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Claims for Patent: 7,067,522

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Claims for Patent: 7,067,522

Title:2,4,DI (hetero-) arylamino (-oxy)-5-substituted pyrimidines as antineoplastic agents
Abstract:Pyrimidine derivatives of formula (I) wherein Q.sub.1, Q.sub.2, G and R.sup.1 are as defined within; and pharmaceutically acceptable salts and in vivo hydrolysable esters thereof are described. Processes for their manufacture, pharmaceutical compositions and their use as cyclin-dependent serine/threonine kinase (CDK) and focal adhesion kinase (FAK) inhibitors are also described.
Inventor(s): Pease; Elizabeth Janet (Macclesfield, GB), Williams; Emma Jane (Macclesfield, GB), Bradbury; Robert Hugh (Macclesfield, GB), Pearson; Stuart Eric (Macclesfield, GB)
Assignee: AstraZeneca AB (Sodertalje, SE)
Application Number:10/995,931
Patent Claims: 1. A pyrimidine derivative of the formula (I): ##STR00020## wherein: Q.sub.1 and Q.sub.2 are independently selected from aryl or heteroaryl linked via ring carbon; and one of Q.sub.1 and Q.sub.2 or both of Q.sub.1 and Q.sub.2 is substituted on a ring carbon by one substituent selected from N-(C.sub.1-2alkyl)amino, N,N-di-(C.sub.1-2alkyl)amino, phenyl, heterocyclic group, phenoxy, heterocyclic group--O--, substituted C.sub.1-2alkyl, substituted C.sub.1-2alkoxy, substituted C.sub.1-2alkoxycarbonyl, substituted N-(C.sub.1-2alkyl)amino, substituted C.sub.1-2alkoxyC.sub.1-2alkyl, substituted C.sub.2-4alkenyl and substituted C.sub.2-4alkynyl; wherein said substituents for C.sub.1-2alkyl, C.sub.1-2alkoxy, C.sub.1-2alkoxycarbonyl, N-(C.sub.1-2alkyl)amino, C.sub.1-2alkoxyC.sub.1-2alkyl, C.sub.2-4alkenyl and C.sub.2-4alkynyl are selected from halo, hydroxy, mercapto, nitro, formyl, formamido, carboxy, cyano, amino, ureido, carbamoyl, sulphamoyl, C.sub.1-4alkanoyl, C.sub.1-4alkoxycarbonyl, phenyl, heterocyclic group, benzoyl, heterocyclic group--C(O)--, C.sub.1-4alkylS(O).sub.a wherein a is 0 to 2, N'-(C.sub.1-4alkyl)ureido, N',N'-di-(C.sub.1-4alkyl)ureido, N'-(C.sub.1-4alkyl)-N-(C.sub.1-4alkyl)ureido, N',N'-di-(C.sub.1-4alkyl)-N-(C.sub.1-4alkyl)ureido, N-C.sub.1-4alkylamino, N,N-di-(C.sub.1-4alkyl)amino, N-(C.sub.1-4alkyl)sulphamoyl, N,N-di-(C.sub.1-4alkyl)sulphamoyl, N-C.sub.1-4alkylcarbamoyl, N,N-di-(C.sub.1-4alkyl)carbamoyl and C.sub.1-4alkanoylamino; wherein any phenyl, benzyl, benzoyl or heterocyclic group is optionally substituted on a ring carbon by one or more groups selected from R.sup.a; and wherein if any heterocyclic group contains an --NH-- moiety that nitrogen may be optionally substituted by a group selected from R.sup.b; G is --O-- or --NR.sup.2--; R.sup.2 is selected from hydrogen, C.sub.1-6alkyl, C.sub.3-6alkenyl and C.sub.3-6alkynyl; wherein said C.sub.1-6alkyl, C.sub.3-6alkenyl and C.sub.3-6alkynyl are optionally