Derivatives of beta-carboline possessing effect of phosphodiesterase inhibitors, pharmaceutical composition (variants), method for its preparing, method for inhibition of phosphodiesterase effect (variants) and method for increasing cgmp concentration

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of β-carboline of the general formula (I)

showing properties of phosphodiesterase V inhibitor (PDE V). In the general formula (I) R1 means hydrogen atom; n = 0; X is taken among the group consisting of oxygen (O), sulfur (S) atoms and NRD; R2 is taken among the following group: phenyl (that can be optionally substituted with 1-3 RB), 6-membered nitrogen-containing heteroaryl and 5-6-membered heterocycloalkyl comprising 1-2 oxygen atoms and condensed with benzene ring (optionally substituted with 1-3 RB); R4 is taken among the group consisting of hydrogen atom, carboxy-group. (C1-C6)-alkylcarbonyl, di-[C1-C8)-alkyl]-aminoalkoxycarbonyl, di-[(C1-C8)-alkyl]-amino-(C1-C8)-alkylaminocarbonyl; a = a whole number from 0 to 1; Y is taken among the group consisting of -CH2, -C(O); Z is taken among the group consisting of -CH2, -CHOH, and -C(O) under condition that when Z represents -CHOH or -C(O) then X represents -NH; is taken among the group consisting of naphthyl, 5-6-membered heteroaryl comprising 1-3 heteroatoms taken among nitrogen, oxygen and/or sulfur atoms possibly condensed with benzene ring; m = a whole number from 0 to 2; R3 is taken independently among the group consisting of halogen atom, nitro-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, trifluorophenyl, phenyl (optionally substituted with 1-3 RB), phenylsulfonyl, naphthyl, (C1-C8)-aralkyl, 5-6-membered heteroaryl comprising 1-3 nitrogen atoms in the ring (optionally substituted with 1-3 RB). Also, invention relates to a pharmaceutical composition, a method for its preparing and methods for inhibition of phosphodiesterase V activity (PDE V), and for increase of the cGMP concentration.

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

14 cl, 11 sch, 7 tbl, 13 ex

 

The present invention relates to new derivatives β-carboline, useful as inhibitors of phosphodiesterase. In addition, the invention relates to the synthesis of derivatives β-carboline and intermediates used in their preparation. Additionally, the present invention relates to the application of the described derivatives for the treatment of diseases and pathological States related to PDE (phosphodiesterase), such as erectile dysfunction in men.

Erectile dysfunction (ED) is defined as the inability to achieve or maintain a fairly stable erections for satisfactory sexual intercourse. According to estimates currently, 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, it is assumed that the percentage of this disease will increase in the future due to the increased average population growth.

Erectile dysfunction in men may be due to psychogenic and/or organic factors. Although ED is multifactorial, it is more likely that some sub-groups of the male population are the symptoms of the disease. In particular, among patients with diabetes, hypertension (high blood pressure), with rtechname diseases and multiple sclerosis has a particularly high prevalence of ED. In addition, patients taking certain classes of drugs, such as protivogipertonicheskoe tools, antidepressants, sedatives and tranquilizers, are more vulnerable to the manifestation of ED.

Treatment of ED includes many pharmacological agents, vacuum devices and prostheses penis. Among the pharmacological agents currently in practice, the use of papaverine, phentolamine and alprostadil. These agents are effective only after direct injection into the cavernous body or be injections and are associated with side effects like priapism (a painful erection of the penis), fibrosis, pain in the penis and hematoma at the injection site. Vacuum devices are noninvasive alternative treatment for ED. Such devices cause erection by creating negative pressure around the axis of the penis, causing increased blood flow in the cavernous body through passive arterial expansion. Although this form of therapy is often successful with ED of organic origin, dissatisfaction leads to the lack of naturalness, and the time required to use the mechanical device, and the difficulties and discomfort during ejaculation. Many semi-rigid or inflatable penile prostheses is Lena has been used with some success, in particular men with diabetes. These devices are usually considered in the case when other treatments have not been successful and associated with an increased risk of infection and ischemia.

Recently, a phosphodiesterase inhibitor V (PDEV), sildenafil (Viagra®), was approved by the Management under the control over products and medicines (FDA) as an effective oral medicine for treatment of ED. Sildenafil, 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)phenyl]-1-methyl-3-n-propyl-6,7-dihydro-1-h-pyrazolo[4,3-d]pyrimidine-7-he and a number of related analogs and their use as an antianginal (protivorevmaticakih) agents is described in U.S. patent 5250534 and 5346901. The use of sildenafil and related analogues for the treatment of erectile dysfunction in men is described in the Published International PCT application no WO 94/28902 published 22 December 1994. In clinical studies, the drug was improved sexual function in about 70% of men who suffered from ED psychogenic and organic etiologies. However, the drug showed less impressive efficacy in patients who underwent radical prostatectomy, while improving erections in 43% of patients who took sildenafil compared with 15% for placebo. In addition, the use of sildenafil is associated with some regulate the elegance side effects including headache, blood flow and impaired color vision, which is the result of non-selective actions on a variety of tissues. Despite these shortcomings, the drug is considered by patients as preferred in comparison with other treatment modalities, which include the introduction of drugs directly into the penis by injections, the use of external devices or surgery.

Daugan and others in the U.S. patent 5859009 (EP 0740668 B1 and WO 95/19978) describe the synthesis of tetracyclic derivatives as inhibitors of cyclic guanosine 3',5'-monophosphate (cGMP), namely phosphodiesterase, and their use for the treatment of cardiovascular diseases. Daugan and others in WO 97/03675 indicate the use of tetracyclic derivatives in the treatment of impotence.

Bombrun and others in WO 97/43287 describe a number of derivatives Carolina, more specifically, 2-(substituted alkylsulphonyl)substituted derivatives of Carolina and their use for the treatment of cardiovascular diseases as inhibitors of cyclic guanosine 3',5'-monophosphate, namely phosphodiesterase.

Ellis and others in WO 94/28902 and EP 0702555 B1 describe a number of derivatives of pyrazolopyrimidinone and their use for the treatment of erectile dysfunction. Campbell S.F. in WO 96/16657 describes the use of bicyclic heterocyclic compounds for the treatment of impotence (piraz loperamide); along with the fact that Campbell and others in WO 96/16644 indicate the use of selective cGMP PDE inhibitors for the treatment of erectile dysfunction.

Ohashi and others in WO 97/45427 describe tetracyclic derivatives iridocorneal with cGMP PDE inhibitory action.

Fourtillan and others in WO 96/08490 A1 describe a number of derivatives Carolina and their use for the treatment of diseases associated with disorders of melatoninbuy activity. Ueki and others in the U.S. patent 5126448 describe derivatives of pyridine and 1,2,3,4-tetrahydropyridine, useful as psychotropic drugs have a calming effect. Atkinson and others in the U.S. patent 3328412 describe derivatives of 1-aryl - and 1-heteroaryl-2-acyl-1,2,3,4-tetrahydro-β-carboline with prolonged analgesic (pain-relieving) properties.

Sexually stimulated erection of the male penis is the result of a complex interaction of physiological processes, including the Central nervous system, peripheral nervous system and muscles smooth muscles. In particular, the release of nitric oxide from neadrenergicheskoy, neholinergichesky nerves and endothelium activates guanililcyclase and increases intracellular cGMP levels in the cavernous body. The increase in intracellular cGMP reduces intracellular levels of calcium, leading to the trabecular relaxation the purpose of smooth muscles, that, in turn, leads to expansion of the volume of the body and reduce subblocking venules, leading to the erection of the male penis.

PDEV was found in human platelets and vascular smooth muscle, suggesting about the role of this enzyme in the regulation of intracellular concentrations of cGMP in cardiovascular tissue. Indeed, it was shown that inhibitors PDEV spend to endothelial-dependent vasodilatation through potentiation of the increase in intracellular cGMP induced by nitric oxide. Moreover, 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 are likely to provide therapeutic benefit in such diseases as heart failure, pulmonary hypertension and angina.

It is assumed that agents that increase cGMP concentration in the tissue of the penis either through increased release or decreased decomposition of cGMP, will be effective drugs for ED. Intracellular levels of cGMP are regulated by enzymes that are included in its formation and decomposition, namely, guanylate cyclase and cyclic nucleotidyltransferase (PDE). To this the straps described, at least nine families of PDE mammals, five of which are able to hydrolyze active cGMP to inactive GMP (guanosine monophosphate) under physiological conditions (PDE I, II, V, VI and IX). PDE V represents the predominant isoform in the cavernous body. Therefore, one would expect that the PDEV inhibitors will increase the concentration of cGMP in the cavernous body and increase the duration and frequency of erection to penis.

In addition, it is known that selective PDE inhibitors can be used in the treatment of various diseases and morbid conditions, including erectile dysfunction in men (ED), dysfunction sexual arousal in women, sexual dysfunction in women is related to blood flow and the production of nitric oxide in the tissues of the vagina and the clitoris, premature birth, dysmenorrhea, cardiovascular disease, atherosclerosis, arterial occlusive disease, venous thrombosis, restenosis of coronary artery, angina, myocardial infarction, heart failure, ischemic heart disease, hypertension, pulmonary hypertension, asthma, alternating lameness and diabetic complications.

Accordingly, the present invention is to identify compounds that increase the concentration of cGMP in the tissue of the penis through ing is berbania phosphodiesterase, in particular PDEV. Another objective of the present invention is the identification of compounds that can be used for the treatment of sexual disorders, including erectile dysfunction and/or impotence in male animals and sexual disorders in female animals. Another object of the invention is the establishment of methods of treatment of sexual disorders, especially erectile dysfunction using the compounds of the present invention.

Another object of the invention is to identify compounds that can be used for the treatment of painful disorders mediated PDEV, such as erectile dysfunction in men, female sexual disorder, cardiovascular disease, atherosclerosis, arterial occlusive disease, venous thrombosis, restenosis of coronary artery, angina, myocardial infarction, heart failure, ischemic heart disease, hypertension, pulmonary hypertension, asthma, intermittent claudication or diabetic complications.

In this paper the authors present invention describe a number of derivatives β-carboline with the ability to inhibit phosphodiesterase type V enzyme analysis and to increase the concentration of cGMP in the cavernous tissue of the body in vitro.

The present invention relates to new production is th β -carboline that can be used as inhibitors of phosphodiesterase. More specifically, the present invention relates to compounds of General formula (I):

where R1independently selected from the group consisting of halogen, nitro, hydroxy, C1-C8of alkyl, C1-C8alkoxy, -NH2-The otherA, -N(RA)2, -O-RA, -C(O)NH2, -C(O)otherA, -C(O)N(RA)2, -NC(O)-RA, -SO2OtherA, -SO2N(RA)2, phenyl (optionally substituted by 1-3 RBand heteroaryl (optionally substituted by 1-3 RB);

where each RAchosen independently from the group consisting of C1-C8of alkyl, aryl (optionally substituted by 1-3 RB)1-C8aralkyl (optionally substituted by 1-3 RBand heteroaryl (optionally substituted by 1-3 RB);

where each RInchosen independently from the group consisting of halogen, hydroxy, nitro, cyano, C1-C8of alkyl, C1-C8alkoxy, C1-C8alkoxycarbonyl, carboxy1-C8of alkyl, C1-C8alkylsulfonyl, trifloromethyl, triptoreline, amino, acetylamino, di(C1-C8alkyl)amino, di(C1-C8alkyl)amino1-C8alkoxy, di(C1-C8alkyl)aminoacetic1With 8of alkyl, di(C1-C8alkyl)aminoethylamino, carboxy1-C8alkylcarboxylic, hydroxys1-C8alkylamino, -otherA, -N(RA)2and heterocyclics1-C8alkoxy;

n is an integer from 0 to 4;

X is chosen from the group consisting of O, S and NRD;

where RDselected from the group consisting of hydrogen, hydroxy, -ORAC1-C8the alkyl (where alkyl optionally substituted with one to three substituents, independently selected from halogen, carboxy, amino, C1-C8alkylamino, di(C1-C8alkyl)amino, C1-C8alkoxycarbonyl, heteroaryl or geterotsiklicheskie), heteroaryl and heteroarylboronic (where heteroaryl optionally may be substituted by phenyl or substituted phenyl, where the phenyl substituents are one to three RB);

R2selected from the group consisting of C5-C10the alkyl (optionally substituted by 1-3 RC), aryl (optionally substituted by 1-3 RB), heteroaryl (optionally substituted by 1-3 RBand geterotsiklicheskie (optionally substituted by 1-3 RB);

where each RCindependently selected from the group consisting of halogen, hydroxy, nitro, NH2, OtherAand N(RA)2;

Z is chosen from the group consisting of CH2SNON and C(O); when the condition is and, that when Z represents SNON or C(O), X represents NH;

R4selected from the group consisting of hydrogen, hydroxy, carboxy, C1-C6alkylcarboxylic,1-C6alkoxycarbonyl, di(C1-C8alkyl)aminocarbonyl, di(C1-C8alkyl)amino1-C8alkylaminocarbonyl and-CORF;

where RFselected from the group consisting of C1-C8of alkyl, NH2, OtherA, NRA2- 1-C8alkyl-NH2- 1-C8alkyl-otherA- 1-C8alkyl-NRA2and-NH-C1-C8NRA2;

and is an integer from 0 to 1;

Y is chosen from the group consisting of CH2With(O), C(O)Oh, C(O)-NH and SO2;

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

m is an integer from 0 to 2;

R3independently selected from the group consisting of halogen, nitro, C1-C8of alkyl, C1-C8alkoxy, trifloromethyl, triptoreline, phenyl (optionally substituted by 1-3 RB), phenylsulfonyl, naphthyl,1-C8aralkyl, heteroaryl (optionally substituted by 1-3 RB), NH2, OtherAand N(RA)2;

provided that ifis 2-furyl or 2-year is nil, then m is an integer from 1 to 2;

and their pharmaceutically acceptable salts.

The invention relates to pharmaceutical compositions comprising pharmaceutically acceptable carrier and any of the above compounds. The invention relates to a pharmaceutical composition obtained by mixing any of the above compounds and a pharmaceutically acceptable carrier. The invention relates to a method for producing a pharmaceutical composition comprising mixing any of the above compounds and a pharmaceutically acceptable carrier.

The invention relates to a method for the treatment of sexual disorders in in need thereof of a subject, for example, erectile dysfunction in men, impotence, female sexual dysfunction, such as dysfunction sexual arousal in women, sexual dysfunction in women is related to blood flow and the production of nitric oxide in the tissues of the vagina and the clitoris, premature birth and dysmenorrhea, including introduction to the subject a therapeutically effective amount of any of the above described compounds or pharmaceutical compositions.

