyl-(C2-C6alkenyl), -C(O)O-(C1-C6alkyl)-, -C(S)-, -SO2-, -(C1-C6alkyl)sulfonyl-, -sulfonyl(C1-C6alkyl)-, -C(O)NH-, -C(O)NH-(C1-C6alkyl)-, -C(O)(C3-C7cycloalkyl)and (C3-C7cycloalkyl)-C(O)-;

selected from the group consisting of phenyl, furil, tanila and pyrrolyl;

selected from the group consisting of aryl, heteroaryl, cycloalkyl and geterotsiklicheskie;

provided that when R1is hydrogen, R3represents hydrogen, b is 0, C is 0, and the Rav is about 1, Y represents-CH2-,represents phenyl andrepresents phenyl, then R2is not trimethoxyphenyl (i.e. the connection is not 1,2,3,4-tetrahydro-2-(phenylmethyl)-3-(3,4,5-trimethoxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-one);

and their pharmaceutically acceptable salts.

The illustration of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compounds described above. The illustration of the invention is a pharmaceutical composition made by mixing any of the compounds described above and a pharmaceutically acceptable carrier. The illustration of the invention is a method of obtaining a pharmaceutical composition comprising mixing any of the compounds described above and a pharmaceutically acceptable carrier.

An example of the invention is a method of treatment of a condition selected from the group consisting of male erectile dysfunction (ED), impotence, female sexual dysfunction irritability, female sexual dysfunction related to blood flow and the production of nitric oxide in the tissues of the vagina and clitoris, premature birth, dysmenorrhea, cardiovascular disorders, atherosclerosis, arterial occlusal disorders, thrombosis, coronary stenosis at rest, the walls of the cardia, myocardial infarction, heart failure, ischemic heart disorders, hypertension, pulmonary hypertension, asthma, intermittent claudication and diabetic complications in a subject in need thereof, comprising administration to the subject a therapeutically effective amount of any of the compounds or the above-described pharmaceutical compositions.

An example implementation of the invention is a method of increasing the concentration of cGMP in the tissue of the penis by inhibiting phosphodiesterase, especially PDEV, a male subject, in need thereof, comprising administration to the subject an effective amount of any of the compounds or pharmaceutical compositions described above.

The following example implementation of the invention is the method of production. endothelial-dependent dilation of the vessels potentiation increases levels of intracellular cGMP induced by nitric oxide, the subject in need thereof, comprising administration to the subject an effective amount of any of the compounds or pharmaceutical compositions described above.

An example embodiment of the invention is the use of any of the compounds described above, to obtain medicines for: (a) treatment of sexual dysfunction, particularly male erectile dysfunction, (b) the treatment of impotence, (C) higher the Oia cGMP concentration in the tissue of the penis by inhibiting phosphodiesterase, especially, PDE V and/or d) treatment of a condition selected from the group consisting of premature birth, dysmenorrhea, cardiovascular disorders, atherosclerosis, arterial occlusal disorders, tremosa, coronary stenosis at rest, angina, myocardial infarction, heart failure, ischemic heart disorders, hypertension, pulmonary hypertension, asthma, intermittent claudication and diabetic complications in a subject in need thereof.

DETAILED description of the INVENTION

The present invention relates to new derivatives of pyrrolopyridine suitable for the treatment of sexual dysfunction, particularly male erectile dysfunction (ED). Although the compounds of the present invention is suitable mainly for the treatment of male sexual dysfunction or erectile dysfunction, they can be also suitable for the treatment of female sexual dysfunction, for example, female sexual dysfunction irritability, female sexual dysfunction related to blood flow and the production of nitric oxide in the tissue of the vagina and clitoris, premature birth and dysmenorrhea.

More specifically, the compounds of the present invention are the compounds of formula (I) or (II):

where all the symbols have the meanings indicated above, and their pharmaceutically acceptable salts.

R1before occhialino, represents hydrogen.

In the exemplary embodiment of the present invention R2selected from the group consisting of phenyl (optionally substituted by one or two substituents selected from halogen, nitro, cyano, C1-C3of alkyl, C1-C3alkoxy, trifloromethyl, triptoreline, NH2, NH(C1-C3alkyl) or N(C1-C3-alkyl)2), heteroaryl and geterotsiklicheskie. Preferably, R2selected from the group consisting of 3,4-methylenedioxyphenyl, 3,4-acid, 5-(2,3-dihydrobenzofuran), 3,4-dihydrobenzo[1,4]dioxin-6-yl, 5-benzofuran, 5-indanyl and 3-tanila. More preferably, R2selected from the group consisting of 3,4-methylendioxyphenyl, 5-(2,3-dihydrobenzofuran), 3,4-dihydrobenzo[1,4]dioxin-6-yl, 3-tanila, 5-indanyl and 5-benzofuran. Even more preferably, R2selected from the group consisting of 3,4-methylendioxyphenyl, 5-(2,3-dihydrobenzofuran), 3,4-dihydrobenzo[1,4]dioxin-6-yl, 3-tanila, 5-indanyl and 5-benzofuran. Most preferably, R2selected from the group consisting of 3,4-methylendioxyphenyl and 5-(2,3-dihydrobenzofuran).

Preferably, R3selected from the group consisting of hydrogen and C1-C4the alkyl. More preferably, R3selected from the group consisting of hydrogen and methyl. Most preferably, R3is in dorog.

Preferably, b is an integer from 0 to 4. More preferably, b is an integer of 0 or 1.

In the exemplary embodiment of the present invention R4selected from the group consisting of halogen, hydroxy, carboxy, oxo, C1-C3of alkyl, C1-C3alkoxy, C1-C3alkoxycarbonyl, phenyl (which phenyl may be optionally substituted by one or two substituents selected from hydroxy, carboxy, C1-C4of alkyl, C1-C4alkylthio, hydroxys1-C4of alkyl, C1-C4alkoxy, C1-C4allyloxycarbonyl, C(O)N(RA)2, trifloromethyl, triptoreline, amino, (C1-C4alkyl)amino, di(C1-C4alkyl)amino, nitro, cyano or formyl), O-aralkyl, heteroaryl (where heteroaryl may be optionally substituted by one or two substituents selected from hydroxy, carboxy, oxo, C1-C3of alkyl, C1-C3alkoxy, C1-C3allyloxycarbonyl, C(O)N(RA)2, trifloromethyl, triptoreline, amino, nitro, C1-C3alkylcarboxylic or1-C4aralkyl), geterotsiklicheskie,

Preferably, R4selected from the group consisting of bromine, hydroxy, carboxy, oxo, methyl, phenyl, 4-hydroxyphenyl, 3-hydroxymethylene, 4-hydrox is methylphenyl, 4-carboxyphenyl, 4-methylphenyl, 4-methoxyphenyl, 3,4-acid, 4-methoxycarbonyl, 4-ethoxycarbonylphenyl, 3-triptoreline, 4-cyanophenyl, 4-AMINOPHENYL, 4-dimethylaminophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-formylphenyl, 4-methylthiophenyl, benzyloxy, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, N-hydroxy-2-pyridinyl, 3-tanila, 2-furil, 1 imidazolyl, 5-(1-benzyl-2-methylimidazole), 5-(1,2-dimethylimidazole), 5-(1-methylimidazole), 5-(1-benzylimidazole), 3,4-methylendioxyphenyl,

More preferably, R4selected from the group consisting of 5-bromo, 2-hydroxy, 6-hydroxy, 4-carboxy, phenyl, 4-hydroxyphenyl, 3-hydroxymethylene, 4-hydroxymethylene, 4-carboxyphenyl, 4-methylphenyl, 4-methylthiophenyl, 4-methoxyphenyl, 3,4-acid, 4-methoxycarbonyl, 4-ethoxycarbonylphenyl, 3-triptoreline, 4-AMINOPHENYL, 4-dimethylaminophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-cyanophenyl, 4-formylphenyl, benzyloxy, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-furil, 3-tanila, N-oxo-2-pyridinyl, 1 imidazolyl, 5-(1-benzyl-2-methylimidazole), 5-(1,2-dimethylimidazole), 3,4-methylendioxyphenyl,

Even more preferably, R4selected from the group consisting of 5-bromo, 2-hydroxy, 6-hydroxy, 4-carboxy, phenyl, 4-guide is oxyphenyl, 3-hydroxymethylene, 4-hydroxymethylene, 4-carboxyphenyl, 4-methylphenyl, 4-methylthiophenyl, 4-methoxyphenyl, 3,4-acid, 4-methoxycarbonyl, 4-ethoxycarbonylphenyl, 3-triptoreline, 4-AMINOPHENYL, 4-dimethylaminophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-cyanophenyl, 4-formylphenyl, benzyloxy, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, N-oxo-2-pyridinyl, 3-tanila, 2-furil, 1 imidazolyl, 5-(1-benzyl-2-methylimidazole), 5-(1,2-dimethylimidazole), 3,4-methylendioxyphenyl,

Even more preferably, R4selected from the group consisting of 6-hydroxy, 4-carboxy, phenyl, 4-hydroxyphenyl, 3-hydroxymethylene, 4-methylphenyl, 4-methylthiophenyl, 4-methoxyphenyl, 3,4-acid, 4-methoxycarbonyl, 3-triptoreline, 3-nitrophenyl, 4-nitrophenyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, N-oxo-2-pyridinyl, 3-tanila, 5-(1-benzyl-2-methylimidazole), 5-(1,2-dimethylimidazole),

Most preferably, R4selected from the group consisting of hydroxy, 4-methylphenyl, 4-methoxyphenyl, 3,4-acid, 4-methoxycarbonyl, 3-triptoreline, 4-nitrophenyl, 2-pyridinyl, 3-pyridinyl,

In the preferred embodiment, C is 0. In another preferred embodiment, as well as C is to scrap the number from 0 to 1.

In the exemplary embodiment of the present invention Y is selected from the group consisting of-C1-C4alkyl-, -C(S)-, -C(O)-, -C(O)O-(C1-C4alkyl)-, -C(O)-(C1-C4alkyl)-, C(O)-(C2-C4alkenyl)-, -C(O)-(C3-C7cycloalkyl)- and-C(O)NH-(C1-C3alkyl)-. Preferably, Y is selected from the group consisting of-CH2-, -C(S)-, -C(O)-, -C(O)O-CH2-, -C(O)-CH2CH2-, -C(O)-CH=CH-, C(O)NH-CH2-, -C(O)-cyclopropyl and-C(O)CH2-. More preferably, Y is selected from the group consisting of-C(O)-, -C(O)O-CH2-, -C(O)-CH2CH2-, -C(O)-CH=CH - and-C(O)-cyclopropyl. Even more preferably, Y is selected from the group consisting of-C(O)-, -C(O)O-CH2and-C(O)-CH=CH-. Most preferably, Y is selected from the group consisting of-C(O)- and-C(O)O-CH2-.

Preferably,represents phenyl.

In one preferred example implementationselected from the group consisting of phenyl, heteroaryl and geterotsiklicheskie. Preferably,selected from the group consisting of phenyl, 2-furil, 2-benzo(b)of furil, 2-pyrimidinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 1 imidazolyl, 2-imidazolyl, 2-thiazolyl and 2-oxabicyclo[2.2.1]heptenyl. More preferably,selected from the group consisting of phenyl, -furil, 2-benzo(b)of furil, 2-pyrimidinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl and 2-thiazolyl. Most preferably,selected from the group consisting of 2-furil, 2-benzo(b)of furil, 4-pyridinyl, 2-pyrimidinyl and 2-thiazolyl.

The term "halogen" includes iodine, bromine, chlorine and fluorine.

The term "alkyl", regardless if they use it separately or as part of a group substituent, means alkanes with unbranched or branched chain, containing from one to ten carbon atoms or any number of atoms in this range. Alkyl radicals include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl and 2-methylpentyl. Similarly, alkeline and alkyline groups include alkenes and alkynes with unbranched or branched chain, containing from two to ten carbon atoms or any number of atoms in this range.

The term "alkoxy" means an oxygen ether radical of the above described alkyl groups with unbranched or branched chain. Alkoxyalkyl include, for example, methoxy, ethoxy, n-propoxy, n-butoxy, sec-butoxy, tert-butoxy and the like.

The term "aryl" means an aromatic group such as phenyl, naphthyl and the like.

The term "aralkyl" OSN which denotes alkyl group, substituted aryl group, for example, benzyl, phenylethyl, and the like. Similarly, the term "aralkyl" means alkenylphenol group, substituted aryl group, for example, phenylethenyl and the like.

The term "heteroaryl", used here, is a system of five - or six-membered monocyclic aromatic ring containing one to three heteroatoms independently selected from N, O or S; and any nine - or decatizing bicyclic aromatic ring containing carbon atoms and from one to four heteroatoms independently selected from N, O or S. the Heteroaryl group may be attached at any heteroatom or carbon atom which results in the formation of a stable structure. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyrimidinyl, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzofuranyl, benzothiazol, benzisoxazole, benzoxazole, indazole, indolyl, benzothiazolyl, benzotriazolyl, benzothiazolyl, chinoline, ethenolysis, purinol. Preferred heteroaryl groups include pyrimidinyl, pyridinyl, furyl, imidazolyl, benzofuranyl and thiazolyl.

The term "cycloalkyl"used here represent the screens structure stable three to eight-membered monocyclic ring, consisting of saturated carbon atoms. Suitable examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The term "heteroseksualci" represents the structure of a stable saturated or partially unsaturated three-to eight-membered monocyclic ring containing carbon atoms and from one to four, preferably from one to two heteroatoms independently selected from N, O or S; or the system of any stable saturated, partially unsaturated or partially aromatic nine-decatizing bicyclic ring that contains carbon atoms and from one to four heteroatoms independently selected from N, O or S. Heteroseksualci can be attached at any carbon atom or heteroatom which results in the formation of a stable structure. Suitable examples geterotsiklicheskikh groups include pyrrolidinyl, pyrazolidine, piperidine, piperazinil, morpholinyl, dithienyl, tritional, DIOXOLANYL, dioxane, thiomorpholine, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuran, 2,3-dihydrobenzo[1,4]dioxin-6-yl, 2,3-dihydrofuro[2,3-b]pyridinyl, 1,2-(methylenedioxy)cyclohexane, indanyl, 2-oxabicyclo[2.2.1]heptenyl and the like. Preferred heterocytolysine group include piperidinyl, pyrrolidinyl, morpholinyl, indanyl, 2-oxabicyclo[2.2.1]hept the Nile, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuran and 2,3-dihydrobenzo[1,4]dioxin-6-yl.

Used herein, the symbol "*" indicates the presence of a stereogenic center.

Have in mind that the definition of any substituent or index at a specific location in a molecule is independent of its definitions elsewhere in this molecule. It is clear that the average person skilled in the art can be selected substituents and their location in the compounds of the present invention to produce compounds that are chemically stable and which can be easily synthesized by methods known in this field, but also in the way proposed here. Next, we mean that when b or C>1, the respective substituents R4or R5may be the same or different.

When the compounds of this invention have at least one chiral center, they may accordingly exist as enantiomers. When the compounds have two or more chiral centers, they may additionally exist as diastereomers. It should be understood that all such isomers and mixtures thereof are included in the scope of the present invention. In addition, some of the crystalline forms of the compounds may exist as polymorphs, and it is implied that they, as such, is clucene in the present invention. In addition, some of the compounds may form a solvate with water (i.e. hydrates) or common organic solvents, and implied that such a solvate is also included in the scope of this invention.

In the standard nomenclature used throughout this description, the end part of the specified side chain describe first and then providing the neighboring functional groups in the direction of joining. Thus, for example, Deputy

"panels1-C6alkylaminocarbonyl1-C6alkyl" refers to a group of the formula

Used herein, the term "sexual dysfunction" includes male sexual dysfunction, male erectile dysfunction, impotence, female sexual dysfunction, female sexual dysfunction excitability and female sexual dysfunction related to blood flow and the production of nitric oxide in the tissues of the vagina and clitoris.

The term "subject"as used herein, refers to an animal, preferably a mammal, most preferably, to a person who is the object of treatment, observation or experiment.

The term "therapeutically effective amount", as used herein, means that amount of active compound or pharmaceutical agent that causes the biological or medical response system tissue from an animal or human, which is determined by the researcher, veterinarian, medical doctor or other Clinician, and which includes relieving symptoms of diseases or disorders, being treated with.

Referring to that used in this description, the term "composition" includes a product containing certain ingredients in certain amounts, as well as any product which is produced directly or indirectly from the combination of certain ingredients in certain amounts.

For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts". However, other salts are suitable for producing compounds according to this invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid additive salts, which can, for example, be obtained by mixing a solution of the compound with a solution of the pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. In addition, when the compounds of the invention have acid part, suitable pharmaceutically acceptable salts may include salts of alkali meta is fishing, for example, salts of sodium or potassium; salts of alkaline earth metals such as calcium salt or magnesium; and salts formed with suitable organic ligands, e.g. Quaternary ammonium salts. Thus, a typical pharmaceutically acceptable salts include salts: acetate, bansilalpet, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, edetate calcium, camphorsulfonate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, Eilat, fumarate, gluceptate, gluconate, glutamate, picolylamine, hexylresorcinol, geranamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isetionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesilate, bromide, methylnitrate, methyl sulfate, mukat, napsylate, nitrate, ammonium salt, N-methylglucamine, oleate, pamoate (embonate), palmitate, Pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannat, tartrate, teoclate, tosylate, triethiodide and valerate.

The present invention includes within its scope prodrugs of the compounds of the invention. In General, such prodrugs will be functional derivatives of the compounds and can easily be transformed in vivo into the required compound. Thus, in the treatment methods of the present invention, the term "introduction" will include the different treatment is cnyh 'described violations of the connection, definitely described, or in connection, which may not be specifically described, but which turns into a certain compound in vivo after administration to the patient. Conventional techniques for selecting and obtaining the appropriate proletarienne derivatives described, for example, in "Design of Prodrugs", ed. H.Bundgaard, Elsevier, 1985.

Abbreviations used in the description, particularly the schemes and examples, are as follows:

BINAP=(R)-(+)-2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl
Connection.=Connection
DBU=2,3,4,6,7,8,9,10-Octahedroid[1,2-a]azepin
DCC=1,3-Dicyclohexylcarbodiimide
DCM=Dichloromethane
DEAD=Diethyldithiocarbamic
DIPEA=Diisopropylethylamine
DMAP=N,N'-Dimethyl-4-pyridylamine
DMF=N,N'-Dimethylformamide
DMSO=The sulfoxide
dppp=1,3-Bis(diphenylphosphino)propane
EDTA =Ethylenedinitrilotetraacetic acid
EtOAc=The ethyl acetate
EtOH=Ethanol
Et3N=The triethylamine
Fmoc-NCS=[(N-Fluoren-9 ylethoxy)carbonyl]thiocyanate
HEPES=2-[4-(2-hydroxyethyl)piperazinil]econsultancy acid
HPLC=High performance liquid chromatography
ID=Identification number of connections
KO-tert-Bu=tert-Piperonyl potassium
Meon=Methanol
mCPBA=3-Chloroperoxybenzoic acid
NaO-t-Bu=tert-Piperonyl sodium
n-Bu=n-Butyl
NMP=N-methyl-2-pyrrolidinone
Pd2dba3=Tris(dibenzylideneacetone)dipalladium(0)
Pd(dppf)(OAc)2=The diacetate 1,1'-bis(diphenylphosphino)ferienparadies
Pd(OAc)2 =The palladium (II)acetate
Pd(dppf)Cl2=Dichloride, 1,1'-bis(diphenylphosphino)ferienparadies (II)
Pd(PPh3)4or Pd(Ph3P)4=Tetrakis(triphenylphosphine)palladium
Ph=Phenyl
PMSF=Phenylmethanesulfonyl
PPh=Triphenylphosphine
PyBrOP=Geksaftortsiklotrifosfazena
TEA=The triethylamine
TFU=Triperoxonane acid
THF=Tetrahydrofuran
TCX=Thin-layer chromatography
TsOH=p-Toluensulfonate acid
SNP=Sodium nitroprusside

The compounds of formula (I), where R3represents hydrogen, can be obtained in accordance with two alternative ways of appropriately substituted compounds of formula (III):

where R1, R2, R5and with what you have above is meant is I, chosen and used as the initial reactant.

The compound of formula (III) is a known compound or a compound obtained by known methods, for example, in accordance with the method represented by the following scheme 1:

Scheme 1

Accordingly, the compound of formula (IV), a known compound or compound obtained by known methods, is subjected to the interaction with the appropriately substituted aldehyde of formula (V) in an organic solvent such as DCM, THF, toluene and the like, in the presence of an acid catalyst, such as TFU, toluensulfonate acid and the like, receiving a corresponding compound of formula (III).

Usually in the first of the two alternative ways of compounds of formula (I) can be obtained by the interaction of the appropriately substituted compounds of formula (III) with a correspondingly substituted derivative of pyrrolopyridine. The second method of the two alternative ways of compounds of formula (I) can be obtained first by the interaction of the appropriately substituted compounds of formula (III) with the formation of the tricyclic pyrrolopyridines part with the subsequent introduction of additional substituents. The second method is particularly preferred for obtaining connection the settings of the formula (I), where Y represents-C(S)-, -C(O)O-RAor-C(O)RA.

More specifically, the compounds of formula (I), where R3represents hydrogen, can be obtained from suitably substituted compound of formula (III) in accordance with the methods presented in figure 2.

Scheme 2

In the first method the appropriately substituted compound of formula (III) is subjected to interaction with a suitably substituted compound of formula (VI), where X represents halogen, hydroxy, toilet, mesilate, p-nitrophenoxy or the like, preferably, X represents halogen, hydroxy or p-nitrophenoxide, in an organic solvent, such as DMF, THF, DCM, toluene and the like, receiving a corresponding compound of formula (VII). For compounds of formula (I), where (Y)ais (Y)0(i.e., where a is 0, so Y is absent), the reaction mixture is preferably heated to a temperature higher than or equal to about 100°C. For compounds of formula (I), where (Y)ais (Y)0(i.e., where a is 0, so Y is absent), andis pyridinyl, the reaction mixture is preferably catalyze at a temperature in the range of about 30-120°With a catalyst such as Pd(OAc)2Pd2dba3, Pd(dppf)Cl2and the like, the solvent content of inorganic fillers, such as 1,4-dioxane, THF, DMF, DCM, toluene and the like, receiving a corresponding compound of formula (VII).

The compound of formula (VII) are then subjected to interaction with oxidizing agent such as NaIO4, KO2singlet oxygen, gaseous oxygen, ozone and the like and, preferably, apply gaseous oxygen at about atmospheric pressure, receiving the corresponding derived pyrrolopyridine formula (Ia). When the oxidizing agent is gaseous oxygen, the interaction is carried out in the presence of a base such as sodium hydride, tert-piperonyl potassium and the like.

In an alternative method, shown in scheme 2, a suitably substituted compound of formula (III) is first subjected to interaction with oxidizing agent such as NaIO4, KO2singlet oxygen, gaseous oxygen, ozone and the like and, preferably, apply gaseous oxygen at about atmospheric pressure, obtaining the corresponding compound of formula (VIII). When the oxidizing agent is gaseous oxygen, the interaction is carried out in the presence of a base such as sodium hydride, tert-piperonyl potassium and the like.

The compound of formula (VIII) are then subjected to interaction with a suitably substituted compound f is rmula (VI), where X represents halogen, hydroxy, toilet, mesilate, p-nitrophenoxy or the like, preferably, X represents halogen, hydroxy or p-nitrophenoxide, in an organic solvent, such as DMF, THF, DCM, toluene and the like, optionally in the presence of a catalyst, such as DMAP, receiving the corresponding substituted pyrrolopyridine formula (Ia). For compounds of formula (I), where (Y)ais (Y)0(i.e., where a is 0, so Y is absent), the reaction mixture is preferably heated to a temperature higher than or equal to approximately 50°C. For compounds of formula (VIII), where (Y)ais (Y)0(i.e., where a is 0, so Y is absent), andis pyridinyl, the reaction mixture is preferably catalyze at a temperature in the range of about 30-120°With a catalyst such as Pd(OAc)2Pd2dba3Pd(dppf)Cl2and the like, in an organic solvent such as 1,4-dioxane, THF, DMF, DCM, toluene and the like, receiving a corresponding compound of formula (Ia).

Alternatively, for compounds of formula (I), where (Y)ais CH2andrepresents unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, the compound of formula (VIII) can be obtained wsimages is of the compounds of formula (Ia) with gaseous hydrogen, where hydrogen gas is used at a pressure in the range from about atmospheric pressure to about 80 psi (551,6 kPa) in the presence of a catalyst, such as Pd, Pt, palladium on coal and the like, in an organic solvent, such as methanol, ethanol, ethyl acetate, and the like. The compound of formula (VIII) can then be further functionalitywith, as described above.

The compound of formula (I), where b is equal to 1 (i.e. where the group represented bysubstituted with one substituent R4), can be obtained from suitably substituted compound of formula (III) in accordance with three alternative ways.

In the first method the appropriately substituted compound of formula (III) is first converted into the corresponding pyrrolopyridine in the manner indicated in scheme 2, followed a two-step substitution at the nitrogen of the pyrrole as described in scheme 3.

Scheme 3

In particular, the compound of formula (VIII) is subjected to interaction with a suitably substituted compound of formula (IX), where X represents a halogen, in the presence of a base such as TEA, DIPEA, and the like, in an organic solvent, such as DMF, DCM, THF and the like, preferably at a temperature in the range from approximately 20 to approximately 150°With, olucha the corresponding compound of formula (X).

The compound of formula (X) is subjected to interaction with the appropriately substituted Bronevoy acid of formula (XI) or appropriately substituted tributylstannyl formula (XII)to give the corresponding compound of formula (Ib). When the selected reagent is baronova acid of formula (XI), the compound of formula (X) are interacting in an organic solvent, such as DMF, THF, dioxane and the like, in the presence of a catalyst such as Pd(Ph3R)4Pd(dppf)(OAc)2and the like, preferably at a temperature in the range of about 80-150°C. When the selected reagent is tributylstannyl formula (XII), the compound of formula (X) are interacting in a solvent such as DMF, in the presence of a catalyst such as Pd(dppf)(OAc)2.

In the second method, the compound of formula (III) first replace poslednymthen turn in the appropriate pyrrolopyridine and then replace theas shown in figure 4.

Scheme 4

More specifically, suitably substituted compound of formula (III) is subjected to interaction with a suitably substituted compound of formula (XIII), where X represents a halogen, in the presence of a base such as TEA, DIPEA, and so on is one, in an organic solvent, such as DMF, toluene and the like, preferably at a temperature in the range from approximately 100 to approximately 150°receiving a corresponding compound of formula (XIV).

The compound of formula (XIV) is subjected to interaction with oxidizing agent such as NaIO4, KO2singlet oxygen, gaseous oxygen, ozone and the like, preferably, use gaseous oxygen at atmospheric pressure, obtaining the corresponding compound of formula (XV).

The compound of formula (XV) is subjected to interaction with the appropriately substituted Bronevoy acid of formula (XI) or appropriately substituted tributylstannyl formula (XII)to give the corresponding compound of formula (Ic). When the selected reagent is baronova acid of formula (XI), the compound of formula (XV) are interacting in an organic solvent, such as DMF, dioxane, water and the like, in the presence of a catalyst such as Pd(Ph3R)4Pd(dppf)(OAc)2and the like, preferably at a temperature in the range from approximately 80 to approximately 160°C. When the selected reagent is tributylstannyl formula (XII), the compound of formula (XV) are interacting in a solvent such as DMF, TEA and the like, in the presence of a catalyst which, such as Pd(dppf)(OAc)2.

In the third method, the compound of formula (III), first zamechaut poslednym, then replace theDeputy R4and then make the appropriate pyrrolopyridine, as shown in figure 5.

Scheme 5

More specifically, the compound of formula (XIV) is subjected to interaction with the appropriately substituted Bronevoy acid of formula (XI) or appropriately substituted tributylstannyl formula (XII)to give the corresponding compound of formula (XVI). When the selected reagent is baronova acid of formula (XI), the compound of formula (XIV) is subjected to interaction in an organic solvent, such as DMF, dioxane, water and the like, in the presence of a catalyst such as Pd(Ph3R)4Pd(dppf)(OAc)2and the like, preferably at a temperature in the range from about 80 to about 120°C. When the selected reagent is tributylstannyl formula (XII), the compound of formula (XIV) is subjected to interaction in a solvent such as DMF, dioxane and the like, in the presence of a catalyst such as Pd(dppf)(OAc)2.

