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US 2003/0144304 A1Published application
Novel hexacyclic compounds
AssigneeChugai Seiyaku Kabushiki Kaisha
InventorsTakeshi Murata, Satoshi Niizuma, Nobuo Shimma, Hitomi Suda, Masao Tsukazaki
Life of this patent
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Abstract
The present invention relates to hexacyclic compound of the formula [1], 1 wherein Z, R3 and R4 are as identified therein, and pharmaceutically acceptable salts thereof. These compounds are useful in the treatment of cell proliferative disorders.
Claims29
A hexacyclic compound of formula [1],
- 32
- wherein
- Z is—NH—(═X)—N(R1)— or —N═C(R2)—N(R1)—;
- R1 is hydrogen;
- (C1-C10) alkyl, (C1-C10) alkyl substituted with one to three moieties independently selected from the group consisting of (C1-C5) alkoxy, hydroxy, halogen, amino, mono-(C1-C5) alkylamino, di-(C1-C5) alkylamino, (C3-C7) cycloalkyl, a heterocyclic ring and an aryl ring in which the aryl ring is unsubstituted or substituted with one to three moieties independently selected from the group consisting of hydroxy, alkoxy, halogen, amino, mono-(C1-C5) alkylamino and di-(C1-C5) alkylamino;
- R2 is hydrogen;
- amino;
- C1-C5) alkyl;
- (C1-C5) alkoxy;
- (C1-C5) alkylthio;
- mono-(C1-C5) alkylamino;
- di-(C1-C5) alkylamino and di-(C1-C5) alkylamino substituted with one to three moieties independently selected from the group consisting of (C1-C5) alkoxy, hydroxy, halogen, amino, (C3-C7) cycloalkyl, a heterocyclic ring and an aryl ring in which the aryl ring is unsubstituted or substituted with one to three moieties independently selected from the group consisting of hydroxy, (C1-C5) alkoxy, amino, mono-(C1-C5) alkylamino and di-(C1-C5) alkylamino;
- R3 and R4 are independently hydrogen, halogen or (C1-C5) alkyl;
- and
- X is oxygen or sulfur;
- or a pharmaceutically acceptable salt thereof:
13 more elements
A pharmaceutical composition comprising a compound of formula [1],
- 36
- wherein
- Z is—NH—(═X)—(R1)— or —N═C(R2)—N(R1)—;
- R1 is hydrogen;
- (C1-C10) alkyl, (C1-C10) alkyl substituted with one to three moieties independently selected from the group consisting of (C1-C5) alkoxy, hydroxy, halogen, amino, mono-(C1-C5) alkylamino, di-(C1-C5) alkylamino, (C3-C7) cycloalkyl, a heterocyclic ring and an aryl ring in which the aryl ring is unsubstituted or substituted with one to three moieties independently selected from the group consisting of hydroxy, alkoxy, halogen, amino, mono-(C1-C5) alkylamino and di-(C1-C5) alkylamino;
- R2 is hydrogen;
- amino;
- (C1-C5) alkyl;
- (C1-C5) alkoxy;
- (C1-C5) alkylthio;
- mono-(C1-C5) alkylamino;
- di-(C1-C5) alkylamino or di-(C1-C5) alkylamino substituted with one to three moieties independently selected from the group consisting of (C1-C5) alkoxy, hydroxy, halogen, amino, (C3-C7) cycloalkyl, heterocyclic ring and an aryl ring in which the aryl ring is unsubstituted or substituted with one to three moieties independently selected from the group consisting of hydroxy, (C1-C5) alkoxy, amino, mono-(C1-C5) alkylamino or di-(C1-C5) alkylamino;
- R3 and R4 are independently hydrogen, halogen or (C1-C5) alkyl;
- and
- X is oxygen or sulfur,
- or a pharmaceutically acceptable salt thereof, as an active ingredient and a pharmaceutically acceptable carrier.
13 more elements
A method for treating a cell proliferative disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula [1],
- 37
- wherein
- Z is—NH—C(═X)—N(R1)— or —N═C(R2)—N(R1)—;
- R1 is hydrogen;
- (C1-C10) alkyl, (C1-C10) alkyl substituted with one to three moieties independently selected from the group consisting of (C1-C5) alkoxy, hydroxy, halogen, amino, mono-(C1-C5) alkylamino, di-(C1-C5) alkylamino, (C3-C7) cycloalkyl, a heterocyclic ring and an aryl ring in which the aryl ring is unsubstituted or substituted with one to three moieties independently selected from the group consisting of hydroxy, alkoxy, halogen, amino, mono-(C1-C5) alkylamino and di-(C1-C5) alkylamino;
- R2 is hydrogen;
- amino;
- (C1-C5) alkyl;
- (C1-C5) alkoxy;
- (C1-C5) alkylthio;
- mono-(C1-C5) alkylamino;
- di-(C1-C5) alkylamino or di-(C1-C5) alkylamino substituted with one to three moieties independently selected from the group consisting of (C1-C5) alkoxy, hydroxy, halogen, amino, (C3-C7) cycloalkyl, heterocyclic ring and an aryl ring in which the aryl ring is unsubstitued or substituted with one to three moieties independently selected from the group consisting of hydroxy, (C1-C5) alkoxy, amino, mono-(C1-C5) alkylamino and di-(C1-C5) alkylamino;
- R3 and R4 are independently hydrogen, halogen or (C1-C5) alkyl;
- and
- X is oxygen or sulfur,
- or a pharmaceutically acceptable salt thereof.
