Aromatic nitrogen-containing 6-membered cyclic compounds and pharmaceutical composition

 

(57) Abstract:

The invention relates to new nitrogen-containing aromatic 6-membered cyclic compounds of the formula (I) or their pharmaceutically acceptable salts, demonstrating excellent selective PDE V inhibitory activity. Therefore, these compounds can be used to treat, for example, disorders associated with erectile dysfunction, diabetic gastroparesis, pulmonary hypertension. In the compounds of formula (I):

ring a represents a substituted 5 - or 6-membered nitrogen-containing heterogeneities group having 1-2 nitrogen atom and also may contain an oxygen atom or sulfur in the heterocyclic residue, or an 8-10-membered nitrogen-containing heterobicyclic group having 1-3 nitrogen atom and also may contain an oxygen atom or sulfur in the heterocyclic residue; R1represents (1) substituted C1-6alkyl group which may be optionally substituted, (2) a group of the formula-NH-Q-R3(in which R3represents a substituted 5 - or 6-membered nitrogen-containing heterogeneities group having 1-2 nitrogen atom, and also may contain an oxygen atom or serta and also may contain an oxygen atom or sulfur in the heterocyclic residue; and Q represents C1-6alkylenes group or a simple bond) or (3) a group of formula: -NH-R4(in which R4represents a substituted C3-8cycloalkyl group which may be optionally substituted by a group selected from the group consisting of hydroxy-group, C1-6alkoxygroup and pyrimidinylidene); R2represents a substituted aryl group, which may be optionally substituted by a group selected from the group consisting of C1-6alkoxygroup, halogen atom, ceanography, nitro, hydroxy-group and C1-6alkyl group; one of Y and Z represents a group of formula =CH-and the other represents a group of formula =N-. 2 C. and 23 C.p. f-crystals, 10 PL.

The technical field to which the invention relates

The present invention relates to new nitrogen-containing aromatic 6-membered cyclic compound, showing cGMP-specific inhibitory activity against phosphodiesterase (PDE) (PDE V inhibitory activity) and which may be useful as a drug, and how to obtain it.

Prior art

It is known that cGMP, which astrotrain in many types of cells and tissues of a living organism and, when reduced activity of the specified PDE, the level of cGMP in the cells increases, as a consequence, there are various kinds farmakologicheskoi activity, such as relaxation of vascular smooth muscle, relaxation of bronchial smooth muscle and inhibition of aggregation of platelets.

In addition, it was reported that such cGMP-specific PDE inhibitors (i.e., PDE V inhibitors) are suitable for the treatment of diseases caused by functional disorders cGMP-communications, including hypertension, angina, infarction myocardi, chronic or acute heart failure, pulmonary hypertension, and so on (see WO 96/05176 and so on), as well as prostatic hyperplasia (AU 9955977). It was also reported that PDE V inhibitors can be used for the treatment of female sexual disorders (Vemulapalli and other Life Sciences, 67, 23-29 (2000)), diabetic gastroparesis (Watkins and others J. Clin. Invest. 106: 373-384 (2000)), achalasia (Bortolotti and other Gastroenterology; 118: 253-257 (2000)), diarrhoea (Mule etc. VG. J. Pharmacol., 127, 514-520 (1999)), constipation (Bakre and other J. Cell. Biochem. 77: 159-167 (2000)) and asthma (Turner and other Br. J. Pharmacol., 111, 1198-1204 (1994)).

In addition, it was reported that 1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl)phenylsulfonyl]-4-methylpiperazin [generic name: sildenafil] with PDE V inhib is so (see Boolell and other Journal of Urology, Supplement, vol. 155, no. 5, R. A (1996); Terrett and other Bioorganic & Medicinal Chemistry Letters, vol. 6, no. 15, p. 1819 (1996); and Ballard and other British Journal Pharmacology, Proceeding Supplement, vol. 118, p. 153(1996)).

However, sildenafil was reported to cause side effects such as headache, blush, intestinal disorders, rhinitis, impaired color perception, prolonging erection, and so on (Irwin and other New England Journal Medicine, vol. 338, no. 20, p. 1397-1404 (1998); Morales and other International Journal Impotence Research, vol. 10, no. 2, p. 69-73 (1998); and Goldenberg, Clinical Therapeutics, vol. 20, no. 6, p. 1033-1048 (1998)).

Moreover, as was shown in experiments on dogs, the effects of sildenafil on retinal tissue in relation to its response to light and its PDE VI inhibitory activity are in communication with each other (Morales and other International Journal Impotence Research, vol. 10, no. 2, p. 69-73 (1998)), it was shown that PDE VI on the retina plays an important role from the point of view of sensitivity to light (Morrales and other International Journal of Impotence Research, vol. 10, no. 2, p. 69-73 (1998); 'estrade and others European Journal of Pharmacology, vol. 352, p. 157-163 (1998)).

The invention

The object of the present invention is a new aromatic nitrogen-containing 6-membered cyclic compound exhibiting excellent inhibitory activity against phosphodiesterase V (PDE V), which may be useful is the effects. Another object of the present invention relates to a method for receipt of a new aromatic nitrogen-containing 6-membered cyclic compounds.

The present invention relates to an aromatic nitrogen-containing 6-membered cyclic compound of the formula (I):

where ring a is a substituted or unsubstituted nitrogen-containing heterocyclic group; R1represents a substituted or unsubstituted lower alkyl group, a group of the formula: -NH-Q-R3(in which R3represents a substituted or unsubstituted nitrogen-containing heterocyclic group, and Q represents a lower alkylenes group or a simple bond or a group of formula: -NH-R4(in which R4represents a substituted or unsubstituted cycloalkyl group; R2represents a substituted or unsubstituted aryl group; one of Y and Z represents a group of formula: =CH-, and the other represents a group of the formula: =N - or its pharmaceutically acceptable salt, as well as how to obtain it.

Among compounds (I) of the present invention, nitrogen-containing heterocyclic group substituted or unsubstituted azotsoderzhashchei nitrogen-containing heterocyclic group, more preferably a 5 - or 6-membered nitrogen-containing heterogeneities group and from 8 - to 10-membered nitrogen-containing heterobicyclic group and most preferably a 5 - or 6-membered nonaromatic nitrogen-containing heterogeneities group, such as pyrrolidinyl group, piperazinilnom group, piperidinyl group, morpholinopropan etc., 5 - or 6-membered aromatic nitrogen-containing heterogeneities group, such as imidazolidine group, pyrrolidine group and so on, and nitrogen-containing heterobicyclic group, such as 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-6-ilen group, 5,6,7,8-tetrahydroimidazo[1,2-a]-pyrazin-7-strong group, 5,6,7,8-tetrahydro-1,7-naphthiridine-7-strong group, 1,2,3,4-tetrahydro-2-sochineniya group, 1H-2,3,4,5,6,7-hexahydropyrazino[4,3-C]pyridine-5-ilen group, 4,5,6,7-tetrahydrothieno[5,4-C]pyridine-6-ilen group, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-6-ilen group, 4,5,6,7-tetrahydro-3H-imidazo[4,5-C]pyridine-3-ilen group, etc.

Nitrogen-containing heterocyclic group of the "substituted or unsubstituted nitrogen-containing heterocyclic group" for R3represents 5 - or 6-membered nitrogen-containing heterogeneities group or a 8 - to 10-membered azacyclonol group, such as morpholinyl group, piperazinilnom group, piperideine group, thiadiazolyl group, dihydropyrimidine group, dihydropyrazolo group, 5 - or 6-membered aromatic nitrogen-containing heterogeneities group, such as pyrimidinyl group, pyridazinyl group, Peregrina group, pyrazolidine group, imidazolidinyl group, oxazoline group, thiazolidine group, piratininga group, and from 8 - to 10-membered nitrogen-containing heterobicyclic group, such as benzothiazolyl group, kinolinna group, dihydroisoxazole group, etc.

Deputy "substituted or unsubstituted nitrogen-containing heterocyclic group" for ring a and R represents, for example, (1) a lower alkyl group, (2) replacement of the lower alkyl group, (3) formyl group, (4) oxoprop, (5) amino group, (6) di-(lower alkyl)amino group, (7) a hydroxy-group, (8) lower alkoxygroup, (9) lower alkoxycarbonyl group, (10) a lower alkoxy-substituted lower alkanoyloxy group, (11) lower alkanoyloxy group, (12) lanzamiento lower alkyl group, and (13) pyrimidinyl group, substituted (i) benzylaminocarbonyl substituted by a halogen atom and n is supplemented flax group "substituted or unsubstituted aryl group" for R2represents, for example, 5 - to 10-membered monocyclic or bicyclic aromatic hydrocarbon group such as phenyl group, naftalina group, etc.

Deputy "substituted or unsubstituted aryl group" for R2represents, for example, the lower alkoxygroup, a halogen atom, a cyano, a nitro-group, a hydroxy-group, a lower alkyl group, etc.

Deputy "substituted or unsubstituted lower alkyl group" for R1and the Deputy of the "substituted or unsubstituted cycloalkyl group" for R4represents, for example, the lower alkoxygroup, the hydroxy-group, morpholinyl group, lower alkylsulfonyl group, di-(lower alkyl)phosphonopropyl, di-(lower alkyl)amino group, pyrimidinylidene lower alkylamino, pyridyloxy group, pyridylamino, lower alkyl substituted piperazinilnom group, pyrimidinylidene etc.

In accordance with the present invention a "lower alkyl group" denotes a linear or branched alkyl group having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl isopropyl, butyl isobutyl, tert-butyl etc., "Lower alkoxygroup" means l is isopropoxy, butylochki isobutoxy, tert-Butylochka etc.

"Cycloalkyl group" means cycloalkyl having from 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc. "Lower Allenova group" denotes a linear or branched alkylenes group having from 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene etc.

"Halogen atom" means a fluorine atom, chlorine atom, bromine atom or iodine atom.

Among compounds (I) of the present invention preferred are the compounds of formula (I), in which nitrogen-containing heterocyclic group of the "substituted or unsubstituted nitrogen-containing heterocyclic group" for ring a represents a 5 - or 6-membered nitrogen-containing heterogeneities group or a 8 - to 10-membered nitrogen-containing heterobicyclic group and Deputy mentioned "substituted or unsubstituted nitrogen-containing heterocyclic group selected from the group consisting of (1) lower alkyl groups, (2) replacement of the lower alkyl group, (3) formyl group, (4) carbonyl group, (5) amino group, (6) hydroxy-group, (7) lower alkoxycarbonyl group and (8) pyrimidinyl group substituted by the group substituted by a hydroxy-group, R1represents a lower alkyl group which may be optionally substituted by a group selected from the group consisting of lower alkoxygroup, hydroxy-group, morpholinyl group, lower alkylsulfonyl groups, di-(lower alkyl)phosphinic group, a di-(lower alkyl)amino group, pyrimidinylidene low alkylamino, peredelnoj group, pyridylamino and lower alkyl substituted piperazinilnom group, a group of the formula: -NH-Q-R3or a group of formula: -NH-R4, nitrogen-containing heterocyclic group of the "substituted or unsubstituted nitrogen-containing heterocyclic group" for R3represents 5 - or 6-membered nitrogen-containing heterogeneities group or a 8 - to 10-membered nitrogen-containing heterobicyclic group and Deputy mentioned "substituted or unsubstituted nitrogen-containing heterocyclic group selected from the group consisting of lower alkyl groups, replacement of the lower alkyl group, carbonyl group, amino group, di(lower alkyl)amino, lower alkanoyloxy group and lanzamientos lower alkyl group, R4represents cycloalkyl group substituted by a group chosen is employed, a phenyl group, substituted by a group selected from the group consisting of lower alkoxygroup, halogen atom, ceanography, nitro, hydroxy-group and lower alkyl groups.

In particular, preferred compounds of the present invention are the compounds of formula (I), in which nitrogen-containing heterocyclic group of the "substituted or unsubstituted nitrogen-containing heterocyclic group" for ring a represents a 5 - or 6-membered nitrogen-containing heterogeneities group of the formula:

or nitrogen-containing heterobicyclic group of the following formula, where the above 5 - or 6-membered nitrogen-containing heterophilically group and 5 - or 6-membered cyclic group are condensed:

and nitrogen-containing heterocyclic group of the "substituted or unsubstituted nitrogen-containing heterocyclic group" for R3represents a non-aromatic nitrogen-containing heterogeneities group of the formula:

or aromatic nitrogen-containing heterocyclic group of the formula:

Among compounds (I) of the present invention, other preferred compounds are compounds of ilicakoy group" for ring a represents a 5 - or 6-membered nitrogen-containing heterogeneities group or a 8 - to 10-membered nitrogen-containing heterobicyclic group and Deputy mentioned "substituted or unsubstituted nitrogen-containing heterocyclic group selected from the group consisting of lower alkyl groups, replacement of the lower alkyl group, formyl group and the carbonyl group, R1represents a lower alkyl group which may be optionally substituted by a group selected from the group consisting of lower alkoxygroup and morpholinyl group, a group of the formula: -NH-Q-R3or a group of formula: -NH-R4, "substituted or unsubstituted nitrogen-containing heterocyclic group" for R3represents 5 - or 6-membered nitrogen-containing heterogeneities group which may be optionally substituted lower alkyl group, R4represents cycloalkyl group substituted by a group selected from the group consisting of hydroxy-group and lowest alkoxygroup, R2represents a phenyl group substituted by a group selected from the group consisting of lower alkoxygroup, halogen atom and ceanography.