The compound of formula (XVI) is subjected to interaction with oxidizing agent such as NaIO4, KO2singlet oxygen gaseous oxygen, ozone and the like and, preferably, apply gaseous oxygen at atmospheric pressure, obtaining the corresponding compound of formula (Ic).

The compounds of formula (I), where b is an integer selected from 2, 3 and 4 (i.e., wheresubstituted 2, 3 or 4 groups R4), can similarly be obtained in accordance with methods set forth in schemes 3, 4 and 5, with a suitable replacement reagent containingcorresponding reagent, which is substituted by 2, 3 or 4 atoms of bromine, the bromine group then subjected interaction for introduction of the desired groups R4.

The compounds of formula (I), where (Y)arepresents C(O), can be obtained in accordance with two alternative ways. In the first method pyrrolopyridine compound of formula (VIII) first, substitute the appropriate selected carboxylic acid or acid chloride of the acid, followed by further substitutionDeputy R4as shown in scheme 6.

Scheme 6

More specifically, suitably substituted pyrrolopyridine compound of formula (VIII) is subjected to interaction with appropriately substituted carboxylic acid or acid chloride of the acid of formula (XVIII), where W is HE or Cl, organic RA is the solvent, such as DMF, THF, dioxane and the like, and, when W is HE, in the presence of a catalyst, such as PyBrop, DCC, and the like, and, when W is Cl, in the presence of a base such as TEA, DIPEA, and the like, preferably at a temperature in the range from about 0 to about 30°receiving a corresponding compound of formula (XVIII).

The compound of formula (XVIII) is subjected to interaction with the appropriately substituted Bronevoy acid of formula (XI) in an organic solvent, such as DMF, dioxane, water and the like, in the presence of a catalyst such as Pd(Ph3R)4and the like, and, preferably, at a temperature in the range from about 80 to about 120°receiving a corresponding compound of formula (Id).

With the second method appropriately substituted compound of formula (III) is first converted into the corresponding pyrrolopyridine with subsequent substitution in two stages using an appropriate selected carboxylic acids and then Bronevoy acid or stannane, as indicated in figure 7.

Scheme 7

More specifically, suitably substituted compound of formula (III) is subjected to interaction with appropriately substituted carboxylic acid of the formula (XVII), where W represents halogen or is hydroxy, in an organic solvent, such as TEA, DIPEA, and the like, preferably at a temperature in the range from approximately 80 to approximately 130°receiving a corresponding compound of formula (XIX).

The compound of formula (XIX) is subjected to interaction with the appropriately substituted Bronevoy acid of formula (XI) or appropriately substituted tributylstannyl formula (XII)to give the corresponding compound of formula (XX). When the selected reagent is baronova acid of formula (XI), the compound of formula (XIX) are interacting in an organic solvent, such as DMF, dioxane, water and the like, in the presence of a catalyst such as Pd(Ph3R)4Pd(dppf)(OAc)2and the like, preferably at a temperature in the range from about 80 to about 120°C. When the selected reagent is tributylstannyl formula (XII), the compound of formula (XIX) are interacting in a solvent such as DMF, dioxane and the like, in the presence of a catalyst such as Pd(dppf)(OAc)2.

The compound of formula (XX) is subjected to interaction with oxidizing agent such as NaIO4, KO2singlet oxygen, gaseous oxygen, ozone and the like, preferably KO2receiving a corresponding compound of formula (Id).

The compounds of formula (I), the de R 3is not hydrogen, and the compounds of formula II can be obtained in accordance with the method given in figure 8.

Scheme 8

More specifically, the compound of formula (Ia) is subjected to interaction with a suitably substituted compound of formula (XXI), where X represents halogen, hydroxy, toilet, mesilate, and the like, preferably, X represents halogen, in an organic solvent, such as THF, DMF, dichloromethane, toluene and the like, preferably THF or DMF, receiving the mixture correspondingly substituted of compounds of formula (Ie) and the corresponding substituted compounds of formula (II). When in the compound of formula (XXI) X is halogen, the reaction is preferably carried out in the presence of organic or inorganic bases, such as triethylamine, diisopropylethylamine, potassium carbonate, sodium hydride, sodium hydroxide, and the like.

Compounds of formula (Ie) and (II), preferably separated by known methods such as recrystallization, column chromatography, HPLC and the like.

The compounds of formula (VII), where Yais Y0(i.e., where Y is absent) andis 2-(4-substituted)thiazolyl, can be obtained in the manner outlined in scheme 9.

SCHEME 9

In line with this, the appropriately substituted compound of formula (III) is subjected to interaction with Fmoc-NCS in an organic solvent such as DCM, DMF, THF and the like, preferably at room temperature, obtaining the corresponding compound of formula (XXII).

The compound (XXII) is subjected to interaction with 20% piperidine in alcohol, such as methanol, ethanol and the like, receiving the corresponding amine of formula (XXIII).

Amine of formula (XXIII) is subjected to interaction with the appropriately substituted α-halogenoalkanes formula (XXIV) in the presence of an organic solvent or mixture of solvents such as DMF, ethanol:dioxane and the like, in the presence of a base such as TEA, DIPEA, and the like, preferably at a temperature of about 70°receiving a corresponding compound of formula (VIIa).

Certain diastereomers of compounds of formula (I), more specifically, the compounds of formula (I), where R1represents hydrogen and the right is R-configuration at the chiral center of R2with pyrrolopyridine, can be obtained in the manner outlined in scheme 10.

Scheme 10

In line with this, the appropriately substituted compound of formula (XXV), a known compound or compound obtained by known methods, where R1PR is dstanley hydrogen and Ar represents an aryl group, preferably, naphthyl, more preferably, 1-naphthyl, subjected to interaction with the appropriately substituted aldehyde, a compound of formula (XXVI), in an organic solvent such as p-xylene, o-xylene, toluene, DCM and the like, at a temperature in the range of about 25-270°in an aprotic or proton conditions with the appropriate mixture of diastereomers of compounds of formulae (XXVII) and (XXVIII).

R-diastereoisomer, the compound of formula (XXVII) is separated from the compounds of formula (XXVIII) by recrystallization or chromatography on silica gel.

The compound of formula (XXVII) (S-diastereoisomer) turn in the desired R-diastereoisomer, the compound of formula (XXVIII), stirring the compound of formula (XXVII) in the acid, such as TFU, HCl, TsOH and the like, in the presence of an organic solvent such as CH2Cl2, DCM, 1,4-dioxane and the like, getting the right R-diastereoisomer, the compound of formula (XXVIII).

The compound of formula (XXVIII) is subjected to interaction with oxidizing agent such as gaseous oxygen, singlet oxygen, KO2, NaIO4, ozone and the like, preferably, gaseous oxygen at about atmospheric pressure, obtaining the corresponding compound of formula (XXIX). When the oxidizing agent is gaseous oxygen, the interaction is carried out in the presence of a base, takoh the as sodium hydride, tert-piperonyl potassium and the like, in an organic solvent, such as DMF, DMSO, NMP and the like.

The compound of formula (XXIX) is subjected to interaction with the regenerating agent such as hydrogen gas, in the presence of a catalyst such as palladium on charcoal, in a polar solvent such as methanol, ethanol and the like, receiving a corresponding compound of formula (VIIIa).

The compound of formula (VIIIa) can then be subjected to interaction to obtain the corresponding compounds of formula (I) in the manner specified above in scheme 3.

The compounds of formula (I), where R1is not hydrogen, may be the second chiral center at the communication group, R1with pyrrolopyridine. If a certain orientation group, R1is present in the source reagent compound of the formula (XXV) in the diagram above 10, its orientation will affect the transformation of diastereomers.

When the means of obtaining the compounds according to the invention give a mixture of stereoisomers, these isomers can be divided by using common methods such as preparative chromatography. Compounds can be obtained in racemic form, or individual enantiomers can be obtained enantioselective synthesis, separation of mixtures of enantiomers or enantiomerically enriched reagents. The connection can, for example be divided into its enantiomeric components by standard methods, such as education diastereomeric pairs by salt formation with an optically active acid such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and obtain the free base. Compounds can also be separated by formation of diastereomeric esters, amides or amines, followed by chromatographic separation and removal of the chiral auxiliary connection. Alternatively, compounds can be separated using chiral HPLC column.

During any of the methods of obtaining the compounds of the present invention may be necessary and/or desirable to protect sensitive or reactive groups on any molecules involved in methods of production. This can be achieved using conventional protective groups such as the groups described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973, and T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, John Willey and Sons, 1991. The protective group can be removed at a convenient subsequent stage using methods known in this field.

The suitability of compounds for the treatment of sexual dysfunction can be identified by the methods described in the examples below, 95, 96 and 97.

The present invention therefore relates to a method for treatment of sexual dysfunction, bol is e specifically, male erectile dysfunction in a subject in need thereof, which includes the introduction of any of the compounds as defined above, in an amount effective for the treatment of ED. Connection, you can enter the patient in any conventional way of introduction, including, but not limited to, intravenous, oral, subcutaneous, intramuscular, intradermal and parenteral. The number of connections, which is effective for the treatment of ED, is between 0.01 mg / kg and 20 mg / kg of body weight of the subject.

The present invention relates also to pharmaceutical compositions comprising one or more compounds of this invention in combination with a pharmaceutically acceptable carrier. These compositions preferably are in the form of a unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, devices for autoinjection or suppositories, for oral, parenteral, intranasal, sublingual or rectal introduction or for introduction of inhalation or insufflate. Alternatively, the composition may be presented in a form suitable for administration once a week or once a month; for example, an insoluble salt of the active compound, such as decanoate salt, m is tenderly adapted to receive the drug depot for intramuscular injection. For solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional for tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water for the formation of a solid to a predetermined composition containing a homogeneous mixture of the compounds of the present invention or its pharmaceutically acceptable salt. When refer to such pre-composed compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition can easily be divided into equally effective dosage forms such as tablets, pills and capsules. Such solid pre-composed song then divided into unit dosage forms of the type described above containing from 1 to about 1000 mg of the active ingredient of the present invention. The tablets or pills of the new compositions can be covered with membrane or to prepare other way to obtain a dosage form that provides the advantages of prolonged action. For example, the tablet or pill may include internal dosed component outer dosage component, the latter is in the form of a shell on the ground. Two components can be divided intersolubility layer, which serves to impart resistance to disintegration in the stomach and permits the inner component to pass intact into the duodenum or delaying its release. For such intersolubility layers or coatings can be used various materials, such materials include a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which it is possible to include new compositions of the present invention for administration orally or by injection include aqueous solutions, syrups, appropriately processed to impart odor and taste, aqueous or oil suspensions, and processed to impart taste and odor emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical excipients. Suitable dispersing or suspendresume agents for aqueous suspensions include synthetic and natural gums, such as tragakant, Arabian gum, alginate, dextran, sodium carboxymethyl cellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

A method of treating sexual dysfunction, more spiral is but male erectile dysfunction described in the present invention can also be accomplished with the use of pharmaceutical compositions comprising any of the compounds as defined above, and pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 1 mg and 1000 mg, preferably, from about 1 to 200 mg, connections, and can be presented in any form suitable for the selected method of administration. Carriers include necessary and inert pharmaceutical excipients, containing, but not limited to the above, a binder, suspendresume agents, lubricants, corrigentov, sweetening agents, preservatives, dyes and coatings. Compositions suitable for oral administration include solid forms, such as pills, tablets, small capsules, capsules (each including the finished form with immediate release, controlled time release and extended release), granules and powders, and liquid forms such as solutions, syrups, elixirs, emulsions and suspensions. Forms suitable for parenteral administration include sterile solutions, emulsions and suspensions.

Compounds of the present invention can be imposed, mainly in the form of a single daily dose or the total daily dose can be administered in wideranging doses of two, three or four times a day. In addition, the compounds of the present invention can be introduced in intranasal form with the local use of suitable intranasal fillers or by percutaneous patches on the skin, a well-known specialist in this field. With the introduction of the uniform system for percutaneous delivery of a metered introduction is, of course, continuous rather than intermittent throughout the dosage regimen of the drug.

For example, for oral administration in the form of a tablet or capsule, the active drug component can be mixed with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. In addition, when it is desirable or necessary, the mixture can enter suitable binders, lubricants, dezintegriruetsja agents and coloring agents. Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose or beta-lactose, sweeteners corn, natural and synthetic gums, such as Arabian gum, tragakant, or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. The disintegrators include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum and so p is such.

Liquid forms may include appropriately processed to impart odor and taste suspendresume or dispersing agents, such as synthetic and natural gums, for example, tragakant, Arabian gum, methylcellulose and the like. For parenteral administration is desirable sterile suspensions and solutions. When it is desirable intravenous use isotonic preparations, which usually contain suitable preservatives.

The compound of the present invention can also be entered in the form of liposomal delivery systems, such as small single-layer vesicles, large single-layer and multi-layered vesicles vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholine.

Compounds of the present invention can also be delivered using monoclonal antibodies as individual carriers, which combine molecules of compound. Compounds of the present invention can also be coupled with soluble polymers as carriers deliver medicines. Such polymers can include polyvinylpyrrolidone, a copolymer of Piran, polyhydroxyethylmethacrylate, polyhydroxyethylmethacrylate or polyethylenepolyamine, substituted residue by Palmitoyl. In addition, the compounds of this is part II of the invention can be combined with the class biorazlagaemykh polymers, suitable for achieving controlled release of drugs, for example, polyacrylic acid, poly-Epsilon-caprolactone, polyhydroxyalkanoic acid, polyarteritis, polyacetylene, polyhydroxyalkane, polycyanoacrylate and sewn or amphipatic block copolymers of hydrogels.

Compounds of the present invention can be introduced in any of the above compositions in accordance with schemes of medication prescribed in this field whenever you need treatment of sexual dysfunction, more specifically, men's erectile dysfunction.

The daily dosage of the products may vary in a wide range from 1 to 1000 mg per adult human per day. For oral administration of the composition, preferably present in the form of tablets containing 1,0, 5,0, 10,0, 15,0, 25,0, 50,0, 100, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment dose for exposed treatment of the patient. An effective quantity of a drug is usually put at the level of the dose from about 0.01 mg/kg to about 20 mg/kg of body weight per day. The range, preferably, is from about 0.1 mg/kg to about 10 mg/kg of body weight per day, and especially from about 0.1 mg/kg to about 3 mg/kg of body weight per day.

The optimal dose, to the which you need to enter, can be easily determined by the person skilled in the art, they will vary depending on the specific compound, the route of administration, efficacy and progress of the disease. In addition, factors associated with the particular patient being treated, including the patient's age, weight, diet and time of administration, will lead to the need for regulation of the doses.

The following examples are provided to assist understanding of the invention and are not intended and should not in any way be construed as limiting the invention claimed in the claims presented below. Unless otherwise stated, spectra1H-NMR were recorded on a Bruker spectrometer.

EXAMPLE 1

1-(3,4-Methylenedioxyphenyl)-2-benzyl-2,3,4,9-tetrahydro-1H-β-carbolin

To a solution of 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (obtained by the method described in WO 97/43287, intermediate 7, page 24) (7,37 g, 25 mmol) in anhydrous DMF (25 ml), add triethylamine (3,52 ml, 25 mmol) and benzylbromide (3,00 ml, 25 mmol). The mixture was stirred at ambient temperature overnight and added dropwise to a solution of sodium hydroxide (25 mmol) in water (200 ml). A precipitate, which is filtered under vacuum, washed with water (2×50 ml) and dried in vacuum over night, getting PR is the product in the form of a free flowing light yellow powder.

MS (m/z 383 (MH+)

1H-NMR (CDCl3) δ to 2.57-2,89 (series of m, 3H), 3,18 is 3.23 (m, 1H), 3,33 (d, J=13,7 Hz, 1H), 3,63 (d, J=13,7 Hz, 1H), 4,55 (s, 1H), 5,94 (nd, J=2.2 Hz, 2H), 6,77-7,52 (series, 13H).

EXAMPLE 1A

(R)-1-(3,4-Methylenedioxyphenyl)-2-benzyl-2,3,4,9-tetrahydro-1H-β-carbolin

According to the method described in example 1, (R)-1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carbolin subjected to interaction with obtaining specified in the connection header.

MS (m/z 383 (MH+)

EXAMPLE 2

1-(2,C-Dihydrobenzofuran-5-yl)-2-benzyl-2,3,4,9-tetrahydro-1H-β-carbolin

Specified in the header of the compound obtained by the method described in example 1, using 1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1H-β-carbolin as starting reagent.

MS (m/z 381 (MH+)

1H-NMR (CDCl3) δ 2,59-2,90 (series of m, 3H), 3,13-3,24 (m, 3H), of 3.33 (d, J=13.5 Hz, 1H), 3,93 (d, J=13.5 Hz, 1H), 4,56 (t, J=8.6 Hz, 2H), 6.75 in (d, J=8,1 Hz, 1H), 7,05-7,35 (series of m, 10H), 7,49-7,52 (m, 1H).

EXAMPLE 2A

(R)-1-(2,3-Dihydrobenzofuran-5-yl)-2-benzyl-2,3,4,9-tetrahydro-1H-β-carbolin

According to the method described in example 2, (R)-1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1H-β-carbolin subjected to interaction with obtaining specified in the connection header.

MS (m/z) 381 (MN+)

[α]=-56,9° (C=0,62, CH3IT)

EXAMPLE 3

1,2,3,4-Tetrahydro-2-benzyl-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-he (#54)

p> 1-(3,4-Methylenedioxyphenyl)-2-benzyl-2,3,4,9-tetrahydro-1H-β-carbolin (0,79 g, 2.0 mmol) (obtained as in example 1) dissolved in anhydrous DMF (15 ml). Add tert-piperonyl potassium (0.56 g, 5.0 mmol), and then through a needle of the syringe bubbled oxygen. The mixture was kept at room temperature for one hour and then poured on a mixture of 1 N. HCl (5 ml), water (35 ml) and ethyl acetate (35 ml). Fluffy yellow precipitate was separated, the organic layer removed and the aqueous solution extracted with ethyl acetate (15 ml). Extracted layer mix and leave overnight. The next day, allocate an additional amount of product (in the form of sediment). Drying of the combined solids gives the product as a yellow powder.

MS (m/z 397 (MH+)

1H-NMR (DMSO-d6) δ to 3.52 (DD, J=11,9, 3 Hz, 1H), 3,63 (d, J=13,2 Hz, 1H), 3,84 (d, J=13,2 Hz, 1H), 3,93 (DD, J=11,9, 3 Hz, 1H), 5,10 (s, 1H), 6,05 (nd, J=3,4 Hz, 2H), 6,98 (s, 3H), 7,26 and 7.36 (m, 6N), 7,54-to 7.59 (m, 2H), 8,10 (d, J=8 Hz, 1H), 11,42 (s, 1H).

EXAMPLE 3A

(R)-1,2,3,4-Tetrahydro-2-benzyl-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-he (#67)

According to the method described in example 3 (R)-1-(3,4-methylenedioxyphenyl)-2-benzyl-2,3,4,9-tetrahydro-1H-β-carbolin subjected to interaction with obtaining specified in the connection header.

MS (m/z 397 (MH+)

EXAMPLE 4

1,2,3,4-Tetrahydro-2-benzyl-3-(2,3-dihydrobenzofuran-5-yl)-N-pyrrolo[3,4-b]quinoline-9-he (#60)

1-(2,S-Dihydro shall benzofuran-5-yl)-2-benzyl-2,3,4,9-tetrahydro-1H-β -carbolin (obtained as in example 2) (3,10 g, 8,15 mmol) dissolved in anhydrous DMF (20 ml). Add tert-piperonyl potassium (to 2.29 g, 20,38 mmol), and then through a needle of the syringe bubbled oxygen. The solution is stirred for 1.5 hours. To the reaction mixture add a solution of HCl in ether (10 ml, 2M) and the solution dropwise contribute to intensively mix the water. The resulting suspension is stirred over night. The brown solid is filtered off and washed with water. The filtrate is neutralized 1 N. NaOH, receiving a yellow precipitate. The solid is filtered off, washed with water, quickly dried and partially dissolved in a mixture of THF/methanol. The precipitated solid is filtered off and washed with ether, receiving the product as a pale yellow solid.

MS (m/z) 395 (MN+)

1H-NMR (DMSO-d6) δ 3,19 (t, J=8.7 Hz, 2H), 3,53 (d, J=11.8 Hz, 1H), 3,61 (d, J=and 12.2 Hz, 1H), 3,82 (d, J=and 12.2 Hz, 1H), 3,92 (d, J=11.8 Hz, 1H), 4,55 (t, J=8.7 Hz, 2H), 5,08 (s, 1H), for 6.81 (d, J=8,1 Hz, 1H), 7,16-to 7.59 (series m, N), 8,10 (d, J=8,1 Hz, 1H), 11,42 (s, 1H).

EXAMPLE 4A

(R)-1,2,3,4-Tetrahydro-2-benzyl-3-(2,3-dihydrobenzofuran-5-yl)-N-pyrrolo[3,4-b]quinoline-9-he (#77)

According to the method described in example 4 (R)-1-(2,3-dihydrobenzofuran-5-yl)-2-benzyl-2,3,4,9-tetrahydro-1H-β-carbolin subjected to interaction with obtaining specified in the connection header.

MS (m/z) 395 (MH+)

[α]=-110,0° (C=0,43, CH3HE); HPLC, Colo the ka Chiralpak 0,46× 25 cm (EXT. the diameter)of 0.1% DEA/MeOH, Tr=5,360 minutes

EXAMPLE 5

Cleaners containing hydrochloride salt of 1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-it (#4)

Method: HCl salt

To a suspension of 1,2,3,4-tetrahydro-2-benzyl-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-she (obtained as in example 3) (1.12 g, 2.82 mmol) in methanol (50 ml) and 10% Pd/C (500 mg) is added HCl in ether solution (1,41 ml, 2 BC). The reaction mixture was stirred in nitrogen atmosphere (45 psi, 310,3 kPa) in a Parr apparatus for 6 hours. The resulting solution was filtered through celite and concentrated in vacuo, obtaining the product as a green solid.

MS (m/z 307 (MH+)

1H-NMR (DMSO-d6) δ 4,39-4,48 (m, 2H), 6,09 (Sirs, 3H), 6,97-7,05 (m, 3H), 7,40 (t, J=7,1 Hz, 1H), 7,60-7,71 (m, 2H), 8,17 (d, J=8.0 Hz, 1H), 9,68 (s, 1H), 11,13 (s, 1H).

Method: Free base

1-(3,4-Methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carbolin known compound (obtained by the method described in WO 97/43287, intermediate 7, page 24) (15,35 g of 52.5 mmol), dissolved in anhydrous DMF (90 ml). One portion is injected tert-piperonyl potassium (10,02 g, 89,3 mmol) and the suspension is stirred until then, until you get a clear solution. Then through the solution by means of a needle of a syringe for 50 min pass gaseous oxygen. The reaction is quenched by adding glacial acetic acid (5,11 ml, 89,3 mmol) and the reaction with the ect poured into diethyl ether (1 l), which leads to the formation of a precipitate, which is filtered off. The product was then purified flash chromatography (0-50% EtOH/THF)to give the product as a yellow powder.

MS (m/z 307 (MN+)

1H-NMR (CD3OD) δ 4,18 (d, J=13,7 Hz, 1H), 4,36 (d, J=13,7 Hz, 1H), 4.92 in (Sirs, 2H), 5,43 (s, 1H), of 5.92 (s, 1H), 6,74 (s, 1H), for 6.81 (s, 1H), was 7.36-7,70 (series, 4H), 8,31 (d, J=8.6 Hz, 1H).

EXAMPLE 5A

Cleaners containing hydrochloride salt of (R)-1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-it (#48)

According to the method described in example 5, method A, (R)-1,2,3,4-tetrahydro-2-benzyl-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-he is subjected to interaction with obtaining specified in the connection header.

MS (m/z 307 (MN+)

EXAMPLE 6

Cleaners containing hydrochloride salt of 1,2,3,4-tetrahydro-3-(2,3-dihydrobenzofuran-5-yl)-N-pyrrolo[3,4-b]quinoline-9-she

Method: HCl salt

Specified in the header of the product is obtained according to the method described in example 4, with the substitution of the appropriate reactants.

MS (m/z) 305 (MN+)

1H-NMR (DMSO-d6) δ 3,17-3,20 (m, 2H), to 4.38-4,60 (m, 4H), 6,10 (s, 1H), 6,85 (d, J=8,2 Hz, 1H), 7,21 (d, J=8,1 Hz, 1H), 7,30 (s, 1H), 7,40 (t, J=7,1 Hz, 1H), to 7.61 (t, J=8,2 Hz, 1H), 7,68 (d, J=7.2 Hz, 1H), 8,17 (d, J=8,9 Hz, 1H), 9,71 (s, 1H), 11,17 (s, 1H).

Method: Free base

1-(2,3-Dihydro-5-benzofuranyl)-2,3,4,9-tetrahydro-1H-β-carbolin (1.06 g, of 3.64 mmol), a known compound (obtained by the method described in WO 97/43287, the intermediate product 10, p is unit 25), dissolved in anhydrous DMF (8 ml). One portion is injected tert-piperonyl potassium (829 mg, 7,38 mmol) and the suspension is stirred until then, until you get a clear solution. Then through the solution by means of a needle of a syringe for 50 min pass gaseous oxygen. The reaction is quenched by adding glacial acetic acid (0,42 ml, 7,34 mmol) and poured into diethyl ether (50 ml), which leads to the formation of a precipitate, which is filtered off. The product was then purified flash chromatography (0-50% Meon/THF)to give the product as a yellow powder.

MS (m/z) 305 (MN+)

1H-NMR (CD3OD) δ 3,17 (t, J=8.7 Hz, 2H), 3,29-of 3.31 (m, 2H), 4,18 (d, J=12.9 Hz, 1H), to 4.38 (d, J=12.9 Hz, 1H), 4,53 (t, J=8.7 Hz, 2H), 5,44 (s, 1H), 6,74 (d, J=8,2 Hz, 1H), 7,07 (d, J=8,2 Hz, 1H), 7,13 (s, 1H), 7,40 (t, J=7.9 Hz, 1H), 7,54 (d, J=8,3 Hz, 1H), 7,65 (t, J=7.9 Hz, 1H), 8,29 (d, J=8,1 Hz, 1H).

EXAMPLE 6A

Cleaners containing hydrochloride salt of (R)-1,2,3,4-tetrahydro-3-(2,3-dihydrobenzofuran-5-yl)-N-pyrrolo[3,4-b]quinoline-9-she

According to the method described in example 6, method A, (R)-1,2,3,4-tetrahydro-2-benzyl-3-(2,3-dihydrobenzofuran-5-yl)-N-pyrrolo[3,4-b]quinoline-9-he is subjected to interaction with obtaining specified in the connection header.

MS (m/z) 305 (MN+)

[α]=+39,0° (C=0,605, 1% TFU in CH3IT)

EXAMPLE 7

Ether (4-pyridinyl)methyl-4-nitrophenylamino acid

To a solution of 4-pyridylcarbinol (50 mol) and triethylamine (50 mmol) in anhydrous dichloromethane (100 ml) add Astor 4-nitrophenylphosphate (50 mmol). The reaction mixture was stirred over night at ambient temperature, resulting in a yellow precipitate, which is filtered off and the mixture concentrated. Semi-solid residue is treated with THF (50 ml) with formation of a white precipitate. The precipitate is filtered, concentrated and purified flash chromatography (20% THF/CHCl3)to give product as an orange solid.

MS (m/z 275 (MN+)

1H-NMR (CDCl3) δ 5,33 (s, 2H), was 7.36 (d, J=5.8 Hz, 2H), 7,41 (d, J=9.4 Hz, 2H), 8,30 (d, J=9.4 Hz, 2H), 8,68 (d, J=5.8 Hz, 2H).

EXAMPLE 8

6-[2-(1-Morpholino)ethoxy]-2-benzofurokaina acid

A solution of methyl ester of 6-methoxy-2-benzofuranol acid (868 mg, to 4.52 mmol) in anhydrous benzene is treated with triphenylphosphine (1.18 g, to 4.52 mmol) and 1-(2-hydroxyethyl)morpholine (0,72 ml of 4.57 mmol) in argon atmosphere. To the reaction mixture at room temperature is added dropwise DEAD (0,55 ml, 4.5 mmol). The solution is stirred over night, concentrated in vacuo and the residue purified flash chromatography (0-10% Meon/CHCl3).

