Nitrate salts of antihypertensive drugs

 

(57) Abstract:

The invention relates to organic chemistry and can find application in medicine. Describes the nitrate salts of the compounds selected from the following classes: Class (A3): 1 isopropylamino-3-(1-naphthyloxy)-2-propanolol (propanolol), (S)-1-(tert-butylamino)-3-(4-morpholino-1,2,5-thiadiazol-3-oxy)-2-propanol (timolol), 4-(2-hydroxy-3-isopropylphenoxy) phenyl-ndimethylacetamide (atenolol), Class (A2): 1-[[3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazole[4,3-d]pyrimidine-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine (sildenafil), 1(2H)-phthalazinone (hydralazine), 2-(2-proproxyphene)-8-agapurin-6-he (zaprinast), 6-(1-piperidinyl)-2,4-pyrimidinediamine-3-oxide (Minoxidil), Class (A1C): (S)-N-valeryl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]valine (valsartan), Class (4b): methyl-2-[methyl(phenylmethyl)-amino]ethyl ester of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridineboronic acid (nicardipine), Class (AA): -[3-[[2-(3,4-acid)-ethyl]methylamino]propyl]-3,4-dimethoxy--(1-methylethyl)benzoylacetonitrile (verapamil), Class (7d): 3,5-diamino-N-(aminoiminomethyl)-6-harperinformation (amiloride), 2-(2,2-dicyclohexylmethyl)piperidine (perhexiline), Class (A1b): 2-N. butyl-4-chloro-5-oxymethyl-1-[2'-(tetrazol-5-yl)biphenyl-4-yl]their nitrate salts under item 1, having hypotensive activity. The technical result obtained new salt compounds with useful biological properties. 2 S. and 6 C.p. f-crystals, 10 PL.

The present invention relates to compounds and compositions on their basis, used in the treatment of hypertension and prevention. More specifically, the present invention relates to the use of the above antihypertensive drugs for General use, in particular for cardiovascular area. More specifically, the present invention relates to new anti-hypertensive compounds with improved characteristics.

Known from the prior art compounds used in the treatment of hypertension, generally have limited effectiveness. Treatment of hypertension is usually carried out by introducing the patient is hypotensive drugs in combination with other drugs, active against vascular system, such as, for example, calcium antagonists, diuretics, beta-blockers, ACE-inhibitors (inhibitors of the angiotensin converting enzyme). For example, hypotensive antagonists of angiotensin (e.g., losartan), calcium antagonists (dihydropyridines), diuretics (NAPA capable when used alone to provide successful therapy.

In addition, you must pay attention to the fact that some antihypertensive drugs cause side effects on the respiratory system, such as bronchostenosis, shortness of breath. For example, antihypertensive drugs used in the treatment of angina and cardiac arrhythmia, such as timolol and propranolol, give the above-mentioned side effects.

Other antihypertensives cause dilation of blood vessels through the inhibition of phosphodiesterase and cause side effects in a variety of vehicles (gastrointestinal, cardiovascular, ocular, and so on). For example, this applies to drugs to the sildenafil and zaprinast.

Felt the need for accessible compositions, active in the treatment of hypertensive pathology for General use, in particular for cardiovascular area, with improved therapeutic profile. In addition, in particular, felt the need for available anti-hypertensive drugs with beta-blocking or antitopoisomerase action with reduced side effects.

The applicant has unexpectedly and surprisingly discovered compounds and pharmaceutical compositions suitable for the treatment of gipercalziemiceski profile and do not cause side effects typical of known anti-hypertensive medicines.

The object of the present invention are nitrate salts of compounds having hypotensive activity, or pharmaceutical compositions based on them for General use, in particular used in the cardiovascular field, and the above-mentioned compounds are characterized in that they contain at least one reactive group that can form a salt, and the above-mentioned compounds are selected from the following classes:

Class (A1b):

RA1- -O RIIIA1- free valence form together with the carbon atom at the 5-position of the ketone group,

RA1together with RIA1and carbon atoms in the 4 and 5 positions of the heterocyclic ring in the compound of formula (A1b), with RIVA1and RIIIA1- free valences, form an aromatic ring having 6 carbon atoms containing a-COOH group:

RIA1- N, CL;

RIA1with RA1, RIVA1, RIIIA1and the carbon atoms in 4 and 5 position of the heterocyclic ring of the formula (A1b) form an aromatic ring, eroticlinks ring of formula (A1b) the following form a saturated ring, having five carbon atoms:

RIIA1- -(CH2)3-CH3, -O-CH2-CH3;

RIIIA1- N., the free valency,

RIIIA1free valency - RIVA1- free valence form a double bond between carbon atoms 4 and 5 positions of the heterocyclic ring of the formula (A1b),

RIIIA1c RIVA1, RIA1and the carbon atoms at the 4 and 5 positions of the heterocyclic ring of the formula (A1b) form an aromatic ring containing a-COOH group (CHD);

RIVA1being a free valence, RIVA1together with RIA1and with the carbon atom at the 4-position of the heterocyclic ring of the formula (A1b) form a saturated ring consisting of five carbon atoms (IXd),

RIVA1with RIIIA1, RIA1and carbon atoms in the 4 and 5 positions of the heterocyclic ring of the formula (A1b) form an aromatic ring containing a-COOH group (CHD),

RIVA1together with RIIIA1being free valences, form a double bond between carbon atoms 4 and 5 positions heterocyclics the SS (A2):

predecessors of this class are the following compounds:

1(2H)-phthalazinone (hydralazine); 6-(1-piperidinyl)-2,4-pyrimidinediamine-3-oxide (Minoxidil); 1-[[3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazole[4,3-d]pyrimidine-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine (sildenafil), 2-(2-proproxyphene)-8-agapurin-6-he (zaprinast);

Class (A3):

RIB1and RIIB1equal to or different from each other and denote H, CH3,

In the formula (XId) t=0,1.

In the formula (XIe) YB1can have the following values:

in the formula (XIf) Z=H, -och3;

in the formula (A3):

XB1- -O-, -S-;

n and m are equal or different from each other and are 0, 1;

in the formula (XIp):

S1IS H, CN, OCH3CH3, -CH2-CH3, -O-CH2-CONH-CH3-THE PINES3, -CO-(CH2)2-CH3, -O-CH2-CH=CH2, -CH2-CH=CH2cyclopentyl or

S2- H, CH3, CL, -S3, -CONH2;

S1with S2and carbon atoms in the 2 and 3 positions of the aromatic ring of six carbon atoms virusology next to the aromatic ring of the formula XIpVII]- - CH2-, -NH-, -CH=CH-,(*)-CO-CH2-;

A - O,(*)-CH2-CH(OH)-, (*)-O-CH2;(*)-S-CH2-, -CH2-CH2-, -CH2-,

when a is a tertiary carbon atom and at the same time1means a free valency, then formed double bond-CH=CH - between a and carbon atom 1' position,

when in the ring consisting of five carbon atoms (XIpVII), is a tertiary carbon atom, which contains a Deputy that he together with the carbon atom at the 1' position and with one of the two radicals W1and W2and the other radical is a free valence, forms an aromatic ring having six carbon atoms, according to the following formula:

W1- N., the free valency, when W1is a free valency and meaning tertiary carbon atom, as defined above, forms a double bond between a and the carbon atom at the 1' position,

W1together with W2carbon atom in the 1'position Deputy And forms an aromatic ring having six carbon atoms;

W2free valency, N., HE, -CH3, -ONO2 is the Rupp,

W2together with W1carbon atom in the 1’ position and Deputy And forms an aromatic ring having six carbon atoms;

S3Is h, F, Cl, HE, NO2, -CH2-CO-NH2, -(CH2)2-OCH3, -NH-PINES3, -CH2-O-CH2-CH2-O-CH(CH3)2, -CH2-CH2SOON3, -NH-CO-N(C2H5)2. -NH-CO-(CH2)2-CH3, -NH-SO2-CH2, -NH-CO-NH-[cyclohexyl], -CH2-CH2-O-CH2[cyclopropyl];

S4- N, Cl, -CH2-CH2- which together with the carbon atoms 1 and 6 position of the aromatic ring of the same radical (HR) and RVIIB1in the formula (A3), is equal to the oxygen, and simultaneously m=n=1 and RVIIB1means a free valency, form the following ring:

S4is a tertiary atom, which carbon atoms in the 1 and 6-position of the aromatic ring radical (HR) and with the following components of the formula (A3): an atom of carbon - |C|n- (n=1), the radical XB1equal to the oxygen (m=1), and RVIIB1and BVIB1- free valency forms the following ring:

RVIB1- N., the free valence is the class, are as follows:

2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]benzamide (labetalol), 1-(4-amino-6,7-dimethoxy-2-hintline)-4-[(tetrahydro-2-furanyl)carbonyl]piperazine (terazosin), 1 -(4-amino-6,7-dimethoxy-2-hintline)-4-(2-fornicator)piperazine (prazosin);

Class (A4):

the following groups of compounds belong to this class:

(AU):

-[(2-methylpropoxy)methyl]-N-phenyl-N-(phenylmethyl)-1-pyrrolidin-atanamir (bepridil), (2S-CIS)-3-(atomic charges)-8-chloro-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-he (clentiazem), (2S-CIS)-3-(atomic charges)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-he (diltiazem), -phenyl-N-(1-phenylethyl)benzoylpropionate (fendilin), -[3-[[2-(3,4-acid)ethyl]methylamino]propyl]-3,4,5-trimetoksi--(1-methylethyl)benzoylacetonitrile (gallopamil), (1S-CIS)metacercaria acid-2-[2[[3-(1H-benzimidazole-2-yl)propyl]methylamino]ethyl]-6-fluoro-1,2,3,4-tetrahydro-1-(1-methylethyl)-2-naphthalene ether (mibefradil), N-(1-methyl-2-phenylethyl)--phenylbenzophenone (prenilamin), (R)-2-[2-[3-[[2-(1,3-benzodioxol-5-yloxy)-ethyl]methylamino]propoxy]-5-methoxyphenyl]-4-methyl-2H-1,4-benzothiazin-3(4H)-he (remotedir), N-(1,1-dimethylethyl)--methyl--finalmente (verapamil);

(4b):

3-ethyl-5-methyl ester 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid (amlodipine), methyl-2-oxopropanoic ether 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridine-carboxylic acid (aranidipine), methyl-1-(phenylmethyl)-3-pyrrolidinyloxy ether [S-(R*, R*)]-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-peridinian-oil acid (barnidipine), methyl-1-(phenylmethyl)-3-piperidinyloxy ether (R*, R*)--1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid (benidipine), 2-methoxyethyl-3-phenyl-2-propenyloxy ether (E)-±-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid (cilnidipine), 2-[phenyl(phenylmethyl)amino]ethyl ester 5-(5,5-dimethyl-1,3,2-dioxaphosphinan-2-yl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridineboronic acid P-oxide (efonidipine), 2-[[(4-forfinal)-methyl]-methylamino]ethyl-1-metaliteracy ether-4-(1,3-benzodioxol-4-yl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid (algtype), utilmately ester of 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid (felodipine), 5-methyl-3-(1-methyl)ethyl ester of 4-(4-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid (isradipine), diethyl ether (E)-42-[(3,3-diphenylpropyl)methylamino]-1,1-dimethyltrimethylene ether 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid (lercanidipine), 2-[4-(diphenylmethyl)-1-piperazinil]-utilmately ether 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid (manidipine), methyl-2-[methyl(phenylmethyl)-amino]ethyl ester of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid (nicardipine), dimethyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid (nifedipine), 3-methyl-5-(1-methylethyl)ester 2-cyano-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid (nilvadipine), 2-methoxyethyl-1-metaliteracy ether 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid (nimodipine), methyl-2-methylpropionyl ether 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid (nisoldipine), utilmately ether 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid (nitrendipin);

(As):

1-(diphenylmethyl)-4-(3-phenyl-2-propenyl)piperazine (Cinnarizine), (E)-1-[bis(4-forfinal)methyl]-4-(3-phenyl-2-propenyl)piperazine (flunarizin), 4-[4,4-bis(4-forfinal)butyl]-N-(2,6-dimetilfenil)-1-piperazineethanol (lidoflazine), 1-[bis(4-forfinal)methyl]-4-[(2,3,4-trimethoxyphenyl)methyl]piperazine (lomerizine);

(A4d):

N,N-dimethyl-3-[[1-(phenylmethyl)-cycloheptyl]oxy]-1-propanamine (Bencik LAN), 1-[2-[2-(diethyl]phenoxy]-propyl]benzenediamine (femtofarad);

Class (A7):

the following groups of compounds belong to this class:

(AU):