substituted by one or more groups selected from R.sup.c; R.sup.1 is selected from hydrogen, halo, hydroxy, nitro, amino, N-(C.sub.1-3alkyl)amino, N,N-di-(C.sub.1-3alkyl)amino, cyano, trifluoromethyl, trichloromethyl, C.sub.1-3alkyl [optionally substituted by 1 or 2 substituents independently selected from halo, cyano, amino, N-(C.sub.1-3alkyl)amino, N,N-di-(C.sub.1-3alkyl)amino, hydroxy and trifluoromethyl], C.sub.3-5alkenyl [optionally substituted by up to three halo substituents, or by one trifluoromethyl substituent], C.sub.3-5alkynyl, C.sub.1-3alkoxy, mercapto, C.sub.1-3alkylsulphanyl, carboxy and C.sub.1-3alkoxycarbonyl; Q.sub.1 is optionally substituted on a ring carbon by one to four substituents independently selected from halo, mercapto, nitro, formyl, formamido, carboxy, cyano, amino, ureido, carbamoyl, sulphamoyl, C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl [wherein said C.sub.1-4alkyl, C.sub.2-4alkenyl and C.sub.2-4alkynyl are optionally substituted by one or more groups selected from R.sup.d], C.sub.1-4alkanoyl, C.sub.1-4alkoxycarbonyl, heterocyclic group, C.sub.1-4alkylS(O).sub.a [wherein a is 0 to 2 and said C.sub.1-4alkyl is optionally substituted by hydroxy], N'-(C.sub.1-4alkyl)ureido, N',N'-di-(C.sub.1-4alkyl)ureido, N'-(C.sub.1-4alkyl)-N-(C.sub.1-4alkyl)ureido, N',N'-di-(C.sub.1-4alkyl)-N-(C.sub.1-4alkyl)ureido, N-C.sub.1-4alkylamino, N,N-di-(C.sub.1-4alkyl)amino, N-(C.sub.1-4alkyl)sulphamoyl, N,N-di-(C.sub.1-4alkyl)sulphamoyl, N-C.sub.1-4alkylcarbamoyl, N,N-di-(C.sub.1-4alkyl)carbamoyl and C.sub.1-4alkanoylamino; and also independently, or in addition to, the above substituents, Q.sub.1 may be optionally substituted by one to two substituents independently selected from aryl, C.sub.3-8cycloalkyl and a heterocyclic group; wherein said aryl, C.sub.3-8cycloalkyl or heterocyclic group may be optionally substituted on a ring carbon by one or more groups selected from R.sup.e; and wherein if said heterocyclic group contains an --NH-- moiety that nitrogen may be optionally substituted by a group selected from R.sup.f; Q.sub.2 is optionally substituted on a ring carbon by one to four substituents independently selected from halo, hydroxy, mercapto, nitro, formyl, formamido, carboxy, cyano, amino, ureido, carbamoyl, sulphamoyl, C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, C.sub.1-4alkoxy [wherein said C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl and C.sub.1-4alkoxy are optionally substituted by one or more groups selected from R.sup.g], C.sub.1-4alkanoyl, C.sub.1-4alkoxycarbonyl, heterocyclic group, C.sub.1-4alkylS(O).sub.a [wherein a is 0 to 2 and said C.sub.1-4alkyl is optionally substituted by