Product comprising a heterotrimeric G protein signal transduction inhibitor associated with anti-hypertensive agent for therapeutic use in the treatment of arterial hypertension

1. A composition comprising a compound of the formula

wherein R 1 is selected from the group consisting of H, alkyl and alkylthio of 1 to 6 carbon atoms;

R 2 and R 3 are independently H or alkyl;

R 4 is H 2 or O,

R 5 is selected from the group consisting of H, alkyl of 1 to 6 carbon atoms, alkenyl of up to 6 carbon atoms, cycloakyl, cycloalkylalkyl with alkyl of 1 to 6 carbon atoms, aryl and arylalkyl with alkyl of 1 to 6 carbon atoms, these groups are unsubstituted or substituted with a member selected from the group consisting of alkyl of 1 to 6 carbon atoms, —O—R 10 , —S(O) m R 10 , m is 0, 1 or 2, —N(R 10 )(R 11 ), —N—C(O)—R 10 , —CO 2 —R 10 , C(O)—N(R 10 )R 11 ), and —(SO 2 )—N(R 10 )(R 11 );

R 6 and R 7 are independently selected from the group consisting of H, —C(O)—NH—CHR 1 —CO 2 R 14 , alkyl of 1 to 6 carbon atoms, aryl and arylalkyl with alkyl of 1 to 6 carbon atoms, these groups being unsubstituted or substituted with a member selected from the group consisting of OH, alkyl and akoxy of 1 to 6 carbon atoms, —N(R 10 )(R 11 ), —COOH, —CON(R 10 )(R 11 ), and halo, or R 6 and R 7 together form aryl or heterocycle;

R 8 and R 9 are independently selected from the group consisting of H or 11 to 6 carbon atoms, aryl and arylalkyl with alkyl of 1 to 6 carbon atoms, these groups are unsubstituted or substituted by a member selected from the group consisting of OH, alkyl and alkoxy of 1 to 6 carbon atoms, —N(R 10 )(R 11 ), —CON(R 10 )(R 11 ) and halo, or R 8 and R 9 form together aryl; R 10 and R 11 are independently selected from the group consisting of H, aryl, alkyl of 1 to 6 carbon atoms, arylalkyl;

R 12 is —NR 9 —, —S—, or —O—;

R 13 is alkyl of 1 to 6 carbon atoms unsubstituted or substituted by a member selected from the group consisting of 1 to 6 carbon atoms, —OR 10 , —S(O) m R 10 , m is 0, 1 or 2, and —N(R 10 )(R 11 );

R 14 is H or alkyl of 1 to 6 carbon atoms; and its pharmaceutically acceptable acid addition salt and at least one other anti-hypertensive agent for the treatment of arterial hypertension.

2. A composition of claim 1 , wherein

X and Y complete a ring with 6 members, X-Y together being —CH(R 8 )—CH(R 9 )—;

R 1 is alkyl of 1 to 6 carbon atoms;

R 2 and R 3 are H;

R 4 is O;

R 5 is selected from the group consisting of H, alkyl of 1 to 6 carbon atoms, alkenyl of up to 6 carbon atoms, alkynyl of up to 6 carbon atoms, cycloalkyl, cycloalkylalkyl with alkyl of 1 to 6 carbon atoms, arylsulfonylalkyl with alkyl 1 of 1 to 6 carbon atoms, aralkoxyalkyl, alkoxy and alkyl of 1 to 6 carbon atoms, these groups are unsubstituted or substituted by alkyl of 1 to 6 carbon atoms or —O—R 10;

R 6 and R 7 are independently H, or aryl unsubstituted or substituted by a member selected from the group consisting of OH, alkyl and lower alkoxy of 1 to 6 carbon atoms,

R 8 and R 9 are H;

and R 10 and R 11 are independently H or alkyl of 1 to 6 carbon atoms.

3. A product composition of claim 1 wherein the compound of formula (1 A ) is selected from the group consisting of

7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;

7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2-(2-methyoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;

bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide;

bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazinedisulfide;

bis-1,1′-7-(2-amino-1-oxo-3-thiopropyl-(2-(1-naphthyl)-8-(2-methylpropyl)5,6,7,8-tetrahydroimidazo[1,2a]pyrazin-7-yl)disulfide;

7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;

7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenylmethoxy)methyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;

7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(1-phenylmethoxy)ethyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;

7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenoxyethyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;

7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenoxyethyl)5,6,7,8-tetraydro-imidazo[1,2a]pyrazine, or its form dimeric;

and 7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-phenylsulfonylethyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine; and its pharmaceutically acceptable acid addition salt.

4. A composition of claim 2 , wherein the compound of formula (I A ) is 7-(2-amino-1-oxo-3-thiopropyl)-8-cyclohexylmethyl)-2-phenyl-5,6,7,8-tetrahydro-imidazo[1,2]pyrazine or its pharmaceutically acceptable acid addition salt.

5. A composition of claim 1 wherein the second anti-hypertensive agent combined with the compound of the formula IA is selected from the group consisting of calcium channel inhibitors, conversion enzyme inhibitors, thiazidic diuretics, loop diuretics, potassium-sparing diuretics, antialdosterones, beta-blockers, angiotensin receptor antagonists, anti-hypertensive agents, alpha-blockers, vasodilatory agents, vasopeptidase inhibitors and endothelin antagonists.

6. A composition of claim 5 wherein the second anti-hypertensive agent is a calcium channel inhibitor.

7. A composition of claim 6 , wherein the second anti-hypertensive agent is verapamil.

8. A composition of claim 5 , wherein the second anti-hypertensive agent is a conversion enzyme inhibitor.

9. A composition of claim 8 , wherein the second anti-hypertensive agent is captopril.

10. A composition of claim 1 , wherein the second anti-hypertensive agent, different from the compound of formula IA are already combined with it.

11. A composition of claim 10 wherein the second anti-hypertensive agent is a loop diuretic and is combined with a hyperkalaemia causing diuretic.

12. A composition of claim 10 , wherein the second anti-hypertensive agent is a thiazidic or related diuretic and is combined with a hyperkalaemia causing diuretic.

13. A composition of claim 10 , wherein the second anti-hypertensive agent is a conversion enzyme inhibitor and is combined with a thiazidic diuretic.

14. A composition of claim 10 , wherein the second anti-hypertensive agent is an antagonist of angiotensin II receptors and is combined with a thiazidic diuretic.

15. A composition of claim 10 , wherein the second anti-hypertensive agent is a beta-blocker and is combined with a diuretic.

16. A composition of claim 10 , wherein the second anti-hypertensive agent is a beta-blocker and is combined with a calcium channel antagonist.

17. A composition of claim 10 , wherein the second anti-hypertensive agent is a beta-blocker and is combined with a vasodilatory agent.

18. A pharmaceutical composition for treating arterial hypertension comprising an amount of a composition of claim 1 sufficient to treat arterial hypertension and a pharmaceutically acceptable excipient.

19. A method of treating arterial hypertension in warm-blooded animals comprising administering to warm-blooded animals in need thereof an amount of a composition of claim 1 sufficient to treat arterial hypertension.

20. A method of treating arterial hypertension in warm-blooded animals comprising administering to warm-blooded animals in need thereof an amount of a composition of claim 10 sufficient to treat arterial hypertension.