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1. (WO2005068452) DERIVES DE PHENYL-[4-(3-PHENYL-1H-PYRAZOL-4-YL)-PYRIMIDIN-2-YL]-AMINE UTILISES COMME INHIBITEURS DU RECEPTEUR IGF-1R
Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

What is claimed is:

1. A compound of formula



wherein
m is from 1 to 5;
RT is lower alkyl-sulfonyl; unsubstituted, mono- or di-substituted amino-sulfonyl;
unsubstituted, mono- or di-substituted amino; a heterocyclic radical; lower alkyl substituted by amino, mono- or di-lower alkyl substituted amino, a heterocyclic radical, heterocyclyl-NH-or heterocyclyl-O- wherein heterocyclyl is bound to NH or O via a carbon ring atom; a radical

R4-lower alkyl-X-, wherein R4 is hydrogen, halogen, unsubstituted, mono- or di-substituted amino, or a heterocyclic radical, and X is -S- or -O-; or a radical R5-C(=O)-, wherein R5 is hydrogen, unsubstituted or substituted lower alkyl, free or etherified hydroxy, unsubstituted, mono- or di-substituted amino, or a heterocyclic radical; wherein the R-j substituents are selected independently of one another if m>1 ;
or two vicinal R-i substituents together with the phenyl carbon atoms to which they are attached form a heterocyclic ring;
R2 is hydrogen, unsubstituted or substituted lower alkyl or a heterocyclic radical; and
Z is benzyloxy;
or a salt of the said compounds, with the proviso that the compound {4-[3-(4-Benzyloxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(2-dimethylamino-ethoxy)-phenyl]-amine is excluded.

2. A compound of claim 1 of formula lb

wherein
m is from 1 to 5;
Ri is lower alkyl-sulfonyl; unsubstituted, mono- or di-substituted amino-sulfonyl;
unsubstituted, mono- or di-substituted amino; a heterocyclic radical; lower alkyl substituted by amino, mono- or di-lower alkyl substituted amino, a heterocyclic radical, heterocyclyl-NH-or heterocyclyl-O- wherein heterocyclyl is bound to NH or O via a carbon ring atom; a radical

R4-lower alkyl-X-, wherein R is hydrogen, halogen, unsubstituted, mono- or di-substituted amino, or a heterocyclic radical, and X is -S- or -O-; or a radical R5-C(=O)-, wherein R5 is hydrogen, unsubstituted or substituted lower alkyl, free or etherified hydroxy, unsubstituted, mono- or di-substituted amino, or a heterocyclic radical; wherein the Ri substituents are selected independently of one another if m>1 ;
or two vicinal R, substituents together with the phenyl carbon atoms to which they are attached form a heterocyclic ring;
R2 is hydrogen, unsubstituted or substituted lower alkyl or a heterocyclic radical; and
Z is benzyloxy;
or a salt of the said compounds, with the proviso that the compound {4-[3-(4-Benzyloxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(2-dimethylamino-ethoxy)-phenyl]-amine is excluded.

3. A compound according to claims 1 or 2, in which R1 is a heterocyclic radical; lower alkyl substituted by mono- or di-lower alkyl substituted amino, a heterocyclic radical, heterocyclyl- NH- or heterocyclyl-O- wherein heterocyclyl is bound to NH or O via a carbon ring atom; a radical R4-lower alkyl-X-, wherein R4 is mono- or di-substituted amino, or a heterocyclic radical, and X is -S- or -O-; or a radical R5-C(=O)-, wherein R5 is unsubstituted, mono- or di-substituted amino, or a heterocyclic radical; m is 1 ;
R2 is hydrogen;
or a or a salt of the said compounds, with the proviso that the compound {4-[3-(4-Benzyloxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(2-dimethylamino-ethoxy)-phenyl]-amine is excluded.

