WO2020262603A1 - Ep2アンタゴニスト - Google Patents
Ep2アンタゴニスト Download PDFInfo
- Publication number
- WO2020262603A1 WO2020262603A1 PCT/JP2020/025187 JP2020025187W WO2020262603A1 WO 2020262603 A1 WO2020262603 A1 WO 2020262603A1 JP 2020025187 W JP2020025187 W JP 2020025187W WO 2020262603 A1 WO2020262603 A1 WO 2020262603A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- amino
- group
- phenyl
- trifluoromethyl
- cyclopropanecarboxylic acid
- Prior art date
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- NJLUBCKHIRJTJI-DHIUTWEWSA-N CC(C)c(c(C(Nc1c(C(F)(F)F)ccc([C@@H](C2)[C@@H]2C(O)=O)c1)=O)ccc1)c1OCCCc1ccccc1 Chemical compound CC(C)c(c(C(Nc1c(C(F)(F)F)ccc([C@@H](C2)[C@@H]2C(O)=O)c1)=O)ccc1)c1OCCCc1ccccc1 NJLUBCKHIRJTJI-DHIUTWEWSA-N 0.000 description 1
- GLEYGEDNIJFQBI-CDNPAEQRSA-N CC[C@H](C)[n]1c(C(Nc2c(C(F)(F)F)ccc([C@@H](C3)[C@@H]3C(O)=O)c2)=O)ccc1CCCc1ccccc1 Chemical compound CC[C@H](C)[n]1c(C(Nc2c(C(F)(F)F)ccc([C@@H](C3)[C@@H]3C(O)=O)c2)=O)ccc1CCCc1ccccc1 GLEYGEDNIJFQBI-CDNPAEQRSA-N 0.000 description 1
- ODTHBFGNSFJOAA-GKBBYZSKSA-N CC[C@H](C)[n]1c(C(Nc2cc(C)cc([C@@H](C3)[C@@H]3C(O)=O)c2)=O)ccc1CCCc1ccccc1 Chemical compound CC[C@H](C)[n]1c(C(Nc2cc(C)cc([C@@H](C3)[C@@H]3C(O)=O)c2)=O)ccc1CCCc1ccccc1 ODTHBFGNSFJOAA-GKBBYZSKSA-N 0.000 description 1
- ODTHBFGNSFJOAA-LZYPDUGYSA-N CC[C@H](C)[n]1c(C(Nc2cc(C)cc([C@@H](C3)[C@H]3C(O)=O)c2)=O)ccc1CCCc1ccccc1 Chemical compound CC[C@H](C)[n]1c(C(Nc2cc(C)cc([C@@H](C3)[C@H]3C(O)=O)c2)=O)ccc1CCCc1ccccc1 ODTHBFGNSFJOAA-LZYPDUGYSA-N 0.000 description 1
- ODTHBFGNSFJOAA-YMSRPXOMSA-N CC[C@H](C)[n]1c(C(Nc2cc([C@H](C3)[C@@H]3C(O)=O)cc(C)c2)=O)ccc1CCCc1ccccc1 Chemical compound CC[C@H](C)[n]1c(C(Nc2cc([C@H](C3)[C@@H]3C(O)=O)cc(C)c2)=O)ccc1CCCc1ccccc1 ODTHBFGNSFJOAA-YMSRPXOMSA-N 0.000 description 1
- ODTHBFGNSFJOAA-XZZVZQAVSA-N CC[C@H](C)[n]1c(C(Nc2cc([C@H](C3)[C@H]3C(O)=O)cc(C)c2)=O)ccc1CCCc1ccccc1 Chemical compound CC[C@H](C)[n]1c(C(Nc2cc([C@H](C3)[C@H]3C(O)=O)cc(C)c2)=O)ccc1CCCc1ccccc1 ODTHBFGNSFJOAA-XZZVZQAVSA-N 0.000 description 1
- AOIZITVVMFSWFT-FGZHOGPDSA-N Cc(cc(cc1)OCCc2ccccc2)c1C(Nc1c(C(F)(F)F)ccc([C@@H](C2)[C@@H]2C(O)=O)c1)=O Chemical compound Cc(cc(cc1)OCCc2ccccc2)c1C(Nc1c(C(F)(F)F)ccc([C@@H](C2)[C@@H]2C(O)=O)c1)=O AOIZITVVMFSWFT-FGZHOGPDSA-N 0.000 description 1
- KQSSLKMXDAIYKO-FGZHOGPDSA-N Cc1cc(OCCc2ccccc2)cc(C)c1C(Nc1c(C(F)(F)F)ccc([C@@H](C2)[C@@H]2C(O)=O)c1)=O Chemical compound Cc1cc(OCCc2ccccc2)cc(C)c1C(Nc1c(C(F)(F)F)ccc([C@@H](C2)[C@@H]2C(O)=O)c1)=O KQSSLKMXDAIYKO-FGZHOGPDSA-N 0.000 description 1
- CIXTWIUAVZLWTF-UHFFFAOYSA-N Cc1cc(OCCc2ccccc2)cc(C)c1C(Nc1cc(CCC(O)=O)ccc1C(F)(F)F)=O Chemical compound Cc1cc(OCCc2ccccc2)cc(C)c1C(Nc1cc(CCC(O)=O)ccc1C(F)(F)F)=O CIXTWIUAVZLWTF-UHFFFAOYSA-N 0.000 description 1
- KQSSLKMXDAIYKO-VXKWHMMOSA-N Cc1cc(OCCc2ccccc2)cc(C)c1C(Nc1cc([C@H](C2)[C@H]2C(O)=O)ccc1C(F)(F)F)=O Chemical compound Cc1cc(OCCc2ccccc2)cc(C)c1C(Nc1cc([C@H](C2)[C@H]2C(O)=O)ccc1C(F)(F)F)=O KQSSLKMXDAIYKO-VXKWHMMOSA-N 0.000 description 1
- AXZLGWKZZWQGCM-WOJBJXKFSA-N OC([C@H](C1)[C@H]1c1cc(NC(c(cc2)c(C(F)(F)F)cc2OCCc2ccccc2)=O)c(C(F)(F)F)cc1)=O Chemical compound OC([C@H](C1)[C@H]1c1cc(NC(c(cc2)c(C(F)(F)F)cc2OCCc2ccccc2)=O)c(C(F)(F)F)cc1)=O AXZLGWKZZWQGCM-WOJBJXKFSA-N 0.000 description 1
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- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Definitions
- salt is a compound or a pharmaceutically acceptable having EP 2 receptor antagonistic activity, and relates to medicaments containing them as active ingredient.
- Prostaglandin E 2 is known as a metabolite in the arachidonic acid cascade, and has cytoprotective action, uterine contraction action, pain threshold lowering action, gastrointestinal peristaltic promotion action, wakefulness action, and gastric acid. It is known to have a secretion inhibitory effect, a blood pressure lowering effect, a diuretic effect, and the like.
- EP 1 receptor there are different subtypes Role respectively, EP 1 receptor, EP 2 receptor, EP 3 receptor is referred to as EP 4 receptor (Non-Patent Document 1).
- the EP 2 receptor is involved in the signal of cAMP, and is therefore known to be involved in the relaxation of the cricothyroid muscles of the trachea and ileum and the dilation of various blood vessels.
- the EP 2 receptor is also known to be involved in the expression of PI3K, Akt, or GSK-3 ⁇ and in IL-1 ⁇ , IL-6, IL-12, IL-23, and IL-27.
- EP 2 receptors suppress MCP-1 production from macrophages, suppress TNF- ⁇ , IL-2, and IFN- ⁇ production from lymphocytes, and anti-inflammatory, vasodilation, and angiogenesis by enhancing IL-10 production.
- EP 2 receptors are thought to be involved in cancer immunoregulation via bone marrow-derived immunosuppressive cells (Myeloid Extended Suppressor Cells), regulatory T cells, and natural killer cells.
- EP 2 receptor anti-inflammatory, neuroprotective has been known to be involved in anti-tumor effect, bound strongly to the EP 2 receptor, compounds having an antagonism, EP 2 receptor Diseases caused by body activation, such as endometriosis, uterine fibroids, menorrhagia, adenomyosis, difficulty menstruation, chronic pelvic pain syndrome, cancer, inflammatory pain, neurogenic pain, headache, migraine , Postoperative pain, interstitial cystitis, uterine fibroids, irritable colon syndrome, Alzheimer's disease, Parkinson's disease, muscular atrophic lateral sclerosis, multiple sclerosis, rheumatism, osteoarthritis, gout, allergic disease, Hypertension, encephalopathy, ischemia, stroke, renal disease, transplant rejection, atherosclerosis, ischemic heart disease, acne vulgaris, asthma, prostatic inflammation, glomerulonephritis, sarcoidosis, vasculitis, and autoimmunity It is considered to be useful for the
- Patent Document 1 the compound represented by the following general formula (A) described in Patent Document 1 is used for the treatment of diseases related to SRS-A, such as allergic diseases, ischemic heart diseases, and inflammation. ing.
- a A represents a hydrogen atom, a phenyl group or a phenoxy group
- n A represents an integer from 3 to 10
- R 1A represents a hydrogen atom or a lower alkoxy group
- X 1A represents -CO-Y 2A- (Y 2A is -NH-, etc.) and the like;
- R 2A represents a hydrogen atom, a halogen, a lower haloalkyl group, etc.
- X 2A represents ⁇ Y 3A ⁇ Y 4A ⁇
- Y 3A represents a single bond or the like
- Y 4A represents an alkylene group consisting of 1 to 6 carbon atoms or the like;
- D A is a carboxy group, a lower alkoxycarbonyl group (an excerpt partially defined group.)).
- EP 2 antagonist for example, a compound represented by the following general formula (B) in Patent Document 2, a compound represented by the following general formula (C) in Patent Document 3, and the like are known.
- a c represents a heteroaryl group ⁇ 12 C5 which may be substituted;
- R 'c represents such -S (O) p -C1 ⁇ C6 alkyl group, p is 0-2;
- R 1c represents a hydrogen atom, a C1-C6 alkyl group, or the like;
- R 2c , R 3c , and R 4c represent hydrogen atoms or halogens, respectively;
- Y c represents ⁇ (CH 2 ) n ⁇ , and n is 2 or 3 (a partial definition of the group is excerpted).
- Patent Document 4 describes methyl 3- [5-( ⁇ [1-tert-butyl-5- (4-fluorophenyl-1H-pyrazole-4-yl] carbonyl ⁇ amino-2-chlorophenyl] methyl propanoate, and 3). -[5-( ⁇ [1-tert-Butyl-5- (4-fluorophenyl-1H-pyrazole-4-yl] carbonyl ⁇ amino-2-chlorophenyl] propanoic acid] is described.
- EP 2 has a potent antagonistic activity for the receptor, it is to find a useful compound as a preventive and / or therapeutic agent for diseases caused by the activation of EP 2 receptor.
- L 1 represents-(CR 38 R 39 )-(CR 40 R 41 )- R 38 , R 39 , R 40 and R 41 independently represent (1) a hydrogen atom, (2) a halogen atom, or (3) a C1-4 alkyl group.
- the C1-4 alkyl groups in R 38 , R 39 , R 40 and R 41 may be independently substituted with halogen atoms.
- the two substituents selected from R 38 , R 39 , R 40 and R 41 are C1-4 alkyl groups, they may be combined with the carbon atoms to be bonded to form a C3-6 saturated carbocycle.
- L 2 represents (1) bond, (2) C1-8 alkylene group, (3) C2-8 alkenylene group, or (4) C2-8 alquinylene group, and the C1-8 alkylene group, C2-8.
- One or two carbon atoms in the alkenylene group and the C2-8 alquinylene group may be replaced by an oxygen atom or a sulfur atom which may be oxidized, and the C1-8 alkylene group and the C2-8 alkenylene group may be replaced.
- the C2-8 alkynylene group may be substituted with 1-8 halogen atoms.
- Y represents (1) a bond, (2) an oxygen atom, or (3) a sulfur atom that may be oxidized.
- R 1 is (1) COOR 10 , (2) SO 3 H, (3) SO 2 NHR 11 , (4) CONHSO 2 R 12 , (5) SO 2 NHCOR 13 , (6) CONR 14 R 15 , (6) Represents a 7) tetrazolyl group, or (8) hydroxamic acid (CONHOH), R 10 , R 11 , R 12 , R 13 , R 14 and R 15 independently represent (1) a hydrogen atom or (2) a C1-4 alkyl group, respectively.
- R 2 represents (1) a hydrogen atom or (2) a C1-4 alkyl group.
- R 3 is (1) halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl group, (4) C2-6 alkynyl group, (5) C1-6 alkoxy group, (6) 3 Represents a -6-membered cyclic group, (7) (3-6-membered cyclic group) -O-, or (8) (3-6-membered cyclic group)-(C1-4alkylene)-. (2) to (8) in R 3 may be replaced with 1 to 9 R 16s .
- R 3 is plural, the plurality of R 3 may be the same or different, R 16 has (1) halogen atom, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C2-6 acyl group, (5) C3-6 cycloalkyl group, (6). Represents a hydroxyl group or (7) -NR 17 R 18 If R 16 is plural, plural R 16 may be the same or different, R 17 and R 18 independently represent (1) a hydrogen atom or (2) a C1-4 alkyl group, respectively.
- R 4 is (1) halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl, (4) C2-6 alkynyl, (5) C1-6 alkoxy group, (6) 3 Represents a -6-membered cyclic group, (7) (3-6-membered cyclic group) -O-, or (8) (3-6-membered cyclic group)-(C1-4alkylene)-.
- R 4 (2) to (8) may be substituted with one to nine R 19, If R 4 is plural, the plurality of R 4 may be the same as or different from each other, R 19 is (1) halogen atom, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C2-6 acyl group, (5) C3-6 cycloalkyl group, (6).
- R 19 is (1) halogen atom, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C2-6 acyl group, (5) C3-6 cycloalkyl group, (6).
- Represents a hydroxyl group or (7) -NR 20 R 21 R 20 and R 21 each independently represent (1) a hydrogen atom or (2) a C1-4 alkyl group.
- R 19 represents a plurality
- the plurality of R 19 may be the same as or different from each other
- R 5 represents (1) hydrogen atom, (2) C3-10 membered heterocycle, or (3) 3-10 membered heterocycle
- the C3-10 membered ring and 3-10 membered heterocycle are 1 to 5 May be replaced with R 22
- L 2 is a bond
- R 5 is not a hydrogen atom.
- R 22 has (1) C1-6 alkyl group, (2) C2-6 alkenyl group, (3) C2-6 alkynyl group, (4) C3-6 cycloalkyl group, (5) C1-6 alkoxy group, (6) C3-6 cycloalkyloxy group, (7) C2-6 acyl group, (8) C2-6 acyloxy group, (9) C1-6 alkylthio group, (10) C3-6 cycloalkylthio group, (11) ) C1-6 alkylsulfinyl group, (12) C3-6 cycloalkylsulfinyl group, (13) C1-6 alkylsulfonyl group, (14) C3-6 cycloalkylsulfonyl group, (15) C1-6 alkoxycarbonyl group, (16) 5-6-membered cyclic group, (17) (5-6-membered cyclic group)-(C1-4alkylene)-, (18) (5-6-membered cyclic group)-(C1-4alkylene) -O -
- R 23 , R 24 , R 25 , R 26 , R 27 and R 28 are independent of (1) hydrogen atom, (2) C1-6 alkyl group, (3) C2-6 acyl group or (4). ) Represents a C1-6 alkylsulfonyl group
- the groups (1) to (19) of R 22 may be substituted with 1 to 9 R 29s .
- R 29 is (1) C1-4 alkyl group, (2) C1-4 alkoxy group, (3) C2-6 acyl group, (4) C3-6 cycloalkyl group, (5) hydroxyl group, (6)- Represents NR 30 R 31 or (7) halogen atom, R 30 and R 31 independently represent (1) a hydrogen atom or (2) a C1-4 alkyl group, respectively.
- Q represents (1) oxygen atom or (2) sulfur atom
- X represents (1) CR 6 or (2) NR 7 .
- R 6 is (1) halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl group, (4) C2-6 alkynyl group, (5) C1-6 alkoxy group, (6) 3 Represents a -6-membered cyclic group, (7) (3-6-membered cyclic group) -O-, or (8) (3-6-membered cyclic group)-(C1-4alkylene)-.
- (2) to (8) in R 6 may be replaced with 1 to 9 R 32 .
- R 32 contains (1) halogen atom, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C2-6 acyl group, (5) C3-6 cycloalkyl group, (6).
- R 33 and R 34 independently represent (1) a hydrogen atom or (2) a C1-4 alkyl group, respectively. If R 32 is plural, plural R 32 may be the same or different, R 7 is a (1) C1-6 alkyl group, (2) C2-6 alkenyl group, (3) C2-6 alkynyl group, (4) 3-6 member cyclic group, or (5) (3-6 member). Cyclic group)-(C1-4alkylene)-represents R 7 may be replaced by 1 to 9 R 35s .
- R 35 is composed of (1) halogen atom, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C2-6 acyl group, (5) C3-6 cycloalkyl group, (6).
- R 35 is plural, a plurality of R 35, may be the same or different
- Ring A represents (1) a benzene ring or (2) a 5-6-membered nitrogen-containing aromatic heterocycle. In ring A
- n represents an integer from 1 to 4 and represents m represents an integer from 0 to 3 and represents However, 3-[3-[(2,6-dimethoxybenzoyl) amino] -4-propoxyphenyl] propanoic acid, Methyl 3- [5-( ⁇ [1-tert-butyl-5- (4-fluorophenyl-1H-pyrazole-4-yl] carbonyl ⁇ amino-2-chlorophenyl] methyl propanoate, 3- [5-( ⁇ [1-tert-Butyl-5- (4-fluorophenyl-1H-pyrazole-4-yl] carbonyl ⁇ amino-2-chlorophenyl] propanoic acid, ⁇ -Ethyl-3- [N- (1'-Phenyl-5'-Methyl-1', 2', 3'-Triazolecarbonyl)] Amino-2,4,6-triiodohydrocinnamic acid, and
- R 6a contains (1) halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl group, (4) C2-6 alkynyl group, (5) C1-6 alkoxy group, (6) ( Represents (3-6 membered cyclic group) -O-, or (7) (3-6 membered cyclic group)-(C1-4alkylene)-. (2) to (7) in R 6a may be replaced with 1 to 9 R 32s .
- R 7a is composed of (1) C1-6 alkyl group, (2) C2-6 alkenyl group, (3) C2-6 alkynyl group, (4) 3-6 member cyclic group, or (5) (3-6 member).
- Cyclic group)-(C1-4alkylene)-represents R 7a may be replaced by 1 to 9 R 35s .
- R 3a , R 3b and R 3c are independently (1) hydrogen atom (2) halogen atom, (3) C1-6 alkyl group, (4) C2-6 alkoxy group, (5) C2-6 alkynyl group. , (6) C1-6 alkoxy group, (7) 3-6 membered cyclic group, (8) (3-6 membered cyclic group) -O-, or (9) (3-6 membered cyclic group)-(C1 -4alkylene)-represents (3) to (9) in R 3a , R 3b and R 3c may be replaced with 1 to 9 R 16s .
- R 3a , R 3b and R 3c represents a substituent other than a hydrogen atom.
- the same symbol as the symbol described in [1] has the same meaning as the symbol described in [1].
- 3-[3-[(2,6-dimethoxybenzoyl) amino] -4-propoxyphenyl] propanoic acid is excluded.
- R 6a contains (1) halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl group, (4) C2-6 alkynyl group, (5) C1-6 alkoxy group, (6) ( Represents (3-6 membered cyclic group) -O-, or (7) (3-6 membered cyclic group)-(C1-4alkylene)-. (2) to (7) in R 6a may be replaced with 1 to 9 R 32s .
- R 7a is composed of (1) C1-6 alkyl group, (2) C2-6 alkenyl group, (3) C2-6 alkynyl group, (4) 3-6 member cyclic group, or (5) (3-6 member).
- Cyclic group)-(C1-4alkylene)-represents R 7a may be replaced by 1 to 9 R 35s .
- R 3a , R 3b and R 3c are independently (1) hydrogen atom (2) halogen atom, (3) C1-6 alkyl group, (4) C2-6 alkoxy group, (5) C2-6 alkynyl group. , (6) C1-6 alkoxy group, (7) 3-6 membered cyclic group, (8) (3-6 membered cyclic group) -O-, or (9) (3-6 membered cyclic group)-(C1 -4alkylene)-represents (3) to (9) in R 3a , R 3b and R 3c may be replaced with 1 to 9 R 16s .
- R 3a , R 3b and R 3c represents a substituent other than a hydrogen atom.
- p represents an integer from 1 to 4
- the same symbol as the symbol described in [1] has the same meaning as the symbol described in [1]. )
- [6] The compound according to any one of [1] to [5] above, wherein ring A is a benzene ring or a 5-membered nitrogen-containing aromatic heterocycle, or a pharmaceutically acceptable salt thereof.
- L 2 is a C1-8 alkylene group, a C2-8 alkenylene group, or a C2-8 alquinylene group, and 1 of the C1-8 alkylene group, a C2-8 alkenylene group, and a C2-8 alquinylene group.
- the ⁇ 2 carbon atoms may be replaced by oxygen atoms, and the C1-8 alkylene group, C2-8 alkenylene group, and C2-8 alquinylene group may be replaced by 1 to 8 halogen atoms.
- R 5 represents a C3-6 carbocycle or a 3-6 membered heterocycle, and the C3-6 carbocycle and the 3-6 membered heterocycle are substituted with 1 to 5 R 22s.
- ring A is a pyrrole ring and Y is a bond, or a pharmaceutically acceptable salt thereof.
- Stuff [15] The pharmaceutical composition according to [14] above, which is an EP 2 receptor antagonist.
- EP 2 is a therapeutic and / or prophylactic agent for diseases caused by activation of the receptor, the [14] or [15]
- the pharmaceutical composition according, [17] Diseases caused by activation of EP 2 receptor are endometriosis, uterine myoma, menorrhagia, adenomyosis, difficulty menstruation, chronic pelvic pain syndrome, cancer, inflammatory pain, neurological factors Sexual pain, headache, migraine, postoperative pain, interstitial cystitis, smooth myoma, irritable colon syndrome, Alzheimer's disease, Parkinson's disease, muscular atrophic lateral sclerosis, multiple sclerosis, rheumatism, osteoarthritis , Gout, allergic disease, hypertension, encephalopathy, ischemia, stroke, renal disease, transplant rejection, atherosclerosis, ischemic heart disease, acne vulgaris, asthma, prostatic inflammation, glomerulonephritis, sarcoidosis , Vascular inflammation, or autoimmune disease, the pharmaceutical composition according to the above [16].
- a disease caused by activation of EP 2 receptor is cancer, and the cancers are breast cancer, ovarian cancer, colon cancer, lung cancer, prostate cancer, head and neck cancer, lymphoma, and malignant black color of vine.
- the compounds of the present invention have strong antagonistic activity against the EP 2 receptor and also have good pharmacokinetic properties (eg, solubility and hepatic microsome stability), thus resulting from activation of the EP 2 receptor. It is a prophylactic and / or therapeutic agent for the disease.
- the halogen atom is a fluorine, chlorine, bromine, and iodine atom.
- the C1-4 alkyl group is a methyl, ethyl, propyl, butyl group, and isomers thereof.
- the C1-6 alkyl group is a methyl, ethyl, propyl, butyl, pentyl, hexyl group, and isomers thereof.
- the C2-6 alkenyl group means, for example, a C2-6 alkenyl group having one or two double bonds, and specifically, ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl. , Hexadienyl groups, and their isomers.
- the C2-6 alkynyl group means, for example, a C2-6 alkynyl group having one or two triple bonds, specifically, ethynyl, propynyl, butynyl, butadynyl, pentynyl, pentadiynyl, hexynyl, Hexadynyl groups and their isomers.
- the C1-4 alkylene group is methylene, ethylene, propylene, butylene group, and isomers thereof.
- the C1-8 alkylene group is methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene group, and isomers thereof.
