RU98109784A

RU98109784A - PHARMACEUTALLY ACTIVE QUINASOLINE DERIVATIVES

Info

Publication number: RU98109784A
Application number: RU98109784/04A
Authority: RU
Inventors: Ричард Джон Хэмли Питер; Дэвид Пимм Остен; Чарльз Тинкер Алан; Грэхэм Битон Хейдн; МакИнэлли Томас
Original assignee: Астра Фармасьютикалз Лимитед
Priority date: 1995-10-17
Filing date: 1996-10-14
Publication date: 2000-04-27

Claims

1. The compound of formula I

where R ¹ and R ¹⁹ independently represent hydrogen, alkyl C1-6, alkoxy C1-6, alkylthio C1-6, halogen, hydroxyl or amino;
R ³ represents phenyl, a 6-membered heterocyclic aromatic ring containing one or two nitrogen atoms, or a 5-membered heterocyclic aromatic ring containing 1 to 3 heteroatoms selected from O, N and S, wherein the phenyl or heterocyclic aromatic ring may be optionally substituted with C1-6 alkyl, C1-6 alkoxy, halogen, hydroxyl, C1-6 alkylthio, cyano, trifluoromethyl, nitro, hydroxymethyl, amino, - (CH ₂ ) _c -NHCO ₂ R ¹⁰ group, - (CH ₂ ) group _c —NR ⁵ R ⁶ or a —CO ₂ R ¹¹ group,
or R ³ represents hydrogen or alkyl from C1-8, which may optionally be substituted with an amino or —NHCO ₂ R ¹⁰ group;
R ⁴ represents hydrogen or alkyl C1-6;
or R ³ and R ⁴ taken together represent a group (CH ₂ ) _a —Z- (CH ₂ ) _b ;
c = 0-2;
a and b, independently, are an integer from 1 to 3;
Z represents CH ₂ , NH, a group> N (CH ₂ ) _n YR ¹³ , a group> NCOX (CH ₂ ) _n YR ¹³ , a group> NCSX (CH ₂ ) _n YR ^13, or a group> NCNHX (CH ₂ ) _n YR ¹³ ;
X represents O, S or a bond;
Y represents O, S, SO, SO ₂ , NR ⁹ or a bond;
n is 0-6;
R ¹³ represents C1-6 alkyl, C1-6 alkyl substituted with one or more halogen atoms, cyano, quinolyl, phenyl, naphthyl, a 6-membered heterocyclic aromatic ring containing one or two nitrogen atoms, a 5-membered heterocyclic aromatic ring containing from 1 to 3 heteroatoms selected from O, N and S, or a benzene ring fused to a 5-membered heterocyclic aromatic ring containing from 1 to 3 heteroatoms selected from O, N and S;
or R ¹³ may be as defined, except that when it contains one or more aromatic rings, these rings may optionally be substituted with one or more groups selected from C1-6 alkyl, halogen, cyano, nitro, hydroxyl , alkoxy C1-6, trifluoromethyl, trifluoromethoxy, methanesulfonyl, sulfamoyl, -NR ¹⁴ R ¹⁵ , -COOR ¹⁶ or -CONR ⁷ R ⁸ ;
or R ¹³ may represent a phenyl ring, a 6-membered heterocyclic aromatic ring containing one or two nitrogen atoms, or a 5-membered heterocyclic aromatic ring containing from 1 to 3 heteroatoms selected from O, N and S, substituted
benzyloxy or optionally substituted phenyl, or
an optionally substituted 5-membered heterocyclic aromatic ring containing from 1 to 3 heteroatoms selected from O, N and S,
where optional substituents are C1-6 alkyl, halogen, cyano, nitro, hydroxyl, C1-6 alkoxy, trifluoromethyl and trifluoromethoxy;
or R ¹³ may be as defined, except that when it contains a heterocyclic aromatic ring containing at least one nitrogen atom, this ring may optionally be substituted with one or more oxo groups adjacent to nitrogen, the ring being attached to the rest of the molecule through one of the nitrogen atoms or otherwise;
R ² , R ⁵ , R ⁶ , R ¹¹ , R ⁹ , R ¹⁴ , R ¹⁵ and R ¹⁶ independently represent hydrogen or C1-6 alkyl;
in addition, when Y represents NR ⁹ , —NR ⁹ R ¹³ may represent a pyrrolidine or piperidine ring;
R ¹⁰ represents C1-6 alkyl, and R ⁷ and R ⁸ independently represent hydrogen, C1-6 alkyl or phenyl optionally substituted with one or more groups selected from C1-6 alkyl, halogen, cyano, nitro, hydroxyl, alkoxy C1-6 trifluoromethyl and trifluoromethoxy; provided that
a) when R ³ and R ⁴ taken together represent a group (CH ₂ ) _a —Z— (CH ₂ ) _b ; in which Z represents a group> NCOX (CH ₂ ) _n YR ¹³ , a group> NCSX (CH ₂ ) _n YR ^13, or a group> NCNHX (CH ₂ ) _n YR ¹³ in which neither X nor Y represent a bond, then n equal to an integer from 2 to 4;
(b) when R ³ and R ⁴ taken together represent a group (CH ₂ ) _a —Z— (CH ₂ ) _b ; in which Z represents a group> NCOX (CH ₂ ) _n YCN, a group> NCSX (CH ₂ ) _n YCN or a group> NCNHX (CH ₂ ) _n YCN, then Y represents a bond and either X also represents a bond or X does not represent a bond and n is an integer from 1 to 4;
or a pharmaceutically acceptable salt thereof for use as a pharmaceutical.