6-chloro-3,4-dihydro-3-[(2-propylthio)methyl]-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide (aliasid), 3,4-dihydro-3-(phenylmethyl)-6-(trifter-methyl)-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide (bendroflumethiazide), 6-chloro-3-[[(phenylmethyl)thio]methyl]-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide (benzthiazide), 6-chloro-3,4-dihydro-3-(phenylmethyl)-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide (benzylhydroxylamine), 6-chloro-3,4-dihydro-3-(2-methylamyl)-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide (bothasig), 6-chloro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide (chlorothiazide), 2-chloro-5-(2,3-dihydro-1-hydroxy-3-oxo-1H-isoindole-1-yl)benzenesulfonamide (chlorthalidone), 6-chloro-3-(cyclopentylmethyl)-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide (inclemencies), 3-bicyclo[2.2.1]-hept-5-EN-2-yl-6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide (cyclothiazide), 6-chloro-3,4-dihydro-3-[[(2,2,2-triptorelin)thio]methyl]-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide (epicized), 6-chloro-3-ethyl-3,4-dihydro-2H-1,2,4-benzo-thiadiazine-7-sulfonamide-1,1-dioxide (aliasid), 7-chloro-1,2,3,4-tetrahydro-4-oxo-2-phenyl-6-ChineseSimplified (venison), 3-(aminosulfonyl-1,1-dioxide (hydrochlorothiazide), 3,4-dihydro-6-(trifluoromethyl)-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide (hydroflumethiazide), 6-chloro-3-(chloromethyl)-3,4-dihydro-2-methyl-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide (methyclothiazide), 3,4-dihydro-6-methyl-2H-1-benzothiophen-7-sulfonamide-1,1-dioxide (meteksan), 7-chloro-1,2,3,4-tetrahydro-2-methyl-3-(2-were)-4-oxo-6-ChineseSimplified (metolazone), 6-chloro-3-[(4-forfinal)-methyl]-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide (parapluie), 6-chloro-3,4-dihydro-2-methyl-3-[[(2,2,2-triptorelin)thio]-methyl]-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide (polythiazide), 7-chloro-2-ethyl-1,2,3,4-tetrahydro-4-oxo-6-ChineseSimplified (chinease), 6-chloro-3,4-dihydro-3-trichloromethyl-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide (telocaset), 6-chloro-3-(dichloromethyl)-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide (trichlormethiazide);

(7b):

3,7-dihydro-1,3-dimethyl-7-(4-morpholinylmethyl)-1H-purine-2,6-dione(7-morpholinomethyl), 3,7-dihydro-1-(2-hydroxypropyl)-3,7-dimethyl-1H-purine-2,6-dione (protobrain), 3,7-dihydro-3,7-dimethyl-1H-purine-2,6-dione (theobromine);

(As):

6-amino-3-ethyl-1-(2-propenyl)-2,4-(1H, 3H)-pyrimidinedione (aminotetralin), 6-amino-3-methyl-1-(2-methyl-2-propenyl)-2,4-(1H, 3H)-pyrimidinedione (anisometry incarbone (amiloride), N-(4-chlorophenyl)-1,3,5-triazine-2,4-diamine (chloranil), ethyl ester of [3-methyl-4-oxo-5-(1-piperidinyl)-2-thiazolidinone]acetic acid (ettlin), 6-hydrazino-3-pyridinecarboxamide (hydrocarbon), 5-amino-2[1-(3,4-dichlorophenyl)ethyl]-2,4-dihydro-3H-pyrazole-3-one (muslimin), 2-(2,2-dicyclohexylmethyl)piperidine (perhexiline), 6-phenyl-2,4,7-peridiniales (triamterene), 3-(aminosulfonyl)-5-(butylamino)-4-phenoxy-benzoic acid (bumetanide), 5-(aminosulfonyl)-4-chloro-2-[(2-furylmethyl)-amino]benzoic acid (furosemide), N-[[(1-methylethyl)amino]carbonyl]-4-[(3-were)amino]-3-pyridinesulfonamide (torasemide);

Class (A8): Apomorphine.

Preferred compounds (A1b) class are the following: when XA1=(IXa), RA1- CH2HE, RIA1- Cl, RIIIA1=RVIA1- free valency, forming a double bond-CH=CH - with carbon atoms at the 4 and 5 positions of the heterocyclic ring of the formula (A1b), RIIA1- -(CH2)3-CH3is the rest of losartan; as losartan, but with RA1- -Oh and RIIIA1- free valence, resulting in combination with the carbon atom in the 5 position of the heterocyclic ring of the formula (A1b) is formed ketone group, RIalso, having 5 carbon atoms (IXd), is the remainder irbesartana; as losartan, but with RIIA1- -O-CH2-CH3, RA1together with RIA1and the carbon atoms in 4 and 5 position of the heterocyclic ring with RIVA1and RIIIA1- free valences forms an aromatic radical containing a-COOH group (CHD), is the remainder of candesartan; as losartan, but with XA1- -COOH, RA1=(IXb), RIA1- H, RIVA1and RIIIA1- free valency forms a double bond between the carbon atoms in 4 and 5 position of the heterocyclic ring of the formula (A1b), is the remainder of eprosartan.

Preferred compounds (A2) of the class are the following:

1-[[3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazole[4,3-d-pyrimidine-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine (sildenafil), 2-(2-proproxyphene)-8-agapurin-6-he (zaprinast).

Preferred compounds (A3) of the class are the following:

when RIB1- N, RIIB1and RIIIB1- CH3, RVB1- N, RVIB1=RVIIB1- N, m=n=1, XB1- -O-, RIVB1=(XIp), where S1=S2=S4- H, S3- -CH2-CO-NH2this AK in atenolol, but with S3=S2=S4- N, S1- -CH2-CH=CH2is the rest of alprenolol;

how to atenolol, but with S1THE PINES3, S3- -NH-CO-(CH2)2-CH3, S2=S4- H is the remainder acebutolol;

how to atenolol, but with S3- -CH2-CH2-O-CH2(cyclopropyl), is the remainder of betaxolol;

how to atenolol, but with S3- -CH2-O-CH2-CH2-O-CH(CH3)2is the rest of bisoprolol;

as in alprenolol, but with S1=(XIpIIand RIB1- CH3is the rest of buretrol;

as in buretrol, but with S1- -CN, is the remainder of bunitrolol;

as in buretrol, but with S1- N, S4- Cl, S2- CH3is the rest of bupranolol;

as in buretrol, but with S1- CO- (CH2)2-CH3, S3- F is the remainder of butoverall;

how to atenolol, but with RIVB1=(XIpVIIIwhere is-NH-, is the remainder of carazolol;

as in buretrol, but with RIVB1=(XIpVII), where a is-CH2HE2- ,- NH-, W2About that W1that represents a free valency, and the carbon atom at the 1' position forms a ketone group, this OS is
is the rest of celiprolol;

as in buretrol, but with S1- -O-CH2-N-CH3is the rest of atemolol;

as in bupranolol, but with S2- Cl is the rest of Chlorella;

how to atenolol, but with S3 - -CH2-CH2SOON3is the rest of esmolol;

how to atenolol, but with RIVB1=(XIu), is the remainder of indenolol;

as in carteolol, but in RIVB1=(HRVII) A - CH2- IN - THE-PINES2-, W1=W2- H is the remainder of levobunolol;

as in carteolol, but with RIB1Is H and RIVB1=(XIpVII) Indicates a tertiary carbon atom and W1means the free valence, resulting in a double bond-CH=CH - between a and the carbon atom in position 1' (XIpVII), W2- CH3is the rest of mepindolol;

how to atenolol, but with S3- -(CH2)2-OCH3is the rest of metoprolol;

as in carteolol, but in RIVB1=(XIpVIIA - -CH2-CH(OH) -,- CH2-, W2HE, W1- H is the remainder of nadolol;

how to atenolol, but with S3 - NO2this remnant of nihinlola;

as in mepindolol, but in RIVB1=(XIpVIIA - Ola, but with S1- -O-CH2-CH=CH2is the rest of oxprenolol;