- the C2-8 alkenylene group means, for example, a C2-6 alkenylene group having one or two double bonds, and is ethenylene, propenylene, butenylene, butadienylene, pentenylene, pentadienylene, hexenylene, hexadienylene, heptenylene. , Heptadienylene, Octenilen, Octadienylene, and their isomers.
- the C2-8 alkynylene group means, for example, a C2-8 alkynylene group having one or two triple bonds, and specifically, ethynylene, propynylene, butynylene, butaziinylene, pentynylene, pentadiinylene, hexynylene, and the like. Hexadinirene, heptinylene, heptadiinylene, octinilene, octadiinylene groups, and isomers thereof.
- the C1-4 alkoxy group is methoxy, ethoxy, propoxy, butoxy group, and isomers thereof.
- the C1-6 alkoxy group is methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy group, and isomers thereof.
- the C1-6 alkylthio group is methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio group, and isomers thereof.
- the C1-6 alkylsulfinyl group is methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, pentylsulfinyl, hexylsulfinyl group, and isomers thereof.
- the C1-6 alkylsulfonyl group is a methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl group, and isomers thereof.
- the C3-6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl group.
- the C3-6 cycloalkyloxy group is cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy group.
- the C3-6 cycloalkylthio group is cyclopropylthio, cyclobutylthio, cyclopentylthio, and cyclohexylthio group.
- the C3-6 cycloalkylsulfinyl group is cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, and cyclohexylsulfinyl group.
- the C3-6 cycloalkylsulfonyl group is a cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, and cyclohexylsulfonyl group.
- the C1-6 alkoxycarbonyl group is a methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl group, and isomers thereof.
- the C1-4 acyl group is a metanoyl, an etanoyl, a propanoyl, a butanoyl group, and isomers thereof.
- the C2-6 acyl group is an etanoyl, propanoyl, butanoyl, pentanoyl, hexanoyl group, and isomers thereof.
- the C2-6 acyloxy group is etanoyloxy, propanoyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy group, and isomers thereof.
- the C3-6 saturated carbocycle is, for example, cyclopropane, cyclobutane, cyclopentane, and cyclohexane ring.
- the 5-membered nitrogen-containing aromatic heterocycle means a 5-membered aromatic heterocycle containing one or more nitrogen atoms, and specifically, pyrol, imidazole, triazole, pyrazole, oxazole, iso. Oxazole, thiazole, and isothiazole rings and the like.
- the 5-6-membered nitrogen-containing aromatic heterocycle means a 5- or 6-membered aromatic heterocycle containing one or more nitrogen atoms, and specifically, pyrrole, imidazole, triazole, and the like. Pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, oxazole, isoxazole, thiazole, and isothiazole rings.
- the 5-6-membered cyclic group represents a C5-6 carbocycle and a 5-6-membered heterocycle.
- Examples of the C5-6 carbocyclic ring include cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, and benzene.
- Examples of the 5-6-membered heterocycle include pyrol, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isooxazole, thiazole, isothiazole, flazan, and oxadiazole.
- the 3-6-membered cyclic group represents a C3-6 carbocycle and a 3-6-membered heterocycle.
- the C3-6 carbocycle includes cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclohexene, cyclobutadiene, cyclopentadiene, cyclohexadiene, and benzene ring.
- the 3-6 membered heterocycle includes aziridine, azetidine, oxylan, oxetane, thielan, thietan, and the 5-6 membered heterocycle.
- the C3-10 carbocycle is referred to as, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclononene, cyclodecene, and the like.
- a hydronaphthalene ring for example, a hydronaphthalene ring.
- the 3-10-membered heterocycle includes, for example, the 5-6-membered heterocycle and aziridine, azetidine, oxylan, oxetane, thiirane, thietan, azepine, diazepine, oxepine, thiepin, oxazepine, oxadiazepine, thiazepine.
- the compound represented by the general formula (IA) is preferably the general formula (I):
- the compound represented by the general formula (IA) is preferably the general formula (IA):
- ring A-1 represents a benzene ring or a 5-membered nitrogen-containing aromatic heterocycle, and other symbols have the same meanings as described above.
- the compound represented by the above, or a pharmaceutically acceptable salt thereof. is there.
- the compound represented by the general formula (IA) is more preferably the general formula (I-1):
- the compound represented by the general formula (IA) is more preferably the general formula (Im) :.
- the compound represented by the general formula (IA) is more preferably the general formula (In):
- the compound represented by the general formula (IA) is more preferably the general formula (IO) :.
- the compound represented by the general formula (IA) is more preferably the general formula (Ip) :.
- the compound represented by the general formula (IA) is more preferably the general formula (Iq) :.
- the compound represented by the general formula (IA) is more preferably the general formula (IC) :.
- the compound represented by the general formula (IA) is preferably the general formula (II):
- R 1 is preferably COOR 10 or CONR 14 R 15 , more preferably COOR 10 , and even more preferably COOH.
- R 10 is preferably a hydrogen atom.
- R 2 is preferably a hydrogen atom.
- R 3 is preferably a halogen atom, a halogen-substituted C1-6 alkyl group, or a halogen-substituted C1-6 alkoxy group, and more preferably a fluorine atom, a chlorine atom, and the like. It is a bromine atom, a methyl group, a methoxy group, or a trifluoromethyl group, most preferably a trifluoromethyl group.
- R 3a , R 3b , and R 3c represents a substituent other than a hydrogen atom.
- R 3b may be a substituent other than a hydrogen atom
- R 3a and / or R 3c may be a hydrogen atom
- R 3c is a substituent other than a hydrogen atom.
- R 3a and / or R 3b may be a hydrogen atom
- R 3a and R 3b may be a substituent other than a hydrogen atom
- R 3c may be a hydrogen atom
- R 3a and R 3c may be a hydrogen atom.
- R 3b may be a hydrogen atom
- R 3b and R 3c may be a substituent other than a hydrogen atom
- R 3a may be a hydrogen atom
- R 3a to R 3c may be a substituent other than a hydrogen atom, but preferably R 3a is a substituent other than a hydrogen atom, and R 3b and / or R 3c is a hydrogen atom. More preferably, R 3a is a substituent other than a hydrogen atom, and R 3b and R 3c are hydrogen atoms.
- the substituent other than the hydrogen atom is preferably a halogen atom, a halogen-substituted C1-6 alkyl group, or a halogen-substituted C1-6 alkoxy group, and more preferably a fluorine atom or a chlorine atom. , Bromine atom, methyl group, methoxy group, or trifluoromethyl group, most preferably a trifluoromethyl group.
- a halogen atom preferably as R 4, a C1-6 alkyl group or C1-6 alkoxy group, more preferably a C1-6 alkyl group, more preferably a methyl group.
- a hydrogen atom R 5 a C3-6 carbocyclic or 3-6 membered heterocyclic ring, more preferably a C3-6 carbocyclic or 3-6 membered heterocyclic ring, or more preferably Is a hydrogen atom, cyclopropane, benzene, or 5-6 membered heterocycle, more preferably a cyclopropane, benzene, imidazole, pyrazole, pyridine, furan, or tetrahydropyran ring, most preferably a benzene ring. .. R 5 may be replaced by 1 to 5 R 22s .
- R 22 is preferably a halogen atom, a hydroxyl group, or a C1-6 alkyl, and more preferably a fluorine atom, a chlorine atom, a hydroxyl group, or a methyl group.
- R 6 is preferably a halogen atom or a C1-6 alkyl group which may be halogen-substituted, more preferably a C1-6 alkyl group, still more preferably a methyl or isopropyl group, and particularly. It is preferably a methyl group.
- R 6a is preferably a halogen atom or a C1-6 alkyl group which may be halogen-substituted, more preferably a C1-6 alkyl group, still more preferably a methyl or isopropyl group, and particularly. It is preferably a methyl group.
- R 7 is C1-6 alkyl group or a 3-6-membered cyclic group, more preferably isopropyl, 2-butyl, 3-pentyl, or cyclopropyl group, more preferably isopropyl, 3 -Pentyl or 2-butyl group, more preferably 2-butyl group.
- R 7 is C1-6 alkyl group or a 3-6-membered cyclic group, more preferably isopropyl, 2-butyl, 3-pentyl, or cyclopropyl group, more preferably isopropyl, 3 -Pentyl or 2-butyl group, more preferably 2-butyl group.
- R 7 does not exist.
- R 7a is preferably a C1-6 alkyl group or a 3-6-membered cyclic group, more preferably an isopropyl, 2-butyl, 3-pentyl, or cyclopropyl group, and more preferably an isopropyl, 3 -Pentyl or 2-butyl group, more preferably 2-butyl group.
- ring A is preferably a C1-6 alkyl group or a 3-6-membered cyclic group, more preferably an isopropyl, 2-butyl, 3-pentyl, or cyclopropyl group, and more preferably an isopropyl, 3 -Pentyl or 2-butyl group, more preferably 2-butyl group.
- R 7a does not exist.
- R 38 , R 39 , R 40 , and R 41 are preferably independent hydrogen atoms or C1-4 alkyl groups, respectively.
- Q is preferably an oxygen atom.
- L 1 is preferably used.
- L 1 is preferably a C3-6 saturated carbocycle.
- the ring A is preferably a benzene ring or a 5-membered nitrogen-containing aromatic heterocycle, more preferably a benzene, pyrrole, or pyrazole ring, and particularly preferably a benzene or pyrrole ring.
- Y is preferably a bond or an oxygen atom.
- the combination of rings A and Y is preferably a combination in which ring A is a benzene ring and Y is an oxygen atom, and ring A is a 5-membered nitrogen-containing aromatic heterocycle (more preferably a pyrrole or pyrazole ring, particularly preferably. Pyrrole ring), a combination in which Y is a bond.
- L 2 is preferably a bond or a C1-8 alkylene group in which one carbon atom may be replaced with an oxygen atom, and more preferably one carbon atom is replaced with an oxygen atom. It is also a good C1-8 alkylene group, more preferably ethylene, propylene, -OCH 2 CH 2- , or -CH 2 OCH 2 CH 2- .
- the ring A-1 is preferably a benzene, pyrrole, or pyrazole ring, and more preferably a benzene or pyrrole ring.
- p is preferably 1 or 2, and more preferably 1.
- m is preferably 0, 1, or 2, and more preferably 0 or 1.
- n is preferably 1, 2, or 3, and more preferably 1.
- R 5 is C3-6 carbocyclic ring or 3-6 membered heterocyclic ring, said C3-6 carbocyclic and 3- 6-membered heterocyclic ring may be substituted with 1-5 R 22, R 1 is COOH are preferred, R 2 is preferably a hydrogen atom.
- the general formula (IA) is preferably R 1 , R 2 , R 3 , R 4 , R 5 , Q, rings A, L 1 , L 2 , X, Y, n, and It is a combination of each preferred definition of m.
- the general formula (I) is preferably R 1 , R 2 , R 3 , R 4 , R 5 , rings A, L 1 , L 2 , X, Y, n, and m, respectively.
- the general formula (I-1) is preferably R 1 , R 2 , R 3 , R 4 , R 5 , R 38 , R 40 , ring A, L 2 , X, Y, p, as described above.
- the general formula (Ib) is preferably R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 1 , L 2 , Y, n, and m, respectively.
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 1 , L 2 , Y, n, and m respectively.
- the general formula (Id) is preferably R 1 , R 2 , R 3 , R 4 , R 5 , R 38 , R 40 , ring A-1, L 2 , X, Y, and so on. It is a combination of preferred definitions of p, n, and m, respectively.
- the general formula (Ie) is preferably R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 38 , R 40 , L 2 , Y, p, n, and so on.
- the general formula (If) is preferably R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 38 , R 40 , L 2 , p, n, and m. Is a combination of preferred definitions of each of the above.
- the general formula (Ig) is preferably R 1 , R 2 , R 3 , R 4 , R 5 , Q, rings A, L 1 , L 2 , X a , Y, n, and so on.
- the general formula (Im) is preferably R 1 , R 2 , R 3 , R 4 , R 5 , R 38 , R 40 , Q, ring A, L 2 , X, Y, and so on. It is a combination of preferred definitions of p, n, and m, respectively.
- the general formula (In) is preferably R 1 , R 2 , R 3 , R 4 , R 5 , R 38 , R 40 , Q, rings A-1, L 2 , X, and so on.
- the general formula (I-o) is preferably R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 38 , R 40 , Q, L 2 , Y, p, as described above. It is a combination of preferred definitions of n and m respectively.
- the general formula (Ip) is preferably R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 38 , R 40 , Q, L 2 , p, n, as described above.
- the general formula (IB) is preferably R 1 , R 2 , R 3a , R 3b , R 3c , R 4 , R 5 , Q, rings A, L 1 , L 2 , X.
- the general formula (IC) is preferably R 1 , R 2 , R 3a , R 3b , R 3c , R 4 , R 5 , R 38 , R 40 , ring A, L 2 , It is a combination of preferred definitions of each of X a , Y, p, and m.
- the general formula (II) is preferably R 1 , R 2 , R 3 , R 4 , R 5 , rings A, L 1 , L 2 , X, Y, n, and m, respectively.
- R 1 , R 2 , R 3 , R 4 , R 5 rings A, L 1 , L 2 , X, Y, n, and m, respectively.
- isomers include all of them unless otherwise specified.
- alkyl groups, alkoxy groups, alkylene groups and the like include linear and branched chains.
- isomers (E, Z, cis, trans isomers) in double bonds, rings, fused rings isomers due to the presence of asymmetric carbon (R, S isomers, ⁇ , ⁇ isomers, enantiomers, diastereomers) , Optically active (D, L, d, l) with optical rotation, polar (highly polar, lowly polar) by chromatographic separation, equilibrium compounds, rotational isomers, mixtures of any proportions thereof, All racemic mixtures are included in the present invention.
- the present invention also includes all isomers due to tautomerism.
- the salt is a pharmaceutically acceptable salt.
- the salt is preferably water-soluble.
- Examples of pharmaceutically acceptable salts include acid addition salts, alkali metal salts, alkaline earth metal salts, ammonium salts, amine salts and the like.
- Acid addition salts include, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, inorganic acid salts such as nitrate, or acetate, lactate, tartrate, benzoic acid.
- Organic acid salts such as salts, citrates, methanesulfonates, ethanesulfonates, trifluoroacetates, benzenesulfonates, toluenesulfonates, ISEthionates, glucronates, or gluconates Can be mentioned.
- alkali metal salt examples include potassium salt and sodium salt.
- alkaline earth metal salts examples include calcium salts and magnesium salts.
- ammonium salt examples include tetramethylammonium salt.
- amine salts include triethylamine salt, methylamine salt, dimethylamine salt, cyclopentylamine salt, benzylamine salt, phenethylamine salt, piperidine salt, monoethanolamine salt, diethanolamine salt, tris (hydroxymethyl) aminomethane salt, and lysine.
- amine salts include triethylamine salt, methylamine salt, dimethylamine salt, cyclopentylamine salt, benzylamine salt, phenethylamine salt, piperidine salt, monoethanolamine salt, diethanolamine salt, tris (hydroxymethyl) aminomethane salt, and lysine.
- examples include salts, arginine salts, and N-methyl-D-glucamine salts.
- the compound of the present invention can be converted into an N-oxide compound by any method.
- the N-oxide compound represents a compound in which the nitrogen atom of the compound represented by the general formula (IA) is oxidized.
- the compound represented by the general formula (IA) and a salt thereof may exist in an unsolvated form, or may exist in a solvated form with a pharmaceutically acceptable solvent such as water or ethanol. May be good.
- the solvate is preferably a hydrate.
- the compound represented by the general formula (IA) and a salt thereof can be converted into a solvate.
- the compound represented by the general formula (IA) can form a co-crystal with an appropriate co-crystal forming agent.
- a pharmaceutically acceptable one formed with a pharmaceutically acceptable co-crystal forming agent is preferable.
- a co-crystal is typically defined as a crystal in which two or more different molecules are formed by intermolecular interactions that differ from ionic bonds. Further, the co-crystal may be a complex of a neutral molecule and a salt.
- Co-crystals can be prepared by known methods, such as by melt crystallization, by recrystallization from a solvent, or by physically grinding the components together. Suitable co-crystal forming agents include those described in WO 2006/007448.
- references to the compounds of the present invention are the compounds represented by the general formula (IA), salts thereof, N-oxides thereof, solvates thereof (eg, hydrates), or co-crystals thereof.
- it includes an N-oxide form of a salt of a compound represented by the general formula (IA), a solvate thereof (for example, a hydrate), or a co-crystal thereof.
- the prodrug of the compound represented by the general formula (IA) refers to a compound that is converted into the compound represented by the general formula (IA) by a reaction with an enzyme, gastric acid, or the like in vivo.
- a prodrug of the compound represented by the general formula (IA) for example, when the compound represented by the general formula (IA) has an amino group, the amino group is acylated, alkylated or phosphorylated.
- the amino group of the compound represented by the general formula (IA) is eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl).
- a compound in which the hydroxyl group is acylated, alkylated, phosphorylated, or booxidized for example, the hydroxyl group of the compound represented by the general formula (IA) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, Fumarylation, alanylation, dimethylaminomethylcarbonylated compound, etc.; when the compound represented by the general formula (IA) has a carboxy group, the compound in which the carboxy group is esterified or amidated.
- the carboxy group of the compound represented by the general formula (IA) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, 1- ⁇ (ethoxy).
- These compounds can be produced by methods known per se.
- the prodrug of the compound represented by the general formula (IA) may be either a hydrated or a non-hydrated product.
- the prodrug of the compound represented by the general formula (IA) is used under physiological conditions as described in Hirokawa Shoten, 1990, "Development of Pharmaceuticals", Vol. 7, “Molecular Design”, pp. 163 to 198. It may be changed to a compound represented by the general formula (IA).
- each atom constituting the compound represented by formula (I-A), the isotopes e.g., 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 16 N, 17 O, It may be replaced with 18 O, 18 F, 35 S, 36 Cl, 77 Br, 125 I, etc.).
- the compound of the present invention represented by the general formula (IA) can be produced by the reaction step formula 1.
- reaction 1-1 represents R 1 which may be protected, and other symbols have the same meanings as described above.
- reaction 1-1 is an amidation reaction.
- the amidation reaction is known, for example. (1) Method using acid halide, (2) Method using mixed acid anhydride, (3) Method using a condensing agent, And so on.
- (1) In the method using acid halide for example, the carboxylic acid is mixed with an acid halide agent (oxalyl chloride, thionyl chloride, etc.) in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) or without a solvent-20.
- an acid halide agent oxalyl chloride, thionyl chloride, etc.
- organic solvent chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.
- the reaction was carried out at ° C to reflux temperature, and the obtained acid halide was subjected to an amine and an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) in the presence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.). It is carried out by reacting at a temperature of 0 to 40 ° C.
- the carboxylic acid is used in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) or in a solvent-free base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropyl, etc.).
- a solvent-free base pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropyl, etc.
- the mixture was reacted with an acid halide (pivaloyl chloride, tosilk chloride, meshyl chloride, etc.) or an acid derivative (ethyl chloroformate, isobutyl chloroformate, etc.) at 0 to 40 ° C. This is done by reacting the acid anhydride with an amine in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) at 0
- carboxylic acid and amine are mixed in an organic solvent (chloroform, dichloromethane, dimethylformamide, diethyl ether, tetrahydrofuran, etc.) or in a solvent-free base (pyridine, triethylamine, dimethylaniline, etc.).
- organic solvent chloroform, dichloromethane, dimethylformamide, diethyl ether, tetrahydrofuran, etc.
- a solvent-free base pyridine, triethylamine, dimethylaniline, etc.
- condensing agents (1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide (EDC), 1,1' 1-Hydroxybenztriazole (HOBt) using -carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodine, 1-propylphosphonic acid cyclic anhydride (1-propanephosphonic acid cyclic anhydride, PPA, etc.) It is carried out by reacting at 0-40 ° C. with or without use.
- reaction 1-2 is a thiolation reaction.
- the thiolation reaction is known, and the compound represented by the general formula 1c is subjected to an organic solvent (for example, tetrahydrofuran, toluene, benzene, acetonitrile, dichloromethane, pyridine, etc.) in the presence or absence of a base (sodium hydrogen carbonate, etc.).
- an organic solvent for example, tetrahydrofuran, toluene, benzene, acetonitrile, dichloromethane, pyridine, etc.
- a base sodium hydrogen carbonate, etc.
- Lawesson's reagent eg, 2,4-bis (4-methoxyphenyl) -1,3,2,4-dithiadiphosphethane-2,4-disulfide
- tetraphosphorus decasulfide di It can be produced by reacting phosphorus pentasulfide, hydrogen sulfide, sulfur, etc.) with a phosphine reagent (for example, trichlorophosphate, etc.) at room temperature to reflux temperature in the presence or absence.
- the compound represented by the general formula (IA) can be produced by subjecting the compound represented by the general formula 1c or 1d to a deprotection reaction as necessary in the reaction step formula 1.
- carboxyl-protecting group examples include methyl, ethyl, tert-butyl, trichloroethyl, benzyl (Bn), phenacyl, p-methoxybenzyl, trityl, 2-chlorotrityl and the like.
- Examples of the protective group for the amino group or the tetrazolyl group include a benzyloxycarbonyl group, a tert-butoxycarbonyl group, an allyloxycarbonyl (Alloc) group and a 1-methyl-1- (4-biphenyl) ethoxycarbonyl (Bpoc) group. , Trifluoroacetyl group, 9-fluorenylmethoxycarbonyl group, benzyl (Bn) group, p-methoxybenzyl group, benzyloxymethyl (BOM) group, 2- (trimethylsilyl) ethoxymethyl (SEM) group and the like. ..
- Protecting groups for hydroxyl groups or hydroxamic acids include, for example, methyl, trityl, methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxymethyl (MEM), 2-tetrahydropyranyl (THP), trimethylsilyl (TMS).
- Triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl, benzoyl, benzyl (Bn), p-methoxybenzyl, allyloxycarbonyl (Allloc) , 2,2,2-Trichloroethoxycarbonyl (Troc) and the like.
- the deprotection reaction is known and can be carried out by the following method. For example (1) Deprotection reaction by alkaline hydrolysis, (2) Deprotection reaction under acidic conditions, (3) Deprotection reaction by hydrogenolysis, (4) Deprotection reaction of silyl group, (5) Deprotection reaction using metal, (6) A deprotection reaction using a metal complex and the like can be mentioned.
- the deprotection reaction by alkali hydrolysis is carried out, for example, in an organic solvent (for example, methanol, tetrahydrofuran, dioxane, etc.), an alkali metal hydroxide (for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), Hydroxides of alkaline earth metals (eg, barium hydroxide, calcium hydroxide, etc.) or carbonates (eg, sodium carbonate, potassium carbonate, etc.) or aqueous solutions thereof or mixtures thereof are used at 0-40 ° C. Will be.
- an organic solvent for example, methanol, tetrahydrofuran, dioxane, etc.
- an alkali metal hydroxide for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.
- Hydroxides of alkaline earth metals eg, barium hydroxide, calcium hydroxide, etc.
- carbonates eg, sodium carbonate, potassium carbonate, etc
- the deprotection reaction under acid conditions is carried out in, for example, an organic acid (for example, acetic acid, trifluoroacetic acid) in an organic solvent (for example, dichloromethane, chloroform, dioxane, ethyl acetate, methanol, isopropyl alcohol, tetrahydrofuran, anisole, etc.). , Methanesulfonic acid, p-tosylic acid, etc.), or inorganic acids (eg, hydrochloric acid, sulfuric acid, etc.) or mixtures thereof (eg, hydrogen bromide / acetic acid, etc.), the presence of 2,2,2-trifluoroethanol. It is carried out at 0-100 ° C. under or in the absence.
- an organic acid for example, acetic acid, trifluoroacetic acid
- organic solvent for example, dichloromethane, chloroform, dioxane, ethyl acetate, methanol, isopropyl
- the deprotection reaction by hydrogenation is performed, for example, as a solvent (for example, ether type (for example, tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, etc.)), an alcohol type (for example, methanol, ethanol, etc.), and a benzene type (for example, for example.
- a solvent for example, ether type (for example, tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, etc.)