hydroxy], N'-(C.sub.1-4alkyl)ureido, N',N'-di-(C.sub.1-4alkyl)ureido, N'-(C.sub.1-4alkyl)-N-(C.sub.1-4alkyl)ureido, N',N'-di-(C.sub.1-4alkyl)-N-(C.sub.1-4alkyl)ureido, N-C.sub.1-4alkylamino, N,N-di-(C.sub.1-4alkyl)amino, N-(C.sub.1-4alkyl)sulphamoyl, N,N-di-(C.sub.1-4alkyl)sulphamoyl, N-C.sub.1-4alkylcarbamoyl, N,N-di-(C.sub.1-4alkyl)carbamoyl, C.sub.2-4alkenyloxy, C.sub.2-4alkynyloxy, C.sub.1-4alkanoylamino; and also independently, or in addition to, the above substituents, Q.sub.2 may be optionally substituted by one to two substituents independently selected from aryl, C.sub.3-8cycloalkyl or a heterocyclic group; wherein said aryl, C.sub.3-8cycloalkyl or heterocyclic group may be optionally substituted on a ring carbon by one or more groups selected from R.sup.h; and wherein if said heterocyclic group contains an --NH-- moiety that nitrogen may be optionally substituted by a group selected from R.sup.i; R.sup.c, R.sup.d and R.sup.g are independently selected from hydroxy, halo, amino, cyano, formyl, formamido, carboxy, nitro, mercapto, carbamoyl, sulphamoyl, N-C.sub.1-4alkylamino, N,N-di-(C.sub.1-4alkyl)amino, C.sub.1-4alkanoyl, C.sub.1-4alkanoyloxy, C.sub.1-4alkoxy, C.sub.1-4alkoxycarbonyl, N-C.sub.1-4alkylcarbamoyl, N,N-di-(C.sub.1-4alkyl)carbamoyl, C.sub.1-4alkanoylamino, C.sub.1-4alkylS(O).sub.a wherein a is 0 to 2, C.sub.1-4alkylsulphonylamino, N-(C.sub.1-4alkyl)sulphamoyl, N-(C.sub.1-4alkyl).sub.2sulphamoyl, N-(C.sub.1-4alkyl)carbamoyl, N-(C.sub.1-4alkyl).sub.2carbamoyl, phenyl, phenylthio, phenoxy, C.sub.3-8cycloalkyl and a heterocyclic group; wherein said phenyl, phenylthio, phenoxy, C.sub.3-8cycloalkyl or heterocyclic group may be optionally substituted on a ring carbon by one or more groups selected from R.sup.j; and wherein if said heterocyclic group contains an --NH-- moiety that nitrogen may be optionally substituted by a group selected from R.sup.k; R.sup.a, R.sup.e, R.sup.h and R.sup.j are independently selected from hydroxy, halo, amino, cyano, formyl, formamido, carboxy, nitro, mercapto, carbamoyl, sulphamoyl, C.sub.1-4alkyl [optionally substituted by one or more groups selected from halo, cyano, amino, N-C.sub.1-4alkylamino, N,N-di-(C.sub.1-4alkyl)amino or hydroxy], C.sub.2-4alkenyl [optionally substituted by one or more groups selected from halo], C.sub.2-4alkynyl, N-C.sub.1-4alkylamino, N,N-di-(C.sub.1-4alkyl)amino, C.sub.1-4alkanoyl, C.sub.1-4alkanoyloxy, C.sub.1-4alkoxy [optionally substituted by one or more groups selected from halo], C.sub.1-4alkoxycarbonyl, N-C.sub.1-4alkylcarbamoyl, N,N-di-(C.sub.1-4alkyl)carbamoyl, C.sub.1-4alkanoylamino, C.sub.1-4alkylS(O).sub.a wherein a is 0 to 2, C.sub.1-4alkylsulphonylamino, N-(C.sub.1-4alkyl)sulphamoyl, N-(C.sub.1-4alkyl).sub.2sulphamoyl, phenyl, C.sub.3-8cycloalkyl and a hetercyclic group; and R.sup.b, R.sup.f, R.sup.i and R.sup.k are independently selected from C.sub.1-4alkyl, C.sub.1-4alkanoyl, C.sub.1-4alkylsulphonyl, carbamoyl, N-(C.sub.1-4alkyl)carbamoyl, N,N-(C.sub.1-4alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof.

