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1. WO2011062927 - MÉTHODE DE TRAITEMENT DE TROUBLES PROLIFÉRATIFS ET D'AUTRES AFFECTIONS PATHOLOGIQUES MÉDIÉS PAR BCR-ABL, C-KIT, DDR1, DDR2 OU L'ACTIVITÉ KINASE DU PDGF-R

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]

We claim:

1. A method of treating a proliferative disorder or other pathological conditions mediated by Bcr-Abl, c-Kit, DDR1 , DDR2 or PDGF-R kinase activity comprising oral administration of an effective dose of a pyrimid laminobenzamide of formula (I):


wherein

(a) Py denotes 3-pyridyl,

Ri represents hydrogen, lower alkyi, lower alkoxy-lower alkyi, acyloxy-lower alkyi, carboxy- lower alkyi, lower alkoxycarbonyl-lower alkyi, or phenyl-lower alkyi;

R2 represents hydrogen, lower alkyi, optionally substituted by one or more identical or different radicals R3, cycloalkyl, benzcycloalkyl, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising 0-, 1-, 2- or 3-ring nitrogen atoms and 0 or 1 oxygen atom and 0 or 1 sulfur atom, which groups in each case are unsubstituted or mono- or poly-substituted; and

R3 represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N- mono- or A/,A/-di-substituted carbamoyl, amino, mono- or di-substituted amino, cycloalkyl, heterocyclyl, an aryl group, or a mono- or bi-cyclic heteroaryl group comprising 0-, 1-, 2- or 3-ring nitrogen atoms and 0 or 1 oxygen atom and 0 or 1 sulfur atom, which groups in each case are unsubstituted or mono- or poly-substituted; or

R and R2, together, represent alkylene with 4, 5 or 6 carbon atoms optionally mono- or di- substituted by lower alkyi, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- or di-substituted amino, oxo, pyridyl, pyrazinyl or pyrimidinyl; benzalkylene with 4 or 5 carbon atoms; oxaalkylene with 1 oxygen and 3 or 4 carbon atoms; or azaalkylene with 1 nitrogen and 3 or 4 carbon atoms, wherein nitrogen is unsubstituted or substituted by lower alkyi, phenyl-lower alkyi, lower alkoxycarbonyl-lower alkyi, carboxy-lower alkyi, carbamoyl-lower alkyi, /V-mono- or N./V-di-substituted carbamoyl-lower alkyi, cycloalkyl, lower alkoxycarbonyl, carboxy, phenyl, substituted phenyl, pyridinyl, pyrimidinyl or pyrazinyl;

R4 represents hydrogen, lower alkyl or halogen;

or

(b) Py denotes 5-pyrimidyl, Ri is hydrogen, R2 is [[(3S)-3-(dimethylamino)- 1-pyrrolidinyl]- methyl]-3-(trifluoromethyl)phenyl and R4 is methyl;

or a pharmaceutically acceptable salt thereof, and, optionally, pharmaceutically acceptable carriers, dispersed in a fruit preparation, to a human patient in need thereof.

2. The method according to claim 1 , wherein the pyrimidylaminobenzamide is 4-methyl-3-[[4- (3-pyridinyl)-2-pyrimidinyl]amino]-/\/-[5-(4-methyl-1 H-imidazol-1-yl)-3-(trifluoromethyl)- phenyl] benzamide.

3. The method according to claim 2, wherein the pyrimidylaminobenzamide is employed in the form of its hydrochloride monohydrate.

4. The method according to any one of claims 1 to 3, wherein the proliferative disorder or other pathological condition is selected from melanoma, breast cancer, cancer of the colon, lung cancer, cancer of the prostate or Kaposi's sarcoma, gastrointestinal stromal tumors (GIST), acute myeloid leukemia (AML), leukemia which responds to an inhibition of the Abl tyrosine kinase activity, mesothelioma, systemic mastocytosis, hypereosino- philic syndrome (HES), fibrosis, rheumatoid arthritis, polyarthritis, scleroderma, lupus erythematosus, graft-versus host diseases, neurofibromatosis, pulmonary hypertension, Alzheimer's disease, seminomas and dysgerminomas and psoriasis.

5. The method according to any one of claims 1 to 3, wherein the proliferative disorder or other pathological condition is selected from GIST, CML, Ph+ ALL, systemic

mastocytosis, HES, fibrosis, scleroderma, neurofibromatosis and pulmonary arterial hypertension.