- an alcohol type for example, methanol, ethanol, etc.
- a benzene type for example, for example.
- a catalyst for example, palladium-carbon, palladium black, palladium-carbon hydroxide, platinum oxide, lane nickel, etc.
- a hydrogen atmosphere under normal pressure or pressure or in the presence of ammonium formate, in the above mixed solvent, etc. It is carried out at 0 to 200 ° C.
- the deprotection reaction of the silyl group is carried out at 0 to 40 ° C. using, for example, tetrabutylammonium fluoride in an organic solvent miscible with water (for example, tetrahydrofuran, acetonitrile, etc.).
- organic acids eg, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosyl acid, etc.
- inorganic acids eg, hydrochloric acid, sulfuric acid, etc.
- mixtures thereof eg, hydrogen bromide / acetic acid, etc.
- the deprotection reaction using a metal complex is carried out in, for example, an organic solvent (for example, dichloromethane, N, N-dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water or a mixed solvent thereof, and a trap reagent.
- an organic solvent for example, dichloromethane, N, N-dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol, etc.
- tributyltin hydride triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine, etc.
- organic acids eg, acetic acid, formic acid, 2-ethylhexanoic acid, etc.
- organic acid salts eg, 2-ethylhexanoic acid.
- phosphine reagents eg, triphenylphosphine, etc.
- metal complexes eg, tetrakistriphenylphosphine palladium (0), bis dichloride.
- a typical example of the carboxylic acid represented by the general formula 1a can be produced by the reaction process formula 2.
- R x represents a protective group of a carboxylic acid
- Z 1 represents a hydroxyl group or a thiol group
- Z 2 represents a halogen atom or a hydroxyl group
- reaction 2 is known, and when Z 2 is a halogen atom, the compound represented by the general formula 2c can be produced by a halogen substitution reaction.
- Halogen substitution reactions are known, for example, in organic solvents (dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, methyl t-butyl ether, etc.) and hydroxides of alkali metals (sodium hydroxide, potassium hydroxide, etc.) Lithium hydroxide, etc.), hydroxides of alkaline earth metals (barium hydroxide, calcium hydroxide, etc.) or carbonates (sodium carbonate, potassium carbonate, etc.) or aqueous solutions thereof, or a mixture thereof, 0 to 100 ° C. It is done by reacting with.
- organic solvents dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, methyl t-butyl ether, etc.
- alkali metals sodium hydroxide, potassium hydroxide, etc.
- the compound represented by the general formula 2c can be produced by the Mitsunobu reaction.
- the Mitsunobu reaction is known, for example, in an organic solvent (dimethane, diethyl ether, tetrahydrofuran, acetonitrile, benzene, toluene, etc.), an azo compound (diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate, 1,1'-( Azodicarbonyl) dipiperidin, 1,1'-azobis (N, N-dimethylformamide), etc.) and phosphine compounds (triphenylphosphine, tributylphosphine, trimethylphosphine, polymer-supported triphenylphosphine, etc.) This is done by reacting with the compound at 0-60 ° C.
- an organic solvent diimethane, diethyl ether, tetrahydrofuran, acetonitrile, benzene, toluene, etc.
- an azo compound diethy
- the compound represented by the general formula 2d is triflated, and then the compound represented by the general formula 2f is subjected to a coupling reaction using a palladium catalyst. be able to.
- Triflate formation is known and typically in bases (eg, pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.) in organic solvents (eg, dichloromethane, diethyl ether, tetrahydrofuran, acetonitrile, benzene, toluene). It can be carried out by reacting 1,1,1-trifluoro-N- (trifluoromethylsulfonyl) methanesulfonamide or trifluoromethanesulfonic anhydride in the presence of.
- bases eg, pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.
- organic solvents eg, dichloromethane, diethyl ether, tetrahydrofuran, acetonitrile, benzene, toluene. It can
- Examples of the coupling reaction using the palladium catalyst include Suzuki coupling, Stille coupling, Buchwald coupling, Negishi coupling, Heck reaction and Hiyama coupling.
- Triethylamine sodium carbonate, sodium hydrogencarbonate, potassium carbonate, cesium carbonate, tallium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, tetrabutylammonium fluoride, etc.)
- the carboxylic acid represented by the general formula 1a can be produced by carrying out the deprotection reaction of the carboxyl group using the compound represented by the general formula 2c.
- a typical example of the amine compound represented by the general formula 1b can be produced by the reaction process formula 3.
- the coupling reaction using a palladium catalyst can produce a compound represented by the general formula 3d or the general formula 1b by subjecting it to the same reaction conditions as described above.
- the reductive amination reaction is known.
- a reducing agent sodium borohydride, sodium cyanoborohydride, etc.
- It is carried out at a temperature of 0 to 40 ° C. in the presence of sodium cyanoborohydride, sodium borohydride, etc. to produce a compound represented by the general formula 3f or the general formula 1b.
- reaction 4-1 is known and is represented by the general formula 4b by subjecting the compound represented by the general formula 3f and the compound represented by the general formula 4a to the conditions of the Suzuki coupling reaction described above. Can be produced.
- the compound represented by the general formula 3f is converted into a boronic acid ester represented by the general formula 4c by the reaction 4-2, and then the compound represented by the general formula 4d is obtained.
- the reaction 4-3 By carrying out the reaction 4-3 using the above, the amine compound represented by the general formula 4b can be produced.
- Reaction 4-2 is known and can be produced, for example, by performing a Suzuki coupling reaction using bis (pinacolato) diboron.
- Reaction 4-3 is known, and the compound represented by the general formula 4b can be produced by subjecting the compound represented by the general formula 4c and the compound represented by the general formula 4d to the Suzuki coupling reaction.
- the compound represented by the general formula 4e By amidating the amine compound represented by the general formula 4b and the carboxylic acid compound represented by the general formula 1a by the above method, the compound represented by the general formula 4e can be produced.
- the compound represented by the general formula (I-1) is prepared by amidating the compound represented by the general formula 1a and the compound represented by the general formula 3f, and then performing a reaction 4-1 with the compound represented by the general formula 4a. It can also be manufactured by deprotecting as needed.
- the compound represented by the general formula (I-1) is a compound represented by the general formula 4d after amidizing the compound represented by the general formula 1a and the compound represented by the general formula 3f and then performing a reaction 4-2. It can also be produced by carrying out the reaction 4-3 with and deprotecting if necessary.
- Q is an oxygen atom
- ring A is a 5-membered nitrogen-containing aromatic heterocycle
- X is NR 7
- Y is a bond
- L 1 Is a C3-6 saturated carbocycle, ie, general formula (I-2):
- X 1 and X 2 independently represent CH, CR 4 , or nitrogen atom, and other symbols have the same meanings as described above.
- the compounds represented by the above are the reaction steps shown below. It can be manufactured by the formula 5.
- Reaction 5-1 is known and can be carried out by a CH activation reaction using norbornene.
- the compound represented by the general formula 5c is an organic solvent (for example, N, N dimethylacetamide, using the compound represented by the general formula 5a and the compound represented by the general formula 5b.
- a base eg, potassium carbonate, potassium hydrogencarbonate, etc.
- norbornene and a palladium catalyst eg, bis (acetonitrile) dichloropalladium (II), etc.
- a base eg, potassium carbonate, potassium hydrogencarbonate, etc.
- a palladium catalyst eg, bis (acetonitrile) dichloropalladium (II), etc.
- Reaction 5-2 is known in the reaction step formula 5, and the compound represented by the general formula 5e can be produced by subjecting it to the halogen substitution reaction or the Mitsunobu reaction.
- Q is an oxygen atom
- ring A is a 5-membered nitrogen-containing aromatic heterocycle
- X is CR 6
- Y is a bond
- L 1 Is a compound in which is a C3-6 saturated carbocycle, that is, the general formula (I-3):
- reaction step formula 6 the halogen substitution reaction and the carboxylic acid deprotection reaction can be carried out under the same conditions as described above.
- Q is an oxygen atom
- ring A is a benzene ring
- Y is an oxygen atom
- L 1 is a C3-6 saturated carbocycle, that is, , General formula (I-4):
- reaction 7 is known, and when Z 3 is a hydroxyl group, the compound represented by the general formula 7c can be produced by carrying out the above-mentioned Mitsunobu reaction.
- the compound represented by the general formula 7c can be produced by the Ulmann etherification reaction.
- This Ulmann etherification reaction is known, for example, in an organic solvent (benzene, toluene, dimethylformamide, dioxane, tetrahydrofuran, methanol, acetonitrile, dimethoxyethane, acetone, etc.) and a phosphine ligand (triphenylphosphine, 4,5-bis).
- organic solvent benzene, toluene, dimethylformamide, dioxane, tetrahydrofuran, methanol, acetonitrile, dimethoxyethane, acetone, etc.
- a phosphine ligand triphenylphosphine, 4,5-bis
- the compound used in the present invention having an amino group, a carboxy group, or a hydroxyl group is a protective group generally used for these groups, for example, T.I. W. It can be produced by performing a known deprotection reaction after an appropriate reaction step using a compound protected by the protecting group described in Greene, Protective Groups in Organic Synthesis, Wiley, New York, 5th Edition, 2014. it can.
- the compound having optical activity is produced by using a starting material or a reagent having optical activity, or the racemic production intermediate is optically resolved and then led to the compound of the present invention.
- it can be produced by optically resolving a racemic compound of the present invention.
- This optical resolution is known.
- a salt / complex or the like is formed with another optically active compound and recrystallized, and then the target compound is isolated or directly separated using a chiral column or the like. How to do it.
- reaction involving heating can be carried out using a water bath, an oil bath, a sand bath or a microwave, as will be apparent to those skilled in the art.
- a solid-phase supporting reagent supported on a high molecular polymer for example, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.
- a high molecular polymer for example, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.
- the reaction product is prepared by conventional purification means, such as distillation under normal pressure or reduced pressure, high speed liquid chromatography with silica gel or magnesium silicate, thin layer chromatography, ion exchange resins. It can be purified by a scavenger resin or a method such as column chromatography or washing or recrystallization. Purification may be performed on a reaction-by-reaction basis or after the completion of several reactions. [toxicity] Since the compound of the present invention has low toxicity, it can be safely used as a pharmaceutical product.
- An object of the present invention EP 2 and creating a compound having a potent antagonistic activity for the receptor, EP 2 to find a compound useful as a prophylactic and / or therapeutic agent for diseases caused by activation of the receptor Is.
- the compounds of the present invention to show a strong antagonistic activity against EP 2 receptor, diseases caused by the activation of EP 2 receptor, for example, endometriosis, uterine fibroids, menorrhagia, adenomyosis, Difficult menstruation, chronic pelvic pain syndrome, cancer, inflammatory pain, neuropathic pain, headache, postoperative pain, interstitial cystitis, smooth myoma, irritable colon syndrome, Alzheimer's disease, Parkinson's disease, muscle atrophy Sexual sclerosis, multiple sclerosis, rheumatism, osteoarthritis, gout, allergic disease, hypertension, brain damage, ischemia, stroke, renal disease, transplant rejection, atherosclerosis, ischemic heart disease, It is useful as a prophylactic and / or therapeutic agent for acne vulgaris, asthma, prostatic inflammation, glomerulonephritis, sarcoidosis, vasculitis, autoimmune diseases and the like.
- the cancers include, for example, breast cancer, ovarian cancer, colon cancer (eg, colon cancer), lung cancer (eg, non-small cell lung cancer), prostate cancer, head and neck cancer (eg, head and neck cancer).
- autoimmune diseases include amyotrophic lateral sclerosis (ALS), multiple sclerosis, Sjogren's syndrome, systemic lupus erythematosus, AIDS and the like.
- allergic diseases include allergic conjunctivitis, allergic rhinitis, contact dermatitis, psoriasis and the like.
- Headaches include, for example, migraine headaches, tension-type headaches or mixed headaches thereof, or cluster headaches.
- the substance as an active ingredient is usually formulated with a pharmaceutically acceptable carrier such as various additives or solvents. It is administered systemically or topically, orally or parenterally.
- the pharmaceutically acceptable carrier means a substance other than the active ingredient, which is generally used in the preparation of pharmaceutical products.
- the pharmaceutically acceptable carrier preferably has no pharmacological action at the dose of the preparation, is harmless, and does not interfere with the therapeutic effect of the active ingredient.
- the pharmaceutically acceptable carrier can be used for the purpose of enhancing the usefulness of the active ingredient and the preparation, facilitating the formulation, stabilizing the quality, or improving the usability.
- substances such as those described in Yakuji Nippo's 2000 "Encyclopedia of Pharmaceutical Additives" (edited by the Japan Pharmaceutical Additives Association) may be appropriately selected according to the purpose.
- the compound of the present invention is administered to a mammal (preferably a human, more preferably a human patient) in a pharmaceutically effective amount.
- the dose of the compound of the present invention depends on age, body weight, symptoms, desired therapeutic effect, administration route, treatment period, etc., it inevitably fluctuates. Generally, it is administered orally in the range of 0.1 mg to 1000 mg per patient, or parenterally in the range of 0.01 mg to 100 mg per patient. Alternatively, it is continuously administered intravenously.
- the dose varies depending on various conditions, so a dose smaller than the above dose may be sufficient, or it may be necessary beyond the range.
- Dosage forms used for administration include, for example, preparations for oral administration (eg, tablets, capsules, granules, powders, oral solutions, suppositories, oral jelly, etc.), oral preparations (eg, oral tablets, etc.).
- preparations for oral administration eg, tablets, capsules, granules, powders, oral solutions, suppositories, oral jelly, etc.
- oral preparations eg, oral tablets, etc.
- injection formulations eg, injections, etc.
- dialysis formulations eg, dialysis agents, etc.
- inhalation formulations eg, in
- preparations for oral administration include, for example, tablets, capsules, granules, powders, oral solutions, syrups, oral jellies and the like.
- preparations for oral administration include fast-disintegrating preparations in which the release of the active ingredient from the preparation is not particularly adjusted, and enteric-coated preparations in which the release is adjusted according to the purpose by a unique formulation design and manufacturing method. There are release-controlled preparations such as preparations and sustained-release preparations.
- Enteric-coated preparations are designed so that the active ingredient is not released in the stomach but mainly in the small intestine for the purpose of preventing the decomposition of the active ingredient in the stomach or reducing the irritating effect of the active ingredient on the stomach.
- the prepared preparation is usually produced by applying a film using an acid-insoluble enteric base.
- a sustained-release preparation is a preparation in which the release rate, release time, and release site of the active ingredient from the preparation are adjusted for the purpose of reducing the number of administrations or side effects, and is usually an appropriate sustained-release preparation.
- capsules, granules, tablets, etc. are coated with appropriate coating agents such as sugars, sugar alcohols, and polymer compounds for the purpose of facilitating administration or preventing decomposition of the active ingredient. It is also possible to apply a skin.
- Tablets Tablets are solid preparations having a certain shape that are orally administered, and are generally called tablets such as uncoated tablets, film-coated tablets, sugar-coated tablets, multi-layer tablets, and nucleated tablets.
- oral quick-disintegrating tablets, chewable tablets, effervescent tablets, dispersion tablets, dissolving tablets and the like are included.
- Additives such as excipients, binders and disintegrants are added to the active ingredient and mixed to homogenize, granulated by an appropriate method using water or a solution containing a binder, and then a lubricant.
- Film-coated tablets can usually be produced by applying a thin coating to an uncoated tablet with an appropriate coating agent such as a polymer compound.
- Sugar-coated tablets can usually be produced by applying a coating agent containing sugar or sugar alcohol to an uncoated tablet.
- the multi-layer tablet can be produced by stacking powders and granules having different compositions in layers and compression molding by an appropriate method.
- the nucleated tablet can be produced by covering the inner core tablet with an outer layer having a different composition.
- the tablets can also be enteric-coated or sustained-release tablets using suitable known techniques.
- Oral quick-disintegrating tablets, chewable tablets, effervescent tablets, dispersion tablets, and dissolving tablets are tablets that have been given unique functions by appropriate selection of additives, and should be manufactured according to the above-mentioned tablet manufacturing method. Can be done. Intraoral rapid disintegration tablets are tablets that can be rapidly dissolved or disintegrated in the oral cavity and taken; chewable tablets are tablets that are chewed and taken; effervescent tablets are tablets that rapidly foam in water. Dissolved or dispersed tablets; Dispersed tablets are tablets that are dispersed in water and taken; Dissolved tablets are tablets that are dissolved and taken in water. Effervescent tablets can be produced by using an appropriate acidic substance, carbonate, hydrogen carbonate or the like as an additive.
- Capsules are formulations that are filled in capsules or encapsulated with a capsule base, and include hard capsules, soft capsules, and the like. Hard capsules are made by adding additives such as excipients to the active ingredient to make them homogeneous, or granulated or molded by an appropriate method, and then filling the capsules as they are or by lightly molding them. Can be manufactured by Soft capsules are manufactured by encapsulating an active ingredient with an additive, using an appropriate capsule base such as gelatin, which has increased plasticity by adding glycerin, D-sorbitol, etc., into a certain shape. can do. Capsules can be enteric-coated capsules or sustained-release capsules using suitable known techniques, or colorants, preservatives, etc. can be added to the capsule base.
- Granules are preparations that are granulated into granules, and include not only those generally called granules but also effervescent granules and the like.
- the following methods (a), (b), or (c) are usually used: (A) Excipients, binders, disintegrants, or other additives are added to the powdered active ingredient and mixed to homogenize, and then granulated by an appropriate method; (B) Add additives such as excipients to the active ingredient prepared in granules in advance and mix them to make them homogeneous; (C) Add an additive such as an excipient to the active ingredient prepared in advance and mix it, and granulate it by an appropriate method; Is used.
- the granules can be coated with a skin, or can be made into enteric-coated granules or sustained-release granules by using an appropriate known method.
- Effervescent granules can be produced by using an appropriate acidic substance, carbonate, hydrogen carbonate or the like as an additive.
- the effervescent granule refers to a granule that dissolves or disperses while rapidly foaming in water.
- the granules can also be made into fine granules by adjusting the size of the particles.
- the powder is a powdery preparation, and can usually be produced by adding an excipient or other additive to the active ingredient and mixing them to make them homogeneous.
- Oral liquid preparations are liquid or fluid viscous gel-like preparations, and in addition to those generally referred to as oral liquid preparations, elixirs, suspensions, emulsions, limonades, etc. included.
- Oral solutions can usually be prepared by adding an additive and purified water to the active ingredient, mixing and uniformly dissolving, emulsifying or suspending, and filtering if necessary.
- An elixir agent is a clear liquid oral solution containing sweet and aromatic ethanol, usually in solid active ingredient or exudate thereof, ethanol, purified water, flavoring agent, and sucrose, other sugars, or It can be produced by adding a sweetener and dissolving it to make a clear liquid by filtration or other methods.
- a suspending agent is an oral solution in which the active ingredient is finely and homogeneously suspended.
- a suspending agent or other additive and purified water or oil are added to a solid active ingredient and suspended by an appropriate method.
- An emulsion is an oral solution in which the active ingredient is finely and homogeneously emulsified. Usually, it can be produced by adding an emulsifier and purified water to the liquid active ingredient, emulsifying it by an appropriate method, and homogenizing the whole. ..
- the limonade agent is a clear liquid oral liquid agent having sweetness and sourness.
- the syrup agent is a viscous liquid or solid preparation containing a sugar or a sweetener, and includes a syrup agent and the like. Syrups are usually dissolved, mixed, suspended, or emulsified by adding the active ingredient to a solution of white sugar, other sugars, or sweeteners, or a simple syrup, and if necessary, the mixture is boiled and then heated. It can be produced by filtering.
- the syrup preparation refers to a granular or powdery preparation that becomes a syrup when water is added, and is sometimes referred to as a dry syrup.
- the syrup preparation can usually be produced by using a sugar or a sweetener as an additive according to the method for producing granules or powders.
- Oral jelly agent is a non-fluid molded gel-like preparation, and is usually mixed by adding an additive and a polymer gel base to an active ingredient and gelled by an appropriate method. It can be manufactured by molding into a certain shape.
- Injections are solutions, suspensions, emulsions, or solids that are dissolved or suspended before use, which are directly administered to internal tissues or organs such as subcutaneous, intramuscular, or blood vessels.
- powder injections, filled syringes, cartridges, infusions, implantable injections, and persistent injections in addition to what is commonly referred to as injections. Is done.
- the following method (a) or (b) is usually used: (A) The active ingredient as it is, or the active ingredient with an additive added, is dissolved, suspended, or emulsified in water for injection, another aqueous solvent, a non-aqueous solvent, etc.
- the powder injection can be usually produced by treating the powder by aseptic filtration, adding the powder obtained by crystallization or a sterilized additive to the powder, and filling the container for the injection.
- Filled syringes can usually be prepared by preparing a solution, suspension, or emulsion with the active ingredient as is or with the active ingredient and additives and filling the syringe barrel.
- a cartridge agent is an injection that is used by putting a cartridge filled with a chemical solution into a dedicated syringe, and a cartridge filled with a chemical solution is usually a solution of the active ingredient as it is or using an active ingredient and an additive.
- Implantable injection refers to a solid or gel-like injection applied subcutaneously, intramuscularly, etc. using an implantable device or by surgery for the purpose of releasing the active ingredient for a long period of time.
- Implantable injections can usually be prepared by using biodegradable polymeric compounds in pellets, microspheres, or gels.
- a long-acting injection is an injection that is applied intramuscularly for the purpose of releasing the active ingredient over a long period of time.
- the active ingredient is dissolved or suspended in vegetable oil or the like, or a biodegradable polymer compound. It can be produced by preparing a suspension of microspheres using.
- the compound of the present invention 1) Complementing and / or enhancing the prophylactic and / or therapeutic effect of the compound, 2) It may be administered as a concomitant drug in combination with other drugs for improving the dynamics / absorption of the compound, reducing the dose, and / or 3) reducing the side effects of the compound.
- the concomitant drug of the compound of the present invention and another drug may be administered in the form of a combination drug in which both components are mixed in one preparation, or may be administered in the form of separate preparations. When administered as separate preparations, simultaneous administration and staggered administration are included. Further, for administration with a time lag, the compound of the present invention may be administered first and another drug may be administered later, or the other drug may be administered first and the compound of the present invention may be administered later. Each administration method may be the same or different.
- the disease that exerts a preventive and / or therapeutic effect by the above-mentioned concomitant agent is not particularly limited, and may be a disease that complements and / or enhances the preventive and / or therapeutic effect of the compound of the present invention.
- agents for complementing and / or enhancing the preventive and / or therapeutic effect of the compounds of the present invention on cancer include, for example, alkylating agents, antimetabolites, anti-cancer antibiotics, plant preparations, hormonal agents. , Platinum compounds, topoisomerase inhibitors, kinase inhibitors, anti-CD20 antibodies, anti-HER2 antibodies, anti-EGFR antibodies, anti-VEGF antibodies, proteasome inhibitors, HDAC inhibitors, immunomodulators and the like.
- alkylating agent examples include cyclophosphamide, ifosfamide, dacarbazine, temozolomide, nimustine hydrochloride, ranimustine, bendamustine, thiotepa, and carbocon.
- Antimetabolites include, for example, methotrexate, pemetrexed, fluorouracil, tegafur, tegafur uracil, tegafur gimestat otastat potassium, doxifluidine, capecitabine, cytarabine, gemcitabine hydrochloride, fludarabin, neralabine, carmofur, and hydrochloric acid. ..
- anticancer antibiotics examples include mitomycin C, doxorubicin hydrochloride, acralubicin hydrochloride, pyrarubicin hydrochloride, epirubicin, chromomycin A3, bleomycin, peplomycin sulfate, and teralubicin.
- Examples of vegetable preparations include irinotecan hydrochloride, etoposide, vincristine sulfate, vinblastine sulfate, vindesine sulfate, vinorelbine tartrate, docetaxel hydrate, eribulin mesylate, and paclitaxel.
- hormonal agents include sodium estramustin phosphate, flutamide, bicalutamide, goserelin acetate, leuprorelin acetate, tamoxifen citrate, tremiphen citrate, anastrozole, letrozole, exemestane, mepitiostane, medroxyprogesterone acetate, and the like.