The purified product is subjected to saponification for 3 h in a mixture of 1:1 methanol and water 1 N. NaOH (80 ml) at the temperature of reflux distilled. The reaction mixture is neutralized with concentrated HCl and concentrated, obtaining a residue, which is triturated with methanol (20 ml). The obtained salt is filtered off and statechartered, receiving a second residue, which is similar triturated with THF. The third residue is dried in vacuum, obtaining the product as a yellow powder.

MS (m/z 292 (MN+)

1H-NMR (DMSO-d6) δ to 2.57 (Sirs, 4H), 2,87 (t, J=5.3 Hz, 2H), to 3.64 (t, J=4.6 Hz, 4H), to 4.23 (t, J=5.5 Hz, 2H), 6,97 (DD, J=8,7, 2 Hz, 1H), 7,31 (s, 1H), 7,53 (s, 1H), 7,63 (d, J=8.7 Hz, 1H).

EXAMPLE 9

1-(3,4-Methylenedioxyphenyl)-2-(tert-butoxycarbonyl)-2,3,4,9-tetrahydro-1H-β-carbolin

To a suspension of 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (27.7 g, or 94.8 mmol) (obtained by the method described in WO 97/43287, intermediate 7, page 24) in anhydrous methanol (300 ml) is added tert-butylpyrocatechol (of 25.0 g, 114 mmol). Soon after adding pyrocarbonate formed a clear solution. The solution was stirred at ambient temperature for 1 hour, which leads to the formation of a white precipitate. The solid is filtered off, washed with a mixture of 1:1 diethyl ether:pentane and dried in vacuum, obtaining the product as a white solid.

MS (m/z) 415 (MNa+)

1H-NMR (CDCl3) δ 1,53 (s, N), 2,75-3,17 (series of m, 3H), 4,22 (width, 1H), to 5.93 (s, 2H), of 6.31 (width, 1H), 6,64-6,72 (m, 2H), 6,80 (s, 1H), 7,12-7,33 (series of m, 3H), 7,54 (d, J=7.7 Hz, 1H), 7,93 (width, 1H).

EXAMPLE 10

1-(3,4-Methylenedioxyphenyl)-2-(benzyloxycarbonyl)-2,3,4,9-tetrahydro-1H-β-carbolin

To a solution of 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-Arboleda (9,11 g, 31,1 mmol) (obtained by the method described in WO 97/43287, intermediate 7, page 24) in anhydrous dichloromethane (100 ml), add triethylamine (8,80 ml, 63.1 mmol) and dimethylaminopyridine (5 mg) followed by the addition dropwise of benzylchloride (4,60 ml of 30.6 mmol) over 30 minutes, the Reaction mixture was stirred for 16 h, transferred into a separating funnel, washed with 2 N. HCl, saturated salt solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. Flash chromatography gives the product as a white solid.

MC (m/z 425 (M-1)

1H-NMR (CDCl3) δ 2,78-2,95 (SIRM, 2H), 3.15 and is 3.25 (m, 1H), 4,40 (width, 1H), 5,14 (d, J=12.3 Hz, 1H), 5,22 (d, J=12.3 Hz, 1H), 5,90 (s, 2H), 6.35mm (width, 1H), 6,80 (width, 3H), 7,09-7,35 (series, 8H), 7,53 (d, J=7,6 Hz, 1H), 7,70 (width, 1H).

EXAMPLE 11

1-(3,4-Acid)-2,3,4,9-tetrahydro-1H-β-carbolin

To a solution of tryptamine (5.0 g, 0,0312 mol) and 3,4-dimethoxybenzaldehyde (5.7 g, 0,0312 mol) in CH2Cl2(220 ml) is added TFU (4,5 ml, 0,0548 mol). Dark blue solution was stirred at room temperature for 20 hours. The reaction mixture is neutralized NaHCO3(4.9 g, 0,0584 mol) in N2O (50 ml) and the organic layer was washed with saturated salt solution (2×100 ml). The reaction mixture is dried with MgSO4and the solvent is evaporated. Product highlight column chromatography (silica gel; CH3HE:EtOAc=1:9) as jetovator the oil, which slowly solidifies upon standing at room temperature.

TPL: 146-148°; MC (m/z 307 (M-1), 309 (MN+)

1H-NMR (CDCl3) δ 2,70˜of 2.92 (m, 2H), 3,05 (m, 1H), and 3.31 (m, 1H), the 3.65 (s, 3H), 3,81 (s, 3H), free 5.01 (s, 1H), 6,72 (m, 2H), 7,12 (m, 3H), 7,52 (m, 1H), 8,18 (s, 1H).

EXAMPLE 12

1-(3,4-Methylenedioxyphenyl)-2-[5-(4-methoxyphenyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-β-carbolin

1-(3,4-Methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carbolin (2,72 g, 9.6 mmol) (obtained by the method described in WO 97/43287, intermediate 7, page 24) and 2-chloro-5-(4-methoxyphenyl)pyrimidine (1.04 g, 4,78 mmol) is stirred in DMF (20 ml, anhydrous) at 120°C for 16 hours. The resulting mixture was quenched with saturated NH4Cl, extracted with ethyl acetate and dried with MgSO4. The solvent of the reaction mixture is evaporated and the residue purified column chromatography (silica gel, ethyl acetate:hexane=1:2)to give product as a white solid.

TPL: 200-202°C; MS (m/z): 477 (MH+)

1H-NMR (DMSO-d6) δ a 2.71 (m, 2H), 3,25 (m, 1H), of 3.78 (s, 3H), is 4.93 (d, J=12 Hz, 1H), of 5.99 (d, J=5 Hz, 2H), 6,76 (d, J=8 Hz, 1H), 6.87 in (d, J=8 Hz, 2H), 7,02 (d, J=9 Hz, 2H), 7,06 (d, J=7 Hz, 1H), 7,11 (s, 1H), 7,31 (d, J=8 Hz, 1H), 7,46 (d, J=8 Hz, 1H), to 7.59 (d, J=9 Hz, 2H), total of 8.74 (s, 2H), 11,00 (s, 1H).

EXAMPLE 13

1-(3,4-Methylenedioxyphenyl)-2-[5-(3,4-acid)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-β-carbolin

By the same procedure as described in example 12, 1-(3,4-methylene shall oxyphenyl)-2,3,4,9-tetrahydro-1H-β -carbolin (of 3.73 g, 12.8 mmol) (obtained by the method described in WO 97/43287, intermediate 7, page 24) and 2-chloro-5-(3,4-acid)pyrimidine (1.60 g, 6.4 mmol) in DMF (50 ml, anhydrous) were interaction, receiving the product as a white solid.

TPL: 173-175°C; MS (m/z 507 (MN+)

1H-NMR (CDCl3) δ 2,89 (d, J=15 Hz, 1H), to 3.02 (m, 1H), 3,39 (m, 1H), 3,92, 3,94 (2C, 6N), to 5.03 (d, J=12 Hz, 1H), of 5.92 (d, J=4 Hz, 2H), of 6.71 (d, J=7 Hz, 1H), 6.87 in-7,32 (m, 6N), 7,56 (d, J=7 Hz, 2H), 7,80 (, 1H), 8,56 (s, 2H).

EXAMPLE 14

1-(3,4-Methylenedioxyphenyl)-2-[5-(4-were)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-β-carbolin

By the same procedure as described in example 12, 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carbolin (2,19 g, 7.5 mmol) (obtained by the method described in WO 97/43287, intermediate 7, page 24) and 2-chloro-5-(4-were)pyrimidine (of 1.03 g, 5 mmol) in toluene (50 ml, anhydrous) and DBU (0.9 ml) is subjected to interaction, receiving the product as a white solid.

MS (m/z 459 (MN+)

1H-NMR (CDCl3) δ 2,43 (s, 3H), 2,85 (d, J=14 Hz, 1H), 3,01 (t, J=12 Hz, 1H), 3,38 (t, J=12 Hz, 1H), 5,04 (DD, J=14 Hz, 1H), 5,88 (d, J=4 Hz, 2H), 6.73 x (d, J=7 Hz, 1H), 6.89 in (d, J=7 Hz, 1H), 7,02 (s, 1H), 7,25 is 7.50 (m, 7H), 7,56 (d, J=7 Hz, 1H), 7,79 (s, 1H), 8,54 (s, 2H).

EXAMPLE 15

1-(3,4-Methylenedioxyphenyl)-2-(pyridin-4-yl)methyl-2,3,4,9-tetrahydro-1H-β-carbolin

A solution of 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (of 2.92 g, 10 mmol who) (obtained by the method described in WO 97/43287, intermediate 7, page 24), hydrochloride 4-picolylamine (1.64 g, 10 mmol) and DBU (3.1 g, 20 mmol) in DMF (50 ml) was stirred at room temperature for 16 hours. To the reaction mixture are added water (100 ml) and ethyl acetate (100 ml). The dissolved substance is present in the organic phase, purified column chromatography (silica gel, ethyl acetate)to give the product as not quite white solid.

MS (m/z 382 (M-1)

1H-NMR (CDCl3) δ to 2.65 (m, 1H), 2,75 (d, 1H), 2,88 (m, 1H), 3.15 in (m, 1H), 3,35 (d, J=15 Hz, 1H), 3,92 (d, J=15 Hz, 1H), 4,57 (s, 1H), 5,94 (s, 1H), 6,79 (d, J=8 Hz, 1H), 6.89 in (m, 2H), 7,20-7,40 (m, 7H), 7,51 (d, J=6 Hz, 1H), 8,53 (d, J=7 Hz, 1H).

EXAMPLE 16

1-(3,4-Methylenedioxyphenyl)-2-(pyrimidine-2-yl)-2,3,4,9-tetrahydro-1H-β-carbolin

1-(3,4-Methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carbolin (2.3 g, 8.0 mmol) (obtained by the method described in WO 97/43287, intermediate 7, page 24) and 2-chloropyrimidine (0,914 g, 8.0 mmol) stirred in anhydrous DMF (15 ml) at 140°C for 24 hours. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous NH4Cl (100 ml). The aqueous layer was extracted with ethyl acetate (2×50 ml). The combined organic layers washed with saturated salt solution (2×80 ml) and dried MgSO4. The solvent is evaporated and the product emit column chromatography (silica gel, EtOAc:hexane=1:9) as a yellowish solid.

TPL 176-177°C;

MS (m/z): 371 (MN+), 369 (M-1); Anal. calculated for C22H18N4O2With 71,34, N 4,90, N 15,13; found 70,57, N 4,92, N 15,38

1H-NMR (CDCl3) δ a 2.71 (m, 1H), 2,92 (m, 1H), 3,29 (m, 1H), 4.92 in (DD, 1H, J=14,7 Hz), 5,91 (d, 2H, J=6 Hz), to 6.43 (t, 1H, J=6 Hz), 6,63 (d, 1H, J=10 Hz), for 6.81 (d, 1H, J=10 Hz), to 6.95 (s, 1H), was 7.08 (m, 3H), 7,21 (d, 1H, J=8 Hz), 7,54 (d, 1H, J=10 Hz)to 8.12 (s, 1H), 8.30 to (d, 2H, J=6 Hz).

EXAMPLE 17

1-(3,4-Methylenedioxyphenyl)-2-[5-(4-chlorophenyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-β-carbolin

By the same procedure as described above in example 12, 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carbolin (295 mg, 1 mmol) (obtained by the method described in WO 97/43287, intermediate 1, page 24) and 2-chloro-5-(4-chlorophenyl)pyrimidine (113 mg, 0.5 mmol) in DMF (5 ml, anhydrous) were interaction, receiving the product as a white solid.

MS (m/z 479 (MN+)

1H-NMR (CDCl3) δ 2,87 (DD, J=4,14 Hz, 1H), 3,01 (dt, J=5,12 Hz, 1H), 3,38 (dt, J=4,14 Hz, 1H), 5,04 (DD, J=5,14 Hz, 1H), 5,91 (d, J=4 Hz, 2H), 6.73 x (d, J=7 Hz, 1H), 6.89 in (d, J=7 Hz, 1H), 7,00 (s, 1H), 7,20 (s, 1H), 7,25 (m, 2H), 7,30 (d, J=7 Hz, 1H), 7,40 (m, 4H), 7,56 (d, J=7 Hz, 1H), 7,83 (s, 1H), 8,54 (s, 2H).

EXAMPLE 18

[5-(3,4-Acid)pyrimidine-2-yl]-1-(3,4-acid)-2,3,4,9-tetrahydro-1H-β-carbolin

By the same procedure as described in example 16, 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carbolin (obtained by the method described in WO 97/43287, the intermediate product is t 7, page 24) and 2-chloro-5-(3,5-acid)pyrimidine subjected to interaction, receiving the product as a white solid.

TPL 184-186°C;

MS (m/z 523 (MN+), 521 (M-1)

1H-NMR (CDCl3) δ 2,81˜3,20 (m, 2H), 3,40 (m, 1H), 3,71 (s, 3H), 3,79 (s, 3H), 3,88 (s, 3H), 3,91 (s, 3H), free 5.01 (DD, 1H, J=14 Hz, 5 Hz), of 6.68 (d, 1H, J=8 Hz), 6,70˜7,19 (m, 7H), 7,28 (t, 1H, J=8 Hz), 7,52 (t, 1H, J=8 Hz), to 8.20 (s, 1H), charged 8.52 (s, 2H).

EXAMPLE 19

1,2,3,4-Tetrahydro-3-(3,4-acid)N-pyrrolo[3,4-b]quinoline-9-he (#12)

1-(3,4-Acid)-2,3,4,9-tetrahydro-1H-β-carbolin (1,854 g, 6,04 mmol) (obtained as in example 11) and KO-tert-Bu (1,14 g, 10,15 mmol) is stirred in DMF (60 ml) at room temperature for 10 minutes Through the solution for 1 hour bubbled oxygen. The reaction mixture is neutralized 1 N. HCl solution (10,15 ml, 10,15 mmol) and water are removed in vacuum in the form of an azeotrope with toluene. To the remaining solution in DMF) add silica gel (˜5 g), then add diethyl ether (600 ml), resulting in precipitation of the product on silica gel. Diethyl ether is decanted and the silica gel washed with diethyl ether (2×100 ml). After decantation of the solvent and the evaporation of any remaining trace amounts of the solvent the residue is purified column chromatography (silica gel; EtOH:EtOAc=1:9)to give the product as a bright yellow solid. The product is recrystallized from methanol.

MP 223-225° C;

MS (m/z): 323 (MN+), 321 (M-1)

1H-NMR (CD3OD) δ 3,71 (s, 3H), 3,88 (s, 3H), 4,18 (d, 1H, J=14 Hz), to 4.38 (d, 1H, J=14 Hz), 5,41 (s, 1H), 6,83 (m, 3H), 7,39 (t, 1H, J=7 Hz), 7,58 (m, 2H), by 8.22 (d, 1H, J=6 Hz), 11,85 (s, 1H).

EXAMPLE 20

1,2,3,4-Tetrahydro-2-[5-(4-methoxyphenyl)pyrimidine-2-yl]-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-he (#2)

Sodium hydride (60% in mineral oil, 36 mg, 0.9 mmol) and 1-(3,4-methylenedioxyphenyl)-2-[5-(4-methoxyphenyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-β-carbolin (186 mg, 0,39 mmol) (obtained as in example 12) in DMF (10 ml, anhydrous) was stirred at room temperature for 30 minutes Through the solution for 16 h bubbled dry air. Add ethyl acetate (100 ml) and saturated NaHCO3, the organic phase is washed with water, saturated salt solution and dried with MgSO4. The solvent is evaporated and the residue triturated with ethyl acetate, receiving the product as a white solid.

TPL: 325-327°C.

MS (m/z 491 (MN+); 489 (M-1)

1H-NMR (DMSO-d6) δ of 3.77 (s, 3H), a 4.86 (d, J=12 Hz, 1H), 4,96 (DD, J=15 Hz, 1H), 5,98 (s, 2H), 6,29 (d, J=2.5 Hz, 1H), 6.87 in (d, J=8 Hz, 1H), 6,95 (d, J=9 Hz, 2H), 6,98 (s, 1H), 7,02 (d, J=4 Hz, 3H), 7,34 (t, J=7 Hz, 1H), EUR 7.57 (d, J=9 Hz, 2H), 7,63 (DD, J=8 Hz, 3H), 8,16 (d, J=8 Hz, 1H), 8,69 (Sirs, 2H), 11,85 (s, 1H).

EXAMPLE 21

1,2,3,4-Tetrahydro-2-[5-(3,4-acid)pyrimidine-2-yl]-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-he (#1)

Sodium hydride (60% in mineral oil, 40mg, 1.0 mmol) and 1-(3,4-methylenedioxyphenyl)-2-[5-(3,4-acid)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-β-carbolin (218 mg, 0.43 mmol) (obtained as in example 13) in DMF (10 ml, anhydrous) was stirred at room temperature for 30 minutes Through the solution for 16 h bubbled dry air. Add ethyl acetate (100 ml) and saturated NaHCO3, the organic phase is washed with water, saturated salt solution and dried with MgSO4. The solvent is evaporated and the residue purified by chromatography (silica gel, ethyl acetate)to give product as a white solid.

MS (m/z 521 (MN+); 519 (M-1)

1H-NMR (DMSO-d6) δ of 3.77 (s, 3H), 3,83 (s, 3H), a 4.86 (d, J=12 Hz, 1H), 4,96 (DD, J=15 Hz, 1H), of 5.99 (s, 2H), of 6.31 (d, J=2.5 Hz, 1H), 6.87 in (d, J=8 Hz, 1H), 6,95 (d, J=9 Hz, 2H), 6,98 (s, 1H), 7,02 (m, 1H), 7,17 (d, J=7 Hz, 1H), 7,22 (s, 1H), 7,35 (t, J=7 Hz, 1H), 7.62mm (m, 2H), 8,17 (d, J=8 Hz, 1H), total of 8.74 (Sirs, 2H), 11,85 (s, 1H).

EXAMPLE 21A

(S)-1,2,3,4-Tetrahydro-2-[5-(3,4-acid)pyrimidine-2-yl]-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-he (#35)

According to the method described in example 21, (S)-1-(3,4-methylenedioxyphenyl)-2-[5-(3,4-acid)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-β-carbolin subjected to interaction, getting listed at the beginning of the connection.

EXAMPLE 21B

(R)-1,2,3,4-Tetrahydro-2-[5-(3,4-acid)pyrimidine-2-yl]-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-he (#36)

According to the method described in example 21, (R)1-(3,4-methylenedioxyphenyl)-2-[5-(3,4-acid)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-β -carbolin subjected to interaction, getting listed at the beginning of the connection.

EXAMPLE 22

1,2,3,4-Tetrahydro-2-[5-(4-were)pyrimidine-2-yl]-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-he (# 7)

By the same procedure as described in example 21, sodium hydride (60% in mineral oil, 43 mg, of 1.09 mmol) and 1-(3,4-methylenedioxyphenyl)-2-[5-(4-were)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-β-carbolin (278 mg, of 0.60 mmol) (obtained as in example 12) in DMF (15 ml, anhydrous) were interaction, receiving the product as a white solid.

MS (m/z) 475 (MN+)

1H-NMR (DMSO-d6) δ 2,32 (s, 3H), a 4.86 (d, J=12 Hz, 1H), 4,96 (DD, J=15 Hz, 1H), 5,98 (s, 2H), 6,30 (d, J=2.5 Hz, 1H), 6.87 in (d, J=8 Hz, 1H), 6,95 (d, J=9 Hz, 2H), 7,02 (d, J=4 Hz, 3H), from 7.24 (d, J=7 Hz, 2H), 7,34 (t, J=7 Hz, 1H), 7,40-the 7.65 (m, 3H), 8,16 (d, J=8 Hz, 1H), 8,69 (Sirs, 2H), 11,85 (s, 1H).

EXAMPLE 23

1,2,3,4-Tetrahydro-[5-(3,4-acid)pyrimidine-2-yl]-3-(3,4-acid)N-pyrrolo[3,4-b]quinoline-9-he (#15)

By the same procedure as described in example 19, [5-(3,4-acid)pyrimidine-2-yl]-1-(3,4-acid)-2,3,4,9-tetrahydro-1H-β-carbolin (obtained as in example 18) is subjected to interaction, receiving the product as a white solid.

MS (m/z 535 (MN+), 537 (MN-)

1H-NMR (CD3OD) δ 3,74 (s, 3H), 3,79 (s, 3H), of 3.80 (s, 3H), 3,85 (s, 3H), 5,0 (m, 2H), of 6.31 (s, 1H), 6.75 in˜to 7.15 (m, 5H), was 7.36 (t, 1H, J=8 Hz), 7,32 (d, 1H, J=8 Hz), to 7.61 (m, 2H), 8,29 (d, N, J=8 Hz), 8,58 (s, 2H).

EXAMPLE 24

1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-(pyridin-4-yl)methyl-N-pyrrolo[3,4-b]quinoline-9-he (#5)

By the same procedure as described in example 21, sodium hydride (60% in mineral oil, 40 mg, 1.0 mmol) and 1-(3,4-methylenedioxyphenyl)-2-(pyridin-4-yl)methyl-2,3,4,9-tetrahydro-1H-β-carbolin (192 mg, 0.50 mmol) (obtained as in example 15) in DMF (10 ml, anhydrous) were interaction, receiving the product as a white solid.

MS (m/z 398 (MN+)

1H-NMR (DMSO-d6) δ to 3.58 (d, J=14 Hz, 1H), 3,76 (d, J=15 Hz, 1H), 3,88 (d, J=15 Hz, 1H), 4,01 (d, J=14 Hz, 1H), 5,17 (s, 1H), 6,03 (s, 1H), 6,97 (s, 3H), 7,35 (m, 3H), 7,60 (m, 2H), 7,34 (t, J=7 Hz, 1H), 8,11 (d, J=8 Hz, 1H), 8,53 (d, J=6 Hz, 2H), of 11.45 (s, 1H).

EXAMPLE 25

1,2,3,4-Tetrahydro-2-(tert-butoxycarbonyl)-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-it (#3)

2-tert-Butoxycarbonyl-1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carbolin (4.09 g, 10.4 mmol) (obtained as in example 9) was dissolved in anhydrous DMF (100 ml). One portion is injected tert-piperonyl potassium (2.55 g, 22.7 mmol) and the suspension is stirred until then, until you get a clear solution. Then passed through a solution of gaseous oxygen through a needle of the syringe for 16 hours. The reaction mixture was quenched by adding glacial acetic acid (25 mmol) and poured into a mixture of diethyl ether and water, which leads to the formation of sludge, which is hoteltravel is so The product was then purified flash chromatography (0-10% Meon/CHCl3)to give product as a white solid.

MS (m/z 405 (M-1)

1H-NMR (CDCl3) δ 1,38-1,65 (series C, N), 4,79-4,88 (m, 2H), 5,86-6,27 (series of m, 3H), of 6.71-7,50 (series of m, 7H), 11,57 and 11,64 (s, 1H).

EXAMPLE 26

1,2,3,4-Tetrahydro-2-(benzyloxycarbonyl)-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-he (#27)

2-Benzyloxycarbonyl-1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carbolin (3,63 g, 8,51 mmol) (obtained as in example 10) was dissolved in anhydrous DMF (25 ml). One portion is injected tert-piperonyl potassium (2,40 g, with 21.4 mmol) and the suspension is stirred until then, until you get a clear solution. Then passed through a solution of gaseous oxygen through a needle of the syringe for 16 hours. The reaction mixture was quenched by adding glacial acetic acid (1.23 ml, or 21.0 mmol) and poured into water (250 ml), which leads to the formation of a precipitate, which is filtered off. The product was then purified flash chromatography (2-10% Meon/CHCl3), and receiving the product as a red powder.

MS (m/z 439 (M-1)

1H-NMR (CDCl3) δ 4,63-5,18 (series m, 4H), 5,71-5,85 (series of m, 3H), 6,54-6,72 (series of m, 3H), 6,98-7,01 (m, 1H), 7,25-EUR 7.57 (series of m, 7H), 8,27-8,32 (m, 1H), 10,04 and 10,33 (s, 1H).

EXAMPLE 27

Methyl ester (E)-4-[3-oxo-3-[1,2,3,4-tetrahydro-3-(2,3-dihydrobenzofuran-5-yl)-N-pyrrolo[3,4-b]quinoline-9-one-2-yl]-1-propenyl]benzoic acid (#20)

A. a Solution of (E)-4-Carbo is mexikoring acid (5,09 g, of 24.7 mmol) dissolved in anhydrous THF (25 ml) and treated in an argon atmosphere by oxalylamino (3,00 ml, to 34.4 mmol) and a drop of anhydrous DMF. After heating at 50°C for 2 hours, the reaction mixture was concentrated in vacuo, obtaining the acid chloride (E)-carboxymethylamino acid in the form of a reddish-brown solid.

C. the Product of part a (78 mg, 0.35 mmol) are added to a solution of 1,2,3,4-tetrahydro-3-(2,3-dihydrobenzofuran-5-yl)-N-pyrrolo[3,4-b]quinoline-9-it-wise (93.5 mg, 0.31 mmol) (obtained as in example 6), THF (3 ml), triethylamine (0,20 ml of 1.43 mmol) and DMAP (5 mg). The mixture is stirred for 16 h at room temperature, diluted with 1 N. HCl (10 ml) and the resulting white precipitate is filtered off. The solid is washed with water (3×), diethyl ether (3×) and dried in vacuum, obtaining the product as a slightly pink solid.

MS (m/z): 493 (MH+)

1H-NMR (DMSO-d6) δ 3,10-3 (m, 2H), a 3.87 (s, 3H), 4,43-to 4.52 (m, 2H), 4,70-5,14 (series of m, 2H), 6,23 and 6.61 (s, 1H), 6,72-6,79 (m, 1H), 7,07-8,19 (series of m, N), 10,69 and 10,77 (s, 1H).

EXAMPLE 28

1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)2-[5-(3-triptoreline)furoyl]-N-pyrrolo[3,4-b]quinoline-9-he (#13)

To a solution of 5-(3-triptoreline)-2-frankenboob acid (80,44 mg, 0,314 mmol) in a mixture of 1:1 DCM:THF (5 ml, anhydrous) add oxalicacid (43,85 mg, 0,345 mmol), followed by two drops of DMF. The mixture was stirred at on the th temperature for 1 hour. Add a suspension of 1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-it (96,2 mg, 0,314 mmol) (obtained as in example 5), triethylamine (0,13 ml) and DMAP (traces) in a mixture of 1:1 DCM/THF (5 ml). The resulting mixture was stirred at room temperature for 16 hours. Add ethyl acetate (50 ml) and the solution washed with aqueous NaHCO3, a saturated solution of salt, 1 N. HCl, saturated salt solution and then dried with MgSO4. The solvent is evaporated and the residue triturated with ethyl acetate, receiving the product as a white solid.

TPL: 219-221°

MS (m/z): 545 (MN+), 567 (M+23), 543 (MN-)

1H-NMR (DMSO-d6) δ 5,09 (d, J=14 Hz, 1H), 5,46 (d, J=14 Hz, 1H), of 5.99 (s, 2H), to 6.39 (s, 1H), 6,91 (d, J=8 Hz, 1H), 6,97 (d, J=8 Hz, 1H), 7,02 (s, 1H), 7,33 (d, J=8 Hz, 1H), 7,38 (d, J=4 Hz, 1H), 7,43 (d, J=4 Hz, 1H), 7,60 (m, J=8 Hz, 2H), to 7.77 (d, J=5 Hz, 2H), 8,16 (d, J=4 Hz, 3H), 11,55 (s, 1H).

EXAMPLE 29

1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)2-(6-hydroxy-2-benzofuranyl]-N-pyrrolo[3,4-b]quinoline-9-he (#9)

To a solution of 6-hydroxy-2-benzofuranol acid (0,054 g, 0.3 mmol) in tetrahydrofuran (5 ml) at 0°With added dropwise oxalicacid (0,046 g, 0.36 mmol)and then DMF (2 drops). The solution is heated to 25°C and stirred for 30 min, then concentrated in vacuo. The residue is dissolved in tetrahydrofuran (5 ml) and added to a solution of 1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-it (0,092 g, 0.3 m is ol) (received as in example 5) in THF (5 ml), triethylamine (0,045 g, 0.45 mmol) and 4-dimethylaminopyridine (0.01 g, cat.). The solution is stirred for 20 hours at 25°and then concentrated in vacuo. The crude residue is purified column chromatography on silica gel with elution with 3% methanol in dichloromethane, receiving the product as a clear oil.

