RU2003103848A

RU2003103848A - Pyrimidine derivatives

Info

Publication number: RU2003103848A
Application number: RU2003103848/04A
Authority: RU
Inventors: Эндрю Питер Томас; Николас Джон НЬЮКОМ; Дэвид Уилльям ХИТОН
Original assignee: Астразенека Аб
Priority date: 2000-07-11
Filing date: 2001-07-06
Publication date: 2004-08-20

Claims

1. The compound of formula (I)

where R ¹ represents halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl;

p = 0-4, where R ¹ may be the same or different;

R ² represents sulfamoyl or a group BE;

q = 0-2, where R ² may be the same or different, and where p + q = 1-5;

R ³ represents hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or C _3-8 cycloalkyl, where R ³ may optionally be substituted at the carbon atom with one or more M;

R ⁴ represents C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl or heterocyclyl, where R ⁴ may optionally be substituted with one or more M, and where, if said heterocyclyl contains the group - NH—, the nitrogen atom may optionally be substituted with a group selected from Z;

or R ³ and R ⁴ taken together with the nitrogen atom to which they are bonded form a heterocyclic ring optionally substituted on the carbon atom by one or more M, where, if said heterocyclic ring contains an —NH— group, then the nitrogen atom may optionally be substituted by a group selected from Q;

B is selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl C _1-6 alkyl, phenyl, a heterocyclic group, phenylC _1-6 alkyl or (heterocyclic group) C _1-6 alkyl, wherein B may optionally be substituted on the carbon atom with one or more D, and where, if said heterocyclic group contains an —NH— group, the nitrogen atom may optionally be substituted with a group selected from G;

E represents —C (O) -, —N (R ^a ) C (O) -, —C (O) N (R ^a ) -, —S (O) _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 1-2;

D is independently 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 alkyl S (O) _a , where a is 0-2, C _1-6 alkoxycarbonyl, N- (C _1-6 alkyl) sulfamoyl and N, N- (C _1-6 alkyl) ₂ sulfamoyl, where D may optionally be substituted at the carbon atom with one or more V;

M is independently selected from halogen, nitro, cyano, hydroxy, 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 0-2, C _1-6 alkoxycarbonyl, N- (C _1-6 alkyl) sulfamoyl, N, N- (C _1-6 alkyl) ₂ sulfamoyl, C _3-8 cycloalkyl, phenyl or heterocyclic groups, where M may optionally be substituted at the carbon atom by one or more kimi P, and where, if said heterocyclic group contains an —NH— group, then the nitrogen atom may optionally be substituted with a group selected from T;

P, X and V 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-methylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfyl, mesulphyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N, N-dimethylsulfon moila, N, N-diethylsulfamoyl or N-methyl-N--ethylsulphamoyl; and

G, Q, T, and Z 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, benzyloxycarbonyl, benzoyl and phenylsulfonyl, where G, Q and T may optionally be substituted at the carbon atom with one or more X;

or a pharmaceutically acceptable salt thereof or an in vivo hydrolyzable ester.

2. The compound of formula (I) according to claim 1, where p = 0, or its pharmaceutically acceptable salt or in vivo hydrolyzable ester.

3. The compound of formula (I) according to claim 1 or 2, where R ² represents sulfamoyl or a group BE, where

B is selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or (heterocyclic group) C _1-6 alkyl, where

B may be optionally substituted at the carbon atom by one or more D, and where, if said heterocyclic group contains a —NH— group, then the nitrogen atom may optionally be substituted by a group selected from G;

E is —S (O) _r or —N (R ^a ) SO ₂ -, where R ^a is hydrogen or C _1-6 alkyl and r is 2;

D is independently selected from halogen, cyano, hydroxy, amino, C _1-6 alkyl, C _1-6 alkoxy, N- (C _1-6 alkyl) amino, N, N- (C _1-6 alkyl) ₂ amino, C _1-6 alkanoylamino and C _1-6 alkylS (O) _a , where a = 0-2, and where D may optionally be substituted at the carbon atom by a group selected from V;

V is selected from hydroxy and dimethylamino; and

G is selected from C _1-4 alkyl;

or a pharmaceutically acceptable salt thereof or an in vivo hydrolyzable ester.