- Examples include epithiostanol, phosfestol, fadrosole hydrochloride hydrate, avilateron, fulvestrant, and aminoglutethimide.
- platinum compound examples include carboplatin, cisplatin, nedaplatin, and oxaliplatin.
- topoisomerase inhibitors examples include topotecan and sobzoxane.
- Kinase inhibitors include, for example, EGFR inhibitors erlotinib, gefitinib, afatinib, HER2 inhibitor lapatinib, BCR-ABL inhibitor imatinib, ALK inhibitor crizotinib, multikinase inhibitor legorafenib, etc. And dasatinib and the like.
- anti-CD20 antibody examples include rituximab, ibritumomab, ibritumomab tiuxetan, and ocrelizumab.
- anti-HER2 antibody examples include trastuzumab, trastuzumab emtansine, and pertuzumab.
- anti-EGFR antibodies examples include cetuximab and panitumumab.
- anti-VEGF antibody examples include bevacizumab.
- proteasome inhibitor examples include bortezomib.
- HDAC inhibitors examples include vorinostat.
- immunomodulators examples include thalidomide, lenalidomide, pomalidomide, BCG, and interferon preparations.
- Other drugs may be administered in combination of any two or more.
- agents that complement and / or enhance the prophylactic and / or therapeutic effect of the compounds of the present invention include those found not only to date but also those found in the future based on the above-mentioned mechanism. Is done.
- the solvent in parentheses shown in the NMR section indicates the solvent used for the measurement.
- ACD / Name registered trademark
- Chemdraw Ultra version 12.0, manufactured by Cambridge Soft
- LC-MS / ELSD was performed under the following conditions.
- Condition A Column: Waters Triart C 18 (particle size: 1.9 x 10 -6 m; column length: 30 x 2.0 mm ID); flow velocity: 1.0 mL / min; column temperature: 30 ° C.; mobile phase (A): 0.1 % Trifluoroacetic acid aqueous solution (hereinafter abbreviated as TFA); mobile phase (B): 0.1% TFA-acetoform solution; gradient (state the ratio of mobile phase (A): mobile phase (B)): [0 minutes ] 95: 5; [0.1 minutes] 95: 5; [1.2 minutes] 5:95; [1.4 minutes] 5:95; [1.41 minutes] 95: 5; [1.5 minutes] ] 95: 5; Detector: UV (PDA), ELSD, MS.
- TFA Trifluoroacetic acid aqueous solution
- HPLC retention time indicates the retention time under the condition A described in the LC-MS / ELSD unless otherwise specified.
- Initiator 60 EXP manufactured by Biotage was used as the microwave reactor.
- HPLC high performance liquid chromatography
- Reference Example 2 Ethyl 1- (butane-2-yl) -5- (3-phenylpropyl) -1H-pyrrole-2-carboxylate A toluene (5 mL) solution of the compound (0.27 g) prepared in Reference Example 1. 2-Butanol (0.78 g) and cyanomethylenetributylphosphorane (hereinafter abbreviated as CMBP) (CAS No. 157141-27-0, 0.76 g) were added to the mixture, and the mixture was used at 130 ° C. for 3 hours using a microwave device. Stirred.
- CMBP cyanomethylenetributylphosphorane
- Reference Examples 3-1 to 3-2 By performing the same reaction as in Reference Example 2 ⁇ Reference Example 3 using the corresponding alcohol compound instead of 2-butanol, a title compound having the following physical property values was obtained.
- DIPEA Diisopropylethylamine
- TCPH chloro-N, N, N', N'-tetramethylformamidinium hexafluorophosphate
- Example 1 rel- (1R, 2S) -2- [3-( ⁇ [1-sec-Butyl-5- (3-phenylpropyl) -1H-pyrrole-2-carbonyl] amino) -4- (tri) Fluoromethyl) phenyl] cyclopropanecarboxylic acid racemic mixture
- a 5N aqueous sodium hydroxide solution (0.5 mL) was added to a solution of the compound (95 mg) prepared in Reference Example 8 in tetrahydrofuran (hereinafter abbreviated as THF) (2.5 mL) and methanol (2.5 mL), and 3.5 at room temperature. Stir for hours.
- the reaction mixture was neutralized with 5N hydrochloric acid and extracted with ethyl acetate.
- the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the compound of the present invention (82 mg) having the following physical properties.
- Example 2 rel- (1R, 2S) -2- ⁇ 3-[( ⁇ 1-[(2S) -2-butanyl] -5- (3-phenylpropyl) -1H-pyrrole-2-yl ⁇ carbonyl ) Amino] -4- (trifluoromethyl) phenyl ⁇ cyclopropanecarboxylic acid diastereomer mixture
- Examples 2-1 to 2-4 Ethyl 2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) cyclo using the corresponding aniline derivative instead of 5-bromo-2- (trifluoromethyl) aniline
- the compound of the present invention having the following physical properties was obtained by performing the same operation as in Reference Example 9 ⁇ Reference Example 10 ⁇ Example 2 using propanecarboxylate or the corresponding boronic acid ester.
- Example 2-1 rel- (1R, 2S) -2- ⁇ 3-[( ⁇ 1-[(2S) -2-butanyl] -5- (3-phenylpropyl) -1H-pyrrole-2-yl ⁇ Carbonyl) amino] -5-methylphenyl ⁇ cyclopropanecarboxylic acid diastereomer mixture
- Example 2-2 rel- (1R, 2R) -2- ⁇ 3-[( ⁇ 1-[(2S) -2-butanyl] -5- (3-phenylpropyl) -1H-pyrrole-2-yl ⁇ Carbonyl) amino] -5-methylphenyl ⁇ cyclopropanecarboxylic acid diastereomer mixture
- Example 2-3 rel- (1R, 2S) -2- ⁇ 5-[( ⁇ 1-[(2S) -2-butanyl] -5- (3-phenylpropyl) -1H-pyrrole-2-yl ⁇ Carbonyl) Amino] -2- (Trifluoromethyl) Phenyl ⁇ Cyclopropane Carboxylic Acid Diastereomer Mixture
- Example 2-4 rel- (1R, 2R) -2- ⁇ 5-[( ⁇ 1-[(2S) -2-butanyl] -5- (3-phenylpropyl) -1H-pyrrole-2-yl ⁇ Carbonyl) Amino] -2- (Trifluoromethyl) Phenyl ⁇ Cyclopropane Carboxylic Acid Diastereomer Mixture
- Examples 3-1 to 3-2 Use isopropanol instead of 2-butanol and the corresponding boronic acid ester instead of ethyl 2- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) cyclopropanecarboxylate.
- the compound of the present invention having the following physical property values was obtained by carrying out the same reaction as in Reference Example 2 ⁇ Reference Example 3 ⁇ Reference Example 9 ⁇ Reference Example 10 ⁇ Example 1.
- Example 3-2 (1R, 2R) -2- [3-( ⁇ [1-isopropyl-5- (3-phenylpropyl) -1H-pyrrole-2-yl] carbonyl ⁇ amino) -4- (tri) Fluoromethyl) phenyl] cyclopropanecarboxylic acid
- Reference Example 12 5-iodo-2-methoxyaniline Water (1 mL) and iron powder (1.4 g) were added to a solution of the compound (2.3 g) prepared in Reference Example 11 in acetic acid (10 mL) for 6 hours at 50 ° C. Stirred. The reaction mixture was diluted with MTBE and hexane and filtered through Celite (trade name). The filtrate was washed with 2N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
- Reference Example 13 1-[(2S) -Butan-2-yl] -N- (5-iodo-2-methoxyphenyl) -5- (3-phenylpropyl) -1H-pyrrole-2-carboxamide Reference Example 4
- the same reaction as in Reference Example 8 is carried out by using the compound produced in Reference Example 12 instead of the compound produced in Reference Example 3 and using the compound produced in Reference Example 3-1 instead of the compound produced in Reference Example 3.
- a title compound having the following physical properties was obtained.
- DIPEA 63 mg
- L-menthol 45 mg
- 4-dimethylaminopyridine hereinafter abbreviated as DMAP
- 1- (chloro-1-pyrroli) in a solution of the compound (50 mg) in dichloromethane (1 mL) and acetonitrile (1 mL).
- Dinyl methylene) pyrrolidinium hexafluorophosphate hereinafter abbreviated as CyCIU
- CyCIU Dinyl methylene) pyrrolidinium hexafluorophosphate
- Example 8 (1R, 2S) -2- ⁇ 3-[( ⁇ 5- [2- (benzyloxy) ethyl] -1-[(2S) -2-butanyl] -1H-pyrrole-2-yl ⁇ Carbonyl) amino] -4- (trifluoromethyl) phenyl ⁇ cyclopropanecarboxylic acid
- Reference Example 22 Ethyl 1-[(2S) -butane-2-yl] -5- ⁇ 2-[(2-fluoropyridin-4-yl) oxy] ethyl ⁇ -1H-pyrrole-2-carboxylate
- Reference example CMBP (2.2 g) was added to a toluene (15 mL) solution of the reaction mixture prepared in No. 21 and 2-fluoropyridine-4-ol (CAS No .: 22228-69-5, 1 g), and the mixture was stirred at 90 ° C. for 2 hours.
- Example 9 rel- (1R, 2S) -2-[3- ⁇ [(1-[(2S) -2-butanyl] -5- ⁇ 2-[(2-fluoro-4-pyridinyl) oxy] ethyl] ⁇ -1H-pyrrole-2-yl) carbonyl] amino ⁇ -4- (trifluoromethyl) phenyl] cyclopropanecarboxylic acid diastereomer mixture
- Example 10 (1R, 2S) -2- [3- ⁇ [(1-[(2S) -2-butanyl] -5- ⁇ 2-[(2-chloro-6-fluoro-4-pyridinyl) oxy) ] Ethyl ⁇ -1H-pyrrole-2-yl) carbonyl] amino ⁇ -4- (trifluoromethyl) phenyl] cyclopropanecarboxylic acid
- Examples 10-1 to 10-3 By performing the same operation as in Reference Example 25 ⁇ Example 10 using the corresponding alcohol compound instead of 2-chloro-6-fluoropyridine-4-ol, the compound of the present invention having the following physical property values was obtained. It was.
- Example 10-1 (1R, 2S) -2- ⁇ 3-[( ⁇ 1-[(2S) -2-butanyl] -5- [2- (2-chloro-3,5-difluorophenoxy) ethyl ] -1H-Pyrrole-2-yl ⁇ carbonyl) amino] -4- (trifluoromethyl) phenyl ⁇ cyclopropanecarboxylic acid HPLC retention time (minutes): 1.37; MS (ESI, Pos.): 585 (M + H) + ; 1 1 H-NMR (CDCl 3 ): ⁇ 0.83, 1.42-1.53, 1.61, 1.68-1.80, 1.83-1.97, 2.02-2.16, 2.63-2.77, 3.26-3.33, 4.22-4.30, 4.71-5.33, 6.07-6.14 , 6.47-6.62, 6.65-6.70, 7.11-7.16, 7.50-7.56, 7.90-7.97, 8.14-8.20.
- Example 10-2 (1R, 2S) -2- ⁇ 3-[( ⁇ 1-[(2S) -2-butanyl] -5- [2- (2,4-difluorophenoxy) ethyl] -1H- Pyrrole-2-yl ⁇ carbonyl) amino] -4- (trifluoromethyl) phenyl ⁇ cyclopropanecarboxylic acid HPLC retention time (minutes): 1.32; MS (ESI, Pos.): 551 (M + H) + ; 1 1 H-NMR (CDCl 3 ): ⁇ 0.82, 1.41-1.52, 1.59, 1.69-1.77, 1.83-1.95, 1.98-2.25, 2.61-2.76, 3.16-3.29, 4.27, 4.69-5.28, 6.08, 6.67, 6.74 -6.98, 7.12, 7.48-7.55, 7.94, 8.18.
- Example 10-3 (1R, 2S) -2-[3- ⁇ [(1-[(2S) -2-butanyl] -5- ⁇ 2-[(1-methyl-1H-pyrazole-4-yl) ) Oxy] ethyl ⁇ -1H-pyrrole-2-yl) carbonyl] amino ⁇ -4- (trifluoromethyl) phenyl] cyclopropanecarboxylic acid HPLC retention time (minutes): 1.14; MS (ESI, Pos.): 519 (M + H) + ; 1 1 H-NMR (CDCl 3 ): ⁇ 0.82, 1.40-1.51, 1.58, 1.67-1.75, 1.78-1.92, 1.95-2.21, 2.60-2.74, 3.15, 3.84, 4.14, 4.66-5.21, 6.03, 6.66, 7.06- 7.16, 7.48-7.56, 7.94, 8.19.
- Reference Example 27 2,6-dimethyl-4- (2-phenylethoxy) benzoic acid A 50% potassium hydroxide aqueous solution (4 mL) was added to an NMP (2 mL) solution of the compound (2 g) prepared in Reference Example 26, and the temperature was 120 ° C. Was stirred for 3 hours. The reaction mixture was washed with ethyl acetate and hexane, acidified with hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was slurry-washed with hexane to give the title compound (0.83 g) having the following physical characteristics. HPLC retention time (minutes): 0.98; MS (ESI, Pos.): 271 (M + H) + .
- Example 11 rel- (1R, 2S) -2- [3- ⁇ [2,6-dimethyl-4- (2-phenylethoxy) benzoyl] amino ⁇ -4- (trifluoromethyl) phenyl] cyclopropanecarboxylic Acid racemic mixture
- Examples 11-1 to 11-3 Reference Example 26 ⁇ Reference Example 27 by using the corresponding phenol compound in place of methyl 4-hydroxy-2,6-dimethylbenzoate and using the compound produced in Reference Example 6 instead of the compound produced in Reference Example 4. ⁇ Reference Example 8 ⁇ The compound of the present invention having the following physical property values was obtained by performing the same operation as in Example 1.
- Example 11-1 (1R, 2S) -2- [3- ⁇ [2-methyl-4- (2-phenylethoxy) benzoyl] amino ⁇ -4- (trifluoromethyl) phenyl] cyclopropanecarboxylic acid
- Example 11-2 (1R, 2S) -2- [3- ⁇ [2-chloro-4- (2-phenylethoxy) benzoyl] amino ⁇ -4- (trifluoromethyl) phenyl] cyclopropanecarboxylic acid
- Example 11-3 (1R, 2S) -2- [3- ⁇ [4- (2-phenylethoxy) -2- (trifluoromethyl) benzoyl] amino ⁇ -4- (trifluoromethyl) phenyl] cyclo Propanecarboxylic acid
- Reference Example 30 2,6-dimethyl-4- (3-phenylpropyl) benzoic acid Water (2 mL) and potassium hydroxide (600 mg) were added to the NMP (2 mL) solution of the compound (160 mg) prepared in Reference Example 29. The mixture was stirred at 120 ° C. for 21 hours. 1N Hydrochloric acid was added to the reaction mixture to make it acidic, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (210 mg) having the following physical characteristics. 1 1 H-NMR (CDCl 3 ): ⁇ 1.89-1.97, 2.40, 2.59, 2.65, 6.88, 7.15-7.24, 7.26-7.33.
- Reference Example 31 Suspension of 4- (acetyloxy) -2,6-dimethylbenzoic acid 4-hydroxy-2,6-dimethylbenzoic acid (CAS number: 75056-97-2, 3 g) in ethyl acetate (18 mL) Acetic anhydride (2 mL) and pyridine (1.8 mL) were added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with dilute hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
- Reference Example 32 Benzyl 4-hydroxy-2,6-dimethylbenzoart Add potassium carbonate (50 g) and benzyl bromide (43 g) to a solution of the compound (50 g) prepared in Reference Example 31 in DMF (175 mL) for 3 hours at room temperature. Stirred. Methanol (125 mL) and potassium carbonate (50 g) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with 5N hydrochloric acid and water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
- Reference Example 34 4- [2- (2,4-difluorophenyl) ethoxy] -2,6-dimethylbenzoic acid 10% palladium / in a solution of the compound (1.8 g) prepared in Reference Example 33 in methanol (20 mL). Carbon (0.6 g) was added, and the mixture was stirred at room temperature for 3.5 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite (trade name), and the filtrate was concentrated under reduced pressure to give the title compound (1.4 g) having the following physical characteristics. 1 1 H-NMR (CDCl 3 ): ⁇ 2.40, 3.08, 4.15, 6.57, 6.76-6.88, 7.17-7.28.
- Example 12 (1R, 2S) -2- [3- ⁇ [2,6-dimethyl-4- (3-phenylpropyl) benzoyl] amino ⁇ -4- (trifluoromethyl) phenyl] cyclopropanecarboxylic acid
- Example 13 (1R, 2S) -2- [3-( ⁇ 4- [2- (2,4-difluorophenyl) ethoxy] -2,6-dimethylbenzoyl ⁇ amino) -4- (trifluoromethyl) Phenyl] Cyclopropanecarboxylic acid
- the present invention having the following physical property values by performing the same operation as in Reference Example 35 ⁇ Example 12 using the compound produced in Reference Example 34 instead of the compound produced in Reference Example 30. The compound was obtained.
- Reference Example 37 Ethyl 2- (2,3-dichloro-4-fluoro-5-nitrophenyl) cyclopropane-1-carboxylate
- a solution of the mixture (150 mg) prepared in Reference Example 36 in concentrated sulfuric acid (0.15 mL) A mixture of concentrated sulfuric acid (0.15 mL) and fuming nitric acid (0.07 mL) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 1 hour.
- the reaction mixture was poured into ice and extracted with ethyl acetate.
- the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was used as it was in the next reaction without purification.
- Reference Example 38 Ethyl 2- (5-amino-2,3-dichloro-4-fluorophenyl) cyclopropane-1-carboxylate Using the compound prepared in Reference Example 37 instead of the compound prepared in Reference Example 11. By performing the same operation as in Reference Example 12, a mixture containing the title compound was obtained.
- Examples 14-1 to 14-2 Using the compound produced in Reference Example 27 instead of the compound produced in Reference Example 30, and using the compound produced in Reference Example 38 instead of the compound produced in Reference Example 6, Reference Example 35 ⁇ the same as in Example 1. After performing the above procedure, the compound of the present invention having the following physical property values was obtained by preparative purification by HPLC.
- Example 14-1 rel- (1R, 2S) -2- (2,3-dichloro-5- ⁇ [2,6-dimethyl-4- (2-phenylethoxy) benzoyl] amino ⁇ -4-fluorophenyl ) Cyclopropane Carboxylic Acid Racemic Mixture
- Example 14-2 rel- (1R, 2R) -2- (2,3-dichloro-5- ⁇ [2,6-dimethyl-4- (2-phenylethoxy) benzoyl] amino ⁇ -4-fluorophenyl ) Cyclopropane Carboxylic Acid Racemic Mixture
- a 5N aqueous sodium hydroxide solution (0.05 mL) was added to a solution of the compound (6 mg) prepared in Reference Example 39 in methanol (0.3 mL), and the mixture was stirred at room temperature for 17 hours.
- a 5N aqueous sodium hydroxide solution (0.05 mL) was added to the reaction mixture, and the mixture was stirred for 3 hours.
- DME (0.1 mL) was added and the mixture was stirred for 1 hour.
- a 5N aqueous sodium hydroxide solution (0.1 mL) was added to the reaction mixture, and the mixture was stirred for 22 hours.
- the reaction mixture was neutralized with 5N hydrochloric acid and extracted with ethyl acetate.
- Examples 17-1 to 17-2 3-Bromo-4,5-dichloronitrobenzene was used in place of the compound prepared in Reference Example 11, and the compound prepared in Reference Example 27 was used in place of the compound prepared in Reference Example 30, and ethyl 2- (4,4) was used. , 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) Using the corresponding boronic acid ester instead of cyclopropanecarboxylate Reference Example 12 ⁇ Reference Example 35 ⁇ Reference Example 10 ⁇ Example 1 After performing the same operation as in the above, the compound of the present invention having the following physical properties was obtained by preparative purification by HPLC.
- Example 17-1 rel- (1R, 2S) -2- (2,3-dichloro-5- ⁇ [2,6-dimethyl-4- (2-phenylethoxy) benzoyl] amino ⁇ phenyl) cyclopropanecarboxylic Acid racemic mixture
- Example 17-2 rel- (1R, 2R) -2- (2,3-dichloro-5- ⁇ [2,6-dimethyl-4- (2-phenylethoxy) benzoyl] amino ⁇ phenyl) cyclopropanecarboxylic Acid racemic mixture
- Reference Example 40 N- [5-bromo-2- (trifluoromethyl) phenyl] -2,6-dimethyl-4- (2-phenylethoxy) benzamide
- DIPEA 0.72 g
- phosphorus oxychloride 0.62 g
- Phosphoryl oxychloride 0.12 g was added to the reaction mixture, and the mixture was stirred for 6 hours.
- a 5N aqueous sodium hydroxide solution (1.5 mL) was added to a solution of the compound (500 mg) prepared in Reference Example 42 in THF (1.5 mL) and methanol (1.5 mL) under ice cooling, and the mixture was stirred at 50 ° C. for 1 hour. .. Water was added to the reaction mixture, and the mixture was washed with hexane. 5N hydrochloric acid was added to the aqueous layer to neutralize the mixture, and the mixture was extracted with MTBE. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
- Example 18 By performing the same operation as in Reference Example 42 ⁇ Example 18 using the corresponding iodine compound instead of ethyl (1S, 2S) -2-iodocyclopropanecarboxylate, the compound of the present invention having the following physical property values was obtained. It was. HPLC retention time (minutes): 1.08; MS (ESI, Pos.): 498 (M + H) + ; 1 1 H-NMR (CDCl 3 ): ⁇ 1.43-1.53, 1.68-1.77, 2.10-2.21, 2.34, 2.63-2.76, 3.10, 4.17, 6.59, 7.17, 7.22-7.36, 7.47-7.58, 8.22.
- Examples 20-1 to 20-23 By performing the same operation as in Example 20 using the corresponding alcohol compound instead of 2- (1-methyl-1H-pyrazole-4-yl) ethanol, the compound of the present invention having the following physical property values was obtained. It was.
- Example 20-1 (1R, 2S) -2-[3- ⁇ [4- (2-cyclopropylethoxy) -2,6-dimethylbenzoyl] amino ⁇ -4- (trifluoromethyl) phenyl] cyclopropane carboxylic acid
- Example 20-2 (1R, 2S) -2- ⁇ 3-[(2,6-dimethyl-4-propoxybenzoyl) amino] -4- (trifluoromethyl) phenyl ⁇ cyclopropanecarboxylic acid HPLC retention time ( Minutes): 1.19; MS (ESI, Pos.): 436 (M + H) + ; 1 1 H-NMR (CDCl 3 ): ⁇ 1.04, 1.45-1.53, 1.66-1.87, 2.11-2.26, 2.35, 2.62-2.74, 3.93, 6.60, 7.20, 7.44-7.58, 8.17.
- Example 20-3 (1R, 2S) -2-[3- ⁇ [4- (hexyloxy) -2,6-dimethylbenzoyl] amino ⁇ -4- (trifluoromethyl) phenyl] cyclopropanecarboxylic acid HPLC Retention time (minutes): 1.14; MS (ESI, Pos.): 478 (M + H) + ; 1 1 H-NMR (CDCl 3 ): ⁇ 0.86-0.98, 1.04-1.16, 1.03-1.55, 1.72-1.83, 1.84-1.95, 2.19-2.31, 3.95, 6.53, 7.07-7.14, 7.31-7.39, 7.46-7.57 , 7.67-7.76.
- Example 20-4 (1R, 2S) -2-[3- ⁇ [4- (benzyloxy) -2,6-dimethylbenzoyl] amino ⁇ -4- (trifluoromethyl) phenyl] cyclopropanecarboxylic acid HPLC Retention time (minutes): 1.22; MS (ESI, Pos.): 484 (M + H) + ; 1 1 H-NMR (CDCl 3 ): ⁇ 1.43-1.55, 1.73, 2.14-2.27, 2.36, 2.65-2.76, 5.07, 6.69, 7.20, 7.31-7.46, 7.49-7.59, 8.17.
