Patent Application
20090209537
The present invention relates to an Aurora inhibitor which comprises, as an active ingredient, an indazole derivative or a pharmaceutically acceptable salt thereof, and the like.
Auroras are serine/threonine kinases that become active during a cell division phase (G2/M phase). It has been reported that Auroras are involved in centrosome duplication, chromosome separation, cytokinesis, etc. Three subtypes of Auroras, namely, types A, B, and C, are known. Among these, Aurora A is located on chromosome 20q13, amplification of which is reported in a variety of cancers. Not only overexpression of Aurora A in breast cancer, colon cancer, bladder cancer, pancreatic cancer, gastric cancer, etc., has been identified at a high frequency but also a correlation between Aurora A and malignancy or prognosis has been reported [Trends in Cell Biology, vol. 9, p. 454 (1999); British Journal of Cancer, vol. 84, p. 824 (2001); and Journal of National Cancer Institute, vol. 94, p. 1320 (2002)]. Overexpression of Aurora B in clinical samples of breast and colon cancer has been reported with Aurora A [Oncogene, vol. 14, p. 2195 (1997); EMBO Journal, vol. 17, p. 3052 (1998)]. With regard to Aurora C, although much of its function remains unknown, expression in cancer cell strains such as breast cancer has been identified [The Journal of Biological Chemistry, vol. 274, p. 7334 (1999)]. These abnormalities in the mitotic kinases are considered to be one of the causes of chromosome instability characteristic of many cancer cells and thus Aurora inhibitors are considered to be useful as therapeutic agents for a variety of cancers such as colon cancer.
As Aurora inhibitors, Hesperadin [The Journal of Cell Biology, vol. 161, p. 281 (2003); US2003/0069299]; ZM447-439 [The Journal of Cell Biology, vol. 161, p. 267 (2003); WO01/21596]; and VX-680 are known. VX-680 has been reported to exhibit antitumor activity in mouse and rat models transplanted with human tumors [Nature Review Cancer, Vol. 4, p. 927, (2004); Nature Medicine, vol. 3, p. 262 (2004)].
Further, various compounds have been reported as indazole derivatives (for example, refer to Patent Documents 1 to 12 and Non-patent Document 1).
Patent Document 1: Japanese Published Unexamined Patent Application (Kokai) No. 32059/1990
Patent Document 2: WO01/53268
Patent Document 3: WO02/10137
Patent Document 4: WO01/02369
Patent Document 5: WO02/083648
Patent Document 6: WO03/101968
Patent Document 7: WO2004/094388
Patent Document 8: WO2004/050088
Patent Document 9: WO2005/0137171
Patent Document 10: WO2005/012257
Patent Document 11: WO2005/012258
Patent Document 12: WO2005/094823
Non-Patent Document 1: Khimiya Geterotsiklicheskikh Soedinenii, vol. 7, pages 957-959 (1978)
An object of the present invention is to provide an Aurora inhibitor which comprises, as an active ingredient, an indazole derivative or a pharmaceutically acceptable salt thereof and the like.
The present invention relates to following (1) to (56).
(1) An Aurora inhibitor which comprises, as an active ingredient, an indazole derivative represented by Formula (I)
(wherein R1 represents substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group) or a pharmaceutically acceptable salt thereof.
(2) An Aurora inhibitor which comprises, as an active ingredient, an indazole derivative represented by Formula (Ia)
[wherein R2 represents CONR4aR4b (wherein R4a and R4b may be the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, or a substituted or unsubstituted heterocyclic group, or R4a and R4b are combined together with the adjacent nitrogen atom thereto to form a substituted or unsubstituted heterocyclic group) or NR5aR5b (wherein R5a represents substituted or unsubstituted lower alkylsulfonyl or substituted or unsubstituted arylsulfonyl and R5b represents a hydrogen atom or substituted or unsubstituted lower alkyl) and R3 represents a hydrogen atom, halogen, cyano, nitro, hydroxy, carboxy, lower alkoxycarbonyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkanoyl, CONR6aR6b (wherein R6a and R6b may be the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl or a substituted or unsubstituted heterocyclic group, or R6a and R6b are combined together with the adjacent nitrogen atom thereto to form a substituted or unsubstituted heterocyclic group) or NR7aR7b (wherein R7a and R7b may be the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkanoyl, substituted or unsubstituted aroyl, substituted or unsubstituted heteroaroyl, substituted or unsubstituted aralkyl, substituted or unsubstituted lower alkylsulfonyl or substituted or unsubstituted arylsulfonyl)], or a pharmaceutically acceptable salt thereof.
(3) The Aurora inhibitor according to (2), wherein R2 is CONR4aR4b (wherein R4a and R4b have the same meanings as defined above, respectively) and R3 is a hydrogen atom.
(4) The Aurora inhibitor according to (2), wherein R2 is NR5aR5b (wherein R5a and R5b have the same meanings as defined above, respectively) and R3 is substituted or unsubstituted lower alkoxy.
(5) The Aurora inhibitor according to (2), wherein R2 is NR5aR5b (wherein R5a and R5b have the same meanings as defined above, respectively) and R3 is a hydrogen atom.
(6) An Aurora inhibitor which comprises, as an active ingredient, an indazole derivative represented by Formula (Ib)
[wherein R8a, R8b and R8c may be the same or different and each represents a hydrogen atom, halogen, nitro, nitroso, carboxy, cyano, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkanoyl, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted aryl, NR9aR9b (wherein R9a and R9b may be the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkanoyl, substituted or unsubstituted aryl, substituted or unsubstituted aroyl, a substituted or unsubstituted heterocyclic group or substituted or unsubstituted heteroaroyl, or R9a and R9b are combined together with the adjacent nitrogen atom thereto to form a substituted or unsubstituted heterocyclic group) or OR10 (wherein R10 represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aroyl or a substituted or unsubstituted heterocyclic group)], or a pharmaceutically acceptable salt thereof.