2. The compound of formula I:

where R ¹ and R ¹⁹ independently represent hydrogen, alkyl C1-6, alkoxy C1-6, alkylthio C1-6, halogen, hydroxyl or amino;
R ³ represents phenyl, a 6-membered heterocyclic aromatic ring containing one or two nitrogen atoms, or a 5-membered heterocyclic aromatic ring containing 1 to 3 heteroatoms selected from O, N and S, wherein the phenyl or heterocyclic aromatic ring may be optionally substituted with C1-6 alkyl, C1-6 alkoxy, halogen, hydroxyl, C1-6 alkylthio, cyano, trifluoromethyl, nitro, hydroxymethyl, amino, - (CH ₂ ) _c -NHCO ₂ R ¹⁰ group, - (CH ₂ ) group _c —NR ⁵ R ⁶ or a —CO ₂ R ¹¹ group,
or R ³ represents hydrogen or alkyl from C1-8, which may optionally be substituted with an amino or —NHCO ₂ R ¹⁰ group;
R ⁴ represents hydrogen or alkyl C1-6;
or R ³ and R ⁴ taken together represent a group (CH ₂ ) -Z- (CH ₂ ) _b ;
c = 0-2;
a and b, independently, are an integer from 1 to 3;
Z represents CH ₂ , NH, a group> N (CH ₂ ) _n YR ¹³ , a group> NCOX (CH ₂ ) _n YR ¹³ , a group> NCSX (CH ₂ ) _n YR ^13, or a group> NCNHX (CH ₂ ) _n YR ¹³ ;
X represents O, S or a bond;
Y represents O, S, SO, SO ₂ , NR ⁹ or a bond;
n is 0-6;
R ¹³ represents C1-6 alkyl, C1-6 alkyl substituted with one or more halogen atoms, cyano, quinolyl, phenyl, naphthyl, a 6-membered heterocyclic aromatic ring containing one or two nitrogen atoms, a 5-membered heterocyclic aromatic ring containing from 1 to 3 heteroatoms selected from O, N and S, or a benzene ring fused to a 5-membered heterocyclic aromatic ring containing from 1 to 3 heteroatoms selected from O, N and S;
or R ¹³ may be as defined, except that when it contains one or more aromatic rings, these rings may optionally be substituted with one or more groups selected from C1-6 alkyl, halogen, cyano, nitro, hydroxyl , alkoxy C1-6, trifluoromethyl, trifluoromethoxy, methanesulfonyl, sulfamoyl, NR ¹⁴ R ¹⁵ , —COOR ¹⁶ or —CONR ⁷ R ⁸ ;
or R ¹³ may represent a phenyl ring, a 6-membered heterocyclic aromatic ring containing one or two nitrogen atoms, or a 5-membered heterocyclic aromatic ring containing from 1 to 3 heteroatoms selected from O, N and S, substituted
benzyloxy or optionally substituted phenyl, or
an optionally substituted 5-membered heterocyclic aromatic ring containing from 1 to 3 heteroatoms selected from O, N and S;
where optional substituents are C1-6 alkyl, halogen, cyano, nitro, hydroxyl, C1-6 alkoxy, trifluoromethyl and trifluoromethoxy;
or R ¹³ may be as defined, except that when it contains a heterocyclic aromatic ring containing at least one nitrogen atom, this ring may optionally be substituted with one or more oxo groups adjacent to nitrogen, the ring being attached to the rest of the molecule through one of the nitrogen atoms or otherwise;
R ² , R ⁵ , R ⁶ , R ¹¹ , R ⁹ , R ¹⁴ , R ¹⁵ and R ¹⁶ independently represent hydrogen or C1-6 alkyl; in addition, when Y represents NR ⁹ , - (CH ₂ ) _c —NR ⁹ R ¹³ may represent a pyrrolidine or piperidine ring;
R ¹⁰ represents alkyl C1-6, and
R ⁷ and R ⁸ independently represent hydrogen, C1-6 alkyl or phenyl optionally substituted with one or more groups selected from C1-6 alkyl, halogen, cyano, nitro, hydroxyl, C1-6 alkoxy, trifluoromethyl and trifluoromethoxy; provided that
a) when R ³ and R ⁴ taken together represent a group (CH ₂ ) _a —Z— (CH ₂ ) _b ; in which Z represents a group> NCOX (CH ₂ ) _n YR ¹³ , a group> NCSX (CH ₂ ) _n YR ^13, or a group> NCNHX (CH ₂ ) _n YR ¹³ in which neither X nor Y represent a bond, then n equal to an integer from 2 to 4; and
(b) when R ³ and R ⁴ taken together represent a group (CH ₂ ) _a —Z— (CH ₂ ) _b ; where Z represents a group> NCOX (CH ₂ ) _n YCN, a group> NCSX (CH ₂ ) _n YCN or a group> NCNHX (CH ₂ ) _n YCN, then Y represents a bond and either X also represents a bond or X does not represent a bond and n is an integer from 1 to 4;
c) when R ¹ , R ¹⁹ , R ² , R ⁴ represent hydrogen, then R ³ does not represent phenyl;
g) when R ¹ represents hydrogen or chlorine and R ¹⁹ and R ² represent hydrogen, then R ³ and R ⁴ both do not represent methyl, or a pharmaceutically acceptable salt thereof.