- Example 20-5 (1R, 2S) -2-[3- ⁇ [4- (2-methoxyethoxy) -2,6-dimethylbenzoyl] amino ⁇ -4- (trifluoromethyl) phenyl] cyclopropanecarboxylic Acid HPLC retention time (minutes): 1.07; MS (ESI, Pos.): 452 (M + H) + ; 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.35-1.43, 1.49-1.59, 2.05-2.15, 2.30, 2.63-2.79, 3.30, 3.60-3.68, 4.08, 6.67, 7.27-7.34, 7.44, 7.58-7.68 , 9.95, 12.03.
- Examples 20-8 (1R, 2S) -2- [3-( ⁇ 4- [2- (2-chlorophenyl) ethoxy] -2,6-dimethylbenzoyl ⁇ amino) -4- (trifluoromethyl) phenyl ] Cyclopropanecarboxylic acid HPLC retention time (minutes): 1.30; MS (ESI, Pos.): 532 (M + H) + ; 1 1 H-NMR (CDCl 3 ): ⁇ 1.43-1.53, 1.67-1.78, 2.18, 2.34, 2.61-2.74, 3.24, 4.20, 6.61, 7.14-7.26, 7.32-7.42, 7.44-7.50, 7.50-7.56, 8.22 ..
- Example 20-11 (1R, 2S) -2- [3-( ⁇ 4- [2- (2,6-difluorophenyl) ethoxy] -2,6-dimethylbenzoyl ⁇ amino) -4- (trifluoro) Methyl) phenyl] cyclopropanecarboxylic acid HPLC retention time (minutes): 1.26; MS (ESI, Pos.): 534 (M + H) + ; 1 1 H-NMR (CDCl 3 ): ⁇ 1.45-1.56, 1.67-1.79, 2.15-2.26, 2.34, 2.65-2.76, 3.18, 4.16, 6.60, 6.83-6.94, 7.14-7.25, 7.45-7.57, 8.19.
- Examples 20-13 (1R, 2S) -2- [3- ⁇ [4- (1H-indazole-5-ylmethoxy) -2,6-dimethylbenzoyl] amino ⁇ -4- (trifluoromethyl) phenyl] Cyclopropanecarboxylic acid HPLC retention time (minutes): 1.09; MS (ESI, Pos.): 524 (M + H) + ; 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.35-1.47, 1.51-1.60, 2.32, 2.65-2.74, 5.21, 6.79, 7.31-7.36, 7.40-7.48, 7.54-7.60, 7.65, 7.84, 8.09, 9.95 , 12.62-13.37.
- Example 20-14 (1R, 2S) -2-[3- ⁇ [2,6-dimethyl-4- (1,2,3,4-tetrahydro-1-naphthalenylmethoxy) benzoyl] amino ⁇ - 4- (Trifluoromethyl) phenyl] cyclopropanecarboxylic acid HPLC retention time (minutes): 1.33; MS (ESI, Pos.): 538 (M + H) + ; 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.34-1.46, 1.49-1.58, 1.62-2.02, 2.04-2.20, 2.28-2.35, 2.65-2.80, 3.16-3.28, 3.99-4.10, 4.15-4.22, 6.73 , 7.07-7.19, 7.29-7.37, 7.46, 7.61-7.70, 9.94, 12.1.
- Example 20-18 (1R, 2S) -2- [3-( ⁇ 4- [2- (2-chloro-1H-imidazol-1-yl) ethoxy] -2,6-dimethylbenzoyl ⁇ amino)- 4- (Trifluoromethyl) phenyl] cyclopropanecarboxylic acid HPLC retention time (minutes): 1.05; MS (ESI, Pos.): 522 (M + H) + ; 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.33-1.47, 1.50-1.59, 2.05-2.18, 2.31, 2.67-2.75, 4.25-4.31, 4.33-4.39, 6.66, 6.91-6.96, 7.30-7.37, 7.38 -7.41, 7.44-7.48, 7.65, 9.95.
- Example 20-21 (1R, 2S) -2- [3-( ⁇ 4- [2- (4-fluorophenyl) ethoxy] -2,6-dimethylbenzoyl ⁇ amino) -4- (trifluoromethyl) Phenyl] cyclopropanecarboxylic acid HPLC retention time (minutes): 1.23; MS (ESI, Pos.): 516 (M + H) + ; 1 1 H-NMR (DMSO-d 6 ): ⁇ 1.38-1.45, 1.50-1.61, 2.08-2.17, 2.31, 2.64-2.73, 3.03, 4.19, 6.68, 7.11-7.19, 7.29-7.42, 7.45, 7.65, 9.94 , 12.06.
- Examples 21-1 to 21-2 By performing the same operation as in Reference Example 45 ⁇ Example 21 using the corresponding chloroform instead of 2,6-dichloropyrazine, the compound of the present invention having the following physical property values was obtained.
- Example 21-1 (1R, 2S) -2- ⁇ 3-[(2,6-dimethyl-4- ⁇ [6- (trifluoromethyl) -2-pyridinyl] oxy ⁇ benzoyl) amino] -4- (Trifluoromethyl) Phenyl ⁇ Cyclopropane Carboxylic Acid
- Example 21-2 (1R, 2S) -2-[3- ⁇ [2,6-dimethyl-4- (pyrazolo [1,5-a] pyrimidin-5-yloxy) benzoyl] amino ⁇ -4-( Trifluoromethyl) phenyl] cyclopropanecarboxylic acid
- Reference Example 48 Carbonate in a DMF (10 mL) solution of 2- ⁇ 4-[(4-methoxybenzyl) oxy] phenyl ⁇ ethanol 4- (2-hydroxyethyl) phenol (CAS number: 501-94-0, 2 g). Potassium (3 g) and 4-methoxybenzyl chloride (CAS number: 824-94-2, 2.5 g) were added, and the mixture was stirred at 50 ° C. for 14 hours. Water was added to the reaction solution, and the precipitated precipitate was collected by filtration.
- reaction mixture is concentrated under reduced pressure, methanol (0.3 mL), THF (0.3 mL) and 5N aqueous sodium hydroxide solution (0.05 mL) are added to the residue, and the mixture is stirred at 50 ° C. for 2 hours and further at room temperature for 21 hours. did.
- the reaction mixture was neutralized with 5N hydrochloric acid and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the obtained residue was used in the next reaction without purification.
- the acetic acid (1 mL) solution of the crude product obtained in Reference Example 49 was heated and stirred at 150 ° C. for 15 minutes using a microwave reactor.
- the compound of the present invention (18 mg) having was obtained.
- Reference Example 51 (2E) -3- ⁇ 3- [2,6-dimethyl-4- (2-phenylethoxy) benzamide] -4- (trifluoromethyl) phenyl ⁇ prop-2-enoic acid
- Reference Example 50 A 2N aqueous sodium hydroxide solution (0.5 mL) was added to a solution of the produced compound in THF / methanol (1 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was used as it was in the next reaction without purification.
- Examples 24-1 to 24-2 By using ethyl crotonate or ethyl methacrylate instead of ethyl acrylate and performing the same operations as in Reference Example 50 ⁇ Reference Example 51 ⁇ Example 24, the compound of the present invention having the following physical property values was obtained. ..
- Reference Example 52 N- [5-iodo-2- (trifluoromethyl) phenyl] -2,6-dimethyl-4- (2-phenylethoxy) benzamide
- Reference Example 27 instead of the compound prepared in Reference Example 31.
- 5-iodo-2- (trifluoromethyl) aniline (CAS number: 1544-89-4) was used instead of the compound prepared in Reference Example 6, and the same operation as in Reference Example 43 was performed. By doing so, a title compound (1.45 g) having the following physical property values was obtained.
- the reaction mixture was washed with a 10% aqueous citric acid solution and a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was not purified and used in the next reaction.
- Reference Example 54 2-Amino-N, N-dimethyl-3-phenylpropanamide hydrochloride The crude product prepared in Reference Example 53 was dissolved in an ethyl acetate solution (25 mL) of 4N hydrochloric acid and stirred at room temperature for 5 minutes. .. An ethyl acetate solution (10 mL) of 4N hydrochloric acid was added, and the mixture was stirred at room temperature for 3 hours. The precipitate was collected by filtration to give the title compound (1.45 g) having the following physical characteristics.
- Reference Example 55 (2S) -N1, N1-dimethyl-3-phenyl-1,2-propanediamine Lithium aluminum hydride (0.94 g) in THF (20 mL) suspension under ice-cooling, Reference Example 54 A THF (30 mL) suspension of the compound (3 g) prepared in 1 was added dropwise and stirred at 50 ° C. for 2 hours. The reaction mixture was ice-cooled, purified water (1 mL), 4N aqueous sodium hydroxide solution (1 mL) and purified water (3 mL) were added, and the mixture was stirred at room temperature for 30 minutes.
- Reference Example 56 N-[(2S) -1- (dimethylamino) -3-phenyl-2-propanil] acetamide
- the compound (2.1 g) prepared in Reference Example 55 was added to dichloromethane (20 mL) under ice-cooling. Acetyl chloride (1 mL) was added, the mixture was stirred at room temperature for 5 minutes, and the reaction solution was concentrated under reduced pressure. The obtained residue was dissolved in MTBE, washed with 5N aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was slurry-washed with hexane to give the title compound (1.5 g) having the following physical characteristics.
- Cyclobutanecarboxylic acid in a solution of compound (50 mg) prepared in Reference Example 52 in 1,1,1,3,3,3-hexafluoro-2-propanol (CAS number: 29463-77-2, 0.5 mL). Number: 3721-95-7, 19 mg), silver carbonate (25 mg), sodium carbonate (15 mg), the compound prepared in Reference Example 56 (4 mg) and palladium acetate (25 mg) were added, and the mixture was stirred at 85 ° C. for 20 hours.
- the compound of the present invention having the following physical property values by performing the same operation as in Example 25 using 1-methylcyclopropane-1-carboxylic acid (CAS number: 6914-76-7) instead of cyclobutane carboxylic acid.
- Example 27 rel- (1R, 2S) -2- (3- ⁇ [2,6-dimethyl-4- (2-phenylethoxy) benzoyl] amino ⁇ -4-methylphenyl) cyclopropanecarboxylic acid racemic mixture
- Reference Example 40 Reference Example 4 ⁇ Same as Example 1 using 5-bromo-2-methylaniline (CAS number: 39478-78-9) instead of 5-bromo-2- (trifluoromethyl) aniline.
- the compound of the present invention having the following physical property values was obtained by performing the above operation.
- Reference Example 58 Methyl 4- (benzyloxy) -2 -isopropenylbenzoart A solution of the compound prepared in Reference Example 57 in ethanol (15 mL) and water (3.6 mL) was degassed to remove 2-isopropenyl-4.
- Reference Example 59 Methyl 4- (benzyloxy) -2-isopropylbenzoate Platinum oxide (CAS number: 1314-15-4, 10 mg) was added to a solution of the compound prepared in Reference Example 58 in methanol (2.4 mL). The mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was used in the next reaction without purification. HPLC retention time (minutes): 2.56; (Condition E) MS (ESI, Pos.): 285 (M + H) + .
- Reference Example 60 4- (benzyloxy) -2-isopropylbenzoic acid Lithium hydroxide in a solution of the compound prepared in Reference Example 59 in methanol (0.5 mL), THF (0.5 mL), and water (0.5 mL). Japanese product (CAS number: 1310-66-3, 88 mg) was added, and the mixture was stirred at 60 ° C. for 16 hours. The reaction mixture was concentrated, acidified with hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was used in the next reaction without purification. HPLC retention time (minutes): 2.20; (Condition E) MS (ESI, Pos.): 271 (M + H) + .
- Example 28 (1R, 2S) -2- [3- ⁇ [4- (benzyloxy) -2-isopropylbenzoyl] amino ⁇ -4- (trifluoromethyl) phenyl] cyclopropanecarboxylic acid
- Example 28-1 (1R, 2S) -2- [3- ⁇ [2-isopropyl-4- (2-phenylethoxy) benzoyl] amino ⁇ -4- (trifluoromethyl) phenyl] cyclopropanecarboxylic acid
- Example 28-2 (1R, 2S) -2- [3- ⁇ [2-isopropyl-4- (3-phenylpropoxy) benzoyl] amino ⁇ -4- (trifluoromethyl) phenyl] cyclopropanecarboxylic acid
- Examples 29-1 to 29-3 Methyl 2-bromo-3-hydroxybenzoate (CAS No .: 1260783-82-1) was used in place of methyl 2-bromo-4-hydroxybenzoate, and the corresponding bromo compound was used in place of benzyl bromide or benzyl bromide.
- the compound of the present invention having the following physical property values was obtained by performing the same operation as in Example 1.
- Example 29-1 (1R, 2S) -2- [3- ⁇ [3- (benzyloxy) -2-isopropylbenzoyl] amino ⁇ -4- (trifluoromethyl) phenyl] cyclopropanecarboxylic acid
- Example 29-2 (1R, 2S) -2- [3- ⁇ [2-isopropyl-3- (2-phenylethoxy) benzoyl] amino ⁇ -4- (trifluoromethyl) phenyl] cyclopropanecarboxylic acid
- Example 29-3 (1R, 2S) -2- [3- ⁇ [2-isopropyl-3- (3-phenylpropoxy) benzoyl] amino ⁇ -4- (trifluoromethyl) phenyl] cyclopropanecarboxylic acid
- Reference Example 61 4-Bromo- 2,3,6-trimethylphenol 2,3,6-trimethylphenol (CAS number: 2416-94-6, 4.0 g) in a solution of bromine (1. A solution of 6 mL) of dichloromethane (30 mL) was added and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, a sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (5.9 g) having the following physical properties. 1 1 H-NMR (CDCl 3 ): ⁇ 2.19, 2.21, 2.34, 4.56, 7.18.
- Reference Example 62 1-Bromo-2,3,5-trimethyl-4- (2-phenylethoxy) benzene 2-phenylethanol (1) in a solution of the compound (2.0 g) prepared in Reference Example 61 in THF (20 mL). .36 g) and triphenylphosphine (4.87 g) were added. Then, DEAD (3.23 g, 40% toluene solution) was added dropwise, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
- Reference Example 63 2,3,5-trimethyl-4- (2-phenylethoxy) benzoic acid n-butyllithium at ⁇ 78 ° C. in a solution of the compound (0.3 g) prepared in Reference Example 62 in THF (6 mL). Hexane solution (2.5 mol / L, 0.46 mL) was added, and the mixture was stirred at ⁇ 78 ° C. for 15 minutes. The reaction mixture was aerated with carbon dioxide gas at ⁇ 78 ° C. for 5 minutes and stirred at ⁇ 78 ° C. for 20 minutes. Hydrochloric acid was added to the reaction solution to stop the reaction, and the mixture was extracted with ethyl acetate.
- Reference Example 64 (1) Methyl 3-isopropyl-1- (3-phenylpropyl) -1H-pyrazole-4-carboxylate, and (2) Methyl 5-isopropyl-1- (3-phenylpropyl) -1H- Pyrazole-4-carboxylate methyl 3-isopropyl-1H-pyrazole-4-carboxylate (CAS number: 1186537-97-2, 0.4 g) in a solution of potassium carbonate (0.985 g), 1- in DMF (5 mL). Bromo-3-phenylpropane (1.42 g) was added, and the mixture was stirred at 60 ° C. for 16 hours.
- Examples 31-1 to 31-2 The compound of the present invention having the following physical property values was obtained by performing the same operation as in Reference Example 27 ⁇ Example 11 using the compound produced in Reference Example 64 instead of the compound produced in Reference Example 26.
- Example 31-1 (1R, 2S) -2- [3-( ⁇ [3-isopropyl-1- (3-phenylpropyl) -1H-pyrazole-4-yl] carbonyl ⁇ amino) -4- (tri) Fluoromethyl) phenyl] cyclopropanecarboxylic acid
- Example 31-2 (1R, 2S) -2- [3-( ⁇ [5-isopropyl-1- (3-phenylpropyl) -1H-pyrazole-4-yl] carbonyl ⁇ amino) -4- (tri) Fluoromethyl) phenyl] cyclopropanecarboxylic acid
- the compound of the present invention having the following physical property values was obtained by performing the same operation as in Example 18 using the compound produced in Reference Example 65 instead of the compound produced in Reference Example 42.
- Reference Example 66 Ethyl 2-sec-Butyl-1H-pyrrole-3-carboxylate ethyl 4-methyl-3-oxohexanoate (CAS number: 98192-72-4, 1.0 g) and 2-chloroacetaldehyde aqueous solution Ammonia water (28% NH 3 aqueous solution 3.2 mL) and water (3.2 mL) were added to a mixed solution of (CAS No .: 107-20-0,50 wt%, 0.815 mL), and the mixture was stirred at 70 ° C. for 20 hours. did. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate.
- Reference Example 67 Ethyl 2-sec-Butyl-1- (3-phenylpropyl) -1H-pyrrole-3-carboxylate of the compound (110 mg) and (3-bromopropyl) benzene (123 mg) prepared in Reference Example 66.
- Cesium carbonate (0.184 g) was added to a DMF (1 mL) solution, and the mixture was stirred at 80 ° C. for 20 hours.
- Reference Example 68 2-sec-Butyl-1- (3-phenylpropyl) -1H-pyrrole-3-carboxylic acid
- a THF / methanol (1: 1, 1 mL) solution of the compound (126 mg) prepared in Reference Example 67 was added, and the mixture was stirred at 80 ° C. for 20 hours.
- the reaction was cooled to room temperature and acetic acid (0.2 mL) was added.
- dichloromethane (5 mL) and water (5 mL) were added.
- the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
- the compound of the present invention having the following physical property values was obtained by performing the same operation as in Reference Example 8 ⁇ Example 1 using the compound produced in Reference Example 68 instead of the compound produced in Reference Example 3.
- Example 34-1 (1R, 2S) -2- [3-( ⁇ [2-isopropyl-1- (3-phenylpropyl) -1H-pyrrole-3-yl] carbonyl ⁇ amino) -4- (tri) Fluoromethyl) phenyl] cyclopropanecarboxylic acid
- Example 34-2 (1R, 2S) -2- [3-( ⁇ [2- (2-methyl-2-propanol) -1- (3-phenylpropyl) -1H-pyrrole-3-yl] carbonyl] ⁇ Amino) -4- (trifluoromethyl) phenyl] cyclopropanecarboxylic acid
- Pharmacological experiment example Pharmaceutical Experiment Example 1: EP 2 antagonistic activity measurement experiment using prostanoid receptor-expressing cells Human EP 2 acceptance according to the method of Nishigaki et al. (FEBS Letters, Vol. 364, pp. 339-341, 1995). body to prepare CHO cells expressing were subjected to experiments that cryopreserved so that 1.5x10 7 cells / mL / vial in CELLBANKER2 (Nihonzen'yakukogyo Co., Ltd.). The cells were thawed and suspended in assay medium (D-PBS coating 1 mmol / L IBMX, 2 ⁇ mol / L Diclofenac) to a concentration of 5x10 5 cells / mL.
- D-PBS coating 1 mmol / L IBMX, 2 ⁇ mol / L Diclofenac
- the reaction was started by adding PGE 2 alone at a final concentration of 10 nmol / L or a solution containing the cell suspension (10 ⁇ L) and the test compound (10 ⁇ L), and after reacting at room temperature for 1 hour, cAMP Gs Dynamic The amount of cAMP in the cells was quantified according to the method described in kit (manufactured by CISBIO).
- the antagonist action (IC 50 value) of the test compound was calculated as the inhibition rate for the reaction of 10 nM, which is a concentration showing a submaximal cAMP producing action of PGE 2 alone, and the IC 50 value was obtained.
- IC 50 values of several compounds of the invention were as shown in Table 1 below.
- CT26 is a mouse colon cancer cell line.
- CT26 is, 10 vol% of inactivated already fetal bovine serum (Fetal Bovine Serum; FBS), and cultured in a CO 2 incubator at RPMI-1640 medium containing Streptomycin of Penicillin and 100 [mu] g / mL of 100 units / mL.
- FBS Fetal Bovine Serum
- PBS phosphate buffer
- the recovered CT26 was suspended in PBS to obtain cells for transplantation. Under anesthesia, 300,000 cells for transplantation were subcutaneously transplanted into the right back of a female Baby / C mouse (Charles River Laboratories, Japan). Four days after transplantation, 10 mice were assigned to two groups, a vehicle group and a compound A group. As a vehicle and compound A, 10 mg / kg of the compound of the present invention was repeatedly administered to mice once on the 4th day of transplantation and twice a day from the 5th day to the 25th day of transplantation. For the tumor volume (mm 3 ), the minor axis and the major axis of the tumor were measured using an electronic caliper, and the tumor volume was calculated by the following formula 1. Mice with tumor ulcers during the administration period were excluded from the evaluation after that time.
- the compound of the present invention had an inhibitory effect on tumor growth.
- the tumor volume of the Compound A-administered group on the 25th day of transplantation was significantly smaller than that of the vehicle-administered group as shown in FIG.
- reaction sample (sample after 60 minutes of reaction) After incubating the reaction solution to be prepared at 37 ° C. for 60 minutes, 20 ⁇ L of this reaction solution was collected and added to 180 ⁇ L of acetonitrile (containing the internal standard candesartan). , Stopped the reaction.
- Residual rate (%) (Y / X) x100
- X Amount of substance to be tested in the standard sample
- Y Amount of substance to be tested in the reaction sample
- Ratio peak area of test substance / peak area of internal standard substance
- Example of Preparation About 10,000 tablets containing 10 mg of the active ingredient in one tablet can be obtained by mixing the following ingredients by a conventional method and then tableting.
- the compound of the present invention has an antagonistic activity against EP 2 receptor, it is effective in the prevention and / or treatment of diseases caused by the activation of EP 2 receptor.
