RU99123368A

RU99123368A - CONNECTIONS

Info

Publication number: RU99123368A
Application number: RU99123368/04A
Authority: RU
Inventors: Томас МакИналли; Алан Тинкер
Original assignee: Астра Фармасьютикалз Лтд.
Priority date: 1997-04-09
Filing date: 1998-04-07
Publication date: 2001-07-20

Claims

1. The compound of formula (I)

R ¹ represents hydrogen, C _1-6 alkyl, C _1-6 alkoxy, halogen or trifluoromethyl;
R ² is hydrogen or C _1-6 alkyl;
A is a five-membered heterocyclic aromatic ring containing 1 to 3 heteroatoms, which may be the same or different and selected from O, N, and S; or a six-membered heterocyclic aromatic ring containing 1 to 3 nitrogen atoms;
(i) R ³ is a phenyl, six-membered heterocyclic aromatic ring containing 1 to 3 nitrogen atoms, or a five-membered heterocyclic aromatic ring containing 1 to 3 heteroatoms, which may be the same or different, and are selected from O, N and S, wherein the phenyl or heterocyclic aromatic ring may be optionally substituted with C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, halogen, hydroxy, C _1-6 alkylthio, cyano, trifluoromethyl, nitro or a group —NR ⁵ R ⁶ ; and
R ⁴ , R ⁵ and R ⁶ independently represent hydrogen or C _1-6 alkyl; or
(ii) R ³ is C _1-8 alkyl, C _2-8 alkenyl; and R ⁴ is hydrogen or C _1-6 alkyl; or
(iii) R ³ and R ⁴ together represent (CH ₂ ) _a Z (CH ₂ ) _b , where Z is N (COOR ⁷ ), where R ⁷ is C _1-6 alkyl or C _1-6 haloalkyl or R ⁷ represents a group (CH ₂ ) _n YR ⁹ , where n is an integer from 2 to 5, Y represents O, S or a bond, R ⁹ represents C _1-6 alkyl, optionally substituted with halogen or nitro, or R ⁹ is optionally substituted with C _1-6 alkyl, halogen or nitro; and a and b independently represent an integer from 1 to 3 with the proviso that a + b is 3 or 4; or
(iv) R ³ and R ⁴ together represent (CH ₂ ) _a Z (CH ₂ ) _b , where Z is N (COR ⁸ ), where R ⁸ is phenyl, a six-membered heterocyclic aromatic ring containing from 1 to 3 atoms nitrogen, or a five-membered heterocyclic aromatic ring containing from 1 to 3 heteroatoms, which may be the same or different and selected from O, N, and S, while these phenyl or heterocyclic aromatic ring may be optionally substituted with C _1-6 alkyl, C _{1 -6} alkoxy, halogen, nitro, cyano, trifluoromethyl, C _1-6 alkoxysulfonyl or a minosulfonyl;
and a and b are independently from each other an integer from 1 to 3, with the proviso that a + b is 3 or 4;
or its pharmaceutically acceptable salts, enantiomers, racemates and tautomers.

2. The compound of formula (I) according to claim 1, wherein A is a thieno or pyrido ring.

3. The compound of formula (I) according to claim 2, wherein the compound is a thieno [2,3-d] pyrimidine derivative or a thieno [3,2-d] pyrimidine derivative.

4. The compound of formula (I) according to claim 2, wherein the compound is a pyrido [2,3-d] pyrimidine derivative, pyrido [3,2-d] pyrimidine derivative, pyrido [3,4-d] pyrimidine or pyrido [4, 3-d] pyrimidine.

5. The compound of formula (I) according to any one of claims ^{1 to 4} , where R ³ is phenyl, cyclopropyl, ethyl, thiazolyl, ethinyl or furanyl.

6. The compound of formula (I) according to any one of claims 1 to 5, where R ³ and R ⁴ correspond to condition (iii) according to claim 1, Z is N (COOC ₂ H ₅ ) and a and b each have value 2.