1H-NMR (CD3OD) δ the 5.25 (d, J=15 Hz, 1H), 5,48 (d, J=15 Hz, 1H), 5,91 (s, 2H), 6,45 (Sirs, 1H), 6,84 (m, 3H), 6,93 (m, 2H), 7,00 (s, 1H), 7,25-7,89 (fuzzy m, 5H), 8,32 (d, 1H).

EXAMPLE 30

Methyl ester (E)-4-[3-Oxo-3-[1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-one-2-yl]-1-propenyl]benzoic acid (#6)

According to the method specified in example 20, 1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-he (398 mg, of 1.30 mmol) (obtained as in example 5) is subjected to interaction with the acid chloride (E)-carboxymethylamino acid (301 mg, of 1.34 mmol) in the presence of triethylamine (0.54 ml, a 3.87 mmol) in a mixture of 1:1 dichloromethane:THF (40 ml)to give the product as a tan solid.

MS (m/z 493 (M-1)

1H-NMR (CD3OD) δ 3,86 (s, 3H), 4,69-of 5.29 (series of m, 2H), 5,93-of 6.02 (m, 2H), 6,27 and 6,62 (s, 1H), 6.89 in-8,21 (series of m, 13H), 9,50 and 11,96 (Sirs, 1H).

EXAMPLE 31

1,2,3,4-Tetrahydro-2-(imidazol-1-yl)thiocarbonyl-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-he (#18)

To a suspension of 1,1'-thiocarbonyldiimidazole (0,192 g, 1.0 mmol) in DMF (5 ml, anhydrous) at 0°add 1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-he (to 0.30 g, 0.98 mmol) (obtained as in example 5). The mixture is heated to room temperature and stirred for 20 hours. The solution was diluted with water and extracted into ethyl acetate. The organic layers are combined and washed with aqueous NaHCO3and saturated salt solution, dried with MgSO4and concentrated in vacuo, obtaining the product as a light tan solid.

TPL: 211 to 215°C (decomp.)

MS (m/z) 415 (M-1)

1H-NMR (CD3OD) δ 4,71˜5,16 (m, 1H), 5,46 (d, J=15 Hz, 1H), 6,36-7,17 (fuzzy m, 5H), 7,42 (m, 2H), 7,52 (m, 1H), 7,58 (m, 2H), 8,28 (m, 1H).

EXAMPLE 32

(E)-4-[3-Oxo-3-[1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-one-2-yl]-1-propenyl]benzoic acid (#8)

Methyl ester (E)-4-[3-oxo-3-[1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-one-2-yl]-1-propenyl]benzoic acid (149 mg, 0.30 mmol) (obtained as in example 30) is suspended in a mixture 1:1 1 N. aqueous sodium hydroxide:methanol (10 ml) and refluxed for 8 hours. The reaction mixture is treated with an aqueous HCl to pH 1, which leads to the formation of a white precipitate. The precipitate is filtered off and washed with water (30 ml) and diethyl ether (160 ml)to give product as a white solid.

MC (m/z) 481 (MN+)

1H-NMR (DM what About the-d 6) δ 4,71-5,13 (series d, 2H), 5,95 is 5.98 (m, 2H), 6,23 and 6.61 (s, 1H), 6,84-7,78 (series of m, 10H), 7,89-a 7.92 (m, 3H), 8,13-8,17 (m, 1H), 11,94 (Sirs, 1H).

EXAMPLE 33

1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-[5-(4-nitrophenyl)furoyl]-N-pyrrolo[3,4-b]quinoline-9-he (#16)

1,2,3,4-Tetrahydro-3-(N,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-he (70,3 mg, 0,229 mmol) (obtained as in example 5), 5-(4-nitrophenyl)-2-frankenboob acid (of 58.9 mg, 0.25 mmol) and PyBrOP (amount of 0.118 g, 0.25 mmol) was stirred in DMF (3 ml) and DIPEA (0,088 ml, 0.50 mmol) for 16 hours. The reaction mixture was poured into ethyl acetate (80 ml) and the resulting organic layer was washed with 1 N. aqueous HCl (3×50 ml), saturated aqueous Na2CO3(1×50 ml) and saturated salt solution (1×50 ml). The organic layer is dried with MgSO4and the solvent is evaporated in vacuum. Column chromatography of the residue (silica gel, 5% SN3HE/CH3Cl) gives the product as a yellow powder.

MC (m/z): 522 (MH+), 520 (M-1)

1H-NMR (DMSO-d6) δ of 5.05 (d, 1H, J=14 Hz), the 5.45 (d, 1H, J=14 Hz), 6,0 (s, 2H), 6.42 per (s, 1H), 6,95 (m, 3H), 7,32˜7,41 (m, 2H), 7,55˜the 7.65 (m, 3H), 8,12 (m, 3H), 8,39 (m, 2H), 11,91 (s, 1H).

EXAMPLE 34

1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-[5-(4-AMINOPHENYL)furoyl]-N-pyrrolo[3,4-b]quinoline-9-he (#26)

1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-[(5-(4-nitrophenyl)furoyl]-N-pyrrolo[3,4-b]quinoline-9-he (25 mg, 0,0479 mmol) (obtained as in example 33) was stirred with 10% Pd on in the Le (5.1 mg, 0,00479 mmol) under 1 ATM of H2and room temperature for 14 hours. The solvent is evaporated and the product emit preparative TLC in the form of a yellow powder.

MS (m/z): 492 (MH+); 490 (M-1)

1H-NMR (CD3OD) δ the 5.25 (d, 1H, J=14 Hz), the 5.45 (d, 1H, J=14 Hz), 5,91 (s, 2H), 6,45 (s, 1H), 6,70˜at 8.60 (m, 13H).

EXAMPLE 35

1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-[2-hydroxynicotinic]-N-pyrrolo[3,4-b]quinoline-9-he (#25)

According to the method specified in example 33, with the appropriate substitution of reagents receive the product as a pale yellow solid.

MS (m/z): 428 (MN+); 426 (M-1)

1H-NMR (CD3OD) δ the 4.65 (d, J=14 Hz), 5,10 (d, 1H, J=14 Hz), to 5.85 (s, 2H), of 5.92 (s, 1H), 6,50˜7,10 (m, 3H), 7,30˜of 7.70 (m, 5H), to 8.25 (m, 2H).

EXAMPLE 36

1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-[5-(4-methoxyphenyl)furoyl]-N-pyrrolo[3,4-b]quinoline-9-he (#21)

According to the method specified in example 33, with the appropriate substitution of reagents receive the product as a pale yellow solid.

MS (m/z 507 (MN+); 505 (M-1)

1H-NMR (CDCl3) δ 3,85 (s, 3H), 5,10 (d, 1H, J=14 Hz), 5,38 (d, 1H, J=14 Hz), of 6.02 (s, 2H), 6,41 (s, 1H), 6,80˜8,35 (m, 13H), RS 11.80 (s, 1H).

EXAMPLE 37

1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-[5-(4-hydroxyphenyl)furoyl]-N-pyrrolo[3,4-b]quinoline-9-he (#22)

According to the method specified in example 33, with the appropriate substitution of reagents receive the product as a pale yellow solid which substances.

MS (m/z 493 (MN+); 491 (M-1)

1H-NMR (DMSO-d6) δ of 5.05 (d, 1H, J=14 Hz), 5,15 (d, 1H, J=14 Hz), of 5.75 (s, 2H), of 6.31 (s, 1H), 6,80˜8,35 (m, 13H), 11,60 (s, 1H).

EXAMPLE 38

1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-[5-(4-ethoxycarbonylphenyl)furoyl]-N-pyrrolo[3,4-b]quinoline-9-he (#24)

According to the method specified in example 33, with the appropriate substitution of reagents receive the product as a pale yellow solid.

1H-NMR (DMSO-d6) δ 4,10 (s, 3H), 5,10 (d, 1H, J=14 Hz), of 5.50 (d, 1H, J=14 Hz), of 6.02 (s, 2H), 6,45 (s, 1H), 6,80˜8,35 (m, 13H).

EXAMPLE 39

1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-[5-(4-formylphenyl)furoyl]-N-pyrrolo[3,4-b]quinoline-9-he (#23)

According to the method specified in example 33, with the appropriate substitution of reagents receive the product as a pale yellow solid.

MS (m/z 503 (M-1)

1H-NMR (DMSO-d6) δ 5,10 (d, 1H, J=14 Hz), of 5.55 (d, 1H, J=14 Hz), of 6.02 (s, 2H), 6,45 (s, 1H), 6,80˜8,35 (m, 13H).

EXAMPLE 40

Methyl ester (E)-4-[3-Oxo-3-[1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-4-methyl-N-pyrrolo[3,4-b]quinoline-9-one-2-yl]-1-propenyl]benzoic acid (#63) and methyl ester (E)-4-[3-Oxo-3-[1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-9-methoxy-N-pyrrolo[3,4-b]quinoline-9-one-2-yl]-1-propenyl]benzoic acid (#64)

A solution of methyl ester (E)-4-[3-oxo-3-[1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-one-2-yl]-1-propenyl]benzoic acid (349 mg, 062 mmol) (obtained as in example 30) and iodomethane (to 0.060 ml, 0.96 mmol) in anhydrous acetone (10 ml) is treated with anhydrous potassium carbonate (241 mg, of 1.74 mmol) and refluxed for 3 hours in argon atmosphere. The reaction mixture was concentrated in vacuo and the residue purified flash chromatography (0-10% methanol in dichloromethane)to give a mixture of N - and O-methylated products.

A mixture of N - and O-methylated products shared by column chromatography (0-10% MeOH/DCM)to give N-methylated product, methyl ester (E)-4-[3-Oxo-3-[1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-4-methyl-N-pyrrolo[3,4-b]quinoline-9-one-2-yl]-1-propenyl]benzoic acid, in the form of a reddish-brown solid.

MS (m/z): 509 (M-1)

1H-NMR (CDCl3) δ 3,55 (s, 3H), 3,93 (s, 3H), 5,10 (m, 2H), 5,94 (nd, J=3,7 Hz, 2H), 6,53 (s, 1H), 6,78 (d, J=7.9 Hz, 1H), 6,86-of 6.96 (m, 3H), 7,44-7,76 (series of m, 6N), with 8.05 (d, J=8,2 Hz, 2H), 8,55 (d, J=7,4 Hz) and O-methylated product, methyl ester (E)-4-[3-Oxo-3-[1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-9-methoxy-N-pyrrolo[3,4-b]quinoline-9-one-2-yl]-1-propenyl]benzoic acid, in the form of a pink solid.

MS (m/z): 509 (M-1)

1H-NMR (CDCl3) δ 3,93 (s, 3H), of 4.38 (s, 3H), of 5.45 (d, J=17,1 Hz, 1H), 5,64 (d, J=17,1 Hz, 1H), 5,91 (s, 2H), of 6.26 (s, 1H), 6.75 in-7,09 (series d, 4H), 7,39-8,23 (series of m, N).

EXAMPLE 41

1,2,3,4-Tetrahydro-2-(pyrimidine-2-yl)-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-he (#11)

To a solution of 1-(3,4-methyl shall dioxyphenyl)-2-(pyrimidine-2-yl)-2, 3, 4, 9-tetrahydro-1H-β-carboline (0,153 g, 0,415 mmol) (obtained as in example 16) in anhydrous DMF (4,1 ml) is added TO tert-Bu (0,079 g, 0.70 mmol, 1.7 EQ.). After 5 min through the solution for 1 hour bubbled gaseous oxygen. To the reaction mixture is added diethyl ether (45 ml) and the supernatant decanted. To the residue add a saturated solution of salt (2 ml) and the pH adjusted to about 7 by adding a few drops of 1 N. HCl. Water is removed in vacuum in the form of an azeotrope with toluene. The obtained dark red residue was dissolved in minimum amount of THF and purified column chromatography (silica gel; EtOH:CH2Cl2=l:9)to give product as a white solid.

MS (m/z): 383 (M-1); 385 (MN+)

1H-NMR (DMSO-d6) δ 4,84 (DD, 2H, J=14 Hz, 10 Hz), 5,98 (s, 2H), and 6.25 (s, 1H), 6,69 (t, 1H, J=5 Hz), 6,85 (d, 1H, J=8 Hz), 6,92 (d, 1H, J=8 Hz), 7,00 (s, 1H), 7,33 (t, 1H, J=7 Hz), 7,60 (m, 2H), 8,15 (d, 1H, J=8 Hz), to 8.41 (Sirs, 2H), 11,9 (s, 1H).

EXAMPLE 42

1,2,3,4-Tetrahydro-2-(pyrimidine-2-yl)-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-he (#11)

1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-he (100 mg, 0,3265 mmol) (obtained as in example 5) and 2-chloropyrimidine (38 mg, 0,3265 mmol) is stirred in DMF (2.5 ml) at 100°C for 16 hours. The solvent is removed in vacuo and the residue purified column chromatography (silica gel, 5% SN3HE/CH3Cl), receiving VC is the OE oil. Rubbing oil with Meon gives the product as a pale yellow solid.

MS (m/z 383 (M-1); 385 (MN+)

1H-NMR (DMSO-d6) δ 4,84 (DD, 2H, J=14 Hz, 10 Hz), 5,98 (s, 2H), and 6.25 (s, 1H), 6,69 (t, 1H, J=5 Hz), 6,85 (d, 1H, J=8 Hz), 6,92 (d, 1H, J=8 Hz), 7,00 (s, 1H), 7,33 (t, 1H, J=7 Hz), 7,60 (m, 2H), 8,15 (d, 1H, J=8 Hz), to 8.41 (Sirs, 2H), 11,9 (s, 1H).

EXAMPLE 43

Cleaners containing hydrochloride salt of 1,2,3,4-tetrahydro-2-[(4-pyridinyl)methoxycarbonyl]-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-it (#37)

A mixture of cleaners containing hydrochloride salt of 1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-she (101 mg, 0.33 mmol) (obtained as in example 5), ether (4-pyridinyl)methyl-4-nitrophenylamino acid (106 mg, 0.38 mmol) (obtained as in example 7) and triethylamine (2 EQ.) refluxed for 1 hour. The reaction mixture was concentrated in vacuo and purified flash chromatography (0-10% Meon/CHCl3). The corresponding salt is obtained by precipitation from a solution of the free base in methanol with a solution of HCl-ether.

MS (m/z) 442 (MN+)

1H-NMR (CD3OD) δ 5,02-5,62 (series m, 4H), 5,93-6,00 (m, 2H), 6,23 and 6,44 (s, 1H), 6,82? 7.04 baby mortality (m, 3H), 7,71-of 7.90 (m, 4H), to 8.12 (d, J=6.2 Hz, 1H), 8,44 (s, 1H), 8,78 (s, 1H), 8,84 (s, 1H).

EXAMPLE 44

1,2,3,4-Tetrahydro-2-[(4-pyridinyl)methoxycarbonyl]-3-(2,3-dihydrobenzofuran-5-yl)-N-pyrrolo[3,4-b]quinoline-9-he (#53)

According to the method specified in example 36, cleaners containing hydrochloride salt of 1,2,3,4-tetrahydro-3-(2,3-Digi robotforum-5-yl)-N-pyrrolo[3,4-b]quinoline-9-she received, as in example 6) and ether (4-pyridinyl)methyl-4-nitrophenylamino acid (obtained as in example 7) is subjected to interaction, receiving the product as a pale pink solid.

MS (m/z 440 (MN+)

1H-NMR (DMSO-d6) δ 2,82-to 2.94 (m, 2H), 4,35-5,26 (series of m, 6N), 5,91 (s, 1H) 6,45-7,58 (series of m, N), 8,30-8,46 (m, 2H), of 12.26 (width, 1H).

EXAMPLE 45

Cleaners containing hydrochloride salt of 1,2,3,4-tetrahydro-2-[[5-[2-(4-morpholinyl)ethoxy]-2-benzofuran]carbonyl]-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-it (#49)

Cleaners containing hydrochloride salt of 1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-she (222 mg, of 0.65 mmol) (obtained as in example 5) and 6-[2-(1-morpholino)ethoxy]-2-benzofuranol acid (209 mg, to 0.72 mmol) (obtained as in example 8) are suspended in anhydrous THF (10 ml). To this mixture is added PyBrOP (358 mg, 0.77 mmol) and triethylamine (and 0.40 ml, 2,87 mmol). The mixture is stirred overnight in an argon atmosphere and concentrated in vacuo. Purification of the residue with flash chromatography (0-10% Meon/CHCl3) gives the free base. The corresponding salt is obtained by precipitation from a solution of the free base in methanol with a solution of HCl-ether.

MC (m/z 580 (MH+)

1H-NMR (DMSO-d6) δ 3,17-3,24 (m, 2H), 3,52-3,61 (m, 4H), 3,80 (t, J=11.7 Hz, 2H), 3,98 (d, J=12.1 Hz, 2H), 4.53-in (Sirs, 1H), 5,10 (d, J=13.3 Hz, 1H), of 5.40 (d, J=13.3 Hz, 1H), 6,00 (s, 2H), 6.42 per (s, 1H), 6.90 to-7,08 (series m, 4H), 7,32-7,66 (series m, 4H), 7,73 (d, J=8,5 Hz, H), is 8.16 (d, J=8.0 Hz, 1H), 10,81 (s, 1H), 12,06 (s, 1H).

EXAMPLE 46

1-(2,3-Dihydrobenzofuranyl)-2-[5-(4-methoxyphenyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-β-carbolin

1-(2,3-Dihydrobenzo-5-furanyl)-2,3,4,9-tetrahydro-1H-β-carbolin (obtained by the method described in WO 97/43287, the intermediate product 10, page 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 in DMF (10 ml, anhydrous) at 120°C for 16 hours. The resulting mixture was quenched with 10% NaCl and extracted with ethyl acetate. The organic layer is washed with 10% NaCl, saturated salt solution and then dried with MgSO4. The solvent of the reaction mixture is evaporated, the resulting residue triturated with CH2Cl2and filtered. The filtrate is purified column chromatography (silica gel, ethyl acetate:hexane=4:6)to give product as a white solid.

TPL: 242-243°

MC (m/z) 475 (MN+), 483 (M-1)

1H-NMR (DMSO-d6) δ 2,50 (s, 1H), and 2.83 (m, 2H), 3,12 (t, J=8.7 Hz, 2H), 3,24 (m, 1H), of 3.78 (s, 3H), of 4.49 (t, J=8.7 Hz, 2H), 4,90 (d, J=12 Hz, 1H), 6,72 (d, J=8,2 Hz, 1H), 7,03 (m, 4H), 7,06 (d, J=7 Hz, 1H), 7,17 (d, J=9,3 Hz, 2H), 7,30 (d, J=8 Hz, 1H), 7,46 (d, J=7,6 Hz, 1H), to 7.59 (d, J=8.6 Hz, 2H), 8,73 (s, 2H), 11,00 (s, 1H).

EXAMPLE 47

1,2,3,4-Tetrahydro-2-[5-(4-methoxyphenyl)pyrimidine-2-yl]-3-(3,4-dihydrobenzofuranyl)-N-pyrrolo[3,4-b]quinoline-9-he (#39)

Sodium hydride (60% in mineral oil, 87 mg of 2.18 mmol) and 1-(2,3-dihydro-5-benzofuranyl)-2,3,,9-tetrahydro-2-[5-(4-methoxyphenyl)-2-pyrimidinyl]-1H-β -carbolin (450 mg, 0.95 mmol) (obtained as in example 4,6) in DMF (30 ml, anhydrous) was stirred at room temperature for 30 minutes and Then through the solution for 16 h bubbled dry air. The solution is then added ethyl acetate (200 ml). The resulting mixture was washed with 10% NaCl solution, saturated salt solution and then dried with MgSO4. The solvent is evaporated and the residue triturated with ethyl acetate, receiving the product as a white solid.

TPL: 301-302°

MS (m/z) 489 (MN+); 487 (M-1)

1H-NMR (DMSO-d6) δ the 3.11 (t, J=8.7 Hz, 2H), of 3.77 (s, 3H), 4,47 (t, J=8.7 Hz, 2H), 4,89 (m, 2H), 6,29 (s, 1H), 6,72 (d, J=8,1 Hz, 1H), 6,95 (d, J=8.7 Hz, 2H), 7,29 (m, 3H), EUR 7.57 (d, J=8.6 Hz, 2H), to 7.64 (d, J=8,2 Hz, 2H), 8,16 (d, J=8.0 Hz, 1H), 8,67 (s, 2H), 11.87 per (s, 1H).

EXAMPLE 47A

(R)-1,2,3,4-Tetrahydro-2-[5-(4-methoxyphenyl)pyrimidine-2-yl]-3-(3,4-dihydrobenzofuranyl)-N-pyrrolo[3,4-b]quinoline-9-he (#66)

(R)-1,2,3,4-Tetrahydro-3-(2,3-dihydrobenzofuran-5-yl)-N-pyrrolo[3,4-b]quinoline-9-he (0,23 g, 0,678 mmol) (obtained as in example 6A) and 5-(4-methoxyphenyl)-2-chloropyrimidine (0.167 g, 0,758 mmol) is stirred with diisopropylethylamine (0.33 ml) and KF (44,8 mg, 0,758 mmol) in DMF (5 ml) at 60°C for 36 hours. The reaction mixture was diluted with CH2Cl2(75 ml) and EtOAc (75 ml). Washed with 1 N. aqueous HCl (3×100 ml). The mixture is then washed with a saturated solution of salt (2×100 ml). After drying over MgSO4her focus to education relegable. The crude product is purified on a column of silica gel, receiving the product as a white solid.

MS (m/z 499 (MN+), 497 (M-1)

1H-NMR (CDCl3) δ to 3.02 (t, 2H, J=11.7 Hz), 3,82 (s, 3H), of 4.44 (t, 2H, J=11.7 Hz), of 4.95 (d, 1H, J=15.6 Hz), to 5.08 (d, 1H, J=15.6 Hz), 6,24 (s, 1H), 6,62 (d, 1H, J=7.8 Hz), 6,92 (d, 2H, J=7.8 Hz), 7,14˜to 7.61 (m, 7H), to 8.45 (m, 3H), 9,65 (s, 1H).

Rf=0,47 (10% CH3HE/CHCl3). Elemental analysis for C30H24N4About3calculated: %73,76, %N Of 4.95, %N 11,47, %O 9,82; found: %73,73, %N 4,87, %N 11,40, %O 9,65.

EXAMPLE 48

(R)-1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-[5-(3-triptoreline)furo-2-yl]-N-pyrrolo[3,4-b]quinoline-9-he (#50)

To a solution of 5-(3-triptoreline)-2-frankenboob acid (504,4 mg, 1.97 mmol) in a mixture of 1:1 DCM:THF (10 ml, anhydrous) add oxalicacid (275 mg, 2,17 mmol), followed by two drops of DMF. The reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture is added triethylamine (1.1 ml), DMAP (trace) and the suspension enantiomerically pure 1,2,3,4-tetrahydro-3-(3,4-methylendioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-it (603 mg, 1.97 mmol) (obtained as in example 5A) in a mixture of 1:1 DCM:THF (10 ml). The resulting mixture was stirred at room temperature for 16 hours. Add ethyl acetate (100 ml) and the solution washed with aqueous NaHCO3, a saturated solution of salt, 1 N. HCl, saturated salt solution and then dried with MgSO4. Solvent d is klonoa mixture is evaporated and the residue triturated with ethyl acetate, receiving the product as a white solid.

TPL: 219-221°

MS (m/z 545 (MN+), 543 (M-1)

1H-NMR (DMSO-d6) δ 5,09 (d, J=13 Hz, 1H), vs. 5.47 (d, J=13 Hz, 1H), 6,00 (s, 2H), to 6.39 (s, 1H), 6,91 (d, J=8 Hz, 1H), 6,97 (d, J=8 Hz, 1H), 7,02 (s, 1H), 7,33 (d, J=7 Hz, 1H), 7,38 (d, J=4 Hz, 1H), 7,43 (d, J=4 Hz, 1H), 7,60 (m, J=8 Hz, 2H), to 7.77 (d, J=5 Hz, 2H), 8,16 (d, J=5 Hz, 3H), 11,90 (s, 1H).

EXAMPLE 49

1-(2,3-Dihydrobenzofuranyl)-2-[5-(2-pyridinyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-β-carbolin

1-(2,3-Dihydrobenzofuranyl)-2,3,4,9-tetrahydro-1H-β-carbolin (obtained by the method described in WO 97/43287, the intermediate product 10, page 25) (1.35 g, of 4.66 mmol), 2-chloro-5-(2-pyridinyl)pyrimidine (893 mg, of 4.66 mmol) and N,N-diisopropylethylamine (1,4 ml) is stirred in DMF (10 ml, anhydrous) at 120°C for 16 hours. The resulting mixture was quenched with 10% NaCl and extracted with ethyl acetate. Extracted organic layer was washed with 10% NaCl, saturated salt solution and then dried with MgSO4. The solvent of the reaction mixture is evaporated and the residue purified column chromatography (silica gel, ethyl acetate:hexane=4:6)to give product as a white solid.

TPL: 170-171°

MS (m/z 446 (MN+), 444 (M-1)

1H-NMR (DMSO-d6) δ 2,85 (d, J=5 Hz, 2H), 3,12 (t, J=8.7 Hz, 2H), 3.27 to (d, J=12,4 Hz, 1H), 4,96 (d, J=12,6 Hz, 1H), 6,72 (d, J=8,2 Hz, 1H), 6,99 (t, J=7,4 Hz, 1H), 7,07 (t, J=7,1 Hz, 2H), 7,21 (s, 2H), 7,31 (d, J=8,2 Hz, 2H), 7,47 (d, J=7,6 Hz, 1H), a 7.85 (d, J=7.8 Hz, 1H), to 7.93 (d, J=8 Hz, 1H), and 62 (d, J=4.5 Hz, 1H), 9,13 (s, 2H), br11.01 (s, 1H).

EXAMPLE 50

1,2,3,4-Tetrahydro-2-[5-(2-pyridinyl)pyrimidine-2-yl]-3-(3,4-dihydrobenzofuranyl)-N-pyrrolo[3,4-b]quinoline-9-he (#61)

Sodium hydride (60% in mineral oil, 182 mg, 4,55 mmol) and 1-(2,3-dihydro-5-benzofuranyl)-2,3,4,9-tetrahydro-2-[5-(2-pyridinyl)-2-pyrimidinyl]-1H-β-carbolin (16176-23) (882 mg, 1,99 mmol) (obtained as in example 49) in DMF (30 ml, anhydrous) was stirred at room temperature for 30 minutes Through the solution for 16 h bubbled dry air. Add ethyl acetate (200 ml) and the resulting mixture was washed with 10% NaCl solution, saturated salt solution and then dried with MgSO4. The solvent of the reaction mixture is evaporated and the residue triturated with ethyl acetate, receiving the product as a white solid.

TPL 201-203°

MS (m/z) 460 (MN+); 458 (M-1)

lH-NMR (DMSO-d6) δ the 3.11 (t, J=8.5 Hz, 2H), 4,46 (t, J=8.5 Hz, 2H), 4,91 (m, 2H), 6,34 (s, 1H), 6.73 x (d, J=8,1 Hz, 1H), 7,31 (m, 4H), to 7.59 (t, J=8.6 Hz, 2H), to 7.84 (d, J=7,1 Hz, 1H), to $ 7.91 (d, J=7.7 Hz, 1H), 8,16 (d, J=7.9 Hz, 1H), at 8.60 (d, J=4.5 Hz, 1H), 8,98 (s, 1H), 9,12 (s, 2H), 11,90 (s, 1H).

EXAMPLE 50A

(R)-1,2,3,4-Tetrahydro-2-[5-(2-pyridinyl)pyrimidine-2-yl]-3-(3,4-dihydrobenzofuranyl)-N-pyrrolo[3,4-b]quinoline-9-he (#65)

A. 1-Methyl-5-(2-pyridinyl)-2(1H)pyrimidone

A mixture of 2-(2-pyridinyl)malondialdehyde (5 g, 0,0335 mol), metallocene (4.72 in g, 0,0637 mol) and toluensulfonate acid (450 mg) is refluxed toluole (100 ml) in the apparatus, equipped with a water separator Dean-stark for 4 hours. The mixture is cooled and the precipitate filtered off. The solid is triturated with water and recrystallized from ethanol, receiving the product.

MS (m/z) (MH+) 188

1H-NMR (DMSO-d6) δ of 7.48 (m, 1H), 7,98 (m, 1H), 8,18 (d, J=8.0 Hz, 1H), 8,75 (c, 1H), 9,41 (s, 2H).

