RU98110881A

RU98110881A - Derivatives of Amidine and Isothiomyochevine as Inhibitors of the Synthesis of Nitrogen Oxide

Info

Publication number: RU98110881A
Application number: RU98110881/04A
Authority: RU
Inventors: Макдоналд Джеймс; Мэтц Джеймс; Шейкспир Вильям
Original assignee: Астра Актиеболаг
Priority date: 1995-11-07
Filing date: 1996-11-06
Publication date: 2000-10-20

Claims

1. The compound of formula I

where X represents NR ⁶ , S, O, CH ₂ or a bond; R ¹ is a C ₁ -C ₃ -S-alkyl or five-membered heterocyclic aromatic ring containing 1 to 4 heteroatoms selected from O, N, and S, optionally substituted on a carbon atom by one or more groups selected from halogen, trifluoromethyl, C ₁ -C ₆ -alkyl, nitro or cyano; R ² is hydrogen, C ₁ -C ₆ -alkyl, - (CH ₂ ) _d OH, - (CH ₂ ) _d OAr or - (CH ₂ ) _n Ar; R ³ is hydrogen, C ₁ -C ₆ -alkyl, - (CH ₂ ) _in OH, - (CH ₂ ) _in OAr or - (CH ₂ ) _n Ar; R ⁴ is hydrogen, C ₁ -C ₆ -alkyl, - (CH ₂ ) _with OH, - (CH ₂ ) _with OAr or - (CH ₂ ) _h Ar; R ⁵ is hydrogen, C ₁ -C ₆ -alkyl, - (CH ₂ ) _q OH, - (CH ₂ ) _q OAr, - (CH ₂ ) _n Ar, - (CH ₂ ) _t COOR ⁸ or - (CH ₂ ) _t CONR ⁹ R ¹⁰ ; or together R ³ and R ⁴ or together R ⁴ and R ⁵ are a chain - (CH ₂ ) _m - or - (CH ₂ ) _r Y (CH ₂ ) _p -; Ar is a phenyl ring, a six-membered heterocyclic aromatic ring containing one or two nitrogen atoms or a five-membered heterocyclic aromatic ring containing 1 to 4 heteroatoms selected from O, N and S, where the phenyl ring, six-membered heterocyclic aromatic ring or five-membered heterocyclic aromatic ring may be optionally substituted by one or more groups selected from C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen, nitro, cyano, C ₁ -C ₆ perfluoroalkyl, phenyl or pyatichlennog heterocyclic aromatic ring containing 1 - 4 heteroatoms selected from O, N and S. Y is O, S or NR ^7; m is an integer from 3 to 5; r and p independently represent integers 1 - 3, while the sum r + p must be in the range 2 - 4; R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ independently represent hydrogen or C ₁ -C ₆ -alkyl; or NR ⁹ R ¹⁰ together represent piperidinyl, pyrrolidinyl, morpholinyl, tetrahydroisoquinolinyl, piperazinyl or piperazinyl, 4-substituted by a group R ¹⁵ ; R ¹⁵ is C ₁ -C ₆ alkyl or the group - (CH ₂ ) _w Q; Q is phenyl, optionally substituted with one or more groups selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, nitro, cyano and trifluoromethyl; n, w and d independently represent an integer of 0-6; h, q and b independently represent an integer of 1-6; c is an integer 2-6; t is an integer from 1 to 5; provided that: (a) when X represents NH, O, CH ₂ or a bond, and at the same time each R ² , R ³ and R ⁵ represents hydrogen, then R ⁴ does not represent hydrogen or C ₁ -C ₆ -alkyl; (b) when X is NR ⁶ , O, or S, then d is an integer of 1-6; and its optical isomers and racemates and its pharmaceutically acceptable salts.

2. The compound of formula (I) according to claim 1, where R ¹ represents a C ₁ -C ₃ -S-alkyl or a ring containing one heteroatom selected from O, N and S.