(7) The Aurora inhibitor according to (6), wherein at least one of R8a, R8b and R8c is NR9aR9b (wherein R9a and R9b have the same meanings as defined above, respectively).
(8) The Aurora inhibitor according to (6), wherein at least one of R8a, R8b and R8c is NR9CR9d (wherein R9c and R9d may be the same or different and each represents a hydrogen atom or substituted or unsubstituted lower alkanoyl, or R9c and R9d are combined together with the adjacent nitrogen atom thereto to form a substituted or unsubstituted heterocyclic group).
(9) The Aurora inhibitor according to (6), wherein at least one of R8a, R8b and R8c is OR10 (wherein R10 has the same meaning as defined above).
(10) The Aurora inhibitor according to (6), wherein at least one of R8a, R8b and R8c is OR10a (wherein R10a represents substituted or unsubstituted lower alkyl).
(11) An Aurora inhibitor which comprises, as an active ingredient, an indazole derivative represented by Formula (Ib-1)
(wherein R8a, R9c and R9d have the same meanings as defind above, respectively) or a pharmaceutically acceptable salt thereof.
(12) An Aurora inhibitor which comprises, as an active ingredient, an indazole derivative represented by Formula (Ib-2)
(wherein R8a and R10a have the same meanings as defind above, respectively) or a pharmaceutically acceptable salt thereof.
(13) An Aurora inhibitor which comprises, as an active ingredient, an indazole derivative represented by Formula (Ic)
{wherein R11 represents a substituted or unsubstituted heterocyclic group [substituent(s) in the substituted heterocyclic group may be the same or different, are 1 to 3 in number, and are oxo, formyl, carboxy, lower alkoxycarbonyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, CONR12aR12b (wherein R12a and R12b may be the same or different and each represents a hydrogen atom or substituted or unsubstituted lower alkyl), NR13aR13b (wherein R13a and R13b may be the same or different and each represents a hydrogen atom, lower alkanoyl, lower alkoxycarbonyl, aralkyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aroyl or a substituted or unsubstituted heterocyclic group) or —O(CR14aR14b)nO— (wherein R14a and R14b may be the same or different and each represents a hydrogen atom or lower alkyl, n represents 2 or 3, and two terminal oxygen atoms are bonded to the same carbon atom in the heterocyclic group of the substituted heterocyclic group)]} or a pharmaceutically acceptable salt thereof.
(14) The Aurora inhibitor according to (13), wherein substituent(s) in the substituted heterocyclic group are amino, oxo, lower alkoxy, lower alkoxycarbonylamino, aroylamino or lower alkoxycarbonyl-substituted lower alkyl.
(15) The Aurora inhibitor according to (13), wherein R11 is 3-pyridyl.
(16) An Aurora A inhibitor which comprises, as an active ingredient, the indazole derivative or the pharmaceutically acceptable salt thereof described in any one of (1) to (15).
(17) An Aurora B inhibitor which comprises, as an active ingredient, the indazole derivative or the pharmaceutically acceptable salt thereof described in any one of (1) to (15).
(18) An Aurora C inhibitor which comprises, as an active ingredient, the indazole derivative or the pharmaceutically acceptable salt thereof described in any one of (1) to (15).
(19) A therapeutic agent for a disease associated with Aurora which comprises, as an active ingredient, the indazole derivative or the pharmaceutically acceptable salt thereof described in any one of (1) to (15).
(20) The therapeutic agent according to (19), wherein Aurora is Aurora A.
(21) The therapeutic agent according to (19), wherein Aurora is Aurora B.
(22) The therapeutic agent according to (19), wherein Aurora is Aurora C.
(23) The therapeutic agent according to any one of (19) to (22), wherein the disease associated with Aurora is cancer.
(24) The therapeutic agent according to (23), wherein cancer is cancer derived from hematopoietic tumor, mammary cancer, uterine body cancer, uterine cervix cancer, prostatic cancer, bladder cancer, renal cancer, gastric cancer, esophageal cancer, hepatic cancer, biliary tract cancer, colon cancer, rectal cancer, pancreatic cancer, lung cancer, oral cavity and pharynx cancer, osteosarcoma, melanoma or brain neoplasm.
(25) The therapeutic agent for cancer according to (23), wherein cancer is leukemia, myeloma or lymphoma.
(26) The therapeutic agent for cancer according to (23), wherein cancer is solid carcinoma.
(27) The therapeutic agent for cancer according to (23), wherein cancer is mammary cancer, colon cancer, bladder cancer, pancreatic cancer or gastric cancer.
(28) The therapeutic agent for cancer according to (23), wherein cancer is colon cancer or pancreatic cancer.
(29) A method for inhibiting Aurora comprising a step of administering an effective amount of the indazole derivative or the pharmaceutically acceptable salt thereof described in any one of (1) to (15).
(30) A method for inhibiting Aurora A comprising a step of administering an effective amount of the indazole derivative or the pharmaceutically acceptable salt thereof described in any one of (1) to (15).
(31) A method for inhibiting Aurora B comprising a step of administering an effective amount of the indazole derivative or the pharmaceutically acceptable salt thereof described in any one of (1) to (15).