Century 2-Chloro-5-(2-pyridinyl)pyrimidine

A mixture of 1-methyl-5-(2-pyridinyl)-2(1H)pyrimidone (8,994 g 0,048 mol), pentachloride phosphorus (2,156 g, 0,0104 mol) and phosphorus oxychloride (24 ml) is refluxed at 120°C for 8 hours. POCL3distilled off under reduced pressure. The residue is cooled to room temperature and add a mixture of ice-water. The mixture is extracted with EtOAc, the organic layer was washed with a 15% NaCl solution, saturated salt solution and dried over MgSO4. The solvent is distilled off under reduced pressure, obtaining a solid substance. the pH of the aqueous layer was adjusted to 6-7 using saturated Na2CO3, then extracted with EtOAc. The organic layer was washed with 15% NaCl, saturated salt solution, dried over MgSO4. The solvent is distilled off under reduced pressure, obtaining a solid substance. After trituration with Meon receive additional product.

MS (m/z) (MH+) 192

1H-NMR (DMSO-d6) δ of 3.56 (s, 3H), 7,33 (m, 1H), 7,89 (d, J=8,8 Hz, 2H), 8,61 (d, J=4,7 Hz, 1H), of 8.95 (s, 1H), 9,31 (s, 1H).

C. (R)-1,2,3,4-Tetrahydro-2-[5-(2-pyridinyl)Piri is one-2-yl]-3-(3,4-dihydrobenzofuranyl)-N-pyrrolo[3,4-b]quinoline-9-he

A mixture of cleaners containing hydrochloride salt of (R)-1,2,3,4-tetrahydro-3-(2,3-dihydrobenzofuran-5-yl)-N-pyrrolo[3,4-b]quinoline-9-it (1,273 g, 0,00373 mol) (obtained in example 6A), 2-chloro-5-(2-pyridinyl)pyrimidine (0,714 g, 0,00373 mol), KF (0,216 g, 0,00373 mol) and diisopropylethylamine of 2.27 ml) in DMF (45 ml) is heated at 55°C for 4 hour. Add EtOAc and the mixture is washed with 0.5 N. citric acid, then 15% NaCl, saturated salt solution and dried over MgSO4. The solvent is distilled off under reduced pressure, obtaining a solid substance. The solid is dissolved in 10% methanol in dichloromethane and purified column chromatography (EtOAc to 10% of CH3HE EtOAc)to give specified in the header of the connection.

TPL 231-233°

MS (m/z) (MH+) 460

1H-NMR (DMSO-d6) δ 3,11 (d, J=8.7 Hz, 2H), 4,46 (d, J=8.7 Hz, 2H), 4.92 in (m, 2H), 6,34 (d, J=1.6 Hz, 1H), 6.73 x (d, J=8,1 Hz, 1H), 7,28 (m, 4H), to 7.59 (m, 2H), 7,82 (m, 1H), to $ 7.91 (d, J=8,0, 1H), 8,16 (d, J=8,0, 1H), 8,60 (J=4.5 Hz, 1H), 8,98 (s, 1H), 9,12 (s, 1H), 11,92 (s, 1H).

Specified in the title compound was dissolved in methanol, add one equivalent of 0.02 M methanesulfonic acid (in methanol). The solvent is distilled off under reduced pressure, obtaining salt methanesulfonic acid.

[α]=-236,2° (C=1,0333 g/DL, CH3IT).

EXAMPLE 51

2-Chloro-5-bromopyrimidine

2-Chloro-5-bromopyrimidine obtained from 2-hydroxypyrimidine (purchased from Frontier Scientific Inc.) according to the method described in U.S. patent No. 5693611, p is torching 6, column 17.

EXAMPLE 52

1-(3,4-Methylenedioxyphenyl)-2-(5-bromopyrimidine-2-yl)-2,3,4,9-tetrahydro-1H-β-carbolin

To a solution of 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (of 4.38 g, 15.0 mmol) (obtained by the method described in WO 97/43287, intermediate 7, page 24) and 2-chloro-5-bromopyrimidine (2,90 g, 15.0 mmol) (obtained as in example 51) in anhydrous degassed DMF (30 ml) is added N,N-diisopropylethylamine of 4.2 ml, 30 mmol). The mixture is heated at 120-130°With during the night. The mixture was then cooled and diluted with ethyl acetate. The solution is washed with 0.5 N. citric acid, water and saturated salt solution, then dried over Na2SO4and concentrated in vacuo. Purification column flash chromatography (silica gel, hexane:ethyl acetate=6:1, about./about., then hexane:ethyl acetate=4:1, vol/about.) gives the product as a white solid.

MS (m/z 451 and 499 (MN+), 447 and 449 (M-1)

1H-NMR (CDCl3) δ 2,82-to 3.02 (m, 2H), 3,30 is 3.40 (m, 1H), 4.92 in (DD, J=18,1 Hz, 1H), of 5.92 (d, J=3.2 Hz, 2H), 6,72 (d, J=8.0 Hz, 1H), 6,85 (d, J=8.0 Hz, 1H), 6,95 (s, 1H), 7,02 (s, 1H), 7,13-7,21 (m, 2H), 7,30 (d, J=7.7 Hz, 1H), 7,55 (d, J=7.5 Hz, 1H), 7,73 (s, 1H), 8.34 per (s, 2H).

EXAMPLE 53

1,2,3,4-Tetrahydro-2-(5-bromopyrimidine-2-yl)-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-he (#55)

Method:

A solution of 1-(3,4-methylenedioxyphenyl)-2-(5-bromopyrimidine-2-yl)-2,3,4,9-tetrahydro-1H-β-carboline (1.0 g, 2.2 mmol) (obtained as in example 52) in baie the water DMF (40 ml) cooled in an ice bath. Add NaH (60% in mineral oil, 0.18 g, 4.4 mmol) and the mixture was stirred at 0°C for 45 minutes Through a solution bubbled air dried and the mixture is allowed to warm to room temperature over night. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase is washed with a saturated solution of salt and water, then dried over Na2SO4concentrate and purify by flash column (silica gel, hexane:ethyl acetate=1:1, vol/about., then only ethyl acetate)to give product as a white solid.

MS (m/z) 465 and 463 (MH+), and 461 463 (M-1)

1H-NMR (DMSO-d6) δ 4,80 (d, J=8,2 Hz, 1H), 4,89 (DD, J=6,8 Hz, 1H), 5,98 (s, 2H), of 6.20 (s, 1H), 6,85-6,93 (m, 2H), 6,98 (s, 1H), 7,34 (t, J=7,3 Hz, 2H), EUR 7.57-to 7.64 (m, 3H), 8,15 (d, J=8.0 Hz, 2H).

Method:

To a solution of 1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-it (31 mg, 0.1 mmol) (obtained as in example 5, a free base) and 2-chloro-5-bromopyrimidine (19 mg, 0.1 mmol) (obtained as in example 51) in anhydrous degassed DMF (2 ml) is added N,N-diisopropylethylamine (28 μl, 0.2 mmol). The mixture is maintained at 120-130°With during the night. The solution is cooled, diluted with ethyl acetate and washed with 0.5 N. citric acid, water and saturated salt solution, then dried over Na2SO4and concentrated in vacuo. Purification on flash column (silica gel, hexane:ethyl acetate=1:1, vol/on the., then ethyl acetate) gives the product as a white solid.

MS (m/z) 465 and 463 (MN+), and 461 463 (M-1)

1H-NMR (DMSO-d6) δ 4,80 (d, J=8,2 Hz, 1H), 4,89 (DD, J=6,8 Hz, 1H), 5,98 (s, 2H), of 6.20 (s, 1H), 6,85-6,93 (m, 2H), 6,98 (s, 1H), 7,34 (t, J=7,3 Hz, 2H), EUR 7.57-to 7.64 (m, 3H), 8,15 (d, J=8.0 Hz, 2H).

EXAMPLE 54

1,2,3,4-Tetrahydro-2-[5-(3-pyridinyl)pyrimidine-2-yl]-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-he (#56)

Method:

Stir a mixture of palladium(II) acetate (0.8 mg, 3.6 mmol) and 1,1'-bis(diphenylphosphino)ferrocene (dppf) (2.4 mg, 4.3 mmol) in anhydrous DMF (1.0 ml) is heated to 50°C for 15 min and cooled. To the solution was added 1,2,3,4-tetrahydro-2-(5-bromopyrimidine-2-yl)-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-he (20 mg, 43 mmol) (obtained as in example 53), pyridine-3-Bronevoy acid (6.0 mg, 43 μmol) and triethylamine (8 μl, 60 μmol) and the mixture is heated to 90°C for 16 hours. The solution is diluted with ethyl acetate and filtered through filter paper. The organic phase is washed with a saturated solution of salt and water and then dried over Na2SO4. A small amount of silica gel was added to the solution and the solution is dried in vacuum. Purification on flash column (silica gel, 10% ammonium hydroxide in a mixture of water:acetonitrile=1:10, vol/about.) gives the product as a white solid.

MS (m/z 460 (M-1)

1H-NMR (DMSO-d6) δ 4,88 (d, J=4,1 Hz, 1H), 4,99 (d, J=4,1 is C, 1H), of 5.99 (s, 2H), of 6.31 (s, 1H), to 6.88 (d, J=7.9 Hz, 1H), of 6.96 (d, J=8,1 Hz, 1H),? 7.04 baby mortality (s, 1H), 7,34 (t, J=6,9 Hz, 1H), 7,43-to 7.50 (m, 1H), 7,56-of 7.70 (m, 2H), 8,08 (d, J=8.0 Hz, 1H), 8,16 (d, J=7.9 Hz, 1H), 8,53 (d, J=4,1 Hz, 1H), 8,72-8,82 (width, 1H), 8,89 (s, 2H), 11.87 per (s, 1H).

Method:

A solution of 1-(3,4-methylenedioxyphenyl)-2-[5-(3-pyridinyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-β-carboline (100 mg, 0.22 mmol) (obtained as in example 55) in anhydrous DMF (4.0 ml) cooled in an ice bath. Add NaH (60% in mineral oil, 31 mg, 0.78 mmol) and the mixture was stirred at 0°C for 45 minutes Through a solution bubbled air dried and the mixture is allowed to warm to room temperature over night. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase is washed with a saturated solution of salt and water, then dried over Na2SO4concentrate and purify by flash column (silica gel, 10% ammonium hydroxide in a mixture of water:acetonitrile=1:10, vol/vol.), receiving the product as a white solid.

MS (m/z 460 (M-1)

1H-NMR (DMSO-d6) δ 4,88 (d, J=4,1 Hz, 1H), 4,99 (d, J=4,1 Hz, 1H), of 5.99 (s, 2H), of 6.31 (s, 1H), to 6.88 (d, J=7.9 Hz, 1H), of 6.96 (d, J=8,1 Hz, 1H),? 7.04 baby mortality (s, 1H), 7,34 (t, J=6, 9 Hz, 1H), 7,43-to 7.50 (m, 1H), 7,56-7,70 (m, 2H), 8,08 (d, J=8.0 Hz, 1H), 8,16 (d, J=7.9 Hz, 1H), 8,53 (d, J=4,1 Hz, 1H), 8,72-8,82 (width, 1H), 8,89 (s, 2H), 11.87 per (s, 1H).

EXAMPLE 55

1-(3,4-Methylenedioxyphenyl)-2-[5-(3-pyridinyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-β-carbolin

Stir a mixture of acetate palla the Oia (II) (27 mg, 0.12 mmol) and 1,1'-bis(diphenylphosphino)ferrocene (dppf) (83 mg, 0.15 mmol) in anhydrous DMF (20 ml) is heated to 50°C for 15 min and then cooled. To the solution was added 1-(3,4-methylenedioxyphenyl)-2-(5-bromopyrimidine-2-yl)-2,3,4,9-tetrahydro-1H-β-carbolin (674 mg, 1.5 mmol) (obtained as in example 52), pyridine-3-Bronevoy acid (203 mg, 1.7 mmol) and triethylamine (0.3 ml, 2.1 mmol) and the mixture is heated to 90°C for 16 hours. The solution is diluted with ethyl acetate and filtered through filter paper. The organic phase is washed with saturated salt solution and water, dried over Na2SO4. To the solution add a small amount of silica gel and the solution is dried in vacuum. Purification on flash column (silica gel, hexane:ethyl acetate=1:1, vol/about., then hexane:ethyl acetate=1:2, vol/vol.), gives the product as a white solid.

MS (m/z 448 (MH+) and 446 (M-1)

1H-NMR (CDCl3) δ 2,85-3,10 (m, 2H), 3.33 and-of 3.48 (m, 1H), is 5.06 (DD, J=8.5 Hz, 1H), 5,94 (d, J=4,7, 2H), 6.73 x (d, J=8,0, 1H), make 6.90 (d, J=8,0, 1H), 7,02 (s, 1H), 7,13-of 7.23 (m, 2H), 7,32-7,42 (m, 2H), 7,56 (d, J=7,4 Hz, 1H), 7,79-to 7.84 (m, 2H), 8,58 (s, 1H), at 8.60 (s, 2H) 8,77 (s, 1H).

EXAMPLE 56

1,2,3,4-Tetrahydro-2-[5-(4-pyridinyl)pyrimidine-2-yl]-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-he (#57)

Stir a mixture of 1,2,3,4-tetrahydro-2-(5-bromopyrimidine-2-yl)-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-she (46 mg, 0.1 mmol) (obtained as in example 53), (PPh3)4Pd (3.5 mg, 3.0 mm is l) and 4-tri-n-butylstannane (37 mg, 0.1 mmol) in anhydrous DMF (2.0 ml) is heated at 140°C for 12 hours. Add the catalyst (3.5 mg) and the mixture 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 a saturated solution of salt and water, then dried over Na2SO4. To the solution add a small amount of silica gel and the solution is dried in vacuum. Purification on flash column (silica gel, only acetonitrile, then with 10% ammonium hydroxide in a mixture of water:acetonitrile=1:10, vol/vol.), gives the product as a white solid.

MS (m/z 460 (M-1)

1H-NMR (DMSO-d6) δ is 4.93 (d, J=4,2 Hz, 1H), 5,00 (d, J=4,2 Hz, 1H), 6,01 (s, 2H), 6,33 (s, 1H), make 6.90 (d, J=8.0 Hz, 1H), 6,98 (d, J=8.0 Hz, 1H), 7,05 (s, 1H), 7,34 (width, 1H), 7.62mm (width, 2N), to 7.77 (d, 2H), 8,19 (d, J=7.9 Hz, 1H), 8,61 (width, 2H), 8,78 (width, 1H), 9,00 (width, 1H).

EXAMPLE 57

1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-(5-(2-bromo)furoyl)-N-pyrrolo[3,4-b]quinoline-9-he (#30)

2-Bromo-2-frankenboob acid (1.44 g, rate of 7.54 mmol) in THF (20 ml) is stirred with oxalylamino (of 1.06 ml, rate of 7.54 mmol) at room temperature. To the mixture add 2 drops of DMF, resulting in a vigorous reaction with evolution of gas. After cessation of gas through a syringe injected more oxalicacid (0.1 ml, 0.71 mmol) and the mixture is stirred at room temperature for 10 mi and then stirred at 90° C for 10 minutes, the Solvent and excess oxalicacid removed in vacuum, which leads to the formation of a pale yellow crystalline solid. To solid substance added THF (20 ml) and a solution of 3-(2,3-dihydro-5-benzofuran)-1,2,3,4-tetrahydro-N-pyrrolo[3,4-b]quinoline-9-she (2.1 g) (obtained as in example 6) in THF (20 ml). To the reaction mixture add Et3N (4,55 ml of 32.6 mmol) and catalytic amount of DMAP (40 mg). Add a few drops of DMF, which leads to the formation of a transparent reaction mixture. The reaction mixture was stirred at room temperature for 4 hours. The solvent of the reaction mixture is evaporated, obtaining a solid residue. The residue is again dissolved in CHCl3(200 ml), washed with water (3×200 ml) and the organic layer is dried over MgSO4. The organic solvent is evaporated, getting the product in the form of not-quite-white solid.

MS (m/z 480 (MN+), 478 (M-1)

1H-NMR (CDCl3) δ to 5.03 (d, 1H, J=15,5 Hz), 5,23 (d, 1H, J=15,5 Hz), to 5.85 (d, 2H, J=8.0 Hz), 6,40 (m, 2H), 6,56 (m, 1H), for 6.81 (m, 2H), 7,00 (d, 1H, J=4.3 Hz), 7,32 (t, 1H, J=8.6 Hz), 7,53 (t, 1H, J=8.6 Hz), 7,65 (d, 1H, J=8.6 Hz), scored 8.38 (d, 1H, J=8.6 Hz), 12,8 (s, 1H).

EXAMPLE 58

4-(4-Methyl)piperidinecarbonitrile acid

4-Carboxybenzeneboronic acid (of 0.332 g, 2 mmol), 1-methylpiperazine (to 0.22 ml, 2 mmol) and PyBrOP (should be located at 0.9334 g, 2 mmol) is mixed with DIPEA (0,696 ml, 4 mmol) in DMF (7 ml) at room is temperature for 16 hours. Preparative TLC (10% Meon/CHCl3) gives the product as a white solid.

MS (m/z 251 (MH+), 249 (M-1)

1H-NMR (CD3OD) δ a 2.36 (s, 3H), 2,43 (s, 2H), 2.57 m (s, 2H), 3,51 (s, 2H), 3,82 (s, 2H), 7,34 (s, 2H), 7,76 (s, 2H).

EXAMPLE 59

1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-(5-(4-(1-(4-methyl)piperazinylcarbonyl)phenyl)furoyl)-N-pyrrolo[3,4-b]quinoline-9-he (#44)

1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-(5-(2-bromo)furoyl)-N-pyrrolo[3,4-b]quinoline-9-he (to 59.6 mg, 0.12 mmol) (obtained as in example 57) was stirred with Pd(PPh3)4(7,37 mg, 0,0062 mmol) in dioxane (5.5 ml) with bubbling N2within 10 minutes Then add a solution of 4 -(4-methyl)piperazineethanesulfonic acid (37,0 mg, 0.15 mmol) and K2CO3(51,5 mg of 0.37 mmol) in N2O (1.1 ml). The reaction mixture was stirred at 100°C for 1 hour. The solvent is evaporated, the residue is purified preparative TLC (10% Meon/CHCl3and then triturated with a mixture of ether/Meon (15 ml/1 ml)to give the product as a pale yellow powder.

MS (m/z): 603 (MN+), 601 (M-1)

1H-NMR (CD3OD) δ 2,32 (s, 3H), 2,53˜2,62 (m, 4H), 3,53 (Sirs, 2H), 3,83 (Sirs, 2H), 5,17 (d, 1H, J=15,5 Hz), 5,41 (d, 1H, J=15,5 Hz), of 5.83 (s, 2H), from 6.22 (s, 1H), 6,70 (m, 1H), PC 6.82 (m, 2H), 7,03 (m, 1H), 7,25˜7,34 (m, 2H), 7,46˜7,56 (m, 4H), to 7.93 (d, 2H, J=8.6 Hz), 8,31 (d, 2H, J=8.6 Hz).

EXAMPLE 59A

(R)-1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-(5-(4-(1-(4-methyl)piperazinyl bonyl)phenyl)furoyl)-N-pyrrolo[3,4-b]quinoline-9-he (#69)

A. Methyl ester 5-(4-(4-methyl)piperazinylcarbonyl)frankenboob acid

A mixture of 4-(4-methyl)piperazineethanesulfonic acid (obtained as in example 58) (1.31 g, 5,28 mmol), methyl ester brompheniramine acid (1.08 g, 5,28 mmol) (obtained from 5-brompheniramine acid in HCl/MeOH for 5 hours at room temperature) in a mixture of dioxane (45 ml) and H2O (9 ml) Tegaserod by bubbling N2within 10 minutes To a mixture of Pd(PPh3)4(0,627 g, 0,528 mmol) and K2CO3(2,185 g, 15,84 mmol). The solution was stirred at 100°C for 3 hours. The solvent is evaporated and the residue dissolved in CH2Cl2(100 ml). The solution was washed with saturated salt solution (3×100 ml), dried over MgSO4, concentrated in vacuo and the crude product is purified on a column of silica gel (5% CH3HE/CHCl3)to give product as a yellow solid.

MS (m/z 315 (MN+), 313 (M-1)

1H-NMR (CDCl3) δ 2,32˜2,48 (m, 7H), of 3.48 (s, 2H), 3,80 (s, 2H), 3,92 (s, 3H), for 6.81 (d, 1H, J=2.0 Hz), 7,24 (d, 1H, J=2.0 Hz), 7,49 (d, 2H, J=7.9 Hz), 7,83 (d, 2H, J=7.9 Hz).

Rfor =0.51 (10% CH3HE/CHCl3).

Century 5-(4-(4-Methyl)piperazinylcarbonyl)francebuy acid

To the product of the above stage (methyl ester 5-(4-(4-methyl)piperazinylcarbonyl)frankenboob acid) (1.08 g, 3,29 mmol)dissolved in T is f (98,7 ml), add LiOH (16,45 ml of 0.2 N. in N2About). The solution was stirred at room temperature for 3.5 hours and neutralized with HCl (3,29 ml, 1.0 M in ether). After concentration the crude substance is used without additional purification.

MS (m/z) 329 (MN+), 327 (M-1)

1H-NMR (CD3OD) δ to 2.35 (s, 3H), 2,36˜2,58 (Sirs, 4H,), of 3.48 (s, 2H), 3,85 (s, 2H), make 6.90 (d, J=2.0 Hz), 7,02 (d, 1H, J=2.0 Hz), 7,46 (d, 2H, J=7.9 Hz), 7,95 (d, 2H, J=7.9 Hz).

C. (R)-1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-(5-(4-(1-(4-methyl)piperazinylcarbonyl)phenyl)furoyl)-N-pyrrolo[3,4-b]quinoline-9-he (#69)

A mixture of cleaners containing hydrochloride salt of R-1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-it (1.12 g, 3,29 mmol) (obtained as in example 5A) and the product stage (to 1.034 g, 3,29 mmol) is stirred with PyBrOP (1,535 g, 3,29 mmol) and diisopropylethylamine (1,716 ml, 9,87 mmol) in DMF (30 ml) at room temperature for 12 hours. The reaction mixture was diluted with CH2Cl2(75 ml) and EtOAc (75 ml). Purified on a column of silica gel (from undiluted CH2Cl2up to 2.5% CH3OH/CH2Cl2), and receiving the product in the form of not-quite-white solid.

MS (m/z): 603 (MN+), 601 (M-1)

1H-NMR (CD3OD) δ 2,32 (s, 3H), 2,43˜to 2.55 (m, 4H), 3,53 (Sirs, 2H), 3,83 (Sirs, 2H), 5.25 in (d, 1H, J=15,5 Hz), the 5.51 (d, 1H, J=15,5 Hz), by 5.87 (s, 2H), 6,29 (s, 1H), 6,70 (m, 1H), PC 6.82 (m, 2H), was 7.08 (m, 1H), 7,20˜7,39 (m, 2H), 7,46˜7,58 (m, 4H), 8,01 (d, 2H, J=8.6 Hz), 8,31 (d, 2H, J=8.6 Hz).

HPLC Chiralpak EXT. the diameter of 4.6×250 mm, 1% DEA/MeOH, Tr=4,846 min)

EXAMPLE 60

Sodium salt of 1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-2-(5-(2-(4-hydroxy)phenyl)furoyl)-N-pyrrolo[3,4-b]quinoline-9-she (Na salt #22)

According to the method described in example 59, with appropriate substitution of reagents receive the product in the form of not-quite-white solid.

MS (m/z 493 (MN+), 491 (M-1)

1H-NMR (CDCl3) δ to 5.21 (d, 1H, J=15.6 Hz), to 5.57 (d, 1H, J=15.6 Hz), 6,12 (s, 2H), 6,51 (2N) of 6.68 (d, 1H, J=4,1 Hz), 6,98˜7,14 (m, 4H), 7,38 (s, 1H), of 7.48 (t, 1H, J=8.6 Hz), 7,62˜7,79 (m, 4H), 8,08 (, 1H), 8,28 (d, 1H, J=8.6 Hz).

EXAMPLE 61

(4-(2-(1-Pyrrolidinyl)ethoxy)phenyl)baronova acid

(Obtained by the procedure described Hoye, T.R. and Chen. M. in J. Org. Chem. 1996, 61, 7940)

To a solution of 1-[2-(4-bromophenoxy-)ethyl]pyrrolidine (2.70 g, 10 mmol) in THF (40 ml) is added n-utility (6.9 ml, 1.6 M in hexano, 11 mmol) at -78°C. the Reaction mixture was stirred at -78°C for 15 min and then at 0°C for 15 minutes Then the reaction mixture at 0°With add trimethylboron (2.5 ml, 22 mmol). The mixture is gradually warmed to room temperature over night. Metalpart in the reaction mixture hydrolyzing interaction with saturated aqueous NH4Cl (100 ml) at room temperature for 30 minutes Separating the upper organic layer. The aqueous layer was extracted with CHCl3(2×100 ml). The organic layers are combined to prom who live with a saturated solution of salt (2× 100 ml) and dried MgSO4. The solvent is evaporated, getting a thick oil, which was purified column chromatography (10% Meon/CHCl3and 1% Et3N)to give product as a white solid.

MS (m/z 236 (MN+), 234 (M-1)

1H-NMR (CD3OD) δ is 1.81 (m, 4H), to 2.67 (m, 4H), 2,89 (t, 2H, J=6.0 Hz), 4,08 (t, 2H, J=6.0 Hz), 6,74 (d, 2H, J=8.6 Hz), a 7.62 (d, 2H, J=8.6 Hz).

EXAMPLE 62

1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-(5-(4-(2-(1-pyrrolidinyl)ethoxy)phenyl)furoyl)-N-pyrrolo[3,4-b]quinoline-9-he (#45)

According to the method described in example 59, with appropriate substitution of reagents receive the product in the form of not-quite-white solid.

MS (m/z): 590 (MN+), 588 (M-1)

1H-NMR (CDCl3) δ to 2.18 (s, 4H), to 2.55 (s, 4H), to 2.75 (m, 2H), 2,90 (m, 2H), 4,67 (d, 1H, J=15.6 Hz), 4,82 (d, 1H, J=15.6 Hz), is 5.18 (s, 2H), of 5.81 (m, 1H), between 6.08 (m, 1H), 6,21 (s, 2H), 6.35mm (s, 1H), 6,60 (s, 1H), 6,82 (m, 3H), 6,92 (m, 1H),? 7.04 baby mortality (m, 1H), 7,21 (s, 2H), a 7.62 (d, 1H, J=8.6 Hz).

EXAMPLE 63

3-(2,3-Dihydro-5-benzofuranyl)-1,2,3,4-tetrahydro-2-(benzyl)-N-pyrrolo[3,4-b]quinoline-9-he (#60)

1-(2,3-Dihydro-5-benzofuranyl)-2-benzyl-2,3,4,9-tetrahydro-1H-β-carbolin (obtained as in example 2) (a 5.25 g, 13,81 mmol), dioxide, potassium (to 3.92 g, 55,24 mmol) and 18-crown-6 (3,65 g, 13,81 mmol) is mixed with DMF (100 ml) in a flask of 200 ml. of the Reaction mixture was kept at room temperature over night. The reaction mixture was slowly added to a separate flask, 500 ml, containing a mixture of EtOAc (172 m is), H2(172 ml) and 1 N. aqueous HCl (50 ml). Observe that the mixture forms gas bubbles of small size. The reaction mixture was stirred at 0°C for 30 min, resulting in formation of a precipitate at the interface of two liquid layers. The precipitate is filtered off, washed with N2O (20 ml) and then dried in a vacuum drying Cabinet, getting the product in the form of not-quite-white solid.

MS (m/z): 395 (MH+), 393 (M-1)

1H-NMR (CDCl2) δ of 3.12 (t, 2H, J=8.7 Hz), 3,50˜the 3.65 (m, 2H), 3,99 (d, 1H, J=13,0 Hz), 4,22 (d, 1H, J=13,0 Hz), 4,55 (t, 2H, J=8.7 Hz), 4,91 (s, 1H), 6,74 (d, 1H, J=8.7 Hz), 7,11˜7,32 (m, N), of 7.48 (t, 1H, J=8.7 Hz), 8,30 (t, 1H, J=8.7 Hz).