Particularly preferred compounds of the present invention are the compounds of formula (I), where nitrogen-containing heterocyclic group of the "substituted or unsubstituted nitrogen-containing heterocyclic group" for ring a represents a 5 - or 6-membered non-aromatic attester group of the following formula, where the above 5 - or 6-membered nonaromatic nitrogen-containing heterophilically group and 5 - or 6-membered aromatic nitrogen-containing heterophilically group are condensed:

nitrogen-containing heterocyclic group of the "substituted or unsubstituted nitrogen-containing heterocyclic group" for R3represents a non-aromatic nitrogen-containing heterogeneities group of the formula:

or aromatic nitrogen-containing heterogeneities group of the formula:

Particularly preferred compounds of the present invention are the compounds of formula (I), where the ring And represents a group of the formula:

R1represents a lower alkyl group, a lower alkoxy-substituted lower alkyl group, morpholinylmethyl lower alkyl group, a group of the formula: -NH-Q-R3or a group of formula: -NH-R4, R3represents a group of the formula:

R4represents a group of the formula:

R2represents a group of the formula:

Among compounds (I) of the present invention intense group "substituted or unsubstituted nitrogen-containing heterocyclic group" for ring a represents a 5 - or 6-membered nitrogen-containing heterogeneities group or a 8 - to 10-membered nitrogen-containing heterobicyclic group and Deputy mentioned "substituted or unsubstituted nitrogen-containing heterocyclic group" is a group, selected from the group consisting of lower alkyl groups, replacement of the lower alkyl group, formyl group and the carbonyl group, R1represents a lower alkoxy-substituted lower alkyl group, a group of the formula: -NH-Q-R3or a group of formula: -NH-R4, "substituted or unsubstituted nitrogen-containing heterocyclic group" for R3represents 5 - or 6-membered nitrogen-containing heterogeneities group which may be optionally substituted lower alkyl group, R4is a replacement cycloalkyl group, and R2represents a phenyl group substituted by a group selected from the group consisting of lower alkoxygroup and halogen atom.

Particularly preferred compounds of the present invention are the compounds of formula (I), in which nitrogen-containing heterocyclic group of the "substituted or unsubstituted nitrogen-containing heterocyclic group" for ring a represents a 5 - or 6-membered nonaromatic nitrogen-containing heterogeneities group of the formula:

or a group of the formula:

nitrogen-containing heterocyclic group "samecase nitrogen-containing heterogeneities group of the formula:

or aromatic nitrogen-containing heterogeneities group of the formula:

Particularly preferred compounds of the present invention are the compounds of formula (I), where the ring And represents a group of the formula:

R1represents a lower alkoxy-substituted lower alkyl group, a group of the formula: -NH-Q-R3or a group of formula: -NH-R4, R3represents a group of the formula:

R4represents a group of the formula: R2represents a group of the formula:

Among compounds (I) of the present invention, the following preferred compounds are the compounds of formula (I), where nitrogen-containing heterocyclic group of the "substituted or unsubstituted nitrogen-containing heterocyclic group" for ring a represents a 5 - or 6-membered nitrogen-containing heterogeneities group or a 8 - to 10-membered nitrogen-containing heterobicyclic group and Deputy mentioned "substituted or unsubstituted nitrogen-containing heterocyclic group" is a replacement lower alkyl group, R1is a gr is represents 5 - or 6-membered nitrogen-containing heterogeneities group, which may be optionally substituted lower alkyl group, and R2represents a phenyl group substituted by a group selected from the group consisting of lower alkoxygroup and halogen atom.

Particularly preferred compounds of the present invention are the compounds of formula (I), in which nitrogen-containing heterocyclic group of the "substituted or unsubstituted nitrogen-containing heterocyclic group" for ring a represents a 5 - or 6-membered nonaromatic nitrogen-containing heterogeneities group of the formula:

or a group of the formula:

nitrogen-containing heterocyclic group of the "substituted or unsubstituted nitrogen-containing heterocyclic group" for R3represents a non-aromatic nitrogen-containing heterogeneities group of the formula:

or aromatic nitrogen-containing heterogeneities group of the formula:

Particularly preferred compounds of the present invention are the compounds of formula (I), where the ring And represents a group of the formula:

R1represents a group of formula: -NH-Q is the UPP formula:

Among compounds (I) of the present invention the most preferred compounds are the compounds of formula (I) in which Y represents a group of the formula: =N -, and Z represents a group of formula: =CH-.

Among compounds (I) of the present invention pharmaceutically preferable compounds are compounds selected from the following group, or their pharmaceutically acceptable salts.

(S)-2-(2-Hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine) - 5-[N-(2-pyrimidinyl)carbarnoyl]pyrimidine;

2-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-6-yl)-4-(3-cyano-4-methoxybenzylamine)-5-[N-(2-pyrimidinyl)carbarnoyl]pyrimidine;

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(TRANS-4-methoxycyclohexyl)carbarnoyl]pyrimidine;

2-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-6-yl)-4-(3-cyano-4-methoxybenzylamine)-5-[N-(TRANS-4-hydroxycyclohexyl)carbarnoyl]pyrimidine;

2-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-6-yl)-4-(3-cyano-4-methoxybenzylamine)-5-[N-(2-morpholinoethyl)carbarnoyl]pyrimidine

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-morpholinoethyl)carbarnoyl]pyrimidine;

2-[(2S)-2-hydroxymethyl-12-[(2S)-2-hydroxymethyl-1-pyrrolidinyl]-4-(3-chloro-4-methoxybenzylamine)-5-[N-[[(2S)-4-methyl-2-morpholinyl]methyl]carbarnoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(4-pyrimidinyl)carbarnoyl]pyrimidine;

2-(4-methyl-3-oxo-1-piperazinil)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(TRANS-4-hydroxycyclohexyl)carbarnoyl]pyrimidine;

2-(4-formyl-1-piperazinil)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(TRANS-4-hydroxycyclohexyl)carbarnoyl]pyrimidine;

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(TRANS-4-hydroxycyclohexyl)carbarnoyl]pyrimidine;

2-[CIS-2,5-bis(hydroxymethyl)-1-pyrrolidinyl]-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-pyrimidinyl)carbarnoyl]pyrimidine;

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-pyrimidinyl)carbarnoyl]pyrimidine;

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-morpholinoethyl)carbarnoyl]pyrimidine;

2-(5,6,7,8-tetrahydro-1,7-naphthiridine-7-yl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-morpholinoethyl)carbarnoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-acetylpyridine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(4-pyridinylmethyl)carbarnoyl]pyrimidine;

(S)-2-(2-hydroc is-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-pyridylmethyl)carbarnoyl]pyrimidine;

(S)-2-[N-(2-pyrimidinyl)carbarnoyl]-3-(3-chloro-4-methoxybenzylamine)-5-[2-hydroxymethyl-1-pyrrolidinyl]pyrazin;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[(2-morpholinoethyl)carbonyl]pyrimidine;

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-[(4-methyl-2-morpholinyl)methyl]carbarnoyl]pyrimidine;

(S)-2-[N-(2-morpholinoethyl)carbarnoyl]-3-(3-chloro-4-methoxybenzylamine)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazin;

2-[N-(2-pyrimidinyl)carbarnoyl]-3-(3-chloro-4-methoxybenzylamine)-5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)pyrazin;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[(2-methoxyethyl)carbonyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(1,3,5-trimethyl-4-pyrazolyl)carbarnoyl]pyrimidine or pharmaceutically acceptable salt.

Among compounds (I) of the present invention pharmaceutically preferable compounds are compounds selected from the following group, or their pharmaceutically acceptable salts.

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-pyrimidinyl)carbarnoyl]pyrimidine;

2-(4-methyl-3-oxo-1-piperazinil)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(TRANS-4-hydroxycyclohexyl)carbarnoyl]pyrimidine;

2-(4-formyl-1-piperazinil)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(TRANS-4-hydroxycyclohexyl)carbarnoyl]pyrimidine;

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-pyrimidinyl)carbarnoyl]pyrimidine;

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-morpholinoethyl)carbarnoyl]pyrimidine;

2-(5,6,7,8-tetrahydro-1,7-naphthiridine-7-yl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-morpholinoethyl)carbarnoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(5-pyrimidinyl)carbarnoyl]pyrimidine;

(S)-2-[N-(2-pyrimidinyl)carbarnoyl]-3-(3-chloro-4-methoxybenzylamine)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazin;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[(2-methoxyethyl)carbonyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(l,3,5-trimethyl-4-pyrazolyl)carbarnoyl]pyrimidine or pharmaceutically acceptable salt.

Among compounds (I) of the present invention other pharmaceutically preferred CLASS="ptx2">

(S)-2-(2-Hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-pyrimidinyl)carbarnoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-morpholinoethyl)carbarnoyl]pyrimidine;

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-pyrimidinyl)carbarnoyl]pyrimidine;

2-(5,6,7,8-tetrahydro-1,7-naphthiridine-7-yl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-morpholinoethyl)carbarnoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(5-pyrimidinyl)carbarnoyl]pyrimidine;

(S)-2-[N-(2-pyrimidinyl)carbarnoyl]-3-(3-chloro-4-methoxybenzylamine)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazin;

(S)-2-[N-(2-morpholinoethyl)carbarnoyl]-3-(3-chloro-4-methoxybenzylamine)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazin;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(1,3,5-trimethyl-4-pyrazolyl)carbarnoyl]pyrimidine or pharmaceutically acceptable salt.

Among compounds (I) of the present invention is particularly pharmaceutically preferable compounds are compounds selected from the following group, or their pharmaceutically acceptable salts.

n or its pharmaceutically acceptable salt, 2-(5,6,7,8-tetrahydro-1,7-naphthiridine-7-yl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-morpholinoethyl)carbarnoyl]pyrimidine or its pharmaceutically acceptable salt; next (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(1,3,5-trimethyl-4-pyrazolyl)carbarnoyl]pyrimidine or its pharmaceutically acceptable salt.

If the compound (I) in accordance with the present invention, or its pharmaceutically acceptable salt has an asymmetric carbon atom in ring A, R1and/or R2it can exist in the form of its optically active isomer relative to its specified asymmetric carbon atom and the present invention also includes optical isomers and their mixtures.

The compound (I) in accordance with the present invention, or its pharmaceutically acceptable salt exhibits an excellent selective PDE V inhibitory activity, but essentially causes several side effects, such as impaired color perception, and therefore it can be used for prevention or treatment of erectile dysfunction.

The compound (I) in accordance with the present invention can be used for the treatment or in free form or in the form of its pharmaceutically acceptable the hydrochloride, sulfate, nitrate or hydrobromide, or its salt with organic acid such as acetate, fumarate, oxalate, citrate, methanesulfonate, bansilalpet, tosylate or maleate.

The compound (I) in accordance with the present invention or its salt includes as its intramolecular or additive salt, or their solvate or hydrate.

The compound (I) in accordance with the present invention, or its pharmaceutically acceptable salt is administered or orally, or parenterally, however, they can be introduced in conventional pharmaceutical preparations such as tablets, granules, fine granules, pills, capsules, powders, injections, inhalations, transbukkalno drugs, sublingual tablets, syrups, dry syrups, jellies, suppositories, ointments, elexir, liniments, lotions, drinks, nasal drops, preparations for subcutaneous injection and tablets are rapidly pulverised in the mouth, and so on. These pharmaceutical preparations can be prepared by molding with pharmaceutically acceptable additives such as excipient, binder, wetting agent, disintegrator, sealing agent, and so forth, the usual method.

The dose of compound (I) in accordance with the present invention is patient. For example, if the drug is administered by injection, the dose is usually in the range of about 0.001-100 mg/kg/day, preferably in the range of about 0.1-10 mg/kg/day. If the drug is administered orally, usually in the range of about 0.1-200 mg/kg/day, preferably in the range of about 0.1-80 mg/kg/day.

In addition, since the compound (I) of the present invention or its pharmaceutically acceptable salt have excellent selective PDE V inhibitory activity, they can also be useful in the prevention or treatment of diseases caused by functional disorders cGMP-communication, such as pulmonary hypertension, diabetic gastroparesis, hypertension, angina pectoris, myocardial infarction, chronic or acute heart failure, female sexual dysfunction, prostatic hyperplasia, asthma, diarrhea, constipation and achalasia in addition to the above-mentioned erectile dysfunction

The preferred implementation of the invention.

The compound (I) in accordance with the present invention can be obtained in accordance with the following methods from a to F.

Method AND

Among compounds (I) in accordance with the present invention the compound of formula (I), in S="ptx2">

(where R11represents a group of formula: -NH-Q-R3or-NH-R4and the other radicals have the meanings as defined above) can be obtained by reacting the compound (II):

where X1represents a halogen atom, R5represents a group protecting the carboxyl group, R9represents a substituted or unsubstituted lower alkyl group or a substituted or unsubstituted aryl group, and other radicals defined above, with a compound of formula (III):

where the values of the radicals defined above, oxidation of the resulting compounds of the formula (IV):

where the radicals have the meanings defined above, to obtain sulfonylurea (or sulfanilimide) the compounds of formula (V):

where n has a value of 1 or 2, and the other radicals have the meanings defined above, the interaction of the compounds of formula (V) with the compound of the formula (VI):

where the radicals have the meanings such as defined above, or its salt, which leads to the production of the compounds of formula (VII):

where the radicals have the meanings such as defined above, removal of the Sabbath.

where the radicals have the meanings such as defined above,

with the subsequent interaction of the compound (VIII) with the compound of the formula (IX-a):

where the radicals have the meanings such as defined above.