(32) A method for inhibiting Aurora C comprising a step of administering an effective amount of the indazole derivative or the pharmaceutically acceptable salt thereof described in any one of (1) to (15).
(33) A method for treating a disease associated with Aurora comprising a step of administering an effective amount of the indazole derivative or the pharmaceutically acceptable salt thereof described in any one of (1) to (15).
(34) The treating method according to (33), wherein Aurora is Aurora A.
(35) The treating method according to (33), wherein Aurora is Aurora B.
(36) The treating method according to (33), wherein Aurora is Aurora C.
(37) The treating method according to any one of (33) to (36), wherein the disease associated with Aurora is cancer.
(38) The treating method according to (37), wherein cancer is cancer derived from hematopoietic tumor, mammary cancer, uterine body cancer, uterine cervix cancer, prostatic cancer, bladder cancer, renal cancer, gastric cancer, esophageal cancer, hepatic cancer, biliary tract cancer, colon cancer, rectal cancer, pancreatic cancer, lung cancer, oral cavity and pharynx cancer, osteosarcoma, melanoma or brain neoplasm.
(39) The treating method according to (37), wherein cancer is leukemia, myeloma or lymphoma.
(40) The treating method according to (37), wherein cancer is solid carcinoma.
(41) The treating method according to (37), wherein cancer is mammary cancer, colon cancer, bladder cancer, pancreatic cancer or gastric cancer.
(42) The treating method according to (37), wherein cancer is colon cancer or pancreatic cancer.
(43) Use of the indazole derivative or the pharmaceutically acceptable salt thereof described in any one of (1) to (15) for the manufacture of an Aurora inhibitor.
(44) Use of the indazole derivative or the pharmaceutically acceptable salt thereof described in any one of (1) to (15) for the manufacture of an Aurora A inhibitor.
(45) Use of the indazole derivative or the pharmaceutically acceptable salt thereof described in any one of (1) to (15) for the manufacture of an Aurora B inhibitor.
(46) Use of the indazole derivative or the pharmaceutically acceptable salt thereof described in any one of (1) to (15) for the manufacture of an Aurora C inhibitor.
(47) Use of the indazole derivative or the pharmaceutically acceptable salt thereof described in any one of (1) to (15) for the manufacture of a therapeutic agent for a disease associated with Aurora.
(48) The use according to (47), wherein Aurora is Aurora A.
(49) The use according to (47), wherein Aurora is Aurora B.
(50) The use according to (47), wherein Aurora is Aurora C.
(51) The use according to any one of (47) to (50), wherein the disease associated with Aurora is cancer.
(52) The use according to (51), wherein cancer is cancer derived from hematopoietic tumor, mammary cancer, uterine body cancer, uterine cervix cancer, prostatic cancer, bladder cancer, renal cancer, gastric cancer, esophageal cancer, hepatic cancer, biliary tract cancer, colon cancer, rectal cancer, pancreatic cancer, lung cancer, oral cavity and pharynx cancer, osteosarcoma, melanoma or brain neoplasm.
(53) The use according to (51), wherein cancer is leukemia, myeloma or lymphoma.
(54) The use according to (51), wherein cancer is solid carcinoma.
(55) The use according to (51), wherein cancer is mammary cancer, colon cancer, bladder cancer, pancreatic cancer or gastric cancer.
(56) The use according to (51), wherein cancer is colon cancer or pancreatic cancer.
The present invention provides an Aurora inhibitor which comprises, as an active ingredient, an indazole derivative or a pharmaceutically acceptable salt thereof, and the like.
Hereinafter, compounds represented by Formula (I), (Ia), (Ib), (Ib-1), (Ib-2) and (Ic) are referred to as Compound (I), (Ia), (Ib), (Ib-1), (Ib-2) and (Ic), respectively. The same shall apply to the compounds of the other formula numbers.
In the definitions for each groups in Formula (I), (Ia), (Ib), (Ib-1), (Ib-2) and (Ic):
(i) The halogen includes fluorine, chlorine, bromine, and iodine atoms.
(ii) Examples of the lower alkyl and the lower alkyl moieties of the lower alkoxy, the lower alkoxycarbonyl, the lower alkoxycarbonylamino, the lower alkoxycarbonyl-substituted lower alkyl and the lower alkylsulfonyl include, for example, linear, branched or cyclic alkyl or alkyl consisting of these alkyls in combination, having 1 to 10 carbon atom(s). More specific examples thereof are as follows.
(ii-a) Examples of the linear or branched lower alkyl include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like;
(ii-b) examples of the cyclic lower alkyl include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, noradamantyl, adamantyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.3.0]octyl, bicyclo[3.3.1]nonyl and the like; and
(ii-c) examples of the lower alkyl consisting of linear or branched alkyl and cyclic alkyl in combination include, for example, cyclopropylmethyl, cyclopentylmethyl, cyclooctylethyl and the like.
(iii) The alkylene moiety of the lower alkoxycarbonyl-substituted lower alkyl and the aralkyl has the same meaning as the group formed by removing one hydrogen atom from the linear or branched lower alkyl (ii-a) defined above.
(iv) Examples of the lower alkenyl include, for example, linear or branched alkenyl having 2 to 10 carbon atoms such as vinyl, allyl, 1-propenyl, 1-butenyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 2-hexenyl, 5-hexenyl, 2-decenyl or 9-decenyl.
(v) Examples of the lower alkynyl include, for example, linear or branched alkynyl having 2 to 10 carbon atoms such as ethynyl, 2-propynyl, 3-butynyl, 4-pentynyl, 5-hexynyl or 9-decynyl.