EXAMPLE 64

3-(3,4-Methylenedioxyphenyl)-1,2,3,4-tetrahydro-2-[5-(3-trifluoromethyl)phenyl-2-furoyl]-N-pyrrolo[3,4-b]quinoline-9-he (#13)

According to the method described in example 63, with appropriate substitution of reagents 1-(3,4-methylenedioxyphenyl)-2-benzyl-2,3,4,9-tetrahydro-1H-β-carbolin (0,381 g, 0,719 mmol) is subjected to interaction with the product in the form of not-quite-white solid. It should be noted that for the full sediment two liquid reaction mixture incubated at room temperature for 48 hours, and not during the night.

MS (m/z): 545 (MN+), 567 (M+23), 543 (M-1)

1H-NMR (DMSO-d6) δ 5,09 (d, J=14 Hz, 1H), 5,46 (d, J=14 Hz, 1H), of 5.99 (s, 2H), to 6.39 (s, 1H), 6,91 (d, J=8 Hz, 1H), 6,97 (d, J=9 Hz, 1H), 7,02 (s, 1H), 7,33 (d, J=8 Hz, 1H), 7,38 (d, J=4 Hz, 1H), and 7.4 (d, J=4 Hz, 1H), 7,60 (m, J=8 Hz, 2H), to 7.77 (d, J=5 Hz, 2H), 8,16 (d, J=4 Hz, 3H), 11,55 (s, 1H).

EXAMPLE 65

1-(3,4-Methylenedioxyphenyl)-2-[4-(4-methoxyphenyl)thiazol-2-yl]-2,3,4,9-tetrahydro-1H-β-carbolin

A. 1-(3,4-Methylenedioxyphenyl)-2-[3-(fluorenylmethoxycarbonyl)thiocarbamoyl]-2,3,4,9-tetrahydro-1H-β-carbolin

A mixture of 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (2.66 g, the remaining 9.08 mmol) (obtained by the method described in WO 97/43287, intermediate 7, page 24) and Fmoc-isothiocyanate (2,82 g, 10,14 mmol) dissolved in anhydrous dichloromethane (50 ml). The mixture is stirred for 16 hours at ambient temperature and then concentrated in vacuo. Purification with flash chromatography (0-10% methanol in dichloromethane) gives the protected thiourea as a pale yellow solid.

MS (m/z 574 (MN+)

1H-NMR (CDCl3) δ of 2.86 (DD, J=12,9, 5,1 Hz, 1H), 3,09 (dt, J=17.1 to and 6.9 Hz, 1H), of 3.56 (dt, J=12,9, 5,1 Hz, 1H), 4,19 (t, J=6,9 Hz, 1H), 4,43-a 4.53 (m, 2H), 5,91 (s, 2H), 6,70 (d, J=8 Hz, 1H), 6.90 to (sird, J=7,6 Hz, 1H), 6,97 (Sirs, 1H), 7,11-7,78 (series of m, 17H).

Century 1-(3,4-Methylenedioxyphenyl)-2-(thiocarbamoyl)-2,3,4,9-tetrahydro-1H-β-carbolin

A solution of the protected thiourea from part a (4,78 g of 8.33 mmol) in 20% (vol./about) piperidine in methanol is refluxed for 5 hours. The mixture was concentrated in vacuo to obtain a yellow solid residue, which was purified flash chromatography (SiO2, 0-10% methanol in chlormethine), getting a yellow solid.

MS (m/z): 352 (MN+)

1H-NMR (CDCl3) δ 2,69-2,87 (series of m, 2H), 3,10-3,19 (m, 1H), 4,24 (Sirs, 1H), 6,00 (d, J=3.3 Hz, 2H), 6,72 (d, J=8.0 Hz, 1H), 6.87 in (d, J=8.0 Hz, 1H), 7,00-7,11 (series of m, 3H), 7,30 (d, J=8.0 Hz, 1H), 7,46 (d, J=7.7 Hz, 1H), 7,74 (Sirs, 3H), 11,06 (s, 1H).

C. 1-(3,4-Methylenedioxyphenyl)-2-[4-(4-methoxyphenyl)thiazol-2-yl]-2,3,4,9-tetrahydro-1H-β-carbolin

To a solution of thiourea from part (223 mg, 0,63 mmol) in a mixture of 1:1 dioxane:ethanol (5 ml) is added 4-methoxyphenyl-2'-bromoacetophenone (175 mg, from 0.76 mmol) and triethylamine (0,40 ml). The mixture is heated to 70°C for 3 h, cooled to room temperature and concentrated on a rotary evaporator. The residue is purified flash chromatography (SiO2, 0-10% methanol in dichloromethane)to give a colorless solid.

MS (m/z 482 (MN+)

1H-NMR (CDCl3) δ 2,86-2-3,07 (series of m, 2H), 3,61-3,71 (m, 1H), of 3.78 (s, 3H), 3,91-was 4.02 (m, 1H), of 5.99 (d, J=3.3 Hz, 2H), return of 6.58 (s, 1H), 6,80-7,11 (series of m, 8H), 7,31 (d, J=7.8 Hz, 1H), of 7.48 (d, J=7,6 Hz, 1H), 7,82 (d, J=8,7 Hz, 2H), of 10.93 (s, 1H).

EXAMPLE 66

1-(3,4-Methylenedioxyphenyl)-2-[4-phenylthiazol-2-yl]-2,3,4,9-tetrahydro-1H-β-carbolin

A. 1-(3,4-Methylenedioxyphenyl)-2-[3-(fluorenylmethoxycarbonyl)thiocarbamoyl]-2,3,4,9-tetrahydro-1H-β-carbolin

A mixture of 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (2.66 g, the remaining 9.08 mmol) (obtained by the method described in WO 97/43287, intermediate 7, page 24) and Fmoc-from the thiocyanate (2,82 g, 10,14 mmol) dissolved in anhydrous dichloromethane (50 ml). The mixture is stirred for 16 hours at ambient temperature and then concentrated in vacuo. Purification with flash chromatography (0-10% methanol in dichloromethane) gives the protected thiourea as a pale yellow solid.

MS (m/z): 574 (MN+)

1H-NMR (CDCl3) δ of 2.86 (DD, J=12,9, 5,1 Hz, 1H), 3,09 (dt, J=17.1 to and 6.9 Hz, 1H), of 3.56 (dt, J=12,9, 5,1 Hz, 1H), 4,19 (t, J=6,9 Hz, 1H), 4,43-a 4.53 (m, 2H), 5,91 (s, 2H), 6,70 (d, J=8 Hz, 1H), 6.90 to (sird, J=7,6 Hz, 1H), 6,97 (Sirs, 1H), 7,11-7,78 (series of m, 17H).

Century 1-(3,4-Methylenedioxyphenyl)-2-(thiocarbamoyl)-2,3,4,9-tetrahydro-1H-β-carbolin

A solution of the protected thiourea from part a (4,78 g of 8.33 mmol) in 20% (vol./about.) of piperidine in methanol is refluxed for 5 hours. The mixture was concentrated in vacuo, obtaining the crude residue, which was purified flash chromatography (SiO2, 0-10% methanol in dichloromethane) to give a yellow solid.

MS (m/z): 352 (MN+)

1H-NMR (CDCl3) δ 2,69-2,87 (series of m, 2H), 3,10-3,19 (m, 1H), 4,24 (Sirs, 1H), 6,00 (d, J=3.3 Hz, 2H), 6,72 (d, J=8.0 Hz, 1H), 6.87 in (d, J=8.0 Hz, 1H), 7,00-7,11 (series of m, 3H), 7,30 (d, J=8.0 Hz, 1H), 7,46 (d, J=7.7 Hz, 1H), 7,74 (Sirs, 3H), 11,06 (s, 1H).

C. 1-(3,4-Methylenedioxyphenyl)-2-[4-phenylthiazol-2-yl]-2,3,4,9-tetrahydro-1H-β-carbolin

To a solution of thiourea part In (227 mg, of 0.65 mmol) is added β-bromoacetophenone (159 mg, 0.80 mmol) and triethylamine(0,40 ml). This mixture is heated to 70°C for 3 h, cooled to room temperature and concentrated in a rotary evaporator. The residue is purified flash chromatography (SiO2, 0-10% methanol in dichloromethane)to give a light yellow solid.

MS (m/z): 452 (MH+)

1H-NMR (CDCl3) δ 2,87-2-3,06 (series of m, 2H), 3,63-to 3.73 (m, 1H), 3,93-to 3.99 (m, 1H), of 5.99 (d, J=3.3 Hz, 2H), 6,59 (s, 1H), for 6.81-7,11 (series of m, 5H), 7,25-7,69 (series of m, 6N), 7,89 (d, J=7,4 Hz, 2H), 10,95 (s, 1H).

EXAMPLE 67

3-(2,3-Dihydrobenzofuran-5-yl)-1,2,3,4-tetrahydro-3R-N-pyrrolo[3,4-b]chinoline

A: [2-(1H-Indol-3-yl)ethyl]-(1-naphthalene-1-retil)amine is obtained by a method described Kawate, T.; Yamanaka, M.; Nakagawa, M. in Heterocycles, 1999, 50, 1033.

In: R - and S-Diastereomers of 1-(2,3-dihydrobenzofuran-5-yl)-2-(1R-1-naphthalene-1-retil)-2,3,4,9-tetrahydro-1H-β-carboline

[2-(1H-Indol-3-yl)ethyl]-(1-naphthalene-1-retil)amine (1.0 g, 3,18 mmol) and 2,3-dihydrobenzofuran-5-carbaldehyde (2,356 g, 15,92 mmol) is stirred in p-xylene (20 ml) at 165°C for 7 hours. To the reaction mixture add silica gel (10 g) and hexane (200 ml). The reaction mixture was filtered and the colorless filtrate is discarded. The silica gel was washed with ethyl acetate (100 ml). The solvent after washing the ethyl acetate is evaporated, concentrated the crude substance was dissolved in a small amount of CH2Cl2and injected into a column of silica gel. Column elute with 5% ethyl acetate in hexane, the floor is th two diastereoisomer.

1-(2,3-Dihydrobenzofuran-5-yl)-2-(1R-1-naphthalene-1-retil)-2,3,4,9-tetrahydro-1S-1N-β-carbolin (side diastereoisomer A) (Rf=0.59 in 30% EtOAc/hexane) receives a yellow solid.

1H-NMR 300 MHz (CDCl3) δ 1,58, of 1.62 (d, 3H, J=6.5 Hz), 2,61 (m, 1H), 2.91 in (m, 1H), 3,05˜3,20 (m, 4H), 4,51 (t, 2H, J=8,8 Hz), 4.72 in (m, 1H), 4,81 (s, 1H), of 6.68 (m, 1H), 6,92 (m, 4H), 7,05-the 7.65 (m, 5H), 7,70˜7,95 (m, 4H).

MS (m/z) MH+(445), MN-(443).

1-(2,3-Dihydrobenzofuran-5-yl)-2-(1R-1-naphthalene-1-retil)-2,3,4,9-tetrahydro-1R-1H-β-carbolin (target diastereoisomer) (Rf=0.51 in 30% EtOAc/hexane) receives a yellow solid.

1H-NMR 300 MHz (CDCl3) δ was 1.58 (d, 3H, J=6.5 Hz), 2,65 (m, 1H), 2.91 in (m, 2H), 3,05 (t, 2H, J=8,8 Hz)and 3.15 (m, 1H), 4,51 (t, 2H, J=8,8 Hz)and 4.65 (m, 1H), 5,10 (s, 1H), of 6.68 (m, 1H), 6,85 (s, 2H), 7,11 (m, 2H), 7,20˜to 7.50 (m, 5H), to 7.68 (m, 2H), 7,81 (m, 1H), 8,21 (m, 1H).

MS (m/z) MH+(445), MN-(443).

C. the Conversion of 3-diastereoisomer in R-diastereoisomer

1-(2,3-Dihydrobenzofuran-5-yl)-2-(1R-1-naphthalene-1-retil)-2,3,4,9-tetrahydro-1S-1N-β-carbolin (side diastereoisomer A) (190 g, 0,428 mmol) is stirred in 1000 ml of CH2Cl2with TFU (52 ml, 701 mol) at room temperature over night. The reaction is quenched with NaOH (35 g, 0,875 mol) in water (100 ml). The reaction mixture is mixed well and then incubated for 0.5 hour, during which time a precipitate. The precipitate is filtered, the solid washed in the Oh and dried in a high vacuum, getting the product in the form of solids.

1H-NMR identical with1H-NMR of 1-(2,3-dihydrobenzofuran-5-yl)-2-(1R-1-naphthalene-1-retil)-2,3,4,9-tetrahydro-1R-1H-β-carboline (target diastereoisomer).

D: 3-(2,3-Dihydrobenzofuran-5-yl)-2-(1R-1-naphthalene-1-retil)-1,2,3,4-tetrahydro-3R-N-pyrrolo[3,4-b]chinoline

1-(2,3-Dihydrobenzofuran-5-yl)-2-(1R-1-naphthalene-1-retil)-2,3,4,9-tetrahydro-1R-1H-β-carbolin (0,6469 g of 1.46 mmol) and tert-piperonyl potassium (0,279 g, 2.48 mmol) was stirred in DMF (14 ml) at room temperature. During the night in the reaction mixture was bubbled gaseous O2. The reaction is quenched with HCl (2,48 ml, 1 N. water). Add ethyl acetate (50 ml) and N2O (50 ml). The organic layer is separated. The aqueous layer was extracted with ethyl acetate (50 ml) and CH2Cl2(50 ml). The organic layers washed with saturated salt solution (3 x 50 ml) and dried over MgSO4. The resulting product is concentrated and purified using silica gel (2% methanol/CH2Cl2)to give product as a yellow solid.

1H-NMR 300 MHz (CDCl3) δ of 1.65 (d, 3H, J=6.5 Hz), 3,05 (t, 2H, J=8,8 Hz)to 4.01 (m, 2H), 4,51 (t, 2H, J=8,8 Hz), and 4.68 (m, 1H), 5,31 (s, 1H), 6,62 (s, 1H), 6,88˜7,89 (m, N), to 8.25 (d, 1H).

MS (m/z) MH+(459), MN-(457).

E: 3-(2,3-Dihydrobenzofuran-5-yl)-1,2,3,4-tetrahydro-3R-N-pyrrolo[3,4-b]chinoline

3-(2,3-Dihydrobenzofuran-5-yl)-2-(1R-1-naphthalene-1-retil)-1,2,3,4-tetrahydro-3R-N-Pierre is lo[3,4-b]chinoline (24 mg, 0,0524 mmol) dissolved in 5 ml of ethanol. To the reaction mixture is added 10% Pd/C (50 mg) and HCl (1.0 M in diethyl ether (0.05 ml, 0.05 ml)). The reaction mixture is stirred at 35 psi (241,3 kPa) gaseous N2for 3 hours at room temperature. The catalyst is filtered off on a tube of celite. The reaction mixture was concentrated, obtaining the crude product. Purification preparative TLC (5% MeOH/CH2Cl2gives specified in title product as a yellowish solid.

1H-NMR 300 MHz (CDCl3) δ 13,23 (d, 2H, J=8,8 Hz), 4,59 (t, 2H, J=8,8 Hz), 4,78 (m, 2H), 5,32 (s, 1H), to 6.88 (m, 1H), 7,31 (m, 2H), 7,72 (m, 3H), 8,32 (m, 1H).

MS (m/z) MN+(305)MN-(303).

EXAMPLE 68

3-Benzo[1,3]dioxol-5-yl-2-(5-bromofuran-2-carbonyl)-1,2,3,4-tetrahydropyrrolo[3,4-b]quinoline-9-he

To a solution of 5-bromo-2-frankenboob acid (2.1 g, 6,856 mmol) in THF (20 ml) add oxalicacid (0,66 ml, 7,541 mmol). To the reaction mixture and then add 2 drops of DMF observed with vigorous bubbling. Then add oxalicacid ((COCl)2) (0.1 ml). The reaction mixture was stirred at room temperature for 10 min and at 90°C for 10 minutes, the Solvent and excess (COCl)2removed in vacuum, obtaining 5-bromofuran-2-carbonylchloride in the form of a light yellow crystalline solid.

Solid 5-bromofuran-2-carbonylchloride dissolve the Yat in THF (20 ml). Then add a solution of 3-(2,3-dihydrobenzofuran-5-yl)-1,2,3,4-tetrahydro-N-pyrrolo[3,4-b]chinoline (2.1 g, 6,856 mmol) in THF (20 ml). Then add triethylamine (4,55 ml, 32,64 mmol) and DMAP (40 mg, 0,327 mmol). To the reaction mixture add a few drops of DMF to preserve the transparency of the solution. The reaction mixture was stirred at room temperature for 4 h and then concentrated in vacuo. The residue is dissolved in CHCl3(200 ml) and washed with H2O (3×200 ml). The organic layer is dried over MgSO4getting listed in title product in the form of not-quite-white solid. Further purification is not required.

1H-NMR 300 MHz (CD3OD) δ to 4.87 (d, 1H, J=11.5 Hz), 5,19 (d, 1H, J=11.5 Hz), 5,78 (m, 2H), 6,24˜of 7.60 (m, 8H), 8,39 (d, 1H, J=8,3 Hz).

MS (m/z): 479, 481 (MN+), 479, 477 (MN-)

EXAMPLES 69-79

The General procedure

3-Benzo[1,3]dioxol-5-yl-2-(5-bromofuran-2-carbonyl)-1,2,3,4-tetrahydropyrrolo[3,4-b]quinoline-9-he (0,100 g, 0,2086 mmol) is stirred with a mixture of appropriately substituted Bronevoy acid (0,2296 mmol, 1.1 equiv.) Pd(PPh3)4(12,4 mg, 0,1043 mmol), K2CO3(to 86.4 mg, 0,6258 mmol) in 1,4-dioxane (8 ml) and H2O (2 ml), degassed using N2and then stirred at 100°C for 1.5 hours. The reaction mixture was loaded onto the plate preparative TLC with silica gel and elute with 5% CH3 OH/CH2Cl2receiving the selected product in the form of solids.

Connection #110 (spend interaction with phenylboronic acid)

1H-NMR 300 MHz (CD3OD) δ 5,19 (d, 1H, J=11.5 Hz), 5,42 (d, 1H, J=11.5 Hz), to 5.93 (s, 2H), 6,38 (s, 1H), 6,74˜8,31 (m, 14N).

MS (m/z): 477 (MH+), 475 (MN-)

Connection #111 (spend interaction with 4-methyldiphenylamine acid)

1H-NMR 300 MHz (CD3OD) δ to 5.21 (d, 1H, J=11.5 Hz), 5,44 (d, 1H, J=11.5 Hz), 5,91 (s, 2H), 6,40 (s, 1H), 6,77 (d, 1H, J=9.0 Hz), 6,98 (s, 2H), 7,21˜7,81 (m, 11N), 8,31 (d, 1H, J=9.0 Hz).

MS (m/z): 523 (MN+), 521 (MN-).

Connection #112 (spend interaction with 3-thienylboronic acid)

1H-NMR 300 MHz (CD3OD) δ 5,22 (d, 1H, J=11.5 Hz), 5,43 (d, 1H, J=11.5 Hz), 5,88 (s, 2H), 6,38 (s, 1H), 6,72˜scored 8.38 (m, N).

MS (m/z): 483 (MN+), 481 (MN-)

Connection #116 (spend interaction with 4-methylphenylacetic acid)

1H-NMR 300 MHz (CD3OD) δ of 2.25 (s, 3H), to 5.21 (d, 1H, J=11.5 Hz), 5,42 (d, 1H, J=11.5 Hz), 5,80 (s, 2H), 6,38 (s, 1H), 6,74˜8,31 (m, 13H).

MS (m/z): 491 (MN+), 489 (MN-).

Connection #113 (spend interaction with 2-by-nitrophenylarsonic acid)

1H-NMR 300 MHz (CD3OD) δ the 5.25 (d, 1H, J=11.5 Hz), 5,42 (d, 1H, J=11.5 Hz), 5,88 (s, 2H), to 6.39 (s, 1H), 6,68˜8,66 (m, 13H).

MS (m/z): 522 (MH+), 520 (MN-).

Connection #117 (spend interaction with 2-by-thienylboronic acid)

1H-I Is R 300 MHz, (CD 3OD) δ 5,19˜5,42 (m, 2H), to 5.93 (s, 2H), 6,40 (s, 1H), 6,74˜8,35 (m, 11N).

MS (m/z): 467 (MH+), 465 (MN-).

Connection #118 (spend interaction with 3,4-methylenedioxyphenylacetic acid)

1H-NMR 300 MHz (CD3OD) δ 5,19˜5,42 (m, 2H), to 5.93 (m, 4H), 6,38 (s, 1H), 6,74˜8,31 (m, N).

MC (m/z): 521 (MH+), 519 (MN-).

Connection #119 (spend interaction with 4-cyanophenylacetic acid)

1H-NMR 300 MHz (CD3OD) δ to 5.21˜5,42 (m, 2H), 5,70 (m, 2H), 6,18 (s, 1H), 6,60˜8,51 (m, 13H).

MC (m/z): 502 (MN+), 500 (MN-).

Connection #120 (spend interaction with 4-gidroksietilirovannogo acid)

1H-NMR 300 MHz (CD3OD) δ rate 4.79 (s, 2H), 5.25 in (d, 1H, J=11.5 Hz), 5,52 (d, 1H, J=11.5 Hz), of 5.89 (s, 2H), 6.48 in (s, 1H), 6,70˜8,31 (m, 13H).

MC (m/z): 507 (MN+), 505 (MN-).

Connection #121 (spend interaction with 3-gidroksietilirovannogo acid)

1H-NMR 300 MHz (CD3OD) δ rate 4.79 (s, 2H), total of 5.21 (d, 1H, J=11.5 Hz), of 5.48 (d, 1H, J=11.5 Hz), of 5.89 (s, 2H), of 6.31 (s, 1H), 6,62˜8,31 (m, 13H).

MC (m/z): 507 (MN+), 505 (MN-).

Connection #122 (spend interaction with 4-dimethylaminopropionic acid)

1H-NMR 300 MHz (CD3OD) δ to 5.21˜of 5.50 (d, 1H, J=11.5 Hz), 5,90 (s, 2H), 6,40 (d, 1H), 6,64˜8,31 (m, 13H).

MC (m/z): 520 (MN+), 518 (MN-).

EXAMPLE 80

3-(2,3-Dihydrobenzofuran-5-yl)-2-pyrimidine-2-yl-1,2,3,4-tetrahydropyrrolo[3,4-b]hee the Olin-9-he (#123)

Salt of 3-(2,3-Dihydrobenzofuran-5-yl)-1,2,3,4-tetrahydropyrrolo[3,4-b]quinoline-9-he·HCl (0.15 g, 0,440 mmol) is stirred with chloropyrimidine (of 60.5 mg, 0,528 mmol), KF (31 mg, 0,528 mmol) and DIEA (to 0.19 ml, 1.1 mmol) at 60°C for 16 hours. The reaction mixture was diluted with H3O (20 ml). The solid is filtered off and dried on the funnel with suction in a vacuum. After preparative TLC on silica gel indicated in the header of the product isolated in the form of a yellow solid.

1H-NMR 300 MHz (CDCl3) δ 3,10 (t, 2H, J=8,8 Hz)to 4.52 (t, 2H, J=8,8 Hz)to 4.92 (m, 2H), 6,15˜to 8.45 (m, 10H), 9,81 (Sirs, 1H).

MS (m/z 383 (MH+), 381 (MN-).

EXAMPLE 81

3-Benzofuran-5-yl-2-(5-pyridin-2-Yeremey-2-yl)-1,2,3,4-tetrahydropyrrolo[3,4-b]quinoline-9-he (#126)

A: Benzofuran-5-carbaldehyde is obtained by a method described Hiroya, K.; Hashimura, K.; Ogasawara, K. in Heterocycles, 1994, vol.38, No. 11, 2463-72.

In: 1-Benzofuran-5-yl-2,3,4,9-tetrahydro-1H-β-carbolin get in the manner specified in example 12.

1H-NMR 300 MHz (CDCl3) δ 2,68˜2,95 (m, 2H), 3,10 (m, 1H), or 3.28 (m, 1H), 5.25 in (s, 1H), 6,65 (s, 1H), 7,15 (m, 3H), 7,38 (m, 2H), 7,51 (m, 1H), 7,58 (s, 1H), they were 8.22 (s, 1H).

MC (m/z) MH+(289), MN-(287).

With: 1-Benzofuran-5-yl-2-(5-pyridin-2-Yeremey-2-yl)-2,3,4,9-tetrahydro-1H-β-carbolin get in the manner specified in example 12.

1H-NMR 300 MHz (CDCl3) δ 3,00 (m, 2H), 3,40 (m, 1H), 5,11 (m, 1H), 6,65 (s, 1H), 7,15˜8,00 (m, N), 8,61 (m, 1H), 8,91 (m, N), by 8.22 (s, 2H).

MC (m/z) MH+(444), MN-(442).

D: 1-(5-Benzofuran)-2,3,4,9-tetrahydro-2-[5-(2-pyridinyl)-2-pyrimidinyl]-1H-β-carbolin (30 mg, 0,06764 mmol) and KO-tert-Bu (12.9 mg, 0,115 mmol) is stirred in DMF (1 ml) in an atmosphere of gaseous O2for 10 hours at room temperature. Preparative TLC (5% methanol in CH2Cl2gives specified in title product as a yellow solid.

1H-NMR 300 MHz (CD3OD) δ 5,15 (m, 2H), 6,55 (s, 1H), 6,82˜8,98 (m, 15 NM).

MC (m/z 383 (MH+), 456 (MN-).

EXAMPLE 82

3-(2,3-Dihydrobenzofuran-5-yl)-2-[5-(1-oxypyridine-2-yl)pyrimidine-2-yl]-1,2,3,4-tetrahydropyrrolo[3,4-b]quinoline-9-he (#125)

3-(2,3-Dihydro-5-benzofuranyl)-1,2,3,4-tetrahydro-2-[5-(2-pyridinyl)-2-pyrimidinyl]-(3R)-N-pyrrolo[3,4-b]quinoline-9-he (4.5 mg, 0,010 mmol) and mCPBA (1.73 mg, 0,010 mmol) stirred in THF (2 ml). To obtain a clear solution add a few drops of DMF. The reaction mixture was stirred at room temperature for 80 hours and then at 60°C for 8 hours. Preparative TLC (10% Meon in CH2Cl2gives specified in the header of the product in the form of not quite white solids with a number of selected source of the connection.

1H-NMR 300 MHz (CD3OD) δ of 3.12 (t, 2H, J=8,8 Hz), of 4.45 (t, 2H, J=8,8 Hz), 6.35mm (s, 1H), 6,55 (d, 1H), 7,21˜8,99 (m, 11N).

MS (m/z 458 (MH+), 456 (MN-).

The REAMERS 83-86

1-(2,3-Dihydrobenzofuran-5-yl)-2-[5-(2,3-dimethyl-3H-imidazol-4-yl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-β-carbolin

2-(5-Bromo-2-pyrimidinyl)-1-(2,3-dihydro-5-benzofuranyl)-2,3,4,9-tetrahydro-1H-β-carbolin (0.45 g, 1.00 mmol), 1,2-dimethyl-1H-imidazole (0.18 g, of 1.87 mmol), Pd(OAc)2(12 mg, 0.05 mmol), PPh3(26 mg, 0.1 mmol) and K2CO3(0.28 g, 2 mmol) is stirred in 3.5 ml of DMF at 140°C for 14 hours. The mixture is then poured into aqueous 10% NaOH solution (50 ml). The resulting solution was extracted with CH2Cl2(3×50 ml) and dried over Na2SO4. Purification preparative TLC network specified in the title product as a yellow powder.

1H-NMR 300 MHz (CDCl3) δ of 2.21 (s, 3H), of 2.35 (s, 3H), 2,90 (m, 2H), 3,10 (t, 2H, J=8,8 Hz)to 3.35 (m, 1H), to 4.52 (t, 2H, J=8,8 Hz), 4,91 (m, 1H), 6,68˜to 7.61 (m, 10H).

MS (m/z 463 (MN+), 461 (MN-).

The following compounds were obtained analogously to the method described above with appropriate selection and substitution of suitably substituted reagents.

2-[5-(3-Benzyl-2-methyl-3H-imidazol-4-yl)pyrimidine-2-yl]-1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1H-β-carbolin

MS (m/z 539 (MN+), 537 (MN-).