4. The compound of formula (I) according to any one of claims 1 to 3, where q = 1, or its pharmaceutically acceptable salt or in vivo hydrolyzable ester.

5. The compound of formula (I) according to any one of claims ^{1 to 4} , where R ³ represents hydrogen or C _1-6 alkyl, and where R ³ may optionally be substituted with one or more M; and

R ⁴ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or C _3-8 cycloalkyl, where R ⁴ may optionally be substituted with one or more M;

M is independently selected from halogen, cyano, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, N, N- (C _1-6 alkyl) ₂ amino, C _1-6 alkoxycarbonyl, C _3-8 cycloalkyl or a heterocyclic group where M may optionally be substituted at the carbon atom by a group selected from P;

P and X are independently selected from hydroxy and methoxy; and

Q is selected from C _1-4 alkyl, C _1-4 alkylsulfonyl or C _1-4 alkoxycarbonyl, where G may optionally be substituted at the carbon atom with one or more X;

or a pharmaceutically acceptable salt thereof or an in vivo hydrolyzable ester.

6. The compound of formula (I) according to claim 1,

where p = 0;

R ² represents sulfamoyl, mesyl, ethylsulfonyl,

2-ethoxyethyl sulfonyl, propylsulfonyl,

3-isopropylaminopropylsulfonyl, 4-isopropylaminobutylsulfonyl,

N- (tetrahydrofur-2-ylmethyl) sulfamoyl,

N- (pyrid-3-ylmethyl) sulfamoyl, N- (pyrid-2-ylmethyl) sulfamoyl,

N- (1,4-dioxan-2-ylmethyl) sulfamoyl, N- (methyl) sulfamoyl,

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

N- (2-morpholinoethyl) sulfamoyl, N- (2-piperidinoethyl) sulfamoyl,

N- (2-pyrid-2-yl-ethyl) sulfamoyl,

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

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

N- (2-isopropylaminoethyl) sulfamoyl, N- (2-mesylethyl) sulfamoyl,

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

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

N- (2-pyrid-2-yl-ethyl) sulfamoyl, N- (2-diethylamino-ethyl) sulfamoyl,

N- (2-pyrid-4-yl-ethyl) sulfamoyl, N- (2-acetamido-ethyl) sulfamoyl,

N- (2-dimethylaminoethyl) sulfamoyl,

N-2 - [(5-methyl-1,3,4-triazol-2-yl) ethyl] sulfamoyl,

N- (2-hydroxyethyl) sulfamoyl, N- (2-cyanoethyl) sulfamoyl,

N- (2-diethylaminoethyl) -N- (methyl) sulfamoyl,

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

N- (2,2,2-trifluoroethyl) sulfamoyl,

N- (3-hydroxy-2,2-dimethylpropyl) sulfamoyl,

N- (3-isopropylaminopropyl) sulfamoyl,

N- (3-methoxypropyl) sulfamoyl,

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

N- (2-hydroxy-3-aminopropyl) sulfamoyl,

N- (3-hydroxypropyl) sulfamoyl, N- (3-ethoxypropyl) sulfamoyl,

N- [3- (2-Dimethylaminoethyl) propyl] sulfamoyl,

N- (3-morpholinopropyl) sulfamoyl,

N- (2-hydroxypropyl) sulfamoyl,

N- (2-hydroxy-3-piperidinopropyl) sulfamoyl,

N- (3-piperidinopropyl) -N- (methyl) sulfamoyl,

N- (2-hydroxybutyl) sulfamoyl, N- (pentyl) sulfamoyl,

N- (5-hydroxypentyl) sulfamoyl, N- (allyl) sulfamoyl or

N- (2-propynyl) sulfamoyl;

q = 1, and R ² is in the para position with respect to the amino group in the aniline of formula (I); and

R ³ and R ⁴ taken together with the nitrogen atom to which they are attached form isobutylamino, ethylamino, 2-fluoroethylamino,

3-ethoxypropylamino, butylamino, 2,2,2-trifluoroethylamino,

3-morpholinopropylamino, cyclopropylamino, cyclopropylmethylamino, cyclohexylamino, tetrahydrofur-2-ylmethyl,