3. The compound of formula I according to claim 1 or 2, where R ³ and R ⁴ taken together represent a group (CH ₂ ) _a —Z- (CH ₂ ) _b ; in which Z represents a group> NCO (CH ₂ ) _n R ¹³ , a group> NCS (CH ₂ ) _n R ¹³ or a group> NCNH (CH ₂ ) _n R ¹³ and R ¹³ represents optionally substituted phenyl, furyl, thienyl, thiazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, pyridyl or pyrazinyl.

4. The compound of formula I according to claim 3, where R ¹³ represents substituted phenyl, where the substituent is in the para position.

5. The compound of formula I according to claim 3 or 4, where n is 0.

6. The compound of formula I according to any preceding paragraph, where R ¹ and R ¹⁹ , independently, represent hydrogen or halogen.

7. The compound of formula I according to claim 6, wherein at least one of R ¹ and R ¹⁹ is fluoro or chloro.

8. The compound of formula I according to claim 7, where R ¹ represents 5-fluoro or 5-chloro.

9. The compound of formula I according to claim 8, wherein R ¹ is 5-fluoro and R ¹⁹ is 8-fluoro.

10. The compound of formula I according to any preceding paragraph, where R ³ and R ⁴ taken together represent a group (CH ₂ ) _a —Z- (CH ₂ ) _b ; in which a and b are each equal to 2.

11. The compound of formula I according to any preceding paragraph, where R ² represents hydrogen.

12. The compound of formula I according to any one of paragraphs. 1, 2, 6-9 and 11, where R ⁴ is hydrogen and R ³ is ethyl, iso-propyl, cyclopropyl, cyclobutyl, furyl, thienyl or substituted phenyl, where the substituent is fluorine or hydroxyl.

13. The compound of formula I according to any one of paragraphs. 1, 2, 6-9 and 11, where R ⁴ and R ³ taken together represent the group (CH ₂ ) _a —Z- (CH ₂ ) _b ; in which Z represents a group> NCO ₂ (CH ₂ ) _n YR ¹³ or> NCSO (CH ₂ ) _n YR ¹³ .

