RU2002107128A

RU2002107128A - IMIDAZO [1,2-A] pyridine and pyrazole [2,3-a] pyridine derivatives

Info

Publication number: RU2002107128A
Application number: RU2002107128/04A
Authority: RU
Inventors: Эндрю Питер Томас; Глория Анн БРО; Джон Франклин БЕЙТТИ; Филлип Джон ДЖУЗБЕРИ
Original assignee: Астразенека Аб
Priority date: 1999-08-21
Filing date: 2000-08-15
Publication date: 2003-09-27

Claims

1. The compound of formula (I):

where cycle A is imidazo [1,2a] pyrid-3-yl or pyrazole [2,3a] pyrid-3-yl;

R ^{2 is} attached to a cyclic carbon atom and is selected from halogen, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, N- (C _1-6 alkyl) amino, N, N- (C _1-6 alkyl) ₂ amino, C _1-6 alkanoylamino, N - (C _1-6 alkyl) carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, C _1-6 alkylS (O) _a , where a is from 0 to 2, C _1-6 alkoxycarbonyl, N- (C _1-6 alkyl) sulfamoyl, N, N- (C _1-6 alkyl) ₂ -sulfamoyl, phenyl, heterocyclic group, phenylthio or (heterocyclic group) thio; where any C _1-6 alkyl, C _2-6 alkenyl, C _3-6 alkynyl, phenyl or heterocyclic group may be optionally substituted at the carbon atom by one or more G; and where, if said heterocyclic group contains an —NH moiety, then nitrogen may optionally be substituted with a group selected from Q;

m is 0-5; wherein the values of R ² may be the same or different;

R ¹ is halogen, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 alkoxy, C _1-3 alkanoyl, N- (C _1-3 alkyl) amino, N, N- (C _1-2 alkyl) ₂ amino, C _1-3 alkanoylamino, N- (C _1-3 alkyl) carbamoyl, N, N - (C _1-2 alkyl) ₂ -carbamoyl, C _1-3 alkylS (O) _and where a is from 0 to 2, N- (C _1-3 alkyl) sulfamoyl or N, N- (C _1-3 alkyl ) ₂ sulfamoyl; where any C _1-2 alkyl, C _1-3 alkyl, C _2-3 alkenyl or C _2-3 alkynyl may optionally be substituted at the carbon atom by one or more J;

n is from 0 to 2, while the values of R ¹ may be the same or different;

Cycle B is phenyl or phenyl fused to a C _5-7 cycloalkyl ring;

R ³ is halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _2-6 alkenyl or C _2-6 alkynyl;

p is 0-4; wherein the values of R ³ may be the same or different;

R ⁴ represents a group AE; Where

A is selected from C _1-6 alkyl, phenyl, a heterocyclic group, C _3-8 cycloalkyl, phenyl C _1-6 alkyl, (heterocyclic group) -C _1-6 alkyl or C _3-8 cycloalkyl C _1-6 cycloalkyl; moreover, C _1-6 alkyl, phenyl, heterocyclic group, C _3-8 cycloalkyl, phenylC _1-6 alkyl, (heterocyclic group) C _1-6 alkyl or C _3-8 cycloalkyl C _1-6 cycloalkyl may optionally be substituted at the carbon atom one or more D; and where, if said heterocyclic group contains an —NH moiety, then nitrogen may optionally be substituted with a group selected from R;

E is a direct bond or —O—, —C (O) -, —OC (O) -, —C (O) O—, —N (R ^a ) C (O) -, —C (O) N ( R ^a ) -, -N (R ^a ) -, -S (О) _r -, -SO ₂ N (R ^a ) - or –N (R ^a ) SO ₂ -; where R ^a is hydrogen or C _1-6 alkyl optionally substituted with one or more D, and r is 0-2;

