Nitrate salts of antihypertensive medicines

Abstract

Nitric acid salts with medicines having an antihypertensive activity.

What is claimed:  
     
         1 . Nitrate salts of the compounds selected from the following classes: 
 Class (a1b) of formula (a1b):                          R I   A1 ═—CH 2 OH,    R 1   A1 ═H, Cl;    R II   A1 ═—(CH 2 ) 3 —CH 3 , —O—H 2 —CH 3 ;    R III   A1 ═H, free valence;    R IV   A1 =free valence;    or R A1 ═—O and R III   A1 =free valence form with the carbon atom in 5 position a keto group,    or R IV   A1 , R III   A1 ,R I   A1  and the carbon atoms in 4 and 5 position of the heterocyclic ring of the formula (A1b) form group (IXc),                          or R I   A1 , R IV   A1  and the carbon atom in 4 position of the heterocyclic ring of the formula (A1b) form group (1Xd);                          and wherein R III   A1 =free valence and R IV   A1 =free valence there is a double bond between the carbon atoms in 4 and 5 position in the heterocyclic ring of the formula (A1b),    when X A1 ═(Ixa), R A1 ═CH 2 OH, R I   A1 ═Cl, R III   A1 ═R IV   A1 =free valences forming a —CH═CH— double bond with the carbon atoms in 4 to 5 position of the heterocyclic ring of the formula (A1b), R II   A1 ═—(CH 2 ) 3 —CH 3 , Losartan residue;    as in Losartan but with R A1 ═—O and R III   A1  free valence, so as to form in combination with the carbon atom in 5 position of the heterocyclic ring of the formula (A1b) a ketonic group, R I   A1  with R IV   A1  and with the carbon atom in 4 position of the heterocyclic ring are such as to form the saturated ring having 5 carbon atoms (IXd), Irbesartan residue;    as in Losartan but with R II   A1 ═—O—CH 2 —CH 3 , R A1  together with R I   A1  and the carbon atoms in 4 and 5 position of the heterocyclic ring with R IV   A1  and R III   A1  free valences, are such as to form the aromatic radical containing a —COOH group (IXc) Candesartan residue;    as in Losartan but with X A1 ═—COOH, R A1 ═(IXb), R I   A1 ═H, and R IV   A1  and R III   A1  free valence from a double bond between the carbon atoms in 4 and 5 position in the heterocyclic ring of formula (A1b), Eprosartan; class (A1c): Valsartan.    
     
     
         2 . Nitrate salts of compounds selected from the following class (A3) of formula (A3):  
       
         
           
           
               
               
           
         
         R VI   B1 ═H;  
         R VII   B1 ═H;  
         R I   B1  and R II   B1 , equal to or different from each other, are H, CH 3 ,  
         
           
             
             
                 
                 
             
           
         
         wherein in the formula (XId) t=0, 1;  
         in the formula (XIe) Y B1  can have the following meanings:  
         
           
             
             
                 
                 
             
           
         
         in the formula (XIf) Z=H, —OCH 3 ;  
         in the formula (A3);  
         X B1 ═—O—, —S—;  
         n and m, equal to or different from each other, are 0, 1;  
         
           
             
             
                 
                 
             
           
           
             
             
                 
                 
             
           
         
         wherein in the formula (XIp):  
         S 1 ═H, CN, OCH 3 , CH 3 , —CH 2 —CH 3 —, —O—CH 2 —CONH—CH 3 , —COCH 3 , —CO—(CH 2 ) 2 —CH 3 , —O—CH 2 —CH═CH 2 , —CH 2 —CH═CH 2 , cyclopentyl, or  
         
           
             
             
                 
                 
             
           
         
         S 2 ═H, CH 3 , Cl, —SOCH 3 , —CONH 2 ; S 3 ═H, F, Cl, OH, NO 2 , —CH 2 —CO—NH 2 , —(CH 2 ) 2 —OCH 3 , —NH—COOH 3 , —CH 2 —O—CH 2 —CH 2 —O—CH(CH 3 ) 2 , —CH 2 —CH 2 COOCH 3 , —NH—CO—N(C 2 H 5 ) 2 , —NH—CO—(CH 2 ) 2 —CH 3 , —NH—SO 2 —CH 3 , —NH—CO—NH-[cyclohexyl], —CH 2 —CH 2 —O—CH 2 -[cyclopropyl];  
         S 4 ═H, Cl, —CH 2 —CH 2 —;  
         or S 1 , S 2  and the carbon atoms in 2 and 3 position of the C 6  aromatic ring of the radical (XIp) form the following ring:  
         