7. The compound of formula (I) according to claim 1, which represents:
7-amino-4,5-dihydro-5-phenylthieno [3,2-d] pyrimidine;
5-cyclopropyl-4,5-dihydro-7-aminothieno [3,2-d] pyrimidine;
5-ethyl-4,5-dihydro-7-aminothieno [3,2-d] pyrimidine;
5- (2-thiazolyl) -4,5-dihydro-7-aminothieno [3,2-d] pyrimidine;
5- (2-furyl) -4,5-dihydro-7-aminothieno [3,2-d] pyrimidine;
7-amino-4,5-dihydro-5-ethynylthieno [3,2-d] pyrimidine;
ethyl 7'-amino-spiro [piperidine-4,5 '(4'H) -thieno [3,2-d] pyrimidine] -1-carboxylate;
ethyl 4'-amino-3'-chlorospiro [piperidine-4,6 '(7'H) thieno [2,3-d] pyrimidine] -1-carboxylate;
4'-amino- (4-cyanobenzoyl) -spiro [piperidine-4,2 '(1'H) - (pyrido [3,2-d] pyrimidine)];
4'-amino- (2-thienoyl) -spiro [piperidine-4,2 '(1'H) - (pyrido [3,2-d] pyrimidine)];
ethyl 4'-amino-spiro [piperidine-4,2 '(1'H) - (pyrido [3,2-d] pyrimidine)] 1-carboxylate;
4'-amino- (4-cyanobenzoyl) -spiro [piperidine-4,2 '(1'H) - (pyrido [3,4-d] pyrimidine)];
ethyl 4'-amino-spiro [piperidine-4,2 '(1'H) - (pyrido [3,4-d] pyrimidine)] 1-carboxylate;
4'-amino- (4-cyanobenzoyl) -spiro [piperidine-4,2 '(1'H) - (pyrido [4,3-d] pyrimidine);
ethyl 4'-amino-spiro [piperidine-4,2 '(1'H) - (pyrido [2,3-d] pyrimidine) -1-carboxylate;
4'-amino-2- (2-thienyl) -pyrido [3,2-d] pyrimidine;
7'-amino-1- (6-cyano-3-pyridinecarbonyl) spiro [piperidine-4,5 '- (4'H) - (thieno [3,2-d] -pyrimidine)].

8. The compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, enantiomer or tautomer thereof for use as a medicine.

9. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, enantiomer or tautomer thereof in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

10. The compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, enantiomer or tautomer thereof for the preparation of a medicament for the treatment or prophylaxis of human diseases or conditions for which inhibition of nitric oxide synthase activity would be beneficial.

11. A compound according to claim 10, wherein the inducible nitric oxide synthase is preferably inhibited.

12. The compound of formula (I) according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, enantiomer or tautomer thereof for the preparation of a medicament for the treatment or prevention of inflammatory diseases.

13. The compound according to claim 12, wherein the disease is asthma or rheumatoid arthritis.

14. The compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, enantiomer or tautomer thereof for the manufacture of a medicament for the treatment or prevention of pain.

15. The compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, enantiomer or tautomer thereof in combination with a COX-2 inhibitor in the preparation of a medicament for the treatment or prevention of inflammatory diseases.

16. A method of treating or reducing the risk of the occurrence of diseases or conditions in humans in which the inhibition of nitric oxide synthase activity would be beneficial, which includes the administration of a therapeutically effective amount of the compound described by formula (I) according to any one of claims. 1-7, or a pharmaceutically acceptable salt thereof, an enantiomer or tautomer thereof, to a patient suffering from or at risk of such diseases or conditions.

17. The method of claim 16, wherein the disease is asthma or rheumatoid arthritis.

18. The method according to claim 16, where the disease is an inflammatory disease.

19. The method of claim 18, wherein the disease is asthma or rheumatoid arthritis.

20. The method according to claim 18, wherein the condition is pain.

21. The method according to p. 18, characterized in that the compound of formula (I) according to any one of paragraphs. 1-7, or its pharmaceutically acceptable salt, enantiomer or tautomer is administered together with an inhibitor of MOR-2.

22. The method of obtaining the compounds of formula (I) according to any one of claims 1 to 7 or its pharmaceutically acceptable salt, enantiomer or tautomer, which includes:
(a) the interaction of the compounds of formula (II),

where A, R ¹ and R ² the same as defined above,
with the compound of the formula (III) or its acetal derivative
R ³ COR ⁴
where R ³ and R ⁴ defined above;
(b) the interaction of the compounds of formula (IV) or (IV '),

where A, R ¹ , R ² , R ³ and R ^{4 are} defined above, and R ⁸ represents an alkyl group;
with ammonia or its equivalent; or
(c) obtaining the compounds of formula (I), in which R ³ and R ⁴ correspond to the condition (i) in the General definition of formula (I) above, and one or both of R ⁵ and R ⁶ are C _1-6 alkyl , by alkylation of the corresponding compound, in which one or both of R ⁵ and R ⁶ are hydrogen; or
(d) obtaining the compound described by formula (I) in which R ² is C _1-6 alkyl, by alkylation of the corresponding compound in which R ² is hydrogen; or
(e) deprotecting a compound of formula (I) in which one or more nitrogen atoms and / or another atom is protected; or
(f) obtaining compounds of formula (I), in which R ³ and R ⁴ meet the condition (iv) in the General definition of formula (I) above, by reacting a compound of formula (V)

where A, R ¹ and R ² , a and b are defined above,
with a compound of formula (VI)
XL,
where X is COOR ⁷ or COR ⁸ , R ⁷ and R ⁸ are as defined above, and L is a removable group;
and where it is desirable or necessary to convert the obtained compound of formula (I), or its salt into its pharmaceutically acceptable salt, or vice versa, and where it is desirable to convert the obtained compound of formula (I) into its optical isomer.