Patent EA-001959-B1 (EA)
Title: New pentaerythritol derivatives, their production and use and intermediatesfor their synthesis
Inventor: HESS ULRICH
IPC: A61K31/6615
Filed: 1997-10-10
Abstract: 1. A compound of general formula I:   in which R<1>, R<2>, R<3> are identical to or different from one another and are CH2-ONO2, CH2-OR<4> or R<5>, at least one of the substituents R<1>, R<2>, R<3> being R<5>, R<4> is H or C1-C6-alkanoyl, R<5> is COR<6>, R<6> is OH, OR<7>, NH2, NHR<7>, NR<7>2, N<+>R<7>3X<->, NR<8>, NR<9>R<10>, NR<11>R<12> or NH-NH2, R<7> is linear or branched C1-C6-alkyl, linear or branched C1-C6-alkenyl, aryl-, aralkyl-, hetaryl- or hetaralkyl, R<8> is C1-C6-alkylidene, R<9>, R<10> are different from one another and are R<7> R<11>, R<12> are identical to or different from one another and are NR<7>2, N<+>R<7>3X<-> or NR<8>, and X is a halogen or a suitable anion, and therapeutically acceptable salts thereof, with the exception of the following compounds: 3-nitryloxy-2,2-bis(nitryloxymethyl)propionic acid and methyl ether 3-nitryloxy-2,2-bis(nitryloxymethyl)propionic acid. 2. The compound according to Claim 1 of formulae II to VII, (O2NOCH2)2C(CH2ONO2)COR<6> (II), (O2NOCH2)2C(COR<6>)2 (III), O2NOCH2C(COR<6>)3 (IV), (O2NOCH2)2C(CH2OR<4>)COR<6> (V), (O2NOCH2)C(CH2OR<4>)2COR<6> (VI), (O2NOCH2)C(CH2OR<4>)(COR<6>)2 (VII). 3. The compound according to Claim 2 in which R<4> is H or C1-C6-alkanoyl, and R<6> is OH, OR<7>, NH2, NHR<7>, NR<7>2 or N<+>R<7>3X<->. 4. The compound according to Claim 2 which is ethyl 3-nitryloxy-2,2-bis(nitryloxymethyl)propionate, propyl 3-nitryloxy-2,2-bis(nitryloxymethyl)propionate, butyl 3-nitryloxy-2,2-bis(nitryloxymethyl)propionate, benzyl 3-nitryloxy-2,2-bis(nitryloxymethyl)propionate, 3-nitryloxy-2,2-bis(nitryloxymethyl)propionamide, 3-nitryloxy-2,2-bis(nitryloxymethyl)propionic acid N-benzylamide, 3-nitryloxy-2,2-bis(nitryloxymethyl)propionic acid hydrazide, dimethyl 2,2-bis(nitryloxymethyl)malonate, and dimethyl 2-methoxycarbonyl-2-nitryloxymethylmalonate. 5. Compounds according to Claim 2 of formulae IX to XIII: 2,2-bis(nitryloxymethyl)malonic acid; 2-carboxy-2-nitryloxymethylmalonic acid; 2,2-bis(nitryloxymethyl)-3-hydroxypropionic acid; 3-hydroxy-2-hydroxymethyl-2-nitryloxymethylpropionic acid; and 2-hydroxymethyl-2-nitryloxymethylmalonic acid; (O2NOCH2)2C(COOH)2 (IX), O2NOCH2C(COOH)3 (X), (O2NOCH2)2C(CH2OH)COOH (XI), (O2NOCH2)C(CH2OH)2COOH (XII), (O2NOCH2)C(CH2OH)(COOH)2 (XIII). 6. Sodium 3-nitryloxy-2,2-bis(nitryloxymethyl)propinate and potassium 3-nitryloxy-2,2-bis(nitryloxymethyl)propionate. 7. A compound of general formula XIV:   in which R<13> is the group of formula XV, -O-CH2-C(CH2OH)q(CH2ONO2)r (XV), and m-r-are integers, wherein m+n+o+p=4, q+r=3, m and/or r>=1 and o and/or p>=1. 8. The compound according to Claim 7, which is 3-nitryloxy-2,2-bis(nitryloxymethyl)propyl ether 3-nitryloxy-2,2-bis(nitryloxymethyl)propionic acid. 9. A compound of general formula XVI:   wherein R<14>, R<15>, R<16> are identical to or different from one another and are H, OR<19>, ONO2, OR<17> or R<18>, R<17> is COR<19> or R<23>, R<18> is O(PO2H)OR<20>, O(PO2H)OR<22>, OSO2OR<22> or COOR<19>, R<19> is H, linear or branched C1-C6-alkyl, R<20> is linear or branched C1-C6-alkyl-R<21>, R<21> is NR<19>2, N<+>R<19>3 or N<+>R<19>3X<->; R<22> is R<19>, aryl or NR<19>2, R<23> is 3- or 5-carbonyl radical substituted, if