RU2001128159A - New connections - Google Patents

Claims (17)

1. The compound of General formula I

or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, where R ₁ represents a C ₁ -C ₆ alkyl substituted with one or more than one basic group, such as amino, amidino and / or guanidino; cycloalkyl substituted with one or more than one basic group, such as amino, amidino and / or guanidino; heterocyclyl containing at least one nitrogen atom; heterocyclyl containing at least one heteroatom selected from S or O and substituted with one or more basic groups, such as amino, amidino and / or guanidino; or aryl substituted with one or more than one basic group, such as amino, amidino and / or guanidino; R ₂ represents H, acyl, acylamino, alkyl, alkylcarbamoyl, alkylthio, alkoxy, aroyl, aroylamino, aryloxy, arylthio, amidino, amino, aryl, carbamoyl, carboxy, cyano, cycloalkyl, formyl, guanidino, halo, hydroxy oxo, nitro, thiol, group Z ₂ N-CO-O-, ZO-CO-NZ- or Z ₂ N-CO-NZ-; R ₃ represents COOR ₅ , SO (OR ₅ ), SO ₃ R ₅ , P = O (OR ₅ ) ₂ , B (OR ₅ ) ₂ , P = OR ₅ (OR ₅ ) or tetrazole, or any carboxylic acid isoster ; R ₄ represents SH, S-CO-C ₁ -C ₆ alkyl or S-CO-aryl; R ₅ represents H, C ₁ -C ₆ alkyl or aryl; R ₆ represents H or C ₁ -C ₆ alkyl; X represents O, S, SO, SO ₂ , C (Z) ₂ , N (Z), NR ₆ SO ₂ , SO ₂ NR ₆ , NR ₆ CO or CONR ₆ ; Y represents C (Z) ₂ ; Z independently represents H, C ₁ -C ₆ alkyl, aryl, cycloalkyl or heterocyclyl. 2. The compound according to claim 1 or a pharmaceutically acceptable salt or solvate or solvate thereof, of such a salt, wherein R ₁ is cycloalkyl substituted with one or more basic groups, such as amino, amidino and / or guanidino; heterocyclyl containing at least one nitrogen atom; heterocyclyl containing at least one heteroatom selected from S or O and substituted with one or more basic groups, such as amino, amidino and / or guanidino; or aryl substituted with one or more than one basic group, such as amino, amidino and / or guanidino; R ₂ represents H, acyl, acylamino, alkyl, alkylcarbamoyl, alkylthio, alkoxy, aroyl, aroylamino, aryloxy, arylthio, amidino, amino, aryl, carbamoyl, carboxy, cyano, cycloalkyl, formyl, guanidino, halo, hydroxy oxo, nitro, thiol, group Z ₂ N-CO-O-, ZO-CO-NZ- or Z ₂ N-CO-NZ-; R ₃ represents COOR ₅ ; R ₄ represents SH, S-CO-C ₁ -C ₆ alkyl or S-CO-aryl; R ₅ represents H, C ₁ -C ₆ alkyl or aryl; R ₆ represents H or C ₁ -C ₆ alkyl; X represents O, S, SO, SO ₂ , C (Z) ₂ , N (Z), NR ₆ SO ₂ , SO ₂ NR ₆ or CONR ₆ ; Y represents C (Z) ₂ ; Z independently represents H, C ₁ -C ₆ alkyl, aryl, cycloalkyl or heterocyclyl. 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, wherein R ₁ is cycloalkyl substituted with one or more basic groups, such as amino, amidino and / or guanidino; heterocyclyl containing at least one nitrogen atom; heterocyclyl containing at least one heteroatom selected from S or O and substituted with one or more basic groups, such as amino, amidino and / or guanidino; R ₂ represents H, C ₁ -C ₃ alkyl, amino, halogen, hydroxy; R ₃ represents COOR ₅ ; R ₄ represents SH, S-CO-C ₁ -C ₆ alkyl or S-CO-aryl; R ₅ represents H, C ₁ -C ₆ alkyl or aryl; X represents C (Z) ₂ ; Y represents C (Z) ₂ ; Z independently represents H or C ₁ -C ₆ alkyl. 4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate or solvate thereof, of such a salt, wherein R ₁ is cycloalkyl substituted with one or more basic groups, such as amino, amidino and / or guanidino; heterocyclyl containing at least one nitrogen atom; R ₂ represents H, F or C ₁ alkyl; R ₃ represents COOR ₅ ; R ₄ represents SH, S — CO — C ₁ -C ₆ alkyl or S — CO-aryl; R ₅ represents H, C ₁ -C ₆ alkyl or aryl; X represents C (Z) ₂ ; Y represents C (Z) ₂ ; Z independently represents H or C ₁ -C ₆ alkyl. 5. The compound according to any one of claims _{1 to 4} , or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, wherein R ₁ is cyclopentyl, pyridyl, pyrimidinyl, piperidinyl or thiazolyl; R ₂ represents H, F or C ₁ alkyl; R ₃ represents COOR ₅ ; R ₄ represents SH; R ₅ represents H; X represents CHZ; Y represents CHZ; Z independently represents H or C ₁ -C ₆ alkyl. 6. The method of obtaining the compound according to any one of claims 1 to 5, where R ₁ , R ₃ , R ₄ and Y are as defined in claim 1, X represents C (Z) ₂ , and R ₂ represents H, comprising a step wherein the compound of formula VI