as in buretrol, but with S1- cyclopentyl, it is the remnant of penbutolol;

as in mepindolol, but with W2- H is the remainder of pindolol;

how to atenolol, but with S3- -NH-PINES3is the rest of practolol;

as in buretrol, but with S1- H, S3- -NH-CO-NH-(cyclohexyl), is the remainder of talinolol;

as in nipradilol, but with RIB1- CH3AND - -S-CH2and W2- H is the remainder of tertatolol;

as in tertatolol, but with RIVB1=(XIn), is the remainder of tilisolol;

as in buretrol, but with RIVB1=(XIo), is the remainder of timolol;

as in buretrol, but with S1=S2- CH3is the rest of xianyou;

as in xibenolol, but with RIB1=S1- H is the remainder of celiprolol;

as in molepolole, but with RIIB1- N and RIIIB1=(XIa), is the remainder of bevantolol;

as in carazolol, but with RIIB1Is H and RIIIB1=(XIb), this residue carvedilola;

when in the formula (A3) RIB1=RIIB1=RIIIB1- CH3, RVB1=(XIh), n=m=1, RVIB1=RVIIB1 - H =(XIt), it is the remnant of boukouvala;

when in the formula (A3) m=n=0 and RIVB1=(XIz) RIB1=RIIB1=RIIIB1- CH3, RVB1- N is the remainder of bufuralol;

how to atenolol, but with RIIIB1=(Ixe), with YB1- N, n=m=0, RIVB1=(XIi), is the remainder of baterina;

as in butterine, but with RIIIB1=(XIe), with YB1=(XIf) Z - N, RIVB1=(XIp), where S3HE and S2- CONH2, S1=S4- N is the remainder of dilevalol;

as in bevantolol, but with S2 - N, S1- CN, RIIIB1=(XIc), is the remainder of epanolol;

as in butterine, but with RIIIB1- CH3, RIVB1=(XIm), where the remainder of naphthalene bound to the carbon atom in the 2 position to provide carbon atom Deputy ORIVB1this remnant of pronethalol;

as in pronethalol, but with m=1 and XB1- -O-, and RIVB1is a residue of naphthalene (XIm), attached carbon atom in the 1 position to the XB1this balance propranolol,

as in pronethalol, but with RIVB1=(XIp), with S1=S2=S4 N and S3- -NH-SO2-CH3is the rest of sotalol;

as in dilevalol, but with S2- SOCH3, S2">

when in the formula (A3) RIB1=RIIB1- N, RIIIB1=(XId) with t=1, RVB1- H, n=m=0, RIVB1=(XId) t=0, the remaining nebivolol;

2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]benzamide (labetalol), 1-(4-amino-6,7-dimethoxy-2-hintline)-4-[(tetrahydro-2-furanyl)-carbonyl]piperazine (terazosin), 1-(4-amino-6,7-dimethoxy-2-hintline)-4-(2-fornicator)piperazine (prazosin), benzonitrile, 2-[2-hydroxy-3-[[2-(1H-indol-3-yl)-1,1-dimethylethyl]amino]propoxy (bucindolol).

In class (A4) following preferred compounds:

(AU):

(2S-CIS)-3-(atomic charges)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-he (diltiazem), -[3-[[2-(3,4-acid)ethyl]methylamino]propyl]-3,4-dimethoxy--(1-methylethyl)-benzoylacetonitrile (verapamil);

(4b):

3-ethyl-5-methyl ester 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid (amlodipine), utilmately ester of 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid (felodipine), 5-methyl-3-(1-methyl)ethyl ester of 4-(4-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid (isradipine), lercanidipine, methyl-2[methyl(phenylmethyl)Amin the IDF 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid (nifedipine), 2-methoxyethyl-1-metaliteracy ether 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid (nimodipine), methyl-2-methylpropionyl ether 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid (nisoldipine), utilmately ether 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid (nitrendipin);

(As):

(E)-1-[bis(4-forfinal)methyl]-4-(3-phenyl-2-propenyl)piperazine (flunarizin).

In class (A7), the preferred compounds are the following:

(AU):

6-chloro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide (chlorothiazide), 2-chloro-5-(2,3-dihydro-1-hydroxy-3-oxo-1H-isoindole-1-yl)benzenesulfonamide (chlorthalidone), 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide (hydrochlorothiazide), 3-(aminosulfonyl)-4-chloro-N-(2,3-dihydro-2-methyl-1H-indol-1-yl)benzamide (indapamide), 7-chloro-1,2,3,4-tetrahydro-2-methyl-3-(2-were)-4-oxo-6-ChineseSimplified (metolazone), 7-chloro-2-ethyl-1,2,3,4-tetrahydro-4-oxo-6-ChineseSimplified (chinease);

(A7d):

3,5-diamino-N-(aminoiminomethyl)-6-harperinformation (amiloride), 6-phenyl-2,4,7-peridiniales (triamterene), 3-(aminosulfonyl)-5-(butylamino)-4-phenoxybenzoic acid (bumetanide), 5-(aminosol is)amino]-3-pyridinesulfonamide (torasemide).

Particularly preferred compounds according to the present invention are the following:

Class (A1b): losartan;

Class (A2): sildenafil, zaprinast;

Class (A3): atenolol, labetalol, timolol, prazosin, terazosin, propanolol;

Class (A4): nicardipine, nifedipine, nimodipine;

Class (A7) chlorthiazide, amiloride, furosemide.

The precursor salts of the above classes receive according to the methods described in "The Merck Index 12aEd." (1996). The method of obtaining zaprinast described in German patent 2162096. The method of obtaining bucindolol described in the patent UK 2001633.

In the compositions according to the present invention can also be used isomers of compounds belonging to the above classes. Examples of isomers are CIS-, TRANS-, optical isomers (D and L or racemic compounds enantiomers. Basically one isomeric form is very active compared to the other, such as D-shape compared to the L-form or Vice versa.

Salts of compounds belonging to these two classes contain at least mole of nitrate ion/mol connection. Preferably, the ratio between the moles of nitrate ions and Kul there are other amino groups, sufficiently basic to form a salt.

Of the salts of the present invention form a corresponding pharmaceutical composition according to well-known in this field techniques in conjunction with conventional fillers; see, for example, that "Remington's Pharmaceutical Sciences 15a Ed."

Dose of salts of the invention in their pharmaceutical compositions is the same and basically it is lower than the dose of their predecessors of the above classes.

Salt of the present invention receive one of the following methods.

When a substance capable of forming a salt, available as a free base or as the corresponding salt, soluble in organic solvent, which preferably does not contain hydroxyl groups, for example in acetonitrile, ethyl acetate, tetrahydrofuran, etc., salt is obtained by dissolving the substance in a solvent at a concentration of, preferably equal to or higher than 10 wt./vol.%, the addition amount of concentrated nitric acid corresponding to the moles of the salt-forming amine groups present in the substance. Nitric acid is preferably dissolved in the same solvent. Preferably, during, and after adding cm

When, on the contrary, the substance is not very soluble or available as a soluble salt in the above-mentioned solvents can be used with an appropriate mixture of gidroksilirovanii solvents. Examples of such solvents are methyl alcohol, ethyl alcohol and water. The precipitation can be accelerated by diluting the thus obtained mixture, after addition of nitric acid, a non-polar solvent.