D is independently selected from oxo, halogen, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, N- (C _1-6 alkyl) amino, N, N- (C _1-6 alkyl) ₂ amino, C _1-6 alkanoylamino, N- (C _{1 -6} alkyl) carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, C _1-6 alkyl S (O) _a , where a is from 0 to 2, C _1-6 alkoxycarbonyl, C _1-6 alkoxy- carbonylamino, benzyloxycarbonylamino, N- (C _1-6 alkyl) sulfamoyl and N, N- (C _1-8 alkyl) ₂ sulfamoyl; where any C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or phenyl may optionally be substituted on the carbon atom with one or more K;

q is 0-2; wherein the values of R ⁴ may be the same or different; and where p + q <5;

G, J and K are independently selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methyl-carbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethyl-sulfamoyl, N, N-dimethylsulfon amoyl, N, N-diethylsulfamoyl or N-methyl-N-ethylsulfamoyl; and

Q and R are independently selected from C _1-4 alkyl, C _1-4 alkanoyl, C _1-4 alkylsulfonyl, C _1-4 alkoxycarbonyl, carbamoyl, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) carbamoyl, benzyl, benzyl-hydroxycarbonyl, benzoyl and phenylsulfonyl;

or a pharmaceutically acceptable salt or ester thereof capable of undergoing in vivo hydrolysis.

2. The compound of formula (I) according to claim 1, where R ¹ is bromo or 2-hydroxyethylthio, and n is 0-1;

3. The compound of formula (I) according to any one of claims 1 or 2, wherein cycle A is imidazo [1,2a] pyrid-3-yl;

4. The compound of formula (I) according to any one of claims 1 to 3, where R ^{2 is} attached to a cyclic carbon atom and is selected from fluorine, chlorine, bromine, cyano, methyl, methoxy, ethylthio, 2-hydroxyethylthio or 2-dimethylaminoethylthio, am equal to 0-2, where the values of R ² may be the same or different;

5. The compound of formula (I) according to any one of claims ^{1 to 4} , where R ³ denotes fluorine, chlorine, bromine or sulfamoyl; and p is 1;

6. The compound of formula (I) according to any one of claims 1 to 5, wherein R ⁴ is methyl, ethyl, methoxy, methylthio, acetyl, benzyloxy,