The compound (I-a) can also be obtained by halogenation of the compound (VIII) with the formation of the compounds of formula (X):

where X2represents a halogen atom, and the other radicals have the meanings such as defined above, followed by interaction of the compound (X) with compound (IX-a). In addition, the above compound (VII) can also be obtained by processing dehalogenase derivative of the formula (XI):

where X3and X4represent a halogen atom, and the other radicals have the meanings such as defined above, with carbon dioxide, the introduction of the protection of the carboxyl group in the resulting compound of formula (XII):

where the radicals have the meanings such as defined above, with the formation of the compounds of formula (XIII):

where the radicals have the meanings such as defined above,

interaction of the compound (XIII) with compound (III), while the e,

with the subsequent interaction of the compound (XIV) with compound (VI). In addition, the above compound (XIV) can also be obtained by hydrolysis of compound (V) with subsequent halogenoalkanes resulting from the compounds of formula (XV):

where the radicals have the meanings such as defined above.

Method IN

Among compounds (I) in accordance with the present invention the compound of formula (I), where R1represents a substituted or unsubstituted lower alkyl group, i.e. a compound of the formula (I-b):

(where R12represents a substituted or unsubstituted lower alkyl group and the other radicals have the meanings such as defined above) can be obtained by oxidation of compounds of formula (XVI):

where the radicals have the meanings such as defined above, which is obtained by reduction of compound (IV) to form the compounds of formula (XVII)

where the radicals have the meanings such as defined above,

then, oxidizing the compound (XVII), obtain the connection formula (XVIII):

where the radicals have the meanings such as defined above,

where the radicals have the meanings such as defined above,

in the interaction of the compound (XIX) with a metal salt of the compounds of formula (IX-b):

where R12such as defined above, obtain the connection formula (XX):

where the radicals have the meanings such as defined above,

with subsequent oxidation of the compound (XX).

In addition, among the compounds (I) of the present invention the compound of formula (I), where R1represents a lower alkoxy-substituted ethyl group, morpholinomethyl ethyl group, 4-lower alkylpiperidines ethyl group, 3-pyridylmethylene ethyl group, 2-pyridyl-lower alkylaminocarbonyl ethyl group, di-lower alkylaminocarbonyl group or hydroxyethylene group, i.e. the compound of formula (I-C):

where R6represents a lower alkoxygroup, morpholinopropan, 4-lower alkylpiperazine group, 3-pyridylamino, 2 pirimidil-lower alkylamino, di-lower alkylamino or hydroxy-group and the other radicals have the meanings such as defined above, can be obtained by reacting compound (XIX) with the>

where the radicals have the meanings such as defined above, which on oxidation gives compound of formula (XXIII):

where the radicals have the meanings such as defined above,

with the subsequent interaction of the compound (XXIII) with the compound of the formula (XXIV):

where a value of R6defined above.

The way TO

The compound (I-a) can be obtained by reacting the compounds of formula (XXV):

where the radicals have the meanings such as defined above, which in turn is obtained by removal of the protective group R with the carboxyl group of the compound (IV) with compound (IX-a) with obrazovanie the compounds of formula (XXVI-a):

where the radicals have the meanings such as defined above,

oxidation of compound (XXVI-a), which leads to the compound of formula (XXVII-a):

where the radicals have the meanings such as defined above,

with the subsequent interaction of the compound (XXVD-a) with compound (VI).

Method D

The compound (I-b) can be obtained by oxidation of compounds of formula (XXVIII):

where the radicals have the meanings such as defined above, which compound of formula (XXVI-b):

where the radicals have the meanings such as defined above, followed by oxidation of the compound (XXVI-b) to obtain the compound of formula (XXVII-b):

where the radicals have the meanings such as defined above,

with the subsequent interaction of the compound (XXVII-b) with compound (VI).

Method E

The compound (I-b) can be obtained by oxidation of compounds of formula (XXX):

where the radicals have the meanings such as defined above, which in turn is produced by the interaction dehalogenase derivative (XI) with the compound of the formula (XXIX):

where R12defined above, to form compounds of formula (XXXI):

where the radicals have the meanings such as defined above,

interaction of the compound (XXXI) with compound (III), which results in obtaining the compounds of formula (HHH):

where the radicals have the meanings such as defined above,

with the subsequent interaction of the compound (HHH) with compound (VI). The above-mentioned compound (HGH) can also be obtained by reacting compound (XXX) with a compound (III) with the formation of the compounds of formula (XXXIII):

Process F

The compound (I-a) can be obtained by reacting compound (XIII) with the compound of the formula (XXXIV):

RSH (XXXIV),

where R represents a substituted or unsubstituted lower alkyl group or a substituted or unsubstituted aryl group, to obtain compounds of the formula (XXXV):

where the radicals have the meanings such as defined above,

interaction of the compound (XXXV) with compound (VI) or its salt with obtaining the compounds of formula (XXXVI):

where the radicals have the meanings defined above,

the removal of the protective group R5with the carboxyl group of compound (XXXVI), obtaining the compounds of formula (XXXVII):

where the radicals have the meanings such as defined above,

interaction of the compound (XXXVII) with compound (IX-a), which gives the compound of formula (XXXIX):

where the radicals have the meanings defined above,

oxidation of compound (XXXIX) with getting sulfonylurea or sulfanilimide connection with the subsequent interaction of the resulting product with the compound (III).

The above methods a to F can be) carried out in the presence or absence of an acid acceptor in a solvent. The acid acceptor includes, for example, an organic base, such as N,N-diisopropylethylamine, N-methylmorpholine, triethylamine, pyridine, and so forth, and an inorganic base such as sodium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, and so on. The solvent may be any solvent which does not violate the mode of reaction, such as dimethyl sulfoxide, tetrahydrofuran, toluene, ethyl acetate, chloroform, dimethoxyethane, xylene, N,N-dimethylformamide and so on. The process is performed at a temperature from-10C to room, preferably at a temperature of from 0C to room.

The oxidation reaction of the compound (IV) to obtain sulfonyl (or sulfinil) of the compound (V) is carried out in the presence of an oxidizing agent and solvent. The oxidizing agent includes, for example, percolate, such as m-chloroperbenzoic acid, peracetic acid, and so forth, and an inorganic oxidizing agent such as manganese dioxide, periodate sodium, hydrogen peroxide, desitny the tetroxide, halogen, hydroperoxide, iodobenzoate, tert-butyl hypochlorite, chloride of Sulfuryl, peroxymonosulfate potassium and so on. The solvent may be any solvent which does not interfere with the mode of reaction, for example chloro 50C, preferably at a temperature from-10C to 10C.

The interaction of the compound (V) with compound (VI) or its salt can be performed in the presence or absence of an acid acceptor in a solvent. The acid acceptor includes, for example, an organic base, such as N,N-diisopropylethylamine, N-methylmorpholine, triethylamine, pyridine, and so forth, and an inorganic base such as sodium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, and so on. The salt of the compound (VI) is preferably a salt of an alkali metal such as sodium salt, potassium salt, and so forth. The solvent may be any solvent which does not violate the mode of reaction, such as N,N-dimethylformamide, tetrahydrofuran, dimethoxyethane, dimethyl sulfoxide and so on. The reaction is performed at a temperature of from 0C to 150C, preferably at a temperature from room temperature to 60C.

The reaction for removing the protective group R5with the carboxyl group of compound (VII) to obtain the compound (VIII) can be performed by a standard method such as hydrolysis, catalytic reduction, and so forth, which are chosen according to the type of removable protective group for the carboxyl presence of a base in a solvent. The base is preferably, for example, alkali metal hydroxide, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, and so forth, or carbonate of an alkali metal such as sodium carbonate, potassium carbonate and so on. The solvent may be water or a mixture of water and methanol, ethanol, tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethyl sulfoxide and so on. The process is performed at a temperature of from 0 to 80 ° C, preferably at temperatures from 5°C to 60C. The protective group for carboxyl group, represented as R5can be any standard group, a carboxyl protecting group such as lower alkyl group, benzyl group, and so on.

The reaction of the compound (VIII) with compound (IX-a) can be carried out in the presence or absence of a condensing agent, a base or an activating agent in a suitable solvent. The condensing agent is, for example, dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, diphenylphosphoryl, diethylthiophosphate and so on, which are usually used in peptide synthesis. The base includes, for example, an organic base such as triethylamine, N-methylmorpholine and so forth,can be any solvent, which does not prevent the mode of reaction, for example, methylene chloride, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, N,N-dimethylacetamide, ethyl acetate and so on. The process is performed at a temperature from-30C to 50C, preferably at a temperature from-10C to 10C.

An alternative process for the conversion of compound (VIII) to the compound (X), which then interacts with the compound (IX-a) may initially be made by reacting the compound (VIII) with a halogenation agent in prisutstvie or absence of the activating agent standard method, and then the interaction of the obtained compound (X) with compound (IX-a). The interaction of the compound (VIII) with a halogenation agent is carried out in a solvent. As the halogenation agent is used preferably thionyl chloride, oxalicacid, pentachloropropane and so on. As the activating agent preferably used amide compound such as N,N-dimethylformamide and so on. The solvent may be any solvent which does not violate the mode of reaction, such as methylene chloride, chloroform, tetrahydrofuran, benzene, toluene, dioxane and so forth. The process is performed at a temperature from-30C to 100C, preferably at a temperature of the RA acid in the solvent. The acid acceptor includes, for example, an organic base, such as N,N-diisopropylethylamine, N-methylmorpholine, triethylamine, pyridine, dimethylaminopyridine and so forth, and an inorganic base such as sodium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, and so on. The solvent may be any solvent which does not violate the mode of reaction, such as tetrahydrofuran, methylene chloride, chloroform, toluene, benzene, dioxane, ethyl acetate and so on. The process is carried out at a temperature from-30C to 100C, preferably at a temperature from-5C to 10C.

The process of interaction dehalogenase compounds (XI) with carbon dioxide to obtain a compound (XII) can be performed in the presence of a base in a solvent. The base includes, for example, salt of an alkali metal organic bases, such as diisopropylamide lithium, lithium 2,2,6,6-tetramethylpiperidine and so on. The solvent may be any solvent which does not violate the mode of reaction, such as tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether, and so forth. The process is carried out at temperatures from-100C to-30C, preferably at temperatures from-100C to-70C.

The reactions the conventional method, for example, by reacting with an alkylating agent in the presence of a base in a solvent, where the protective group is a lower alkyl group. The alkylating agent is preferably a lower alkyl halide such as methyl iodide. The base is bicarbonate of an alkali metal such as sodium bicarbonate, the solvent can be any solvent which does not violate the mode of reaction, such as N,N-dimethylformamide, tetrahydrofuran, and so forth. The process is carried out at a temperature from 0C to 100C, preferably at a temperature from room temperature to 70 ° C.

The interaction of the compound (XIII) with compound (III) to obtain a compound (XIV) can be performed in the same way as the interaction of compound (II) with compound (III).

The reaction of the compound (XIV) with compound (VI) to obtain compound (VII) can be performed in the same way as the interaction of the compound (V) with compound (VI).

Hydrolysis of compound (V) to obtain compound (XV) is carried out in the presence of a base in a solvent. The base includes, for example, alkali metal hydroxide, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, and so forth, and ka is the battle is preferably water or a mixture of water and methanol, ethanol, tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethyl sulfoxide and so on. The reaction is carried out at a temperature from-20C to 80C, preferably at a temperature from-5C to 60C.

The halogenation reaction of the compound (XV), leading to the compound (XIV) can be carried out in the same way that the reaction of obtaining compound (X) by halogenation of the compound (XIII) halogenation agent.

Method IN

The reduction of the compound (IV) to obtain the compound (XVI) can be performed in the presence of a reducing agent in a suitable solvent. Reducing agent is preferably alumoweld alkali metal, such as alumaguard lithium borohydride of an alkali metal such as lithium borohydride, and so on. The solvent can be used, which does not violate the mode of reaction, such as tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane and so on. The process is carried out at a temperature from C to the boiling point of the solvent used, preferably at temperatures from-10C to room temperature.

The oxidation reaction of compound (XVI) to obtain the compound (XVII) perform at ebonyline connection, for example, manganese dioxide, permanganate barium, permanganate potassium, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, chlorproma pyridine, pyridine dichromate, and so forth. The solvent may be selected from any solvent which does not violate the mode of reaction, such as chloroform, toluene, ethyl acetate, 1,2-dichloroethane, methylene chloride, tetrahydrofuran and so forth. The process is performed at a temperature of from 0C to 100C, preferably at a temperature from room temperature to 70 ° C.

The oxidation reaction of compound (XVII) to obtain a compound (XVIII) is performed in the same conditions as the reaction of obtaining the compound (V) by oxidation of the compound (IV).

The reaction of interaction of the compound (XVIII) with the compound (VI) to obtain the compound (XIX) is performed in the same manner as the reaction of the compound (V) with compound (IV).

The reaction of interaction of the compound (XIX) with a metal salt (IX-b) to obtain a compound (XX) can be performed in a suitable solvent.

The metal salt of the compound (IX-b) is preferably a lithium salt, and so forth. The solvent may be any solvent which does not violate the mode of reaction, such as tetrahydrofuran, dioxane, diethyl temperature.

The oxidation reaction of compound (XX), leading to the compounds (I-b) may be performed in the same manner as the reaction of receipt (XVII) by oxidation of the compound (XVI).

The reaction of interaction of the compound (XIX) with a compound of the Grignard reagent can be performed in a suitable solvent. The solvent is a preferably tetrahydrofuran, dioxane, diethyl ether and so on. The reaction can be preferably carried out at a temperature of from-C to 60C, preferably at a temperature of from-S to room temperature.