3. The compound of formula (I) according to claim 2, wherein R ¹ is thienyl.

4. The compound of formula (I) according to claim 3, wherein R ¹ is 2-thienyl.

5. The compound of formula (I) according to claim 2, wherein R ¹ is S-ethyl.

6. The compound of formula (I), which is: N- (3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide; N- (3-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide; N- (1,3,4,6,7,11b-hexahydro-2H-benzo [a] quinolizin-10-yl) -2-thiophenecarboximidamide; N- (1,2,3,5,6,7,10-B-hexahydropyrrolo [2,1-a] isoquinolinyl-9-yl) -2-thiophenecarboximidamide; N- (4-hydroxy-2,3,4,5-tatrahydro-1H-2-benzazepin-8-yl) -2-thiophenecarboximidamide; N- (1- (2-hydroxyethyl) -1,2,3,4-Tatrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide; N- (1-methoxycarbonylmethyl-1,2,3,4-Tatrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide; N- (1,2,3,4-Tatrahydroisoquinolin-1-acetic acid-7-yl) -2-thiophenecarboximidamide; N- (1-aminocarbonylmethyl-1,2,3,4-tatrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide; N- (2,3-dimethyl-1,2,3,4-Tatrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide; N- (3-propyl-1,2,3,4-Tatrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide; (+) - N- (3-ethyl-1,2,3,4-tatrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide; (-) - N- (3-ethyl-1,2,3,4-tatraghydroisoquinolin-7-yl) -2-thiophenecarboximidamide; N- (3-ethyl-2-methyl-1,2,3,4-tatraghydroisoquinolin-7-yl) -2-thiophenecarboximidamide; N- (1,3,4,6,11,11a-hexahydro-2H-benzo [in] quinolizin-8-yl) -2-thiophenecarboximidamide; N- (5,7,8,9,10,11a, 12-octahydroazepino [1,2-b] isoquinolin-3-yl) -2-thiophenecarboximidamide; N- (2- (2-hydroxyethyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide; N- (6,6a, 7,8,9,10-hexahydro-12H-pyrido [2,1-c] [1,4] benzoxazepin-2-yl) -2-thiophenecarboximidamide; (+) - N- (1H, 5H-2,3,11,11a-tetrahydropyrrolo- [2,1-s] [1,4] benzoxazepin-7-yl) -2-thiophenecarboximidamide; (-) - N- (1H, 5H-2,3,11,11a-tetrahydropyrrolo- [2,1-c] [1,4] benzoxazepin-7-yl) -2-thiophenecarboximidamide; N- (2-ethyl-2,3,4,5-tetrahydro-1,4-benzoxazin-7-yl) -2-thiophenecarboximidamide; N- (1-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazapin-7-yl) -2-thiophenecarboximidamide; N- (3-benzyl-1-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazapin-7-yl) -2-thiophenecarboximidamide; N- (1- (N, N-diethylamino) carbonylmethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide; N- (1-pyrrolidinylcarbonylmethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide; N- (1-morpholinylcarbonylmethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide; N- (1 - (((ethyl) amino) carbonyl) methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide; N- (1-Piperidinylcarbonylmethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide; N- (2- (2-hydroxyethyl-2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl) -2-thiophenecarboximidamide; (+) - N- (1,2,3,5, 6,10-hexahydropyrrolo [2,1-a] isoquinolin-9-yl) -2-thiophenecarboximidamide; (-) - N- (1,2,3,5,6,10-β-hexahydropyrrolo [2,1-a] isoquinolin-9-yl) -2-thiophenecarboximidamide; N- (3,4,5,6,11,11v-hexahydro-1H- [1,4] oxazino [4,3-b] isoquinolin-8-yl) - 2-thiophenecarboximidamide; N- (2,3,4,6,11,11a-hexahydro-1H-pyrazino [1,2-b] isoquinolin-8-yl) -2-thiophenecarboximidamide; N- (1-methyl-1 , 2,3,4-tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide; N- (1-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide; N- [1- ( 3-methyl-1,2,4-oxadiazo -5-ylmethyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide; N- (1,2,3,5,10,10a-hexahydropyrrolo [1,2-b] isoquinolin-7-yl) -2-thiophenecarboximidamide; N- (1-propyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide; N- (2-methyl-1-propyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide; N- (1-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide; N- (1,3,4,6,11,11a-hexahydro-2H-benzo [c] quinolysin-8-yl) carbamidothioic acid ethyl ester; N- (1,2,3,5,10,10a-hexahydro-1H-pyrrolo [1,2-b) isoquinolin-7-yl) carbamidothioic acid ethyl ester; N- (1,2,3,5,10,10a-hexahydro-1H-pyrrolo [1,2-b) isoquinolin-9-yl) carbamidothioic acid ethyl ester; (+) - N- (1,2,3,4,11,11a-tetrahydro-1H, 5H-pyrrolo [2,1-s] [1,4] benzoxazepin-7-yl) carbamidothioic acid ethyl ester;
or its one any optical isomer or racemate or its one any pharmaceutically acceptable salt.