           
             
             
                 
                 
             
           
         
         wherein:  
         (*) designates the atom adjacent to the aromatic ring of the formula XIp VII    
         B═—CH 2 —, —NH—, —CH═CH—, (*)-CO—CH 2 —;  
         A=-O—, (*)-CH 2 —CH(OH)—, (*)-O—CH 2 —, (*)-S—CH 2 —, —CH 2 CH 2 —, —CH 2 —,  
         W 1 ═H, free valence;  
         W 2 =free valence, H, OH, —CH 3 , —ONO 2 , —O;  
         or A is a tertiary carbon atom and at the same time W 1 =free valence to form a double bond —CH═CH— between A and the carbon atom in 1′ position, or W 1 , W 2  the carbon atom in 1′ position and A form an aromatic ring having 6 carbon atoms to form the following group:  
         
           
             
             
                 
                 
             
           
         
         when W 2 ═—O and W 1 =free valence at the carbon atom in 1′ position of radical (XIp VII ) it is formed a ketonic group;  
         or when in formula (XIp) S 4 ═—CH 2 —CH 2 —, and in formula (A3) X B1  is oxygen, m=n=1 and (R VII   B1 ) is a free valence, the following ring is formed with the carbon atoms in 1 and 6 position of the aromatic ring of radical (XIp):  
         
           
             
             
                 
                 
             
           
         
         or when in formula (A3) n=m=1, both R VII   B1  and R VI   B1  are free valences, S 4  and the carbon atoms in 1 and 6 position of the aromatic ring of formula (XIp), S 1  being —CH 2 —CH 3 , together with the carbon atom —|C| n — and X B1 =oxygen of formula (A3) form the following ring:  
         
           
             
             
                 
                 
             
           
         