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Abstract
Description
nAは、3から10の整数を表し;
R1Aは、水素原子または低級アルコキシ基を表し;
X1Aは、-CO-Y2A-(Y2Aは、-NH-等)等を表し;
X2Aは、-Y3A-Y4A-を表し、Y3Aは、単結合等を表し、Y4Aは、1~6個の炭素原子からなるアルキレン基等を表し;
DAは、カルボキシ基、低級アルコキシカルボニル基等を表す(基の定義を一部抜粋した。))である。
UBは、CX5BまたはNを表し;
WBは、CX6BまたはNを表し;
nBは、1、2、3、または4を表し;
R1Bは、炭素環、アリール、ヘテロ環などを表し;
X1B、X2B、X3B、X4Bはそれぞれ同じでも異なっていてもよく、水素原子、アルキル基、ハロゲン等を表し;
R5Bは、水素原子またはアルキル基等を表し;
X5B、X6Bはそれぞれ同じでも異なっていてもよく、水素原子またはアルキル基等を表す。(基の定義を一部抜粋した。))である。
R’cは‐S(O)p-C1~C6アルキル基などを表し、pは0~2であり;
R1cは水素原子またはC1~C6アルキル基などを表し;
R2c、R3c、R4cはそれぞれ水素原子またはハロゲン等を表し;
Xcは、-C=C-等を表し;
Ycは、-(CH2)n-を表し、nは2または3である(基の定義を一部抜粋した。))である。
〔1〕一般式(I-A):
L1は-(CR38R39)-(CR40R41)-を表し、
R38、R39、R40およびR41は、それぞれ独立して、(1)水素原子、(2)ハロゲン原子、または(3)C1-4アルキル基を表し、
R38、R39、R40およびR41中のC1-4アルキル基は、それぞれ独立して、ハロゲン原子で置換されていてもよく、
R38、R39、R40およびR41から選択される2個の置換基がC1-4アルキル基の時、結合する炭素原子と一緒になってC3-6飽和炭素環を形成してもよく、
L2は、(1)結合手、(2)C1-8アルキレン基、(3)C2-8アルケニレン基、または(4)C2-8アルキニレン基を表し、該C1-8アルキレン基、C2-8アルケニレン基、およびC2-8アルキニレン基中の1~2個の炭素原子は、酸素原子または酸化されていてもよい硫黄原子で置き換わっていてもよく、該C1-8アルキレン基、C2-8アルケニレン基、およびC2-8アルキニレン基は1~8個のハロゲン原子で置換されていてもよく、
Yは、(1)結合手、(2)酸素原子、または(3)酸化されていてもよい硫黄原子を表し、
R1は、(1)COOR10、(2)SO3H、(3)SO2NHR11、(4)CONHSO2R12、(5)SO2NHCOR13、(6)CONR14R15、(7)テトラゾリル基、または(8)ヒドロキサム酸(CONHOH)を表し、
R10、R11、R12、R13、R14およびR15は、それぞれ独立して(1)水素原子または(2)C1-4アルキル基を表し、
R2は、(1)水素原子または(2)C1-4アルキル基を表し、
R3は、(1)ハロゲン原子、(2)C1-6アルキル基、(3)C2-6アルケニル基、(4)C2-6アルキニル基、(5)C1-6アルコキシ基、(6)3-6員環状基、(7)(3-6員環状基)-O-、または(8)(3-6員環状基)-(C1-4アルキレン)-を表し、
R3中の(2)~(8)は1~9個のR16で置換されていてもよく、
R3が複数の場合、複数のR3は、それぞれ同じでも異なっていてもよく、
R16は、(1)ハロゲン原子、(2)C1-4アルキル基、(3)C1-4アルコキシ基、(4)C2-6アシル基、(5)C3-6シクロアルキル基、(6)水酸基、または(7)-NR17R18を表し、
R16が複数の場合、複数のR16は、それぞれ同じでも異なっていてもよく、
R17およびR18は、それぞれ独立して、(1)水素原子または(2)C1-4アルキル基を表し、
R4は、(1)ハロゲン原子、(2)C1-6アルキル基、(3)C2-6アルケニル基、(4)C2-6アルキニル基、(5)C1-6アルコキシ基、(6)3-6員環状基、(7)(3-6員環状基)-O-、または(8)(3-6員環状基)-(C1-4アルキレン)-を表し、
R4中の(2)~(8)は1~9個のR19で置換されていてもよく、
R4が複数の場合、複数のR4は、それぞれ同じでも異なっていてもよく、
R19は、(1)ハロゲン原子、(2)C1-4アルキル基、(3)C1-4アルコキシ基、(4)C2-6アシル基、(5)C3-6シクロアルキル基、(6)水酸基、または(7)-NR20R21を表し、
R20およびR21は、それぞれ独立して、(1)水素原子または(2)C1-4アルキル基を表し、
R19が複数の場合、複数のR19は、それぞれ同じでも異なっていてもよく、
R5は、(1)水素原子、(2)C3-10炭素環、または(3)3-10員複素環を表し、該C3-10炭素環および3-10員複素環は、1~5個のR22で置換されていてもよく、
但し、L2が結合手の場合は、R5は水素原子でなく、
R22は、(1)C1-6アルキル基、(2)C2-6アルケニル基、(3)C2-6アルキニル基、(4)C3-6シクロアルキル基、(5)C1-6アルコキシ基、(6)C3-6シクロアルキルオキシ基、(7)C2-6アシル基、(8)C2-6アシルオキシ基、(9)C1-6アルキルチオ基、(10)C3-6シクロアルキルチオ基、(11)C1-6アルキルスルフィニル基、(12)C3-6シクロアルキルスルフィニル基、(13)C1-6アルキルスルホニル基、(14)C3-6シクロアルキルスルホニル基、(15)C1-6アルコキシカルボニル基、(16)5-6員環状基、(17)(5-6員環状基)-(C1-4アルキレン)-、(18)(5-6員環状基)-(C1-4アルキレン)-O-基、(19)(5-6員環状基)-C1-4アシル基、(20)ハロゲン原子、(21)水酸基、(22)ニトロ基、(23)シアノ基、(24)-NR23R24、(25)-CONR25R26または(26)-SO2NR27R28を表し、
R23、R24、R25、R26、R27およびR28は、それぞれ独立して、(1)水素原子、(2)C1-6アルキル基、(3)C2-6アシル基または(4)C1-6アルキルスルホニル基を表し、
R22のうち(1)~(19)の基は、1~9個のR29で置換されていてもよく、
R22が複数の場合、複数のR22は、それぞれ同じでも異なっていてもよく、
R29は、(1)C1-4アルキル基、(2)C1-4アルコキシ基、(3)C2-6アシル基、(4)C3-6シクロアルキル基、(5)水酸基、(6)-NR30R31または(7)ハロゲン原子を表し、
R30およびR31は、それぞれ独立して、(1)水素原子または(2)C1-4アルキル基を表し、
R29が複数の場合、複数のR29は、それぞれ同じでも異なっていてもよく、
Qは(1)酸素原子または(2)硫黄原子を表し、
Xは(1)CR6または(2)NR7を表し、
R6は、(1)ハロゲン原子、(2)C1-6アルキル基、(3)C2-6アルケニル基、(4)C2-6アルキニル基、(5)C1-6アルコキシ基、(6)3-6員環状基、(7)(3-6員環状基)-O-、または(8)(3-6員環状基)-(C1-4アルキレン)-を表し、
R6中の(2)~(8)は1~9個のR32で置換されていてもよく、
R32は、(1)ハロゲン原子、(2)C1-4アルキル基、(3)C1-4アルコキシ基、(4)C2-6アシル基、(5)C3-6シクロアルキル基、(6)水酸基、または(7)-NR33R34を表し、
R33およびR34は、それぞれ独立して、(1)水素原子または(2)C1-4アルキル基を表し、
R32が複数の場合、複数のR32は、それぞれ同じでも異なっていてもよく、
R7は、(1)C1-6アルキル基、(2)C2-6アルケニル基、(3)C2-6アルキニル基、(4)3-6員環状基、または(5)(3-6員環状基)-(C1-4アルキレン)-を表し、
R7は1~9個のR35で置換されていてもよく、
R35は、(1)ハロゲン原子、(2)C1-4アルキル基、(3)C1-4アルコキシ基、(4)C2-6アシル基、(5)C3-6シクロアルキル基、(6)水酸基、または(7)-NR36R37を表し、
R36およびR37は、それぞれ独立して、(1)水素原子または(2)C1-4アルキル基を表し、
R35が複数の場合、複数のR35は、それぞれ同じでも異なっていてもよく、
環Aは、(1)ベンゼン環、または(2)5-6員含窒素芳香族複素環を表し、
環A中の
nは1~4の整数を表し、
mは0~3の整数を表し、
ただし、3-[3-[(2,6-ジメトキシベンゾイル)アミノ]-4-プロポキシフェニル]プロパン酸、
3-[5-({[1-tert-ブチル-5-(4-フルオロフェニル-1H-ピラゾール-4-イル]カルボニル}アミノ-2-クロロフェニル]プロパン酸メチル、
3-[5-({[1-tert-ブチル-5-(4-フルオロフェニル-1H-ピラゾール-4-イル]カルボニル}アミノ-2-クロロフェニル]プロパン酸、
α-エチル-3-[N-(1’-フェニル-5’-メチル-1’,2’,3’-トリアゾールカルボニル)]アミノ-2,4,6-トリヨードヒドロシンナム酸、および
α-エチル-3-{N-(1’-(4”-ヨードフェニル)-5’-メチル-1,2,3-トリアゾールカルボニル]}アミノ-2,4,6-トリヨードヒドロシンナム酸は除外される。)で示される化合物、またはその薬学的に許容される塩、
〔2〕一般式(I):
R6aは、(1)ハロゲン原子、(2)C1-6アルキル基、(3)C2-6アルケニル基、(4)C2-6アルキニル基、(5)C1-6アルコキシ基、(6)(3-6員環状基)-O-、または(7)(3-6員環状基)-(C1-4アルキレン)-を表し、
R6a中の(2)~(7)は1~9個のR32で置換されていてもよく、
R7aは、(1)C1-6アルキル基、(2)C2-6アルケニル基、(3)C2-6アルキニル基、(4)3-6員環状基、または(5)(3-6員環状基)-(C1-4アルキレン)-を表し、
R7aは1~9個のR35で置換されていてもよく、
R3a、R3bおよびR3cはそれぞれ独立して(1)水素原子(2)ハロゲン原子、(3)C1-6アルキル基、(4)C2-6アルケニル基、(5)C2-6アルキニル基、(6)C1-6アルコキシ基、(7)3-6員環状基、(8)(3-6員環状基)-O-、または(9)(3-6員環状基)-(C1-4アルキレン)-を表し、
R3a、R3bおよびR3c中の(3)~(9)は1~9個のR16で置換されていてもよく、
ただし、R3a、R3bおよびR3cのうち少なくとも一つは水素原子以外の置換基を表し、
前記〔1〕記載の記号と同じ記号は前記〔1〕記載の記号と同じ意味を表し、
ただし、3-[3-[(2,6-ジメトキシベンゾイル)アミノ]-4-プロポキシフェニル]プロパン酸は除外される。)で示される前記〔1〕記載の化合物、またはその薬学的に許容される塩、
〔4〕一般式(I-1):
R6aは、(1)ハロゲン原子、(2)C1-6アルキル基、(3)C2-6アルケニル基、(4)C2-6アルキニル基、(5)C1-6アルコキシ基、(6)(3-6員環状基)-O-、または(7)(3-6員環状基)-(C1-4アルキレン)-を表し、
R6a中の(2)~(7)は1~9個のR32で置換されていてもよく、
R7aは、(1)C1-6アルキル基、(2)C2-6アルケニル基、(3)C2-6アルキニル基、(4)3-6員環状基、または(5)(3-6員環状基)-(C1-4アルキレン)-を表し、
R7aは1~9個のR35で置換されていてもよく、
R3a、R3bおよびR3cはそれぞれ独立して(1)水素原子(2)ハロゲン原子、(3)C1-6アルキル基、(4)C2-6アルケニル基、(5)C2-6アルキニル基、(6)C1-6アルコキシ基、(7)3-6員環状基、(8)(3-6員環状基)-O-、または(9)(3-6員環状基)-(C1-4アルキレン)-を表し、
R3a、R3bおよびR3c中の(3)~(9)は1~9個のR16で置換されていてもよく、
ただし、R3a、R3bおよびR3cのうち少なくとも一つは水素原子以外の置換基を表し、
pは1~4の整数を表し、
前記〔1〕記載の記号と同じ記号は前記〔1〕記載の記号と同じ意味を表す。)で示される前記〔1〕~〔4〕のいずれか1項に記載の化合物、またはその薬学的に許容される塩、
〔6〕環Aがベンゼン環または5員含窒素芳香族複素環である、前記〔1〕~〔5〕のいずれか1項記載の化合物、またはその薬学的に許容される塩、
〔7〕L2が、C1-8アルキレン基、C2-8アルケニレン基、またはC2-8アルキニレン基であり、該C1-8アルキレン基、C2-8アルケニレン基、およびC2-8アルキニレン基中の1~2個の炭素原子は、酸素原子で置き換わっていてもよく、該C1-8アルキレン基、C2-8アルケニレン基、およびC2-8アルキニレン基は1~8個のハロゲン原子で置換されていてもよい、前記〔1〕~〔6〕のいずれか1項に記載の化合物、またはその薬学的に許容される塩、
〔8〕R5が、C3-6炭素環、または3-6員複素環を表し、該C3-6炭素環および3-6員複素環は、1~5個のR22で置換されていてもよい、前記〔1〕~〔7〕のいずれか1項に記載の化合物、またはその薬学的に許容される塩、
〔9〕環Aが、ベンゼン環、またはピロール環である、前記〔1〕~〔8〕のいずれか1項に記載の化合物、またはその薬学的に許容される塩、
〔10〕環Aがピロール環であり、Yが結合手である、前記〔1〕~〔9〕のいずれか1項に記載の化合物、またはその薬学的に許容される塩、
〔11〕環Aがベンゼン環であり、Yが酸素原子である、前記〔1〕~〔9〕のいずれか1項に記載の化合物、またはその薬学的に許容される塩、
〔12〕
(1)rel-(1R,2S)-2-[3-({[1-sec-ブチル-5-(3-フェニルプロピル)-1H-ピロール-2-カルボニル]アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(2)rel-(1R,2S)-2-{3-[({1-[(2S)-2-ブタニル]-5-(3-フェニルプロピル)-1H-ピロール-2-イル}カルボニル)アミノ]-4-(トリフルオロメチル)フェニル}シクロプロパンカルボン酸、
(3)rel-(1R,2S)-2-{3-[({1-[(2S)-2-ブタニル]-5-(3-フェニルプロピル)-1H-ピロール-2-イル}カルボニル)アミノ]-5-メチルフェニル}シクロプロパンカルボン酸、
(4)rel-(1R,2R)-2-{3-[({1-[(2S)-2-ブタニル]-5-(3-フェニルプロピル)-1H-ピロール-2-イル}カルボニル)アミノ]-5-メチルフェニル}シクロプロパンカルボン酸、
(5)rel-(1R,2S)-2-{5-[({1-[(2S)-2-ブタニル]-5-(3-フェニルプロピル)-1H-ピロール-2-イル}カルボニル)アミノ]-2-(トリフルオロメチル)フェニル}シクロプロパンカルボン酸、
(6)rel-(1R,2R)-2-{5-[({1-[(2S)-2-ブタニル]-5-(3-フェニルプロピル)-1H-ピロール-2-イル}カルボニル)アミノ]-2-(トリフルオロメチル)フェニル}シクロプロパンカルボン酸、
(7)(1S,2R)-2-[3-({[1-イソプロピル-5-(3-フェニルプロピル)-1H-ピロール-2-イル]カルボニル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(8)(1R,2R)-2-[3-({[1-イソプロピル-5-(3-フェニルプロピル)-1H-ピロール-2-イル]カルボニル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(9)(1R,2S)-2-{3-[({1-[(2S)-2-ブタニル]-5-(3-フェニルプロピル)-1H-ピロール-2-イル}カルボニル)アミノ]-4-メトキシフェニル}シクロプロパンカルボン酸、
(10)(1S,2R)-2-{3-[({1-[(2S)-2-ブタニル]-5-(3-フェニルプロピル)-1H-ピロール-2-イル}カルボニル)アミノ]-4-(トリフルオロメチル)フェニル}シクロプロパンカルボン酸、
(11)(1R,2S)-2-{3-[({1-[(2S)-2-ブタニル]-5-(3-フェニルプロピル)-1H-ピロール-2-イル}カルボニル)アミノ]-4-(トリフルオロメチル)フェニル}シクロプロパンカルボン酸、
(12)(1R,2S)-2-{3-[({1-[(2S)-2-ブタニル]-5-(3-フェニルプロピル)-1H-ピロール-2-イル}カルボニル)アミノ]-4-クロロフェニル}シクロプロパンカルボン酸、
(13)(1R,2S)-2-{3-[({5-[2-(ベンジルオキシ)エチル]-1-[(2S)-2-ブタニル]-1H-ピロール-2-イル}カルボニル)アミノ]-4-(トリフルオロメチル)フェニル}シクロプロパンカルボン酸、
(14)rel-(1R,2S)-2-[3-{[(1-[(2S)-2-ブタニル]-5-{2-[(2-フルオロ-4-ピリジニル)オキシ]エチル}-1H-ピロール-2-イル)カルボニル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(15)(1R,2S)-2-[3-{[(1-[(2S)-2-ブタニル]-5-{2-[(2-クロロ-6-フルオロ-4-ピリジニル)オキシ]エチル}-1H-ピロール-2-イル)カルボニル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(16)(1R,2S)-2-{3-[({1-[(2S)-2-ブタニル]-5-[2-(2-クロロ-3,5-ジフルオロフェノキシ)エチル]-1H-ピロール-2-イル}カルボニル)アミノ]-4-(トリフルオロメチル)フェニル}シクロプロパンカルボン酸、
(17)(1R,2S)-2-{3-[({1-[(2S)-2-ブタニル]-5-[2-(2,4-ジフルオロフェノキシ)エチル]-1H-ピロール-2-イル}カルボニル)アミノ]-4-(トリフルオロメチル)フェニル}シクロプロパンカルボン酸、
(18)(1R,2S)-2-[3-{[(1-[(2S)-2-ブタニル]-5-{2-[(1-メチル-1H-ピラゾール-4-イル)オキシ]エチル}-1H-ピロール-2-イル)カルボニル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(19)rel-(1R,2S)-2-[3-{[2,6-ジメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(20)(1R,2S)-2-[3-{[2,6-ジメチル-4-(3-フェニルプロピル)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(21)(1R,2S)-2-[3-({4-[2-(2,4-ジフルオロフェニル)エトキシ]-2,6-ジメチルベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(22)rel-(1R,2S)-2-(2,3-ジクロロ-5-{[2,6-ジメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-フルオロフェニル)シクロプロパンカルボン酸、
(23)rel-(1R,2R)-2-(2,3-ジクロロ-5-{[2,6-ジメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-フルオロフェニル)シクロプロパンカルボン酸、
(24)(1R,2S)-2-[2-クロロ-5-{[2,6-ジメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(25)(1R,2S)-2-(4-クロロ-3-{[2,6-ジメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}フェニル)シクロプロパンカルボン酸、
(26)rel-(1R,2S)-2-(2,3-ジクロロ-5-{[2,6-ジメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}フェニル)シクロプロパンカルボン酸、
(27)rel-(1R,2R)-2-(2,3-ジクロロ-5-{[2,6-ジメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}フェニル)シクロプロパンカルボン酸、
(28)(1R,2S)-2-[3-{[2,6-ジメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(29)(1S,2R)-2-[3-{[2,6-ジメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(30)(1R,2S)-2-[3-({2,6-ジメチル-4-[2-(1-メチル-1H-ピラゾール-4-イル)エトキシ]ベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(31)(1R,2S)-2-[3-{[4-(2-シクロプロピルエトキシ)-2,6-ジメチルベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(32)(1R,2S)-2-{3-[(2,6-ジメチル-4-プロポキシベンゾイル)アミノ]-4-(トリフルオロメチル)フェニル}シクロプロパンカルボン酸、
(33)(1R,2S)-2-[3-{[4-(ヘキシルオキシ)-2,6-ジメチルベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(34)(1R,2S)-2-[3-{[4-(ベンジルオキシ)-2,6-ジメチルベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(35)(1R,2S)-2-[3-{[4-(2-メトキシエトキシ)-2,6-ジメチルベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(36)(1R,2S)-2-[3-({2,6-ジメチル-4-[2-(テトラヒドロ-2H-ピラン-2-イル)エトキシ]ベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(37)(1R,2S)-2-[3-({4-[2-(2-フリル)エトキシ]-2,6-ジメチルベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(38)(1R,2S)-2-[3-({4-[2-(2-クロロフェニル)エトキシ]-2,6-ジメチルベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(39)(1R,2S)-2-[3-({4-[2-(3-クロロフェニル)エトキシ]-2,6-ジメチルベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(40)(1R,2S)-2-[3-({4-[2-(1H-イミダゾール-1-イル)エトキシ]-2,6-ジメチルベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(41)(1R,2S)-2-[3-({4-[2-(2,6-ジフルオロフェニル)エトキシ]-2,6-ジメチルベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(42)(1R,2S)-2-[3-({4-[2-(3,5-ジフルオロフェニル)エトキシ]-2,6-ジメチルベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(43)(1R,2S)-2-[3-({4-[(6-クロロ-2-ピラジニル)オキシ]-2,6-ジメチルベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(44)(1R,2S)-2-[3-{[4-(6-フルオロ-3-ピリジニル)-2,6-ジメチルベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(45)(1R,2S)-2-[3-({4-[2-(4-ヒドロキシフェニル)エトキシ]-2,6-ジメチルベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(46)3-[3-{[2,6-ジメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]プロパン酸、
(47)3-[3-{[2,6-ジメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]ブタン酸、
(48)3-[3-{[2,6-ジメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]-2-メチルプロパン酸、
(49)(1R,2S)-2-[3-{[2,6-ジメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロブタンカルボン酸、または
(50)(1R,2R)-2-[3-{[2,6-ジメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]-1-メチルシクロプロパンカルボン酸から選択される、前記〔1〕記載の化合物、またはその薬学的に許容される塩、
〔13〕
(1)(1R,2S)-2-[3-{[2-メチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(2)(1R,2S)-2-[3-{[2-クロロ-4-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(3)(1R,2S)-2-[3-{[4-(2-フェニルエトキシ)-2-(トリフルオロメチル)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(4)(1R,2S)-2-[3-{[4-(1H-インダゾール-5-イルメトキシ)-2,6-ジメチルベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(5)(1R,2S)-2-[3-{[2,6-ジメチル-4-(1,2,3,4-テトラヒドロ-1-ナフタレニルメトキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(6)(1R,2S)-2-[3-({2,6-ジメチル-4-[2-(3-ピリジニル)エトキシ]ベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(7)(1R,2S)-2-[3-({2,6-ジメチル-4-[2-(4-ピリジニル)エトキシ]ベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(8)(1R,2S)-2-[3-({2,6-ジメチル-4-[2-(2-ピリジニル)エトキシ]ベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(9)(1R,2S)-2-[3-({4-[2-(2-クロロ-1H-イミダゾール-1-イル)エトキシ]-2,6-ジメチルベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(10)(1R,2S)-2-[3-({4-[2-(2-フルオロフェニル)エトキシ]-2,6-ジメチルベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(11)(1R,2S)-2-[3-({4-[2-(3-フルオロフェニル)エトキシ]-2,6-ジメチルベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(12)(1R,2S)-2-[3-({4-[2-(4-フルオロフェニル)エトキシ]-2,6-ジメチルベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(13)(1R,2S)-2-[3-{[2,6-ジメチル-4-(3,3,3-トリフルオロプロポキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(14)(1R,2S)-2-[3-{[2,6-ジメチル-4-(3,3,3-トリフルオロ-2-メチルプロポキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(15)(1R,2S)-2-{3-[(2,6-ジメチル-4-{[6-(トリフルオロメチル)-2-ピリジニル]オキシ}ベンゾイル)アミノ]-4-(トリフルオロメチル)フェニル}シクロプロパンカルボン酸、
