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Claims for Patent: 7,153,964

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Claims for Patent: 7,153,964

Title:Pyrimidine compounds
Abstract: Pyrimidine derivatives of formula (I) wherein: Qh.sub.1 and Q.sub.2 are independently selected from aryl or carbon linked heteroaryl optionally substituted as defined within; and one of Q.sub.1 and Q.sub.2 or both Q.sub.1 and Q.sub.2 is substituted on a ring carbon by one group selected from sulphamoyl, N--(C.sub.1-4alkyl)sulphamoyl (optionally substituted by halo or hydroxy), N,N-di-(C.sub.1-4alkyl)sulphamoyl (optionally substituted by halo or hydroxy), C.sub.1-4alkylsulphonyl (optionally substituted by halo or hydroxy) or a substituent of the formula (Ia) or (Ia'): wherein Q.sub.1, Q.sub.2, G, R.sup.1, Y, Z, Q.sub.3, n and m 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) inhibitors are also described ##STR00001##
Inventor(s): Pease; Elizabeth Janet (Macclesfield, GB), Breault; Gloria Anne (Macclesfield, GB), Morris; Jeffrey James (Macclesfield, GB)
Assignee: AstraZeneca AB (Sodertalje, SE)
Application Number:10/220,139
Patent Claims: 1. A pyrimidine derivative of the formula (I): ##STR00034## wherein: Q.sub.1 and Q.sub.2 are independently selected from aryl or carbon linked heteroaryl; and Q.sub.1 is substituted on a ring carbon by a sulphamoyl group, or one of Q.sub.1 and Q.sub.2 or both Q.sub.1 and Q.sub.2 is substituted on a ring carbon by one group selected from N--(C.sub.1-4alkyl)sulphamoyl (optionally substituted by halo or hydroxy), N,N-di-(C.sub.1-4alkyl)sulphamoyl (optionally substituted by halo or hydroxy), C.sub.1-4alkylsulphonyl (optionally substituted by halo or hydroxy) or a substituent of the formula (Ia) or (Ia'): ##STR00035## wherein: Y is --NHS(O).sub.2--, --S(O).sub.2NH-- or --S(O).sub.2--; Z is R.sup.aO--, R.sup.bR.sup.cN--, R.sup.dS--, R.sup.eR.sup.fNNR.sup.g--, C.sub.3-8cycloalkyl, phenyl or a heteroc wherein said phenyl, C.sub.3-8cycloalkyl or heterocyclic group are optionally substituted on a rig 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.a, R.sup.b, R.sup.c, R.sup.d, R.sup.e, R.sup.f and R.sup.g are independently selected from hydrogen, C.sub.1-4alkyl, C.sub.2-4alkenyl, phenyl, heterocyclic group and C.sub.3-8cycloalkyl; wherein said C.sub.1-4alkyl, C.sub.2-4alkenyl and C.sub.3-8cycloalkyl are optionally substituted by one or more groups selected from R.sup.j; n is 0 or 1; m is 1, 2 or 3, in addition m may be 0 when Z is C.sub.3-8cycloalkyl, phenyl or a heterocyclic group; Q.sub.3 is a nitrogen linked heterocycle; wherein said heterocycle is optionally substituted on a ring carbon by one or more groups selected from R.sup.k; and wherein if said heterocyclic group contains an --NH-- moiety that nitrogen may be optionally substituted by a group selected from R.sup.m G is --O--, --S-- 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.n; R.sup.1 is selected from hydrogen, halo, hydroxy, 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, 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.o], C.sub.1-4alkanoyl, C.sub.1-4alkoxycarbonyl, heterocyclic group, C.sub.1-4alkylS(O).sub.a wherein a is 0 or 1 [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.1-4alkylcarbamoyl, 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.p; and wherein if said heterocyclic group contains an --NH-- moiety that nitrogen may be optionally substituted by a group selected from R.sup.q; and also independently, or in addition to, the above substituents, Q.sub.1 may be optionally substituted by one C.sub.1-4alkoxy or by one hydroxy substituent; 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, 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.1], C.sub.1-4alkanoyl, C.sub.1-4alkoxycarbonyl, heterocyclic group, C.sub.1-4alkylS(O).sub.a wherein a is 0 or 1 [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.1-4alkylcarbamoyl, N,N-di-(C.sub.1-4alkyl)carbamoyl, C.sub.1-4alkenyloxy, C.sub.2-4alkynyloxy and 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.s; and wherein if said heterocyclic group contains an --NH-- moiety that nitrogen may be optionally substituted by a group selected from R.sup.t; R.sup.j, R.sup.n, R.sup.o and R.sup.r 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.u; and wherein if said heterocyclic group contains an --NH-- moiety that nitrogen may be optionally substituted by a group selected from R.sup.v; R.sup.h, R.sup.k, R.sup.p R.sup.s and R.sup.u 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 heterocyclic group; and R.sup.i, R.sup.q, R.sup.t and R.sup.v are independently selected from C.sub.1-4alkyl, C.sub.1-4alkanoyl, C.sub.1-4alkylsulphonyl, C.sub.1-4alkoxycarbonyl, 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 compound 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 compound as claimed in claims 1 wherein Q.sub.2 is phenyl or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof.