3-(2,3-Dihydrobenzofuran-5-yl)-2-[5-(2,3-dimethyl-3H-imidazol-4-yl)pyrimidine-2-yl]-1,2,3,4-tetrahydropyrrolo[3,4-b]quinoline-9-he (#128)

1H-NMR 300 MHz (CD3OD) δ is 3.08 (t, 2H, J=9.5 Hz), or 3.28 (s, 3H), 3,50 (s, 3H), 4,42 (t, 2H, J=9.5 Hz), 5,02 (Sirs, 2H), 6,24 (s, 1H) 6,63 (m, 1H), 6,84 (s, 1H), 7,19 (m, 2H), 7,31 (m, 1H), 7,53 (s, 2H), 8,35 (m, 3H).

MS (m/z 477 (MN+), 475 (MN-).

2-[5-(3-Benzyl-2-methyl-3H-imidazol-4-yl)pyrimidine-2-yl]-3-(2,3-dihydrobenzofuran-5-yl)-1,2,3,4-tetrahydropyrrolo[3,4-b]quinoline-9-he (#127)

1H-NMR 300 MHz (CD3OD) δ 1,90 (s, 3H), of 2.21 (s, 2H), 3,12 (t, 2H, J=8,8 Hz), 4,48 (t, 2H, J=8,8 Hz), 5,12 (m, 2H), x 6.15 (s, 1H), 6,61˜cent to 8.85 (m, 15 NM).

MS (m/z) MN+(553), MN-(551).

EXAMPLE 87

3-[2,3-Dihydrobenzofuran-5-yl)-2-pyridin-2-yl-1,2,3,4-tetrahydropyrrolo[C,4-b]quinoline-9-he (#129)

3-(2,3-Dihydro-5-benzofuranyl)-1,2,3,4-tetrahydro-N-pyrrolo[3,4-b]quinoline-9-he·HCl (0,30 g, 0.88 mmol) and 2-bromopyridine (2 ml), Pd2dba3(to 0.23 g, 0.25 mmol), BINAP (0,47 g, 0.75 mmol) and NaO-t-Bu (0.66 g, 6,87 mmol) was stirred in 1,4-dioxane (4 ml) at 90°C for 1 hour. The resulting mixture was concentrated and then filtered over a plug of celite with CH2Cl2. Purification preparative TLC (5% CH3HE/CH2Cl2gives specified in title product as a yellow solid.

1H-NMR 300 MHz (CD3OD) δ of 2.92 (t, 2H, J=9.5 Hz), and 4.40 (t, 2H, J=9.5 Hz), of 4.54 (d, 1H, J=22 Hz), is 4.85 (d, 1H, J=22 Hz), 6,55 (m, 2H), 7,10 (m, 3H), 7,35 (m, 4H), 8,02 (m, 1H), 8.30 to (d, 1H, J=9,3 Hz).

MS (m/z 382 (MH+), 380 (MN-).

EXAMPLE 88

3-Benzo[1,3]dioxol-5-yl-2-(4-imidazol-1-ylphenyl)-1,2,3,4-tetrahydropyrrolo[3,4-b]quinoline-9-he (#133)

3-(1,3-Benzodioxol-5-yl)-1,2,3,4-tetrahydro-N-pyrrolo[3,4-b]quinoline-9-he (30,6 mg, 0.1 mm is l), 1-(4-bromophenyl)-1H-imidazole (22,3 mg, 0.1 mmol), Pd2dba3(4.6 mg, of 0.005 mmol), biphenyl-2-yl-di-tert-butylphosphine (3.0 mg, 0.01 mmol) and NaO-t-Bu (14 mg, 0.14 mmol) was stirred in 1,4-dioxane (0.6 ml) at 89°C for 17 hours. Purification preparative TLC (5% CH3OH/CH2Cl2gives specified in title product as a yellow powder.

1H-NMR 300 MHz (CD3OD) δ 4,70 (d, 1H), 5,02 (d, 1H), 5,48 (s, 2H), 5,88 (s, 2H), 6.75 in-8,32 (m, 14N).

MS (m/z) MH+(449), MN-(447).

EXAMPLE 89

2-[2,3']Bipyridinyl-6'-yl-3-(2,3-dihydrobenzofuran-5-yl)-1,2,3,4-tetrahydropyrrolo[3,4-b]quinoline-9-he (#134)

A. 2-(5-Bromopyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1H-β-carbolin

1-(2,3-Dihydro-5-benzofuranyl)-2,3,4,9-tetrahydro-1H-β-carbolin (11.6 g, 40 mmol), 2,5-dibromopyridine (10,42 g, 44 mmol), Pd2dba3(1,465 g, 1.6 mmol, dppp (1,32 g, 3.2 mmol) and NaO-t-Bu (5,38 g, 56 mmol) is stirred in 60 ml of DMF at 80°C for 3 days. The reaction mixture was filtered through a plug of celite with CH2Cl2. The reaction mixture was then concentrated and the crude mixture was then loaded into a column Foxy (110 g of silica gel and elute with a mixture of ethyl acetate/hexane (3:7). The product crystallizes in test tubes. The product is concentrated and then recrystallized from THF, getting the product in the form of yellow crystals.

1H-NMR 400 MHz (THF-d8) δ of 0.91 (m, 1H)and 1.15 (m, 1H), 1,25 (t, 2H, J=9.5 Hz) to 1.60 (m, 1H), 2,31 (m, 1H), 2,60 (t, 2H, J=9.5 Hz), and 4.75 (d, 1H, J=7,6 Hz), 5,02 (d, 1H, J=7,6 Hz), 5,10˜5,28 (m, 4H), 5,380 (m, 2H), 5,58 (m, 1H), 5,72 (m, 1H), 6,28 (s, 1H), 8,12 (s, 1H).

MC (m/z 446, 448 (MN+), 444, 446 (MN-).

In: 2-[2,3']Bipyridinyl-6'-yl-1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1H-β-carbolin

The product of the above stage (0.4 g, 0,896 mmol), 2-tributylstannyl (0.8 g, 2,17 mmol) and Pd(PPh3)4(0.12 g, 0.104 g mmol) was stirred in 1,4-dioxane (5 ml) at 88°C for 24 hours. The reaction mixture was filtered through a plug of celite with CH2Cl2and then concentrated to small volume. Preparative TLC (mixture of 3:7 ethyl acetate/hexane; then 5% CH3OH/CH2Cl2) gives the product as a yellow solid.

1H-NMR (CDCl3) δ 2,82 (m, 1H), 3,10 (m, 3H), to 3.58 (m, 1H), or 4.31 (m, 1H), 4.53-in (t, 2H, J=9.5 Hz), of 6.71 (d, 1H, J=7,6 Hz), 6,85 (d, 1H, J=7,6 Hz).

MC (m/z) 445 (MN+), 443 (MN-).

From: 2-[2,3']Bipyridinyl-6'-yl-3-(2,3-dihydrobenzofuran-5-yl)-1,2,3,4-tetrahydropyrrolo[3,4-b]quinoline-9-he (#134)

According to the method described in example 19, with appropriate selection and substitution of reagents receive specified in the header of the product in the form of solids.

1H-NMR 300 MHz (CDCl3) δ and 3.16 (t, 2H, J=9.5 Hz), 4,43 (t, 2H, J=9.5 Hz), 4,98˜5,20 (m, 2H), 6,12 (s, 1H), 6,60˜8,70 (15 NM).

MC (m/z 459 (MN+), 457 (MH-).

EXAMPLE 90

3-(2,3-Dihydrobenzofuran-5-yl)-2-[5-(3-methyl-3H-imidazol-4-yl)pyridine-2-the l]-1,2,3,4-tetrahydropyrrolo[3,4-b]quinoline-9-he (#137)

A. 2-Chloro-5-(3-methyl-3H-imidazol-4-yl)pyridine

2-Chloro-4-iodopyridine (0,239 g, 1 mmol), 1-methyl-1H-imidazole (0,41 g, 5 mmol), Pd(OAc)2(to 22.5 mg, 0.1 mmol), PPh3(53 mg, 0.2 mmol) and Cs2CO3(0,326 g, 1 mmol) is stirred in DMF (3 ml) at 120°C for 6 hours. Purification preparative TLC gives the product in the form of oil containing 1-methyl-1H-imidazole. The product is used in the next stage without additional purification.

1H-NMR (CDCl3) δ 3,68 (s, 3H), 7,19 (s, 1H), 7,27 (s, 1H), 7,56 (s, 1H), 7,68 (DD, 1H), 8,45 (d, 1H).

MS (m/z) MH+(194).

In: 3-(2,3-Dihydrobenzofuran-5-yl)-2-[5-(3-methyl-3H-imidazol-4-yl)pyridine-2-yl]-1,2,3,4-tetrahydropyrrolo[3,4-b]quinoline-9-he (#137)

3-(2,3-dihydrobenzofuran-5-yl)-1,2,3,4-tetrahydropyrrolo[3,4-b]quinoline-9-he (to 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-indicatorutility (5,43 mg, 0,0155 mmol) and NaO-t-Bu (0.104 g g 1,085 mmol) was stirred in 1,4-dioxane (0.6 ml) at 90°C. Purification preparative TLC (5% Meon in CH2Cl2) gives the product as a yellow solid.

1H-NMR 300 MHz (CDCl3) δ of 3.12 (t, 2H), 3,60 (s, 3H), 3,50 (t, 2H), 5,12 (m, 2H), between 6.08 (s, 1H), 6,70 (m, 2H), 7,20˜8,55 (m, 10H).

MS (m/z) MH+(462), MN-(460).

EXAMPLE 91

2-[5-(3-Benzyl-3H-imidazol-4-yl)pyridine-2-yl]-3-(2,3-dihydrobenzofuran-5-yl)-1,2,3,4-tetrahydropyrrolo[3,4-b]quinoline-9-he (#138)

A: 5-(3-Benzin-imidazol-4-yl)-2-chloropyridin

According to the method described in example 90, step A, with appropriate selection and substitution of reagents receive the product in the form of solids.

1H-NMR (CDCl3) δ further 5.15 (s, 2H), 6,86˜8,30 (m, 10H).

MS (m/z) MH+(270).

Q: According to the method described in example 90, step In, with appropriate selection and substitution of reagents receive the product in the form of solids.

1H-NMR 300 MHz (CD3OD) δ of 3.12 (t, 2H), 3,60 (m, 2H), 4,55 (t, 2H), 5,10 (m, 2H), equal to 6.05 (s, 1H), 6,45˜8,54 (m, N).

MS (m/z) MN+(538), MN-(536).

EXAMPLE 92

3-(2,3-Dihydrobenzofuran-5-yl)-2-pyridin-2-yl-1,2,3,4-tetrahydropyrrolo[3,4-b]quinoline-9-he (#136)

3-(2,3-Dihydro-5-benzofuranyl)-1,2,3,4-tetrahydro-(3R)-N-pyrrolo[3,4-b]quinoline-9-he·HCl (0,0341 g, 0.1 mmol), 2-iodopyridine (0,0341 g, 0.2 mmol), Pd2dba3(22.9 mg, of 0.025 mmol), BINAP (46,7 mg of 0.075 mmol) and NaO-t-Bu (58 mg, 0.6 mmol) was stirred in 1,4-dioxane (0.8 ml) at 50°C for 3 hours. Purification preparative TLC (5% methanol/CH2Cl2) gives the product as a yellow solid.

1H-NMR 300 MHz (CD3OD) δ of 2.92 (t, 2H, J=9.5 Hz), and 4.40 (t, 2H, J=9.5 Hz), of 4.54 (d, 1H, J=22 Hz), is 4.85 (d, 1H, J=22 Hz), 6,55 (m, 2H), 7,10 (m, 3H), 7,35 (m, 4H), 8,02 (m, 1H), 8.30 to (d, 1H, J=9,3 Hz).

MS (m/z) MN+(382), MH-(380).

HPLC with separation of impurities: chiral phase, OD, methanol, 25°C, tr=5,201 minutes

EXAMPLE 93

3-(2,3-Dihydrobenzofuran-5-yl)-2-[5-(3H-imidazol-4-yl)pyridine-2-yl]1,2,3,4-tetrahydropyrrolo[3,4-b]quinoline-9-he

Mix a solution of 2-[5-(3-benzyl-3H-imidazol-4-yl)pyridine-2-yl]-3-(2,3-dihydrobenzofuran-5-yl)-1,2,3,4-tetrahydropyrrolo[3,4-b]quinoline-9-it (for example, 0.005 mmol, 1 equivalent), obtained as in example 91, and p-toluensulfonate (0.25 mmol, 50 equivalents) in CH3HE (3 ml) at about 80°added to a solution of sodium acetate (0.5 mmol, 100 equiv.) in N2About (2 ml) for approximately 2 hours. The mixture is stirred for approximately 3 hours at about 80°, then cooled to about 25°and the solvent is evaporated. The residue is dissolved in CH2Cl2(20 ml), washed with saturated aqueous NaCl (10 ml), dried (Na2SO4and concentrate, receiving specified in the header of the product.

EXAMPLE 94

3-(2,3-Dihydrobenzofuran-5-yl)-2-[5-(2-methyl-3H-imidazol-4-yl)pyrimidine-2-yl]-1,2,3,4-tetrahydropyrrolo[3,4-b]quinoline-9-he

According to the method described in example 93, 2-[5-(3-benzyl-2-methyl-3H-imidazol-4-yl)pyrimidine-2-yl]-3-(2,3-dihydrobenzofuran-5-yl)-1,2,3,4-tetrahydropyrrolo[3,4-b]quinoline-9-he obtained as in example 86, is subjected to the interaction, getting listed at the beginning of the connection.

EXAMPLE 95

TEST IN VITRO

Analysis cyclooctatetraenes (PDE)

Selection PDEV

PDEV were isolated from the tissues of rabbits and humans according to the Protocol described Boolell et al. [Boolell, M., Allen, M.J., Ballard., S.A., Gelo-Aktee, S., Muirhead, G.J., Naylor, .M., Osterloh, N., and Gingell, C) in International Journal of Impotence Research 1996 8, 47-52, with minor modifications.

Briefly, the tissue of rabbit or human homogenized in ice buffer solution containing 20 mm HEPES (pH of 7.2), 0.25 M sucrose, 1 mm EDTA and 1 mm phenylmethylsulfonyl (PMSF). The homogenates centrifuged at 100000 g for 60 minutes at 4°C. the Supernatant filtered through a 0.2 μm filter and loaded into the anion exchange column, Pharmacia Mono Q (volume of the pellet 1 ml), which was equilibrated to 20 mm HEPES, 1 mm EDTA and 0.5 mm PMSF. After washing away unbound protein, the enzyme elute with a linear gradient of 100 to 600 mm NaCl in the same buffer (total of 35 to 50 ml, depending on the fabric. The enzymes of the skeletal muscles that surround the cavernous body, retina, heart and platelets elute 35, 40, 45, 50 and 50 ml, respectively). Experiments to perform column at a volumetric flow of 1 ml/min and collect 1 ml fractions. Fractions with different PDE activity were pooled separately and used in subsequent studies.

Measurement of inhibition PDEV

The PDE analysis were performed as described by Thompson and Appleman in Biochemistry, 1971 10, 311-316 with minor modifications, as described below.

The tests have been adapted to a 96-well format. The enzymes were analyzed in 5 mm MgCl2, 15 mm Tris HCl (pH 7.4), 0.5 mg/ml bovine serum albumin, 1 μm cGMP or camp, of 0.1 µci [3H]-cGMP and [3 H]-camp and 2-10 ál of the eluate from the column. The total volume of the assay was 100 μm. 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. Formed [3N]-5'-mononucleotides then turned into uncharged [3N]-nucleosides by adding 25 μl (1 mg/ml) the venom of the snake (Ophiophagus Hannah) and incubation at 30°C for 10 minutes. The reaction was stopped by adding 1 ml of a suspension of resin Bio-Rad AG1-X2 (1:3). All charged nucleotides were bound with resin and only uncharged [3N]-nucleosides remained in the supernatant after centrifugation. An aliquot of 200 μl were collected and counted by scintillation. The PDE activity was expressed as pcmall hydrolyzed cyclic nucleotides/min/ml of enzyme.

Studies of inhibitors was performed in buffer for analysis with the final concentration of DMSO 10%. Under these conditions, the hydrolysis product increases with time and concentration of enzyme in a linear manner.

EXAMPLE 96

Determination of in vitro Kiinhibitors of phosphodiesterase:

The tests have been adapted to a 96-well format. Phosphodiesterase analyzed in 5 mm MgCl2, 15 mm Tris HCl (pH 7.4), 0.5 mg/ml bovine serum albumin, 30 nm3H-cGMP and at various concentrations of the test compounds. The number used for the reaction is AI enzyme was such to less than 15% of the initial substrate was developed during the analysis. For all measurements the test compound was dissolved and diluted in 100% DMSO (2% DMSO in the analysis). The total volume for analysis 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 cooled by transfer to ice bath. To each well was then added 25 μl (1 mg/ml snake venom [Ophiophagus Hannah) and the reaction mixture is incubated at 30°C for 10 minutes. The reaction was stopped by adding 1 ml of a suspension of resin Bio-Rad AG1-X2 (1:3). Selected aliquot of 200 µl and counted using a scintillation counter.

Inhibition in % of the maximum conversion of substrate (enzyme in the absence of inhibitor) was calculated for each concentration of the test compounds. Using nonlinear regression analysis GraphRadPrism (sigmoid function dose-response curves built % inhibition depending on the log concentration of the test compound to determine the IC50. In conditions when the substrate concentration "Kmenzyme (Km=concentration of the substrate, which is half the maximum velocity of the enzyme), Kiis equivalent to the value of the IC50.

According to the methods described above, the compounds listed is in tables 1-6. PDEV-inhibiting activity for these compounds are presented either as IC50(μm), as the percent inhibition at a given concentration of the test compound, either as the value of Kiin the following tables. Unless otherwise noted, PDEV-inhibiting activity was measured using human tissues. The abbreviation "stereo" refers to the stereogenic configuration, the abbreviation "Rac" means the racemic mixture.

Table 1
ID#R2StereoIC50(HM)
43,4-methylenedioxyphenylRac664
123,4-acidRac549a
175-(2,3-dihydrobenzofuran)Rac65% ing. @10 microns
483,4-methylenedioxyphenylR

3,4-methylenedioxyphenyl
Table 2
ID#R2StereoIC50(nm)
3Rac340a

0,230
Table 3
ID#R2StereoR4IC50

(nm)
13,4-methylenedioxyphenylRac2-pyrimidinyl5-(3,4-acid)0,165
23,4-methylenedioxyphenylRac2-pyrimidinyl5-(4-methoxyphenyl)0,191
73,4-methylenedioxyphenylRac2-pyrimidinyl5-(4-were)0,325
113,4-methylenedioxyphenylRac2-pyrimidinylnoto 3.73
353,4-methylenedioxyphenylS2-pyrimidinyl5-(3,4-acid)1,42and
363,4-methylenedioxyphenylR2-pyrim Danil 5-(3,4-acid)0,075
553,4-methylenedioxyphenylRac2-pyrimidinyl5-bromo4,48
563,4-methylenedioxyphenylRac2-pyrimidinyl5-(3-pyridinyl)1,24
573,4-methylene-dioksifenilRac2-pyrimidinyl5-(4-pyridinyl)0,84
153,4-acidRac2-pyrimidinyl5-(3,4-acid)1156
395-(2,3-dihydrobenzofuran)Rac2-pyrimidinyl5-(4-methoxyphenyl)0,47
665-(2,3-dihydrobenzofuran)R2-pyrimidinyl5-(4-methoxyphenyl)0,19
425-(2,3-dihydrobenzofuran)Rac2-pyrimidinyl5-(4-hydroxyphenyl)1,06
515-(2,3-dihydrobenzofuran)Rac2-pyrimidinyl 1,70a
525-(2,3-dihydrobenzofuran)Rac2-pyrimidinyl0,40a
615-(2,3-dihydrobenzofuran)Rac2-pyrimidinyl5-(2-pyridinyl)1,03
655-(2,3-dihydrobenzofuran)R2-pyrimidinyl5-(2-pyridinyl)0,23
705-(2,3-dihydrobenzofuran)Rac2-pyrimidinyl5-(3-pyridinyl)2,10
735-(2,3-dihydrobenzofuran)R2-pyrimidinyl5-(4-methoxyphenyl)0,170
745-(2,3-dihydrobenzofuran)Rac2-pyrimidinyl5-bromo1,90
765-(2,3-dihydrobenzofuran)R2-pyrimidinyl5-(2-pyridinyl)0,230
815-(2,3-dihydrobenzofuran)R2-pyrimidinyl5-(3,4-acid)
845-(2,3-dihydrobenzofuran)S2-pyrimidinyl5-(4-methoxyphenyl)2,42
853,4-methylenedioxyphenylRac2-pyrimidinyl0,90
913,4-methylenedioxyphenylRac2-thiazolyl3-(4-methoxyphenyl)0,410
963,4-dihydrobenzo[1,4]di-oxin-6-ylRac2-pyrimidinyl5-(4-methoxyphenyl)0,520
993,4-methylenedioxyphenylRac2-pyrimidinyl5-(4-pyridinyl)0,840
1003,4-methylenedioxyphenylRac2-pyrimidinyl5-(3-pyridinyl)0,520
1145-indanylRac2-pyrimidinyl5-(3,4-methylenedioxyphenyl)1,14
1235-(2,3-dihydrobenzofuran)Rac2-pyrimidinylno12,8
1243-thienylRac2-pyrimidinyl5-(3,4-acid)4,132
1255-(2,3-dihydrobenzofuran)Rac2-pyrimidinylN-oxo-2-pyridinylKi=0,144
1265-benzofuranRac2-pyrimidinyl5-(2-pyridinyl)Ki=was 0.138
1275-(2,3-dihydrobenzofuran)Rac2-pyrimidinyl5-(1-benzyl-2-methylimidazole)Ki=0,140
1285-(2,3-dihydrobenzofuran)Rac2-pyrimidinyl5-(1,2-dimethylimidazole)Ki=0,300
1295-(2,3-dihydrobenzofuran)Rac2-pyridinylnoKi=0,650
1305-(2,3-dihydrobenzofuran)Rac2-pyrimidinyl5-bromo1,9
1315-(2,3-dihydrobenzofuran)Rac2-pyridinyl5-bromoKi=1,55
1323,4-methylendioxy the Il Rac2-pyridinylno
1333,4-methylenedioxyphenylRacphenyl4-(1-imidazolyl)Ki=1,75
1345-(2,3-dihydrobenzofuran)Rac2-pyridinyl5-(2-pyridinyl)Ki=1,10
1365-(2,3-dihydrobenzofuran)R2-pyridinylnoKi=0,18
1375-(2,3-dihydrobenzofuran)Rac2-pyridinyl5-(5-(1-methyl)imidazolyl)
385-(2,3-dihydrobenzofuran)Rac2-pyridinyl5-(5-(1-benzyl)imidazolyl)

phenyl
Table 4
ID#R2StereoYR4IC50(nm)
53,4-methylenedioxyphenylRacCH 4-pyridinylno688
63,4-methylenedioxyphenylRacC(O)CH=CHphenyl4-methoxycarbonyl0,507
83,4-methylenedioxyphenylRacC(O)CH=CHphenyl4-carboxy0,828
93,4-methylenedioxyphenylRacC(O)2-benzo(b)furyl6-hydroxy0,460
133,4-methylenedioxyphenylRacC(O)2-furyl5-(3-triptoreline)0,227
163,4-methylenedioxyphenylRacC(O)2-furyl5-(4-nitrophenyl)0,390
183,4-methylenedioxyphenylRacC(S)1-imidazolylno54% ing. @ 10 microns
193,4-methylenedioxyphenylRacCH2phenylno234
213,4-methylenedioxyphenylRacC(O)2-furyl5-(4-shall ethoxyphenyl) 1,93
223,4-methylenedioxyphenylRacC(O)2-furyl5-(4-hydroxyphenyl)0,86
233,4-methylenedioxyphenylRacC(O)2-furyl5-(4-formylphenyl)1,76
243,4-methylenedioxyphenylRacC(O)2-furyl5-(4-methoxy-carbonyl-phenyl)1,21
253,4-methylenedioxyphenylRacC(O)3-pyridinyl2-hydroxyof 1.57
263,4-methylenedioxyphenylRacC(O)2-furyl5-(4-AMINOPHENYL)1,92
273,4-methylenedioxyphenylRacC(O)-O-CH2phenylno3,40and
283,4-methylenedioxyphenylSCH2phenylno6881a
293,4-methylenedioxyphenylRacC(O)2-furyl5-(4-carboxyphenyl)1,05
303,4-methylenedioxyphenylRacC(O)2-furyl5-bromo5,20a
313,4-methylenedioxyphenylRacC(O)-CH2-CH2phenyl4-methoxycarbonyl11,20
323,4-methylenedioxyphenylRacC(O)2-benzo(b) furyl3,40
333,4-methylenedioxyphenylRacC(O)-CH2-CH2phenyl4-carboxy3,40
343,4-methylenedioxyphenylRacC(O)-CH2-CH2phenyl59,50and
373,4-methylenedioxyphenylRacC(O)O-CH24-pyridinylno5,72
443,4-methylenedioxyphenylRacC(O)2-furyl1,58
693,4-methylenedioxyphenylRC(O)2-furyl 0,32
453,4-methylenedioxyphenylRacC(O)2-furyl1,33
473,4-methylenedioxyphenylRCH2phenylno
493,4-methylenedioxyphenylRacC(O)2-benzo(b) furyl1,127a
503,4-methylenedioxyphenylRC(O)2-furyl5-(3-triptoreline)0,61a
543,4-methylenedioxyphenylRacCH2phenylno234
583,4-methylenedioxyphenylRacC(O)2-furyl5-(4-hydroxyphenyl)0,86
593,4-methylenedioxyphenylRacC(O)2-furyl5-(3-triptoreline)0,66
205-(2,3-dihydrobenzofuran)RacC(O)-CH=CH4-methoxycarbonyl0,530
535-(2,3-dihydrobenzofuran)RacC(O)O-CH24-pyridinylno5,340a
605-(2,3-dihydrobenzofuran)RacCH2phenylno
753,4-methylenedioxyphenylRacC(O)phenylno51,51
775-(2,3-dihydrobenzofuran)RCH2phenylno62,67
793,4-methylenedioxyphenylRC(O)O-CH24-pyridinylno34,78
803,4-methylenedioxyphenylSC(O)O-CH24-pyridinylno2,710
823,4-methylenedioxyphenylRWith(O)2-furyl0,320
865-(2,3-dihydrobenzofuran)RacC(O)O-CH2 phenyl4-carboxy3,310
873,4-methylenedioxyphenylRacC(O)O-CH2phenyl4-carboxy1,560
883,4-methylenedioxyphenylRacC(O)2-benzofuran6-benzyloxy1,430
925-(2,3-dihydrobenzofuran)RacC(O)O-CH2phenyl4-methoxycarbonyl2,880
973,4-methylenedioxyphenylRacC(O)O-CH2phenylno2,120
985-(2,3-dihydrobenzofuran)RacC(O)2-benzofuranno1,020
1013,4-methylenedioxyphenylRacC(O)-cyclopropylphenylno2,90
1023,4-methylenedioxyphenylRacC(O)CH23-pyridinylno95,10
1033,4-methylenedioxyphenylRacC(O)-CH=CH phenylno0,540
1043,4-methylendioxyphenylRacC(O)-CH24-pyridinylno87,050
1065-(2,3-dihydrobenzofuran)RacWith(O)2-furyl1,30
1073,4-methylenedioxyphenylRacC(O)-NH-CH24-pyridinylno40,550
1103,4-methylenedioxyphenylRacWith(O)2-furyl5-phenyl0,755
1113,4-methylenedioxyphenylRacWith(O)2-furyl5-(4-methylthiophenyl)0,952
1123,4-methylenedioxyphenylRacWith(O)2-furyl5-(3-thienyl)0,699
1133,4-methylenedioxyphenylRacWith(O)2-furyl5-(3-nitrophenyl)0,812
1155-(2,3-dihydrobenzofuran)RacWith(O)2-imidazolyl no14,3
1163,4-methylenedioxyphenylRacWith(O)2-furyl5-(4-were)4,01
1173,4-methylenedioxyphenylRacC(O)2-furyl5-(2-furyl)4,75
1183,4-methylenedioxyphenylRacC(O)2-furyl5-(3,4-methylenedioxyphenyl)1,97
1193,4-methylenedioxyphenylRacC(O)2-furyl5-(4-cyanophenyl)1,19
1203,4-methylenedioxyphenylRacC(O)2-furyl5-(4-hydroxymethylene)1,22
1213,4-methylenedioxyphenylRacC(O)2-furyl5-(3-hydroxymethylene)0,56
1223,4-methylenedioxyphenylRacC(O)2-furyl5-(4-dimethylaminophenyl)2,05
1355-(2,3-dihydrobenzofuran)RC(O)S-2-oxa-bicyclo[2.2.1]heptenyl3-oxo-4,7,7-trimethy the Ki=13,9
1395-(2,3-dihydrobenzofuran)RC(0)R-2-oxa-bicyclo[2.2.1]heptenyl3-oxo-4,7,7-trimethyl

Table 5
< / br>
(racemate)
ID#R2YR3R4IC50
633,4-methylenedioxyphenylC(O)-CH=CHmethylphenyl4-methoxycarbonyl511a

Table 6
< / br>
(racemate)
ID#R2YR3R4IC50(nm)
633,4-methylenedioxyphenylC(O)-CH=CHmethylphenyl4-methoxycarbonyl113a
aConnection, IP is tannie using tissue of rabbits.