4. A compound according to claims 1, 2 or 3, in which R1is is a lower alkyl substituted by a di-lower alkyl substituted amino, an alkyl substituted 5- or 6- membered heterocyclyl -NH-, heterocyclyl-NH- wherein heterocyclyl is bound to NH via a carbon ring atom; a radical R4-lower alkyl-O-, wherein R4 is di-substituted amino; or a radical R -C(=O)-, wherein R5 is unsubstituted, mono- or di-substituted amino, or a heterocyclic radical; m is 1 ;
R2 is hydrogen;
or a or a salt of the said compounds, with the proviso that the compound {4-[3-(4-Benzyloxy-phenyl)-1 H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(2-dimethylamino-ethoxy)-phenyl]-amine is excluded.

5. A compound according to claims 1 , 2, 3 or 4, in which R-i is a lower alkyl substituted by a di-lower alkyl substituted amino, or a C C4 alkyl-substituted piperazinyl, or a pyrrolidinyl; piperidinyl wherein piperidinyl is bound to NH via a carbon ring atom; a radical R4- lower alkyl-O-, wherein R4 is amino di-substituted by lower alkyl; or R5-C(=O)~, wherein R5 is a C,-C alkyl-substituted piperazinyl;
m is 1 ;
R2 is hydrogen;
or a or a salt of the said compounds, with the proviso that the compound {4-[3-(4-Benzyloxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(2-dimethylamino-ethoxy)-phenyl]-amine is excluded.

6. A compound chosen from the group consisting of;
{4-[3-(3-Benzyloxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)-amine;
{4-[3-(3-Benzyloxy-phenyl)-1 H-pyrazol-4-yl]-pyrimidin-2-yl}-(4-dimethyl aminomethyl-phenyl)-amine;
(4-{4-[3-(3-Benzyloxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-phenyl)-(4-methyl-piperazin-1 -yl)-methanone;
{4-[3-(3-Benzyloxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine;and
4-{4-[3-(3-Benzyloxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-N-(2,2,6,6-tetramethyl~ piperidin-4-yl)-benzamide.

7. A compound of claim 2 wherein R^ is lower alkyl substituted by amino, lower alkyl substituted by a heterocyclic radical or R5-C(O)-.

8. A compound of claim 7 wherein R^ is lower alkyl substituted by amino.

9. A compound of claim 7 wherein R^ is lower alkyl substituted by a heterocyclic radical.

10. A compound of claim 9 wherein the alkyl portion is methylene and the heterocyclic radical is a five or six membered ring containing one or two nitrogens and is unsubstituted or substituted on one or more carbon atoms by a lower alkyl group. .

11. A compound of claim 7 wherein R^ is R5-C(O)-.

12. A compound of claim 11 wherein R5 is substituted amino or a heterocyclic radical, wherein the heterocyclic radical is a five or six membered ring containing one or two nitrogens and is unsubstituted or substituted on one or more carbon atoms by a lower alkyl group.

13. A compound of any one of claims 7-12 wherein R2 is H.

14. A compound of any one of claims 7-13 wherein m is 1.

15. A compound according to formula I

wherein
m is from 1 to 5;
RT is lower alkyl-sulfonyl; unsubstituted, mono- or di-substituted amino-sulfonyl;
unsubstituted, mono- or di-substituted amino; a heterocyclic radical; lower alkyl substituted by amino, mono- or di-lower alkyl substituted amino, a heterocyclic radical, heterocyclyl-NH-or heterocyclyl-O- wherein heterocyclyl is bound to NH or O via a carbon ring atom; a radical

R -lower alkyl-X-, wherein R is hydrogen, halogen, unsubstituted, mono- or di-substituted amino, or a heterocyclic radical, and X is -S- or -O-; or a radical R5-C(=O)-, wherein R5 is hydrogen, unsubstituted or substituted lower alkyl, free or etherified hydroxy, unsubstituted, mono- or di-substituted amino, or a heterocyclic radical; wherein the R^ substituents are selected independently of one another if m>1 ;
or two vicinal R substituents together with the phenyl carbon atoms to which they are attached form a heterocyclic ring;
R2 is hydrogen, unsubstituted or substituted lower alkyl or a heterocyclic radical; and
Z is benzyloxy;
or a salt of the said compounds, for medical use.