The invention relates to a method of increasing the concentration of cGMP in the tissue of the penis by inhibiting phosphodiesterase, specifically PDEV, in need thereof a male subject, comprising the administration to a subject BJ the CSOs described above, the compounds or pharmaceutical compositions.

In addition, the invention relates to a method for producing endothelial-dependent dilation of the vessels in need of this subject through potentiation of the increase in intracellular cGMP induced by nitric oxide, comprising an introduction to the subject any of the above described compounds or pharmaceutical compositions.

In addition, the invention relates to a method of treatment of a pathological state selected from the group consisting of erectile dysfunction (ED) in men, impotence, female sexual dysfunction, dysfunction sexual arousal in women, sexual dysfunction in women is related to blood flow and the production of nitric oxide in the tissues of the vagina and the clitoris, premature birth, dysmenorrhea, cardiovascular disease, atherosclerosis, arterial occlusive diseases, thrombosis, restenosis of coronary artery, angina, myocardial infarction, heart failure, ischemic heart disease, hypertension, pulmonary hypertension, asthma, intermittent claudication and diabetic complications in need thereof of a subject, comprising the administration to a subject any of the above described compounds or pharmaceutical compositions.

The invention also relates to the application of any of the above compounds for obtaining medicines for: (a) treatment sex what about the disorder, especially erectile dysfunction in men, (b) the treatment of impotence, (C) increasing the concentration of cGMP in the tissue of the penis by inhibiting phosphodiesterase, specifically, PDEV and/or (d) treatment of a disease selected from the group consisting of premature birth, dysmenorrhea, cardiovascular disease, atherosclerosis, arterial occlusive diseases, thrombosis, restenosis of coronary artery, angina, myocardial infarction, heart failure, ischemic heart disease, hypertension, pulmonary hypertension, asthma, intermittent claudication and diabetic complications, the need for this entity.

In the present invention developed new derivatives of β-carboline that can be used for the treatment of sexual disorders, in particular male erectile dysfunction (ED). Although the compounds of the present invention is primarily useful for the treatment of sexual disorders in men or erectile dysfunction, they can also be used for the treatment of female sexual disorders such as dysfunction of sexual arousal in women, sexual dysfunction in women is related to blood flow and the production of nitric oxide in the tissues of the vagina and the clitoris, premature birth and dysmenorrhea.

More specifically, the compounds of the present invention have the formula

where all values radicals are as defined above.

Preferably n is 0. Preferably m is an integer from 0 to 1.

In the embodiment of the present invention X is selected from S or NRDwhere RDselected from the group consisting of hydrogen, Halogens1-C6of alkyl, di(C1-C4alkyl)amino1-C6of alkyl, heteroaryl, heteroaryl1-C4of alkyl, heterocyclics1-C4of alkyl, carboxy1-C4of alkyl, C1-C4alkoxycarbonyl1-C4the alkyl and heteroarylboronic; where heteroaryl optionally additionally substituted by phenyl or substituted phenyl where the substituents at the phenyl are one or two substituent independently selected from RB; and where each RBindependently selected from the group consisting of halogen, nitro, C1-C4of alkyl, C1-C4alkoxy, trifloromethyl, triptoreline, amino and di(C1-C4alkyl)amino. Preferably X is selected from S or NRDwhere RDselected from the group consisting of hydrogen, di(methyl)aminoethyl, di(methyl)amino-n-propyl, di(ethyl)aminoethyl, di(ethyl)amino-n-butyl, N-pyrrolidinyl, N-morpholinomethyl, 2-pyridylmethyl, 4-pyridylmethyl, 5-(4-were)-2-pyrimidinyl, carboxy is Atila, carboxyethyl, 4-chloro-n-butyl, 2-(5-(3-triptoreline)furyl)carbonyl, 2-(5-(3-nitrophenyl)furyl)carbonyl, methoxycarbonylmethyl, methoxycarbonylethyl and 2-benzoxazolyl. More preferably, X represents NRDwhere RDselected from the group consisting of hydrogen, di(methyl)aminoethyl, 4-pyridylmethyl, 2-pyridylmethyl, N-morpholinomethyl, carboxyethyl, carboxymethyl, di(ethyl)aminoethyl, N-pyrrolidinyl and 5-(4-were)-2-pyrimidinyl. Most preferably, X represents NRDwhere RDselected from the group consisting of hydrogen, di(methyl)aminoethyl, N-morpholinomethyl, carboxymethyl and N-pyrrolidinyl.

Preferably Z is selected from the group consisting of CH2and C(O); provided that when Z is C(O), X represents NH.

Preferably Y is selected from the group consisting of C(O), SO2and CH2. More preferably Y is selected from the group consisting of C(O) and CH2. Most preferably Y is S(O).

In the embodiment of the present inventionselected from the group consisting of naphthyl and heteroaryl. Preferablyselected from the group consisting of naphthyl, 2-pyrimidinyl, 2-furil, 3-furil, 2-benzofuran, 2-tanila, 2-benzothiazyl, 2-benzothiazolyl, 2-benzoxazolyl, 2-Benson gasolina, 4-thiazolyl, 2-thiazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-prosolia, 3-(1,2,5-triazolyl), 4-isoxazolyl, 2-pyridyl and 3-pyridyl. More preferablyselected from the group consisting of naphthyl, 2-pyrimidinyl, 2-furil, 2-benzofuran, 2-tanila, 2-benzothiazyl, 2-benzothiazolyl, 2-benzoxazolyl, 2-thiazolyl, 4-thiazolyl and 2-pyridyl. Most preferablyselected from the group consisting of 2-pyrimidinyl, 2-furil, 2-benzofuran, 2-benzoxazolyl, 2-thiazolyl and 2-pyridyl.

In the embodiment of the present invention R2selected from the group consisting of 3,4-methylenedioxyphenyl, 3,4-(debtor)methylenedioxyphenyl, 2,3-dihydrobenzofuran, 2,3-dihydrobenzo[1,4]dioxin-6-yl, pyridyl, phenyl and substituted phenyl, where the phenyl substituents are one to two substituent independently selected from halogen, C1-C4of alkyl, C1-C4alkoxy, trifloromethyl, cyano, nitro, C1-C4alkoxycarbonyl, di(C1-C4)alkyl)amino or di(C1-C4alkyl)amino1-C4alkoxy. Preferably R2selected from the group consisting of phenyl, 3,4-methylenedioxyphenyl, 3,4-(debtor)methylenedioxyphenyl, 2,3-dihydrobenzofuran, 2,3-dihydrobenzo[1,4]dioxin-6-yl, 4-pyridyl, 3-pyridyl, 4-cyanophenyl, 3-nitrophenyl, 4-nitrophen the La, 4-trifloromethyl, 4-methoxyphenyl, 3,4-dimetilfenil, 3,5-dimetilfenil, 3,4-acid, 3-trifluoromethyl-4-chlorphenyl, 3,4-dichlorophenyl, 4-chlorphenyl, 4-ethoxycarbonylphenyl, 3,4-acid, 4-(dimethylamino)phenyl and 4-(N-(3-dimethylamino)-n-propoxy)phenyl. More preferably R2selected from the group consisting of 3,4-methylenedioxyphenyl, 2,3-dihydroxybenzophenone and 2,3-dihydrobenzo[1,4]dioxin-6-yl. Most preferably, R2selected from the group consisting of 3,4-methylendioxyphenyl and 2,3-dihydroxybenzophenone.

Preferably R4selected from the group consisting of hydrogen, carboxy, C1-C4alkoxycarbonyl, di(C1-C4alkyl)amino1-C4alkoxycarbonyl and di(C1-C4alkyl)amino1-C4alkylaminocarbonyl. More preferably R4selected from the group consisting of hydrogen, carboxy, dimethylaminoethoxide, dimethylaminoethylmethacrylate and methoxycarbonyl. Most preferably, R4represents hydrogen.

In the embodiment of the present invention R3independently selected from the group consisting of halogen, nitro, C1-C4of alkyl, C1-C4alkoxy, trifloromethyl,1-C4aralkyl, pyrazinyl, pyridyl, substituted with halogen of pyridyl, dimethylselenide imidazo the sludge, phenyl, phenylsulfonyl and substituted phenyl, where the substituents in the phenyl are one or more substituents independently selected from halogen, hydroxy, C1-C4of alkyl, C1-C4alkoxy, trifloromethyl, triptoreline, nitro, amino, acetylamino,1-C4alkylsulfonyl, carboxy1-C4alkylcarboxylic, hydroxys1-C4alkylamino, di(C1-C4alkyl)amino1-C4alkoxy, di(C1-C4alkyl)aminoethylamino or heterocyclics1-C4alkoxy. Preferably R3independently selected from the group consisting of chlorine, bromine, methyl, n-propyl, tert-butyl, methoxy, trifloromethyl, nitro, phenyl, benzyl, phenylsulfanyl, 4-hydroxyphenyl, 4-chlorphenyl, 4-methylphenyl, 3,4-acid, 3-triptoreline, 4-trifloromethyl, 5-triptoreline, 4-methoxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-AMINOPHENYL, 4-AMINOPHENYL, 2-nitro-4-chlorphenyl, 2-nitro-4-methylphenyl 2-nitro-4-methylsulfinylphenyl, 3-acetylaminophenol, 4-acetylaminophenol, 4-(3-carboxy-n-propyl)carbonylmethyl, 2-chloro-5-triptoreline, 4-(4-hydroxy-n-butyl)AMINOPHENYL, 2-(dimethylamino)acetylaminophenol, 4-[2-(N-pyrrolidinyl)ethoxy]phenyl, 4-[2-(4-morpholinyl)ethoxy]phenyl, 4-(2-(dimethylamino)ethoxy)phenyl, 4-pyrazine, 2,3-imethyl-3H-imidazolyl, 2-pyridyl and 3-pyridyl. More preferably R3selected from the group consisting of bromide, tert-butyl, methoxy, trifloromethyl, nitro, phenyl, 4-chlorphenyl, 3,4-acid, 3-triptoreline, 4-methylphenyl, 4-methoxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-AMINOPHENYL, 2-nitro-4-chlorphenyl, 2-nitro-4-methylphenyl, 2-nitro-4-methylsulfinylphenyl, 4-(3-carboxy-n-propyl)carbonylmethyl, 2-chloro-5-triptoreline, 4-(4-hydroxy-n-butyl)AMINOPHENYL, 2,2-(dimethylamino)acetyl aminophenol, 4-pyrazinyl, 2-pyridyl and 2,3-dimethyl-3H-imidazol-4-yl. Most preferably, R3selected from the group consisting of tertbutyl, methoxy, nitro, phenyl, 4-chlorphenyl, 4-methylphenyl, 4-methoxyphenyl, 3,4-acid, 3-triptoreline, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-AMINOPHENYL, 2-nitro-4-methylsulfinylphenyl, 2-(dimethylamino)acetylaminophenol, 2-pyridyl and 2,3-dimethyl-3H-imidazol-4-yl.

For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts". However, other salts can be used to obtain the compounds according to the invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid additive salts, which, for example, can be obrazovaniyasiga solution of the compound with a solution of the pharmaceutically acceptable acid, such as chloride-hydrogen 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 contain acid fragment, suitable pharmaceutically acceptable salts may include alkali metal salts, for example 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 salt. Thus, examples of pharmaceutically acceptable salts are the following:

acetate, bansilalpet, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, potassium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, Eilat, fumarate, gluceptate, gluconate, glutamate, picolylamine, hexylresorcinol, geranamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, 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, t is Strat, teoclate, tosylate, triethiodide and valerate.

In the scope of the present invention includes prodrugs of the compounds of the present invention. In General, such prodrugs will be functional derivatives of the compounds that are readily converted in vivo in the target connection. Thus, in the methods of treatment according to the present invention, the term "introduction" will cover the treatment described various diseases using specific disclosed compounds or compounds which are not specifically disclosed, but which turns into a well-defined compound in vivo after administration to the patient. The usual methods of selecting and obtaining the appropriate proletarienne derivatives described, for example, in "Design of Prodrugs", ed. H.Bundgaard, Elsevier, 1985.

When the compounds according to this invention have at least one chiral center, they may exist as enantiomers. When the compounds have two or more chiral centers, they may additionally exist in the form of 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, included in the present invention. Additionally, some with the organisations may form a solvate with water (hydrates) or common organic solvents, implying that such a solvate is included in the scope of this invention.

As used in this description, unless otherwise stated, "halogen" shall mean chlorine, bromine, fluorine and iodine.

The term "alkyl", when it is used by itself or as part of a replacement group, will mean a linear or branched alkanes having one to ten carbon atoms or any number within this range. For example, alkyl radicals include 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.

The term "alkoxy" denote simple oxygen ether radical of the above described linear or branched alkyl groups. For example, alkoxyalkyl include methoxy, ethoxy, n-propoxy, n-butoxy, sec-butoxy, tert-butoxy and the like.

The term "aryl" refers to aromatic groups such as phenyl, naphthyl and the like.

The term "aralkyl" means alkyl group, substituted aryl group. For example, benzyl, phenethyl and the like.

The term "heteroaryl", as used herein, represents a stable five-or six-membered monocyclic aromatic ring system containing one to three heteroatoms independently selected from N, O or S; and any nine is whether deletechannel bicyclic aromatic ring system, containing carbon atoms and one to four heteroatoms independently selected from N, O or S. the Heteroaryl group may be attached via any heteroatom or carbon atom that results in the creation of a stable structure. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzofuranyl, benzothiazol, benzisoxazole, benzoxazole, indazole, indolyl, benzothiazolyl, benzotriazolyl, benzothiazolyl, chinoline or ethenolysis. Particularly preferred heteroaryl groups include pyridyl, pyrazolyl, furyl, thiazolyl, thienyl, imidazolyl, isoxazolyl, pyrazinyl, pyrimidinyl, triazolyl, benzofuran, benzothiazyl, benzimidazolyl, benzothiazolyl and benzoxazolyl.

The term "cycloalkyl", as used herein, represents a stable three to eight-membered monocyclic ring structure consisting of a saturated carbon atoms. Suitable examples include cyclopropyl, cyclobutyl, cyclopentyl, celexin, cycloheptyl and cyclooctyl.