When the original product forms a salt with hydrochloric acid, can be obtained salt with nitric acid, adding the silver nitrate directly to the solution of the connection. After filtering off the silver chloride solution is concentrated and cooled to highlight nitrate salt.

When the original product is a salt, it is possible to release the corresponding base by treatment with a saturated solution of carbonate or bicarbonate of sodium or potassium or a diluted solution of sodium hydroxide or potassium. The base is then extracted with a suitable organic solvent (for example, halogenated solvents, esters, ethers), which is then dehydrated. The organic solvent is evaporated and then act according to the previous

Nitrate salts can also be obtained using the predecessors of the above classes, containing in the molecule the bond-TNA2the group, through a bridge, obtained as described in European patent 759899 on behalf of the applicant.

The following examples are for illustrative purposes only and are not restrictive.

Example 1

Receiving nitrate timolol.

To saturated aqueous sodium bicarbonate solution (100 ml) add timolol maleate (7 g). The mixture is extracted with ethyl acetate (300 ml). The organic phase is dried with sodium sulfate and then evaporated under vacuum, obtaining the corresponding base of timolol (4.9 g), which was dissolved in acetonitrile (25 ml). This solution was cooled with ice, treated with 65% nitric acid solution (1.08 ml) in acetonitrile (5 ml) and after 30 minutes of stirring in the cold is treated with ethyl ether (100 ml) to obtain a solid, which was filtered, washed with ethyl ether and dried under vacuum. Obtain 4.6 g of nitrate timolol with a melting point of 115 S.

1H-NMR (D2On memorial plaques: 4.34 (1H, m), 3.76 (4H, t), 3.39 (4H, t), 3.23 (2H, m), 3.04 (2H, m), 1.29 (9H, s).

Elemental analysis (C13H25<8,31;

Example 2

Receiving nitrate propranolol.

To saturated aqueous sodium bicarbonate solution (70 ml) add propranolol hydrochloride (5 g). The mixture is extracted with ethyl acetate (250 ml). The organic phase is dried with sodium sulfate and then evaporated under vacuum, obtaining the corresponding base propranolol (4,2 g) which was dissolved in acetonitrile/tetrahydrofuran 5/2 (70 ml). This solution was cooled with ice, treated with 65% nitric acid (1.13 ml) in acetonitrile (10 ml) and after 30 minutes of stirring in the cold is treated with ethyl ether (50 ml) to obtain a solid, which was filtered, washed with ethyl ether and dried under vacuum. Get a 5.1 g of nitrate propranolol with a melting point 127-130C.

1H-NMR (D2On memorial plaques: 8.15 (1H, m), 7.80 (1H, m), 7.48-7.32 (4H, m), 6.86 (1H, d), 4.32 (1H, m), 4.13 (2H, d), 3.36 (1H, m), up 3.22 (2H, d), 1.24 (6N, d).

Elemental analysis (C16H22N2O5):

calculated (%): 59,62; N 6,88; N 8,69;

found (%): 59,99; N 6,97; N 8,65.

Example 3

Receiving nitrate sildenafil.

The solution of sildenafil (7.7 g, 16.3 mmol) in a mixture with acetonitrile (100 ml) and tetrahydrofuran (40 ml) is treated with 65% attname by evaporation under reduced pressure and added slowly ethyl ether (100 ml). The precipitate is filtered, washed with ethyl ether and dried under vacuum. Get a white amorphous solid (6.5 g).

Elemental analysis (C22H31N7O7S):

calculated (%): 49,15; N. OF 5.81; N 18,24; S 5,96;

found (%): 49,34; N. Of 5.75; N 18,38; S 6,00.

Example 4

Getting salt of valsartan.

A solution of valsartan (3,48 g, 8 mmol) are dissolved in a mixture of acetonitrile (30 ml) and tetrahydrofuran (10 ml). Nitric acid, dissolved in acetonitrile, add in the cold (take 2 ml of the solution obtained by the addition of 2.7 ml of 65% nitric acid in acetonitrile and bring to a final volume of 10 ml). After 30 minutes, slowly add ethyl ether (100 ml) while maintaining the temperature of +4C. The formed precipitate is filtered, washed with acylovir ether and dried under vacuum. Get a white amorphous solid (3.1 g).

Elemental analysis (C24H30N6O6):

calculated (%): 57,82; N 6,07; N 16,86;

found (%): 58,02; N. Of 6.02; N 16,77.

Example 5

Receiving hydralazine nitrate.

The hydralazine hydrochloride (3 g) is added to aqueous potassium carbonate solution (50 ml). Then spend extremum. The residue (1 g, 6.25 mmol) dissolved in a mixture of acetonitrile (30 ml) and methanol (20 ml). The solution is cooled to +4 and add 65% solution of nitric acid (0.6 g, 6.24 mmole) in acetonitrile (10 ml). A white precipitate is formed, which is filtered and dried under vacuum (1 g, temp. pl. 237-S).

Elemental analysis (C8H9N5O3):

calculated (%): 43,05; N 4,06; N 31,38;

found (%): 43,32; N Is 4.03; N 31,22.

Example 6

Receiving nitrate of nicardipine.

A solution of the hydrochloride of nicardipine (0.1 g, 0,194 mmol) in acetonitrile (20 ml) is treated in the dark with silver nitrate (0.33 g, 0,194 mmole). Under stirring at room temperature for 30 minutes, a precipitate in the form of a white solid. It is filtered, concentrated to half volume under reduced pressure, cooled to +4C and treated with ethyl alcohol. The precipitate is filtered. Dried out. Receives a yellow solid (0.5 g, temp. pl. 193-S).

Elemental analysis (C26H30N4O9):

calculated (%): 57,56; N TO 5.57; N 10,33;

found (%): 57,44; N 5,63; N 10,44.

Example 7

Receiving nitrate of verapamil.

The solution of verapamil hydrochloride (3,44 g, 7 mmol). The solution was stirred at room temperature for one hour. The precipitate formed slowly, and it sucked in the end. The solution is concentrated to half volume, cooled to +4 and the formed precipitate filtered off. After drying receive a white amorphous solid (2.8 g).

Elemental analysis (C27H39N3O7):

calculated (%): 62,65; N TO 7.59; N 8,12;

found (%): 62,48; N. Of 7.68; N 8,11.

Example 8

Receiving nitrate amiloride.

The solution of amiloride hydrochloride (2 g, 7.5 mmol) in methanol (100 ml) is treated with silver nitrate in the dark (1.28 g, 7.5 mmol). Quickly produces sludge. The solution is allowed to mix for 30 minutes at room temperature. Ultimately, the solid is filtered off and the solution concentrated under reduced pressure to half the initial volume. The solution is treated with ethyl ether (50 ml) and after cooling to +4C filter the resulting solid substance. After drying, the solid is separated (0.8 g, temp. pl. >280S).