The oxidation reaction of compound (XXII) to obtain the compound (XXIII) perform as well as the reaction of obtaining compound (XVII) by oxidation of the compound (XVI).

The interaction of the compound (XXIII) with the compound (XXIV), where6is morpholinopropan, 4-lower alkylpiperazine group, 3-pyridylamino, 2 pirimidil-lower alkylamino or di-lower alkylamino to obtain the compound (I-C), where R6is morpholinopropan, 4-lower alkylpiperazine group, 3-pyridylamino, 2-pyrimidinyl-lower alkylamino or di-lower alkylamino can be performed in the presence or OTS is N,N-diisopropylethylamine, N - methylmorpholine, triethylamine, pyridine, and so forth, and an inorganic base such as sodium hydroxide, sodium carbonate, potassium carbonate, potassium bicarbonate, and so on. The solvent may preferably be ethanol, N,N-dimethylformamide, tetrahydrofuran, dimethoxyethane, dimethylsulfoxide and so on. The reaction can be preferably carried out at a temperature of from 0C to 150C, preferably at a temperature from room temperature to 60C.

On the other hand, the reaction of the compound (XXIII) with the compound (XXIV), where R6the hydroxy - group or lower alkoxygroup, to obtain the compound (XXI), where R6represents a hydroxy-group or a lower alkoxygroup can be performed in the presence of an acid in a solvent or without solvent. The acid is, for example, inorganic acid such as sulfuric acid, and so forth, or an organic acid, such as methanesulfonate, camphorsulfonate, toluensulfonate, benzosulfimide and so on. The solvent may be preferably diethyl ether, toluene, benzene, N,N-dimethylformamide, dimethoxyethane, dimethyl sulfoxide and so on. The reaction can preferably take place at temperatures>The reaction of removing the protective group R5with the carboxyl group of the compound (IV) to obtain the compound (XXV) can be performed in the same conditions as the reaction of obtaining compound (VIII) by removing the protective group R5with the carboxyl group of compound (VII).

The reaction of the compound (XXV) with a compound (IX-a) to obtain the compound (XXVI-a) can be performed in the same manner as the reaction of the compound (VIII) with compound (IX-a).

The oxidation reaction of the compound (XXVI-a) to obtain the compound (XXVII-1) can be performed in the same manner as the reaction of obtaining the compound (V) by oxidation of the above compound (IV).

The reaction of the compound (XXVII-a) with compound (VI) to obtain the compound (I-a) in accordance with the present invention can be performed in the same manner as the reaction of the compound (V) with compound (VI).

Method D

The reaction of the compound (XVII) with a metal salt of the compound (IX-b) to obtain the compound (XXVIII) can be performed in the same manner as the reaction of the compound (XIX) with a metal salt of the compound (IX-b).

The oxidation reaction of compound (XXVIII) to obtain the compound (XXVI-b) can be performed in the same way that the(XXVI-b) oxidised that gives compound (XXVII-b), which is further converted into the compound (I-b) in accordance with the present invention, can be performed in the same manner as the process in which the compound (XXVI-a) oxidized with obtaining compound (XXVII-b), which is further converted into the compound (I-a) in accordance with the present invention.

Method E

The interaction of the compound (XI) with compound (XXIX) to obtain the compound (XXX) is carried out in the presence of a base in a suitable solvent. The base includes, for example, salt of an alkali metal organic bases, such as diisopropylamide lithium 2,2,6,6-tetramethylpiperidine lithium and so on. The solvent may be any solvent which does not violate the mode of reaction, such as tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether, and so forth. The reaction is carried out at temperatures from-100C to-30C, preferably at temperatures from-100C to-70C.

The oxidation reaction of compound (XXX) to obtain the compound (XXXI) can be performed in the same manner as the oxidation reaction of compound (XVI) upon receipt of the compound (XVII).

The interaction of the compound (XXXI) with compound (III) to obtain compounds (HHH) can be fulfilled is unity (VI) or its salt with the to obtain the compound (I-b) in accordance with the present invention, can be performed in the same manner as the reaction of the compound (V) with compound (VI).

The interaction of the compound (XXX) with a compound (III) to obtain the compound (XXXIII) can be performed in the same manner as the reaction of the compound (II) with compound (III). In addition, the oxidation reaction of compound (XXXIII) to obtain compounds (HHH) can be performed in the same manner as the oxidation reaction of compound (XVI) to obtain the compound (XVII).

Method F

The reaction of the compound (XIII) with compound (XXXIV) can be performed in the presence or absence of an acid acceptor in a solvent. The acid acceptor includes, for example, an organic base, such as N,N-diisopropylethylamine, N-methylmorpholine, triethylamine, pyridine, etc., or inorganic base such as sodium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, and so on. The solvent can be any solvent that does not violate the mode of response, for example, N,N-dimethylformamide, tetrahydrofuran, toluene, ethyl acetate, chloroform, dimethoxyethane, xylene, dimethylformamide and so on. The reaction is performed at a temperature from-10C to rooms is soedineniya (XXXV) with compound (VI) or its salt can be performed in the same way, as the reaction of the compound (V) with compound (VI).

The reaction of removing the protective group R5with the carboxyl group of compound (XXXVI) to obtain the compound (XXXVII) can be performed in the same manner as the reaction of removing the protective group R5with the carboxyl group of compound (VII) with a compound (VIII).

The reaction of the compound (XXXVII) with compound (IX-a) can be performed in the same manner as the reaction of the compound (VIII) with compound (IX-a).

The oxidation reaction of compound (XXXIX) can be performed in the same manner as the reaction of the compound (IV) with a compound (V). The oxidizing agent is preferably a m-chloroperbenzoic acid and so on. The solvent may be any solvent which does not violate the mode of reaction, such as chloroform, methylene chloride, dichloroethane, acetic acid and so on. The reaction is carried out at a temperature from C to 50C, preferably at a temperature from-10C to 10C.

Subsequent reaction with compound (III) can be performed in the same manner as the reaction of the compound (II) and compound (III).

The compound (I) obtained above may be converted into its pharmaceutically acceptable salt.

IP

Examples of compound (I) in accordance with the present invention, which can be obtained by the above methods, illustrates the present invention but it should not be limited by them.

Example 1

(1) Under cooling with ice to a solution of 4-chloro-5-etoxycarbonyl-2-methylthiopyrimidine (at 25.33 g) in N,N-dimethylformamide (85 ml) add a solution of 3-chloro-4-methoxybenzylamine (19.62 g) in N,N-dimethylformamide (15 ml) and triethylamine (16.7 ml). The mixture is stirred at room temperature for 20 minutes, then add 3-chloro-4-methoxybenzylamine (940 mg) and stirred for 15 more minutes. Then added to the mixture specified Amin (940 mg) and stirred for 15 more minutes. The reaction mass is poured into a mixture of ice water and citric acid and extracted with ethyl acetate. The extract is washed successively 10% aqueous citric acid solution, water and brine, and then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, the residue was washed with n-hexane, giving 4-(3-chloro-4-methoxybenzylamine)-5-etoxycarbonyl-2-methylthiopyrimidine (38.34 g), so pl. S.

(2) Under ice cooling to a solution of the above compound (5.00 g), as specified in (1), in chloroform (50 ml) Then the reaction mixture was washed with saturated aqueous sodium bicarbonate and brine, the organic layer is dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure, giving crude 4-(3-chloro-4-methoxybenzylamine)-5-etoxycarbonyl-2-methylsulfinylphenyl, MS (m/e): 447 (MH+).

(3) Obtained above crude product as specified in (2), dissolved in tetrahydrofuran (40 ml), and then at room temperature is added a solution of L-prolinol (1.50 g) and triethylamine (1.60 g) in tetrahydrofuran (10 ml). The mixture is stirred overnight, the reaction mixture was diluted with ethyl acetate and washed with aqueous sodium hydrogen carbonate solution and brine. The organic layer is dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure. The residue is purified on a chromatographic column with silica gel (solvent; chloroform) and crystallized from a mixture of ether and n-hexane, giving (S)-4-(3-chloro-4-methoxybenzylamine)-5-etoxycarbonyl-2-(2-hydroxymethyl-1-pyrrolidinyl)pyrimidine (4.72 g), so pl. 88-90 ° C, MS (m/e): 421 (MH+).

(4) the above mixture of the compound (3.4 g) as indicated in (3) and 10% aqueous sodium hydroxide solution (23 ml) and dimethylsulfoxide (34 ml) was stirred at room temperature for 15 hours. The reaction mixture was poured into 10% aqueous, dibenzylamino)-5-carboxy-2-(2-hydroxymethyl-1-pyrrolidinyl)pyrimidine (2.52 g), so pl. 205-C, MS (m/e): 391 (M-N)-.

(5) a Mixture of compound (600 mg), as indicated in (4), 2-aminomethylpyrimidine (217 mg), hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (323 mg), monohydrate of 1-hydroxybenzotriazole (227 mg) and N,N-dimethylformamide (12 ml) was stirred at room temperature for 8 hours, after which the reaction mixture is poured into aqueous sodium hydrogen carbonate solution. The mixture is extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the residue purified on a chromatographic column with silica gel (solvent; chloroform : methanol = 50:1), giving (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-pyrimidinyl)carbarnoyl]pyrimidine (610 mg), so pl. 160-C. Example 2

(1) To a suspension of almoguera lithium (4.15 g) in tetrahydrofuran (150 ml) add a solution of 2-methylthio-4-(3-chloro-4-methoxybenzylamine)-5-ethoxycarbonylpyrimidine (38.32 g) in tetrahydrofuran (100 ml) under cooling with ice at temperatures from 5 C to 10 ° C for more than one hour. After the addition the ice bath removed and the reaction mixture was stirred at room temperature for one hour. Then to the reaction mixture added to the mixture was added water (4.15 ml) three times and stirred at room temperature for one hour. The reaction mixture is treated with magnesium sulfate and the precipitated solid precipitate filtered. The precipitate is washed with tetrahydrofuran. The filtrate and wash water are combined and concentrated under reduced pressure and then triturated with a mixture of ethyl acetate and isopropyl ether. The resulting crystals are collected by filtration and washed thoroughly with isopropyl ether gives 2-methylthio-4-(3-chloro-4-methoxybenzylamine)-5-hydroxyethylpyrrolidine in the form of a pale yellow crystalline powder.

The first portion: output 25.10 g, so pl. 162-S.

Second serving: yield 2.32 g, so pl. 159-160S.

Additionally obtained above solid residue is washed again with isopropyl ether and the filtrate concentrated under reduced pressure, giving colorless crystals. The obtained solid is suspended in isopropyl ether, filtered and the precipitate washed thoroughly with isopropyl ether and hexane, and then get 2-methylthio-4-(3-chloro-4-methoxybenzylamine)-5-hydroxyethylpyrrolidine (4.26 g) in the form of colorless crystals, so pl. 161-S.

(2) To a suspension of 2-methylthio-4-(3-chloro-4-methoxybenzylamine)-5-hydroxyethylpyrrolidine (25.10 g) obtained above in (1), in chloroform (150 ml) is added a powder of manganese dioxide is make powder of manganese dioxide (12.6 g, 0.5 part of the initial connection), and the mixture is again stirred for three days. Insoluble products are rapidly removed by filtration on celite, and the filtrate concentrated under reduced pressure. The residue is suspended in a mixture of ethyl acetate and isopropyl ether. The precipitate is filtered and washed successively with isopropyl ether and hexane, giving 2-methylthio-4-(3-chloro-4-methoxybenzylamine)-5-formylpyridine (at 22.43 g) as colourless crystals, so pl. 124-125C.

(3) a Solution of 2-methylthio-4-(3-chloro-4-methoxybenzylamine)-5-formylpyridine (2.057 g) in chloroform (20 ml) was treated with m-chloroperbenzoic acid (80%, 1.468 g) at 0°C for 30 minutes. To the reaction mixture add L-prolinol (0.901 g) and then triethylamine (1.33 ml), and the reaction proceeds at 0°C for one hour. The reaction mixture is heated to room temperature and diluted with ethyl acetate. The mixture is washed successively with a saturated aqueous solution of sodium bicarbonate, water and saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The precipitate is removed by filtration through silicagel pillow. The filtrate is concentrated under reduced pressure, giving (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine) 5S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-formylpyridine (91.0 mg) in tetrahydrofuran (20 ml) is added 1.10 M solution metallice in ether (1.1 ml) at-S, after which the mixture react for 10 minutes, then to it was added an aqueous solution of sodium bicarbonate. The reaction mixture was extracted with ethyl acetate, giving crude (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-(1-hydroxyethyl)pyrimidine, MS (m/e): 393 (MH+).

(5) the Crude product obtained above, as indicated in (4), is treated with manganese dioxide (0.5 g) at room temperature, after which the mixture is stirred over night. Then the reaction mixture is heated at the boil under reflux for 5 hours and the insoluble products are removed by filtration. The filtrate is concentrated under reduced pressure and purified through column chromatography with silica gel (solvent; chloroform : ethyl acetate = 3:1), giving (S)-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-acetylpyridine (56.7 mg) as colorless oil, MS (m/e): 391 (MH+).

Example 3

(1) To a solution of (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-formylpyridine (84 mg) in tetrahydrofuran (about 1 ml) add one drop of 1.0 M solution of vinylboronic magnesium in tetrahydrofuran in a dry bath of ice and acetone. The reaction mixture was stirred at-S within 10 mine aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer is washed successively with water and brine, dried over anhydrous sodium sulfate, then concentrated under reduced pressure.