necessary, in 2, 4 and/or 6-position 1,4-dihydropyrydin-3,5-dicarboxylic acid, 1-substituted pyrrolidine-2-carbonyl radical, substituted sydnonimine N-carbonyl radical, radical -CO-CH(NHCOR<19>)-CR<19>2-S-NO, radical -CO-CH(NH2)-CR<19>2-S-NO or radical -NH-CH(COOR<19>)-CR<19>2-S-NO and X is halo or a suitable anion and therapeutically acceptable salts thereof, with the exception of the following combinations, wherein: R<14> = R<15> = R<16> = ONO2; R<14> = OH, R<15> = R<16> = ONO2; R<14> = R<15> = OH, R<16> = ONO2; R<14> = R<15> = R<16> = OH; R<14> = R<15> = ONO2, R<16> = H; R<14> = ONO2, R<15> = R<16> = H; R<14> = ONO2, R<15> = R<16> = OR<19>, R<19> = C3H7; R<14> = R<15> = ONO2, R<16> = OR<19>, R<19> = C3H7; R<14> = ONO2, R<15> = OR<19>, R<16> = H, R<19> = H; R<14> = R<15> = OR<19>, R<16> = H, R<19> = H; R<14> = R<15> = OR<17>, R<16> = H, R<17> = COR<19>, R<19> = CH3; R<14> = ONO2, R<15> = OR<17>, R<16> = H, R<17> = COR<19>, R<19> = CH3; R<14> = R<15> = ONO2, R<16> = OR<17>, R<17> = COR<19>, R<19> = H, CH3, C2H5, C4H9, C5H11, and also R<14> = R<15> = R<16> = H. 10. The compound according to Claim 9, wherein R<14> is OR<19> or R<18>; R<15>, R<16> are ONO2 and R<18> is COOR<19>. 11. The compound according to Claim 10 of formula XVII, (O2NOCH2)3C-CH2-COOR<19> (XVII). 12. The compound according to Claim 11, wherein R<19> is H, methyl or ethyl. 13. The compound according to Claim 9 corresponding to formulas (O2NOCH2)3C-CH2-COONa and (O2NOCH2)3C-CH2-COOK: sodium 3,3-bis(nitryloxymethyl)-4-nitryloxybutyrate and potassium 3,3-bis(nitryloxymethyl)-4-nitryloxybutyrate. 14. The compound according to Claim 10 of formula XVIII, (O2NOCH2)3C-CH2-OR<19> (XVIII). 15. The compound according to Claim 14, wherein R<19> is methyl or ethyl. 16. The compound of general formula XIX,   wherein R<24> is H, NO2, acyl, alkyl, or alkenyl, R<25> is H, or CH3, and R<26> is H. 17. The compound of Claim 16, corresponding to general formula XX,   18. The compound of Claim 17, corresponding to general formula XXI, (O2NOCH2)3C-CH2-O-(PO2)<->-O-CH2-CH2-N<+>(CH3)3 (XXI) [2,2-bis(nitryloxymethyl)-3-nitryloxypropyl]-phosphorylcholine. 19. The compound of general formula XXII,   wherein R<27> is independently NO2 or R<17>-R<23>, with corresponding meaning mentioned in Claim 9, and n is integer from 0 to 10, preferably from 0 to 4, with the exception of the following combinations, wherein n=0, R<27>= NO2, n=1, R<27>=NO2, and n=2, R<27>=NO2. 20. The compound of Claim 19, corresponding to formula XXIV, bis-[2,2-bis(nitryloxymethyl)-2-hydroxymethyl]ethyl ether   21. The compound of Claim 19, corresponding to formula XXV, [2,2-bis(nitryloxymethyl)-3-nitryloxypropyl]-2,2-bis(nitryloxymethyl)-3-hydroxypropyl ether (O2NO-CH2)3C-CH2-O-CH2-C(CH2-OXH)(CH2-ONO2)2 (XV) 22. The compound of general formula I   in which R<1>, R<2>, R<3> are identical to or different from one another and are CH2-ONO2, CH2-OR<4> or R<5>, at least one of the substituents R<1>-R<3> being identical R<5>, R<4> is H or C1-C6-alkanoyl, R<5> is COR<6>, R<6> is at least in one meaning Cl or Br, further OH, OR<7>, NH2, NHR<7>, NR<7>2, N<+>R<7>3X<->, NR<8>, NR<9>R<10>, NR<11>R<12> or NH-NH2, R<7> is linear or branched C1-C6-alkyl, linear or branched C1-C6-alkenyl, aryl-, aralkyl-, hetaryl- or hetaralkyl, R<8> is C1-C6-alkylidene, R<9>, R<10> are different from one another and are R<7> R<11>, R<12> are identical to or different from one another and are NR<7>2, N<+>R<7>3X<-> or NR<8>, and X is a halogen or a suitable anion group. 23. A compound according to Claim 22 3-nitryloxy-2,2-bis(nitryloxymethyl)propionyl chloride, 2,2-bis(nitryloxymethyl)malonyl dichloride, and 2-chlorocarbonyl-2-nitryloxymethymalonyl dichloride. 24. The compound of general formula XIV   in which R<13> is at least in one meaning Cl or Br, further is the group of formula XV, -O-CH2-C(CH2OH)q(CH2ONO2)r (XV), and m-r are integers, wherein m+n+o+p=4, q+r=3, m and/or r>=1 and o and/or p>=1. 25. The compound of general formula XVI,   wherein R<14>, R<15>, R<16> are identical to or different from one another and are H, OR<19>, ONO2, OR<17> or R<18>, R<17> is COR<19> or R<23>, R<18> is at least in one meaning COCl or COBr, further is O(PO2H)OR<20>, O(PO2H)OR<22>, OSO2OR<22> or COOR<19>, R<19> is H, linear or branched C1-C6-alkyl, R<20> is linear or branched C1-C6-alkyl-R<21>, R<21> is NR<19>2, N<+>R<19>3 or N<+>R<19>3X<->; R<22> is R<19>, aryl or NR<19>2, R<23> is 3- or 5-carbonyl radical substituted, if necessary, in 2, 4 and/or 6-position 1,4-dihydropyrydin-3,5-dicarboxylic acid, 1-substituted pyrrolidine-2-carbonyl radical, substituted sydnonimine N-carbonyl radical, radical -CO-CH(NHCOR<19>)-CR<19>2-S-NO, radical -CO-CH(NH2)-CR<19>2-S-NO or radical -NH-CH(COOR<19>)-CR<19>2-S-NO and X is a halogen or a suitable anion group. 26. The use of a compound according to Claims 1-21 as drugs. 27. The use of a compound according to Claims 1-21 as vasodilators. 28. The use of a compound according to Claims 1-21 as endothelium-protecting agents. 29. The use of a compound according to Claims 1-21 as agents for the treatment of oxidative stress in organisms. 30. The use of a compound according to Claims 1-21 as agents for the treatment of oxidative stress in vessels and tissues of organism. 31. The use of a compound according to Claims 1-21 as platelet aggregation inhibitors. 32. The use of a compound according to Claims 1-21 as agents for the treatment of erectile dysfunctions. 33. The use of a compound according to Claims 1-21 for obtaining pharmaceutical compositions. 34. 3-nitryloxy-2,2-bis(nitryloxymethyl)propionic acid, 3-nitryloxy-2,2-bis(nitryloxymethyl)propionic acid methyl ether, compounds of general formula XVI,   wherein R<14> = ONO2, R<15> = R<16> = H; R<14> = ONO2, R<15> = R<16> = OR<19>, R<19> = C3H7; R<14> = R<15> = ONO2, R<16> = OR<19>, R<19> = C3H7; R<14> = ONO2, R<15> = OR<19>, R<16> = H, R<19> = H; R<14> = R<15> = OR<19>, R<16> = H, R<19> = H; R<14> = R<15> = OR<17>, R<16> = H, R<17> = COR<19>, R<19> = CH3; R<14> = ONO2, R<15> = OR<17>, R<16> = H, R<17> = COR<19>, R<19> = CH3; R<14> = R<15> = ONO2, R<16> <=> OR<17>, R<17> = COR<19>, R<19> = H, CH3, C2H5, C4H9, C5H11; and also R<14> = R<15> = R<16> = H and compounds of formula XXII   wherein n = 0, R<27> = NO2; n = 1, R<27> = NO2, and also n = 2, R<27> = NO2, as drugs, in particular, as vasodilators and endothelium-protecting agents, as agents for the treatment of oxidative stress in organisms, as agents for the treatment of oxidative stress in mammalian vessels and tissues, as platelet aggregation inhibitors, as agents for the treatment of erectile dysfunctions. 35. The use of compounds according to Claim 34 for obtaining pharmaceutical compositions. 36. The pharmaceutical composition comprising one or more compounds according to Claims