The term "heteroseksualci" is a stable saturated or partially unsaturated three-to eight-membered monocyclic ring structure containing ATO is s carbon and one to four, preferably one or two heteroatoms, independently selected from N, O or S; or any stable saturated, partially unsaturated or partially aromatic nine-decatizing bicyclic ring system containing carbon atoms and one to four heteroatoms independently selected from N, O or S. Heteroseksualci can be attached via any heteroatom or carbon atom that results in the creation 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]pyridyl, 1,2-(methylenedioxy)cyclohexane and the like. Especially preferred heterocytolysine group include pyrrolidinyl, morpholinyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuran and 2,3-dihydrobenzo[1,4]dioxin-6-yl.

As used in this description, the symbol "*" will indicate the presence of a stereogenic center.

In accordance with the standard nomenclature used in this description, the terminal portion of the designated side chain is described first, followed by a description of related functional groups Peredistyy at the place of joining. In affect, the, for example, the Deputy panels1-C6alkylaminocarbonyl1-C6alkyl refers to a group of the formula

It is implied that the definition of any substituent or variable in a specific location of the molecule is independent of its definitions elsewhere in the molecule. It should be understood that substituents and examples of substitution in the compounds of this invention can be selected average person skilled in the art to create compounds that are chemically stable and that can be easily synthesized by methods known in this field, as well as methods set forth in this description. In addition, it is understood that when n or m>1, the respective substituents R1or R3may be the same or different.

The term "sexual dysfunction"as used in this description, includes male sexual dysfunction, male erectile dysfunction, impotence, female sexual dysfunction, dysfunction sexual arousal in women, sexual dysfunction in women is related to blood flow and the production of nitric oxide in the tissue of the vagina and clitoris.

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

The term "therapeutically effective amount", as used herein, refers to an amount of active compound or pharmaceutical agent that causes the biological or medicinal response in a system tissue of an animal or person, which is required for the researcher, veterinarian, physician, or other clinical physician that includes the weakening of the symptoms being treated diseases or conditions.

As used herein, the term "composition" is intended to encompass a product comprising certain ingredients in certain amounts, as well as any product which results, directly or indirectly, the combination of certain ingredients in certain amounts.

The following abbreviations are used in this description, in particular in reactions and examples:

DMF
Conn. No.The connection identification number
DCC1,3-Dicyclohexylcarbodimide
DHMDichloromethane
DDQDichlorodicyanoquinone
DICDiisopropylcarbodiimide
DIPEADiisopropylethylamine
N,N-Dimethylformamide
DMSOThe sulfoxide
dppp1,3-Bis(diphenylphosphino)propane
EDTAEthylenedinitrilotetraacetic acid
Fmoc9-Fluorenylmethoxycarbonyl
Fmoc-NCSIsothiocyanate 9-fluorenylmethoxycarbonyl
HEPES2-[4-(2-Hydroxyethyl)piperazinil]econsultancy acid
'lahSociallyengaged
PDEPhosphodiesterase
Pd2dba3Tris(dibenzylideneacetone)dipalladium(0)
Pd(OAc)2The palladium (II)acetate
Pd(PPh3)4Tetrakis(triphenylphosphine)palladium
PhPhenyl
PMSFPhenylmethanesulfonyl
PPh3Triphenylphosphine
PyBop(1-Hydroxy-1H-benzotriazole-O)tri-1-pyrrolidineethanol
PyBropBromine-three-1-piridinievom
SNPSodium nitroprusside
TEAThe triethylamine
TFATriperoxonane acid
THFTetrahydro the furan
TsOHTasilova acid

The compounds of formula (I) can be obtained by methods described in more detail below.

The compounds of formula (I), where (Y)arepresents C(O), can be obtained in accordance with the method shown in General scheme 1.

More specifically, to obtain the tricyclic compounds of the formula (IV) compound of the formula (II), where X represents O, S or NH, representing a well-known compound or compound obtained by known methods, is subjected to the interaction with the appropriately substituted aldehyde of formula (III) in an organic solvent, such as DHL, THF, toluene and the like, in the presence of an acid catalyst, such as NFA, tasilova acid and the like.

To obtain the corresponding compound of formula (Ia), the compound of formula (IV) is subjected to interaction with a suitably substituted compound of formula (V), where a represents a halogen, in the presence of a base such as triethylamine (TEA), diisopropylethylamine (DIPEA), sodium carbonate and the like, in an organic solvent, such as dichloromethane (DHM), N,N'-dimethylformamide (DMF), tetrahydrofuran (THF) and the like; or with a suitably substituted compound of formula (V), where a is the guide is hydroxy, in the presence of a condensing agent such as DCC, DIC, PyBop, PyBrop, and the like, in an organic solvent, such as dichloromethane (DHM), N,N'-dimethylformamide (DMF), tetrahydrofuran (THF) and the like.

Alternatively, the compounds of formula (I), where X represents O, S or NH, and (Y)arepresents C(O), can be obtained in accordance with the method shown in General scheme 2.

More specifically, the compound of formula (II), where X represents O, S or NH, is subjected to the interaction with the appropriately substituted compound of formula (VI), where a is halogen or hydroxy, in an organic solvent, such as DHL, THF, DMF and the like, receiving a corresponding compound of formula (VII).

The compound of formula (VII) is subjected to cyclization, processing POCl3in an organic solvent, such as toluene, benzene and the like, with subsequent restoration NaBH4in organic solvents, such as ethanol, isopropanol and the like, receiving a corresponding compound of formula (IV).

The compound of formula (IV) is then subjected to interaction with the appropriately substituted compound of formula (V), obtaining the compound of formula (Ia), as shown in General scheme 1.

The compounds of formula (I), where X predstavljaet, S or NH, and (Y)ais SO2can be obtained by the method as shown in General form in figure 3.

Accordingly, a suitably substituted compound of formula (IV) is subjected to interaction with a suitably substituted compound of formula (VIII), where a is halogen or hydroxy, which is a known compound or a compound obtained by known methods, in an organic solvent, such as THM, chloroform, THF and the like, with the formation of the compounds of formula (Ib).

The compounds of formula (I), where X represents O, S or NH, and (Y)ais CH2can be obtained by the method as shown in General form in figure 4.

Accordingly, a suitably substituted compound of formula (Ia) is treated regenerating agent such as LAH, diboron and other, preferably'lah, in an organic solvent, such as methanol, THF, diethyl ether, and the like, preferably at a temperature in the range of (-20)-40°receiving a corresponding compound of formula (Ic).

The compounds of formula (I), where (Y)ais CH2and X represents NH, alternatively, can be obtained in accordance with the method presented in General form in figure 5.

Accordingly, the compound of formula (IVa) is subjected to interaction with the appropriately substituted compound of formula (IX), where Q is halogen,-toilet and On-mazalat, in an organic solvent, such as DHL, THF and the like, receiving a corresponding compound of formula (Id).

The compounds of formula (I), where X represents O, S or NH, and (Y)ais (Y)0(i.e. where a is 0, so Y is absent), can be obtained in accordance with the method shown in General form in figure 6.

More specifically, the compound of formula (IV), a known compound or compound obtained by known methods, is subjected to the interaction with the appropriately substituted by a halide of formula (X), a known compound or compound obtained by known methods, in an organic solvent, such as toluene, DMF, 1-methyl-2-pyrrolidinone and the like, preferably at a temperature in the range of from about 80 to 250°receiving a corresponding compound of formula (Ie).

The compounds of formula (I), where X represents NRDcan be obtained in accordance with the method shown in General form in figure 7.

Accordingly, the compound of formula (If) is subjected to interaction with soy is inanam formula (XI), where Z represents halogen, hydroxy, O-tosylate or On-mazalat, and a base such as sodium hydride, tert-piperonyl potassium and the like, in a solvent such as DMF, 1-methyl-2-pyrrolidinone and the like, receiving a corresponding compound of formula (Ig).

The compounds of formula (I)where Z represents CH HE or S(O), can be obtained in accordance with the method shown in General form in scheme 8.

More specifically, the compound of formula (If) is treated with an oxidant such as DDQ, chloranil and the like, in a solvent such as THF, methanol, water and the like, preferably at a temperature in the range of from about -78 to about 30°receiving a mixture of the corresponding compounds of formula (Ih) and (Ii). Preferably compounds of formula (Ih) and (Ii) separated by known methods such as recrystallization, column chromatography and the like.

The compounds of formula (I), whereis 2-thiazolyl, can be obtained in accordance with the method shown in General form in scheme 9.

Accordingly, the appropriately substituted compound of formula (IVa) is subjected to interaction with Fmoc-NCS in an organic solvent, such as DHL, DMF, THF and the like, preferably at room temperature is, receiving a corresponding compound of formula (XII).

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

Amine of formula (XIII) is subjected to interaction with the appropriately substituted α-halogenoalkanes formula (XIV) in the presence of an organic solvent or mixture, 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 (Ij).

The compounds of formula (I), where (Y)arepresents C(O)Oh, can be obtained in accordance with the method shown in General form in scheme 10.

More specifically, the compound of formula (IV) is subjected to interaction with the appropriately substituted by chloroformiate formula (XV) or anhydride of the formula (XVI) in an organic solvent, such as DHL, DMF, THF and the like, receiving a corresponding compound of formula (Ik).

The compounds of formula (I), where (Y)arepresents C(O)-NH, can be obtained in accordance with the method shown in General form in scheme 11.

Accordingly, the compound of formula (IV) is subjected to interaction with substituted podhodyashaya compound of formula (XVII) in an organic solvent, such as DHL, DMF, THF and the like, receiving a corresponding compound of formula (Im).

In the case when the means of obtaining the compounds according to the invention lead to a mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compound can be obtained in racemic form, or can be obtained from the individual enantiomers or using enantioselective synthesis or separation. For example, the compounds can be separated into their component enantiomers by standard techniques, such as education diastereoisomeric 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 regenerierung free base. The connection can also be separated by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary additives. Alternative compounds can be separated using chiral HPLC column.

In the process of 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 of rassmatrivaemykh molecules. This can be done using conventional protective groups such, for example as described in Protective Groups in Organic Chemistry, ed. J.F.W.McOmie, Plenum Press, 1973; and .W.Greene & P.G..Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. Protective groups can be removed at a suitable subsequent stage using methods known to experts in this field.

The usefulness of the compounds for the treatment of sexual dysfunction can be defined in accordance with the techniques described in this description and in the examples 10, 11 and 12.

Therefore, the present invention relates to a method of treating sexual dysfunction in in need thereof of a subject, comprising introducing him to any of the defined in the description of the compounds in amounts effective for the treatment of sexual disorders. Connection, you can enter the patient using any conventional route of administration, including, but not limited to, intravenous, oral, subcutaneous, intramuscular, intradermal and parenteral. The amount of compound that is effective for the treatment of sexual disorders is between 0.1 mg to 1 kg and 2 mg per 1 kg of body weight of the subject.

The present invention also relates to pharmaceutical compositions comprising one or more compounds according to this invention in combination with a pharmaceutically acceptable carrier. Suppose the equipment data of the composition are in the form of single preparative dosage forms, such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral, parenteral, vnutripuzarnogo, sublingual or rectal introduction or for introduction via inhalation or insufflation. An alternative 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, can be adapted for the development of a depot preparation 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, to obtain a solid tablet composition containing a homogeneous mixture of the compounds of the present invention or its pharmaceutically acceptable salt. At the mention of the preliminary compositions as homogeneous is meant that the active ingredient is evenly distributed in the comp the positions so the composition can be easily divided into equally effective preparative dosage forms such as tablets, pills and capsules. Such solid pre-composition is subsequently divided into individual preparative dosage forms of the type indicated above containing from 1 to 1000 mg of the active ingredient of the present invention. The tablets or pills of the new compositions can be coated or compounded other way to create a preparative dosage forms, which give the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, where the latter one is a wrapper for the first. Two components can be separated enteral (enteric) layer, which serves to suppress the degradation in the stomach and permits the inner component to pass intact into the duodenum or slow to escape. For such enteric layers or coatings you can use a variety of materials, such materials include a number of polymeric acids with such substances as shellac, cetyl alcohol and cellulose acetate.

Liquid forms for oral administration or administration by injection, which can be introduced new compositions of the present invention, on the less liquid solutions flavored appropriately syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical migration tools. Suitable dispersing or suspendresume agents for aqueous suspensions include synthetic and natural gums, such as tragakant, gum Arabic, alginate, dextran, sodium carboxymethyl cellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

A method of treating sexual disorders, in particular erectile dysfunction in men (ED), described in the present invention can also be carried out using a pharmaceutical composition comprising any of the compounds described herein and a pharmaceutically acceptable carrier. The pharmaceutical composition can contain from 1 mg to 1000 mg, preferably 10 to 500 mg of the compounds and can be obtained in the form of any shape suitable for the selected method of administration. Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspendresume agents, lubricating agents, flavorings, sweeteners, preservatives, dyes and agents covering membranes. Compositions suitable for oral introduced the I, include solid forms, such as pills, tablets, caplet, capsules (each of which includes the formulation of immediate release, timed release and long-term continuous release), granules and powders, and liquid forms such as solutions, syrups, elixirs, emulsions and suspensions. The forms used for parenteral administration include sterile solutions, emulsions and suspensions.

Primarily, the compounds of the present invention can be introduced in the form of single daily doses of medicines, or the total daily dosage can be entered in divided doses of two, three or four times a day. In addition, the compounds of the present invention can be introduced in the form vnutripuzarnoe forms by local application using the appropriate vnutriskalnyh media or through percutaneous patches for the skin, well known to the average person skilled in the art. With the introduction in the form of a percutaneous delivery system, the administration of a medicinal product for dispensing, of course, is more likely to be continuous than periodic.

For example, for oral administration in the form of tablets or capsules, the active ingredient of medicines can be combined with oral non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, if desired or if necessary, the mixture can be included suitable binders, lubricants, dezintegriruetsja agents and dyes. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums, such as gum Arabic, tragakant or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. The disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum and the like.

Liquid forms may include appropriately flavored suspendresume or dispersing agents, such as synthetic and natural gums, for example, tragakant, gum Arabic, methylcellulose. For parenteral administration requires 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 obtained from a variety of phospholipids, such as hol is a Sterol, stearylamine or phosphatidylcholine.

Compounds of the present invention can also be delivered using monoclonal antibodies as individual carriers to which the attached molecule compounds. Compounds of the present invention can also be associated with soluble polymers as carriers of drugs that can achieve the goal. Such polymers can include polyvinylpyrrolidone, copolymers of Piran, polyhydroxyethylmethacrylate, polyhydroxyethylmethacrylate or polyethylenepolyamine, substituted residues of Palmitoyl. In addition, the compounds of the present invention can be associated with a class biorazlagaemykh polymers used to achieve controlled release of drugs, for example, polictically acid, polietilentireftalat, polyhydroxystearic acid complex prioritaire, polyacetylene, policyidreference, polycyanoacrylate and sewn or amphipatic block copolymers of hydrogels.