The result of the above crude product is subjected to preparative thin-layer chromatography (solvent; ethyl acetate : methanol = 20:1), giving (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-(1-hydroxy-2-propen-1-yl)pyrimidine (30 mg) as a colourless oil, MS (m/e): 405 (MH+).

(2) To a solution of (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-(1-hydroxy-2-propen-1-yl)pyrimidine (144 mg) in chloroform (2.5 ml) is added manganese dioxide (432 mg) and the mixture vigorously stirred at room temperature for three days. Insoluble products are separated by filtration on celite and the filtrate concentrated under reduced pressure, giving a pale yellow oil (124 mg). The resulting crude product was then purified through column chromatography with silica gel (silica gel 20 g, solvent; chloroform : ethyl acetate = 2:1), giving (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-(acryloyl)pyrimidine (90 mg) as colorless crystals, so pl. 113-115S, MS (m/e): 403 (MH+).

(3) To a solution of (S)-2-(2-hydroxymethyl-1-pyrrole anatoy temperature and the mixture is stirred at room temperature for 40 minutes. Then the reaction mixture was concentrated under reduced pressure and the residue poured into water, whereupon the mixture is extracted with ethyl acetate. The organic layer is washed successively with water and brine, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure, giving (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[(2-morpholinoethyl)carbonyl]pyrimidine (91 mg).

The result of the above crude product is dissolved in ethyl acetate (10 ml) and the solution treated with a saturated solution of hydrochloric acid in methanol (5 ml) and concentrate under reduced pressure. To the residue is added ethyl acetate and the mixture filtered. The obtained solid is washed with hexane, giving (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[(2-morpholinoethyl)carbonyl]pyrimidine of dihydrochloride (65 mg), MS (m/e): 490 (MN+).

Example 4

(1) Under cooling with ice to a solution of 4-(3-chloro-4-methoxybenzylamine)-5-etoxycarbonyl-2-methylthiopyrimidine (972 mg) obtained above, as described in example 1-(1) in chloroform (8 ml) add a solution of m-chloroperbenzoic acid (80%, 598 mg) in chloroform (10 ml) over 30 minutes. The reaction mixture was stirred under ice cooling in motorowy layer is collected, washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure, which gives a quantitative yield of 2-methylsulfinyl-4-(3-chloro-4-methoxybenzylamine)-5-ethoxycarbonylpyrimidine in the form of colorless caramels, MS (m/e): 384 (MH+).

(2) Under ice cooling to a solution of 2-methylsulfinyl-4-(3-chloro-4-methoxybenzylamine)-5-ethoxycarbonylpyrimidine (total number) obtained above, as specified in (1), in tetrahydrofuran (6 ml) is added drop by drop 2N aqueous sodium hydroxide solution (1.32 ml) for more than 2 minutes. The reaction mixture was stirred under ice cooling for 30 minutes and to it was added tetrahydrofuran (8 ml) and N,N-dimethylacetamide (6 ml). Then again stirred under ice cooling for 30 minutes and then add water (5 ml) and N,N-dimethylacetamide (2 ml) and then stirred under ice cooling for one hour. The reaction mixture was acidified with 10% aqueous citric acid solution, diluted with water and extracted twice with ethyl acetate. The extracts are combined, washed with water and saturated aqueous sodium chloride, dried over besod the e with silica gel (silica gel: 20 g, solvent; chloroform : ethyl acetate = 5:1 chloroform : isopropanol = 30:1), which gives 2-hydroxy-4-(3-chloro-4-methoxybenzylamine)-5-ethoxycarbonylpyrimidine (618 mg) as a slightly yellow crystalline powder, so pl. 195-S.

(3) a Mixture of 2-hydroxy-4-(3-chloro-4-methoxybenzylamine)-5-ethoxycarbonylpyrimidine (500 mg) obtained above, as specified in (2), diethylaminobenzoic (2 ml) and phosphorus oxychloride (4 ml) was stirred at 80C for 30 minutes and then at 100C for 5 hours. After cooling reaktsionny the solution is poured into ice water and the mixture is stirred at room temperature for 30 minutes. Then it is extracted with ethyl acetate and the organic layer washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified on a chromatographic column with silica gel (silica gel: 7 g, solvent; chloroform), giving 2-chloro-4-(3-chloro-4-methoxybenzylamine)-5-ethoxycarbonylpyrimidine (375 mg) as a slightly yellow crystalline powder, so pl. 114-115, MS (m/e): 356 (MH+).

(4) a Mixture of 2-chloro-4-(3-chloro-4-methoxybenzylamine)-5-ethoxycarbonylpyrimidine (285 mg) obtained above, as indicated in (3), 5,6,7,8-tetrahydroimidazo[1,2-a]feast the and then for a further 2.5 hours at 60C. The reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate and the organic layer washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified on a chromatographic column with silica gel (silica gel: 10 g, solvent; chloroform : methanol = 50:1) and concentrate under reduced pressure. The reaction mixture was treated with isopropyl ether gives 2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamine)-5-ethoxycarbonylpyrimidine (290 mg) as colorless crystalline powder, so pl. 179-C, MS (m/e): 443 (MH+).

(5) a Suspension of 2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamine)-5-ethoxycarbonylpyrimidine (290 mg), obtained as described in (4), and 2N aqueous solution of sodium hydroxide (1.64 ml) in a mixture of dimethyl sulfoxide (5 ml) and water (1 ml) was stirred at room temperature for one hour. Then the mixture was added tetrahydrofuran (5 ml) and stirred at room temperature for 13 hours. The tetrahydrofuran evaporated under reduced pressure and the resulting solution was diluted with water and neutralized 10% aqueous ), that gives 2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamine)-5-carboxyamide (187 mg) as colorless crystalline powder, so pl. 223-C (decomposition), MS (m/e): 413 (M-N)-.

(6) a Mixture of 2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamine)-5-carboxamidine (60 mg), 4-methyl-2-aminoadamantane (22.7 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30.6 mg), 1-hydroxybenzotriazole (21.6 mg) and N,N-dimethylformamide (3 ml) was stirred at room temperature for 22 hours. In the reaction mixture, pour the water and the mixture extracted with ethyl acetate. The organic layer is washed successively with water, saturated aqueous sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, giving colorless crystals (70.0 mg), which is recrystallized from a mixture of chloroform and hexane, which leads to 2-(5,b,7,8 tetrahydroimidazo[1,2-a]-pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-[(4-methyl-2-morpholinyl)methyl]carbarnoyl]pyrimidine (51.7 mg) as colourless needles, so pl. 132-C, MS (m/e): 527 (MN+).

Examples 5-6

The corresponding source products similarly processed the tx2">

Example 7-21

The corresponding source products similar process that gives the compounds presented in table 2.

Example 22

(1) To a solution of Diisopropylamine (0.78 g) in tetrahydrofuran (40 ml) drop by drop add 1.6 M solution of n-utility in hexane (4.82 ml) in a dry bath of ice and acetone for more than 3 minutes. The mixture is stirred in the same bath for 30 minutes. Then added to the mixture drop by drop a solution of 2,6-dichloropyrazine (0.50 g) in tetrahydrofuran (5 ml) at the same temperature for 15 minutes, after which the mixture is stirred for one hour. The reaction mixture was poured into dry ice and the mixture is stirred at room temperature for one hour. Then diluted with 10% aqueous solution of hydrochloric acid to bring the pH value to about 2, and then extracted with ethyl acetate. The combined organic layers extracted with saturated aqueous sodium hydrogen carbonate and aqueous extract is washed with ethyl acetate, acidified with 10% aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous sulfate on the Sabbath.-carboxy-3,5-dichloropyrazine (234 mg) as a slightly brown crystalline powder so pl. 139-C, MS (m/e): 191 (M-N)-.

(2) a Mixture of 2-carboxy-3,5-dichloropyrazine (226 mg) obtained above, as specified in (1), sodium hydrogen carbonate (118 mg), methyl iodide (0.5 ml) and N,N-dimethylformamide (1.8 ml) was stirred at room temperature for 14 hours. The mixture is diluted with 10% aqueous citric acid solution and extracted with ethyl acetate. The combined organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure, giving 2-methoxycarbonyl-3,5-dichloropyrazine (245 mg) as a pale brown crystalline powder, so pl. 60-S, MS (m/e): 206 (M+).

(3) a Mixture of 2-methoxycarbonyl-3,5-dichloropyrazine (234 mg) obtained above, as specified in (2), 3-chloro-4-methoxybenzylamine (204 mg), triethylamine (0.17 ml) and dry toluene (3 ml) was stirred at room temperature for 7 hours. The reaction mixture was diluted with 10% aqueous citric acid solution and extracted with ethyl acetate. The extract is washed with water and saturated aqueous sodium chloride, dried over sodium sulfate and concentrate under reduced pressure. The residue was separated and purified through column chromatography with silica gel (silical 2-methoxycarbonyl-3-(3-chloro-4-methoxybenzylamine)-5-chloropyrazine (102 mg) as a pale yellow crystalline powder, so pl. 149-C, MS (m/e): 342 (MN+).

(4) a Mixture of 2-methoxycarbonyl-3-(3-chloro-4-methoxybenzylamine)-5-chloropyrazine (150 mg), 2-hydroxyethylpyrrolidine (88.6 mg) and triethylamine (0.12 ml) in tetrahydrofuran (5 ml) was stirred at room temperature for 4 hours and heated at 50C for 2 hours. Then to the mixture is added 2-hydroxyethylpyrrolidine (44.3 mg) and stirred at 50C for one hour. After cooling, add water to the mixture and extracted with ethyl acetate. The extract is washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained yellow oil is purified on a chromatographic column with silica gel (solvent; chloroform : hexane = 1:1), giving (S)-2-methoxycarbonyl-3-(3-chloro-4-methoxybenzylamine)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazin (123 mg) as a pale yellow powder, MS (m/e): 407 (MH+).

(5) To a solution of (S)-2-methoxycarbonyl-3-(3-chloro-4-methoxybenzylamine)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazine (775 mg) obtained above, as indicated in (4), in ethanol (8 ml) is added 4N aqueous sodium hydroxide solution (1.43 ml) and the mixture is stirred at room temperature for 24 hours. The reaction mixture was acidified with 10% aqueous solution with the m sodium sulfate, concentrate under reduced pressure and washed disapprovin alcohol, which gives (S)-2-carboxy-3-(3-chloro-4-methoxybenzylamine)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazin (537 mg) as yellow crystals, so pl. 169-171°C; MS (m/e): 391 (M-N)-.

(6) a Mixture of (S)-2-carboxy-3-(3-chloro-4-methoxybenzylamine)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazine (80 mg) obtained above, as indicated in (5), 2-aminomethylpyrimidine (26.7 mg), 1,2-dichloroethane (43 mg), 1-hydroxybenzotriazole (30.3 mg) in N,N-dimethylformamide (3 ml) was stirred at room temperature for 18 hours. In the reaction mixture is poured onto water and extracted with ethyl acetate. The extract is washed with water, saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified on a chromatographic column with silica gel (solvent; ethyl acetate), giving (S)-2-[N-(2-pyrimidinyl)carbarnoyl]-3-(3-chloro-4-methoxybenzylamine)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazin (87.6 mg), MS (m/e):484 (MN+).

Examples 23-24

The corresponding source products similar process as outlined in example 22, which gives the compounds presented in table 3.

The use of the g), methanol (1 ml) and concentrated sulfuric acid (one drop) is heated at the boil under reflux for 2 days. After the reaction completed, the solvent is evaporated under reduced pressure and the residue separated by thin-layer chromatography on silica gel (solvent; chloroform : methanol = 30:1), giving (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[(2-methoxyethyl)carbonyl] pyrimidine (27 mg) as a colourless oil, MS (m/e): 435 (MH+).

Example 26

A solution of (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-pyrimidinyl)carbarnoyl]pyrimidine (82.48 g) and monohydrate benzosulfimide (60.06 g) in methanol (1000 ml), concentrated and recrystallized from a mixture of methanol and acetone, which gives (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-pyrimidinyl)-carbarnoyl]pyrimidine dibenzosuberane (121.8 g) as colourless crystals, so pl. 158.5-161.5 C.

Example 27

A mixture of (S)-4-(3-chloro-4-methoxybenzylamine)-5-carboxy-2-(2-hydroxymethyl-1-pyrrolidinyl)pyrimidine (100 mg) obtained above in example 1-(4), 4-amino-1,3,5-trimethylpyrazole (47.9 mg), hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (58.7 mg), monoscene 8 hours and poured into aqueous sodium hydrogen carbonate solution. The mixture is extracted with ethyl acetate and the organic layer washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the residue purified on a chromatographic column with silica gel (solvent; chloroform : methanol = 5:1), giving (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(1,3,5-trimethyl-4-pyrazolyl)carbarnoyl] pyrimidine (115 mg), MS (m/e): 500 (MN+).

Example 28

(1) a Solution of 4-chloro-5-etoxycarbonyl-2-methylthiopyrimidine (5.0 g) in sulfurylchloride (20 ml) is heated at 50C for one hour. The reaction mixture was concentrated and then she poured a saturated aqueous solution of sodium bicarbonate. The mixture is extracted with ethyl acetate and the organic layer washed with water and brine, dried over sodium sulfate and concentrated. The residue is purified flash chromatography on a column of silica gel (solvent; ethyl acetate : hexane = 1:10), which gives a quantitative yield of 2,4-dichloro-5-ethoxycarbonylpyrimidine (4.87 g) as a yellow oil, MS (m/e): 220 (M+).

(2) To a solution of 2,4-dichloro-5-ethoxycarbonylpyrimidine (4.2 g) obtained above, as specified in (1), and mercaptobenzoic (2.30 g) in toluene (40 ml) add sodium carbonate at 50 ° C for one hour, and then at 100C for 10 minutes. Then the mixture pour in water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue is purified flash chromatography on a column of silica gel (solvent; ethyl acetate : hexane = 1:20 ethyl acetate : hexane = 1:10), which gives 2-chloro-4-phenylthio-5-ethoxycarbonylpyrimidine (4.16 g) as colourless crystals, MS (m/e): 295 (MN+).

(3) To a solution of 2-chloro-4-phenylthio-5-ethoxycarbonylpyrimidine (4.05 g), obtained above, as specified in (2), in tetrahydrofuran (40 ml), add L-prolinol (1.66 g) and triethylamine (2.77 g) and the mixture is stirred at room temperature for 20 hours. In the reaction mixture pour in water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrate under reduced pressure. The residue is purified flash chromatography on a column of silica gel (solvent; ethyl acetate : hexane = 1:2), giving (S)-2-(2-hydroxymethyl - 1-pyrrolidinyl)-4-phenylthio-5-ethoxycarbonylpyrimidine (4.16 g) as colorless viscous oil, MS (m/e): 360 (MH+).

(4) To a solution of (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-phenylthio-5-ethoxycarbonylpyrimidine (4.10 g) obtained above as indicated is the temperature for 15 hours. To the reaction solution was added 10% aqueous citric acid solution (30 ml) until the solution is weakly acidic, and the mixture is extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated, giving (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-phenylthio-5-carboxyamide (3.65 g) as colourless crystals, MS (m/e): 330 (M-N)-.

(5) a Mixture of (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-phenylthio-5-carboxamidine (2.55 g) obtained above, as indicated in (4), 2-aminomethylpyrimidine (1.09 g), 1,2-dichloroethane (1.77 g) and 1-hydroxybenzotriazole (1.25 g) in N,N-dimethylformamide (40 ml) was stirred at room temperature for 16 hours. Then the mixture pour in water and extracted with ethyl acetate. The organic layer is washed with water, saturated aqueous sodium hydrogen carbonate solution and brine, dried over sodium sulfate and concentrated, giving a pale-yellow crystals (4.05 g), which further purified flash chromatography on a column of silica gel (solvent; ethyl acetate), giving 2-(2-hydroxymethyl-1-pyrrolidinyl)-4-phenylthio-5-[N-(2-pyrimidinyl)carbarnoyl]pyrimidine (2.39 g) as colourless crystals, so pl. 154-C, IR (Nujol): 1633 cm-1MS (m/e): 423 (MH+).

obtained above, as indicated in (5), in chloroform (3 ml) is added m-chloroperbenzoic acid (70.1 mg) at 0C and the mixture was stirred at 0C for 30 minutes. Then to the mixture is added 3-chlorobenzylamino (50.3 mg) and triethylamine (48.0 mg) at 0C and stirred at room temperature for 17 hours. After that, the mixture pour in water and extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure, giving a yellow oil (169 mg), which was purified flash chromatography on a column of silica gel (solvent; ethyl acetate) and ground to powder with a mixture of ethyl acetate and hexane, giving (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chlorobenzylamino)-5-[N-(2-pyrimidinyl)carbarnoyl]pyrimidine (95.3 mg) as colorless powder, so pl. 153-C, IR (Nujol): 3241, 1637 cm-1MS (m/e): 454 (MH+).

(7) To a solution of (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-phenylthio-5-[N-(2-pyrimidinyl)carbarnoyl]pyrimidine (100 mg) obtained above, as indicated in (5), in chloroform (3 ml) is added m-chloroperbenzoic acid (70%, 70.1 mg) at 0C and the mixture was stirred at 0C for 30 minutes. Then to the mixture is added 4-methoxybenzylamine (48.8 mg) and triethylamine (48.0 mg) at 0C and stirred at room temperature for 20 the d sodium sulfate and concentrated, that gives a yellow oil (143 mg), which was purified flash chromatography on a column of silica gel (solvent; ethyl acetate), giving (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(4-methoxybenzylamine)-5-[N-(2-pyrimidinyl)carbarnoyl]pyrimidine (88.2 mg) as colorless powder, IR (pure): 3296, 1633 cm-1MS (m/e): 450 (MH+).

Example 29

(1) a Solution of (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-formylpyridine (10.0 mg) in tetrahydrofuran (1.0 ml) obtained above in example 2 (3), treated with 1.6 m solution of n-utility in hexane (83 μl) S for 3 minutes, then add aqueous solution of sodium bicarbonate. The reaction mixture was extracted with ethyl acetate, giving (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-(1-hydroxyphenyl] pyrimidine (13.7 mg) in the form of butter.

(2) (S)-2-(2-Hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-(1-hydroxyphenyl)pyrimidine, obtained as above, is treated with manganese dioxide (25 mg) at room temperature and the resulting mixture was gradually add the additional amount of manganese dioxide (100 mg), then stirred overnight. The reaction mixture is heated at boiling with reverse holodilnikovoj and separated using preparative thin-layer chromatography, that gives (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-pentanolide (5.8 mg) as colorless oil, MS (m/e): 433 (MH+).

Examples 30-83

The corresponding starting compound is treated in the similar method that gives the compounds listed in table 4.

Examples 84-86

The corresponding starting compound is treated in the same method that network connections are listed in table 5.

Example 87

A mixture of (S)-2-carboxy-3-(3-chloro-4-methoxybenzylamine)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazine (80 mg) obtained above in example 22 (5), 2-aminomethyl-4-methylmorpholine (31.9 mg), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (43 mg), 1-hydroxybenzotriazole (30.3 mg) in N,N-dimethylformamide (3 ml) stirred at room temperature for 18 hours. In the reaction mixture pour in water and extracted with ethyl acetate. The extract is washed with water, saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified flash chromatography on a column of silica gel (solvent; e is pyrrolidinyl)pyrazin (80.5 mg), MS (m/e): 505 (MH+), IR (Nujol): 3295, 1635 cm-1.

Examples 88-91

The corresponding starting compound is treated in the similar method that gives the compounds listed in table 6.

Examples 92-145

The corresponding starting compound is treated in the similar method that gives the compounds listed in table 7.

Example 146

The corresponding starting compound is treated in the similar method that gives compound of the following formula in the form of a foam, MS (m/e): 464 (MH+)

Example 147

The corresponding starting compound is treated in the similar method that gives compound of the following formula, so pl. 140--144 P

Example 148

To a solution of (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-pyrimidinyl)carbarnoyl]pyrimidine (307 mg) obtained above in example 1-(5), in methylene chloride (6 ml) is added drop by drop bromide bromide (300 μl) under ice cooling. The reaction mixture is stirred at 0C for 4 hours, and then add methanol and a saturated aqueous solution hydrocarbons washed successively with water and brine. The mixture is dried over sodium sulfate and concentrated under reduced pressure, giving a slightly brown amorphous substance (227 mg). It is suspended in chloroform and the resulting insoluble products are removed by filtration. The filtrate is subjected to chromatography on a column of silica gel and then purified using column chromatography on NH-silica gel, which gives (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-hydroxybenzylidene)-5-[N-(2-pyrimidinyl)carbarnoyl]pyrimidine (129 mg) as a colourless foam, MS (m/e): 470 (MH+), IR (Nujol): 3279, 1632, 1593, 1569, 1518, 1463 cm-1.

Example 149

(1) a Suspension of 2-methylthio-4-(3-chloro-4-methoxybenzylamine)-5-ethoxycarbonylpyrimidine (2.00 g) obtained above in example 1 (1), in dimethyl sulfoxide (10 ml) is treated with 10% aqueous sodium hydroxide solution (10 ml) at room temperature. To the reaction mixture are added dimethyl sulfoxide (5 ml) and stirred at room temperature overnight. To the resulting colorless solution was added citric acid until the solution becomes acidic. To the solution was added an excess amount of water (about 50 ml) and the precipitate collected by filtration. Sludge is washed with isopropyl alcohol and isopropyl(1.864 g) as pale yellow fine powder so pl. 238-C (decomposition).

(2) To a suspension of 4-(3-chloro-4-methoxybenzylamine)-5-carboxy-2-methylthiopyrimidine (200 mg) in methylene chloride (5 ml) add oxalicacid (150 mg) and N,N-dimethylformamide and the mixture is stirred at room temperature for 30 minutes and concentrated. To a suspension of the obtained acid chloride and 5-aminopyrimidine (84.0 mg) in methylene chloride (5 ml) add dimethylaminopyridine (144 mg) at room temperature and the mixture is stirred at room temperature. Then the mixture pour in water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate, water and brine, dried over sodium sulfate and concentrated. The residue is treated with a mixture of ethyl acetate and n-hexane, giving 4-(3-chloro-4-methoxybenzylamine)-5-(5-pyrimidinemethanol)-2-methylthiopyrimidine (216 mg) as pale yellow needles, so pl. 238-C, IR (Nujol): 3251, 1666 cm-1MS (m/e): 416 (M+).

(3) To a suspension of the compound (150 mg) obtained above, as specified in (2), in chloroform (10 ml) is added m-chloroperbenzoic acid (107 mg) at 0C and the mixture was stirred at 0C for one hour, then at room temperature for another one hour. Then to the mixture is added m-globerman the min (72.9 mg) at 0C and the mixture is stirred at room temperature for 20 hours. Then the mixture pour in water and extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure, giving a yellow viscous oil (201 mg), which was purified using flash chromatography on NH-silikagelevye column (solvent; ethyl acetate), washed with a mixture of ethyl acetate and hexane, giving (S)-4-(3-chloro-4-methoxybenzylamine)-5-(5-pyrimidinemethanol)-2-(hydroxymethyl-1-pyrrolidinyl)pyrimidine (81 mg) as colourless needles, so pl. 192-S, IR (Nujol): 3279, 1669 cm-1MS (m/e): 470 (MH+).

Examples 150-157

The corresponding starting compound is treated in the similar method that gives the compounds listed in table 8.

Example 158

(1) a Suspension of 4-(3-chloro-4-methoxybenzylamine)-5-carboxy-2-methylthiopyrimidine (154.0 mg) obtained above in example 149 (1), in methylene chloride (5 ml) is treated with oxalylamino (119 μl) at room temperature and to it was added N,N-dimethylformamide. The mixture is stirred for one hour and the solvent evaporated under reduced pressure. The residue is treated with ether and kept in the refrigerator over night. Volatile products are removed under reduced pressure and the OST is of zakolerovat methanol and the mixture is purified using chromatography on silica gel (solvent; hexane : ethyl acetate = 2:1), giving 4-(3-chloro-4-methoxybenzylamine)-5-(diazomethylene)-2-methylthiopyrimidine (21.5 mg) as a pale yellow solid, IR (Nujol): 3277, 2115, 1607, 1567, 1461, 1377, 1357, 1141 cm-1MS (m/e): 364 (MH+), so pl. 162-C (decomposition).

(2) Suspension of the compound, obtained above, as specified in (1), (16.5 mg) in methanol (3 ml) is treated with toluenesulfonic acid monohydrate (16.5 mg) at room temperature. The solvent is evaporated under reduced pressure and the residue purified preparative TLC (solvent; hexane : ethyl acetate = 2:1), giving 4-(3-chloro-4-methoxybenzylamine)-5-(ethoxymethylene)-2-methylthiopyrimidine (11.0 mg) as a colourless oil.

(3) Solution of the compound (11.0 mg) obtained above (2), in chloroform (1 ml) was treated with m-chloroperbenzoic acid (7.4 mg) at 0C. The mixture is treated with triethylamine (8.3 ml) and L-prolinol (36 mg) at room temperature and the resulting reaction mixture is stirred over night. Then it is diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride and dried over sodium sulfate. The residue is purified preparative TLC (solvent; chloroform : ethyl acetate = 1:1), giving (S)-4-(stvennogo oil, MS (m/e): 421 (MH+).

Industrial applicability

The compound (I) in accordance with the present invention and its pharmaceutically acceptable salt demonstrate excellent PDE V inhibitory activity and they are used as pharmaceutical compounds for the prevention and treatment of diseases such as erectile dysfunction, dysfunction, etc.

The results of pharmacological experiments

Experiment 1. Inhibitory activity against phosphodiesterase (PDE V)

[PDE V]

The lung homogenate extracted from the half-male, centrifuged, and the supernatant fractionary method anion-exchange column chromatography. Fractions satisfying the following conditions 1-5, mix and get a sample of partially purified PDE V

Condition 1. It can selectively hydrolyze cGMP.

Condition 2. On gidrolizuemye activity against cGMP is not affected by EGTA*1or calmodulin.

Condition 3. Its activity is not inhibited by selective inhibitors of phosphodiesterase III From1930*2.

Condition 4. Its activity is not inhibited by selective inhibitors of phosphodiesterase IV rolipram*3.

The us is eczane]

*1 - EGTA represents forming a chelate complex with the calcium agent of the formula (xv)

[-CH2OCH2CH2N(CH2COOH)2]2(XV),

which can inhibit the activity of PDE I, forming a chelate complex with calcium ion in the enzyme solution.