mesyl, N, N-diethylaminoethoxy,

3-N, N-dimethylamino-2-hydroxypropoxy, phenoxy,

N-methylcarbamoyl, N, N-dimethylcarbamoyl,

N- (3-imidazol-1-ylpropyl) carbamoyl,

N- [3- (2-oxo-pyrrolidin-1-yl) propyl] carbamoyl,

3,5-dioxapiperidin-1-ylsulfonyl,

N-cyclopropylsulfamoyl,

N-cyclopropylmethylsulfamoyl, anilinosulfonyl,

N-pyrimidin-2-yl sulfamoyl, N-methylsulfamoyl,

N-propylsulfamoyl, N- (2-methoxyethyl) sulfamoyl,

N- (2-methylaminoethyl) sulfamoyl,

N- (2-Isopropylaminoethyl) sulfamoyl,

N- (2-dimethylaminoethyl) sulfamoyl,

N- (2-diethylaminoethyl) sulfamoyl,

N- [2- (hydroxyethylamino) ethyl] sulfamoyl,

N- [2- (diethylaminoethyl) ethyl] sulfamoyl,

N- (pyrrolidin-1-yl-ethyl) sulfamoyl,

N- [2- (1-methylpyrrolidin-2-yl) ethyl] sulfamoyl,

N- (2-piperidin-1-yl-ethyl) sulfamoyl,

N- (2-piperazin-1-yl-ethyl) sulfamoyl,

N- (2-morpholinethyl) sulfamoyl,

N- (2-imidazol-4-yl-ethyl) sulfamoyl,

N- (3-hydroxypropyl) sulfamoyl,

N- (2,3-dihydroxypropyl) sulfamoyl,

N- (3-methoxypropyl) sulfamoyl,

N- (3-aminopropyl) sulfamoyl,

N- (3-methylaminopropyl) sulfamoyl,

N- (3-dimethylaminopropyl) sulfamoyl,

N- (3-diethylaminopropyl) sulfamoyl,

N- (3-isopropylaminopropyl) sulfamoyl,

N- (3-tert-butoxycarbonylaminopropyl) sulfamoyl,

N- (3-benzyloxycarbonylaminopropyl) sulfamoyl,

N- [3- (2-oxopyrrolidin-1-yl) propyl] sulfamoyl,

N- (3-morpholinpropyl) sulfamoyl,

N- [3- (4-methylpiperazin-1-yl) propyl] sulfamoyl,

N- (3-imidazol-1-ylpropyl) sulfamoyl or

N- (5-hydroxypentyl) sulfamoyl; and

q is 1;

7. The compound of formula (I) according to any one of claims 1 to 6, where cycle B is phenyl;

8. The compound of formula (I) selected from:

2- (4-sulfamoylaniline) -4- (imidazo [1,2a] pyrid-3-yl) pyrimidine;

2- [4- (N-methylsulfamoyl) aniline] -4- (imidazo [1,2a] pyrid-3-yl) pyrimidine;

2- {4- [N- (2-methoxyethyl) sulfamoyl] aniline} -4- (imidazo [1,2a] pyrid-3-yl) pyrimidine;

2- {4- [N- (3-methoxypropyl) sulfamoyl] aniline) -4- (imidazo [1,2a] pyrid-3-yl) pyrimidine;

2- {4- [N- (3-isopropylaminopropyl) sulfamoyl] aniline} -4- (imidazo [1,2a] pyrid-3-yl) pyrimidine;

2- {4- [N- (3-dimethylaminopropyl) sulfamoyl] aniline} -4- (imidazo [1,2a] pyrid-3-yl) pyrimidine;

2- {4- [N- (2-dimethylaminoethyl) sulfamoyl] aniline} -4- (imidazo [1,2a] pyrid-3-yl) pyrimidine;

2- {4- [N- (2-methylaminoethyl) sulfamoyl] aniline} -4- (imidazo [1,2a] pyrid-3-yl) pyrimidine or

2- {4- [N- (2-methoxyethyl) sulfamoyl] aniline} -4- [5- (2-hydroxyethylthio) imidazo [1,2a] pyrid-3-yl] pyrimidine;

9. A method of obtaining a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or ester thereof capable of undergoing in vivo hydrolysis, this method (where R ¹ , R ² , R ³ , R ⁴ , cycle A, cycle B, m, p, q and n, unless otherwise indicated, are as defined in formula (I)) includes:

a) the interaction of pyrimidine of the formula (II):

where L is a substitutable group; with an amine of formula (III):

b) the interaction of pyrimidine of the formula (IV):

with a compound of formula (V):

where one of M and Q is a substitutable group X, and the other is a metal reagent Y; or

c) the interaction of the compounds of formula (VI):

with a compound of formula (VII):

where R ⁵ denotes C _1-6 alkyl, and R ⁶ denotes hydrogen or R ¹ ; and then, if necessary:

i) converting a compound of formula (I) into another compound of formula (I);

ii) removal of all protecting groups;

iii) obtaining a pharmaceutically acceptable salt or ester capable of undergoing in vivo hydrolysis.

10. A pharmaceutical composition that comprises a compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or ester thereof capable of undergoing in vivo hydrolysis in combination with a pharmaceutically acceptable diluent or carrier.

11. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or ester thereof capable of undergoing in vivo hydrolysis for use in a therapeutic method for treating a human or animal body.

12. The use of a compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or ester thereof capable of undergoing in vivo hydrolysis in the industrial production of a medicament for treating cancers (solid tumors and leukemias) fibroproliferative and differential disorders, psoriasis, rheumatoid arthritis, Kaposi’s sarcoma, hemangioma, acute and chronic nephropathy, atheroma, atherosclerosis, arterial repeated stenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation.