Analogues of the gamma Aminobutyric acid (GABA), which Release nitric oxide for the treatment of neuropathic pain and Preparation Process

摘要

Nitrooxilo acid analogues derived from G - aminobutyric (GABA analogues) to treat neuropathic pain, and particularly the Diabetic Neuropathy. Pharmaceutical formulation comprising Said Derivatives. Process for their Preparation.Claim 1: a compound of formula (1) or stereoisomers or salts thereof wherein RC is a hydrogen or a formula (2), or a pharmaceutically acceptable RC is cation is Hydrogen; ra and RB is (CH3) 2chch2 - or ra and RB, together with the carbon Atom at they are United, Form a Cyclohexyl; R is selected from the group consisting of (i) - N - (R0) CH (R1, ono2)(ii) - (R0) n (ono2) - ch - ch (A1a) - ono2), III (R0) n (T) - X (q) - M - P - Q - (CH2) CH (R1) - ono2), IV (R0) n - M - X (T) - (q) P - (CH2) CH (Q - ono2) CH (A1A ono2), (V) The Compound of formula (3), (VI) The Compound of formula (4), VII (R0) - N (CH) - ono2) - (CH2) Q1 - X - (CH2) q2ch (R1) - ono2), VIII (R0) n - (cr6r7) - (CH2) QCH (R1, ono2)Where n is 0 OR 1; M is 0 OR 1; and P is 0 OR 1; n is 0 OR 1; Q is an integer between 0 and 10; Q1 is an integer between 1 and 10; Q2 is an integer between 1 and 10; t is an integer between 1 and 4 alquileno; R0 is a linear or branched C1 - 10; r1 is selected from Hydrogen, c1-4 alkyl linear Or branched;- (CH2) OCH3; A1A is Hydrogen or a c1-4 linear or branched alkyl; X is selected from an oxygen Atom, - NH -, - N (CH3) or a Covalent Bond; T and Q - cr2r3 - R2 and R3, where, in each case, are selected in the form Independent between c1-4 alkyl Hydrogen, linear or branched, or4, NHR5; R4 is Hydrogen or c1-4 alkyl linear or branched; R5 is Hydrogen, alkyl c1-4 linear or branched.- C (o) - C (o) CH3 or oC (CH3) 3; R6 is c1-4 alkyl Hydrogen or linear or branched; R7 is (CH2) R1 (QCH ono2), where Q and R1 are as defined previously.Claim 21: a process for preparing a compound of formula (1) According to claim 1, characterized in that it comprises: (i) reacting a compound of formula (5) where a is a group Activator selected from formulas (2a) - (2H) and R is selected from the group that I Ste in) - N - (R0) CH (R1) - ono2), B (R0) n (- ch - ch (ono2) A1A, ono2)(c) - (R0) n (T) - X (q) - M - P - Q - (CH2) CH (R1) - ono2), D (R0) n - M - X (T) - P (q) - (CH2) CH (Q - ono2) CH (ono2) A1a), and the compound of formula (3), (f) The Compound of formula (4), G (R0) - N (CH) - ono2) - (CH2) Q1 - X - (CH2) q2ch (R1) - ono2), H (R0) - (N - (cr6r7) QCH (CH2) R1, ono2)Where n is 0 OR 1; M is 0 OR 1; and P is 0 OR 1; n is 0 OR 1; Q is an integer between 0 and 10; Q1 is an integer between 1 and 10; Q2 is an integer between 1 and 10; t is an integer between 1 and 4 alquileno; R0 is a linear or branched C1 - 10; r1 is selected from Hydrogen, c1-4 alkyl linear Or branched;- (CH2) OCH3; A1A is Hydrogen or a c1-4 linear or branched alkyl; X is selected from an oxygen Atom, - NH -, - N (CH3) or a Covalent Bond; T and Q - cr2r3 - R2 and R3, where, in each case, are selected in the form Independent between c1-4 alkyl Hydrogen, linear or branched, or4, NHR5; R4 is Hydrogen or c1-4 alkyl linear or branched; R5 is Hydrogen, alkyl c1-4 linear or branched.- C (o) - C (o) CH3 or oC (CH3) 3; R6 is c1-4 alkyl Hydrogen or linear or branched; R7 is (CH2) R1 (QCH ono2), where Q and R1 are as defined previously, with a compound of formula (6) or (7 where p is a protecting Group such as a carboxylic acid, T - butyl Group, or Group d protector And in a aprotico silyl, polar / nonpolar Solvent,In the presence of an organic or inorganic base; (ii) to remove the protective Group P by an Acid processing or with known methods, depending on the Group P, to produce a compound of formula (1), where cr is H, R is as defined above and the remaining variables are As defined in claim 1; ii) optionallyReacting The Compound of formula (1) with a compound (8), where X0 is CL, Br or I, in the presence of an organic or inorganic base in a aprotico polar / nonpolar Solvent, to produce a compound of formula (1) where RC is the compound of formula (ii) (2); Optionally, React The compounds of formula (1), where cr is H, with the appropriate basis.So as to obtain a compound of formula (1) where RC is the cation pharmaceutically acceptable; (iii) reacting a compound of formula rcoox1 where r is as defined above and X1 is AG + and Hg +, with a compound of formula (9) where is it defined ANTERIORI Dad, X0 is CL, Br or I,With a molar ratio between the compounds of formulas rcoox1 and (9) of between 0.5 and 2, in an organic Solvent, to produce a compound of formula (5) where a and R are as defined above; (iv) reacting a carboxylic acid nitrate formula r-cooh, where r is As defined previously, with Ag2O or hg2o,With a molar ratio between the compound formula r-cooh and Ag2O or hg2o between 1 and 0.5, in an organic Solvent, to obtain Salt of carboxylic acid coox1 formula Where R -, Ag +, Hg + X1.