(vi) Examples of the aryl and the aryl moieties of the aralkyl, the aroyl, the aroylamino and the arylsulfonyl include, for example, monocyclic aryl or fused aryl in which two or more rings are fused, and more specific examples include aryl having 6 to 14 carbon atoms as ring-constituting members, such as phenyl, naphthyl, indenyl or anthranyl.
(vii) Examples of the lower alkanoyl include, for example, linear, branched, or cyclic lower alkanyol, or lower alkanoyl consisting of these lower alkanoyls in combination, having 1 to 8 carbon atom(s), such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopropylcarbonyl, cyclopropylmethylcarbonyl, cyclohexylcarbonyl, 1-methylcyclopropylcarbonyl or cycloheptylcarbonyl.
(viii) Examples of the heterocyclic group include, for example, heteroaromatic group, heteroalicyclic group and the like.
(viii-a) Examples of the heteroaromatic group include, for example, monocyclic heteroaromatic group, fused heteroaromatic group in which two or more rings are fused and the like. The type and number of the heteroatom contained in heteroaromatic group are not specifically limited and the heteroaromatic group may contain, for example, one or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. More specific examples include heteroaromatic group having 5 to 14 atoms as ring-constituting members, such as furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, purinyl or coumarinyl.
(viii-b) Examples of the heteroalicyclic group include, for example, monocyclic heteroalicyclic group or fused heteroalicyclic group in which two or more rings are fused. The type and number of the heteroatom contained in heteroalicyclic groups are not specifically limited and the heteroalicyclic group may contain, for example, one or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. More specific examples include, for example, pyrrolidinyl, 2,5-dioxopyrrolidinyl, thiazolidinyl, oxazolidinyl, piperidyl, 1,2-dihydropyridyl, piperazinyl, homopiperazinyl, morpholinyl, thiomorpholinyl, pyrazolinyl, oxazolinyl, dioxolanyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuryl, tetrahydroquinolyl, tetrahydroisoquinolyl, tetrahydroquinoxalinyl, octahydroquinolyl, dihydroindolyl, 1,3-dioxoisoindolinyl and the like.
(ix) Examples of the heterocyclic group formed together with the adjacent nitrogen atom include 5- or 6-membered monocyclic heterocyclic group containing at least one nitrogen atom (the monocyclic heterocyclic group may further contain any other of a nitrogen atom, an oxygen atom and a sulfur atom) and bicyclic or tricyclic fused heterocyclic group containing at least one nitrogen atom in which 3- to 8-membered rings are fused (the fused heterocyclic group may further contain any other of a nitrogen atom, an oxygen atom and a sulfur atom). More specific examples include, for example, pyrrolidinyl, piperidino, piperazinyl, morpholino, thiomorpholino, homopiperidino, homopiperazinyl, tetrahydropyridyl, tetrahydroquinolyl, tetrahydroisoquinolyl and the like.
(x) The heteroaryl moiety in the heteroaroyl has the same meaning as the heteroaromatic group (viii-a) defined above.
(xi) Examples of the substituents in the substituted lower alkyl, the substituted lower alkoxy, the substituted lower alkenyl, the substituted lower alkynyl, the substituted lower alkanoyl, the substituted lower alkoxycarbonyl and the substituted lower alkylsulfonyl which may be the same or different and in number of 1 to 3, include
(xi-a) hydroxy,
(xi-b) lower alkoxy,
(xi-c) oxo,
(xi-d) carboxy,
(xi-e) lower alkoxycarbonyl,
(xi-f) heteroaroyl,
(xi-g) arylsulfonyl,
(xi-h) substituted or unsubstituted aryl (the substituent(s) in the substituted aryl is carboxy, lower alkoxy, lower alkoxycarbonyl or the like),
(xi-i) a substituted or unsubstituted heterocyclic group (the substituent(s) in the substituted heterocyclic group is carboxy, lower alkoxy, lower alkoxycarbonyl or the like),
(xi-j) CONR15aR15b {wherein R15a and R15b may be the same or different and each represents a hydrogen atom or substituted or unsubstituted lower alkyl [the substituent(s) in the substituted lower alkyl, which is 1 to 3 in number, is for example, halogen, hydroxy, oxo, nitro, cyano, carboxy, lower alkanoyl, lower alkoxycarbonyl, aroyl, substituted or unsubstituted lower alkoxy (the substituent(s) in the substituted lower alkoxy, which is 1 to 3 in number, is for example, hydroxy or the like) or the like] or R15a and R15b are combined together with the adjacent nitrogen atom thereto to form a substituted or unsubstituted heterocyclic group [the substituent(s) in the substituted heterocyclic group formed together with the adjacent nitrogen atom, which is 1 to 3 in number, is for example, halogen, hydroxy, oxo, nitro, cyano, carboxy, lower alkanoyl, lower alkoxycarbonyl, aralkyl, aroyl, substituted or unsubstituted lower alkyl (the substituent(s) in the substituted lower alkyl, which is 1 to 3 in number, is for example, hydroxy or the like), substituted or unsubstituted lower alkoxy (the substituent(s) in the substituted lower alkoxy, which is 1 to 3 in number, is for example, hydroxy or the like) or the like]},
(xi-k) NR16aR16b (wherein R16a and R16b have the same meanings as R15a and R15b defined above, respectively),
(xi-l) lower alkanoylamino,
(xi-m) N-(lower alkanoyl)-N-(lower alkyl)amino, and the like.