7. The compound of formula I according to any one of paragraphs.1 - 6, used as a pharmaceutical product.

8. Drug containing a compound of the formula I according to any one of paragraphs. 1 to 6 or its optical isomer or racemate or its pharmaceutically acceptable salt, optionally in a mixture with a pharmaceutically acceptable diluent or carrier.

9. A method of treating or preventing human diseases or conditions in which it is advantageous to inhibit nitric oxide synthase activity, comprising administering to the patient a therapeutically effective amount of a compound of formula I in one of claims 1 to 6, or its optical isomer, or racemate, or its pharmaceutically acceptable salt.

10. The treatment method of claim 9, wherein it is preferable to inhibit the neural isoform of nitric oxide synthase.

11. A method of treating or preventing hypoxia or stroke, or ischemia, or neurodegenerative conditions, or pain, or migraine, or preventing and changing tolerance to opiates and diazepines, or treating addiction to excessive drug use, including administering to a patient a therapeutically effective amount of a compound of formula I in one of claims 1 to 6 or its optical isomer or racemate or its pharmaceutically acceptable salt.

12. The treatment method of claim 11, wherein the condition being treated is selected from the group consisting of hypoxia, ischemia, stroke or amyotrophic lateral sclerosis or pain.

13. The treatment method of claim 12, wherein the condition being treated is a stroke.

14. The treatment method of claim 12, wherein the condition being treated is amyotrophic lateral sclerosis.

15. The treatment method of claim 12, wherein the condition being treated is pain.

16. The use of the compounds of formula I according to any one of paragraphs 1 to 6 in the manufacture of pharmaceuticals for the treatment or prevention of human diseases or conditions in which the inhibition of nitric oxide synthase activity is beneficial.

17. The use according to claim 16, wherein it is preferable to inhibit the neural isoform of nitric oxide synthase.

18. The use of a compound of formula I in any one of claims 1-6 in the manufacture of a medicament for the treatment or prophylaxis of hypoxia or stroke, or ischemia, or neurodegenerative conditions, or pain, or migraine, or for the prevention and change of tolerance to drugs and diazepines, or treating addiction to excessive drug use.

19. The use according to claim 18, wherein the condition is selected from the group consisting of hypoxia, ischemia, stroke, amyotrophic lateral sclerosis, and pain.

20. The application of claim 19, where the state is a hit.

21. The application of claim 19, where the condition is amyotrophic lateral sclerosis.

22. The use according to claim 19, wherein the condition is pain.

23. A method of obtaining a compound of formula I in one of claims 1 to 6, and its optical isomers and racemates and its pharmaceutically acceptable salts, comprising: (a) preparing a compound of formula I by reacting the corresponding compound of formula II;

where X, R ² , R ³ , R ⁴ and R ⁵ are as defined in claim 1, with a compound of formula III

where R ¹ is as defined in claim 1, and L is a leaving group; (C) obtaining the compounds of formula I by reacting the corresponding compounds of formula IV

where X, R ² , R ³ , R ⁴ and R ⁵ are as defined in claim 1 of the formula and HA is an acid, with a compound of the formula V

where R ¹ is as defined in claim 1; (c) obtaining a compound of formula I, where R ¹ is C ₁ -C ₃ -S-alkyl, by reacting the corresponding compound of formula VI