2-dimethylaminoethylamino, cyanomethylamino, pyrid-3-ylmethylamino, butoxycarbonylmethylamino, 2- (methoxycarbonyl) ethylamino,

2-hydroxyethylamino, methylamino, 2-propynylamino,

2-methoxyethylamino, 2-imidazol-4-yl-ethylamino,

2- (2-hydroxyethoxy) ethylamino, 2,3-dihydroxypropylamino,

2,2-dimethyldioxolan-4-ylmethylamino, propylamino,

N-methyl-N-allylamino, N-methyl-N-ethoxycarbonylmethylamino,

N-methyl-N- (2-cyanoethyl) amino, diethylamino,

N-methyl-N- (2-methoxyethyl) amino, bis- (2-cyanoethyl) amino,

N-ethyl-N-cyclohexylamino, N-methyl-N- (2,2,2-trifluoroethyl) amino,

N-methyl-N- (2-propynyl) amino, morpholino, 2,6-dimethylmorpholino,

3,5-dimethylpiperidino, piperidino,

4- (2-methoxyethyl) piperazin-1-yl, 4-methylpiperazin-1-yl,

4-isopropylpiperazin-1-yl, 4-ethylsulfonylpiperazin-1-yl,

4-ethoxycarbonylpiperazin-1-yl, 4- (2-hydroxyethyl) piperazin-1-yl and 3-hydroxypyrrolidin-1-yl;

or a pharmaceutically acceptable salt thereof or an in vivo hydrolyzable ester.

7. The compound of formula (I) selected from

5-cyano-4-n-butylamino-2- (4-mesylanilino) pyrimidine;

5-cyano-4-ethylamino-2- {4- [N- (2-methoxyethyl) sulfamoyl] anilino} pyrimidine;

5-cyano-4-ethylamino-2- {4- [N- (3-methoxypropyl) sulfamoyl] anilino} pyrimidine;

5-cyano-4-cyclopropylamino-2- {4- [N- (2-methoxyethyl) sulfamoyl] anilino} pyrimidine;

5-cyano-4-cyclopropylamino-2- {4- [N- (3-methoxypropyl) sulfamoyl] anilino} pyrimidine;

5-cyano-4-cyclopropylamino-2- [4- (ethylsulfonyl) anilino] pyrimidine;

5-cyano-4-cyclopropylamino-2- (4-mesylanilino) pyrimidine;

5-cyano-4-ethylamino-2- [4- (N-methylsulfamoyl) anilino] pyrimidine;

5-cyano-4-cyclopropylamino-2- {4- [N- (2-methoxyethyl) -N- (methyl) sulfamoyl] anilino} pyrimidine and

5-cyano-4- (ethylamino) -2- (4-ethylsulfonylanilino) pyrimidine;

or a pharmaceutically acceptable salt thereof or an in vivo hydrolyzable ester.

8. A pharmaceutical composition that contains a compound of formula (I) or a pharmaceutically acceptable salt thereof or an in vivo hydrolyzable ester according to any one of claims 1 to 7 in combination with a pharmaceutically acceptable diluent or carrier for use in treating cancer.

9. The compound of formula (I) or its pharmaceutically acceptable salt or in vivo hydrolyzable ester according to any one of claims 1 to 7 for use as a medicine.

10. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof or an in vivo hydrolyzable ester according to any one of claims 1 to 7 in the manufacture of a medicament for inhibiting the cell cycle (inhibiting cell proliferation) in a warm-blooded animal such as a human.

11. A method of inhibiting a cell cycle (inhibiting cell proliferation) in a warm-blooded animal, such as a person in need of such treatment, wherein said method comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or an in vivo hydrolyzable ester of to any one of claims 1 to 7.

12. A pharmaceutical composition that contains a compound of formula (I) or a pharmaceutically acceptable salt thereof or an in vivo hydrolyzable ester according to any one of claims 1 to 7 in combination with a pharmaceutically acceptable diluent or carrier, and which is used to inhibit the cell cycle (inhibiting proliferation cells) in a warm-blooded animal such as humans.