         when R I   B1 ═H, R II   B1  and R III   B1 ═CH 3 , R V   B1 ═H, R VI   B1 ═R VII   B1 ═H, m=n=1, X B1 ═—O—, R IV   B1 ═(XIp) wherein S 1 ═S 2 ═S 4 ═H, S 3 ═—CH 2 —CO—NH 2 , Atenolol residue;  
         as in Atenolol but with R IV   B1 ═(XIs), Befunolol residue;  
         as in Atenolol, but with S 1 ═S 2 ═S 4 ═H, S 1 ═—CH 2 —CH═CH 2 , Alprenolol residue;  
         as in Atenolol, but with S 1 ═COCH 3 , S 3 ═—NH—CO—(CH 2 ) 2 —CH 3 , S 2 ═S 4 ═H, Acebutolol residue;  
         as in Atenolol, but with S 3 ═—CH 2 —CH 2 —O—CH 2 -(cyclopropyl), Betaxolol residue;  
         as in Atenolol but with S 3 ═—CH 2 —O—CH 2 —CH 2 —O—CH(CH 3 ) 2 , Bisoprolol residue  
         as in Alprenolol but with S 1 ═(XIp II ) and R I   B1 ═CH 3 , Bufetolol residue;  
         as in Bufetolol, but with S 1 ═—CN, Bunitrolol residue;  
         as in Bufetolol, but with S 1 ═H, S 4 ═Cl, S 2 ═CH 3 , Bupranolol residue;  
         as in Bufetolol but with S 1 ═—CO—(CH 2 ) 2 —CH 3 , S 3 ═F, Butofilolol residue;  
         as in Mepindolol but in R IV   B1 ═(XIp VII ) A=-O—CH 2 —, B═—CH 2 —, W2=-ONO 2 ,  
         W1=H, Nipradilol residue;  
         as in Alprenolol, but with S 1 ═—O—CH 2 —CH═CH 2 , Oxprenolol residue;  
         as in Bufetolol, but with S 1 =cyclopentyl, Penbutolol residue;  
         as in Mepindolol but with W2=H, Pindolol residue;  
         as in Atenolol but with S 3 ═—NH—COCH 3 , Practolol residue;  
         as in Bufetolol but with S 1 ═H, S 3 ═—NH—CO—NH-(cyclohexyl), Talinolol residue;  
         as in Nipradilol but with R I   B1 ═CH 3 , A=-S—CH 2 — and W2=H, Tertatolol residue;  
         as in Tertatolol but with R IV   B1 ═(XIn), Tilisolol residue;  
         as in Bufetolol but with R IV   B1 ═(XIo), Timolol residue;  
         as in Bufetolol but with S 1 ═S 2 ═CH 3 , Xibenolol residue;  
         as in Xibenolol but with R I   B1 ═S 1 ═H, Toliprolol residue;  
         as in Toliprolol, but with R II   B1 ═H and R III   B1 ═(XIa), Bevantolol residue;  
         as in Carazolol but with R II   B1 ═H and R III   B1 ═(XIb), Carvedilol residue;  
         when in the formula (A3) R I   B1 ═R II   B1 ═R III   B1 ═CH 3 , R V   B1 ═(XIh), n=m=1, R VI   B1 ═R VII   B1 ═H, X B1 ═—O—, R IV   B1 ═(XIg), Bopindolol residue;  
         as in Atenolol but with R IV   B1 ═(XIp VIII ), wherein B═—NH—, Carazolol residue;  
         as in Bufetolol, but with R IV   B1 ═(XIp VII ) wherein A=-CH 2 —CH 2 —, B═—NH—, W2=-O which with W1=free valence and the carbon atom in 1′ position forms a ketonic group, Carteolol residue;  
         as in Bufetolol but with S 3 ═—NH—CO—N(C 2 H 5 ) 2 , S 1 ═—CO—CH 3  Celiprolol residue;  
         as in Bufetolol but with S 1 ═—O—CH 2 —CONH—CH 3 , Cetamolol residue;  
         as in Bupranolol, but with S 2 ═Cl Cloranolol residue;  
         as in Atenolol but with S 3 ═—CH 2 —CH 2 —COOCH 3 , Esmolol residue;  
         as in Atenolol but with R IV   B1 ═(Xiu) Indenolol residue;  
         as in Carteolol, but in R IV   B1 ═(XIp VII ) A=-CH 2 —, B═—COCH 2 —, W1=W2=H, Levobunolol residue;  
         as in Carteolol but with R I   B1 ═H and in R IV   B1 ═(XIp VII ) A is a tertiary carbon atom and W1 free valence, so as to form a —CH═CH— double bond between A and the carbon atom in 1′ position of (XIp VII ), W2=CH 3 , Mepindolol residue;  
         as in Atenolol, but with S 3 ═—(CH 2 ) 2 —OCH 3 , Metoprolol residue;  
         as in Carteolol but in R IV   B1 ═(XIp VII ) A=-CH 2 —CH(OH)—, B═—CH 2 —, W2=OH,  
         W1=H, Nadolol residue;  
         as in Atenolol but with S 3 ═NO 2 , Nifenalol residue;  
         as in Bufetolol but with R IV   B1 ═(XIt), Bucumolol residue;  
         when in the (A3) formula m=n=0 and R IV   B1 ═(XIz) R I   B1 ═R II   B1 ═R III   B1 ═CH 3 , R V   B1 ═H, Bufuralol residue;  
         as in Atenolol but with R III   B1 ═(XIe) with Y B1 ═H, n=m=0, R IV   B1 ═(XIi) Butidrine residue;  
         as in Butidrine, but with R III   B1 ═(XIe) with Y B1 ═(XIf) with Z=H, R IV   B1 ═(XIp)  
         wherein S 3 ═OH and S 2 ═CONH 2 , S 1 ═S 4 ═H, Dilevalol residue;  
         as in Bevantolol but with S 2 ═H, S 1 ═CN, R III   B1 ═(XIc), Epanolol residue;  
         as in Butidrine but with R III   B1 ═CH 3 , R IV   B1 ═(XIm), wherein the naphthalenic residue is linked by the carbon atom in 2 position to the carbon atom bringing the —OR IV   B1  substituent, Pronethalol residue;  
         as in Pronethalol but with m=1 and X B1 ═—O—, and R IV   B1  is the naphthalenic residue (XIm) linked by the carbon atom in 1 position to X B1  Propranolol residue;  
         as in Pronethalol but with R IV   B1 ═(XIp) with S 1 ═S 2 ═S 4 ═H and S 3 ═—NH—SO 2 —CH 3 , Sotalol residue;  
         as in Dilevalol but with S 2 ═—SOCH 3 , and in para position to the other aromatic ring (form. XIf) Z=-OCH 3 , Sulfinalol residue;  
         when in the formula (A3) R I   B1 ═R II   B1 ═H, R III   B1 ═(XId) with t=1, R V   B1 ═H, n=m=0, R IV   B1 ═(XId) with t=0, Nebivolol residue;  
         2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]benzamide (Labetalol), 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[(tetrahydro-2-furanyl)carbonyl]piperazine(Terazosin), 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furanylcarbonyl)piperazine (Prazosin).  
       