where X, R ² , R ³ , R ⁴ and R ⁵ are as defined in claim 1, with a compound of formula VII

where R ¹ is C ₁ -C ₃ -alkyl, and L is a leaving group; (d) obtaining compounds of formula I, in which R ⁴ represents a C ₁ -C ₆ -alkyl, - (CH ₂ ) _c OH, - (CH ₂ ) _c OAr or - (CH ₂ ) _n Ar, by reacting the corresponding compound formula I, in which R ⁴ represents hydrogen, with a compound of formula VIII

where R ¹¹ is C ₁ -C ₆ alkyl, - (CH ₂ ) _c OH, - (CH ₂ ) _c OAr or - (CH ₂ ) _n Ar, and L is a leaving group; (e) obtaining the compounds of formula I, in which X represents NR ⁶ and R ⁶ represents a C ₁ -C ₆ -alkyl, by reacting the corresponding compounds of formula I, in which R ⁶ represents hydrogen, with a compound of formula IX

wherein R ¹² is C ₁ -C ₆ alkyl and L is a leaving group; (f) obtaining compounds of formula I in which R ³ and R ⁴ or R ⁴ and R ^{5 are} connected with the formation of the chain - (CH ₂ ) _r Y (CH ₂ ) _p -, Y represents NR ⁷ and R ⁷ represents C ₁ -C ₆ -alkyl, by reacting the corresponding compound of the formula I, in which R ⁷ is hydrogen, with a compound of the formula IX; (g) preparing a compound of formula I in which R ⁵ is - (CH ₂ ) _t COOR ⁸ and R ⁸ represents C ₁ -C ₆ alkyl by esterifying the corresponding compound of formula I in which R ⁸ is hydrogen; (h) obtaining a compound of the formula I in which R ⁵ is - (CH ₂ ) _t COOR ⁸ and R ⁸ is hydrogen by hydrolysis of the corresponding compound of the formula I in which R ⁸ is C ₁ -C ₆ alkyl; (i) obtaining the compounds of formula I, in which R ⁵ represents - (CH ₂ ) _t CONR ⁹ R ¹⁰ and R ⁹ and / or R ¹⁰ represents C ₁ -C ₆ -alkyl, by alkylation of the corresponding compounds of formula I, in where R ⁹ and / or R ¹⁰ represent (et) a hydrogen; (j) obtaining the compounds of formula I, in which R ⁵ represents - (CH ₂ ) _t CONR ⁹ R ¹⁰ , where R ⁹ and R ¹⁰ represent hydrogen, or R ⁵ represents - (CH ₂ ) _t COOR ⁸ and R ⁸ is hydrogen, by hydrolysis of the corresponding cyano compound; (k) obtaining a compound of formula I in which R ⁵ is - (CH ₂ ) _t CONR ⁹ R ¹⁰ by reacting the corresponding amine HNR ⁹ R ¹⁰ with the corresponding acid; (l) obtaining a compound of formula I in which R ² is - (CH ₂ ) _d OAr, R ³ is (CH ₂ ) _in OAr, R ⁴ is - (CH ₂ ) _with OAr or R ⁵ is - ( CH ₂ ) _q OAr, by reacting the corresponding halogen or sulphonate compound of formula I with an aryl hydroxide; (m) preparing a compound of formula I, in which R ⁴ is methyl, by reacting the corresponding compound of formula (I), in which R ⁴ is hydrogen, with formaldehyde and formic acid; or (n) obtaining a compound of formula I in which R ⁴ is —CH ₂ CH ₂ OH, by reacting the corresponding compound of formula I in which R ⁴ is hydrogen, with an oxirane; and the desired or necessary conversion of the obtained compound of formula I or its other salt to its pharmaceutically acceptable salt or vice versa.

24. The compound of formula II

where X, R ² , R ³ , R ⁴ and R ⁵ are as defined in claim 1.

25. The compound of formula VI

where X, R ² , R ³ , R ⁴ and R ⁵ are as defined in claim 1.

26. The compound of formula X

where X, R ² , R ³ , R ⁴ and R ⁵ are as defined in claim 1.