In each case, when you want treatment of sexual disorders, including erectile dysfunction (ED) in men, the compounds of this invention can be introduced in the form of any of the above compositions and according to dosage regimes, defined in this field.

The optimal dosage for the introduction can easily be determined by experts in the field, and they will vary depending on the specific compound, the route of administration, the intensity of the drug, the route of administration and development of the disease. In addition to the need to adjust the dosage cite factors related to concrete subjected to treatment by the patient, including the patient's age, weight, diet and time of administration.

In order to help understanding of the invention presents the following examples, which are not intended and shall not be interpreted as limiting in any way the invention set forth in the following formula and is gaining.

Unless otherwise stated, spectra1H NMR were recorded on the instrument Bruker AC-300.

Example 1

1-(3,4-Methylenedioxyphenyl)-2-[5-(3-triptoreline)furoyl]-2,3,4,9-tetrahydro-1H-β-carbolin (No. 58)

To a suspension of 5-(3-triptoreline)frankenboob acid (256 mg, 1 mmol) in DHM (20 ml, anhydrous) was added oxalicacid (165 mg, 1.3 mmol) followed by addition of two drops of DMF. The mixture was stirred at room temperature for 1 hour. Solution was added 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (292 mg, 1 mmol) (obtained in accordance with the method described in WO 97/43287, intermediate compound 7, p.24) and triethylamine (0.4 ml) in DHM (10 ml, anhydrous), and the mixture was stirred at room temperature for 16 hours, washed successively aqueous NaHCO3saturated salt solution (2x), 1H. HCl and saturated salt solution (2x) and dried MgSO4. After evaporation of the solvent was obtained a white solid substance.

TPL: 126-129°

Mass spectrum (m/z): 531 (MH+);

1H-NMR (CDCl3) δ: 2,96 (d, J=8 Hz, 1H), 3,24 (m, 1H), of 3.56 (m, 1H), 4,60 (d, J=8 Hz, 1H), 5,90 (s, 2H), 6,70 (d, J=8 Hz, 1H), 6,83-6,99 (m, 4H), 7,13-7,34 (m, 4H), at 7.55 (m, 3H), 7,87 (d, J=7 Hz, 1H), of 7.95 (s, 1H), 8,23 (s, 1H).

Example 2

9-[2-(Pyrrolidin-1-yl)ethyl]-1-(3,4-methylenedioxyphenyl)-2-[5-(3-triptoreline)furoyl]-2,3,4-trihydro-1H-β-carbolin (No. 75)

To a solution of 1-(3,4-methylendioxyphenyl is)-2-[5-(3-triptoreline)furoyl]-2,3,4,9-tetrahydro-1H-β -carboline (obtained as in example 1) (600 mg, to 1.14 mmol) in DMF (15 ml, anhydrous) was added at room temperature sodium hydride (60%, 105 mg, 2.6 mmol). The mixture was stirred at room temperature for 30 minutes. Added hydrochloride N-chlorethylene (214 mg, of 1.26 mmol) and 15-crownether-5 (1 drop). The mixture was stirred at room temperature for 16 hours, extinguished NH4Cl was extracted with ethyl acetate and dried MgSO4. After evaporation of the solvent the residue was purified column chromatography (silica gel, ethyl acetate:hexane=3:1)to give white solid.

Mass spectrum (m/z): 628 (MH+);

1H-NMR (CDCl3) δ: of 1.26 (m, 4H), of 2.64 (m, 4H), 2,89 (m, 2H), 3,05 (d, J=8 Hz, 1H), or 3.28 (t, J=8 Hz, 1H)and 3.59 (t, J=8 Hz, 1H), 3.96 points (m, 1H), 4,16 (m, 1H), 4,58 (d, J=8 Hz, 1H), 5,96 (s, 2H), 6.75 in (d, J=8 Hz, 1H), 6,84 (m, 2H), 7,02 (d, J=8 Hz, 1H), 7,15-7,29 (m, 4H), 7,43 (s, 1H), to 7.59 (m, 3H), 7,89 (d, J=7 Hz, 1H), of 7.96 (s, 1H).

To obtain a product for the biological testing of the corresponding salt methanesulfonic acid was obtained by adding 1.0 equivalent methanesulfonic acid to a solution of the compounds in DHM.

TPL: 122-124°

Example 3

1-(3,4-Methylenedioxyphenyl)-2-[5-(3,4-acid)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-β-carbolin (No. 7)

A solution of 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (of 3.73 g, 12.8 mmol) (obtained in accordance with the method described in WO 97/4287, intermediate compound 7, page 24) and 2-chloro-5-(3,4-acid)pyrimidine (1.6 g, 6.4 mmol) in DMF (50 ml, anhydrous) was heated at 120°With stirring for 16 hours. The reaction mixture was extinguished NH4Cl and extracted with ethyl acetate. The organic phase is washed with saturated salt solution (2x) and dried MgSO4. Column chromatography (silica gel, ethyl acetate:hexane=2:3) gave a white solid.

TPL: 173-175°

Mass spectrum (m/z): 507 (MH+);

1H-NMR (CDCl3) δ: only 2.91 (d, J=9 HZ, 1H), to 3.02 (TD, J=9.1 Hz, 1H), 3,39 (TD, J=9.1 Hz, 1H), 3,92 (s, 3H), of 3.94 (s, 3H), 5,02 (d, J=9.1 Hz, 1H), of 5.92 (s, 2H), 6,72 (d, J=8 Hz, 1H), 6.87 in-7,03 (m, 4H), 7,11-7,17 (m, 3H), 7,31 (d, J=8 Hz, 1H), 7,56 (d, J=8 Hz, 1H), 7,80 (s, 1H), 8,56 (s, 2H).

Example 4

1-(3,4-Methylenedioxyphenyl)-2-[5-(3,4-acid)pyrimidine-2-yl]-9-dimethylaminoethyl-2,3,4-trihydro-1H-β-carbolin (No. 5)

In accordance with the procedure described in example 1 was subjected to the interaction of 1-(3,4-methylenedioxyphenyl)-2-[5-(3,4-acid)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-β-carbolin (obtained as described in example 3) (1.0 g, 1.97 mmol), hydrochloride of 2-chloro-N,N-dimethylethylamine (0,342 g, is 2.37 mmol), sodium hydride (60%, 0,190 g, 4,74 mmol) and 15-crownether-5, receiving the product as a slightly yellowish solid after column chromatography on silica gel, ethyl acetate).

Mass spectrum (m/z): 578 (MH+);

1H-NMR (CDCl3) δ: of 2.21 (s, 6H, 2,22 (m, 1H), 2,61 (m, 1H), 2,89 (DD, J=a 13.4 Hz, 1H), 3,03 (TD, J=a 13.4 Hz, 1H), 3,35 (TD, J=a 13.4 Hz, 1H), 3,91 (m, 1H), 3,92 (s, 3H), of 3.95 (s, 3H), 4,06 (m, 1H), 4,96 (DD, J=a 13.4 Hz, 1H), to 5.93 (s, 2H), 6,72 (d, J=8 Hz, 1H), 6,83 (s, 1H), 6,85-6,98 (m, 4H), 7,12 (d, J=8 Hz, 1H), 7,21 (d, J=8 Hz, 1H), 7,31 (d, J=8 Hz, 1H), 7,34 (s, 1H), 7,58 (d, J=8 Hz, 1H), 8,56 (s, 1H).

Example 5

1-(3,4-Methylenedioxyphenyl)-2-[5-(4-methoxyphenyl)pyrimidine-2-yl]-4-oxo-2,3,4,9-tetrahydro-1H-β-carbolin (No. 157), and

1-(3,4-Methylenedioxyphenyl)-2-[5-(4-methoxyphenyl)pyrimidine-2-yl]-4-hydroxy-2,3,4,9-tetrahydro-1H-β-carbolin (No. 158)

To a mixture of DDQ (113,5 mg, 0.5 mmol) and 1-(3,4-methylenedioxyphenyl)-2-[5-(3,4-acid)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-β-carbolin (obtained as described in example 3) (51 mg, 0.1 mmol) at -78°C was added a mixed solvent of THF:water (9:1). The mixture was stirred at 0°and left to warm to room temperature for 15 hours. Column chromatography (silica gel, hexane:ethyl acetate=1:1) gave oxo - and hydroxy, respectively, as white solids.

No. 157,

Mass spectrum (m/z): 521 (MH+), 519 (M-1);

1H-NMR (CDCl3) δ: 3,90 (d, J=18 Hz, 1H), with 3.89 (s, 3H), 3,91 (s, 3H), 5,43 (d, J=18 Hz, 1H), of 5.84 (s, 2H), 6,62 (d, J=8 Hz, 1H), of 6.71 (d, J=8 Hz, 1H), 6,88-7,00 (m, 4H), 7,29-the 7.43 (m, 3H), 7,53 (s, 1H), of 8.25 (m, 1H), 8,51 (s, 2H), of 9.55 (s, 1H).

No. 158

Mass spectrum (m/z): 523 (MN+), 521 (MH+);

1H-NMR (CDCl3) δ: 3,30 (t, J=6 Hz, 1H), 3,69 (d, J=6 Hz, 1H), 3,92 (s, 3H), of 3.94 (s, 3H), 5,97 (s, 2H), 6,11 (s, 1H), of 6.71 (d, J=8 G is, 1H), 6,93-7,05 (m, 4H), 7,18 (d, J=8 Hz, 1H), 7.23 percent (d, J=8 Hz, 1H), 7,40 (t, J=6 Hz, 1H), 7,49 (d, J=8 Hz, 1H), 7,82 (d, J=8 Hz, 1H), 8,43 (s, 2H), 9,15 (s, 1H).

Example 6

1-(3,4-Methylenedioxyphenyl)-2-[4-(4-methoxyphenyl)thiazol-2-yl]-2,3,4,9-tetrahydro-1H-β-carbolin (No. 169)

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 in accordance with the method described in WO 97/43287, intermediate compound 7, p.24) and Fmoc-isothiocyanate (2,82 g, 10,14 mmol) was dissolved in dry dichloromethane (50 ml). The mixture was stirred for 16 hours at ambient temperature and then concentrated in vacuum. Purification with flash chromatography (0-10% methanol in dichloromethane) gave the protected thiourea as a pale yellow solid.

Mass spectrum (m/z): 574 (MH+);

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 (userd, J=7,6 Hz, 1H), 6,97 (users, 1H), 7,11-7,78 (series of m, 17H).

In: 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.) the piperidine in methanol was heated at the boil under reflux for 5 hours. The mixture was concentrated in vacuum, not receiving the untreated residue, which was purified flash chromatography (SiO2, 0-10% methanol in dichloromethane)to give a yellow solid.

Mass spectrum (m/z): 352 (MH+);

1H-NMR (CDCl3) δ: 2,69-2,87 (series of m, 2H), 3,10-3,19 (m, 1H), 4,24 (users, 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 (users, 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 (No. 169)

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

Mass spectrum (m/z): 482 (MH+);

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 7

1-(3,4-Methylenedioxyphenyl)-2-[4-phenylthiazol-2-yl]-2,3,4,9-tetrahydro-1H-β-carbolin (No. 170)

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 remaining 9.08 mmol) (obtained in accordance with the method, described in WO 97/43287, intermediate compound 7, p.24) and Fmoc-isothiocyanate (2,82 g, 10,14 mmol) was dissolved in dry dichloromethane (50 ml). The mixture was stirred for 16 hours at ambient temperature and then concentrated in vacuum. Purification with flash chromatography (0-10% methanol in dichloromethane) gave the protected thiourea as a pale yellow solid.

Mass spectrum (m/z): 574 (MH+);

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 (userd, J=7,6 Hz, 1H), 6,97 (users, 1H), 7,11-7,78 (series of m, 17H).

In: 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.) the piperidine in methanol was heated at the boil under reflux for 5 hours. The mixture was concentrated in vacuum, obtaining the crude residue, which was purified flash chromatography (SiO2, 0-10% methanol in dichloromethane)to give a yellow solid.

Mass spectrum (m/z): 352 (MH+);

1H-NMR (CDCl3) δ: 2,69-2,87 (series of m, 2H),3,10-3,19 (m, 1H), 4,24 (users, 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 (users, 3H), 11,06 (s, 1H).

C. 1-(3,4-Methylenedioxyphenyl)-2-[4-phenylthiazol-2-yl]-2,3,4,9-tetrahydro-1H-β-carbolin (No. 170)

RA is Toru thiourea from part b (227 mg, of 0.65 mmol) was added β-bromoacetophenone (159 mg, 0.80 mmol) and triethylamine (0,40 ml). This mixture was heated at 70°C for 3 hours, cooled to room temperature and concentrated on a rotary evaporator. The residue was purified flash chromatography (SiO2, 0-10% methanol in dichloromethane)to give a pale yellow solid.

Mass spectrum (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, 6H), 7,89 (d, J=7,4 Hz, 2H), 10,95 (s, 1H).

Example 8

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 (No. 190)

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) was stirred in 3.5 ml of DMF at 140°C for 14 hours. The mixture was 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 gave specified in 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).

Mass spectrum (m/z): 463 (MH+), 461 (MH-).

Example 9

2-[2,3']Bipyridinyl-6'-yl-1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1H-β-carbolin (No. 191)

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 NaOt-Bu (5,38 g, 56 mmol) was stirred in 60 ml of DMF at 80°C for 3 days. The reaction mixture was filtered through a layer of celite using CH2Cl2. Then the reaction mixture was concentrated, the crude mixture was loaded on a column Foxy (110 g silica gel) and suirable a mixture of ethyl acetate/hexane (3:7). The product crystallized in test tubes. The product was 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), 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).

Mass spectrum (m/z): 446, 448 (MH+), 444, 446 (MH-).

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 is ionic mixture was filtered through a layer of celite using CH 2Cl2and then concentrated to small volume. Preparative TLC (3:7 ethyl acetate/hexane; then 5% CH3OH/CH2Cl2) gave 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).

Mass spectrum (m/z): 445 (MH+), 443 (MH-).

In accordance with the above-described methods were obtained for the compounds listed in tables 1-6.

