Molecular Chaperone Function Regulator
According to the present invention, a molecular chaperone function regulator containing a quinazoline derivative represented by the following formula (I) wherein each symbol is as defined in Claims, or a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, an optically active form or racemate thereof or a diastereomer mixture thereof as an active ingredient can be provided.
1 . A method for the prophylaxis and/or treatment of a disease involving a heat shock protein, or for a thermotherapy enhancing action, which comprises administering to a patient in need thereof a molecular chaperone function regulator comprising, as an active ingredient, a quinazoline derivative represented by the following formula (I)
wherein n is an integer of 0 to 3, R 1 is a hydrogen atom, a halogen atom, hydroxy, cyano, nitro, trifluoromethyl, C 1-5 alkyl, C 1-5 alkoxy, —S(O) f R 13 (wherein f is an integer of 0 to 2, and R 13 is C 1-5 alkyl), —NR 14 R 15 (wherein R 14 and R 15 are each independently a hydrogen atom, C 1-5 alkyl, C 1-5 alkanoyl or C 1-5 alkylsulfonyl), C 2-5 alkenyl, C 2-5 alkynyl or C 1-5 alkanoyl, one of R 2 and R 3 is
R 27 SO 2 NH— (wherein R 27 is C 1-5 alkyl optionally substituted by morpholino), (R 28 SO 2 ) 2 N— (wherein R 28 is C 1-5 alkyl optionally substituted by morpholino), C 1-5 alkoxy, CH 3 COCH 2 CONH—, CH 3 SCH 2 CH 2 CONH—, NCCH 2 CONH—,
(wherein X is —C(O)— or SO 2 —, and R 4 , R 5 and R 6 are each independently a hydrogen atom, a halogen atom or C 1-5 alkyl optionally substituted by a halogen atom, morpholino, 4-C 1-5 alkylpiperazin-1-yl or di(C 1-5 alkyl)amino), or
(wherein R 7 is C 1-5 alkyl optionally substituted by a hydrogen atom, a halogen atom, morpholino, 4-C 1-5 alkylpiperazin-1-yl or di(C 1-5 alkyl)amino), and
the other of R 2 and R 3 is
wherein R 8 and R 9 are each independently [a] a hydrogen atom, [b] C 1-5 alkyl optionally substituted by hydroxy or C 1-5 alkoxy, [c] R 8 and R 9 in combination show C═O, or [d] R 8 and R 9 in combination form a ring to show C 3-8 cycloalkylene optionally via —O—, —S— or —NR 10 — (wherein R 10 is a hydrogen atom or C 1-5 alkyl), m is an integer of 0 to 3, R 11 and R 12 are each independently a hydrogen atom or C 1-5 alkyl, and
Y is a hydrogen atom, hydroxy, C 1-5 alkoxy, C 1-5 alkanoyloxy, —N(R 16 )—(CO)u-(CR 17 R 18 )v-(CO)j-R 19 (wherein R 16 is [a] a hydrogen atom or [b] C 1-5 alkyl optionally substituted by cyano or C 1-5 alkoxy, R 17 and R 18 are each independently a hydrogen atom or C 1-5 alkyl, u and j are each 0 or 1, v is an integer of 1 to 5, and R 19 is a hydrogen atom, hydroxy, cyano, amino, C 1-5 alkoxy, morpholino, 4-C 1-5 alkylpiperazin-1-yl or di(C 1-5 alkyl)amino,
provided that when (i) u and j are simultaneously 0, then v is an integer of 2 to 5, and when (ii) R 19 is a cyano group, then j is 0),
wherein p and q are each independently 2 or 3, and Z is —O—, —S(O) g — (wherein g is an integer of 0 to 2), carbonyl or —NR 20 — (wherein R 20 is [a] a hydrogen atom, [b] C 1-5 alkylsulfonyl, [c] C 1-5 alkanoyl, [d] C 1-5 alkoxycarbonyl, or [e] C 1-5 alkyl optionally substituted by cyano or C 1-5 alkoxy), or
wherein r and t are each independently an integer of 1 to 3, k is 0 or 1, and W is a hydrogen atom, hydroxy, C 1-5 alkoxy, C 1-5 alkanoyloxy, carboxyl, cyano, di(C 1-5 alkyl)amino, morpholino, pyrrolidin-1-yl, piperidin-1-yl, 4-C 1-5 alkylpiperazin-1-yl or CONR 21 R 22 (wherein R 21 and R 22 are each independently a hydrogen atom or C 1-5 alkyl), or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, or an optically active form or racemate thereof or a diastereomer mixture thereof.