EXAMPLE 97

TEST, IN VIVO

According to the method described by Carter et al. (Carter, A.J., Ballard, S.A., and Naylor, A.M.) in The Journal of Urology 1998, 160, 242-246, the compounds listed in table 7, were tested to determine the effectiveness of In vivo results shown in the table below.

Table 7
ID#Efficiency
36Active
37Active
65Active
66Active

EXAMPLE 98

As a particular example, the oral composition, 100 mg of the compound of example 21 combine with enough powdered lactose obtaining the total number of from 580 to 590 mg to fill a solid gel capsules size O.

Although the above description explains the principles of the present invention, together with examples, are presented for the purpose of illustration, it should be clear that, in practice, the invention includes all of the usual variations, adaptations and/or modifications that are included in the scope of the following claims and their equivalents.

1. The compound of formula (I) or (II):

where

R1represents hydrogen;

R2selected and the group, consisting of aryl and heteroaryl;

R3selected from the group consisting of halogen, nitro, cyano, C1-C6of alkyl, C1-C6alkoxy, trifloromethyl, triptoreline, NH2, NH(C1-C6alkyl) and N(C1-C6alkyl)2;

b is an integer from 0 to 4;

R4independently selected from the group consisting of halogen, hydroxy, carboxy, oxo, C1-C6of alkyl, C1-C6alkoxy, C1-C6-alkoxycarbonyl, phenyl (where the phenyl group can be optionally substituted with one to three substituents, independently selected from RD), phenylsulfonyl, heteroaryl (where heteroaryl may be optionally substituted with one to three substituents, independently selected from RD), geterotsiklicheskie, NH2, OtherAN(RA)2,

where each RDindependently selected from halogen, hydroxy, carboxy, oxo, C1-C4of alkyl, C1-C4alkylthio, hydroxys1-C4of alkyl, C1-C4alkoxy, C1-C4alkoxycarbonyl,1-C4alkylcarboxylic, trifloromethyl, triptoreline, NH2, OtherAN(RA)2C(O)N(RA)2, SO2N(RA)2, acetylamino, nitro, cyano, FD is Mila, C1-C6alkylsulfonyl, carboxy1-C6the alkyl and aralkyl;

with 0;

and is an integer from 0 to 1;

Y is selected from the group consisting of residue-C1-C4alkyl-, -C(O)-, -(C2-C6alkenyl) carbonyl-, carbonyl (C1-C6alkyl)-, -C(S)-, -C(O)NH-(C1-C6alkyl)-, -C(O)(C3-C7cycloalkyl)and (C3-C7cycloalkyl)-C(O)-;

represents phenyl;

selected from the group consisting of phenyl, heteroaryl and cycloalkyl;

provided that when R1is hydrogen, R3represents hydrogen, b is 0, C is 0 and is 1, Y is-CH2-,represents phenyl andrepresents phenyl, then R2is not trimethoxyphenyl;

and its pharmaceutically acceptable salts.

2. The compound according to claim 1, where

R1represents hydrogen;

R2selected from the group consisting of phenyl or heteroaryl;

R3is1-C4alkyl;

b is an integer from 0 to 4;

R4selected from the group consisting of halogen, hydroxy, carboxy, oxo, C1-C3of alkyl, C1-C3alkoxy, C1-C3alkoxy is of arbonia, phenyl (where the phenyl may be optionally substituted by one or two substituents selected from hydroxy, carboxy, C1-C4of alkyl, C1-C4alkylthio, hydroxys1-C4of alkyl, C1-C4alkoxy, C1-C4allyloxycarbonyl, C(O)N(RA)2, trifloromethyl, triptoreline, amino, (C1-C4alkyl)amino, di(C1-C4alkyl) amino, nitro, cyano or formyl), heteroaryl (where heteroaryl may be optionally substituted by one or two substituents selected from hydroxy, carboxy, oxo, C1-C3of alkyl, C1-C3alkoxy, C1-C3allyloxycarbonyl, C(O)N(RA)2, trifloromethyl, triptoreline, amino, nitro, C1-C3alkylcarboxylic or C1-C4aralkyl), geterotsiklicheskie,

with 0;

and is an integer from 0 to 1;

Y is selected from the group consisting of residues With1-C4alkyl-, -C(S)-, -C(O)-, -C(O)-(C1-C4alkyl)-, -C(O)-(C2-C4alkenyl)-, -C(O)-(C3-C7cycloalkyl)- and-C(O)NH-(C1-C3-alkyl)-;

represents phenyl;

selected from the group consisting of phenyl, heteroaryl and geterotsiklicheskie;

and supplied with the ski acceptable salt.

3. The compound according to claim 2, where

R2selected from the group consisting of 3,4-methylenedioxyphenyl, 3,4-acid, 5-(2,3-dihydrobenzofuran), 3,4-dihydrobenzo[1,4]dioxin-6-yl, 5-benzofuran, 5-indanyl and 3-tanila;

R3is methyl;

R4selected from the group consisting of bromine, hydroxy, carboxy, oxo, methyl, phenyl, 4-hydroxyphenyl, 3-hydroxymethylene, 4-hydroxymethylene, 4-carboxyphenyl, 4-methylphenyl, 4-methoxyphenyl, 3,4-acid, 4-methoxycarbonyl, 4-ethoxycarbonylphenyl, 3-triptoreline, 4-cyanophenyl, 4-AMINOPHENYL, 4-dimethylaminophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-formylphenyl, 4-methylthiophenyl, benzyloxy, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, N-oxo-2-pyridinyl, 3-tanila, 2-furil, 1 imidazolyl, 5-(1-benzyl-2-methylimidazole), 5-(1,2-dimethylimidazole), 5-(1-methylimidazole, 5-(1-benzylimidazole), 3,4-methylendioxyphenyl,

Y is selected from the group consisting of-CH2-, -C(S)-, -C(O)-, -C(O)-CH2CH2-, -C(O)-CH=CH-, C(O)NH-CH2-, -C(O)-cyclopropyl and-C(O)CH2-;

selected from the group consisting of phenyl, 2-furil, 2-benzo(b)of furil, 2-pyrimidinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 1 imidazolyl, 2-imidazolyl, 2-thiazolyl and-oxabicyclo[2.2.1]heptane;

and its pharmaceutically acceptable salts.

4. The compound according to claim 3, where

R2selected from the group consisting of 3,4-methylendioxyphenyl, 5-(2,3-dihydrobenzofuran), 3,4-dihydrobenzo[1,4]dioxin-6-yl, 3-tanila, 5-indanyl and 5-benzofuran;

b is an integer from 0 to 1;

R4selected from the group consisting of 5-bromo, 2-hydroxy, 6-hydroxy, 4-carboxy, phenyl, 4-hydroxyphenyl, 3-hydroxymethylene, 4-hydroxymethylene, 4-carboxyphenyl, 4-methylphenyl, 4-methylthiophenyl, 4-methoxyphenyl, 3,4-acid, 4-methoxycarbonyl, 4-ethoxycarbonylphenyl, 3-triptoreline, 4-AMINOPHENYL, 4-dimethylaminophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-cyanophenyl, 4-formylphenyl, benzyloxy, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-furil, 3-tanila, N-oxo-2-pyridinyl, 1 imidazolyl, 5-(1-benzyl-2-methylimidazole), 5-(1,2-dimethylimidazole), 3,4-methylendioxyphenyl,

Y is selected from the group consisting of-C(O)-, -C(O)-CH2CH2-, and-C(O)-cyclopropyl;

selected from the group consisting of phenyl, 2-furil, 2-benzo[b]Furie, 2-pyrimidinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl and 2-thiazolyl;

and its pharmaceutically acceptable salts.

5. The compound according to claim 4, where

R2selected from the group consisting of 3,4-methyland is oxyphenyl, 5-(2,3-dihydrobenzofuran), 3,4-dihydrobenzo[1,4]dioxin-6-yl, 3-tanila, 5-indanyl and 5-benzofuran;

R4selected from the group consisting of 5-bromo, 2-hydroxy, 6-hydroxy, 4-carboxy, phenyl, 4-hydroxyphenyl, 3-hydroxymethylene, 4-hydroxymethylene, 4-carboxyphenyl, 4-methylphenyl, 4-methylthiophenyl, 4-methoxyphenyl, 3,4-acid, 4-methoxycarbonyl, 4-ethoxycarbonylphenyl, 3-triptoreline, 4-AMINOPHENYL, 4-dimethylaminophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-cyanophenyl, 4-formylphenyl, benzyloxy, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, N-oxo-2-pyridinyl, 3-tanila, 2-furil, 1 imidazolyl, 5-(1-benzyl-2-methylimidazole), 5-(1,2-dimethylimidazole), 3,4-methylendioxyphenyl,

Y represents-C(O)-;

and its pharmaceutically acceptable salts.

6. The compound according to claim 5, where

R4selected from the group consisting of 6-hydroxy, 4-carboxy, phenyl, 4-hydroxyphenyl, 3-hydroxymethylene, 4-methylphenyl, 4-methylthiophenyl, 4-methoxyphenyl, 3,4-acid, 4-methoxycarbonyl, 3-triptoreline, 3-nitrophenyl, 4-nitrophenyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, N-oxo-2-pyridinyl, 3-tanila, 5-(1-benzyl-2-methylimidazole), 5-(1,2-dimethylimidazole),

and its pharmaceutically acceptable salts.

7. Connect the imposition of claim 6, where

R2selected from the group consisting of 3,4-methylendioxyphenyl and 5-(2,3-dihydrobenzofuran);

R4selected from the group consisting of hydroxy, 4-methylphenyl, 4-methoxyphenyl, 3,4-acid, 4-methoxycarbonyl, 3-triptoreline, 4-nitrophenyl 2-pyridinyl, 3-pyridinyl,

Y represents-C(O)-;

selected from the group consisting of 2-furil, 2-benzo(b)of furil, 4-pyridinyl, 2-pyrimidinyl and 2-thiazolyl;

and its pharmaceutically acceptable salts.

8. The connection according to claim 7, selected from the group consisting of 1,2,3,4-tetrahydro-2-[5-(3,4-acid)pyrimidine-2-yl]-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-it;

1,2,3,4-tetrahydro-2-[(4-pyridinyl)methoxycarbonyl]-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-it;

1,2,3,4-tetrahydro-2-[5-(2-pyridinyl)pyrimidine-2-yl]-3-(3,4-dihydrobenzofuranyl)-N-pyrrolo[3,4-b]quinoline-9-it;

1,2,3,4-tetrahydro-2-[5-(4-methoxyphenyl)pyrimidine-2-yl]-3-(3,4-dihydrobenzofuranyl)-N-pyrrolo[3,4-b]quinoline-9-it;

1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-2-(5-(4-(1-(4-methyl)piperazinylcarbonyl)phenyl)furoyl)-N-pyrrolo[3,4-b]quinoline-9-it;

1,2,3,4-tetrahydro-2-[2,3'-piperidin]-6'-yl-3-(2,3-dihydro-5-benzofuranyl)-N-pyrrolo[3,4-b]quinoline-9-it;

1,2,3,4-tetrahydro-2-(2-pyridinyl)-3-(2,3-dihydro-benzofuranyl)-N-pyrrolo[3,4-b]quinoline-9-it;

and their pharmaceutically acceptable salts.

9. The compound of claim 8 selected from the group consisting of

R-1,2,3,4-tetrahydro-2-[5-(3,4-acid)pyrimidine-2-yl]-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b] quinoline-9-it;

R-1,2,3,4-tetrahydro-2-[(4-pyridinyl)methoxycarbonyl]-3-(3,4-methylenedioxyphenyl)-N-pyrrolo[3,4-b]quinoline-9-it;

R-1,2,3,4-tetrahydro-2-[5-(2-pyridinyl)pyrimidine-2-yl]-3-(3,4-dihydrobenzofuranyl)-N-pyrrolo[3,4-b]quinoline-9-it;

R-1,2,3,4-tetrahydro-2-[5-(4-methoxyphenyl)pyrimidine-2-yl]-3-(3,4-dihydrobenzofuranyl)-N-pyrrolo[3,4-b]quinoline-9-it;

R-1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-2-(5-(4-(1-(4-methyl)piperazinylcarbonyl)phenyl)furoyl)-N-pyrrolo[3,4-b]quinoline-9-it;

R-1,2,3,4-tetrahydro-2-(2-pyridinyl)-3-(2,3-dihydro-5-benzofuranyl)-N-pyrrolo[3,4-b]quinoline-9-it;

and their pharmaceutically acceptable salts.

10. The compound of formula (I) or (II):

where

R1represents hydrogen;

R2selected from the group consisting of aryl and heteroaryl;

R3selected from the group consisting of hydrogen, C1-C6of alkyl, C1-C6alkylcarboxylic,2-C6alkenylboronic and C2-C6alkynylaryl;

b is an integer from 0 to 4;

R4independently selected from the group SOS is oasa from halogen, hydroxy, carboxy, phenyl, phenylsulfonyl, heteroaryl, NH2, OtherAN(RA)2,

where each RDindependently selected from halogen, hydroxy, carboxy, C1-C4of alkyl, C1-C4alkoxy, C1-C4allyloxycarbonyl,1-C4alkylcarboxylic, trifloromethyl, triptoreline, NH2, OtherAN(RA)2C(O)N(RA)2, SO2N(RA)2, acetylamino, nitro, cyano, formyl, C1-C6alkylsulfonyl and carboxin1-C6of alkyl;

with 0;

and is an integer from 0 to 1;

Y is selected from the group consisting of residue-C1-C6alkyl-, -C(O)-, -(C2-C6alkenyl) carbonyl-, carbonyl(C1-C6alkyl)-, -C(S)-, -C(O)NH-(C1-C6alkyl)-, -C(O)(C3-C7cycloalkyl)- and -(C3-C7cycloalkyl)-C(O)-;

represents phenyl;

selected from the group consisting of phenyl, heteroaryl and cycloalkyl;

provided that when R1is hydrogen, R3represents hydrogen, b is 0, C is 0 and is 1, Y is-CH2-,represents phenyl andrepresents phenyl, R 2can't be trimethoxyphenyl;

and its pharmaceutically acceptable salts.

11. The pharmaceutical composition intended for the inhibition of phosphodiesterase, comprising a pharmaceutically acceptable carrier and a compound according to claim 1.

12. A method of obtaining a pharmaceutical composition, comprising mixing the compound according to claim 1 and a pharmaceutically acceptable carrier.

13. A method of treating sexual dysfunction in a subject in need thereof, comprising administration to the subject a therapeutically effective amount of a compound according to claim 1.

14. A method of treating sexual dysfunction in a subject in need thereof, comprising administration to the subject a therapeutically effective amount of the composition according to item 11.

15. A method of treating sexual dysfunction in item 13, where sexual dysfunction is a male sexual dysfunction, male erectile dysfunction, impotence, female sexual dysfunction excitability and female sexual dysfunction related to blood flow and the production of nitric oxide in the tissues of the vagina and clitoris.

16. The method of increasing the concentration of cGMP in the tissue of the penis of the subject is male, in need thereof, comprising administration to the subject an effective amount of a compound according to claim 1.

17. The method of treatment of a condition where inhibition of phosphodiesterase has a beneficial effect n the subject, in need thereof, comprising administration to the subject a therapeutically effective amount of a compound according to claim 1.



 

Same patents:

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new anellated carbamoyl azaheterocycles of the general formula (1)

or (2) possessing the inhibitory effect on protein kinase activity, a focused library comprising these compounds, and pharmaceutical composition based on thereof. In the general formula (1) or (2) R1 represents hydrogen atom or optionally substituted (C1-C6)-alkyl; R2 and R3 represent independently of one another hydrogen atom, inert substitute, optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; R4 represents optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; A and B in common with carbon and nitrogen atoms joined to the form an optionally substituted and optionally condensed azaheterocycle; D and F in common with carbon atoms joined form an optionally substituted and optionally condensed phenyl or aryl, optionally substituted and optionally condensed azaheterocycle. K and L in common with carbon and nitrogen atoms joined to them form an optionally substituted azaheterocycle. Also, invention related to methods for preparing compounds of the general formulae (1) or (2).

EFFECT: improved preparing methods.

10 cl, 2 sch, 25 tbl, 7 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of pyridothienodiazepine. Invention describes derivatives of pyridothienodiazepine of the general formula (I):

as a racemate or in form of enantiomers or diastereomers, or their mixture wherein R1 represents hydrogen atom or radical of the formula: R'1-NH-C(Y)- wherein R' represents phenyl radical optionally substituted with one or more similar or different substitutes taken among lower alkyl, lower alkoxy-group, lower alkylthio-group, lower alkoxycarbonyl, lower alkylsulfonyl, halogen atom, trifluoromethyl, trifluoromethyloxy-group, hydroxy-, nitro-, cyano-group, phenyl, phenoxy-group, cycloalkyl or heterocycloalkyl; R2 represents lower alkyl, trifluoromethyl or phenyl radical optionally substituted with one or more similar or different substitutes taken among hydroxy-group, halogen atom, lower alkyl or lower alkoxy-group; X and Y represent independently oxygen (O) or sulfur (S) atom; R3a represents hydrogen atom, lower alkyl, hydroxy-group or radical of the formula -OC(O)R'3a wherein R'3a represents alkyl radical comprising from 1 to 10 carbon atoms optionally substituted with radical of the formula: NR''3aR'''3a wherein NR''3a and R'''3a represent independently hydrogen atom, lower alkyl, phenyl, lower phenylalkyl, alkylcarbonyl or alkoxycarbonyl; R3b represents hydrogen atom or lower alkyl radical; R4 represents radical of the formula: -(CH2)n-CHR'4R''4 wherein n represents a whole number 0, 1, 2, 3, 4, 5 or 6; R'4 and R''4 represent independently hydrogen atom, lower alkyl, cycloalkyl, lower cycloalkylalkyl, phenyl, pyridyl, phenylcarbonyl or adamantyl wherein indicated radicals are substituted optionally with one or more similar or different substitutes taken among hydroxy-group, halogen atom, trifluoromethyl, lower alkyl or lower alkoxy-group; A----B represents -C=N- or -C-N(R5)- wherein R5 represents hydrogen atom, amino-radical, lower alkylamino-group, di-(lower alkyl)-amino-group, cycloalkyl, heterocycloalkyl, guanidyl optionally substituted with nitro- or cyano-group, phenyl optionally substituted with one or more similar or different substitutes taken among alkyl or alkoxyalkyl wherein indicated alkyl or alkoxyalkyl are substituted optionally with oxy- or amino-group; indolyl or radical of the formula: -NH-C(O)-(CH2)c-NH-C(O)(CH2)d-NH2; p represents a whole number 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; c and d represent independently a whole number 0, 1, 2 or 3; or salts of these compounds. Also, invention describes methods for preparing compounds of the general formula (I), pharmaceutical composition based on compounds of the general formula (I) eliciting activity to inhibit binding somatostatin-14 and an intermediate compound of the formula (2) given in the invention description. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

17 cl, 70 ex

The invention relates to new 3-substituted derivatives 3,4,5,6,7,8-hexahydropyrazino[4', 3': 4,5] -thieno[2,3-d] pyrimidine of the General formula I and their physiologically acceptable salts with selective action of antagonists 5HT1Band 5HT1Aand has inhibiting effect of reuse of serotonin

The invention relates to new biologically active chemical substance, namely 6-methyl-8-methoxymethyl-3-phenylisoxazole[3', 4': 4,5]thieno[2,3-b]pyridine of formula 1, showing the growth regulating and anti-stress activity

The invention relates to novel condensed pyrrolo (2,3-C)carbazole-6-Onam represented by the General formulas (I) and (II)

The invention relates to novel condensed isoindoline formula I

< / BR>
where ring b and F are independently from each other represent a 6-membered carbocyclic ring; R1means H, C1-C4alkyl; AND1and2pairs are selected from the group including =O, N, -OR", where R" denotes N;1and2pairwise mean =O; X in all positions independently from each other selected from the group: a) unsubstituted WITH1-C3alkylen, b) -S-; R3, R4, R5, R6independently from each other selected from the group comprising H1-C4alkyl; compounds 1 can be used for inhibiting protein kinase C (PKC) and inhibit the activity of tyrosine kinase (trk)

--carboline" target="_blank">

The invention relates to bellrowan-carbolines, formula I, where R3denotes-CO-R1or group (a); R1- C1-C6alkoxy; R2- N2C1-C4alkyl, C1-C4alkoxy - C1-C2alkyl; And -- 5-6-membered unsaturated cycle, in which 1-2 carbon atoms may be replaced by N, O and/or S, which may be substituted with one R5or R6; R5and R6identical or different, denote H, C1-C6alkyl, NR7R8C1-C6alkyl which may be substituted by hydroxyl or C1-C4alkoxyl, phenyl, 5-6-membered heteroaryl residue, which contains one or two atoms of N, O or S, and phenyl and heteroaryl residue may be substituted C1-C4the alkyl, C1-C4alkoxyl, halogen, or R5and R6together,- CH2)nwhere n = 4; R7and R8- H, C1-C4alkyl, acyl, as well as their isomers, tautomers and salts

The invention relates to new derivatives of imidazo/1,2-a/ thieno /2,3-d/azepino having antiallergic activity

FIELD: organic synthesis.

SUBSTANCE: invention provides methods for preparing lamellarine compounds of general formula II: (II) via intramolecular cyclization of compounds having general formula I: (I), in which formulas moiety RA1RA2C-CRA3RA4 forms optionally monosubstituted aryl group or optionally monosubstituted aromatic 3-6-membered heteromonocyclic group with one nitrogen atom; Y represents hydrogen atom, optionally monosubstituted C1-C20-alkyl, optionally monosubstituted C2-C20-alkenyl, optionally monosubstituted C2-C20-alkynyl, hydroxy, optionally monosubstituted amino, optionally monosubstituted C1-C20-alkoxy, optionally monosubstituted C1-C20-alkenoxy, optionally monosubstituted C1-C20-alkynoxy, optionally monosubstituted aryl, optionally monosubstituted saturated or unsaturated 3-6-membered heteromonocyclic group with one nitrogen atom, carboxy, carboxyester, carboxamide, C1-C20-acyl, C1-C20-acyloxy, mercapto, optionally monosubstituted C1-C20-alkylthio, halogen, nitro, sulfate, phosphate, or cyano; W and X, together with nitrogen and carbon atoms to which they are linked, form group selected from quinoline, isoquinoline, dehydroquinoline, and pyridyl groups all optionally monosubstituted, dihydro- or tetrahydro-derivatives of indicated groups, and optionally monosubstituted phenantridine; wherein optional substituent is selected from C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, aryl, halogen, halo-C1-C20-alkyl, halo-C2-C20-alkenyl, halo-C2-C20-alkynyl, haloaryl, hydroxy, C1-C20-alkoxy, C2-C20-alkenyloxy, aryloxy, benzyloxy, halo-C1-C20-alkoxy, halo-C1-C20-alkenyloxy, haloaryloxy, nitro, nitro-C1-C20-alkyl, nitro-C2-C20-alkenyl, nitro-C2-C20-alkynyl, nitroaryl, nitro-substituted 3-6-membered heteromonocyclic group with one nitrogen atom, amino, C1-C20-alkylamino, di-C1-C20-alkylamino, C2-C20-alkenylamino, C2-C20-alkynylamino, arylamino, diarylamino, benzylamino, dibenzylamino, C1-C20-acyl, C2-C20-alkenylacyl, C2-C20-alkynylacyl, arylamino, diarylamino, benzylamino, dibenzylamino, C1-C20-acyl, C2-C20-alkenylacyl, C2-C20-alkynylacyl, arylacyl, C1-C20-acylamino, di-C1-C20-acylamino, C1-C20-acyloxy, C1-C20-alkylsulfonyloxy, arylsulfenyloxy, 3-6-membered heteromonocyclic group with one nitrogen atom, oxy-, amino-, and halogen-derivatives of the latter, C1-C20-alkylsulfenyl, arylsulfenyl, carbo-C1-C20-alkyloxy, carbo-C6-C24-aryloxy, mercapto, C1-C20-alkylthio, benzylthio, C1-C20-acylthio, cyano, sulfate, and phosphate; V represents halogen, hydrogen, or oxygen atom; and intermediates having general formulas Ia and Ib:

EFFECT: expanded synthetic possibilities in lamellarine series.

28 cl, 1 dwg, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new substance eliciting an antiviral and antibacterial activity that is based on derivatives of 2,8-dithioxo-1H-pyrano[2,3-d;6,5-d']dipyrimidine and their 10-aza-analogues. This substance comprises derivative of indicated group of the general formula: A1*M: wherein X is taken among the group: oxygen atom (O), NH, N-alkyl; R1 is taken among the group: hydrogen atom (H), OH, chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, NH-Ar, N-(alkyl)2, SH, S-alkyl; R2 is taken among the group: unsubstituted or substituted phenyl, naphthyl, thienyl; R3 is taken among the group: hydrogen atom (H), chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, S-dihydroxypyrimidinyl; M is absent or taken among the group: cation Na, K, Li, ammonium or any other pharmacologically acceptable cation; or complex of pharmacologically acceptable cation (see above) with anion of one of derivatives of A1 (variants R1-R3 are given above). Invention provides preparing new compounds eliciting an antiviral and antibacterial activity.

EFFECT: valuable medicinal properties of substance.

17 cl, 7 tbl, 16 ex

The invention relates to a method for producing a condensed polycyclic alkaloids of General formula I, including new, including phase cyclization of azometynoylid General formula II, where a is optionally substituted aryl, Z is oxygen, n = 1, Y is optionally substituted aryl, W and X together with the nitrogen atoms and the carbon to which they are attached, form a saturated or unsaturated nitrogen-containing heterocyclic group, possibly substituted and possibly condensed with aryl, carbocyclic or heterocyclic group

The invention relates to novel condensed pyrrolo (2,3-C)carbazole-6-Onam represented by the General formulas (I) and (II)

The invention relates to novel condensed pyrrolo (2,3-C)carbazole-6-Onam represented by the General formulas (I) and (II)

The invention relates to new derivatives of 5H-pyrano[2,3-d:6,5-d']dipyrimidine General formula I possess anti-microbial, antiviral and immunomodulatory effects

The invention relates to a new process for the preparation of 9-amino-20/S/-camptothecin formula /I/

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which is a well-known anti-cancer agent: Wani, etc

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new substance eliciting an antiviral and antibacterial activity that is based on derivatives of 2,8-dithioxo-1H-pyrano[2,3-d;6,5-d']dipyrimidine and their 10-aza-analogues. This substance comprises derivative of indicated group of the general formula: A1*M: wherein X is taken among the group: oxygen atom (O), NH, N-alkyl; R1 is taken among the group: hydrogen atom (H), OH, chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, NH-Ar, N-(alkyl)2, SH, S-alkyl; R2 is taken among the group: unsubstituted or substituted phenyl, naphthyl, thienyl; R3 is taken among the group: hydrogen atom (H), chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, S-dihydroxypyrimidinyl; M is absent or taken among the group: cation Na, K, Li, ammonium or any other pharmacologically acceptable cation; or complex of pharmacologically acceptable cation (see above) with anion of one of derivatives of A1 (variants R1-R3 are given above). Invention provides preparing new compounds eliciting an antiviral and antibacterial activity.

EFFECT: valuable medicinal properties of substance.

17 cl, 7 tbl, 16 ex

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