In the definition of the substituents (xi) in the substituted lower alkyl, the substituted lower alkoxy, the substituted lower alkenyl, the substituted lower alkynyl, the substituted lower alkanoyl, the substituted lower alkoxycarbonyl and the substituted lower alkylsulfonyl, the halogen has the same meaning as (i) defined above; the lower alkyl and the lower alkyl moiety of the lower alkoxy, the lower alkoxycarbonyl and the N-(lower alkanoyl)-N-(lower alkyl)amino have the same meanings as (ii) defined above; the alkylene moiety of the aralkyl has the same meaning as (iii) defined above; the aryl and the aryl moiety of the aralkyl, the aroyl and the arylsulfonyl have the same meanings as (vi) defined above; the lower alkanoyl and the lower alkanoyl moiety of the lower alkanoylamino and the N-(lower alkanoyl)-N-(lower alkyl)amino have the same meanings as (vii) defined above; the heterocyclic group has the same meaning as (viii) defined above; the heterocyclic group formed together with the adjacent nitrogen atom has the same meaning as (ix) defined above; and the heteroaroyl has the same meaning as (x) defined above.
(xii) Examples of the substituents in the substituted aryl, the substituted aroyl, the substituted aralkyl, the substituted arylsulfonyl, the substituted heteroaroyl, the substituted heterocyclic group and the substituted heterocyclic group formed together with the adjacent nitrogen atom, which may be the same or different and is 1 to 3 in number, include
(xii-a) halogen,
(xii-b) nitro,
(xii-c) nitroso,
(xii-d) carboxy,
(xii-e) substituted or unsubstituted lower alkyl [the substituent(s) in the substituted lower alkyl has the same meaning as (xi) defined above],
(xii-f) substituted or unsubstituted lower alkenyl [the substituent(s) in the substituted lower alkenyl has the same meaning as (xi) defined above],
(xii-g) substituted or unsubstituted lower alkynyl [the substituent(s) in the substituted lower alkynyl has the same meaning as (xi) defined above],
(xii-h) substituted or unsubstituted lower alkoxycarbonyl [the substituent(s) in the substituted lower alkoxycarbonyl has the same meaning as (xi) defined above],
(xii-i) substituted or unsubstituted lower alkanoyl [the substituent(s) in the substituted lower alkanoyl has the same meaning as (xi) defined above],
(xii-j) substituted or unsubstituted aryl [the substituent(s) in the substituted aryl, which is 1 to 3 in number, is for example, halogen, hydroxy, nitro, cyano, carboxy, lower alkanoyl, lower alkoxycarbonyl, aralkyl, aroyl, substituted or unsubstituted lower alkyl (the substituent(s) in the substituted lower alkyl, which is 1 to 3 in number, is for example hydroxy or the like), substituted or unsubstituted lower alkoxy (the substituent(s) in the substituted lower alkoxy, which is 1 to 3 in number, is for example hydroxy or the like) or the like],
(xii-k) NR17aR17b {wherein R17a and R17b may be the same or different and each represents a hydrogen atom, lower alkyl sulfonyl, substituted or unsubstituted lower alkyl [the substituent(s) in the substituted lower alkyl has the same meaning as (xi) defined above], substituted or unsubstituted lower alkenyl [the substituent(s) in the substituted lower alkenyl has the same meaning as (xi) defined above], substituted or unsubstituted lower alkynyl [the substituent(s) in the substituted lower alkynyl has the same meaning as (xi) defined above], substituted or unsubstituted lower alkoxy [the substituent(s) in the substituted lower alkoxy has the same meaning as (xi) defined above], substituted or unsubstituted lower alkanoyl [the substituent(s) in the substituted lower alkanoyl has the same meaning as (xi) defined above], substituted or unsubstituted aryl [the substituent(s) in the substituted aryl, which is 1 to 3 in number, is for example, halogen, hydroxy, nitro, cyano, carboxy, lower alkanoyl, lower alkoxycarbonyl, aralkyl, aroyl, substituted or unsubstituted lower alkyl (the substituent(s) in the substituted lower alkyl, which is 1 to 3 in number, is for example hydroxy or the like), substituted or unsubstituted lower alkoxy (the substituent(s) in the substituted lower alkoxy, which is 1 to 3 in number, is for example hydroxy or the like) or the like], substituted or unsubstituted aroyl [the substituent(s) in the substituted aroyl, which is 1 to 3 in number, is for example, halogen, hydroxy, nitro, cyano, carboxy, lower alkanoyl, lower alkoxycarbonyl, aralkyl, aroyl, substituted or unsubstituted lower alkyl (the substituent(s) in the substituted lower alkyl, which is 1 to 3 in number, is for example hydroxy or the like), substituted or unsubstituted lower alkoxy (the substituent(s) in the substituted lower alkoxy, which is 1 to 3 in number, is for example hydroxy or the like) or the like] or a substituted or unsubstituted heterocyclic group [the substituent(s) in the substituted heterocyclic group, which is 1 to 3 in number, is for example, halogen, hydroxy, nitro, cyano, carboxy, lower alkanoyl, lower alkoxycarbonyl, aralkyl, aroyl, substituted or unsubstituted lower alkyl (the substituent(s) in the substituted lower alkyl, which is 1 to 3 in number, is for example hydroxy or the like), substituted or unsubstituted lower alkoxy (the substituent(s) in the substituted lower alkoxy, which is 1 to 3 in number, is for example hydroxy or the like) or the like], or R7a and R7b are combined together with the adjacent nitrogen atom thereto to form a substituted or unsubstituted heterocyclic group [the substituent(s) in the substituted