(16)(1R,2S)-2-[3-{[2,6-ジメチル-4-(ピラゾロ[1,5-a]ピリミジン-5-イルオキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(17)rel-(1R,2S)-2-(3-{[2,6-ジメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-メチルフェニル)シクロプロパンカルボン酸、
(18)(1R,2S)-2-[3-{[4-(ベンジルオキシ)-2-イソプロピルベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(19)(1R,2S)-2-[3-{[2-イソプロピル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(20)(1R,2S)-2-[3-{[2-イソプロピル-4-(3-フェニルプロポキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(21)(1R,2S)-2-[3-{[3-(ベンジルオキシ)-2-イソプロピルベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(22)(1R,2S)-2-[3-{[2-イソプロピル-3-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(23)(1R,2S)-2-[3-{[2-イソプロピル-3-(3-フェニルプロポキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(24)(1R,2S)-2-[4-(トリフルオロメチル)-3-{[2,3,5-トリメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}フェニル]シクロプロパンカルボン酸、
(25)(1R,2S)-2-[3-({[3-イソプロピル-1-(3-フェニルプロピル)-1H-ピラゾール-4-イル]カルボニル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(26)(1R,2S)-2-[3-({[5-イソプロピル-1-(3-フェニルプロピル)-1H-ピラゾール-4-イル]カルボニル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(27)(1R,2S)-2-[3-({[2,6-ジメチル-4-(2-フェニルエトキシ)フェニル]カルボノチオイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(28)(1R,2S)-2-[3-({[4-(2-シクロプロピルエトキシ)-2,6-ジメチルフェニル]カルボノチオイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(29)(1R,2S)-2-[3-({[2-sec-ブチル-1-(3-フェニルプロピル)-1H-ピロール-3-イル]カルボニル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(30)(1R,2S)-2-[3-({[2-イソプロピル-1-(3-フェニルプロピル)-1H-ピロール-3-イル]カルボニル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、または
(31)(1R,2S)-2-[3-({[2-(2-メチル-2-プロパニル)-1-(3-フェニルプロピル)-1H-ピロール-3-イル]カルボニル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸から選択される前記〔1〕記載の化合物、またはその薬学的に許容される塩、
〔14〕前記〔1〕~〔13〕のいずれか1項に記載の化合物、またはその薬学的に許容される塩を有効成分として含有し、さらに薬学的に許容される担体を含有する医薬組成物、
〔15〕EP2受容体拮抗剤である、前記〔14〕記載の医薬組成物、
〔16〕EP2受容体の活性化に起因する疾患の治療および/または予防剤である、前記〔14〕または〔15〕記載の医薬組成物、
〔17〕EP2受容体の活性化に起因する疾患が、子宮内膜症、子宮筋腫、月経過多、腺筋症、月経困難症、慢性骨盤痛症候群、がん、炎症性疼痛、神経因性疼痛、頭痛、片頭痛、術後の痛み、間質性膀胱炎、平滑筋腫、過敏性大腸症候群、アルツハイマー病、パーキンソン病、筋萎縮性側索硬化症、多発性硬化症、リウマチ、骨関節炎、痛風、アレルギー性疾患、高血圧、脳障害、虚血、脳卒中、腎疾患、移植拒絶反応、アテローム性動脈硬化症、虚血性心疾患、尋常性ざ瘡、喘息、前立腺炎、糸球体腎炎、サルコイドーシス、血管炎、または、自己免疫疾患である、前記〔16〕記載の医薬組成物、
〔18〕EP2受容体の活性化に起因する疾患ががんであり、がんが、乳がん、卵巣がん、大腸がん、肺がん、前立腺がん、頭頸部がん、リンパ腫、ぶどう膜悪性黒色腫、胸腺腫、中皮腫、食道がん、胃がん、十二指腸がん、肝細胞がん、胆管がん、胆のうがん、膵臓がん、腎細胞がん、腎盂・尿管がん、膀胱がん、陰茎がん、精巣がん、子宮がん、膣がん、外陰がん、皮膚がん(例えば、悪性黒色腫など)、悪性骨腫瘍、軟部肉腫、軟骨肉腫、白血病、骨髄異形成症候群、脳腫瘍または多発性骨髄腫である、前記〔16〕または〔17〕記載の医薬組成物、
〔19〕アルキル化剤、代謝拮抗剤、抗癌性抗生物質、植物性製剤、ホルモン剤、白金化合物、トポイソメラーゼ阻害剤、キナーゼ阻害剤、抗CD20抗体、抗HER2抗体、抗EGFR抗体、抗VEGF抗体、プロテアソーム阻害剤、HDAC阻害剤、および免疫調整薬から選ばれる少なくとも1種以上と組み合わせて投与されることを特徴とする、前記〔14〕~〔18〕のいずれか1項に記載の医薬組成物、
〔20〕前記〔1〕~〔13〕のいずれか1項に記載の化合物、または薬学的に許容されるその塩、あるいは前記〔14〕または〔15〕記載の組成物を、EP2受容体の活性化に起因する疾患の予防および/または治療を必要とする患者に投与することを特徴とする、EP2受容体の活性化に起因する疾患の予防および/または治療方法、
〔21〕EP2受容体の活性化に起因する疾患の予防および/または治療に使用される、前記〔1〕~〔13〕のいずれか1項に記載の化合物、またはその薬学的に許容される塩、
〔22〕EP2受容体の活性化に起因する疾患の予防および/または治療剤を製造するための、前記〔1〕~〔13〕のいずれか1項に記載の化合物、またはその薬学的に許容される塩の使用、に関する。
一般式(I-A)で示される化合物のプロドラッグとは、生体内において酵素や胃酸などによる反応により一般式(I-A)で示される化合物に変換される化合物をいう。一般式(I-A)で示される化合物のプロドラッグとしては、例えば、一般式(I-A)で示される化合物がアミノ基を有する場合、該アミノ基がアシル化、アルキル化、リン酸化された化合物(例えば、一般式(I-A)で示される化合物のアミノ基がエイコサノイル化、アラニル化、ペンチルアミノカルボニル化、(5-メチル-2-オキソ-1,3-ジオキソレン-4-イル)メトキシカルボニル化、テトラヒドロフラニル化、ピロリジルメチル化、ピバロイルオキシメチル化、アセトキシメチル化、tert-ブチル化された化合物など);一般式(I-A)で示される化合物が水酸基を有する場合、該水酸基がアシル化、アルキル化、リン酸化、ホウ酸化された化合物(例えば、一般式(I-A)で示される化合物の水酸基がアセチル化、パルミトイル化、プロパノイル化、ピバロイル化、サクシニル化、フマリル化、アラニル化、ジメチルアミノメチルカルボニル化された化合物など)が挙げられ;一般式(I-A)で示される化合物がカルボキシ基を有する場合、該カルボキシ基がエステル化、アミド化された化合物(例えば、一般式(I-A)で示される化合物のカルボキシ基がエチルエステル化、フェニルエステル化、カルボキシメチルエステル化、ジメチルアミノメチルエステル化、ピバロイルオキシメチルエステル化、1-{(エトキシカルボニル)オキシ}エチルエステル化、フタリジルエステル化、(5-メチル-2-オキソ-1,3-ジオキソレン-4-イル)メチルエステル化、1-{[(シクロヘキシルオキシ)カルボニル]オキシ}エチルエステル化、メチルアミド化された化合物など)などが挙げられる。これらの化合物はそれ自体公知の方法によって製造することができる。また、一般式(I-A)で示される化合物のプロドラッグは水和物および非水和物のいずれであってもよい。また、一般式(I-A)で示される化合物のプロドラッグは、廣川書店1990年刊「医薬品の開発」第7巻「分子設計」163~198頁に記載されているような、生理的条件において一般式(I-A)で示される化合物に変化するものであってもよい。
本発明化合物は、公知の方法、例えば、以下に示す方法、これらに準ずる方法、Comprehensive Organic Transformations : A Guide to Functional Group Preparations, 3rd Edition (Richard C. Larock, John Wiley & Sons Inc, 2018)に記載された方法、または実施例に示す方法等を適宜改良し、組み合わせて用いることで製造することができる。出発原料は、塩を用いてもよい。それぞれの反応を行う順序は、導入されている保護基や反応条件によって適宜いれかえることができる。
反応工程式1中、反応1-1はアミド化反応である。アミド化反応は公知であり、例えば、
(1)酸ハライドを用いる方法、
(2)混合酸無水物を用いる方法、
(3)縮合剤を用いる方法、
等が挙げられる。これらの方法を具体的に説明すると、
(1)酸ハライドを用いる方法は、例えば、カルボン酸を有機溶媒(クロロホルム、ジクロロメタン、ジエチルエーテル、テトラヒドロフラン等)中または無溶媒で、酸ハライド化剤(オキザリルクロライド、チオニルクロライド等)と-20℃~還流温度で反応させ、得られた酸ハライドを塩基(ピリジン、トリエチルアミン、ジメチルアニリン、ジメチルアミノピリジン、ジイソプロピルエチルアミン等)の存在下、アミンと有機溶媒(クロロホルム、ジクロロメタン、ジエチルエーテル、テトラヒドロフラン等)中、0~40℃の温度で反応させることにより行なわれる。また、得られた酸ハライドを有機溶媒(ジオキサン、テトラヒドロフラン等)中、アルカリ水溶液(重曹水または水酸化ナトリウム溶液等)を用いて、アミンと0~40℃で反応させることにより行なうこともできる。
(1)アルカリ加水分解による脱保護反応、
(2)酸性条件下における脱保護反応、
(3)加水素分解による脱保護反応、
(4)シリル基の脱保護反応、
(5)金属を用いる脱保護反応、
(6)金属錯体を用いる脱保護反応、等が挙げられる。
(1)アルカリ加水分解による脱保護反応は、例えば有機溶媒(例えば、メタノール、テトラヒドロフラン、ジオキサン等)中、アルカリ金属の水酸化物(例えば、水酸化ナトリウム、水酸化カリウム、水酸化リチウム等)、アルカリ土類金属の水酸化物(例えば、水酸化バリウム、水酸化カルシウム等)または炭酸塩(例えば、炭酸ナトリウム、炭酸カリウム等)あるいはその水溶液もしくはこれらの混合物を用いて、0~40℃で行われる。
反応工程式2中、反応2は公知であり、Z2がハロゲン原子の場合、ハロゲン置換反応により一般式2cで示される化合物を製造することができる。
反応工程式3中、ニトロ基の還元反応は公知であり、例えば水に混和する溶媒(エタノール、メタノール、テトラヒドロフラン等)中、酸(塩酸、臭化水素酸、塩化アンモニウム、酢酸、ギ酸アンモニウム等)の存在下または非存在下、金属試薬(亜鉛、鉄、スズ、塩化スズ、塩化鉄、サマリウム、インジウム、水素化ホウ素ナトリウム-塩化ニッケル等)を用いて、0~150℃の温度で行なわれる。
反応工程式4中、反応4-1は公知であり、一般式3fで示される化合物と一般式4aで示される化合物とを前記の鈴木カップリング反応の条件に付すことで、一般式4bで示される化合物を製造することができる。一般式4bで示される化合物を製造する別の方法として、一般式3fで示される化合物を反応4-2によって一般式4cで示されるボロン酸エステルに変換した後、一般式4dで示される化合物を用いて反応4-3を行うことにより、一般式4bで示されるアミン化合物を製造することができる。
反応5-1は公知であり、ノルボルネンを用いたC-H活性化反応で実施することができる。例えば、Angewandte Chemie-International Edition,2013,vol.52,#23,p.6080‐6083に記載されているように、一般式5cで示される化合物は、一般式5aで示される化合物および一般式5bで示される化合物を用いて、有機溶媒(例えば、N,Nジメチルアセトアミド、アセトニトリル等)中、塩基(例えば、炭酸カリウム、炭酸水素カリウム等)の存在下でノルボルネン、およびパラジウム触媒(例えば、ビス(アセトニトリル)ジクロロパラジウム(II)等)を加え、70℃~90℃の温度で反応を行うことにより製造することができる。
本明細書中の各反応において、出発原料として用いた、各々一般式2a、一般式2b、一般式2d、一般式2f、一般式3a、一般式3c、一般式3e、一般式4a、一般式4d、一般式5a、一般式5b、一般式5d、一般式6a、一般式6bおよび一般式7aで示される化合物は公知であるか、あるいは公知の方法、例えば、Comprehensive Organic Transformations:A Guide to Functional Group Preparations、3rd Edition(Richard C.Larock,John Wiley & Sons Inc,2018)等に記載された方法、または公知の方法を一部改変した方法等を組み合わせて用いることで容易に製造することができる。
[毒性]
本発明化合物の毒性は低いものであるため、医薬品として安全に使用することができる。
[医薬品への適用]
本発明の課題は、EP2受容体に対して強力な拮抗活性を有する化合物を創製し、EP2受容体の活性化に起因する疾患の予防および/または治療薬として有用である化合物を見出すことである。
経口投与用製剤には、例えば、錠剤、カプセル剤、顆粒剤、散剤、経口液剤、シロップ剤、経口ゼリー剤等が含まれる。また、経口投与用製剤には、製剤からの有効成分の放出性を特に調節していない速崩性製剤と、固有の製剤設計および製法により放出性を目的にあわせて調節した、例えば、腸溶性製剤や徐放性製剤等の放出調節製剤がある。腸溶性製剤は、有効成分の胃内での分解を防ぐ、または有効成分の胃に対する刺激作用を低減させる等の目的で、有効成分を胃内で放出せず、主として小腸内で放出するよう設計された製剤をいい、通常、酸不溶性の腸溶性基剤を用いて皮膜を施すことにより製造することができる。徐放性製剤は、投与回数の減少または副作用の低減を図る等の目的で、製剤からの有効成分の放出速度、放出時間、放出部位を調節した製剤をいい、通常、適切な徐放化剤を用いることにより製造することができる。経口投与用製剤のうち、カプセル剤、顆粒剤、錠剤等では、服用を容易にする、または有効成分の分解を防ぐ等の目的で、糖類または糖アルコール類、高分子化合物等適切なコーティング剤で剤皮を施すこともできる。
錠剤は、経口的に投与される一定の形状を有する固形の製剤であり、素錠、フィルムコーティング錠、糖衣錠、多層錠、有核錠等の一般的に錠剤と称されるもののほか、口腔内速崩錠、チュアブル錠、発泡錠、分散錠、溶解錠等が含まれる。素錠を製造する際には、通常、下記の(a)、(b)、または(c)の手法:
(a)有効成分に賦形剤、結合剤、崩壊剤等の添加剤を加えて混和して均質とし、水または結合剤を含む溶液を用いて適切な方法で粒状とした後、滑沢剤等を加えて混和し、圧縮成形する;
(b)有効成分に賦形剤、結合剤、崩壊剤等の添加剤を加えて混和して均質としたものを、直接圧縮成形するか、または予め添加剤で製した顆粒に有効成分および滑沢剤等を加えて混和して均質とした後、圧縮成形する;
(c)有効成分に賦形剤、結合剤等の添加剤を加えて混和して均質とし、溶媒で湿潤させた練合物を一定の型に流し込んで成形した後、適切な方法で乾燥する;
が用いられる。フィルムコーティング錠は、通常、素錠に高分子化合物等の適切なコーティング剤で薄く剤皮を施すことにより製造することができる。糖衣錠は、通常、素錠に糖類または糖アルコールを含むコーティング剤で剤皮を施すことにより製造することができる。多層錠は、適切な方法により、組成の異なる粉粒体を層状に積み重ね、圧縮成形することにより製造することができる。有核錠は、内核錠を組成の異なる外層で覆うことにより製造することができる。また、錠剤は、公知の適切な手法を用いて腸溶錠または徐放錠とすることもできる。口腔内速崩錠、チュアブル錠、発泡錠、分散錠、および溶解錠は、添加剤の適切な選択により錠剤に独特の機能を付与したものであり、前記錠剤の製造手法に準じて製造することができる。なお、口腔内速崩錠とは、口腔内で速やかに溶解または崩壊させて服用できる錠剤を;チュアブル錠とは、咀嚼して服用する錠剤を;発泡錠とは、水中で急速に発泡しながら溶解または分散する錠剤を;分散錠とは、水に分散して服用する錠剤を;溶解錠とは、水に溶解して服用する錠剤をいう。発泡錠は、適切な酸性物質、炭酸塩、炭酸水素塩等を添加剤に用いることにより製造することができる。
カプセル剤は、カプセルに充填またはカプセル基剤で被包成形した製剤であり、硬カプセル剤、軟カプセル剤等が含まれる。硬カプセル剤は、有効成分に賦形剤等の添加剤を加えて混和して均質としたもの、または適切な方法で粒状もしくは成形物としたものを、カプセルにそのまま、または軽く成形して充填することにより製造することができる。軟カプセル剤は、有効成分に添加剤を加えたものを、グリセリン、D-ソルビトール等を加えて塑性を増したゼラチン等の適切なカプセル基剤で、一定の形状に被包成形することにより製造することができる。カプセル剤は、公知の適切な手法を用いて腸溶性カプセル剤または徐放性カプセル剤とすることもでき、また、カプセル基剤に着色剤または保存剤等を加えることもできる。
顆粒剤は、粒状に造粒した製剤であり、一般的に顆粒剤と称されるもののほか、発泡性顆粒剤等も含まれる。顆粒剤を製造する際には、通常、下記の(a)、(b)、または(c)の手法:
(a)粉末状の有効成分に賦形剤、結合剤、崩壊剤、またはその他の添加剤を加えて混和して均質にした後、適切な方法により粒状とする;
(b)予め粒状に製した有効成分に賦形剤等の添加剤を加えて混和し、均質とする;
(c)予め粒状に製した有効成分に賦形剤等の添加剤を加えて混和し、適切な方法により粒状とする;
が用いられる。顆粒剤には、必要に応じて剤皮を施すこともでき、また、公知の適切な手法を用いて腸溶性顆粒剤または徐放性顆粒剤とすることもできる。発泡顆粒剤は、適切な酸性物質、炭酸塩、炭酸水素塩等を添加剤に用いることにより製造することができる。なお、発泡顆粒剤とは、水中で急速に発泡しながら溶解または分散する顆粒剤をいう。顆粒剤は、粒子の大きさを調節することにより、細粒剤とすることもできる。
散剤は、粉末状の製剤であり、通常、有効成分に賦形剤またはその他の添加剤を加えて混和し、均質とすることにより製造することができる。
経口液剤は、液状または流動性のある粘稠なゲル状の製剤であり、一般的に経口液剤と称されるもののほか、エリキシル剤、懸濁剤、乳剤、リモナーデ剤等が含まれる。経口液剤は、通常、有効成分に添加剤および精製水を加え、混和して均質に溶解、または乳化もしくは懸濁し、必要に応じて濾過することにより製造することができる。エリキシル剤とは、甘味および芳香のあるエタノールを含む澄明な液状の経口液剤をいい、通常、固形の有効成分またはその浸出液に、エタノール、精製水、着香剤、および白糖、その他の糖類、または甘味剤を加えて溶かし、濾過またはその他の方法によって澄明な液とすることにより製造することができる。懸濁剤とは、有効成分を微細均質に懸濁した経口液剤をいい、通常、固形の有効成分に懸濁化剤またはその他の添加剤と精製水または油を加え、適切な方法で懸濁し、全体を均質とすることにより製造することができる。乳剤とは、有効成分を微細均質に乳化した経口液剤をいい、通常、液状の有効成分に乳化剤と精製水を加え、適切な方法で乳化し、全体を均質とすることにより製造することができる。なお、リモナーデ剤とは、甘味および酸味のある澄明な液状の経口液剤をいう。
シロップ剤は、糖類または甘味剤を含む粘稠性のある液状または固形の製剤であり、シロップ用剤等が含まれる。シロップ剤は、通常、白糖、その他の糖類、もしくは甘味剤の溶液、または単シロップに有効成分を加えて溶解、混和、懸濁、または乳化し、必要に応じて混液を煮沸した後、熱時濾過することにより製造することができる。シロップ用剤とは、水を加えるとシロップ剤となる顆粒状または粉末状の製剤をいい、ドライシロップ剤とも称されることがある。シロップ用剤は、通常、糖類または甘味剤を添加剤として用いて、前記顆粒剤または散剤の製造手法に準じて製造することができる。
経口ゼリー剤は、流動性のない成形したゲル状の製剤であり、通常、有効成分に添加剤および高分子ゲル基剤を加えて混和し、適切な方法でゲル化させ一定の形状に成形することにより製造することができる。
(1)注射剤
注射剤は、皮下、筋肉内、または血管等の体内組織や器官に直接投与する、溶液、懸濁液、もしくは乳濁液、または用時溶解もしくは用時懸濁して用いる固形の無菌製剤であり、一般的に注射剤と称されるもののほか、凍結乾燥注射剤、粉末注射剤、充填済みシリンジ剤、カートリッジ剤、輸液剤、埋め込み注射剤、および持続性注射剤等が含まれる。注射剤を製造する際には、通常、下記の(a)または(b)の手法:
(a)有効成分をそのまま、または有効成分に添加剤を加えたものを注射用水、他の水性溶剤、または非水性溶剤等に溶解、懸濁、もしくは乳化して均質としたものを注射剤用の容器に充填して密封し、滅菌する;
(b)有効成分をそのまま、または有効成分に添加剤を加えたものを注射用水、他の水性溶剤、または非水性溶剤等に溶解、懸濁、もしくは乳化して均質としたものを無菌濾過するか、無菌的に調製して均質としたものを注射剤用の容器に充填して密封する;
が用いられる。凍結乾燥注射剤は、通常、有効成分をそのまま、または有効成分および賦形剤等の添加剤を注射用水に溶解し、無菌濾過し、注射剤用の容器に充填した後に凍結乾燥するか、または専用容器で凍結乾燥した後に直接の容器に充填することにより製造することができる。粉末注射剤は、通常、無菌濾過により処理した後、晶析により得た粉末またはその粉末に滅菌処理した添加剤を加えて注射剤用の容器に充填することにより製造することができる。充填済みシリンジ剤は、通常、有効成分をそのまま、または有効成分および添加剤を用いて溶液、懸濁液、または乳濁液を調製して注射筒に充填することにより製造することができる。カートリッジ剤とは、薬液が充填されたカートリッジを専用の注射器に入れて用いる注射剤をいい、薬液が充填されたカートリッジは、通常、有効成分をそのまま、または有効成分および添加剤を用いて溶液、懸濁液、または乳濁液を調製してカートリッジに充填することにより製造することができる。輸液剤とは、静脈内に投与される通常100mL以上の注射剤をいう。埋め込み注射剤とは、長期にわたる有効成分の放出を目的として、皮下、筋肉内等に埋め込み用の器具を用いて、または手術により適用する固形またはゲル状の注射をいう。埋め込み注射剤は、通常、生分解性高分子化合物を用い、ペレット、マイクロスフェア、またはゲル状にすることにより製造することができる。持続性注射剤とは、長期にわたる有効成分の放出を目的として、筋肉内等に適用する注射剤をいい、通常、有効成分を植物油等に溶解もしくは懸濁するか、または生分解性高分子化合物を用いたマイクロスフェアの懸濁液とすることにより製造することができる。
1)その化合物の予防および/または治療効果の補完および/または増強、
2)その化合物の動態・吸収改善、投与量の低減、および/または
3)その化合物の副作用の軽減
のために他の薬剤と組み合わせて、併用剤として投与してもよい。
クロマトグラフィーによる分離の箇所およびTLCに示されるカッコ内の溶媒は、使用した溶出溶媒または展開溶媒を示し、割合は体積比を表す。
条件A;
カラム:Waters Triart C18(粒子径:1.9 x 10-6 m;カラム長:30 x 2.0 mm I.D.);流速:1.0mL/min;カラム温度:30℃;移動相(A):0.1%トリフルオロ酢酸水溶液(以下、TFAと略記);移動相(B):0.1%TFA-アセトニトリル溶液;グラジエント(移動相(A):移動相(B)の比率を記載):[0分]95:5;[0.1分]95:5;[1.2分]5:95;[1.4分]5:95;[1.41分]95:5;[1.5分]95:5;検出器:UV(PDA)、ELSD、MS。
条件B;
カラム:Waters Triart C18(粒子径:1.9 x 10-6 m;カラム長:30 x 2.0 mm I.D.);流速:1.0mL/min;カラム温度:30℃;移動相(A):0.1%TFA;移動相(B):0.1%TFA-アセトニトリル溶液;グラジエント(移動相(A):移動相(B)の比率を記載):[0分]95:5;[0.15分]95:5;[1.15分]5:95;[2.80分]5:95;[2.81分]95:5;[3分]95:5;検出器:UV(PDA)、ELSD、MS。
条件C;
カラム:ACQUITY UPLC BEH C18(粒子径:1.7 x 10-6 m;カラム長:50 x 2.1 mm);流速:0.6mL/min;カラム温度:35℃;移動相(A):0.1%TFA;移動相(B):0.1%TFA-アセトニトリル溶液;グラジエント(移動相(A):移動相(B)の比率を記載):[0分]97:3;[0.4分]97:3;[2.5分]2:98;[3.5分]2:98;[4.01分]97:3;検出器:UV(PDA)、ELSD、MS。
条件D;
カラム:Xbridge C18(粒子径:3.5 x 10-6 m);流速:1.000mL/min;カラム温度:35℃;移動相(A):10mM 炭酸水素アンモニウム水溶液;移動相(B):アセトニトリル;グラジエント(移動相(A):移動相(B)の比率を記載):[0分]95:5;[0.8分]95:5;[5分]2:98;[6分]2:98;[8.01分]95:5;検出器:UV(PDA)、ELSD、MS。
条件E;
カラム:ACQUITY UPLC BEH C18(粒子径:1.7 x 10-6 m;カラム長:50 x 2.1 mm);流速:0.6mL/min;カラム温度:35℃;移動相(A):0.05%TFA;移動相(B):0.05%TFA-アセトニトリル溶液;グラジエント(移動相(A):移動相(B)の比率を記載):[0分]97:3;[0.4分]97:3;[2.5分]2:98;[3.5分]2:98;[3.8分]97:3;検出器:UV(PDA)、ELSD、MS。
条件F;