14. The compound of formula I according to claim 13, where n is 0, Y represents a bond and R ¹³ represents alkyl C1-6 or chloralkyl C3-6.

15. The compound of formula I according to claim 13, where n is 2, Y is oxygen and R ¹³ is optionally substituted phenyl.

16. The use of the compounds of formula I according to claim 1 in the preparation of a medicament for the treatment or prophylaxis of diseases or conditions in which the inhibition of the nitric oxide synthase enzyme is beneficial.

17. A pharmaceutical preparation containing a therapeutically effective amount of a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

18. A method for the treatment or prevention of diseases or conditions in which the inhibition of nitric oxide synthase enzyme is beneficial, which consists in administering a therapeutically effective amount of a compound of formula I according to claim 1 to a patient suffering from or at risk of such diseases or conditions.

19. The use of the compounds of formula I according to claim 1 in the preparation of a medicament for the treatment of inflammatory diseases.

20. The use of the compounds of formula I according to claim 1 in the preparation of a medicament for the treatment of pain.

21. A method for the treatment or prevention of inflammatory diseases, which consists in administering a therapeutically effective amount of a compound of formula I according to claim 1 to a patient suffering from or at risk of such diseases.

22. A method of treating or preventing pain, which consists in administering a therapeutically effective amount of a compound of formula I according to claim 1 to a patient suffering from or at risk of such a condition.

23. A method for producing a compound of formula I according to claim 2 or a pharmaceutically acceptable salt thereof, which comprises:
(a) the interaction of the compounds of formula II:

where R ¹ , R ² and R ¹⁹ are as defined above, or its salts with acids, with a compound of formula III:

where R ³ and R ⁴ are as defined above, or a protected derivative thereof;
(b) obtaining a compound of formula I, where R ² is alkyl C1-6 by alkylation of the corresponding compound of formula I, where R ² is hydrogen;
(c) preparing a compound of formula I in which one or more substituents contain an amino group by reducing the corresponding nitro or azido compound;
(d) preparing a compound of formula I where R ¹³ contains a —CONR ⁷ R ⁸ substituent by reacting a compound of formula I where R ¹³ contains —COOH substituent with an amine R ⁷ R ⁸ NH;
(d) obtaining a compound of formula I, where R ³ and R ⁴ together represent (CH ₂ ) _a —Z- (CH ₂ ) _b and Z represents> NCOX (CH ₂ ) _r YR ¹³ , by reacting compounds of formula I, where R ³ and R ⁴ together represent (CH ₂ ) _a —Z— (CH ₂ ) _b and Z represents> NH, with a compound of formula IV:
R ¹³ Y (CH ₂ ) _n XCOL
where R ¹³ , X, Y and n are as defined above, and L represents a leaving group;
(e) obtaining a compound of formula I, where R ³ and R ⁴ together represent (CH ₂ ) _a —Z- (CH ₂ ) _b and Z represents> NSO ₂ R ¹³ , by reacting a compound of formula I, where R ³ and R ⁴ together represent (CH ₂ ) _a —Z- (CH ₂ ) _b and Z represents> NH, with a compound of formula V:
R ¹³ SO ₂ L
where R ¹³ is as defined above, and L represents a leaving group;
(g) preparing a compound of formula I, wherein R ³ or R ¹³ is a ring substituted with a group —COOR ¹¹ or —COOR ¹⁶ , respectively, and R ¹¹ or R ¹⁶ is alkyl C1-6 by esterification of a compound where R ¹¹ or R ¹⁶ represents hydrogen.

(i) deprotecting a compound of formula I, wherein one or more atoms are protected;
(k) the interaction of the compounds of formula XXII:

where R ¹ , R ² , R ³ , R ⁴ and R ¹⁹ are as defined above, and L ″ represents a leaving group, or a protected derivative thereof, with ammonia or its deprotonated derivative.

(k) oxygen removal from tautomeric compounds of the formula XXVIII or XXVIII (b):

where R ¹ , R ² , R ³ , R ⁴ and R ¹⁹ are as defined above, or their protected derivatives; or
m) obtaining a compound of formula I, where R ² and R ⁴ both represent hydrogen, by reducing the compounds of formula XXIX:

where R ¹ , R ² and R ¹⁹ are as defined above, or a protected derivative thereof;
and, where desired or necessary, converting the resulting compound of formula I or another salt thereof into a pharmaceutically acceptable salt thereof, or vice versa.