heterocyclic group formed with the adjacent nitrogen atom, which is 1 to 3 in number, is for example, halogen, amino, nitro, hydroxy, oxo, cyano, carboxy, lower alkoxycarbonyl, aralkyl, aroyl, heteroaroyl, substituted or unsubstituted lower alkyl (the substituent(s) in the substituted lower alkyl, which is 1 to 3 in number, is for example, hydroxy, lower alkoxy or the like), substituted or unsubstituted lower alkoxy (the substituent(s) in the substituted lower alkoxy, which is 1 to 3 in number, is for example, hydroxy, lower alkoxy or the like), substituted or unsubstituted lower alkanoyl (the substituent(s) in the substituted lower alkanoyl, which is 1 to 3 in number, is for example, amino, hydroxy, lower alkoxy, lower alkanoylamino, N-(lower alkanoyl)-N-(lower alkyl)amino or the like), substituted or unsubstituted heteroalicyclic-carbonyl (the substituent(s) in the substituted heteroalicyclic-carbonyl, which is 1 to 3 in number, is for example, halogen, hydroxy, oxo, lower alkyl, lower alkoxy or the like) or the like]},
(xii-l) CONR18aR18b (wherein R18a and R18b have the same meanings as R17a and R17b defined above, respectively),
(xii-m) OR19 (wherein R19 represents a hydrogen atom, substituted or unsubstituted lower alkyl [the substituent(s) in the substituted lower alkyl has the same meaning as (xi) defined above], substituted or unsubstituted aryl [the substituent(s) in the substituted aryl, which is 1 to 3 in number, is for example, halogen, hydroxy, nitro, cyano, carboxy, lower alkanoyl, lower alkoxycarbonyl, aralkyl, aroyl, substituted or unsubstituted lower alkyl (the substituent(s) in the substituted lower alkyl, which is 1 to 3 in number, is for example hydroxy or the like), substituted or unsubstituted lower alkoxy (the substituent(s) in the substituted lower alkoxy, which is 1 to 3 in number, is for example hydroxy or the like) or the like], a substituted or unsubstituted heterocyclic group [the substituent(s) in the substituted heterocyclic group, which is 1 to 3 in number, is for example, halogen, hydroxy, nitro, cyano, carboxy, lower alkanoyl, lower alkoxycarbonyl, aralkyl, aroyl, substituted or unsubstituted lower alkyl (the substituent(s) in the substituted lower alkyl, which is 1 to 3 in number, is for example hydroxy or the like), substituted or unsubstituted lower alkoxy (the substituent(s) in the substituted lower alkoxy, which is 1 to 3 in number, is for example hydroxy or the like) or the like] or the like},
(xii-n) heteroaroyl,
(xii-o) substituted or unsubstituted heteroalicyclic-carbonyl [the substituent(s) in the substituted heteroalicyclic-carbonyl, which is 1 to 3 in number, is for example, halogen, hydroxy, oxo, lower alkyl, lower alkoxy or the like], and the like.
The substituent(s) in the substituted heterocyclic group, and the substituent(s) in the substituted heterocyclic group formed with the adjacent nitrogen atom may be, in addition to (xii-a) to (xii-o), the following (xii-p) or (xii-q):
(xii-p) oxo
(xii-q)-O(CR20aR20b)naO— (wherein R20a and R20b may be the same or different and each represents a hydrogen atom or lower alkyl, na represents 2 or 3, and the two terminal oxygen atoms are combined to the same carbon atom in the heterocyclic group of the substituted heterocyclic group or the substituted heterocyclic group formed with the adjacent nitrogen atom).
In the definition of the substituents (xii) in the substituted aryl, the substituted aroyl, the substituted aralkyl, the substituted arylsulfonyl, the substituted heteroaroyl, the substituted heterocyclic group and the substituted heterocyclic group formed with the adjacent nitrogen atom, the halogen has the same meaning as (i) defined above; the lower alkyl and the lower alkyl moiety of the lower alkoxy, the lower alkoxycarbonyl and the lower alkylsulfonyl have the same meanings as (ii) defined above; the alkylene moiety of the aralkyl has the same meaning as (iii) defined above; the lower alkenyl has the same meaning as (iv) defined above; the lower alkynyl has the same meaning as (v) defined above; the aryl and the aryl moiety of the aroyl and the aralkyl have the same meanings as (vi) defined above; the lower alkanoyl and the lower alkanoyl moity of the lower alkanoylamino and the N-(lower alkanoyl)-N-(lower alkyl)amino have the same meaning as (vii) defined above; the heterocyclic group has the same meaning as (viii) defined above; the heteroalicyclic moiety of the heteroalicyclic-carbonyl has the same meaning as (viii-b) defined above; the heterocyclic group formed with the adjacent nitrogen atom has the same meaning as (ix) defined above; the heteroaroyl has the same meaning as (x) defined above.
Examples of the pharmaceutically acceptable salts of Compound (I), (Ia), (Ib), (Ib-1), (Ib-2) and (Ic) include, for example, pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like. The acid addition salts include, for example, inorganic acid salts such as hydrochlorides, sulfates and phosphates; and organic acid salts such as acetate, maleate, fumarate, tartrates, citrates, lactates, aspartates, and glutamates. The metal salts include, for example, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; as well as aluminum salts, zinc salts and the like. The ammonium salts include, for example, salts of ammonium, tetramethylammonium and the like. The organic amine addition salts include, for example, morpholine salts, piperidine salts and the like. The amino acid addition salts include, for example, lysine salts, glycine salts, phenylalanine salts and the like.