4. A pyrimidine compound as claimed in claims 1 wherein Q.sub.1 is substituted on a ring carbon by sulphamoyl group or one of Q.sub.1 and Q.sub.2 or both of Q.sub.1 and Q.sub.2 are substituted on a ring carbon by one group selected from mesyl, N-(2-diethylaminoethyl)sulphamoyl, 2-(N-methyl-N-phenylamino)ethylsulphonyl, 2-morpholinoethylsulphonyl, N-(5-methylthiadiazol-2-yl)sulphamoyl, N,N-di-(2-hydroxyethyl)sulphamoyl, N-(thiazol-2-yl)sulphamoyl, N-(3,4-dimethylisoxazol-5-yl)sulphamoyl, N-(pyrid-2-yl)sulphamoyl and N-methylsulphamoyl or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof.

5. A pyrimidine compound as claimed in claims 1 wherein Q.sub.1 is phenyl substituted in the para- or meta-position relative to the --NH-- by sulphamoyl, N--(C.sub.1-4alkyl)sulphamoyl (optionally substituted by halo or hydroxy), N,N-di-(C.sub.1-4alkyl)sulphamoyl (optionally substituted by halo or hydroxy), C.sub.1-4alkylsulphonyl (optionally substituted by halo or hydroxy) or a substituent of the formula (Ia) or (Ia') or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof.

6. A pyrimidine compound as claimed in claims 1 wherein G is --O--, --NH--, (4,4,4-trifluorobutyl)N--, -(3-bromo-2-propenyl) N-- or -(3-phenyl-2-propenyl)N-- or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof.

7. A pyrimidine compound as claimed in claims 1 wherein R.sup.1 is hydrogen or halo or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof.

8. A pyrimidine compound as claimed in claims 1 wherein Q.sub.1 is optionally substituted by one C.sub.1-4alkoxy substituent or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof.

9. A pyrimidine compound as claimed in claims 1 wherein Q.sub.2 is optionally substituted on a ring carbon by one to two substituents independently selected from halo, cyano, methyl, methoxy and morpholino or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof.

10. A pyrimidine compound as claimed in claims 1 selected from: 2-(4sulphamoylanilino)-4-(2-cyanoanilino)pyrimidine; 2-(4-N-methylsulphamoylanilino)-4-anilino-5-bromopyrimidine; 2-(4-sulphamoylanilino)-4-anilino-5-bromopyrimidine; 2-(4sulphamoylanilino)-4-(4-methoxyphenoxy)-5-chloropyrimidine; or pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof.

11. A process for preparing a pyrimidine compound, or pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof, as claimed in claims 1 which comprises of: a) for compounds of formula (I) where G is --NR.sup.2--; reacting a pyrimidine of formula (II): ##STR00036## wherein L is a displaceable group as defined below, with a compound of formula (III): ##STR00037## where G is --NR.sup.2--; b) reaction of a pyrimidine of formula (IV): ##STR00038## wherein L is a displaceable group as defined below, with a compound of formula (V): ##STR00039## c) for compounds of formula (I) wherein the sidechain is of formula (Ia) and Y is --S(O).sub.2NH--; by reaction of a compound of formula (VI): ##STR00040## where L is a displaceable group; with an amine of formula (VII): Z-(CH.sub.2).sub.m--NH.sub.2 (VII) d) for compounds of formula (I) wherein the sidechain is of formula (Ia) and Y is --NHS(O).sub.2-- by reaction of an amine of formula (VIII): ##STR00041## with a compound of formula (IX): Z-(CH.sub.2).sub.m--SO.sub.2L (IX) where L is a displaceable group; e) for compounds of formula (I) wherein the sidechain is of formula (Ia'); by reaction of a compound of formula (VI) with an amine of formula (X): ##STR00042## and thereafter optionally: 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 thereof.

12. A pharmaceutical composition which comprises a pyrimidine 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 10, in association with a pharmaceutically acceptable diluent or carrier.
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