*2 - CI930 is a selective inhibitor of PDE III of the formula (xvi)

It is used to confirm the absence of impurities PDE III in a solution of the enzyme PDE V

*3 - Rolipram is a selective inhibitor of PDE IV formula (xvii)

It is used to confirm the absence of impurities PDE IV enzyme solution PDEV.

*4th-4021 is a selective inhibitor of PDE V formula (xviii)

[Measurement of the activity of PDE V]

The measurement is carried out using a partially modified method of procedure Thompson et al. (see Advances in Cyclic Nucleotide Research, Vol. 10, Raven Press, New York, pp. 69-92, 1979) as follows.

A sample of partially purified PDE V diluted in 50 mm Tris-Hcl (pH 8.0) so that it was possible to hydrolyze about 10% of the total substrate. The specified sample (100 µl) was injected into the glass tube. In a test tube add buffer for analysis (50 mm Tris-HCl, pH 8.0, soderjatelinii examples) (100-fold concentration) in dimethyl sulfoxide. After incubation at C for 5 minutes add 2.5 μm [3H]-cGMP (3,7 kBq/200 ml) (200 ml) to initiate the reaction (final concentration 50 mm Tris-HCl, pH 8.0, 5 mm MgCb, 4 mm 2-mercaptoethanol). After interaction with S within 30 minutes, the test tube is transferred to a boiling water bath to terminate the reaction. After 90 seconds, the tube is transferred to the bath with a mixture of ice water to cool the reaction mixture to room temperature. After pre-incubation at C for 5 minutes in a test tube add an aqueous solution (100 µl) of snake venom and conduct the reaction mixture at C within 30 minutes. The reaction is stopped by adding in a test tube methanol (500 μl) and the reaction mixture (1 ml) was loaded into a column Packed with resin Dowex (trade name Dowex 18, is made by Sigma Inc.) (200 ml). The resin is washed with methanol (1 ml). The reaction solution passed through the column, together with a wash solution, and determine the activity of PDE V in the combined solution, determining the radioactivity of [3H]-guanosine in solution.

The same procedure is carried out for solution-dummy (use only buffer for analysis without adding the sample enzyme) and solvent (DMSO) instead of experiencing any determine calculating the percentage inhibitory activity of each test compound relative to the inhibitory activity of control solution, and inhibitory activity against PDE V is assessed according to the IC50(i.e. the number (nm) of the test compound showing the degree of inhibition of 50% relative to control). IC50calculated by the method of linear regression-based inhibitory concentrations for 3 or more concentrations of the test compounds. The results are shown in table 9.

Experiment 2. Relaxation of cavernous bodies, dissected from rabbit

[Sample]

Using new Zealand white rabbits (aged 10-20 weeks). Immediately after rabbits killed, his blood under anaesthesia, the penis of excised rabbit cavernous body. After removal of connective tissue isecheno the cavernous body cut into strips (approximately 5 mm) and receive samples. For samples in the form of strips give a residual load of 1.5 g in vitro Magnus containing nutrient fluid* (10 ml), and the voltage on the sample stabilize for approximately 60 minutes. After podtverzdeniye. During the test, the culture fluid is maintained at a temperature of 37±0.5 s when passing gas 95% O2- 5% CO2. Isometric tension was measured using a U-shaped sensor and amplifier deformation (series A, manufactured by Nippon Koden) and recorded on a pen recorder (Graphtec Multicorder MC6621).

*) Culture fluid contains 118,0 mm NaCl; 4,7 mm KCl; 1.5 mm l2; 1.2 mm KN2RHO4; 1.2 mm MgSO4; 25.0 mm NaHCO3; 11,0 mm glucose and 0,023 mm etc.

[Relaxation of the sample reduced by phenylephrine]

The sample is reduced under the action of phenylephrine. After reduction of the samples, which became the continuous phase, the cumulative added test compound in an amount of 0.1, 1, 10, 100 and 1000 nm with an interval of 30 minutes. Finally, add papaverine (100 μm), which determine the maximum response of relaxation. The degree of relaxation of the test compounds at each concentration is calculated based on the maximum relaxation under the action of papaverine (100 μm) which is taken for 100%. The degree of relaxation of the test compounds was evaluated as EU30(i.e., the number (nm) of the test compounds, in which observe the degree of relaxation in 30% of relaxation in the case of the second composition in the form of tablets.

To (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-pyrimidinyl)carbarnoyl]pyrimidine (i.e., the inhibitor of PDE-V) (250 g), mannitol (325 g) and fumaric acid (100 g) added 25 wt.% an aqueous solution of hydroxypropylcellulose (HPC-SL, Nippon Soda Co., Ltd.) (70 g) and mixed for granulation using a planetary mixer (5DMV-01-r, Dalton Co., Ltd.). The granules are dried, sorted by size using a classifier (P-02S, Dalton Co., Ltd.) and sieved through sieve No. 22. To the aliquot (650 g) of the obtained granules add hydroxypropylcellulose with a low degree of substitution (L-LDCs, Shin-Etsu Chemical Co., Ltd.) (41,9 g) and magnesium stearate (7.0 g) and mixed using a drum mixer of double conical type (Yashima Chemical Engineering Co., Ltd.) at 55 rpm for 3 minutes and get a granule for tableting. The granules are compressed on a rotary teletrauma machine (SRS HUK-DC-AWC, Kikusui Seisakusyo Ltd., punch 07,5, 11R, a pressure of 6 kN/punch) and receive a tablet containing an inhibitor of PDE-V (150 mg/tablet).

Data on the toxicity of:

Oral introduction of the short-legged hounds compound of example 1 at a dose of 100 mg/kg in one week no animal died.

1. Aromatic nitrogen-containing 6-membered cyclic compound of the formula (I)

1-6alkyl group, (2) replacement C1-6alkyl group, (3) formyl group, (4) carbonyl group, (5) amino, (6) hydroxy-group, (7) (C1-6alkoxy)carbonyl group, (8)pyrimidines group, substituted (i) benzylaminocarbonyl substituted by a halogen atom, and C1-6alkoxygroup, and (ii) (C3-8cycloalkyl)carbamoyl group substituted by a hydroxy-group;

R1represents (1) substituted C1-6alkyl group which may be optionally substituted by a group selected from the group consisting of C1-6alkoxygroup, hydroxy-group, morpholinyl group, C1-6alkylsulfonyl group, di(C1-6alkyl)phosphinic group, di(C1-6alkyl)amino group, pyrimidinylidene C1-6alkylamino, peredelnoj group, pyridylamino and C1-6alkyl substituted piperazine: -NH-R4where R4has the values defined below, (2) a group of the formula-NH-Q-R3(in which R3represents a substituted nitrogen-containing heterocyclic group, where the nitrogen-containing heterocyclic group is a 5 - or 6-membered nitrogen-containing heterogeneities group having 1-2 nitrogen atom, and also may contain an oxygen atom or sulfur in the heterocyclic residue, or an 8-10-membered nitrogen-containing heterobicyclic group having 1-3 nitrogen atom and also may contain an oxygen atom or sulfur in the heterocyclic residue; Deputy nitrogen-containing heterocyclic group selected from the group consisting of C1-6alkyl groups, replacement of the C1-6alkyl group, carbonyl group, amino group, di(C1-6alkyl)amino, C2-7alkanoyloxy group and lanzamientos C1-6alkyl group, and Q represents C1-6alkylenes group or a simple bond) or (3) a group of the formula-NH-R4(in which R4represents a substituted C3-8cycloalkyl group which may be optionally substituted by a group selected from the group consisting of hydroxy-group, C1-6alkoxygroup and pyrimidinylidene group, selected from the group consisting of C1-6alkoxygroup, halogen atom, ceanography, nitro, hydroxy-group and C1-6alkyl groups;

one of Y and Z represents a group of formula =CH-and the other represents a group of formula =N-

or its pharmaceutically acceptable salt.

2. Connection on p. 1, in which the nitrogen-containing heterocyclic group substituted nitrogen-containing heterocyclic group" for ring a represents a 5 - or 6-membered nitrogen-containing heterogeneities group of the formula

or nitrogen-containing heterobicyclic group of the following formula, where the above 5 - or 6-membered nitrogen-containing heterophilically group and 5 - or 6-membered cyclic group are condensed:

and nitrogen-containing heterocyclic group substituted nitrogen-containing heterocyclic group" for R3represents a non-aromatic nitrogen-containing heterocyclic group of the formula

or aromatic nitrogen-containing heterocyclic group of the formula

or proppa "substituted nitrogen-containing heterocyclic group" for ring a represents a 5 - or 6-membered nitrogen-containing heterogeneities group or an 8-10-membered nitrogen-containing heterobicyclic group and Deputy mentioned "substituted nitrogen-containing heterocyclic group selected from the group consisting of a1-6alkyl groups, replacement of the C1-6alkyl group, a formyl group, a carbonyl group, R1represents a C1-6alkyl group which may optionally have a Deputy selected from the group consisting of C1-6alkoxygroup, morpholinyl group, a group of the formula-NH-Q-R3or a group of the formula-NH-R4, "substituted nitrogen-containing heterocyclic group" for R3represents 5 - or 6-membered nitrogen-containing heterogeneities group which may be optionally substituted C1-6alkyl group; R4is ciclos3-8alkyl group having a Deputy selected from the group consisting of hydroxy-group, C1-6alkoxygroup; R2represents a phenyl group having a Deputy selected from the group consisting of C1-6alkoxygroup, halogen atom, ceanography.

4. Connection on p. 3, in which the nitrogen-containing heterocyclic group substituted nitrogen-containing heterocyclic group" for ring a represents a 5 - or 6-membered nonaromatic nitrogen-containing heterogeneities group of the formula

or nitrogen-containing hemeroby romantiska group and 5 - or 6-membered aromatic nitrogen-containing heterophilically group are condensed:

nitrogen-containing heterocyclic group substituted nitrogen-containing heterocyclic group" for R3represents a non-aromatic nitrogen-containing heterogeneities group of the formula

or aromatic nitrogen-containing heterogeneities group of the formula

5. Connection on p. 1, in which ring a represents a group of the formula

R1represents a C1-6alkyl group, a C1-6alkoxy-substituted C1-6alkyl group, morpholinylmethyl C1-6alkyl group, a group of the formula-NH-Q-R3or a group of the formula-NH-R4; R3represents a group of the formula

R4represents a group of the formula

or

and R2represents a group of the formula

6. Connection on p. 1, in which the nitrogen-containing heterocyclic group substituted nitrogen-containing heterocyclic group" for ring a represents a 5 - or 6-membered nitrogen-containing heterogeneities group or an 8-10-membered nitrogen-containing heterobicyclic group and Deputy specified "froze hydroxyzinesee C1-6alkyl group, a formyl group, a carbonyl group; R1represents a C1-6alkoxy-substituted C1-6alkyl group, a group of the formula-NH-Q-R3or a group of the formula-NH-R4, "substituted nitrogen-containing heterocyclic group" for R3represents 5 - or 6-membered nitrogen-containing heterogeneities group which may be optionally substituted C1-6alkyl group; R4is a replacement WITH3-8cycloalkyl group; R2represents a phenyl group having a Deputy selected from the group consisting of C1-6alkoxygroup and halogen atom.

7. Connection on p. 6, in which the nitrogen-containing heterocyclic group substituted nitrogen-containing heterocyclic group" for ring a represents a 5 - or 6-membered nonaromatic nitrogen-containing heterogeneities group of the formula

or a group of the formula

nitrogen-containing heterocyclic group substituted nitrogen-containing heterocyclic group" for R3represents a non-aromatic nitrogen-containing heterogeneities group of the formula

aromaticas also And represents a group of the formula

or

R1represents a C1-6alkoxy-substituted C1-6alkyl group, a group of the formula-NH-Q-R3or a group of the formula-NH-R4, R3represents a group of the formula

or

R4represents a group of the formula

and R2represents a group of the formula

9. Connection on p. 1, in which the nitrogen-containing heterocyclic group substituted nitrogen-containing heterocyclic group" for ring a represents a 5 - or 6-membered nitrogen-containing heterogeneities group or an 8-10-membered nitrogen-containing heterobicyclic group and Deputy mentioned "substituted nitrogen-containing heterocyclic group" is a replacement C1-6alkyl group; R1represents a group of formula-NH-Q-R3, "substituted nitrogen-containing heterocyclic group" for R3represents 5 - or 6-membered nitrogen-containing heterogeneities group which may be optionally substituted C1-6alkyl group; R2represents a phenyl group substituted by a group selected the nitrogen-containing heterocyclic group substituted nitrogen-containing heterocyclic group" for ring a represents a 5 - or 6-membered nonaromatic nitrogen-containing heterogeneities group of the formula

or a group of the formula

nitrogen-containing heterocyclic group substituted nitrogen-containing heterocyclic group" for R3represents a non-aromatic nitrogen-containing heterogeneities group of the formula

or aromatic nitrogen-containing heterogeneities group of the formula

or

11. Connection on p. 1, in which ring a represents a group of the formula

or

R1represents a group of formula-NH-Q-R3where R3is a group of the formula

and R2represents a group of the formula

12. The compound according to any one of paragraphs.1-11, in which Y represents a group of formula =N-, and Z represents a group of formula =CH-.