When it is desired to obtain salts of Compound (I), (Ia), (Ib), (Ib-1), (Ib-2) and (Ic), the salt may be purified as it is, if Compound (I), (Ia), (Ib), (Ib-1), (Ib-2) and (Ic) are obtained in a form of a salt; and if Compound (I), (Ia), (Ib), (Ib-1), (Ib-2) and (Ic) is obtained in a free form, it is dissolved or suspended in an appropriate solvent followed by adding an acid or a base thereto to form a salt.
There can be isomers such as positional isomers, geometrical isomers or optical isomers in Compound (I), (Ia), (Ib), (Ib-1), (Ib-2) and (Ic). All possible isomers including these isomers, and mixtures of the isomers in any ratio can be used as Aurora inhibitor of the present invention.
Compound (I), (Ia), (Ib), (Ib-1), (Ib-2) and (Ic) or the pharmaceutically acceptable salts thereof may exist in a form of adducts to water or various solvents. These adducts can also be used as Aurora inhibitors of the present inhibition.
The disease associated with Aurora includes, for example, cancer of hematopoietic tumor, mammary cancer, uterine body cancer, uterine cervix cancer, prostatic cancer, bladder cancer, renal cancer, gastric cancer, esophageal cancer, hepatic cancer, biliary tract cancer, colon cancer, rectal cancer, pancreatic cancer, lung cancer, oral cavity and pharynx cancer, osteosarcoma, melanoma, brain neoplasm, and the like.
The hematopoietic tumor refers to tumors typically in hemocytes. Examples of pathosis based on the hematopoietic tumor include leukemia such as chronic myeloid leukemia, acute myeloid leukemia, chronic lymphoid leukemia and acute lymphoid leukemia; myeloma such as multiple myeloma; lymphoma; and the like.
Compounds (I), (Ia), (Ib), (Ib-1), (Ib-2) and (Ic) of the present invention can be synthesized, for example, by the method discribed in WO2005/012257, WO2005/012258 and the like.
Example of the compounds (I), (Ia), (Ib), (Ib-1), (Ib-2) and (Ic) used in the present invention include compounds described in the Table 1-1 and 1-2. In the Table 1-1 and 1-2, Me represents methyl.
Next, the pharmacological activity of Compound (I) is described with reference to test examples.
The following procedure was employed to measure the Aurora A inhibitory activity.
A 20 μL sample containing Aurora A protein (Carna Biosciences) at a final concentration of 0.35 mg/mL, 20 mmol/L HEPES (pH 7.4), 0.01% Tween-20, 2 mmol/L DTT, 100 nmol/L PKAtide, 1 mmol/L magnesium acetate, 10 μmol/L adenosine-5′-triphosphate (ATP), 1% dimethylsulfoxide (DMSO), and 1 μmol/L test compound was prepared and enzyme reaction was conducted at room temperature for 60 minutes. Phosphorylation reaction was detected by using IMAP Screening Express kit (Molecular Devices Corp., R8073).
While assuming the observed value of a control to which ATP was added to be 100% and the observed value of a control to which no ATP was added to be 0%, the relative activity (%) of the radio activity of a sample containing a test compound was calculated, and the difference between 100 and the obtained percentage value was assumed to be the Aurora A inhibitory rate (%) of that test compound.
Compounds 4, 6, 7, 8, 9, 10, and 11 exhibited Aurora A inhibitory activity of 90% or higher at a concentration of 1 μmol/L. These results show that Compound (I) has effective Aurora A inhibitory activity.
The following procedure was employed to measure the Aurora B inhibitory activity.
A 20 μL sample containing Aurora B protein (Carna Biosciences) at a final concentration of 0.3 mg/mL, 20 mmol/L HEPES (pH 7.4), 0.01% Tween-20, 2 mmol/L DTT, 100 nmol/L Histone H3, 1 mmol/L magnesium acetate, 10 μmol/L ATP, 1% DMSO, and 1 μmol/L test compound was prepared and enzyme reaction was conducted at room temperature for 60 minutes. Phosphorylation reaction was detected by using IMAP Screening Express kit (Molecular Devices Corp., R8073).
While assuming the observed value of a control to which ATP was added to be 100% and the observed value of a control to which no ATP was added to be 0%, the relative activity (%) of the radio activity of a sample containing a test compound was calculated, and the difference between 100 and the obtained percentage value was assumed to be the Aurora B inhibitory rate (%) of that test compound.
Compounds 4, 6, 7, 8, 9, 10, and 11 exhibited Aurora B inhibitory activity of 90% or higher at a concentration of 1 μmol/L. These results show that Compound (I) has effective Aurora B inhibitory activity.
The following procedure was employed to measure the Aurora C inhibitory activity.
A 20 μL sample containing Aurora C protein (Carna Biosciences) at a final concentration of 1 mg/mL, 20 mmol/L HEPES (pH 7.4), 0.01% Tween-20, 2 mmol/L DTT, 100 nmol/L S6K (AKRRRLSSKRAK(FITC-NH2)), 1 mmol/L magnesium acetate, 10 μmol/L ATP, 1% DMSO, and 1 μmol/L test compound was prepared and enzyme reaction was conducted at room temperature for 60 minutes. Phosphorylation reaction was detected by using IMAP Screening Express kit (Molecular Devices Corp., R8073).
While assuming the observed value of a control to which ATP was added to be 100% and the observed value of a control to which no ATP was added to be 0%, the relative activity (%) of the radio activity of a sample containing a test compound was calculated, and the difference between 100 and the obtained percentage value was assumed to be the Aurora C inhibitory rate (%) of that test compound.