Elemental analysis (C6H9ClN8O4):

calculated (%): 24,63; N 3,10; N 38,29; Cl 12,11;

found (%): 24,75; N 3,03; N 38,19; Cl 12,24.

Join the dose of 10 mg/kg and the corresponding carrier was injected Guinea pigs (groups of 6 animals each) intraperitoneally for three days in a row.

Animals were prepared according to the method Del Soldato et al., J. Pharmacol. Methods, 5, 279, 1981. After 45 minutes, 0.1 ml of physiological solution of capsaicin (1 µg/kg) was administered to the animals intravenously. The change of the respiratory air volume before and after injection of capsaicin was measured by means of the apparatus Konzett, modified as described in the above link connected to the printing system.

The effects of the compounds and their respective nitrates on experimental bronchostenosis induced in Guinea pigs by injection of capsaicin presented in Table I.

Example 10

The pharmacological activity of nitrate sildenafil compared with sildenafil.

Compounds were administered in saline. The control group was treated with only the vehicle (physiological saline).

The vasodilator activity of nitrate sildenafil was determined using the experimental model of contraction of prostatic discharge vessels, caused by the electrical stimulation, lower than maximalnych described by Ribeiro et al., Hypertension, 20, 298, 1992. Adult male Wistar rats (235-284 g) within 6 weeks received L-NAME in drinking water with a concentration of 60-70 mg/100 ml, which is equivalent to a daily dose of 60 mg/kg the animals were received within five days subcutaneously daily dose of 10 mg/kg of nitrate sildenafil, sildenafil or carrier, respectively. One hour after the last treatment, animals were killed and took the prostatic part of the discharge vessel, immersed her in a physiological solution and dilute transmural stimulation (95% of maximum stimulation, 0.2 Hz).

The reduction reaction of neurogenic contraction, which was obtained after 5 minutes after adding the test substance at a concentration of 10-6M, was assumed to measure vasodilator activity (see Table II).

From this table it is evident that the muscle relaxant activity of the nitrate salt is higher than its predecessor, taken as reference compounds.

Also studied the effect of relaxation of the cavernous artery and the cavernous bodies (vasodilator effect on the peripheral level). To apply the methodology described by R. G. Hempelmann et al., European Journal of Pharmagology 276, 277-280 (1995), using the cavernous tissue obtained from patients undergoing heermance about 2 mm in length and placed in a myograph.

After building the experimental curve diameter/tension samples were brought to the diameter corresponding to 90% of the diameter, achieved with transluminal pressure of 100 mm RT.article; after a period of stabilization for 60 min reduction caused by adrenaline 310-6M. After 15 minutes was added dose of each test compound corresponding to 10-6M, and recorded the percentage of relaxation. The results are shown in Table III.

The second series of experiments were conducted according to the same Protocol on the selected strips 335 mm cavernous tissue, isometrically suspended trays for selected agencies, at a voltage of 5-10 mN. The results are shown in Table IV.

In both experimental models relaxing obvious effect to reduce caused by adrenaline achieved by treatment with sildenafil and donor of nitric oxide SIN-1. The derivative according to the present invention has a higher pharmacological activity than its predecessor, sildenafil and SIN-1.

Example 11

The study of the antihypertensive and antiangiogenic activity of nitrate of losartan compared with losartan.

Compounds were introduced in the S="ptx2">

Inhibitory effect of nitrate losartan for hypertension was tested using two experimental models: the arterial hypertension caused by L-NAME (see the previous example), and muscle contraction induced by angiotensin II. In the first experiment, adult male Wistar rats (235-284 g) was obtained within 6 weeks of drinking water containing L-NAME with a concentration of 60-70 mg/100 ml, which is equivalent to a daily dose of approximately 60 mg/kg, the Animals received within five days subcutaneously daily dose of 10 mg/kg nitrate losartan, losartan or carrier, respectively. One hour after the last treatment were identified systemic arterial pressure by caudal, as described Zatz, Lab. Anim. Sci., 42, 198, 1990.

In the second experiment (reduction caused by angiotensin II) the method described by P. C. Wong et al., Hypertension, 13, 489-497, 1989, consisted of the following. Segments of ileum isolated from Guinea pigs (300-350 g) were immersed in a physiological solution containing angiotensin II (10 μg/ml), angiotensin II + nitrate losartan 10-6M and angiotensin II + losartan 10-6M respectively. The results are presented in Table V.

The table shows that the inhibiting effect of nitrate with whom soedineniya. Both products are effective against muscle relaxant activity, as they inhibit the contraction induced by angiotensin II, but the connection according to the present invention shows more efficiency.

Example 12

The study of the antihypertensive and vasodilator activity of nitrate of Minoxidil compared with Minoxidil.

Compounds were administered in saline. The control group was treated with only the vehicle (physiological saline).

Inhibitory effect of nitrate of Minoxidil for hypertension was defined using two experimental models: the arterial hypertension caused by L-NAME (see Example 10), and vascular contraction induced by electrical stimulation. In the first pharmacological experiment, rats were treated as described in pharmacological experiment with L-NAME Example 11. In the second experiment (the contraction induced by angiotensin II) the method described by Taylor (see Example 10), was carried out as described above. Took prostatic part of the spermatic duct of rats (200-220 g) was immersed in a physiological solution at S and then narrowed transmural stimulation (95% of maximum stimulation, 0.2 Hz).

Casadores the add test compounds with a concentration of 10-6M (see Table VI).

As is evident from Table VI, the inhibitory effect of nitrate of Minoxidil for hypertension caused by L-NAME, which is longer than the compounds used as references. As for the vasodilator activity, both products are effective in inhibiting the narrowing of blood vessels caused by electrical stimulation.

Example 13

The study of the antihypertensive and beta-adrenolytic activity of nitrate timolol compared with timolol.

Used two experimental models: the arterial hypertension caused by L-NAME, and inotrope positive effect caused by izoprenalin.

In the first experiment hypotensive activity was studied according to the experimental model described in Example 11.

In the second experiment, the method described Grodzinski et al., Arch. Int. Phramacodyn, 191, 133-141, 1971, was as follows. Pieces of the left Atria of Guinea pigs (300-350 g) kept at 32C in physiological solution, where the concentration of calcium ions was below 1/3, and stimulated by izoprenalin (1=µg/ml). Beta-adrenolytic activity was expressed as a reduction inotrope positive effect (increase the reduction of the heart muscle), the following From Table VII it is evident, that the inhibitory effect of nitrate timolol on hypertension caused by L-NAME, higher than that of timolol. As for adrenolytic activity, both of these products are effective in the inhibition inotrope positive effect caused by izoprenalin, but the connection of the present invention is very effective.

Example 14

The study of the antihypertensive and calcium-antagonistic activity of nitrate of nicardipine compared with nicardipine.