2. A pyrimidine derivative as claimed in claim 1 wherein Q.sub.1 is phenyl or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof.

3. A pyrimidine derivative as claimed in claim 1 wherein Q.sub.2 is phenyl or pyridyl or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof.

4. A pyrimidine derivative as claimed in claim 1 wherein one of Q.sub.1 and Q.sub.2 or both of Q.sub.1 and Q.sub.2 is substituted on a ring carbon by one substituent selected from dimethylamino, 4-methylpiperazino, aminomethyl, 2-hydroxyethoxymethyl, succinimid-1-ylmethyl, 2-pyrrolidin-1-ylethyl, 2-aminoethyl, piperid-4-yloxy, 1-methylpiperid-4-yloxy, 1-methylpiperid-3-yloxy, carboxymethoxy, 1-methylpiperid-2-ylmethoxy, 1-methylpiperid-3-ylmethoxy, piperid-4-ylmethoxy, 4-isopropylpiperazinocarbonylmethoxy, 2-pthalimid-1-ylethoxy, 2-morpholinoethoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 2-(4-methylpiperazino)ethoxy, 2-imidazol-1-ylethoxy, 2-pyrrolidin-1-ylethoxy, 2-aminoethynyl, 2-dimethylaminoethynyl, 2-methylaminoethynyl, 2-(3-hydroxyquinuclidin-3-yl)ethynyl, 2-morpholinoethoxymethyl, 2-diethylaminoethoxymethyl, 2-pyrrolidin-1-ylethoxymethyl, 2-(4-methylpiperazino)ethoxymethyl, 2-diethylaminoethoxycarbonyl, 2-piperidinoethylamino or 2-isopropylaminoethylamino or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof.

5. A pyrimidine derivative as claimed in claim 1 wherein Q.sub.1 is substituted in the para- or meta-position relative to the --NH-- or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof.

6. A pyrimidine derivative as claimed in claim 1 wherein G is --NH-- or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof.

7. A pyrimidine derivative as claimed in claim 1 wherein R.sup.1 is hydrogen, chloro, or bromo or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof.

8. A pyrimidine derivative as claimed in claim 1 wherein Q.sub.2 is unsubstituted or substituted by one group selected from fluoro, bromo, methyl, methoxy and cyano or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof.

9. A pyrimidine derivative as claimed in claim 1 selected from: 4-anilino-5-bromo-2-[4-(2-dimethylaminoethoxy)anilino]pyrimidine; 4-anilino-5-bromo-2-[4-(caroxymethoxy)anilino]pyrimidine; 4-anilino-5-bromo-2-[4-(1-methylpiperid-4-yloxy)anilino]pyrimidine; 4-(6-methylpyrid-2-yl)-5-bromo-2-[4-(2-piperid-1-ylethylamino)anilino]pyr- imidine; 4-anilino-5-bromo-2-[4-(2-isopropylaminoethylamino)anilino]pyrimi- dine; or 4-anilino-5-bromo-2-[4-(3-methylamino-1-propynyl)anilino]pyrimidi- ne; or pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof.

10. A process for preparing a pyrimidine derivative as claimed in any one of claims 1 to 9 selected from: a) for compounds of formula (I) where G is --NR.sup.2--; reacting a pyrimidine of formula (II): ##STR00021## wherein L is a displaceable group as defined below, with a compound of formula (III): ##STR00022## where G is --NR.sup.2--; b) reaction of a pyrimidine of formula (IV): ##STR00023## wherein L is a displaceable group as defined below, with a compound of formula (V): ##STR00024## and thereafter if necessary: i) converting a compound of the formula (I) into another compound of the formula (I); ii) removing any protecting groups; iii) forming a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group.

11. A pharmaceutical composition which comprises a pyrimidine derivative of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof, as claimed in any one of claims 1 to 9, in association with a pharmaceutically acceptable diluent or carrier.

12. A method for producing a cell cycle inhibitory effect in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective amount of a pyrimidine derivative as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof.

13. A method for producing a FAK enzyme inhibitory effect in a warm-blooded animal in need of such treatment, which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof as claimed in any one of claims 1 to 9.

14. A method for producing a selective CDK2, CDK4 or CDK6 enzyme inhibitory effect in a warm-blooded animal in need of such treatment, which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof as claimed in any one of claims 1 to 9.

15. A method for producing an anti-cell proliferation effect in a warm-blooded animal in need of such treatment, which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof as claimed in any one of claims 1 to 9.
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