Table 1

Conn. No.RDR2R3
1H3,4-methylene

dioksifenil
-
2dimethyl

aminoethyl
3,4-methylene

dioksifenil
2-benzothiazolyl-
3N3,4-methylene

dioksifenil
2-benzothiazolyl-
4dimethyl

aminoethyl
3,4-methylene

dioksifenil
2-pyrimidinyl5-(4-chlorophenyl)
5dimethyl

aminoethyl
3,4-methylene

deoxit the Nile
2-pyrimidinyl5-(3,4-dimethoxy

phenyl)
6dimethyl

aminoethyl
3,4-methylene

dioksifenil
2-pyrimidinyl5-(4-methoxy

phenyl)
7N3,4-methylene

dioksifenil
2-pyrimidinyl5-(3,4-dimethoxy

phenyl)
8N3,4-methylene

dioksifenil
2-pyrimidinyl5-(2-nitro-4-methyl

sulfonyl)phenyl
9N3,4-methylene

dioksifenil
2-pyrimidinyl5-(4-methoxy

phenyl)
10N3,4-methylene

dioksifenil
2-pyrimidinyl5-(4-chlorophenyl)
1482-(N-pyrrolidinyl)ethyl3,4-methylene

dioksifenil
2-pyrimidinyl5-(4-methoxy

phenyl)
1502-benzoxazolyl3,4-methylene

dioksifenil
2-benzoxazolyl-
151N3,4-methylene

dioksifenil
2-benzoxazolyl-
153N3,4-methylene

dioksifenil
2-pyrimidinyl5-(2-pyridyl)
1542-(N-pyrrolidinyl)ethyl3,4-methylene

dioksifenil
2-pyrimidinyl5-(2-nitro-4-methyl

sulfonyl

phenyl)

Continuation of table 1
155dimethylaminoethyl3,4-methylene

dioksifenil
2-benzoxazolyl-
156dimethylaminoethyl3,4-methylene

dioksifenil
2-pyrimidinyl5-(2-pyridyl)
161N3,4-methylene

dioksifenil
2-pyrimidinyl5-(4-were)
1665-(4-were)-2-pyrimidinyl3,4-methylene

dioksifenil
2-pyrimidinyl5-(4-were)
167N3,4-acid2-pyrimidinyl5-(3,4-dimethoxy

phenyl)
168N3,4-methylene

dioksifenil
2-pyrimidinyl-
169N3,4-methylene

dioksifenil
2-thiazolyl4-(4-methoxy

phenyl)
170N3,4-methylene

dioksifenil
2-thiazolyl4-phenyl
172N3,4-methylene

dioksifenil
2-benzimidazolyl-
173N3,4-methylene

dioksifenil
2-pyrimidinyl-
174N5-(2,3-dihydro)benzofuran2-pyrimidinyl5-(4-methoxy

phenyl)
175N3,4-methylene

dioksifenil
2-pyrimidinyl5-(3,4-dimethoxy

phenyl)
176HR-3,4-methylene

dioksifenil
2-pyrimidinyl5-(3,4-dimethoxy

phenyl)
177N5-(2,3-dihydro)benzofuran2-pyrimidinyl5-(4-hydroxy

phenyl)
178N5-(2,3-dihydro)benzofuran2-pyrimidinyl5-(4-[2-N-pyrrolidinyl)ethoxy]phenyl)
179N3,4-methylene

dioksifenil
2-pyrimidinyl5-bromo
180N5-(2,3-dihydro)benzofuran2-pyrimidinyl5-(4-(2-(4-morpholinyl)ethoxy)

phenyl)
181N5-(2,3-dihydro)benzofuran2-PI is imaginal 5-(4-(2-(dimethyl

amino)

ethoxy)

phenyl)

Continuation of table 1
182N5-(2,3-dihydro)benzofuran2-pyrimidinyl5-(2-pyridyl)
183N3,4-methylene

dioksifenil
2-pyrimidinyl5-(2-pyridyl)
184N6(2,3-dihydrobenzo

[1,4]dioxin-6-yl
2-pyrimidinyl5-(4-methoxyphenyl)
185N5-(2,3-dihydro)benzofuran2-pyrimidinyl5-(3-pyridyl)
186N5-(2,3-dihydro)benzofuran2-pyrimidinyl5-bromo
187N5-(2,3-dihydro)benzofuran2-pyrimidinyl5-(2-pyridyl)
188N 6(2,3-dihydrobenzo

[1,4]dioxin-6-yl
2-pyrimidinyl5-(4-methoxy

phenyl)
189N3,4-methylene

dioksifenil
2-pyrimidinyl5-(2-pyridyl)
190N5-(2,3-dihydro)benzofuran2-pyrimidinyl5-(2,3-dimethyl-3H-imidazol-4-yl)
191N5-(2,3-dihydro)benzofuran2-pyridyl5-(2-pyridyl)
Table 2

Conn. No.RDR2YR3
11N3,4-methylene

deoxy

phenyl
CH22-furyl5-(2-chloro-5-trifter

were)

Continuation of table 2
12the 3,4-methylene

deoxy

phenyl
CH22-furyl5-(3-trifter

were)
13dimethyl

aminoethyl
3,4-methylene

deoxy

phenyl
With(About)2-benzo(b)

furyl
5-nitro
14N3,4-methylene

deoxy

phenyl
With(About)2-benzo(b)

furyl
5-nitro
15N3,4-methylene

deoxy

phenyl
With(About)2-benzo(b)

furyl
6-methoxy
16N3,4-methylene

dioksifenil
With(About)2-benzo(b)

furyl
-
17dimethyl

aminoethyl
3,4-methylene

dioksifenil
With(About)2-benzo(b)

Teenel
-
18N3,4-methylene

deoxy

phenyl
With(About)2-benzo(b)

Teenel
-
192-(3-nitro

phenyl)-5-furyl

carbonyl
3,4-(debtor

methylene

dioxy)phenyl
With(About)2-furyl5-(3-nitrophenyl)
202-(3-t is iftor

methyl

phenyl)-5-furyl

carbonyl
3,4-(debtor

methylene

dioxy)

phenyl
With(About)2-furyl5-(3-trifter

were)
21N3,4-(debtor

methylene

dioxy)

phenyl
With(About)2-furyl5-(3-nitrophenyl)
22N3,4-(debtor

methylene

dioxy)

phenyl
With(About)2-furyl5-(3-trifter

were)
232-methoxy

carbonyl

ethyl
3,4-methylene

deoxy

phenyl
With(About)2-furyl5-(3-trifter

were)

Continuation of table 2
242-methoxy

carbonyl

methyl
3,4-methylene

deoxy

phenyl
With(About)2-furyl5-(3-nitrophenyl)
252-methoxy

carbonyl

methyl
3,4-methylene

deoxy

phenyl
With(About)2-furyl5-(3-trifter

were)
262-pyridyl

methyl
3,4-methylene

deoxy

phenyl
With(About) 2-furyl5-(3-trifter

were)
274-chloro-n-butyl3,4-methylene

deoxy

phenyl
With(About)2-furyl5-(3-trifter

were)
284-morpholinyl

ethyl
3,4-methylene

deoxy

phenyl
With(About)2-furyl5-(3-trifter

were)
29carboxy

ethyl
3,4-methylene

deoxy

phenyl
With(About)2-furyl5-(3-trifter

were)
30carboxy

methyl
3,4-methylene

deoxy

phenyl
With(About)2-furyl5-(3-nitrophenyl)
31carboxy

methyl
3,4-methylene

deoxy

phenyl
With(About)2-furyl5-(3-trifter

were)
33diethyl

aminoethyl
3,4-methylene

deoxy

phenyl
With(About)2-furyl5-(3-trifter

were)
34dimethyl

aminobutyl
3,4-methylene

dioksifenil
With(About)2-furyl5-(3-trifter

were)
35Dimity aminoethyl 3,4-methylene

deoxy

phenyl
With(About)2-furyl5-(3-trifter

were)
36dimethyl

aminoethyl
3,4-methylene

deoxy

phenyl
With(About)2-furyl5-tert-butyl
37dimethyl

aminoethyl
3,4-methylene

deoxy

phenyl
With(About)2-furyl5-(4-nitrophenyl)

With(About)
Continuation of table 2
38dimethyl

aminoethyl
3,4-methylene

dioksifenil
With(About)2-furyl5-(3-nitrophenyl)
39dimethyl

aminoethyl
3,4-methylene

dioksifenil
With(About)2-furyl5-(4-chlorophenyl)
40dimethyl

aminoethyl
3,4-methylene

dioksifenil
With(About)2-furyl5-(2-nitro-4-chlorophenyl)
41dimethyl

aminoethyl
3,4-methylene

dioksifenil
With(About)2-furyl5-(2-nitrophenyl)
42dimethyl

aminoethyl
3,4-methylene

dioksifenil
2-furyl5-(2-nitro-4-were)
43dimethyl

aminoethyl
3,4-methylene

dioksifenil
With(About)2-furyl5-(2-chloro-5-trifluoromethyl

phenyl)
44dimethyl

amino

cut
3,4-methylene

dioksifenil
With(About)2-furyl5-(3-trifluoromethyl

phenyl)
744-pyridyl

methyl
3,4-methylene

dioksifenil
With(About)2-furyl5-(3-trifluoromethyl

phenyl)
75pyrrole

dinletir
3,4-methylene

dioksifenil
With(About)2-furyl5-(3-trifluoromethyl

phenyl)
45N3,4-methylene

dioksifenil
With(About)2-furyl5-(4-amino

phenyl)
46N3,4-methylene

dioksifenil
With(About)2-furyl5-(4-chloro

phenyl)
47N3,4-methylene

dioksifenil
With(About)2-furyl5-(2-nitro-4-chlorophenyl)
48N3,4-methylene

dioksifenil
With(About)2-Furi is 5-[4-(3-carboxy)-n-propylnitrosamine]
49N3,4-methylene

dioksifenil
With(About)2-furyl5-(4-acetyl

AMINOPHENYL)
50N3,4-methylene

dioksifenil
With(About)2-furyl5-(4-nitro

phenyl)
51N3,4-methylene

dioksifenil
With(About)2-furyl5-(2-nitro-4-chlorophenyl)
52N3,4-methylene

dioksifenil
With(About)2-furyl5-[4-(3-carboxy)-n-propylnitrosamine]
53N3,4-methylene

dioksifenil
With(About)2-furyl5-(2-nitro-4-were)
54N3,4-methylene

dioksifenil
With(About)2-furyl5-(3-nitrophenyl)
55N3,4-methylene

dioksifenil
With(About)2-furyl5-(3-acetyl-AMINOPHENYL)
56N3,4-methylene

dioksifenil
With(About)2-furyl5-(2-nitrophenyl)

Continuation of table 2
57N3,4-methylene

dioksifenil
With(About)2-furyl5-(2-chloro-5-trifluoromethyl phenyl)
58N3,4-methylene

dioksifenil
With(About)2-furyl5-(3-trifter were)
59N3,4-methylene

dioksifenil
With(About)2-furyl5-(3-amino phenyl)
60N3,4-methylene

dioksifenil
With(About)2-furyl5-[4-(4-hydroxy-n-butyl)amino phenyl]
61N3,4-methylene

dioksifenil
With(About)2-furyl5-[2-(dimethylamino)methylcarbamoylmethyl]
62N3,4-methylene

dioksifenil
With(About)2-furyl5-trifluoromethyl
63N3,4-methylene

dioksifenil
With(About)2-furyl5-bromo
64N3,4-methylene

dioksifenil
With(About)2-furyl5-nitro
65N3,4-methylene

dioksifenil
With(About)2-furyl5-the pet-butyl
66N3,4-methylene

dioksifenil
With(About)2-furyl5-(2-nitro-4-chlorophenyl)
78N3-pyridylWith(About)2-furyl5-(3-trifter were)
79N4-chlorophenylWith(About)2-furyl5-(3-trifter were)
80N4-cyanophenylWith(About)2-furyl5-(3-nitrophenyl)
81N4-cyanophenylWith(About)2-furyl5-(3-trifter were)
82N4-dimethyl AMINOPHENYLWith(About)2-furyl5-(3-trifter were)
83N4-dimethyl AMINOPHENYLWith(About)2-furyl5-(3-nitrophenyl)
84N4-nitrophenylWith(About)2-furyl5-(3-trifter were)
85N4-nitrophenylWith(About)2-furyl5-(3-nitrophenyl)
86N4-pyridylWith(About)2-furyl5-(3-nitrophenyl)
87N4-pyridylWith(About)2-furyl5-(3-trifter were)
88NphenylWith(About)2-furyl5-(3-trifter were)
89N3,4-methylene

dioksifenil
With(About)2-thiazolyl4-methyl-5-(4-trifluoromethyl phenyl)

Continuation of table 2
90N3,4-methylene

dioksifenil
With(About)2-thienyl4-phenyl-5-trifluoromethyl
91N3,4-methylene

dioksifenil
With(About)2-thienyl5-(4-chlorophenyl)
92N3,4-dimetilfenilWith(About)3-(1,2,5-triazolyl)1-phenyl-4-methyl
93N3,4-dichlorophenylWith(About)3-(1,2,5-triazolyl)1-phenyl-4-methyl
94N3,4-dimethoxy phenylWith(About)3-(1,2,5-triazolyl)1-phenyl-4-methyl
95N3,4-dimetilfenilWith(About)3-(1,2,5-triazolyl)1-Fe the Il-4-methyl
96N3,4-methylenedioxyphenylWith(About)3-(1,2,5-triazolyl)1-phenyl-4-methyl
97N3,4-methylenedioxyphenylWith(About)3-(1,2,5-triazolyl)5-(3-pyridyl)
98N3-trifluoromethyl-4-chlorophenylWith(About)3-(1,2,5-triazolyl)1-phenyl-4-methyl
99N4-cyanophenylWith(About)3-(1,2,5-triazolyl)1-phenyl-4-methyl
100N4-methoxy carbonyl phenylWith(About)3-(1,2,5-triazolyl)1-phenyl-4-methyl
101N4-methoxy phenylWith(About)3-(1,2,5-triazolyl)1-phenyl-4-methyl
102N4-nitrophenylWith(About)3-(1,2,5-triazolyl)1-phenyl-4-methyl
103dimethyl aminoethyl3,4-methylene dioksifenilWith(About)3-furyl2-methyl-5-(4-chlorophenyl)
104N3,4-methylene dioksifenilWith(About)3-furyl2-methyl-5-phenyl
105N3,4-methylene shall oxyphenyl With(About)3-furyl2-trifluoromethyl-5-(4-chlorophenyl)
106N3,4-methylene dioksifenilWith(About)3-pyrazolyl1-phenyl-5-methyl
107N4-[N-(3-dimethylamino)-n-propoxy]With(About)3-pyrazolyl1-phenyl-5-methyl
108N3,4-methylene dioksifenilWith(About)3-pyridyl6-chloro