Used two experimental models: the arterial hypertension caused by L-NAME, and muscle contraction induced by calcium chloride.

In the first experiment hypotensive activity was studied according to the experimental model described in Example 11.

In the second experiment, adapted the experimental design was a contraction of the ileum caused by calcium chloride according to the method described by M. J. Spedding, J. Pharmacology, 83, 211-220, 1984. Segments of ileum extracted from Guinea pigs (300-500 g), kept at C in physiological solution containing no calcium ions, and then stimulated by the addition of calcium chloride (final concentration 20 μg/ml). Calcium-antagonistic of the tested compounds with a concentration of 10-6M (see Table VIII).

From the Table it is clear that the inhibitory effect of nitrate salt on hypertension caused by L-NAME, more than the impact of predecessor nicardipine. As for the calcium-antagonistic activity, these compounds are both effective in the inhibition of narrowing calcinating effect, although to varying degrees.

Example 15

A study on rats hypotensive and diuretic activity of nitrate amiloride compared to amiloride.

Pharmacological profile of amiloride was determined using the following experimental models: the arterial hypertension caused L-NAME, and diuretic effect.

In the first experiment hypotensive activity was studied according to the experimental model described in Example 11.

In the second experiment, the diuretic effect was studied according to the method described by W. L. Lipschwitz et al. J. Pharmacol. Exp. Ther., 79, 97-110, 1943. 3 groups of 6 rats each (200-220 g) were kept in the cells for metabolic studies in experimental animals and has been drinking distilled water (25 ml/kg, by mouth). Each group then was subcutaneously injected nitrate amiloride (10 mg/kg), amiloride (10 mg/kg) or the media is to function effectively expressed as a percentage of the collected amount of urine in relation to the volume of urine group, processed by the media (see Table IX).

As is evident from Table IX, the inhibitory effect of nitrate amiloride for hypertension caused by L-NAME exceeds the impact of amiloride. As for the vasodilator activity, both compounds exhibit similar diuretic activity.

Example 16

Study of acute toxicity of salts of nitric acid sildenafil and zaprinast.

Both products were introduced in a 2% suspension of carboxymethylcellulose.

Acute toxicity of the above salts were evaluated oral introduction of increased doses of the compounds in groups of 10 rats each. Each group was administered a single dose.

The animals were observations within 14 days. Estimated deaths and any toxic symptomatology.

Even after a dose of 50 mg/kg was not marked signs of toxicity. All animals remained alive.

Example 17

The study of gastric toxicity of the salts of nitric acid sildenafil and zaprinast in comparison with their predecessors.

5 groups of male rats Sprague-Dawley (n=10) were starved for 24 hours. Then 4 groups, respectively, were treated intraperitoneally with sildenafil, zaprinast and n the ut animal through the mouth gave 1 ml of 50% ethanol in water.

An hour later, the animals were killed. Remove the stomach and examined macroscopically gastric tissue. This survey was conducted by the researcher, unaware of what treatment was exposed rats before killing. Damage was examined as described Gretzer et al. (Br. J. Pharmacol. 123, 927, 1998).

The results are presented in Table X. this Table gastric toxicity is given as % of the number of rats in the group who had discovered gastric damage.

As can be seen from the Table, in groups of rats treated with sildenafil and zaprinast, gastric pathology worsened compared to the controls. Gastric toxicity of the corresponding nitrates of the above drugs is lower than in the control group.

Example 18

Receiving nitrate perhexiline.

65% nitric acid (0.75 ml) is added to a solution of perhexiline (3,02 g, 10.9 mmol) in acetonitrile and methanol (10 ml), cooled to 0C.

The resulting solution was stirred with a magnetic stirrer for 30 minutes at 0C, then at room temperature for 30 minutes. The solvent is evaporated under reduced pressure and the crude product is suspended in ethyl ether and then filter2">

Elemental analysis:

calculated (%): C 67,00%; H 10,65%; N compared to 8.26%;

found (%): C 67,05%; H 10,79%; N 8,40%.

Example 19

Receiving nitrate of apomorphine.

Silver nitrate (2,72 g, 16 mmol) are added to a solution of apomorphine hydrochloride (5 g, 16 mmol) in acetonitrile (70 ml) and the mixture is stirred in the dark under nitrogen atmosphere for 30 minutes. Silver chloride is filtered and the solution was diluted with diethyl ether. The formed precipitate is filtered off, washed with diethyl ether and dried under vacuum, obtaining a 4.3,

C, H, N analysis

calculated (%): C 61,81; H 5,49; N 8,48;

found (%): C 61,84; H the 5.45; N 8,51.

Example 20

Receiving nitrate zaprinast.

0.5 ml of 65% nitric acid/acetonitrile (2.7 oz/7.3 ml) is added at 0C to a solution of zaprinast (0.5 g, 1.84 mmol) in acetonitrile (10 ml) and the resulting mixture was stirred in the dark under nitrogen atmosphere for 30 minutes. Then the solution was diluted with diethyl ether and the formed precipitate was filtered, washed with diethyl ether and dried under vacuum (0.4 g).

C, H, N analysis

calculated (%): 46,71; N 4,22; N 25,14;

found (%): Of 46.68; H 4.26 Deaths; N 25,11.

Example 21

With adenoma to 0C, added dropwise 65% nitric acid (1.3 ml).

The mixture was stirred at 0C for 30 minutes Add n-hexane (20 ml). The precipitate is filtered and washed with n-hexane.

Receive the product (3 g) as a white solid. The pace. pl. 123-127S.

Elemental analysis:

calculated (%): C 51,05; H 7,03; N OF 12.73;

found (%): C 51,10; H 7,02; N of 12.73.

1. Nitrate salts of the compounds selected from the following classes:

Class (A3):

1 isopropylamino-3-(1-naphthyloxy)-2-propanolol(propanolol),

(S)-1-(tert-butylamino)-3-(4-morpholino-1,2,5-thiadiazol-3-oxy)-2-propanol(timolol),

4-(2-hydroxy-3-isopropylphenoxy)phenyl-ndimethylacetamide(atenolol);

Class (A2):

1-[[3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazole[4,3-d]pyrimidine-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine(sildenafil),

1(2H)-phthalazinone(hydralazine),

2-(2-proproxyphene)-8-agapurin-6-he(zaprinast),

6-(1-piperidinyl)-2,4-pyrimidinediamine-3-oxide(Minoxidil);

Class (A1c):

(S)-N-valeryl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]valine(valsartan),

Class (4b):

methyl-2-[methyl(phenylmethyl)-amino]ethyl ester of 1,4-dihydro-2,6-dimethyl-4-(3-neath the Teal]methylamino]propyl]-3,4-dimethoxy -(1-methylethyl)benzoylacetonitrile(verapamil);

Class(A7d):

3,5-diamino-N-(aminoiminomethyl)-6-harperinformation (amiloride),

2-(2,2-dicyclohexylmethyl)piperidine (perhexiline);

Class (A1b):

2-N. butyl-4-chloro-5-oxymethyl-1-[2'-(tetrazol-5-yl)biphenyl-4-yl]imidazole(losartan),

and nitrate 3,4-dihydroxymorphinan (apomorphine).

