Hydroximic acid derivatives and medical applications therof
View Patent ↗The present invention relates to a kind of new hydroximic acid derivatives, in particular, hydroximic acid derivatives of pyrazolopyrimidine and their medical applications, which have inhibition to histone deacetylase 1 and two kinds of tyrosine kinases (vascular endothelial cell growth factor receptors as well as platelet-derived growth factor receptors) simultaneously, and thus can be used for treatment of diseases related to those three kinds of enzymes. This kind of compounds both exerts a synergistic effect sufficiently to increase biological activity, and avoids problems caused by different properties and metabolisms, therefore is more practical and has good prospects.
1. A compound of formula I, and a pharmaceutically acceptable salt and a hydrate thereof,
wherein in formula I,
R 1 , R 2 and R 3 are independently selected from hydrogen, alkyl and hetero alkyl;
R 4 is selected from the group consisting of: halogen; hydroxyl; sulfhydryl; cyano; amino or alkyl-substituted amino; nitryl; C 1 -C 6 alkyl unsubstituted or substituted by one or more of halogen, hydroxyl, sulfhydryl, cyano, amino, alkyl-substituted amino and nitryl; C 1 -C 6 alkoxy unsubstituted or substituted by one or more of halogen, hydroxyl, sulfhydryl, cyano, amino, alkyl-substituted amino and nitryl; COR 5 ; CONHR 6 ; COOR 7 ; NHCOR 8 ; OCOR 9 ; NHC(═O)OCH 3 ; NHC(═O)O CH 2 CH 3 ;
M is N or CH;
Y is CH 2 , CH(CH 3 ) or C═O;
Z has a straight-chain structure consisting of 3-12 atoms and connecting Y and carbonyl of compound of formula I;
x is an integer between 0 and 5; and
R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from C 1 -C 6 alkyl unsubstituted or substituted by halogen.
2. The compound of formula I according to claim 1 , and the pharmaceutically acceptable salt and the hydrate thereof, wherein,
in formula I,
R 1 , R 2 and R 3 are independently selected from hydrogen or C 1 -C 3 alkyl;
R 4 is selected from the group consisting of: fluoro, chloro, bromo, iodo, hydroxyl, sulfhydryl, cyano, amino, methylamino, ethylamino, nitryl, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, trifluoromethoxy, ethoxy, hydroxymethyl, mercaptomethyl, C(═O)CH 3 , C(═O)CH 2 CH 3 , C(═O)NHCH 3 , C(═O) NHCH 2 CH 3 , NHC(═O)OCH 3 , NHC(═O)O CH 2 CH 3 , NHCH 3 , N(CH 3 ) 2 , and NH CH 2 CH 3 ;
x is 0, 1, 2, 3 or 4;
M, Y and Z are defined as in claim 1 .
3. The compound of formula I according to claim 1 , and the pharmaceutically acceptable salt and the hydrate thereof, wherein, in formula I, x is 1 or 2.
4. The compound of formula I according to claim 1 , and the pharmaceutically acceptable salt and the hydrate thereof, wherein, the straight-chain structure consists of 3-8 carbon atoms as well as 0-4 oxygen atom(s) and/or nitrogen atom(s).
5. The compound of formula I according to claim 4 , and the pharmaceutically acceptable salt and the hydrate thereof, wherein, the straight-chain structure consists of 4-7 carbon atoms as well as 0-2 oxygen atom(s) and/or nitrogen atom(s).
6. The compound of formula I according to claim 5 , and the pharmaceutically acceptable salt and the hydrate thereof, wherein, the straight-chain structure consists of 5 or 6 carbon atoms as well as 0 or 1 oxygen atom and/or nitrogen atom.
7. The compound of formula I according claim 1 , and the pharmaceutically acceptable salt and the hydrate thereof, wherein the straight-chain structure consists of 4-8 atoms.
8. The compound of formula I according to claim 1 , and the pharmaceutically acceptable salt and the hydrate thereof, wherein, the straight-chain structure is a saturated or unsaturated C 3 -C 8 alkyl straight chain uninterrupted or interrupted by 1-2 oxygen atom(s) and/or nitrogen atom(s).
9. The compound of formula I according to claim 8 , and the pharmaceutically acceptable salt and the hydrate thereof, wherein, the straight-chain structure is a saturated or unsaturated C 5 -C 7 alkyl straight chain uninterrupted or interrupted by 1-2 oxygen atom(s) and/or nitrogen atom(s).
10. The compound of formula I according to claim 1 , and the pharmaceutically acceptable salt and the hydrate thereof, wherein in formula I, Z further includes one or two branch chain(s) connecting with the central section of the straight-chain structure, the branch chain(s) being a C 1 -C 6 alkyl unsubstituted or substituted by halogen.
11. The compound of formula I according to claim 10 , and the pharmaceutically acceptable salt and the hydrate thereof, wherein, the branch chain(s) is(are) methyl, ethyl or propyl.
12. The compound of formula I according to claim 1 , and the pharmaceutically acceptable salt and the hydrate thereof, wherein, in formula I, Z is (CH 2 ) 5 , (CH 2 ) 6 , (CH 2 ) 7 , CH 2 CH 2 TCH 2 CH 2 CH 2 , CH 2 CH 2 TCH 2 CH 2 or CH 2 CH 2 CH 2 TCH 2 CH 2 CH 2 , wherein T is O or NR 10 , wherein R 10 is hydrogen, methyl, ethyl or propyl.