     
     
         3 . Nitrate salts of the following compounds of class (A4): 
 (A4a):    (2S-cis)-3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-di-hydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (Diltiazem), α-[3-[[2-(3,4-dimethoxyphenyl)ethyl]-methylamino]propyl]-3,4-dimethoxy-α-(1-methylethyl)-benzeneacetonitrile (Verapamil);    (A4b):    2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-di-hydro-6-methyl-3,5-pyridynedicarboxylic acid 3-ethyl 5-methyl ester (Amlodipine), 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl ester (Felodipine) 4-(4-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid 5-methyl 3-(1-methyl)ethyl ester (Isradipine), Lercanidipine, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine-dicarboxylic acid methyl 2[methyl(phenylmethyl)amino]ethyl ester (Nicardipine), 1,4-dihydro-2,6-dimethyl-4-(2-nitro-phenyl)-3,5-pyridinedicarboxilic acid dimethyl ester (Nifedipine), 1,4-dinhydro-2,6-dimethyl-4-(3-nitrophenil)-3,5-pyridinedicarboxylic acid 2-methoxyethyl 1-methylethyl ester (Nimodipine), 1,4-dihydro-2,6-dimethyl-4-(2-nitro-phenyl)-3,5-pyridinedicarboxylic acid methyl 2-methyl-propyl ester (Nisoldipine) 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid ethyl methyl ester (Nitrendipine);    (A4c):    (E)-1-[bis(4-fluorophenyl)methyl]4-(3-phenyl-2-propenyl)piperazine (Flunarizine).    
     
     
         4 . Nitrate salts of the following compounds of class (A7): 
 (A7a):    6-chloro-2H-1,2,4-benzothiadiazine-7-sulphonamide 1,1-dioxide (Chlorothiazide), 2-chloro-5-(2,3-dihydro-1-hydroxy-3-oxo-1H-isoindol-1-yl)benzebesulphonamide (Chlortalidone), 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulphonamide 1,1-dioxide (Hydrochlorothiazide), 3-(aminosulphonyl)-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-methylphenyl)-4-oxo-6-quinazolinesulphonamide (Metolazone), 7-chloro-2-ethyl-1,2,3,4-tetra hydro-4-oxo-6-quinazolinesulphonamide (Quinethazone);    (A7d):    3,5-diamino-N-(aminoiminomethyl)-6-chloropyrazinecarboxamide (Amiloride), 6-phenyl-2,4,7-pteridinetriamine (Triamterene),3-(aminosulphonyl)-5-(butylamino)-4-phenoxy-benzoic acid (Bumetanide), 5-(amino sulphonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic acid (Furosemide), N-[[(1-methylethyl)amino]carbonyl]-4-[(3-methylphenyl)amino]-3-pyridinesulphonamide (Torasemide);    (A8):    Apomorphine.    
     
     
         5 . Nitrate salts according to claims  1 - 4  of the following compounds: 
 class A1b): Losartan;  
 Class A3): Atenolol, Labetalol, Timolol, Prazosin, Terazosin, Propranolol;  
 Class A4): Nicardipine, Nifedipine, Nimodipine;  
 Class A7): Chlorothiazide, Amiloride, Furosemide.  
 
     
     
         6 . Salts according to claims  1 - 4 , wherein the salts of said compounds contain at least one nitrate ion mole/compound mole.  
     
     
         7 . Pharmaceutical compositions of the nitrate salts according to claims  1 - 4  and a pharmaceutically acceptable carrier.  
     
     
         8 . A method for treating hypertension, said method comprising administering to a patient in need thereof a hypertension treating effective amount of at least one compound of claims  1 - 4 .  
     
     
         9 . A method for treating cardiovascular disease, said method comprising administering to a patient in need thereof a cardiovascular disease treating effective amount of at least one compound of claims  1 - 4 .  
     
     
         10 . A method for treating hypertension, said method comprising local administration to a patient in need thereof a hypertension treating effect amount of at least one compound of claims  1 - 4 .