16. A compound according to claims any one of 1-14 or 15 for medical use.

17. Use of a compound according to claims 1-14 or 15 for the manufacture of a medicament to be used in the treatment of a proliferative disease.

18. Use according to claim 17, in which the disease is chosen form the group consisting of;

tumours, for example breast, renal, prostate, colorectal, thyroid, ovarian, pancreas, neuronal, lung, uterine and gastro-intestinal tumours as well as osteosarcomas and melanomas.

19. Use of a compound according to claims 1-14 or 15 for the manufacture of a medicament to be used in the treatment of a graft vessel disease, or for preventing or treating vein graft stenosis, restenosis and/or vascular occlusion following vascular injury.

20. A method of treating a disease which responds to inhibition of IGF-1R in a mammal, which comprises administering to the mammal an effective IGF-1 R inhibiting amount of a compound of formula la



wherein
m is from 1 to 5;
RΛ is lower alkyl-sulfonyl; unsubstituted, mono- or di-substituted amino-sulfonyl;
unsubstituted, mono- or di-substituted amino; a heterocyclic radical; lower alkyl substituted by amino, mono- or di-lower alkyl substituted amino, a heterocyclic radical, heterocyclyl-NH-or heterocyclyl-O- wherein heterocyclyl is bound to NH or O via a carbon ring atom; a radical

R4-lower alkyl-X-, wherein R4 is hydrogen, halogen, unsubstituted, mono- or di-substituted amino, or a heterocyclic radical, and X is -S- or -O-; or a radical R5-C(=O)-, wherein R5 is hydrogen, unsubstituted or substituted lower alkyl, free or etherified hydroxy, unsubstituted, mono- or di-substituted amino, or a heterocyclic radical; wherein the Ri substituents are selected independently of one another if m>1 ;
or two vicinal R^ substituents together with the phenyl carbon atoms to which they are attached form a heterocyclic ring;

R2 is hydrogen, unsubstituted or substituted lower alkyl or a heterocyclic radical; and
Z is benzyloxy;
or a pharmaceutically acceptable salt thereof.

21. A method of claim 20, which comprises administering to the mammal an effective IGF-IR inhibiting amount of a compound of formula lb



wherein
m is from 1 to 5;
RT is lower alkyl-sulfonyl; unsubstituted, mono- or di-substituted amino-sulfonyl;
unsubstituted, mono- or di-substituted amino; a heterocyclic radical; lower alkyl substituted by amino, mono- or di-lower alkyl substituted amino, a heterocyclic radical, heterocyclyl-NH-or heterocyclyl-O- wherein heterocyclyl is bound to NH or O via a carbon ring atom; a radical

R4-lower alkyl-X-, wherein R4 is hydrogen, halogen, unsubstituted, mono- or di-substituted amino, or a heterocyclic radical, and X is a -S- or -O-; or a radical R5-C(=O)-, wherein R5 is hydrogen, unsubstituted or substituted lower alkyl, free or etherified hydroxy, unsubstituted, mono- or di-substituted amino, or a heterocyclic radical; wherein the RT substituents are selected independently of one another if m>1 ;
or two vicinal RT substituents together with the phenyl carbon atoms to which they are attached form a heterocyclic ring;
R2 is hydrogen, unsubstituted or substituted lower alkyl or a heterocyclic radical; and
Z is benzyloxy;

or a pharmaceutically acceptable salt thereof.

22. Use of a compound according to any one of claims 1-14 or 15 for the preparation of a pharmaceutical composition for the therapeutic and/or prophylactic management of a disease that responds to inhibition of IGF-1R.

23. A pharmaceutical composition which comprises a pharmaceutically effective amount of a compound of any one of claims 1-14 or 15 and a pharmaceutically acceptable carrier.

24. A pharmaceutical composition which comprises a pharmaceutically effective amount of a compound of any one of claims 1-14 or 15, together with inhibitors of the enzymes of polyamine synthesis, inhibitors of protein kinase C, inhibitors of other tyrosine kinases, cytokines, negative growth regulators, for example TGF-β or IFN-β, aromatase inhibitors, antioestrogens and/or cytostatic drugs; and a pharmaceutically acceptable carrier.