2. Nitrate salts under item 1, containing one or more isomers of the above compounds.

3. Nitrate salts on PP.1 and 2, where salts of the above compounds contain at least one mole of nitrate ions/mol connection.

4. Pharmaceutical compositions of nitrate salts under item 1, having hypotensive activity.

5. Nitrate salts and compositions on PP.1 and 4 to obtain drugs, such as cardiovascular drugs.

6. Nitrate salts and compositions on PP.1 and 4 to obtain medicines for relaxation of the cavernous artery and the cavernous bodies of man.

7. Nitrate salts and compositions by p. 6, where the compound is a nitrate sildenafil.

8. Nitrate salts under item 1, containing in the molecule one group-ONO2.

 

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or their pharmaceutically acceptable salts, in which the dotted lines indicate optional double bonds; A is-CR7or N; - - NR1R2, -CR1R2R11, -C(= CR2R12R1, -NHCHR1R2, -ОСHR1R2, -SCHR1R2, -CHR2OR12,

-CHR2SR12, -C(S)R2or-C(O)R2N-ethyl-2,2,2-triptorelin; G is oxygen, sulfur, NH, NH3hydrogen, methoxy, ethoxy, triptoreline, methyl, ethyl, dimethoxy, NH2, NHCH3N(CH3)2or trifluoromethyl; Y Is N; Z is NH, O, S, -N(C1-C2alkyl) or-C(R13R14), where R13and R14independently of one another represent hydrogen, trifluoromethyl or methyl, or one of the elements of R13and R14is cyano and the other is hydrogen or stands; R1- C1-C6alkyl which may be optionally substituted by one or two substituents R8independently from each other selected from the group comprising hydroxy, fluorine, chlorine, bromine, iodine, CF3C1-C4alkoxy, -O-CO-(C1-C4alkyl), where (C1-C2- C1-C12alkyl, aryl or -(C1-C4alkylene)aryl, where aryl is phenyl, naphthyl; R3is methyl, ethyl, fluorine, chlorine, bromine, iodine, cyano, methoxy, OCF3, methylthio, methylsulphonyl, CH2HE or CH2OCH3; R4is hydrogen, C1-C4alkyl, fluorine, chlorine, bromine, iodine, C1-C4alkoxy, triptoreline, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CF3, amino, nitro, -NH(C1-C4alkyl), -N(CH3)2, -NHCOCH3, -NHCONHCH3, hydroxy, -CO(C1-C4alkyl), -Cho, COOH, cyano, or-COO(C1-C4alkyl), where C1-C4the alkyl may be substituted by one Deputy chosen from the group comprising hydroxy, amino, -NHCOCH3, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, fluorine, chlorine, cyano, nitro; R5is phenyl, naphthyl, pyridyl, pyrimidyl, where each of the above groups R5substituted with one to three substituents that are independently from each other selected from fluorine, chlorine, C1-C6the alkyl or C1-C6alkoxyl, or one Deputy chosen from the group comprising hydroxy, iodine, bromine, formyl, cyano, nitro, trifluoromethyl, amino, -(C1-C6these groups of R5may be optionally substituted with one hydroxy-group; R6is hydrogen or C1-C6alkyl; R7is hydrogen, methyl; R11is hydrogen, hydroxy, fluorine or methoxy; R12is hydrogen or C1-C4alkyl, and R16and R17independently of one another represent hydrogen, hydroxy, methyl, ethyl, methoxy or ethoxy, except that both R16and R17cannot both be methoxy or ethoxy; or R16and R17together form oxo (=O) group; provided that if G is an atom of oxygen, sulfur, NH or NCH3he is joined by a double bond to a five-membered ring of the formula III, and further provided that R6is absent when the nitrogen atom to which it is linked, is attached by a double bond to an adjacent carbon atom in the ring

The invention relates to 4-hydroxy-3-chinainternational and hydrazides of General formula (I), where a represents a-CH2- or-NH-, a R1, R2, R3and R4such as defined in the claims

The invention relates to new derivatives pyrazolopyrimidinones General formula (1) or their pharmaceutically acceptable salts that may be used in the treatment of impotence, and method of production thereof

The invention relates to new derivatives of 1,5-dihydropyrazolo[3,4-d] pyrimidinone General formula (I) having the properties of an inhibitor of phosphodiesterase, which can be used, for example, high blood pressure, angina and heart disease

The invention relates to the field of organic chemistry, namely to new bicyclic derivative

The invention relates to 4-(allumination)-2,4-dihydropyrazol-3-Onam General formula I, where R1denotes benzyl, alkoxybenzyl with 1-3 C-atoms in the alkyl part, unsubstituted or substituted once to three - fold amino, acyl, halogen, nitro, CN, AO, carboxyla, carbamoyl, N-allylcarbamate, N, N-dialkylammonium (with 1-6 C-atoms in the alkyl part), A-CO-NH-, AND-O-CO-NH-, AND-O-CO -, NA-, SO2NR4R5(R4and R5can denote H or alkyl with 1-6 C-atoms or NR4R5represents 5 - or 6-membered ring, optionally with other heteroatoms, like N, or O, which may be substituted),-CO-NH-SO2-, A-CO-NA-SO2- (AND-SO2-)2N-, tetrazolium phenyl; or pyridyl; R2denotes alkyl with 1-5 C-atoms, ethoxycarbonylmethyl, hydroxycarbonylmethyl; R3denotes unbranched or branched alkyl with 1-5 C-atoms, unbranched or branched alkoxy with 1-5 C-atoms or CF3And denotes unbranched or branched alkyl with 1-6 C-atoms or CF3and their salts

The invention relates to new 1-(biphenyl-4-yl)methyl-1H-1, 2,4-triazole compounds and 1-(biphenyl-4-yl)methyl-4H-1,2,4-triazole compounds, and each of them has as a substituent in the 2'-position (2,4-dioxopyrimidine-5-ilidene)methyl or (2,4-dioxotetrahydrofuran-5-ilidene)methyl, and their salts

The invention relates to new Amida condensed terracarbon acid of General formula I, where G is Q(C)k-W-(C)m-Z, Q is phenyl, 2-, 3-, 4-pyridyl, which may be substituted; T is halogen, hydrogen, hydroxyl, amino, C1-C6alkoxy; W is-O-, -N-, -S-, CR7R8where R7and R8the same or different and represent H, C1-C6alkyl; X is hydrogen; Z is hydroxyl, C1-C6alkoxy, C3-C7cycloalkylation, NH2and other, NR9COR10where R9and R10the same or different represent H, C1-C6alkyl, etc

The invention relates to new sulfonamide of General formula I, where R1-R8A and B have the meanings indicated in the formula, which are inhibitors of endothelin and can be used for the treatment of diseases associated with the activity of endothelin, such as high blood pressure, as well as to pharmaceutical compositions based on
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