6. The method according to claim 1 , wherein the human patient is a elderly or a pediatric patient.

7. The method according to claim 1 , wherein the fruit preparation is a juice, sauce or puree prepared from fruits.

8. The method according to claim 1 , wherein the fruit preparation is applesauce.

9. A commercial package containin a pyrimidylaminobenzamide of formula I


(a) Py denotes 3-pyridyl,

represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, carboxy- lower alkyl, lower alkoxycarbonyl-lower alkyl, or phenyl-lower alkyl;

R2 represents hydrogen, lower alkyl, optionally substituted by one or more identical or different radicals R3, cycloalkyl, benzcycloalkyl, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted; and

R3 represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N- mono- or Ν,Ν-disubstituted carbamoyl, amino, mono- or disubstituted amino, cycloalkyl, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted;

or wherein Ri and R2 together represent alkylene with four, five or six carbon atoms optionally mono- or disubstituted by lower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- or disubstituted amino, oxo, pyridyl, pyrazinyl or pyrimidinyl; benzalkylene with four or five carbon atoms; oxaalkylene with one oxygen and three or four carbon atoms; or azaalkylene with one nitrogen and three or four carbon atoms wherein nitrogen is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl, N-monb- or N,N- disubstituted carbamoyl-lower alkyi, cycloalkyi, lower alkoxycarbonyl, carboxy, phenyl, substituted phenyl, pyridinyl, pyrimidinyl, or pyrazinyl;

R4 represents hydrogen, lower alkyi, or halogen;

wherein the prefix "lower" denotes a radical having up to and including a maximum of 7 carbon atoms,

or

(b) Py denotes 5-pyrimidyl, is hydrogen, R2 is [[(3S)-3-(dimethylamino)- 1-pyrrolidinyl]- methyl]-3-(trifluoromethyl)phenyl and R4 is methyl;

or a pharmaceutically acceptable salt thereof, respectively,

together with instructions to disperse the compound of formula I or a pharmaceutically acceptable salt thereof in a fruit preparation.

10. A pyrimidylaminobenzamide of formula I


wherein

(a) Py denotes 3-pyridyl,

Ri represents hydrogen, lower alkyi, lower alkoxy-lower alkyi, acyloxy-lower alkyi, carboxy- lower alkyi, lower alkoxycarbonyl-lower alkyi, or phenyl-lower alkyi;

R2 represents hydrogen, lower alkyi, optionally substituted by one or more identical or different radicals R3, cycloalkyi, benzcycloalkyi, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising 0-, 1-, 2- or 3-ring nitrogen atoms and 0 or 1 oxygen atom and 0 or 1 sulfur atom, which groups in each case are unsubstituted or mono- or poly-substituted; and

R3 represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N- mono- or Λ/,/V-di-substituted carbamoyl, amino, mono- or di-substituted amino, cycloalkyi, heterocyclyl, an aryl group, or a mono- or bi-cyclic heteroaryl group comprising 0-, 1-, 2- or 3-ring nitrogen atoms and 0 or 1 oxygen atom and 0 or 1 sulfur atom, which groups in each case are unsubstituted or mono- or poly-substituted; or

Ri and R2, together, represent alkylene with 4, 5 or 6 carbon atoms optionally mono- or di- substituted by lower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- or di-substituted amino, oxo, pyridyl, pyrazinyl or pyrimidinyl; benzalkylene with 4 or 5 carbon atoms; oxaalkylene with 1 oxygen and 3 or 4 carbon atoms; or azaalkylene with 1 nitrogen and 3 or 4 carbon atoms, wherein nitrogen is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl, A/-mono- or A/,/V-di-substituted carbamoyl-lower alkyl, cycloalkyl, lower alkoxycarbonyl, carboxy, phenyl, substituted phenyl, pyridinyl, pyrimidinyl or pyrazinyl;

R4 represents hydrogen, lower alkyl or halogen;

or

(b) Py denotes 5-pyrimidyl, R-\ is hydrogen, R2 is [[(3S)-3-(dimethylamino)- 1-pyrrolidinyl]- methyl]-3-(trifluoromethyl)phenyl and R4 is methyl;

or a pharmaceutically acceptable salt thereof, for the treatment of a proliferative disorder or other pathological conditions mediated by Bcr-AbI, c-Kit, DDR1 , DDR2 or PDGF-R kinase activity, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof and, optionally, pharmaceutically acceptable carriers, are dispersed in a fruit preparation.