13. Connection on p. 1, selected from the group including

(S)-2-(2-Hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-pyrimidinyl)carbarnoyl]pyrimidine;

2-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-6-yl)-4-(3-cyano-4-methoxybenzylamine)-5-[N-(2-pyrimidinyl)carbarnoyl]pyrimidine;

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-who lo[3,4-b]pyridine-6-yl)-4-(3-cyano-4-methoxybenzylamine)-5-[N-(TRANS-4-hydroxycyclohexyl)carbarnoyl]pyrimidine;

2-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-6-yl)-4-(3-cyano-4-methoxybenzylamine)-5-[N-(2-morpholinoethyl)carbarnoyl]pyrimidine

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-morpholinoethyl)carbarnoyl]pyrimidine;

2-[(2S)-2-hydroxymethyl-1-pyrrolidinyl]-4-(3-chloro-4-methoxybenzylamine)-5-[N-[[(2R)-4-methyl-2-morpholinyl]methyl]carbarnoyl]pyrimidine;

2-[(2S)-2-hydroxymethyl-1-pyrrolidinyl]-4-(3-chloro-4-methoxybenzylamine)-5-[N-[[(2S)-4-methyl-2-morpholinyl]methyl]carbarnoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(4-pyrimidinyl)carbarnoyl]pyrimidine;

2-(4-methyl-3-oxo-1-piperazinil)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(TRANS-4-hydroxycyclohexyl)carbarnoyl]pyrimidine;

2-(4-formyl-1-piperazinil)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(TRANS-4-hydroxycyclohexyl)carbarnoyl]pyrimidine;

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(TRANS-4-hydroxycyclohexyl)carbarnoyl]pyrimidine;

2-[CIS-2,5-bis(hydroxymethyl)-1-pyrrolidinyl]-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-pyrimidinyl)carbarnoyl]pyrimidine;

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-Piri is a melamine)-5-[N-(2-morpholinoethyl)carbarnoyl]pyrimidine;

2-(5,6,7,8-tetrahydro-1,7-naphthiridine-7-yl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-morpholinoethyl)carbarnoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-acetylpyridine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(4-pyridinylmethyl)carbarnoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(5-pyrimidinyl)carbarnoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-pyridylmethyl)carbarnoyl]pyrimidine;

(S)-2-[N-(2-pyrimidinyl)carbarnoyl]-3-(3-chloro-4-methoxybenzylamine)-5-[2-hydroxymethyl-1-pyrrolidinyl]pyrazin;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[(2-morpholinoethyl)carbonyl]pyrimidine;

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-[(4-methyl-2-morpholinyl)methyl]carbarnoyl]pyrimidine;

(S)-2-[N-(2-morpholinoethyl)carbarnoyl]-3-(3-chloro-4-methoxybenzylamine)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazin;

2-[N-(2-pyrimidinyl)carbarnoyl]-3-(3-chloro-4-methoxybenzylamine)-5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)pyrazin;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-(3-chloro-4-methoxybenzylamine)-5-[N-(1,3,5-trimethyl-4-pyrazolyl)carbarnoyl]pyrimidine

or its pharmaceutically acceptable salt.

14. Connection on p. 1, selected from the group including

(S)-2-(2-Hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-pyrimidinyl)carbarnoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(4-pyrimidinyl)carbarnoyl]pyrimidine;

2-(4-methyl-3-oxo-1-piperazinil)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(TRANS-4-hydroxycyclohexyl)carbarnoyl]pyrimidine;

2-(4-formyl-1-piperazinil)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(TRANS-4-hydroxycyclohexyl)carbarnoyl]pyrimidine;

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-pyrimidinyl)carbarnoyl]pyrimidine;

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-morpholinoethyl)carbarnoyl]pyrimidine;

2-(5,6,7,8-tetrahydro-1,7-naphthiridine-7-yl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-morpholinoethyl)carbarnoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(5-pyrimidinyl)carbarnoyl]pyrimidine;

(S)-2-[N-(2-pyrimidinyl)carbarnoyl]-3-(3-chloro-4-methoxybenzylamine)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazin;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(1,3,5-trimethyl-4-pyrazolyl)carbarnoyl]pyrimidine

or its pharmaceutically acceptable salt.

15. Connection on p. 1, selected from the group including:

(S)-2-(2-Hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-pyrimidinyl)carbarnoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-morpholinoethyl)carbarnoyl]pyrimidine;

2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-pyrimidinyl)carbarnoyl]pyrimidine;

2-(5,6,7,8-tetrahydro-1,7-naphthiridine-7-yl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-morpholinoethyl)carbarnoyl]pyrimidine;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(5-pyrimidinyl)carbarnoyl]pyrimidine;

(S)-2-[N-(2-pyrimidinyl)carbarnoyl]-3-(3-chloro-4-methoxybenzylamine)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazin;

(S)-2-[N-(2-morpholinoethyl)carbarnoyl]-3-(3-chloro-4-methoxybenzylamine)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazin;

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(1,3,5-trimethyl-4-pyrazolyl)carbarnoyl]pyrimidine

or geroliminis)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-pyrimidinyl)carbarnoyl]pyrimidine or its pharmaceutically acceptable salt.

17. Connection on p. 1 representing 2-(5,6,7,8-tetrahydro-1,7-naphthiridine-7-yl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(2-morpholinoethyl)carbarnoyl]pyrimidine or its pharmaceutically acceptable salt.

18. Connection on p. 1 representing 2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamine)-5-[N-(1,3,5-trimethyl-4-pyrazolyl)carbarnoyl]pyrimidine or its pharmaceutically acceptable salt.

19. The compound or its pharmaceutically acceptable salt according to any one of paragraphs.1-18 with PDE V inhibitory activity, suitable for treatment of the patient from dysfunction associated with erectile dysfunction.

20. The compound or its pharmaceutically acceptable salt according to any one of paragraphs.1-18 with PDE V inhibitory activity, suitable for patient treatment of diabetic gastroparesis.

21. The compound or its pharmaceutically acceptable salt according to any one of paragraphs.1-18 with PDE V inhibitory activity, suitable for treatment of the patient from pulmonary hypertension.

22. Pharmaceutical composition having PDE V inhibitory activity, containing as active ingredient a compound according to any one of paragraphs.1-18 or its pharmaceutically acceptable salt.

23. The connection of the CIP, associated with erectile dysfunction.

24. The compound according to any one of paragraphs.1-18 or its pharmaceutically acceptable salt for use in the treatment of the patient from pulmonary hypertension.

25. The compound according to any one of paragraphs.1-18 or its pharmaceutically acceptable salt for use in the treatment of diabetic gastroparesis.

Priority items:

28.04.200 under item 1 (with the exception of the compounds described in paragraph 16 and 17), 2-15. 18-25;

16.09.1999 on PP.16 and 17.

 

Same patents:

The invention relates to new physiologically active substituted oxazolo[4,5-d]pyridazine General formula (1), (2) or (3) and combinatorial library designed to search among them physiologically active substances, compounds leaders and candidates (drug-candidates) on the basis of screening

The invention relates to new cyclic diamine compounds of the formula I, where

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represents an optionally substituted divalent residue of benzene, where the substituents are selected from unsubstituted lower alkyl groups, unsubstituted lower alkoxygroup, unsubstituted lower acyl group, a lower allylthiourea, lower alkylsulfonyl group, halogen atom, etc. or unsubstituted pyridine; Ar represents a phenyl group which may be substituted by one to four groups selected from unsubstituted lower alkyl group, the unsubstituted alkoxygroup, low allylthiourea, lower alkylsulfonyl group, and so on, optional substituted amino group, alkylenedioxy; X is-NH-, oxygen atom or sulfur atom; Y is a sulfur atom, sulfoxide or sulfon; Z represents a single bond or-NR2-; R2- the atom of hydrogen or unsubstituted lower alkyl group; l = 2 or 3; m = 2 or 3; n = 1, 2, or 3, or their salts, or their solvate

The invention relates to new heterocyclic o-dicarbonitrile formula (I), where

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The compounds obtained can be used to obtain hexatriene-fluorophores

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

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The invention relates to novel ortho-sulfonamidophenylhydrazine heteroaryl hydroxamic acids of the formula

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where W and X are both carbon, T is nitrogen, U represents CR1where R1represents hydrogen, or alkyl containing 1-8 carbon atoms, R represents-N(CH2R5)-SO2Z, Q represents -(C=O)-NHOH, with

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is a benzene ring, or is a heteroaryl ring of 5 to 6 atoms in the cycle, which may contain 0-2 heteroatoms selected from nitrogen, oxygen and sulfur, in addition to the heteroatom of nitrogen, denoted as W, where benzene or heteroaryl ring may optionally contain one or two substituent R1where permissible; Z is phenyl, which is optionally substituted by phenyl, alkyl with 1-8 carbon atoms, or a group OR2; R1represents halogen, alkyl with 1-8 carbon atoms, alkenyl with 2-6 carbon atoms, perfluoroalkyl from 1 to 4 carbon atoms, phenyl, optionally substituted by 1-2 groups OR2group-NO2group -(CH2)nZ, where Z is a phenyl which allows an alkyl with 1-8 carbon atoms, phenyl, optionally substituted with halogen, or heteroaryl radical containing 5 to 6 atoms in the cycle, including 1-2 heteroatoms selected from nitrogen, oxygen and sulfur; R5represents hydrogen, alkyl with 1-8 carbon atoms, phenyl, or heteroaryl containing 5 to 6 atoms in the cycle, including 1-2 heteroatoms selected from nitrogen, oxygen and sulfur; or their pharmaceutically acceptable salts

The invention relates to the field of organic chemistry, namely to new bicikliski derived pyrimidine

The invention relates to new benzoxazine and piridokshinom compounds of formula I, where part of the Q - condensed phenyl, or condensed pyridyl; Z1is hydrogen, halogen, C1-C6alkyl, phenyl, nitro, sulfonylamino or trifluoromethyl; Z2is hydrogen or halogen; X is hydrogen or oxygen; And - C1-C6-alkyl, C1-C6-alkylaryl or C1-C6-Alkylglucoside, where aryl and heterocyclyl described in the claims, n = 0 to 3; Y is the portion described in the claims, and their pharmaceutically acceptable salts, esters and proletarienne forms

The invention relates to compounds of General formula I:

where n is 1, 2 or 3; R1and R2independently selected from hydrogen and alkyl; R3represents alkyl; R4-R7independently selected from hydrogen, halogen, hydroxy, alkyl, aryl, alkoxy, aryloxy, alkylthio, aaltio, alkylsulfonyl, alkylsulfonyl, arysulfatase, arylsulfonyl, amino, monoalkylamines, dialkylamino, nitro, cyano, carboxaldehyde, alkylcarboxylic, arylcarbamoyl, aminocarbonyl, monoalkylammonium, dialkylaminoalkyl, alkoxycarbonyl, aminocarbonyl, monoalkylammonium, dialkylaminoalkyl, monoalkylammonium, dialkylaminomethyl, or R5and R6together form a carbocyclic or heterocyclic ring, its pharmaceutically acceptable salts and prodrugs and a method of treatment and pharmaceutical compositions having the properties of agonist 5-HT2

The invention relates to the field of medicine and organic chemistry and relates to new derivatives of azobenzenes formula I, II or III, modulating the function of serine/threonine protein kinases, methods of modulating the function of serine/threonine protein kinases, the method of identifying compounds modulating the function of serine/threonine protein kinase, the method of treatment-related serine/threonine protein kinase pathological conditions using such compounds, methods of synthesis of the above on the basis of the compounds of formula I, II or III

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

The invention relates to new derivatives of 1,3-diaryl-2-pyridin-2-yl-3-(pyridine-2-ylamino)propanol of the formula (I)

where Z denotes-NH-(C1-C16-alkyl)-(C=O)-; -(C=O)-(C1-C16-alkyl)-(C=O)-;

-(C=O)-phenyl-(C=O)-; AND1AND2AND3AND4denote independently of each amino-acid residue, E represents-SO2-R4and-CO-R4; R1- phenyl, thiazolyl, oxazolyl, thienyl, thiophenyl and others, R2- N., HE, CH2HE, OMe; R3Is h, F, methyl, OMe; R4denotes -(C5-C16-alkyl), -(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylene)-NH-R5and others, R5denotes-COO-R6, -(C=O)-R6-(C1-C6-alkylen)-R7, phenyl, naphthyl and others, R6denotes H, -(C1-C6) alkyl; R7denotes H, -(C1-C7-cycloalkyl, phenyl, naphthyl and others, l, q, m, n, o, p denote 0 or 1, and l+q+m+n+o+p is greater than or equal to 1, and their pharmaceutically acceptable salts

The invention relates to cavemosum derivative of formula (1) with a broad spectrum of antibacterial activity against different species of pathogenic bacteria, including MRSA

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where X Is N or CY and Y denotes H or halogen; R1is amino or a protected amino group; R2is hydrogen or optionally substituted (ness.)alkyl; R3denotes hydrogen or lower alkyl; R4indicates Bogoroditse optionally substituted (NISS

The invention relates to new imidazolidine formulas (I) and (II) in which a is a =N-CR=CR-CR=, =CR-N=CR-CR=, =CR-CR=N=CR or = CR-CR= CR-N= ; B represents-NR-C(R)2-C(R)2-C(R)2C(R)2-NR-C(R)2-C(R)2, -C(R)2-C(R)2-NR-C(R)2or C(R)2-C(R)2-C(R)2-NR, where R is hydrogen, R1is hydrogen, unsubstituted or substituted C1-20-alkyl, C1-20-alkylene-NR3-Q-X-R4where Q represents-CO-or-SO2-, X is a simple bond, -O - or-NR3and R4- aryl, heteroaryl, heterocyclyl or1-20-alkyl or C2-20alkenyl

The invention relates to tetracyclic analogues of camptothecins formula (I), where R1, R2, R3, R4, R5and R10such as defined in the claims
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