Compounds 8 and 9 exhibited Aurora C inhibitory activity of 90% or higher at a concentration of 1 mol/L. These results show that Compound (I) has effective Aurora C inhibitory activity.
The cytostatic rate of Compound (I) against a human pancreatic cancer cell line (MIA-PaCa-2) was measured according to the following procedure.
MIA-PaCa-2 cells were cultured in a minimum essential medium (MEM) (GIBCO) containing a 10% fetal calf serum (FCS).
Each well of a TC Microwell 96F plate (Nalge Nunc) was inoculated with 50 μL of MIA-PaCa-2 cells at a density of 1000 cells/well, and the cells were incubated at 37° C. for 24 hours in a 5% carbon dioxide gas incubator. To each well, 50 μL of a solution containing a test compound prepared by stepwise dilution with the incubation medium of the respective cells was added and the resulting mixture was again incubated at 37° C. for 72 hours in a 5% carbon dioxide gas incubator. To each well, 10 μL of a WST-1 reagent (4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate sodium salt) (Roche Diagnostics K. K.) was added, followed by incubation at 37° C. for 2 hours and analysis with a microplate spectrometer, SpectraMax 340PC (Molecular Devices) to determine the absorbance at 450 nm (reference wavelength: 690 nm). The cytostatic rate was determined from the equation below by assuming the absorbance of the well containing cells similarly cultured by adding a solvent of the test compound solution to be 100%. Furthermore, the observed absorbance of a blank to which WST-1 was added immediately after addition of the solvent was used.
Compounds 4, 6, 7, 8, 9, 10, and 11 exhibited growth inhibitory activity of 50% or higher at a concentration of 10 μmol/L. These results show that Compound (I) of the present invention exhibits cytostatic activity against a human pancreatic cancer cell line MIA-PaCa-2.
Compounds (I), (Ia), (Ib), (Ib-1), (Ib-2) and (Ic), or pharmaceutically acceptable salts thereof may be used as it is or in various pharmaceutical forms depending upon the pharmacological effect, purpose of administration, etc. A pharmaceutical composition of the present invention can be manufactured by uniform mixing of Compounds (I), (Ia), (Ib), (Ib-1), (Ib-2) and (Ic), or pharmaceutically acceptable salts thereof in an amount which is effective as an active ingredient with pharmaceutically acceptable carriers. These carriers can have forms in a wide range according to desired dosage form for administration. It is preferred that the pharmaceutical composition is in a unit dosage form for oral administration or parental administration such as injection.
In the manufacture of tablets, excipient such as lactose and mannitol, disintegrator such as starch, lubricant such as magnesium stearate, binder such as polyvinyl alcohol and hydroxypropyl cellulose, and surfactant such as sucrose fatty acid esters and sorbitol fatty acid esters, etc. may be used in accordance with a conventional procedure. Tablets containing 1 to 200 mg of an active ingredient per tablet are preferred.
In the manufacture of injections, water, physiological saline, vegetable oil such as olive oil and peanut oil, solvent such as ethyl oleate and propylene glycol, dissolving agent such as sodium benzoate, sodium salicylate and urethane, isotonizing agent such as sodium chloride and glucose, preservative such as phenol, cresol, p-hydroxybenzoate and chlorobutanol, and antioxidant such as ascorbic acid and sodium pyrosulfite, etc. may be used by a conventional procedure.
Compounds (I), (Ia), (Ib), (Ib-1), (Ib-2) and (Ic), or pharmaceutically acceptable salts thereof can be administered either orally or parentally by means of injection solution, etc. The effective dose and frequency of administration vary depending on the dosage form, age, body weight and symptom of a patient, etc. In general, Compounds (I), (Ia), (Ib), (Ib-1), (Ib-2) and (Ic), or pharmaceutically acceptable salts thereof may preferably be administered in an amount of 0.01 to 100 mg/kg per day.
Compounds 1, 2, 3, 4, 5, 7, 8, 9, 10, 12, 13 and 14 used in the present invention can be synthesized according to examples 5, 2, 22, 38, 54, 69, 70, 64, 74, 59, 51 and 29 of WO2005/012258, respectively. Compounds 6 and 11 can be synthesized according to examples 13 and 158 of WO2005/012257, respectively.
Tablets having the following composition are prepared by a usual method.
250 g of Compound 4, 1598.5 g of mannitol, 100 g of sodium carboxylmethyl starch, 10 g of light anhydrous silicic acid, 40 g of magnesium stearate, and 1.5 g of yellow iron sesquioxide are mixed by an usual method. The resultant mixture is tableted with a tableting machine (Manufactured by Kikusui Seisakusho Ltd., Purepress Correct-12 model) having a punch and die of 8 mm in diameter to prepare tablets (containing 25 mg of an active component per tablet).
Injections having the following composition are prepared by a usual method.
Compound 6 (1 g) and 5 g of D-mannitol are added to distilled water for injection and mixed, and further hydrochloric acid and an aqueous sodium hydroxide solution are added to the mixture to adjust pH to 6. Then, distilled water is added to a total of 1000 mL. Each glass vial is aseptically filled with 2 mL of the resultant mixture to prepare injections (containing 2 mg of an active component per vial).
The present invention provides an Aurora inhibitor which comprises, as an active ingredient, an indazole derivative or a, pharmaceutically acceptable salt thereof, and the like.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2006-180531 | Jun 2006 | JP | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/JP2007/063096 | 6/29/2007 | WO | 00 | 12/16/2008 |