124
Continuation of table 2
109N3,4-dichlorophenylWith(About)4-isoxazolyl3-phenyl-5-methyl
110N3,4-dimethoxy phenylWith(About)4-isoxazolyl3-phenyl-5-methyl
111N3,4-dimetilfenilWith(About)4-isoxazolyl3-phenyl-5-methyl
112N3,4-methylene dioksifenilWith(About)4-isoxazolyl3-phenyl-5-methyl
113N3,5-dimethyl phenylWith(About)4-isoxazolyl3-phenyl-5-methyl
114N-trifluoromethyl-4-chlorophenyl With(About)4-isoxazolyl3-phenyl-5-methyl
115N4-cyanophenylWith(About)4-isoxazolyl3-phenyl-5-methyl
116N4-methoxy carbonyl phenylWith(About)4-isoxazolyl3-phenyl-5-methyl
117N4-methoxy phenylWith(About)4-isoxazolyl3-phenyl-5-methyl
118N4-nitrophenylWith(About)4-isoxazolyl3-phenyl-5-methyl
119N3,4-dimetilfenilWith(About)4-pyrazolyl1-phenyl-5-trifluoromethyl
120N3,4-dichlorophenylWith(About)4-pyrazolyl1-phenyl-5-trifluoromethyl
121N3,4-dimethoxy phenylWith(About)4-pyrazolyl1-phenyl-5-trifluoromethyl
122N3,4-methylene dioksifenilWith(About)4-pyrazolyl1-phenyl-5-n-propyl
123N3,4-methylene dioksifenilWith(About)4-pyrazolyl1-phenyl-5-trifluoromethyl
N3,4-methylene dioksifenilWith(About)4-pyrazolyl1-(4-chlorophenyl)-5-trifluoromethyl
125N3,4-methylene dioksifenilWith(About)4-pyrazolyl1-(4-nitrophenyl)-5-trifluoromethyl
126N3,5-dimethyl

phenyl
With(About)4-pyrazolyl1-phenyl-5-trifluoromethyl

1-benzyl-3-tert-butyl
Continuation of table 2
127N3 trifter

methyl-4-chlorophenyl
With(About)4-pyrazolyl1-phenyl-5-trifluoromethyl
128N4-cyanophenylWith(About)4-pyrazolyl1-phenyl-5-trifluoromethyl
129N4-methoxy carbonyl phenylWith(About)4-pyrazolyl1-phenyl-5-trifluoromethyl
130N4-methoxy

phenyl
With(About)4-pyrazolyl1-phenyl-5-trifluoromethyl
131N4-nitrophenylWith(About)4-pyrazolyl1-phenyl-5-trifluoromethyl
132N3,4-methylene di is XI

phenyl
With(About)4-thiazolyl2-(4-pyrazinyl)
133N3,4-dichloro

phenyl
With(About)5-pyrazolyl1-benzyl-3-tert-butyl
134N3,4-dimethoxy phenylWith(About)5-pyrazolyl1-benzyl-3-tert-butyl
135N3,4-dimethyl phenylWith(About)5-pyrazolyl1-benzyl-3-tert-butyl
136N3,4-methylene dioksifenilWith(About)5-pyrazolyl1-benzyl-3-tert-butyl
137N3, 5dimethylphenylWith(About)5-pyrazolyl1-benzyl-3-tert-butyl
138N3-trifluoromethyl-4-chlorophenylWith(About)5-pyrazolyl1-benzyl-3-tert-butyl
139N4-cyanophenylWith(About)5-pyrazolyl1-benzyl-3-tert-butyl
140N4-methoxy

carbonyl phenyl
With(About)5-pyrazolyl1-benzyl-3-tert-butyl
141N4-methoxyphenylWith(About)5-pyrazolyl
142N4-nitrophenylWith(About)5-pyrazolyl1-benzyl-3-tert-butyl
143dimethyl aminoethyl3,4-methylene, dioxi

phenyl
With(About)naphthyl-
144N3,4-methylene, dioxi

phenyl
With(About)naphthyl-

Continuation of table 2
145N3,4-methylene, dioxi

phenyl
SO22-thienyl5-phenyl sulfonyl
146N3,4-methylene, dioxi

phenyl
SO22-thienyl3-phenyl sulfonyl
147dimethyl aminoethyl3,4-methylene, dioxi

phenyl
With(About)2-benzofuran-
149N3,4-methylene, dioxi

phenyl
With(About)2-furyl5-phenyl
152dimethyl aminoethyl3,4-methylene, dioxi

phenyl
With(About)2-furyl5-phenyl
185N3,4-methylene, dioxi

phenyl
CH2phenyl-
Table 3

Conn. No.R2R4YR3
673,4-methylene, dioxi

phenyl
carboxyWith(About)2-furyl5-(3-nitrophenyl)
683,4-methylene, dioxi

phenyl
2-(dimethyl amino)ethoxy carbonylWith(About)2-furyl5-(3-nitrophenyl)
693,4-methylene, dioxi

phenyl
2-(dimethyl amino)ethyl aminocarbonylWith(About)2-furyl5-(3-trifter were)

703,4-methylene, dioxi

phenyl
carboxyWith(About)2-furyl5-(3-trifter were)
713,4-methylene, dioxi

phenyl
methoxy

carbonyl
With(About)2-furyl5-(3-trifter were)
723,4-methylene, dioxi

phenyl
methoxy

carbonyl
With(About)2-furyl5-(3-trifter were)
733,4-methylene, dioxi

phenyl
methoxy

carbonyl
With(About)2-furyl5-(3-nitrophenyl)
Table 4

Conn. No.R2YR3
763,4-methylene dioksifenilWith(About)2-furyl5-(3-nitrophenyl)
773,4-methylene dioksifenilWith(About)2-furyl5-(4-chlorophenyl)

Table 5

Conn. No.R2ZR3
1573,4-methylene dioksifenilWith(About)2-pyrimidinyl5-(3,4-acid)
1583,4-methylene dioksifenilSNON2-pyrimidinyl5-(3,4-acid)
1593,4-methylene dioksifenilWith(About)2-pyrimidinyl5-(4-methoxyphenyl)
1603,4-methylene dioksifenilSNON2-pyrimidinyl5-(4-methoxyphenyl)
1623,4-methylene dioksifenilWith(About)2-pyrimidinyl5-(4-methoxyphenyl)
1633,4-methylene dioksifenilWith(About)2-pyrimidinyl5-(4-methoxyphenyl)
1643,4-methylene dioksifenilSNON2-pyrimidinyl5-(4-methoxyphenyl)
165 3,4-methylene dioksifenilWith(About)2-pyrimidinyl5-(4-methoxyphenyl)

Example 10

In vitro

Analysis of cyclic nucleotidyltransferase (PDE)

Selection PDEV

PDEV were isolated from the tissues of the rabbit and human rights in accordance with the Protocol described Boolell et al. (Boolell M, Allen .J., Ballard S.A., Geo-Attee, S., Muirhead G.J., Naylor AM, Osterloh I.H., 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 a cooled ice buffer solution containing 20 mm HEPES (pH of 7.2), 0.25 M sucrose, 1 mm EDTA and 1 mm phenylmethylsulfonyl (PMSF). Homogenizate was centrifuged at 100000g for 60 minutes at 4°C. the Supernatant was filtered through 0.2 μm filter and loaded in a Pharmacia Mono Q anion-exchange column (layer volume 1 ml), which was balanced 20 mm HEPES, 1 mm EDTA and 0.5 mm PMSF. After washing away unbound proteins, the enzymes were suirable using a linear gradient of 100 to 600 mm NaCl in the same buffer (30 to 50 ml in total, depending on fabric). Enzymes in skeletal muscle, the cavernous body, retina, heart, and platelets were suirable 35, 40, 45, 50 and 50 ml, respectively. The column was treated at a flow rate of 1 ml/min and collected fractions of 1 ml Fractions containing different PDE activity, collected separately and used in subsequent research the studies.

Measurement of inhibition PDEV

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

The tests were adapted to the 96-well plate. The enzyme was analyzed in 5 mm MgCl2, 15 mm Tris-HCl (pH 7,4), 0.5 mg/ml bovine serum albumin, 1 mm cGMP or camp, of 0.1 µci [3H]-cGMP and [3H]-camp and 2-10 ál of eluent for the column. Total volume for analysis was 100 µl. The reaction mixture was incubated at 30°C for 30 minutes. The reaction was stopped by boiling for 1 minute and then cooled on ice. Obtained [3H] 5'-mononucleotides were additionally transformed into uncharged [3H]-nucleosides by adding 25 μl of 1 mg/ml snake venom (Ophiophagus Hannah) and incubation at 30°C for 10 minutes. The reaction was stopped by adding 1 ml of Bio-Rad AG1-X2 suspension resin (1:3). All charged nucleotides contacted by the resin and only uncharged [3H]-nucleosides remained in the supernatant after centrifugation. Selected aliquot of 200 µl and cheated using liquid scintillation. PDE activity was expressed as part of the mole hydrolyzed cyclic nucleotides/min/ml of enzyme preparation.

The inhibition studies were carried out in buffer for analysis at 10%final concentration of DMSO. In the data the conditions of the hydrolysis product increased with time and increasing concentrations of the enzyme in a linear relationship.

Example 11

In Vitro determination of Kithe phosphodiesterase inhibitor

Analysis adapted for 96-well plate. Phosphodiesterase analyzed in the presence of 5 mm MgCl2, 15 mm Tris-HCl (pH 7,4), 0.5 mg/ml bovine serum albumin, 30 nm of [3H]-cGMP and the compounds in different concentrations. The amount of enzyme used for each reaction was such that less than 15% of the initial substrate was converted during the analysis. For all measurements the investigated compound was dissolved and diluted in 100% DMSO (2% DMSO in the analysis). Overall the analyzed volume 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, transferring in an ice bath. To each well was then added 25 μl of 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 cheated using liquid scintillation.

% Inhibition of the maximum conversion of substrate (enzyme in the absence of inhibitor) was calculated for each concentration of tested compound. To determine the IC50build a graph of % inhibition relative to the log concentrations of the studied compounds the Oia using GraphPad Prism nonlinear regression analysis (sigmoidal curve dose-response). In conditions when the substrate concentration ≪menzyme (Kmis the substrate concentration, which is half the maximum velocity of the enzyme), Kiequivalent to the value of the IC50.

The data of mass spectra and PDEV inhibitory activity of illustrative compounds of the present invention are described in tables 6 and 7. These inhibition represented either as IC50(μm), as the percent inhibition at a given concentration of the test compounds, or as a value of Ki.

Table 6
Conn. No.Molecular weightMass spectrum (M+1)% Inhib @ 10 μm (rabbit)
1288,3028967
2496,6349743
3425,5142684
4552,0855394
5577,68578
6547,6654895
7506,5650791
8569,6058089
947,53 47780
10480,9548179
11550,9655153
12516,5251776
13552,5855394
14481,4648288
15466,4946790
16436,4743788
17523,6552488
18452,5345387
19758,6475915
20804,648054
21543,4854432
22566,4856716

88
Continuation of table 6
23616,5961730
24579,5658040
25602,5660320
26621,61622
27621,0562256
28643,6664494
29602,56601* (M-1) No M+1 ion79
30565,5456493
31588,54587* (M-1) No M+1 ion75
33629,6863088
33629,6863063
34629,6863067
35601,6260298
36513,6351497
37578,6257995
38578,6257991
39568,0756993
40613,0761478
41578,6257993
42592,6559389
43636,0763722
44615,6561665
45 477,52478
46496,95497
47541,9454283

Continuation of table 6
48577,5957860
49519,5552060
50507,5050876
51541,94542
52577,5957876
53521,5352285
54507,5050881
55519,5552070
56507,50508
57564,9556576
58530,50531
59477,5247892
60549,6255089
61562,6256390
62454,4 45586
63465,3046578
64431,4043283
65442,5144366
66541,9454223
67550,50549* (M-1) No M+1 ion50
68622,6362335
69644,6564521
70574,5157346
71588,54587* (M-1) No M+1 ion21
72588,54587* (M-1) No M+1 ion15

Continuation of table 6
73565,54564* (M-1) No M+1 ion20
74621,6162284
75627,66628
76524,5552527
77514,0051558
78487,4848835
79520,9452137
80488,5048927
81511,50510* (M-1) No M+1 ion18
82529,5653013
83506,5650727
84531,4953220
85508,4950926
86464,4846569
87487,4848834
88486,4948749
89561,58562
90546,5754769
91513,0151482
92461,5746239
93502,4050344
94493,5649419
95461,5746213
96477,5247857
97480,55 48171

Continuation of table 6
98535,9553638
99458,5245940
100491,5549224
101463,5446448
102478,5147940
103510,9751155
104476,5347772
105564,9556540
106476,5347770
107533,6753415
108431,8843248
109502,4050331
110493,5649432
111461,5646235
112477,5247833
113461,5646229
114535,95536 27
115458,5245930
116491,5449232
117463,5346432
118478,5147928
119514,5551528
120555,3955618
121546,5554710
122504,5950565

Continuation of table 6
123530,5053156
124564,9556553
125575,5057654
126514,5551512
127588,9458913
128511,5151211
129544,5354546
130516,5251745
131531,4953212
132480,5548176
133557,525561
134548,685475
135516,695178
136532,6453318
137516,69517-3
138591,0759213
139513,64514-9
140546,675478
141518,6651911
142533,63534-5
143517,6351860
144446,5044776
145578,69579* (M-1) No M+1 ion43
146578,6957935

Table 7
Conn. No.Molecular weightMass spectrum (M+1)IC50(µm)% Inhib @ 10 μm (rabbit)
147507,595085,252
148573,695744,466
149462,504630,7580
150526,555274
151409,444100,1395
152533,635341,280
153447,504480,1295
154666,766670,1197
155480,564819,257
156518,625190,0075
157520,545210,0087a
158522,5652349
159474,524750,024
160476,534778,95
161460,544610,789
162490,524910,024a
164492,5349382
166628,7362958
167522,605231,49
168370,413712,15a
169481,574820,042
170451,554520,049

Continuation of table 7
172408,4640944a
174474,564750,150a
175506,565070,214
176506,565070,056
178557,7055837
179449,314501,58
180573,6957440
182445,524460,058
183447,504480,122a
1840,640a
185446200,40a
186448240,10and
187446of 49.79and
188491642,69and
189448121,60a
190463Ki=14,21 nm
191443Ki=0,69 nm
andCompounds were analyzed using human tissue

Example 12

In vivo

In accordance with the methods described by Carter et al., (Carter et al., Ballard S.A. and Naylar A.M.) in the Journal of Urology 1998, 160, 242-246, was researched and developed by who and the effectiveness in vivo of the compounds of the present invention.