13. The compound of formula I according to claim 1 , and the pharmaceutically acceptable salt and the hydrate thereof, wherein, the compound has a structure as shown in formula II:
in formula II,
R 1 , R 2 and R 3 are independently selected from hydrogen or C 1 -C 3 alkyl;
R 4 is selected from the group consisting of: fluoro, chloro, bromo, iodo, hydroxy, sulfhydryl, cyano, amino, methylamino, ethylamino, nitryl, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, trifluoromethoxy, ethoxy, hydroxymethyl, mercaptomethyl, C(═O)CH 3 , C(═O)CH 2 CH 3 , C(═O)NHCH 3 , C(═O) NHCH 2 CH 3 , NHC(═O)OCH 3 , NHC(═O)O CH 2 CH 3 , NHCH 3 , N(CH 3 ) 2 , and NH CH 2 CH 3 ;
Z has a straight structure connecting methylene and carbonyl, the straight-chain structure being a saturated or unsaturated C 3 -C 8 alkyl straight chain uninterrupted or interrupted by 1-2 oxygen atom(s) and/or nitrogen atom(s); and
x is 0, 1, 2, 3 or 4.
14. The compound of formula I according to claim 13 , and the pharmaceutically acceptable salt and the hydrate thereof, wherein, the compound is a compound as shown in formula IIa, IIb, IIc and IId,
15. A method for inhibiting tyrosine kinase in a patient in need thereof by providing to said patient in an effective amount a compound of formula I, and a pharmaceutically acceptable salt and a hydrate thereof,
wherein in formula I,
R 1 , R 2 and R 3 are independently selected from hydrogen, alkyl and hetero alkyl;
R 4 is selected from the group consisting of: halogen; hydroxyl; sulfhydryl; cyano; amino or alkyl-substituted amino; nitryl; C 1 -C 6 alkyl unsubstituted or substituted by one or more of halogen, hydroxyl, sulfhydryl, cyano, amino, alkyl-substituted amino and nitryl; C 1 -C 6 alkoxy unsubstituted or substituted by one or more of halogen, hydroxyl, sulfhydryl, cyano, amino, alkyl-substituted amino and nitryl; COR 5 ; CONHR 6 ; COOR 7 ; NHCOR 8 ; OCOR 9 ;
M is N or CH;
Y is CH 2 , CH(CH 3 ) or C═O;
Z has a straight-chain structure consisting of 3-12 atoms and connecting Y and carbonyl of compound of formula I;
x is an integer between 0 and 5; and
R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from C 1 -C 6 alkyl unsubstituted or substituted by halogen.
16. A pharmaceutical composition comprising the compound of formula I according to claim 1 , and the pharmaceutically acceptable salt, and hydrate thereof.
17. A method of preparing a compound of formula I:
wherein in formula I,
R 1 , R 2 and R 3 are independently selected from hydrogen, alkyl and hetero alkyl;
R 4 is selected from the group consisting of: halogen; hydroxyl; sulfhydryl; cyano; amino or alkyl-substituted amino; nitryl; C 1 -C 6 alkyl unsubstituted or substituted by one or more of halogen, hydroxyl, sulfhydryl, cyano, amino, alkyl-substituted amino and nitryl; C 1 -C 6 alkoxy unsubstituted or substituted by one or more of halogen, hydroxyl, sulfhydryl, cyano, amino, alkyl-substituted amino and nitryl; COR 5 ; CONHR 6 ; COOR 7 ; NHCOR 8 ; OCOR 9 ; NHC(═O)OCH 3 ; NHC(═O)OCH 2 CH 3 ;
M is N or CH;
Y is CH 2 , CH(CH 3 ) or C═O;
Z has a straight-chain structure consisting of 3-12 atoms and connecting Y and carbonyl of compound of formula I;
x is an integer between 0 and 5;
R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from C 1 -C 6 alkyl unsubstituted or substituted by halogen;
by reacting the compound of formula III,
with a hydroxylamine methanol solution with stirring at room temperature,
in formula III,
R 3 are independently selected from hydrogen, alkyl and hetero alkyl;
R 4 is selected from the group consisting of: halogen; hydroxyl; sulfhydryl; cyano; amino or alkyl-substituted amino; nitryl; C 1 -C 6 alkyl unsubstituted or substituted by one or more of halogen, hydroxyl, sulfhydryl, cyano, amino, alkyl-substituted amino and nitryl; C 1 -C 6 alkoxy unsubstituted or substituted by one or more of halogen, hydroxyl, sulfhydryl, cyano, amino, alkyl-substituted amino and nitryl; COR 5 ; CONHR 6 ; COOR 7 ; NHCOR 8 ; OCOR 9 ; NHC(═O)OCH 3 ; NHC(═O)O CH 2 CH 3 ;
M is N or CH;
Y is CH 2 , CH(CH 3 ) or C═O;
Z has a straight-chain structure consisting of 3-12 atoms and connecting Y and carbonyl of compound of formula I;
x is an integer between 0 and 5;
R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from C 1 -C 6 alkyl unsubstituted or substituted by halogen;
R 11 is C 1 -C 6 alkyl unsubstituted or substituted by halogen; and when neither of R 1 and R 2 is hydrogen, R 1 and R 2 are defined as in formula I; and when at least one of R 1 and R 2 is hydrogen, R 1 and R 2 are defined as in formula I, or at least one of R 1 and R 2 is amino protection group.
18. The method according to claim 17 , the method comprising a step of producing the compound of formula III by dissolving a compound of formula IV with a compound of formula V in ethyl alcohol/water, adding TEA and Pd(dppf) Cl 2 .CH 2 Cl 2 in the solution, and refluxing the solution under nitrogen protection:
in formula IV, R 1 , R 2 , M, Y, Z and R 11 are defined as in formula III, X is chloro, bromo or iodo; and
in formula V, R 3 , R 4 and x are defined as in formula III.