2 . The method of claim 1 , wherein, in the quinazoline derivative of the aforementioned formula (I),
R 2 is R 27 SO 2 NH— (wherein R 27 is C 1-5 alkyl optionally substituted by morpholino), (R 28 SO 2 ) 2 N— (wherein R 28 is C 1-5 alkyl optionally substituted by morpholino), C 1-5 alkoxy, CH 3 COCH 2 CONH—, CH 3 SCH 2 CH 2 CONH—, N≡CCH 2 CONH—, or
(wherein X is —C(O)— or SO 2 —, and R 4 , R 5 and R 6 are each independently a hydrogen atom, a halogen atom or C 1-5 alkyl optionally substituted by a halogen atom, morpholino, 4-C 1-5 alkylpiperazin-1-yl or di(C 1-5 alkyl)amino), and
R 3 is
wherein m is an integer of 0 to 3,
R 8 and R 9 are each independently a hydrogen atom, hydroxy or C 1-5 alkyl optionally substituted by C 1-5 alkoxy, R 8 and R 9 in combination show —C(O)—, or R 8 and R 9 in combination form a ring to show C 3-8 cycloalkylene optionally via —O—, —S— or —NR 10 —
(wherein R 10 is a hydrogen atom or C 1-5 alkyl),
R 11 and R 12 are each independently a hydrogen atom or C 1-5 alkyl, and
Y is a hydrogen atom, hydroxy, C 1-5 alkoxy, C 1-5 alkanoyloxy, —N(R 16 )—(CO)u-(CR 17 R 18 )v-(CO)j-R 19 (wherein R 16 is a hydrogen atom, or C 1-5 alkyl optionally substituted by cyano or C 1-5 alkoxy,
R 17 and R 18 are each independently a hydrogen atom or C 1-5 alkyl,
u and j are each independently 0 or 1, v is an integer of 1 to 5, and
R 19 is a hydrogen atom, hydroxy, cyano, amino, C 1-5 alkoxy, morpholino, 4-C 1-5 alkylpiperazin-1-yl, or di(C 1-5 alkyl)amino,
provided that when (i) u and j are simultaneously 0, then v is an integer of 2 to 5, and when (ii) R 19 is cyano, then j is 0),
wherein p and q are each independently 2 or 3, and Z is —O—, —S(O) g — (wherein g is an integer of 0 to 2), —C(O)— or —NR 20 — (wherein R 20 is a hydrogen atom, C 1-5 alkylsulfonyl, C 1-5 alkanoyl, C 1-5 alkoxycarbonyl, or C 1-5 alkyl optionally substituted by cyano or C 1-5 alkoxy), or
wherein r and t are each independently an integer of 1 to 3, k is 0 or 1, and W is a hydrogen atom, hydroxy, C 1-5 alkoxy, C 1-5 alkanoyloxy, carboxyl, cyano, di(C 1-5 alkyl)amino, morpholino, pyrrolidin-1-yl, piperidin-1-yl, 4-C 1-5 alkylpiperazin-1-yl or CONR 21 R 22 (wherein R 21 and R 22 are each independently a hydrogen atom or C 1-5 alkyl).
3 . The method of claim 2 , wherein, in the quinazoline derivative of the aforementioned formula (I),
R 3 is
wherein m is an integer of 0 to 3,
R 8 and R 9 are each independently a hydrogen atom or C 1-5 alkyl optionally substituted by C 1-5 alkoxy, or R 8 and R 9 in combination form a ring to show C 3-8 cycloalkylene optionally via —O— or —NH—,
R 11 and R 12 are each independently a hydrogen atom or C 1-5 alkyl, and
Y is a hydrogen atom, hydroxy, C 1-5 alkoxy, C 1-5 alkanoyloxy, —N(R 16 )—(CO)u-(CR 17 R 18 )v-(CO)j-R 19 (wherein R 16 is a hydrogen atom, or C 1-5 alkyl optionally substituted by cyano or C 1-5 alkoxy, R 17 and R 18 are each independently a hydrogen atom or C 1-5 alkyl, u and j are each independently 0 or 1, v is an integer of 1 to 5, and R 19 is a hydrogen atom, hydroxy, cyano, amino, C 1-5 alkoxy, morpholino, 4-C 1-5 alkylpiperazin-1-yl, or di(C 1-5 alkyl)amino, provided that when (i) u and j are simultaneously 0, then v is an integer of 2 to 5, and when (ii) R 19 is cyano, then j is 0),
wherein p and q are each independently 2 or 3, and Z is —O—, —C(O)— or —NR 20 — (wherein R 20 is a hydrogen atom, C 1-5 alkylsulfonyl, C 1-5 alkanoyl, C 1-5 alkoxycarbonyl, or C 1-5 alkyl optionally substituted by cyano or C 1-5 alkoxy), or
wherein r and t are each independently an integer of 1 to 3, k is 0 or 1, and W is a hydrogen atom, hydroxy, C 1-5 alkoxy, C 1-5 alkanoyloxy, carboxyl, cyano, di(C 1-5 alkyl)amino, morpholino or CONR 21 R 22 (wherein R 21 and R 22 are each independently a hydrogen atom or C 1-5 alkyl).