Example 13

As a specific variant of implementation of the oral composition, 100 mg of the compound of example 7 was introduced in the composition of the medicinal product, together with enough powdered lactose, getting the total number 580-590 mg for filling hard gelatin capsules 0 size.

Although the above description, together with examples, are given for purposes of illustration, shows the principles of the present invention, it should be understood that the practical implementation of the invention encompasses all of the usual options, adapted and/or modified, manifested in the scope of the following claims and its equivalents.

1. The compound of formula (I):

where

R1means hydrogen;

n 0;

X is chosen from the group consisting of O, S and NRD;

R2choose from the group of phenyl (optionally substituted by 1-3 RB), 6-membered nitrogen-containing heteroaryl and 5-6-membered geterotsiklicheskie containing 1 to 2 oxygen atoms and condensed with benzene ring (optionally substituted by 1-3 RB);

R4selected from the group consisting of hydrogen, carboxy, C1-C6alkylsulphonyl,di(C1-C8alkyl)aminocarbonyl, di(C1-C8alkyl)amino1-C8 alkylaminocarbonyl;

and is an integer from 0 to 1;

Y is chosen from the group consisting of CH2With(About);

Z is chosen from the group consisting of CH2SNON and C(O); provided that when Z represents SNON or C(O), X represents NH;

selected from the group consisting of naphthyl, a 5-6-membered heteroaryl containing 1-3 heteroatoms selected from nitrogen, oxygen and/or sulfur, possibly condensed with a benzene ring;

m is an integer from 0 to 2;

R3independently selected from the group consisting of halogen, nitro, C1-C8of alkyl, C1-C8alkoxy, trifloromethyl, phenyl (optionally substituted by 1-3 RB), phenylsulfonyl, naphthyl,1-C8aralkyl, 5-6-membered heteroaryl containing 1-3 nitrogen atom in the cycle (optionally substituted by 1-3 RB);

where each RInchosen independently from the group consisting of halogen, hydroxy, nitro, cyano, C1-C8of alkyl, C1-C8alkoxy, C1-C8alkoxycarbonyl, carboxy1-C8of alkyl, C1-C8alkylsulfonyl, trifloromethyl, amino, acetylamino, di(C1-C8alkyl)amino, di(C1-C8alkyl)amino1-C8alkoxy, di(C1-C8alkyl)aminoacetic1- 8of alkyl, di(C1-C8alkyl)aminoethylamino, carboxy1-C8alkylcarboxylic, hydroxys1-C8alkylamino;

where RDselected from the group consisting of hydrogen, di(C1-C4alkyl)amino1-C6of alkyl,5-6-membered heteroaryl, 5-6-membered heteroaryl1-C4of alkyl, 5-6-membered heterocyclics1-C4of alkyl, (and, in each of the last three values heteroaryl or heteroseksualci contains 1 to 2 heteroatoms selected from nitrogen and/or oxygen, and may be condensed with benzene ring), carboxin1-C4of alkyl, C1-C8alkoxycarbonyl1-C4of alkyl, 5-6-membered oxygen-containing heteroarylboronic (where heteroaryl optionally may be substituted by phenyl or substituted phenyl, where the phenyl substituents are one to three RB);

where each RInchosen independently from the group consisting of halogen, hydroxy, nitro, cyano, C1-C8of alkyl, C1-C8alkoxy, C1-C8alkoxycarbonyl, carboxy1-C8of alkyl, C1-C8alkylsulfonyl, trifloromethyl, amino, acetylamino, di(C1-C8alkyl)amino, di(C1-C8alkyl)amino1-C8alkoxy, di(C1-C8alkyl)aminoacetic1 -C8of alkyl, di(C1-C8alkyl)aminoethylamino, carboxy1-C8alkylcarboxylic, hydroxys1-C8alkylamino;

provided that ifis 2-furyl or 2-thienyl, m is an integer from 1 to 2;

and its pharmaceutically acceptable salts.

2. The compound according to claim 1, where n is 0;

X is chosen from S, or NRDwhere RDselected from the group consisting of hydrogen, di(C1-C4alkyl)amino1-C6of alkyl,5-6-membered heteroaryl, 5-6-membered heteroaryl1-C4of alkyl, 5-6-membered heterocyclics1-C4of alkyl, (and, in each of the last three values heteroaryl or heteroseksualci contains 1 to 2 heteroatoms selected from nitrogen and/or oxygen, and may be condensed with benzene ring), carboxin1-C4of alkyl, C1-C8alkoxycarbonyl1-C4of alkyl, 5-6-membered oxygen-containing heteroarylboronic where heteroaryl optionally may be substituted by phenyl or substituted phenyl, where the phenyl substituents are one to three RB;

where each RBchosen independently from the group consisting of halogen, nitro, C1-C4of alkyl, C1-C4alkoxy, trifloromethyl, amino and di(C1-C4alkyl)am the but;

R2selected from the group consisting of 3,4-methylenedioxyphenyl, 3,4-(debtor)methylenedioxyphenyl, 2,3-dihydrobenzofuran, 2,3-dihydrobenzo[1,4]dioxin-6-yl, pyridyl, phenyl and substituted phenyl, where the phenyl substituents are one to two substituent independently selected from halogen, C1-C4of alkyl, C1-C4alkoxy, trifloromethyl, cyano, nitro, C1-C4alkoxycarbonyl, di(C1-C4alkyl)amino or di(C1-C4alkyl)amino1-C4alkoxy;

R4selected from the group consisting of hydrogen, carboxy, C1-C4alkoxycarbonyl, di(C1-C4alkyl)amino1-C4alkoxycarbonyl and di(C1-C4alkyl)amino1-C4alkylaminocarbonyl;

Y is chosen from the group consisting of CH2With(About);

selected from the group consisting of naphthyl and 5-6-membered heteroaryl containing 1-3 heteroatoms selected from nitrogen, oxygen and/or sulfur, possibly condensed with a benzene ring;

R3independently selected from the group consisting of halogen, nitro, C1-C4of alkyl, C1-C4alkoxy, trifloromethyl,1-C4aralkyl, pyrazinyl, pyridyl, substituted with halogen of pyridyl, dimethylselenide imidazo the sludge, phenyl, phenylsulfonyl and substituted phenyl, where the substituents in the phenyl are one or more substituents independently selected from halogen, hydroxy, C1-C4of alkyl, C1-C4alkoxy, trifloromethyl, triptoreline, nitro, amino, acetylamino,

With1-C4alkylsulfonyl, carboxy1-C4alkylcarboxylic, hydroxys1-C4alkylamino, di(C1-C4alkyl)amino1-C4alkoxy, di(C1-C4alkyl)aminoethylamino or heterocyclics1-C4alkoxy;

provided that whenis 2-furyl or 2-thienyl, then m is an integer 1 or 2;

and its pharmaceutically acceptable salts.

3. The compound according to claim 2, where

X is chosen from S, or NRDwhere RDselected from the group consisting of hydrogen, di(methyl)aminoethyl, di(methyl)amino-n-propyl, di(ethyl)aminoethyl, di(ethyl)amino-n-butyl, N-pyrrolidinyl, N-morpholinomethyl, 2-pyridylmethyl, 4-pyridylmethyl, 5-(4-were)-2-pyrimidinyl, carboxymethyl, carboxyethyl, 2-(5-(3-triptoreline)furyl)carbonyl, 2-(5-(3-nitrophenyl)furyl)carbonyl,methoxycarbonylmethyl, methoxycarbonylethyl and 2-benzoxazolyl;

R2selected from the group consisting of phenyl, 3,4-methylenedioxyphenyl, 3,4-(debtor)m is telangiectasia, 2,3-dihydrobenzofuran, 2,3-dihydrobenzo[1,4]dioxin-6-yl, 4-pyridyl, 3-pyridyl, 4-cyanophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-trifloromethyl, 4-methoxyphenyl, 3,4-dimetilfenil, 3,5-dimetilfenil, 3,4-acid, 3-trifluoromethyl-4-chlorphenyl, 3,4-dichlorophenyl, 4-chlorphenyl, 4-ethoxycarbonylphenyl, 3,4-acid, 4-(dimethylamino)phenyl and 4-(N-(3-dimethylamino)-n-propoxy)phenyl;

R4selected from the group consisting of hydrogen, carboxy, dimethylaminoethoxide, dimethylaminoethylmethacrylate and methoxycarbonyl;

selected from the group consisting of naphthyl, 2-pyrimidinyl, 2-furil, 3-furil, 2-benzofuran, 2-tanila, 2-benzothiazyl, 2-benzothiazolyl, 2-benzoxazolyl, 2-benzimidazolyl, 4-thiazolyl, 2-thiazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-(1,2,5-triazolyl), 4-isoxazolyl, 2-pyridyl and 3-pyridyl;

R3independently selected from the group consisting of chlorine, bromine, methyl, n-propyl, tert-butyl, methoxy, trifloromethyl, nitro, phenyl, benzyl, phenylsulfanyl, 4-hydroxyphenyl, 4-chlorphenyl, 4-methylphenyl, 3,4-acid, 3-triptoreline, 4-trifloromethyl, 5-triptoreline, 4-methoxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-AMINOPHENYL, 4-AMINOPHENYL, 2-nitro-4-chlorphenyl, 2-nitro-4-methylphenyl 2-nitro-4-methylsulphonyl Anila, 3-acetylaminophenol, 4-acetylaminophenol, 4-(3-carboxy-n-propyl)carbonylmethyl, 2-chloro-5-triptoreline, 4-(4-hydroxy-n-butyl)AMINOPHENYL, 2-(dimethylamino)acetylaminophenol,4-[2-N-pyrrolidinyl)ethoxy]phenyl, 4-[2-(4-morpholinyl)ethoxy]phenyl, 4-(2-dimethylamino)ethoxy)phenyl, 4-pyrazinyl, 2,3-dimethyl-3H-imidazolyl, 2-pyridyl and 3-pyridyl;

provided that whenis 2-furyl or 2-thienyl, then m is an integer 1 or 2;

and its pharmaceutically acceptable salts.

4. The compound according to claim 3, where

X represents NRDwhere RDselected from the group consisting of hydrogen, di(methyl)aminoethyl, 4-pyridylmethyl, 2-pyridylmethyl, N-morpholinomethyl, carboxyethyl, carboxymethyl, di(ethyl)aminoethyl, N-pyrrolidinyl and 5-(4-were)-2-pyrimidinyl;

R2selected from the group consisting of 3,4-methylenedioxyphenyl, 2,3-dihydroxybenzophenone and 2,3-dihydrobenzo[1,4]dioxin-6-yl;

R4represents hydrogen;

Y is chosen from the group consisting of C(O) and CH2;

selected from the group consisting of naphthyl, 2-pyrimidinyl, 2-furil, 2-benzofuran, 2-tanila, 2-benzothiazyl, 2-benzothiazolyl, 2-benzoxazolyl, 2-thiazolyl, 4-thiazolyl and 2-pyridyl;

m is an integer from 0 to 1;

R3 selected from the group consisting of bromide, tert-butyl, methoxy, trifloromethyl, nitro, phenyl, 4-chlorphenyl, 3,4-acid, 3-triptoreline, 4-methylphenyl, 4-methoxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-AMINOPHENYL, 2-nitro-4-chlorphenyl, 2-nitro-4-methylphenyl, 2-nitro-4-methylsulfinylphenyl,4-(3-carboxy-n-propyl)carbonylmethyl, 2-chloro-5-triptoreline, 4-(4-hydroxy-n-butyl)AMINOPHENYL, 2,2-(dimethylamino)acetylaminophenol, 4-pyrazinyl, 2-pyridyl and 2,3-dimethyl-3H-imidazol-4-yl;

provided that whenis 2-furyl or 2-thienyl, then m is 1;

and its pharmaceutically acceptable salts.

5. The compound according to claim 4, where

X represents NRDwhere RDselected from the group consisting of hydrogen, di(methyl)aminoethyl, N-morpholinomethyl, carboxymethyl and N-pyrrolidinyl;

R2selected from the group consisting of 3,4-methylendioxyphenyl and 2,3-dihydroxybenzophenone;

Z is chosen from the group consisting of CH2and C(O); provided that when Z is C(O), then X is NH;

Y represents C(O);

selected from the group consisting of 2-pyrimidinyl, 2-furil, 2-benzofuran, 2-benzoxazolyl, 2-thiazolyl and 2-pyridyl;

R3choose from the group consisting and is tert-butyl, methoxy, nitro, phenyl, 4-chlorphenyl, 4-methylphenyl, 4-methoxyphenyl, 3,4-acid, 3-triptoreline, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-AMINOPHENYL, 2-nitro-4-methylsulfinylphenyl, 2-(dimethylamino)acetylaminophenol, 2-pyridyl and 2,3-dimethyl-3H-imidazol-4-yl;

provided that whenrepresents 2-furyl, then m is 1;

and its pharmaceutically acceptable salts.

6. The compound according to claim 3, selected from the group consisting of

1-(3,4-methylenedioxyphenyl)-2-[(5-phenyl-2-furyl)carbonyl]-2,3,4,9-tetrahydro-1H-β-carbolin;

1-(3,4-methylenedioxyphenyl)-2-[5-(2-pyridyl)-2-pyrimidinyl]-9-di(methyl)aminoethyl-2,3,4,9-tetrahydro-1H-β-carbolin;

1-(3,4-methylenedioxyphenyl)-2-[5-(3,4-acid)-2-pyrimidinyl]-1,2,3,9-tetrahydro-4-oxo-4H-β-carbolin;

1-(3,4-methylenedioxyphenyl)-2-[5-(4-were)-2-pyrimidinyl]-1,2,3,9-tetrahydro-4-oxo-4H-β-carbolin;

1-(3,4-methylenedioxyphenyl)-2-[5-(4-methoxyphenyl)-2-pyrimidinyl]-1,2,3,4-tetrahydro-4-oxo-4H-β-carbolin;

1-(3,4-methylenedioxyphenyl)-2-[4-(4-methoxyphenyl)-2-thiazolyl]-2,3,4,9-tetrahydro-1H-β-carbolin;

1-(3,4-methylenedioxyphenyl)-2-(4-phenyl-2-thiazolyl)-2,3,4,9-tetrahydro-1H-β-carbolin;

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

1-(2,3-dihydrobenzo the EN-5-yl)-2-[5-(2,3-dimethyl-3H-imidazol-4-yl)-2,3,4,9-tetrahydro-1H-β -carbolin; and their pharmaceutically acceptable salts.