13 more elements
A process for producing a compound of formula [2],
- 38
- wherein R1 is hydrogen;
- (C1-C10) alkyl, (C1-C10) alkyl substituted with one to three moieties independently selected from the group consisting of (C1-C5) alkoxy, hydroxy, halogen, amino, mono-(C1-C5) alkylamino, di-(C1-C5) alkylamino, (C3-C7) cycloalkyl, a heterocyclic ring and an aryl ring in which the aryl ring is unsubstituted or substituted with one to three moieties independently selected from the group consisting of hydroxy, alkoxy, halogen, amino, mono-(C1-C5) alkylamino and di-(C1-C5) alkylamino;
- R3 and R4 are independently hydrogen, halogen or (C1-C5) alkyl;
- X is oxygen or sulfur, and
- R5 is (C1-C5) alkanoyl,
- which comprises reacting a compound of the formula [3] or its salt,
- 39
- wherein R1, R3, R4 and R5 are the same as defined above, with a compound of the formula [4],
- 40
- wherein X is the same as defined above, and L1 and L2 is a leaving group;
- in the presence of a base.
9 more elements
A process for producing a compound of formula [5],
- 41
- wherein R1 is hydrogen;
- (C1-C10) alkyl;
- (C1-C10) alkyl substituted with one to three moieties independently selected from the group consisting of (C1-C5) alkoxy, hydroxy, halogen, amino, mono-(C1-C5) alkylamino, di-(C1-C5) alkylamino, (C3-C7) cycloalkyl, a heterocyclic ring and an aryl ring in which the aryl ring is unsubstituted or substituted with one to three moieties independently selected from the group consisting of hydroxy, alkoxy, halogen, amino, mono-(C1-C5) alkylamino and di-(C1-C5) alkylamino;
- R2 is hydrogen;
- amino;
- (C1-C5) alkyl;
- (C1-C5) alkoxy;
- (C1-C5) alkylthio;
- mono-(C1-C5) alkylamino;
- di-(C1-C5) alkylamino and di-(C1-C5) alkylamino substituted with one to three moieties independently selected from the group consisting of (C1-C5) alkoxy, hydroxy, halogen, amino, (C3-C7) cycloalkyl, a heterocyclic ring and an aryl ring in which the aryl ring is unsubstituted or substituted with one to three moieties independently selected from the group consisting of hydroxy, (C1-C5) alkoxy, amino, mono-(C1-C5) alkylamino and di-(C1-C5) alkylamino;
- R3 and R4 are independently hydrogen, halogen or (C1-C5) alkyl;, and
- R5 is (C1-C5) alkanoyl,
- which comprises reacting a compound of the formula [3] or its salt,
- 42
- wherein R1, R3, R4 and R5 are the same as defined above, with a compound of the formula [6],
- 43
- wherein
- R2is as defined above;
- R6 is oxygen or sulfur;
- ═(OR7)2 wherein R7 is (C1-C3) alkyl;
- ═NR8 wherein R8 is hydrogen, (C1-C3) alkyl, (C1-C3) alkanoyl or alkoxycarbonyl;
- ═N+R9R10 wherein R9 and R10 are independently (C1-C3) alkyl or halogen;
- and L1 is a leaving group.
21 more elements
A process for producing a compound of formula [1] or a pharmaceutically acceptable salt thereof,
- 44
- wherein Z is—NH—C(═X)—N(R1)— or —N═C(R2)—N(R1)—;
- R1 is hydrogen;
- (C1-C10) alkyl,;
- (C1-C10) alkyl substituted with one to three moieties independently selected from the group consisting of (C1-C5) alkoxy, hydroxy, halogen, amino, mono-(C1-C5) alkylamino, di-(C1-C5) alkylamino, (C3-C7) cycloalkyl, a heterocyclic ring and an aryl ring in which the aryl ring is unsubstituted or substituted with one to three moieties independently selected from the group consisting of hydroxy, alkoxy, halogen, amino, mono-(C1-C5) alkylamino and di-(C1-C5) alkylamino;
- R2 is hydrogen;
- amino;
- (C1-C5) alkyl;
- (C1-C5) alkoxy;
- (C1-C5) alkylthio;
- mono-(C1-C5) alkylamino;
- di-(C1-C5) alkylamino and di-( C1-C5) alkylamino substituted with one to three moieties independently selected from the group consisting of (C1-C5) alkoxy, hydroxy, halogen, amino, (C3-C7) cycloalkyl, a heterocyclic ring and an aryl ring in which the aryl ring is unsubstituted or substituted with one to three moieties independently selected from the group consisting of hydroxy, (C1-C5) alkoxy, amino, mono-(C1-C5) alkylamino and di-(C1-C5) alkylamino;
- and
- R3 and R4 are independently hydrogen, halogen or (C1-C5) alkyl;
- which comprises subjecting a compound of the formula [1],
- 45
- wherein Z, R , R and R are as defined above;
- and R5 is (C1-C5) alkanoyl, to deacylation with a hydrazine or its derivative.
15 more elements
Dependencies are inferred from the claim text.