where R ₁ , R ₃ and Y are as defined in claim 1; X represents C (Z) ₂ , is reacted with a compound of formula IX R ₅ -SH (IX) where R ₅ is a suitable protecting group such as acetyl (Ac), benzoyl (Bz), 4-methoxybenzyl (PMB) or benzyl (Bn), alone or in the presence of a suitable base, such as NaOMe, NaH or triethylamine, or, alternatively, in the presence of a free radical initiator, such as α, α’-azoisobutyronitrile (AIBN), under standard conditions. 7. The method of obtaining the compound according to any one of claims 1 to 5, where R ₁ , R ₂ , R ₃ and R ₄ are as defined in claim 1, Y represents CH ₂ , and X represents O, S, C (Z) ₂ or N (Z), comprising a step wherein the compound of formula XIV

where R ₁ , R ₂ and R ₃ are as defined in claim 1; X represents O, S, C (Z) ₂ or N (Z), reacted with a compound of general formula IX R ₅ -SH (IX) where R ₅ is a suitable protecting group, such as Ac or Bz, in the presence of a suitable reagent such as triphenylphosphine / diisopropylazodicarboxylate (PPh ₃ / DIAD), under standard conditions. 8. The method of obtaining the compound according to any one of claims 1 to 5, where R ₁ , R ₂ , R ₃ , R ₄ and Y are as defined in claim 1, and X represents NR ₆ CO, NR ₆ SO ₂ , comprising a step wherein the compound of general formula XV

where R ₂ , R ₃ , R ₆ and Y are as defined in claim 1; R ₅ is a suitable protecting group such as Ac, Bz, PMB or Bn, reacted with a compound of the general formula XVI R ₁ -X (XVI) where R ₁ is as defined in claim 1; X represents COOH or SO ₂ Cl, in the presence of suitable binding reagents, such as (benzotriazol-1-yloxy) tripyrrolidine phosphonium hexafluorophosphate / diisopropylethylamine (PyBOP / DIPEA), dicyclohexylcarbodiimide / 1-hydroxybenzotriazole (DCC / HOBt), 1- (3-ethyl-dimethyl-dimethyl-dimethyldimethyl) N, N-dimethylaminopyridine (EDC / TEA / DMAP) or pyridine, under standard conditions. 9. A pharmaceutical preparation containing a compound according to any one of claims 1 to 5 as an active ingredient in combination with a pharmaceutically acceptable adjuvant, diluent or carrier. 10. The use of compounds according to any one of claims 1 to 5 in therapy. 11. The use of a compound according to any one of claims 1 to 5 for the manufacture of a medicament for the inhibition of carboxypeptidase U. 12. A method for treating or preventing conditions associated with the inhibition of carboxypeptidase U by administering to a mammal, including a person in need of such treatment, an effective amount of a compound according to any one of claims 1 to 5. 13. A pharmaceutical preparation for use in the treatment or prevention of conditions associated with the inhibition of carboxypeptidase U, containing the compound according to any one of claims 1 to 5 in combination with a pharmaceutically acceptable adjuvant, diluent or carrier. 14. A pharmaceutical preparation comprising: 1) a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and 2) one or more antithrombotic agents with a different mechanism of action, such as an antiplatelet agent, a thromboxane receptor inhibitor, an inhibitor synthetases, fibrinogen receptor antagonist, prostacyclin mimetic, phosphodiesterase inhibitor or adenosine 5'-diphosphate receptor antagonist (P ₂ T) (ADP receptor (P ₂ T)), in a mixture with a pharmaceutically acceptable adjuvant, diluent or wearer oil. 15. A kit of components, including: 1) a pharmaceutical preparation containing a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; and 2) a pharmaceutical preparation containing one or more antithrombotic agents with a different mechanism of action, such as an antiplatelet agent, a thromboxane receptor inhibitor, a synthetase inhibitor, a fibrinogen receptor antagonist, a prostacyclin mimetic, a phosphodiesterase inhibitor or an ADP receptor antagonist (P ₂ T) in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, wherein compound (1) and agent (2) are presented in forms which are suitable for administration together with each other. 16. A method of treating a patient suffering from a condition in which inhibition of the carboxypeptidase U and another antithrombotic mechanism are required or are subject to such a condition by administering to the patient a therapeutically effective total amount of 1) a compound of formula I or a pharmaceutically acceptable salt or solvate or solvate thereof salts, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; together with 2) one or more antithrombotic agents with a different mechanism of action, such as an antiplatelet agent, thromboxane receptor inhibitor, synthetase inhibitor, fibrinogen receptor antagonist, prostacyclin mimetic, phosphodiesterase inhibitor or (P ₂ T) adenosine-5'- receptor antagonist diphosphate (ADP receptor (P2T)), in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. 17. A method of treating a patient suffering from a condition in which inhibition of the carboxypeptidase U and another antithrombotic mechanism are required or desirable, or subject to such a condition, by administering to the patient the preparation of claim 14.