7. Pharmaceutical composition having the properties of a phosphodiesterase inhibitor, comprising a pharmaceutically acceptable carrier and a compound according to claim 1.

8. Pharmaceutical composition having the properties of a phosphodiesterase inhibitor, which is obtained by mixing the compound according to claim 1 and a pharmaceutically acceptable carrier.

9. A method of obtaining a pharmaceutical composition having the properties of a phosphodiesterase inhibitor, comprising mixing the compound according to claim 1 and a pharmaceutically acceptable carrier.

10. Method of inhibiting the action of phosphodiesterase V(PDEV) at a sexual disorder in in need thereof of a subject, comprising administration to the subject a therapeutically effective amount of compounds of General formula I according to claim 1.

11. The method of inhibition of claim 10, characterized in that the sexual disorder is a erectile dysfunction in men.

12. The method according to claim 10, characterized in that the sexual disorder selected from the group consisting of male sexual disorder erectile dysfunction in men, impotence, female sexual disorders, dysfunction sexual arousal in women and sexual dysfunction in women is related to blood flow and the production of nitric oxide in the tissues of the vagina and the clitoris.

13. The method of increasing the concentration of the cGMP in the tissue of the penis in need of this subject is male, includes introduction to the subject an effective amount of compounds of General formula I according to claim 1.

14. Method of inhibiting the action of phosphodiesterase V(PDEV) for erectile dysfunction in men (ED), impotence, dysfunction sexual arousal in women, sexual dysfunction in women is related to blood flow and the production of nitric oxide in the tissues of the vagina and the clitoris, premature birth, dysmenorrhea, cardiovascular disease, atherosclerosis, arterial occlusive diseases, thrombosis, restenosis of coronary artery, angina, myocardial infarction, heart failure, ischemic heart disease, hypertension, pulmonary hypertension, asthma, intermittent claudication and diabetic complications in need thereof of a subject, comprising administration to the subject a therapeutically effective amounts of compounds of General formula I according to claim 1.



 

Same patents:

FIELD: biochemistry, medicine, in particular new bioactive compounds having peptide hormone vasopressin agonistic activity.

SUBSTANCE: disclosed are compounds of general formula 1 or 2 or tautomers, or pharmaceutically acceptable salts thereof, wherein W represents N or C-R4; R1-R4 are independently H, F, Cl, Br, alkyl, O-alkyl, NH2, NH-alkyl, N(alkyl)2, NO2 or R2 and R3 together may form -CH=CH-CH=CH-; G1 represents bicyclic or tricyclic condensed azepine derivatives selected from general formulae 3-8 wherein A1, A4, A7, and A10 are independently CH3, O, and NR5; A2, A3, A9, A11, A12, A14, and A15 are independently CH and N; or A5 represents covalent bond and A6 represents S; or A5 represents N=CN and A6 represents covalent bond; A8 and A12 are independently NH, N-CH3 and S; A16 and A17 both represent CH2 or one of A16 and A17 represents CH2 and the other represents CH(OH), CF2, O, SOa, and NR5; R5 represents H, alkyl, CO-alkyl, and (CH2)bR6; R6 represents phenyl, pyridyl, OH, CO2H; a = 0-2; b = 1-4; Y represents CH or N; Z represents CH=CH or S; and G2 represents group selected from groups of formulae 9-11 wherein Ar represents phenyl, pyridyl, naphthyl, and mono- or polysubstituted phenyl, pyridyl, wherein substituents are selected from F, Cl, Br, alkyl, NO2; D represents covalent bond or NH; E1 and E2 both are H, OMe, F, or one of E1 and E2 represents OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N2, NH2, NHBn or NHAc and the other represents H; or E1 and E2 together form =O, -O(CH2)gO- or -S(CN2)gS-; F1 and F2 both represent H or together form =O or =R; L represents OH, O-alkyl, NH2, NH-alkyl, and NR9R10; R7 represents COR8; R8 represents OH, O-alkyl, NH2, NH-alkyl, N(alkyl)2, pyrolidinyl, and piperidinyl; R9 and R10 both are alkyl or together form -(CH2)h-; V represents O, N-CN or S; c = 0 or 1; d = 0 or 1, e = 0 or 1; f = 0-4; g = 2 or 3; h = 3-5, with the proviso, that both d and e are not 0. Also disclosed are pharmaceutical composition having agonistic activity in relate to V2 receptor, method for treatment one or more diseases (e.g., enuresis, nycturia, diabetes insipidus, hemorrhage disorders, urinary incontinence.

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

EFFECT: improved treatment method, valuable medicinal properties of compounds and agents.

40 cl, 51 tbl, 741 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds. Invention describes compounds or their salts of the general formula (I): A-B-N(O)s (I) wherein s = 2; A means R-T1- wherein R represents radical of a medicinal substance under condition that a medicinal substance by the formula R-T1-Z or R-T1-OZ wherein Z represents hydrogen atom (H) or (C1-C5)-alkyl is taken among paracetamol, salbutamol, ambroxol, alendronic acid,, cetirizine, ampicillin, aciclovir, doxorubicin, simvastatin, diphylline, tacrine, clopidogrel, dimethylomeprazol, diclofenac, ferulic acid, enalapril, propranolol, benfurodil hemisuccinate, tolrestate or sulindac; T1 means (CO), oxygen atom (O) or NH; B means TB-X2-O- wherein TB means bivalent radical R1B-X-R2B wherein R1B and R2B are similar or different and represent linear or branched (C1-C6)-alkylenes and X represents a bond, oxygen (O), sulfur (S) atom or NR1C wherein NR1C represents hydrogen atom (H) or linear or branched (C1-C6)-alkyl; corresponding precursor B is represented by the formula -TB-X2-OH wherein TB means (CO) and free valence in TB represents -OZ wherein Z is determined above, or TB means oxygen atom (O), and free valence in TB represents hydrogen atom (H) under condition that in the formula (I) when X2 in precursor B represents linear or branched (C2-C20)-alkylene then a medicinal substance by the formula R-T1-Z or R-T1-OZ used in the formula (I) doesn't belong to the following substances: enalapril (ACE inhibitors) and diclofenac (NSAID). Also, invention describes pharmaceutical compositions for using in cases of oxidative stress and 4-nitroxybutanoic acid 4'-acetylaminophenyl ester. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of medicinal substances and compositions.

7 cl, 8 tbl, 32 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to 2-aminomethylthieno[2,3-d]pyrimidines of the general formula (I): wherein R1 and R2 in common with C-atoms with which they are bound form 5-7-membered monounsubstituted cycloalkenyl ring; R3 and R4 are similar or different and represent independently of one another (C1-C8)-alkoxy-group or halogen atom; R5 and R6 can be similar or different and represent independently of one another hydrogen atom, linear or branched (C1-C8)-alkyl group that can be substituted with one or more hydroxyl, (C1-C8)-alkoxy-group, amine, mono-(C1-C8-alkyl)-amine or di-(C1-C8-alkyl)-amine groups, or in common with nitrogen atom to which they are bound form a heterocyclic ring that comprises optionally one or more additional nitrogen atoms and substituted with one or more hydroxyl, (C1-C8)-alkoxy- or (C1-C8)-alkylol groups. Compounds elicit the inhibitory effect with respect to activity of phosphodiesterase V and can be used in treatment of cardiovascular system states and in disturbance in the potency injury. Also, invention describes a medicinal preparation based on compounds said, a method for its preparing and a method for preparing compounds.

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

6 cl, 1 tbl, 16 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (1)

wherein A represents bicyclic or tricyclic azepine derivative; V1 and V2 both represent hydrogen atom (H) or one among V1 and V2 represents hydrogen atom (H), OMe, OBn, OPh, O-acyl, Br, Cl, F, N3, NH2, NHBn and another represents hydrogen atom (H); or V1 and V2 represent in common =O or -O(CH2)pO-; W1 represents oxygen (O) or sulfur (S) atom; X1 and X2 both represent hydrogen atom (H) or in common represent =O or =S; Y represents OR5 or NR6R7; R1 means hydrogen atom (H), lower alkyl, F, Cl and Br; R2 means lower alkoxy-group or values given for R1; R3 and R5 are taken independently among hydrogen atom (H) and lower alkyl; R4 means hydrogen atom (H); R6 and R7 are taken independently among hydrogen atom (H) and lower alkyl, or they in common mean -(CH2)n-; n = 3, 4, 5 or 6; p = 2 or 3. These compounds are agonists of vasopressin V2 receptors and useful as antidiuretic and procoagulants, and also to pharmaceutical compositions comprising these vasopressin agonists. These compositions are useful especially in treatment of diabetes insipidus of the central origin and night enuresis.

EFFECT: valuable medicinal properties of compounds, improved method for treatment.

26 cl, 1 tbl, 119 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of piperazine of the general formula (I): wherein Y represents lower alkylene; R1 represents phenyl substituted with one or two similar or different substitutes taken among a group including lower alkoxy-group, mono- (or di-, or tri-)-halogen-lower)-alkyl, nitro-, amino-, lower alkylamino-, di-(lower)-alkylamino-, lower alkylthio-group,alkylsulfonyl, lower alkylaminosulfonyl, di-(lower)-alkylaminosulfonyl, and pyrrolyl; R2 means phenyl substituted with hydroxy-group at position 3 and with lower alkyl and halogen atom additionally; R3 means hydrogen atom; R4 represents (2,6-dimethylmorpholino)-(lower)-alkyl, (2-methoxymethylmorpholino)-(lower)-alkyl, (3-methoxymethylmorpholino)-(lower)-alkyl. Also, invention relates to their pharmaceutically acceptable salts, to method for their preparing, pharmaceutical composition and a method for vomiting inhibition. Proposed compounds are antagonists of tachykinin and can be used for vomiting inhibition.

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

9 cl, 47 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new oxathiepino[6,5-b]dihydropyridines of the formula (I):

wherein: (a) R1, R2, R3, R4 and R5 are taken independently among group consisting of hydrogen atom (H), halogen atom, nitro-group (NO2); (b) R6 is taken among group consisting of unbranched or branched (C1-C5)-alkyl wherein indicated alkyl can be substituted with phenylacetyloxy-, hydroxy- carboalkoxy-group or group NR'R'' wherein R' and R'' are taken independently among group consisting of hydrogen atom (H), unbranched or branched (C1-C8)-alkyl, benzyl; (c) R7 is taken among group consisting of hydrogen atom (H), alkyl; (d) R9 represents oxygen atom; (e) n is a whole number from 1 to 2, or its pharmaceutically acceptable salt. Compounds are useful as antagonists of calcium channels and elicit cardiovascular, anti-asthmatic and anti-bronchoconstricting activity. Also, invention describes the pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds and composition.

28 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

EFFECT: improved treatment method, valuable medicinal properties of compounds and agents.

40 cl, 51 tbl, 741 ex

FIELD: organic chemistry, peptides, medicine, pharmacy.

SUBSTANCE: invention relates to peptide derivatives named as memnopeptides that are used as an active component for manufacturing a medicinal preparation used in treatment of bacterial infection. Invention proposes compound of the formula (I): wherein radicals R1, R2, R3, R4, R5, R6, R7, R8 and (A)n have corresponding values, or its salt. Compounds of the formula (I) are prepared by culturing microorganism Memnoniella echinata FH 2272, DSM 13195 under suitable conditions in the nutrient medium containing at least one source of carbon atoms and at least one source of nitrogen atoms and the process is carrying out until the accumulation of at least one compound of the formula (I) in the nutrient medium followed by isolation of indicated compound. The attained technical result involves the development of a pharmaceutical composition eliciting an antibacterial activity. The development of the preparation provides expanding assortment of agents used in treatment of diseases said above.

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

10 cl, 2 tbl, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

The invention relates to derivatives of 6-sulfamoylbenzoic-4-carboxylic acid of formula (1), where R1, R2, R3and R4such as defined in the claims

3-piperidine, methods for their preparation and pharmaceutical composition based on them" target="_blank">

The invention relates to tricyclic3-piperidinol General formula (1), where X is O or S, R1means hydrogen, halogen, C1-6alkyl or C1-4alkyloxy, Alk means C1-6alcander, a D such as defined in the claims

The invention relates to a new 1.8-fused derivative of 2-Hinayana formula (I), where A, X, R1, R2, R3, R4, R5, R6such as defined in the claims

The invention relates to compounds which inhibit the protease encoded by human immunodeficiency virus, or their pharmaceutically acceptable salts, and such compounds are used for the prevention of infection by HIV, treating infection by HIV and the treatment of acquired as a result immunodeficiency syndrome (AIDS)

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention describes phenyl-substituted heterocyclic 1,3-ketoenols of the formula (I): wherein R1 and R3 mean independently of one another ethyl or (C1-C2)-alkoxy-group; Q means the group of the formula (Q1): or (Q2): wherein R4 and R5 in common with atoms to which they are joined form 5-7-membered cycle that can comprise additionally anellated alkylene chain consisting of 2-6 carbon atoms that, in turn, can comprise two heteroatoms taken among oxygen atom, and indicated cycle can be substituted with halogen atom, hydroxy-group, (C1-C6)-alkoxy-group, (C1-C6)-alkoxy-(C1-C6)-alkoxy-group, (C1-C4)-alkylcarbonyloxy-group, hydroxy-(C1-C4)-alkoxy-group, hydroxycarbonyl-(C1-C2)-alkoxy-group, methoxycarbonyl-(C1-C2)-alkoxy-group, methoxyimino-, methoxyethoxyethoxy-group; R6 and R7 means (C1-C10)-alkyl; R8 means hydrogen atom; X means oxygen atom; R20 means (C1-C10)-alkyl, and also agronomically acceptable salts and isomers of these compounds. Also, invention describes a method for preparing compounds of the formula (I), herbicide agent and a method for control of weed growth based on compounds of the formula (I). Invention provides preparing compounds possessing the herbicide activity.

EFFECT: improved preparing method, valuable properties of compounds and agents.

5 cl, 28 tbl, 5 ex

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