4 . The method of claim 2 , wherein, in the quinazoline derivative of the aforementioned formula (I), R 3 is
wherein m is an integer of 0 or 1,
R 8 and R 9 are each independently a hydrogen atom or C 1-5 alkyl optionally substituted by C 1-5 alkoxy, or R 8 and R 9 in combination form a ring to show C 3-8 cycloalkylene optionally via —O— or —NH—, and
Y is C 1-5 alkoxy, —N(R 16 )—(CO)u-(CH 2 ) 2 —(CO)j-R 19 (wherein u and j are each 0 or 1, R 16 is a hydrogen atom, or C 1-5 alkyl optionally substituted by C 1-5 alkoxy, and R 19 is a hydrogen atom, cyano, C 1-5 alkoxy, morpholino, 4-C 1-5 alkylpiperazin-1-yl or di(C 1-5 alkyl)amino, provided that when R 19 is cyano, then j is 0),
wherein p and q are each independently 2 or 3, and Z is —O— or —NR 20 — (wherein R 20 is a hydrogen atom, C 1-5 alkylsulfonyl, C 1-5 alkanoyl, C 1-5 alkoxycarbonyl, or C 1-5 alkyl optionally substituted by cyano or C 1-5 alkoxy), or
wherein r and t are each independently 1 or 2, and
W is a hydrogen atom, hydroxy, C 1-5 alkoxy, C 1-5 alkanoyloxy or carboxyl.
5 . The method of claim 2 , wherein, in the quinazoline derivative of the aforementioned formula (I), R 3 is
wherein m is 0 or 1,
R 8 and R 9 are each independently a hydrogen atom or C 1-5 alkyl optionally substituted by C 1-5 alkoxy, or R 8 and R 9 in combination form a ring to show C 3-8 cycloalkylene optionally via —O— or —NH—, and
Y is C 1-5 alkoxy, —N(R 16 )—(CH 2 ) 2 —R 19 (wherein R 16 is a hydrogen atom or C 1-5 alkyl optionally substituted by C 1-5 alkoxy, and R 19 is a hydrogen atom, cyano, C 1-5 alkoxy, morpholino, 4-C 1-5 alkylpiperazin-1-yl, or di(C 1-5 alkyl)amino, provided that when R 19 is cyano, then j is 0),
wherein p and q are each independently 2 or 3, and
Z is —O— or —NR 20 — (wherein R 20 is a hydrogen atom, C 1-5 alkylsulfonyl, C 1-5 alkanoyl, C 1-5 alkoxycarbonyl, or C 1-5 alkyl optionally substituted by cyano or C 1-5 alkoxy), or
wherein r and t are each independently 1 or 2, and
W is a hydrogen atom, hydroxy, C 1-5 alkoxy, C 1-5 alkanoyloxy, carboxyl.
6 . The method of claim 5 , wherein, in the quinazoline derivative of the aforementioned formula (I), R 2 is R 27 SO 2 NH— (wherein R 27 is C 1-5 alkyl), C 1-5 alkoxy or
wherein each symbol is as defined above.
7 . The method of claim 6 , wherein, in the quinazoline derivative of the aforementioned formula (I), n is 1 or 2, and R 1 is a halogen atom, cyano, C 1-5 alkyl, C 1-5 alkoxy, —NR 14 R 15 (wherein R 14 and R 15 are each independently a hydrogen atom, C 1-5 alkyl, C 1-5 alkanoyl or C 1-5 alkylsulfonyl), C 2-5 alkynyl, or C 1-5 alkanoyl.
8 . The method of claim 7 , wherein, in the quinazoline derivative of the aforementioned formula (I), n is 2, R 1 is a halogen atom, R 2 is
R 3 is
wherein R 8 and R 9 are each C 1-5 alkyl optionally substituted by C 1-5 alkoxy, and
Y is —N(R 16 )—(CH 2 ) 2 —R 19 (wherein R 16 is C 1-5 alkyl optionally substituted by C 1-5 alkoxy, and R 19 is di(C 1-5 alkyl)amino), or
wherein R 20 is C 1-5 alkyl optionally substituted by C 1-5 alkoxy.
9 . The method of claim 8 , wherein the quinazoline derivative is N-{4-[(3-chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazinyl)-1-butynyl]-6-quinazolinyl}acrylamide bis(4-methylbenzenesulfonate).
10 . (canceled)
11 . The method of claim 1 , wherein the disease involving a heat shock protein is a hormone-dependent disease, a hematopoietic tumor or a malignant soft tissue tumor.
12 . The method of claim 11 , wherein the hormone-dependent disease is prostatic hyperplasia, endometriosis or a hormone-sensitive cancer.
13 . The method of claim 12 , wherein the hormone-sensitive cancer is a hormone-sensitive breast cancer, a hormone-sensitive prostate cancer or a hormone-sensitive endometrial cancer.
14 . The method of claim 11 , wherein the hematopoietic tumor is leukemia, malignant lymphoma or myeloma.
15 . The method of claim 11 , wherein the malignant soft tissue tumor is osteosarcoma or soft tissue sarcoma.
16 - 21 . (canceled)