A method of inhibiting the activity of transglutaminases containing a cysteine residue comprising administering to a mammal an effective amount of a sulfonamide derivative of imidazo[1,2-d]-1,2,4-thiadiazoles sufficient to inhibit the activity.

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are as follows:

1.  Sulfonamide compounds and its pharmaceutically acceptable salts, having the general formula (I): 45wherein B is a 3-substituted imidazo[1,2-d]-1,2,4-thiadiazoles having the formula: 46wherein X³ and X⁴ are independently hydrogen, lower alkyl, halo, nitro, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, benzyloxycarbonyl, amino, lower alkylamino, lower dialkylamino, lower alkylcarbamoyl; or B is a group having the formula: 47wherein X³ and X⁴ has the same definition as defined above; X¹ is hydrogen, lower alkyl, aryl-[lower alkyl]-, heterocyclyl-[lower alkyl]-, a group of formula --(CH₂)_n--CO--W wherein n and W is hydroxy, lower alkoxy, amino, lower alkylamino, n=1 to 6; A is a spacer selected from the group consisting of (1) C_2-10 alkylene, (2) C_4-10 alkylene, wherein the C_4-10 alkylene is optionally substituted with one or two hydroxy groups at the non-terminal carbon atom of the carbon chain; Y is a spacer selected from the group consisting of: (1) 48X⁵ is lower alkyl, aryl-[lower alkyl]-, heterocyclyl-[lower alkyl]-, a group of formula --(CH₂)_n--CO--W wherein W is as defined above or X⁵ is the following group: 49wherein W is as defined above; X² is: (1) heterocyclyl, heterocyclyl-[lower alkyl]-, the heterocyclic ring being attached at any heteroatom or carbon atom which results in the creation of a stable structure, and the heterocyclic ring being optionally substituted with 1-3 substituents selected from lower alkyl, halo, hydroxy, nitro, amino, lower alkylamino, di-lower alkylamino, lower alkoxy, lower acyl, lower alkoxycarbonyl, lower alkyl-sulfonyl, amido, allyl, benzyl, trifluoroacetyl, trifluoromethyl, carboxy; the [lower alkyl] portion of heterocyclyl-[lower alkyl]-group is optionally substituted with 1-3 substituents selected from hydroxy, lower alkylcarbamoyl, phenyl, heterocyclyl, carboxy and lower alkoxycarbonyl; (2) aryl, aryl-[lower alkyl]-, or lower cycloalkyl, with the aryl group being optionally substituted with 1 to 3 substituents selected from lower alkyl, halo, nitro, amino, hydroxy, lower alkoxy, lower alkylamino, lower dialkylamino, trifluoromethyl, trifluoromethoxy, carboxy, 2-carboxyethyl, 2-methoxycarboxyethyl, piperazinylmethyl, 3-amino-3-oxopropyl, amidino, NR'R", OC(O)R', OC(O)OR', OC(O)NR'R", NR'(COR'), NHC(O)NR'R", NHC(O)OR', with R' and R" being independently hydrogen, lower alkyl, aryl, aryl-[lower alkyl]-, or lower alkyl substituted with hydroxy, amino, lower alkylamino, carboxy or lower alkoxycarbonyl, or R' and R" in NR'R" when taken together forming a five or six membered heterocyclic ring selected from piperidinyl, pyrrolidinyl, morpholinyl and prolyl, the heterocyclic ring being optionally substituted with lower alkyl, carboxy, amino, phenyl, lower alkoxycarbonyl or lower dialkylamino; the [lower alkyl] portion of aryl-[lower alkyl]-group is optionally substituted with 1-3 substituents selected from hydroxy, lower alkylcarbamoyl, phenyl, heterocyclyl, carboxy and lower alkoxycarbonyl; (3) monosubstituted alkyl with substituent selected from halo, nitro, amino, hydroxy, lower alkoxy, lower alkylamino, lower dialkylamino. NR'R", OC(O)R', NR'(COR'), NHC(O)NR'R", NHC(O)OR', with R' and R" being as defined above. or the group Y--SO₂--X² when taken together form a cyclic radical: 50

2.  Sulfonamide compounds of claim 1, having the general formula (II): 51

3.  Sulfonamide compounds of claim 1, having the general formula (III): 52

4.  Sulfonamide compounds of claim 2, wherein A is an C₅ to C₈ alkylene-having the formula CH₂CH₂CH₂CH₂--(CH₂)_m, wherein m is 1 to 3, Y is NH, having the general formula (IV): 53wherein X¹, X², X³, X⁴ are as previously defined.

5.  A compound according to claim 2 wherein X³=X⁴=X¹=H, Y=NH,
A=--CH₂CH₂CH₂CH₂CH₂CH₂- --, having the general formula: 54wherein X² is as previously defined.

6.  The compound of claim 5, wherein X² is aryl, with the aryl group being optionally substituted with 1 to 3 substituents selected from lower alkyl, halo, nitro, amino, hydroxy, lower alkoxy, trifluoromethyl, trifluromethoxy, NR'R", with R' and R" being independently hydrogen, lower alkyl.

7.  The compound of claim 6 wherein X² is phenyl, 4-methylphenyl, 2,4,6-trimethylphenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 4-phenylphenyl, 4-trifluoromethoxyphenyl, 2-naphthyl, 2-bromophenyl, 3-bromophenyl, 4-tert-butylphenyl, 3-fluorophenyl, 2-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 2-chlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 2,3-dichlorophenyl, 3-nitrophenyl, 2-nitrophenyl, 4-nitrophenyl, 3-chlorophenyl, 2-methyl-5-nitrophenyl, 4-chloro-2,4-dimethylphenyl, 2,5-dimethyl, 1-bromo-2,4-difluorophenyl, 3-bromo-4-methoxyphenyl, 2-methoxy-4-methylphenyl, 4-methoxy-2,5,6-trimethylphenyl, 3-chloro-2-methylphenyl, 4-fluoro-2-methylphenyl, 3-trifluoromethylphenyl- , 4-carboxylphenyl, 2-nitro-4-trifluorophenyl, 3-carboxyphenyl, 2-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 2-methoxycarbonylphenyl, 2-cyanophenyl, 4-cyanophenyl, 2-carboxyphenyl, 2-aminophenyl, 4-bromo-2-trifluoromethoxyhenyl, 2-chloro-4-fluorophenyl, 2-methylphenyl, 2,4-dibromophenyl, 4-trifluoromethyphenyl.

8.  The compound of claim 5 wherein X² is heterocyclyl.

9.  A compound of claim 8 wherein the heterocyclyl is quinolin-8-yl, the compound is N-[6-(imidazo[1,2-d][1,2,4]thiadiazol-3-ylamino)hexyl]quinoli- ne-8-sulfonamide.

10.  The compound of claim 8 wherein the heterocyclyl is optionally substituted with 1 substitutent selected from trifluoroacetyl.

11.  A compound of claim 10 wherein the heterocyclyl is 2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-5-yl, the compound is N-[6-(imidazo[1,2-d][1,2,4]thiadiazol-3-ylamino)hexyl]-2-(trifluoroacetyl- )-1,2,3,4-tetrahydroisoquinoline-5-sulfonamide.

12.  The compound according to claim 2 wherein Y=--NX⁵ wherein X⁵ is methyl, A is --CH₂CH₂CH₂CH₂CH₂CH₂--, X³=H, X⁴=H, X¹ is hydrogen.

13.  A compound of claim 12 wherein X² is 2-nitrophenyl, phenyl, 1-naphthyl.

14.  The compound of claim 2 wherein X¹ is H, Y=NH, A is
--CH₂CH₂CH₂CH₂CH₂--, X³=H, X⁴=H, X² is 5-dimethylamino-1-naphthyl, the compound is 5-(dimethylamino)-N-[5-(imidazo[1,2-d][1,2,4]thiadiazol-3-ylamino)pentyl]- -naphthalene-1-sulfonamide.

15.  The compound of claim 2 wherein X¹ is H, Y=NH, A is
--CH₂CH₂CH₂CH₂--, X³=H, X⁴=H, X² is 5-dimethylamino-1-naphthyl, the compound is 5-(dimethylamino)-N-[4-(imidazo[1,2-d][1,2,4]thiadiazol-3-ylamino)butyl]-- naphthalene-1-sulfonamide.

16.  The compound of claim 2 wherein X¹ is --(CH₂)n--CO--W, n is 3, W is ethoxy, X³ is H, X⁴ is H, A is --CH₂CH₂CH₂CH₂CH₂CH₂--, Y is --NH--, X² is 1-naphthyl, the compound is ethyl 4-[[6-(imidazo[1,2-d][1,2,4]thiadiazol-3-ylamino)hexyl]- (1-naphthylsulfonyl)amino]-butanoate.

17.  The compound of claim 2 wherein X¹ is --(CH₂)n--CO--W, n is 1, W is ethoxy, X³ is H, X⁴ is H, A is --CH₂CH₂CH₂CH₂CH₂CH₂--, Y is --NH--, X² is 1-naphthyl, the compound is ethyl N-[6-(imidazo[1,2-d][1,2,4]thiadiazol-3-ylamino)hexyl]-- N-(1-naphthylsulfonyl)glycinate.

18.  The compound of claim 2 wherein X¹ is --(CH₂)n--CO--W, n is 2, W is ethoxy, X³ is H, X⁴ is H, A is --CH₂CH₂CH₂CH₂CH₂CH₂--, Y is --NH--, X² is 2,4-difluorophenyl, the compound is ethyl N-[(2,4-difluorophenyl)sulfonyl]-N-[6-(imidazo[1,2-- d][1,2,4]thiadiazol-3-ylamino)hexyl]-.beta.-alaninate.

19.  The process for the preparation of compounds of claim 2 which comprises of the following steps: a. reacting a compound of formula (VI) with a compound of formula (XII) to give a compound of formula (II) wherein X¹, X², X³, X⁴, A, Y are as in claim 2; or b. reacting a compound of formula (VI) with a compound of formula (VIII) to give a compound of formula (X) wherein X¹, X², X³, X⁴, A, Y are as in claim 2; and c. then reacting the compound of formula (X) from step b with a compound of formula (XI) wherein X¹, X², X³, X⁴, A, Y are as in claim 2; or d. reacting a compound of formula (VI) with a compound of formula (VII) to give a compound of formula (IX) wherein wherein X¹, X³, X⁴, A, Y are as in claim 2; and e. reacting the compound of formula (IX) from step d with HCl to give a compound of formula (X); and f. then reacting the compound of formula (X) from step e with a compound of formula (XI) wherein X¹, X², X³, X⁴, A, Y are as in claim 2; 55

20.  A Factor XIIIa inhibitor with the chemical structure of formula (I) according to claim 1 or 2.

21.  A pharmaceutical formulation comprising a compound according to claims 1 or 2 and a pharmaceutically acceptable carrier, diluent or excipient thereof.

22.  A pharmaceutical formulation according claims 1 or 2, for administration with a thrombolytic agent.

23.  The pharmaceutical formulation according to claim 22, wherein the thrombolytic agent comprises a tissue plasminogen activator, or a recombinant tissue plasminogen activator.

24.  A method of inhibiting the activity of transglutaminases containing a cysteine residue comprising administering to a mammal an effective amount of a sulfonamide derivative of imidazo[1,2-d]-1,2,4-thiadiazoles of claims 1 or 2 sufficient to inhibit the activity.

25.  The method of claim 24 wherein the activity of the transglutaminase is prevented by forming a disulfide bond.

26.  The method of the claim 24 wherein the indication is the inhibition of fibrin cross linking.

27.  The compounds of claims 1 or 2 for use as transglutaminase inhibitors.

28.  Factor IIIa inhibitors of claim 24 as an adjunct therapy to the use of thrombolytics in the treatment of acute myocardial infarction.

29.  Factor IIIa inhibitors of claim 24 for the treatment of acute myocardial infarction.

30.  The use of sulfonamide derivatives of 3-substituted imidazo[1,2-d]-1,2,4-thiadiazoles and 3-substituted-[1,2,4]thiadiazolo[4,- 5-a]benzimidazole of claim 1 as plasma transglutaminse inhibitors in the prevention of fibrin cross-linking.
 

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