カラム:ACQUITY UPLC BEH C18(粒子径:1.7 x 10-6 m;カラム長:50 x 2.1 mm);流速:0.6mL/min;カラム温度:35℃;移動相(A):0.07%TFA;移動相(B):0.07%TFA-アセトニトリル溶液;グラジエント(移動相(A):移動相(B)の比率を記載):[0分]97:3;[0.4分]97:3;[2.5分]2:98;[3.5分]2:98;[3.8分]97:3;検出器:UV(PDA)、ELSD、MS。
移動相A(0.1%TFA):移動相B(0.1%TFA/アセトニトリル)=95:5→5:95
エチル 1H-ピロール-2-カルボキシラート(CAS番号:2199-43-1、2.50g)のN,N-ジメチルアセトアミド(以下、DMAと略記)(3mL)溶液に、ビシクロ[2.2.2]-2-ヘプテン(以下、ノルボルネンと略記)(CAS番号:498-66-8、3.40g)、炭酸水素カリウム(5.40g)、ビス(アセトニトリル)ジクロロパラジウム(II)(CAS番号:14592-56-4、230mg)を加え、超音波により脱気した。反応混合液に1-ブロモ-3-フェニルプロパン(CAS番号:637-59-2、7.20g)を加え、90℃で20時間撹拌した。反応液を酢酸エチル:ヘキサン(1:1)で希釈し、セライト(商品名)でろ過した。ろ液を飽和塩化アンモニウム水溶液及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=95:5→3:1)によって精製することにより、以下の物性値を有する表題化合物(3.82g)を得た。
HPLC保持時間(分):1.12;
MS(ESI, Pos.):258(M+H)+。
参考例1で製造した化合物(0.27g)のトルエン(5mL)溶液に2-ブタノール(0.78g)及びシアノメチレントリブチルホスホラン(以下、CMBPと略記)(CAS番号:157141-27-0、0.76g)を加え、マイクロウェーブ装置を用いて130℃で3時間撹拌した。反応液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=100:0→9:1)によって精製することにより、以下の物性値を有する表題化合物(0.24g)を得た。
HPLC保持時間(分):1.34;
MS(ESI, Pos.):314(M+H)+。
参考例2で製造した化合物(0.24g)の1,2-ジメトキシエタン(以下、DMEと略記)(2mL)溶液にメタノール(2mL)及び50%水酸化カリウム水溶液(1mL)を加え90℃で22時間撹拌した。反応液を放冷後1N塩酸で酸性にし、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=95:5→4:1)によって精製することにより、以下の物性値を有する表題化合物(0.18g)を得た。
HPLC保持時間(分):1.13;
MS(ESI, Pos.):286(M+H)+。
2-ブタノールの代わりに対応するアルコール体を用いて、参考例2→参考例3と同様の反応を行うことにより以下の物性値を有する表題化合物を得た。
HPLC保持時間(分):1.10;
MS(ESI, Pos.):286(M+H)+。
HPLC保持時間(分):1.10;
MS(ESI, Pos.):272(M+H)+。
5-ブロモ-2-(トリフルオロメチル)アニリン(CAS番号:703-91-3、3g)の1,4-ジオキサン(60mL)溶液にエチル 2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)シクロプロパンカルボキシラート(CAS番号:1215107-29-1、3g)、2Mリン酸カリウム水溶液(18.8mL)及び[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド-ジクロロメタン付加物(CAS番号:95464-05-4、1g)を加え100℃で2時間撹拌した。反応液を酢酸エチルで希釈し、水及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後減圧濃縮した。得られた残渣をHPLCにより精製し、以下の物性値を有する表題化合物(0.8g)を得た。
HPLC保持時間(分):1.03;
MS(ESI, Pos.):273(M+H)+。
5-ブロモ-2-(トリフルオロメチル)アニリン(1g)及びビス(ネオペンチルグリコラート)ジボロン(CAS番号:201733-56-4、1.9g)のジメチルスルホキシド(以下、DMSOと略記)(10mL)溶液に、酢酸カリウム(1.2g)及び[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド-ジクロロメタン付加物(340mg)を加え100℃で2時間撹拌した。反応液を水で希釈し、2-メトキシ-2-メチルプロパン(以下、MTBEと略記)で抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=9:1→0:1)によって精製することにより、以下の物性値を有する表題化合物(1g)を得た。
1H-NMR(CDCl3):δ1.55, 3.76, 4.06-4.15, 7.16-7.21, 7.39-7.42。
参考例5で製造した化合物(491mg)及びエチル (1S,2S)-2-ヨードシクロプロパンカルボキシラート(CAS番号:1629125-76-3、400mg)の1,4-ジオキサン(10mL)溶液に、2M炭酸セシウム水溶液(2.2mL)、クロロ(2-ジシクロヘキシルホスフィノ-2’,4’,6’-トリイソプロピルビフェニル)(2’-アミノビフェニル-2-イル)パラジウム(II)(以下、XPhos Pd G2と略記)(CAS番号:1310584-14-5、236mg)を加えて100℃で4.5時間撹拌した。反応液を酢酸エチルで希釈し水及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(NHシリカ)(ヘキサン:酢酸エチル=9:1→0:1)及びシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=9:1→1:1)によって精製することにより、以下の物性値を有する表題化合物(110mg)を得た。
HPLC保持時間(分):0.95;
MS(ESI, Pos.):274(M+H)+。
参考例6で製造した化合物(50mg)のDMF(1mL)溶液にN-クロロスクシンイミド(CAS番号:128-09-6、37mg)を加え60℃で1時間撹拌した。反応液をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=9:1→0:1)で精製することにより、以下の物性値を有する表題化合物(13mg)を得た。
HPLC保持時間(分):1.02;
MS(ESI, Pos.):308(M+H)+。
参考例4で製造した化合物(105mg)及び参考例3で製造した化合物(100mg)のジクロロメタン(1mL)溶液にN,N-ジイソプロピルエチルアミン(以下、DIPEAと略記)(CAS番号:7087-68-5、135mg)及びクロロ-N,N,N’,N’-テトラメチルホルムアミジニウムヘキサフルオロホスファート(以下、TCFHと略記)(CAS番号:94790-35-9、147mg)を加え室温で13時間撹拌した。反応液を減圧濃縮しHPLCで精製することにより、以下の物性値を有する表題化合物(100mg)を得た。
HPLC保持時間(分):1.39;
MS(ESI, Pos.):541(M+H)+。
HPLC保持時間(分):1.22;
MS(ESI, Pos.):513(M+H)+;
1H-NMR(CDCl3):δ0.58-0.82, 1.34-1.53, 1.61-2.22, 2.54-2.81, 4.63-5.18, 5.93-6.04, 6.58-6.71, 7.07-7.13, 7.17-7.24, 7.28-7.35, 7.46-7.54, 7.86-7.97, 8.06-8.18。
参考例4で製造した化合物の代わりに5-ブロモ-2-(トリフルオロメチル)アニリンを用いて、参考例3で製造した化合物の代わりに参考例3-1で製造した化合物を用いて、参考例8と同様の反応を行うことにより、以下の物性を有する表題化合物を得た。
HPLC保持時間(分):1.43;
MS(ESI, Pos.):507(M+H)+。
参考例9で製造した化合物(200mg)の1,4-ジオキサン溶液(2mL)にエチル 2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)シクロプロパンカルボキシラート(94mg)、2Mリン酸カリウム水溶液(0.59mL)及び[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド-ジクロロメタン付加物(96mg)を加えマイクロウェーブ装置を用いて120℃で1時間撹拌した。この反応液を精製せずそのまま次反応に用いた。
HPLC保持時間(分):1.22;
MS(ESI, Pos.):513(M+H)+;
1H-NMR(CDCl3):δ0.76, 1.36-1.45, 1.51, 1.62-1.72, 1.73-1.87, 1.90-2.14, 2.57-2.79, 4.58-5.27, 5.98, 6.65, 7.03, 7.17-7.24, 7.28-7.35, 7.47, 7.94, 8.22。
5-ブロモ-2-(トリフルオロメチル)アニリンの代わりに対応するアニリン誘導体を用い、エチル 2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)シクロプロパンカルボキシラートまたは対応するボロン酸エステルを用いて、参考例9→参考例10→実施例2と同様の操作を行うことにより、以下の物性を有する本発明化合物を得た。
MS(ESI, Pos.):459(M+H)+;
1H-NMR(CDCl3):δ0.68-0.81, 1.31-1.39, 1.50, 1.61-1.87, 1.96-2.12, 2.26-2.30, 2.51-2.80, 4.21-5.10, 5.95, 6.61, 6.83, 7.11-7.36, 7.58。
MS(ESI, Pos.):459(M+H)+;
1H-NMR(CDCl3):δ0.76, 1.36-1.47, 1.52, 1.57-1.66, 1.71-2.08, 2.31, 2.49-2.61, 2.65-2.81, 4.43-5.37, 5.95, 6.59, 6.65, 7.09-7.36, 7.49-7.57。
MS(ESI, Pos.):513(M+H)+;
1H-NMR(CDCl3):δ0.73-0.80, 1.42-1.57, 1.95-2.09, 2.14-2.28, 2.61-2.87, 4.32-5.33, 5.97, 6.67, 7.17-7.36, 7.42, 7.54-7.59, 7.62-7.78。
MS(ESI, Pos.):513(M+H)+;
1H-NMR(CDCl3):δ0.77, 1.47-1.57, 1.63-1.88, 1.90-2.08, 2.63-2.93, 4.26-5.25, 5.98, 6.66, 7.12-7.34, 7.39, 7.44-7.50, 7.57-7.62, 7.68。
2-ブタノールの代わりにイソプロパノールを用いて、エチル 2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)シクロプロパンカルボキシラートの代わりに対応するボロン酸エステルを用いて、参考例2→参考例3→参考例9→参考例10→実施例1と同様の反応を行うことにより、下記物性値を有する本発明化合物を得た。
MS(ESI, Pos.):499(M+H)+;
1H-NMR(CDCl3):δ1.39-1.47, 1.52, 1.64-1.74, 1.96-2.13, 2.58-2.80, 5.00-5.21, 5.97, 6.65, 6.90-7.17, 7.17-7.24, 7.28-7.36, 7.48, 7.95, 8.26。
MS(ESI, Pos.):499(M+H)+;
1H-NMR(CDCl3):δ1.45-1.51, 1.54, 1.66-1.76, 1.96-2.09, 2.60-2.83, 5.05-5.18, 5.97, 6.65, 6.89, 7.18-7.24, 7.28-7.34, 7.51, 7.98, 8.17。
1-フルオロ-4-ヨード-2-ニトロベンゼン(CAS番号:364-75-0、3.2g)のメタノール(10mL)溶液に28%ナトリウムメトキシドのメタノール溶液(7.3mL)を加え50℃で15時間撹拌した。反応液を酢酸エチルで希釈し、水及び飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し減圧濃縮することで以下の物性値を有する表題化合物(3.3g)を得た。
HPLC保持時間(分):0.94;
1H-NMR(CDCl3):δ3.95, 6.87, 7.81, 8.12。
参考例11で製造した化合物(2.3g)の酢酸(10mL)溶液に水(1mL)及び鉄粉(1.4g)を加え50℃で6時間撹拌した。反応液をMTBE及びヘキサンで希釈し、セライト(商品名)でろ過した。ろ液を2N水酸化ナトリウム水溶液及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(NHシリカ)(ヘキサン:酢酸エチル=9:1→1:1)によって精製することにより、以下の物性値を有する表題化合物(1.8g)を得た。
HPLC保持時間(分):0.63;
MS(ESI, Pos.):250(M+H)+。
参考例4で製造した化合物の代わりに参考例12で製造した化合物を用いて、参考例3で製造した化合物の代わりに参考例3-1で製造した化合物を用いて、参考例8と同様の反応を行うことにより、以下の物性を有する表題化合物を得た。
HPLC保持時間(分):1.41;
MS(ESI, Pos.):517(M+H)+。
参考例13で製造した化合物(50mg)及びビス(ネオペンチルグリコラート)ジボロン(43mg)のDMSO(1mL)溶液に酢酸カリウム(28mg)及び[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド-ジクロロメタン付加物(8mg)を加え100℃で1時間撹拌した。反応液をMTBEで希釈して水及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=9:1→0:1)によって精製することにより、以下の物性値を有する表題化合物(35mg)を得た。
HPLC保持時間(分):1.14。
参考例14で製造した化合物(35mg)及びエチル (1S,2S)-2-ヨードシクロプロパンカルボキシラート(22.3mg)の1,4-ジオキサン溶液(1mL)に2M炭酸セシウム水溶液(0.17mL)及びXPhos Pd G2(11mg)を加えて100℃で30分撹拌した。反応液は精製せずにそのまま次反応に使用した。
HPLC保持時間(分):1.39;
MS(ESI, Pos.):475(M+H)+;
1H-NMR(CDCl3):δ0.72-0.81, 1.33-1.44, 1.48-1.55, 1.62-1.71, 1.75-2.16, 2.59-2.79, 3.83-3.87, 4.62-5.16, 5.93-5.99, 6.59-6.66, 6.75-6.81, 6.87-6.94, 7.14-7.24, 7.27-7.35, 8.17-8.27, 8.32-8.36。
実施例2で製造した化合物(50mg)のジクロロメタン(1mL)及びアセトニトリル(1mL)溶液にDIPEA(63mg)、L-メントール(45mg)、4-ジメチルアミノピリジン(以下、DMAPと略記)及び1-(クロロ-1-ピロリジニルメチレン)ピロリジニウムヘキサフルオロホスファート(以下、CyCIUと略記)(CAS番号:135540-11-3、65mg)を加え70℃で2時間撹拌した。反応液を濃縮し次の分割に用いた。
参考例16で得られた混合物をHPLCによって精製することにより、以下の物性値を有する表題化合物を得た。
HPLC保持時間(分):1.67(条件B);
MS(ESI, Pos.):651(M+H)+。
HPLC保持時間(分):1.70(条件B);
MS(ESI, Pos.):651(M+H)+。
HPLC保持時間(分):1.29;
MS(ESI, Pos.):513(M+H)+;
1H-NMR(CDCl3):δ0.72-0.81, 1.17-1.47, 1.48-1.54, 1.63-1.87, 1.92-2.16, 2.58-2.80, 4.38-4.84, 5.95-6.01, 6.62-6.68, 7.03-7.08, 7.17-7.24, 7.28-7.35, 7.44-7.51, 7.91-7.98, 8.19-8.24。
HPLC保持時間(分):1.29;
MS(ESI, Pos.):513(M+H)+;
1H-NMR(CDCl3):δ0.76, 1.37-1.46, 1.52, 1.62-1.72, 1.73-1.86, 1.89-2.17, 2.56-2.82, 4.34-5.29, 5.98, 6.65, 7.02, 7.17-7.24, 7.27-7.35, 7.47, 7.94, 8.22。
HPLC保持時間(分):1.41;
MS(ESI, Pos.):479(M+H)+;
1H-NMR(DMSO-d6):δ0.62-0.69, 1.11-1.51, 1.63-2.12, 2.34-2.80, 4.58-5.26, 5.88-6.00, 6.83-6.88, 6.97-7.07, 7.12-7.41, 7.50-7.56, 9.20-9.24, 11.90。
エチル 1H-ピロール-2-カルボキシラート(37g)及びノルボルネン(50g)のDMA(265mL)溶液に炭酸水素カリウム(80g)、2-ブロモエトキシメチルベンゼン(CAS番号:1462-37-9、57g)及びビス(アセトニトリル)ジクロロパラジウム(II)(3.5g)を加え100℃で24時間撹拌した。反応液に水を加えセライト(商品名)でろ過し、ろ液を酢酸エチルで抽出した。有機層を水及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=8:1→6:1)で精製した。得られた残渣をヘプタンに溶解し、メタノールと水1:1の混合液で洗浄し、へプタン層を無水硫酸ナトリウムで乾燥後減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=99:1→6:4)で精製することにより、以下の物性値を有する表題化合物(11g)を得た。
TLC:Rf 0.34 (ヘキサン:酢酸エチル=5:1);
HPLC保持時間(分):1.04;
MS(ESI, Pos.):274(M+H)+。
参考例17で製造した化合物(6g)のトルエン(22mL)溶液に(R)-(-)-2-ブタノール(CAS番号:14898-79-4、12mL)及びCMBP(12mL)を加えてマイクロウェーブ装置を用いて130℃で3時間撹拌した。反応液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=95:5)で精製することにより、以下の物性値を有する表題化合物(4.6g)を得た。
HPLC保持時間(分):1.32;
MS(ESI, Pos.):330(M+H)+。
参考例18で製造した化合物(3g)の1-メチルピロリジノン(以下、NMPと略記)(8mL)及びメタノール(2.7mL)の溶液に50%水酸化カリウム水溶液(2.7mL)を加え85℃で1時間撹拌した。反応液にMTBEを加え氷冷して10%のリン酸水溶液でpH5にし、酢酸エチルで抽出した。有機層を水及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後減圧濃縮することで、以下の物性値を有する表題化合物(2.7g)を得た。
1H-NMR(CDCl3):δ0.69-0.80, 1.45-1.55, 1.74-1.92, 1.96-2.08, 2.91-3.11, 3.69-3.78, 4.53-4.59, 5.16-5.92, 5.95-6.02, 7.09-7.15, 7.27-7.40。
参考例3で製造した化合物の代わりに参考例19で製造した化合物を用いて、参考例4で製造した化合物の代わりに参考例6で製造した化合物を用いて、参考例8と同様の操作を行うことにより、以下の物性値を有する表題化合物(305mg)を得た。
HPLC保持時間(分):1.27;
MS(ESI, Pos.):557(M+H)+。
HPLC保持時間(分):1.13;
MS(ESI, Pos.):529(M+H)+;
1H-NMR(CDCl3):δ0.61-0.70, 1.05-1.31, 1.33-1.46, 1.80-2.03, 2.20-2.39, 2.93-3.02, 3.69-3.75, 4.53-4.57, 4.64-4.95, 5.94-5.98, 6.61-6.66, 7.13-7.39, 7.41-7.48, 7.57-7.64, 7.80-7.87。
参考例18で製造した化合物(1.5g)の酢酸エチル(30mL)溶液に水酸化パラジウム(CAS番号:12135-22-7、300mg)を加え、水素雰囲気下、室温で6時間撹拌した。反応液をセライト(商品名)でろ過し減圧濃縮した。得られた残渣は精製せずそのまま次反応に用いた。
参考例21で製造した反応混合物と2-フルオロピリジン-4-オール(CAS番号:22282-69-5、1g)のトルエン(15mL)溶液にCMBP(2.2g)を加え90℃で2時間撹拌した。反応液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=9:1→0:1)で精製することにより、以下の物性値を有する表題化合物(0.95g)を得た。
HPLC保持時間(分):1.20;
MS(ESI, Pos.):335(M+H)+。
参考例22で製造した化合物(0.95g)のNMP(15mL)溶液に5N水酸化ナトリウム水溶液(5mL)を加え80℃で2時間撹拌した。反応液をMTBEで洗浄後、水層を5%リン酸水溶液で中和し、MTBEで抽出した。有機層を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=9:1→0:1)及びジオールシリカ(富士シリシア社製、クロマトレックスDIOL60)を用いたカラムクロマトグラフィーで精製することにより、以下の物性値を有する表題化合物(0.19g)を得た。
HPLC保持時間(分):0.95;
MS(ESI, Pos.):307(M+H)+。
HPLC保持時間(分):1.11;
MS(ESI, Pos.):534(M+H)+;
1H-NMR(DMSO-d6):δ0.70, 1.20-1.28, 1.32-1.39, 1.42-1.57, 1.71-1.87, 2.04-2.12, 2.63-2.74, 3.12-3.20, 4.35-4.41, 4.68-5.27, 6.05, 6.81, 6.92-6.96, 7.29, 7.36-7.41, 7.61, 8.04, 9.44, 11.98。
参考例20で製造した化合物(220mg)のジクロロメタン(10mL)溶液に氷冷下、1Mの三臭化ホウ素のジクロロメタン溶液(CAS番号:10294-33-4、0.6mL)を加え室温で2.5時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えて酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=1:9→0:1)で精製することにより、以下の物性値を有する表題化合物(140mg)を得た。
HPLC保持時間(分):1.02;
MS(ESI, Pos.):467(M+H)+。
参考例24で製造した化合物(0.8g)のトルエン(20mL)懸濁液に2-クロロ-6-フルオロピリジン-4-オール(CAS番号:1807206-99-0、0.3g)およびCMBP(0.5g)を加え90℃で1時間撹拌した。反応液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=3:97→1:1)で精製することにより、以下の物性値を有する表題化合物(0.9g)を得た。
HPLC保持時間(分):1.43;
MS(ESI, Pos.):596(M+H)+。
HPLC保持時間(分):1.31;
MS(ESI, Pos.):568(M+H)+;
1H-NMR(DMSO-d6):δ0.67-0.73, 1.21-1.29, 1.33-1.41, 1.43-1.50, 1.51-1.58, 1.71-1.84, 2.03-2.20, 2.63-2.73, 3.10-3.19, 4.39-4.45, 4.94-5.44, 6.02-6.07, 6.77-6.84, 6.87-6.93, 7.15-7.20, 7.25-7.31, 7.37-7.40, 7.61, 9.42-9.46, 11.98。
2-クロロ-6-フルオロピリジン-4-オールの代わりに対応するアルコール体を用いて、参考例25→実施例10と同様の操作を行うことにより、以下の物性値を有する本発明化合物を得た。
HPLC保持時間(分):1.37;
MS(ESI, Pos.):585(M+H)+;
1H-NMR(CDCl3):δ0.83, 1.42-1.53, 1.61, 1.68-1.80, 1.83-1.97, 2.02-2.16, 2.63-2.77, 3.26-3.33, 4.22-4.30, 4.71-5.33, 6.07-6.14, 6.47-6.62, 6.65-6.70, 7.11-7.16, 7.50-7.56, 7.90-7.97, 8.14-8.20。
HPLC保持時間(分):1.32;
MS(ESI, Pos.):551(M+H)+;
1H-NMR(CDCl3):δ0.82, 1.41-1.52, 1.59, 1.69-1.77, 1.83-1.95, 1.98-2.25, 2.61-2.76, 3.16-3.29, 4.27, 4.69-5.28, 6.08, 6.67, 6.74-6.98, 7.12, 7.48-7.55, 7.94, 8.18。
HPLC保持時間(分):1.14;
MS(ESI, Pos.):519(M+H)+;
1H-NMR(CDCl3):δ 0.82, 1.40-1.51, 1.58, 1.67-1.75, 1.78-1.92, 1.95-2.21, 2.60-2.74, 3.15, 3.84, 4.14, 4.66-5.21, 6.03, 6.66, 7.06-7.16, 7.48-7.56, 7.94, 8.19。
4-ヒドロキシ-2,6-ジメチル安息香酸メチル(CAS番号:83194-70-1、2.5g)のDMF(10mL)溶液に炭酸カリウム(5.8g)及び2-ブロモエチルベンゼン(CAS番号:103-63-9、7.7g)を加え80℃で15時間撹拌した。さらに2-ブロモエチルベンゼン(1.4g)及び炭酸カリウム(1g)を追加して終夜撹拌した。反応液を酢酸エチルとヘキサンで希釈し、水及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=9:1→7:3)で精製することにより、以下の物性値を有する表題化合物(3.3g)を得た。
HPLC保持時間(分):1.15;
MS(ESI, Pos.):285(M+H)+;
1H-NMR(CDCl3):δ 2.29, 3.08, 3.88, 4.16, 6.56, 7.11-7.46。
参考例26で製造した化合物(2g)のNMP(2mL)溶液に50%水酸化カリウム水溶液(4mL)を加え120℃で3時間撹拌した。反応液を酢酸エチルとヘキサンで洗浄し、塩酸で酸性にして酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し無水硫酸ナトリウムで乾燥後減圧濃縮した。得られた残渣をヘキサンでスラリー洗浄することにより、以下の物性値を有する表題化合物(0.83g)を得た。
HPLC保持時間(分):0.98;
MS(ESI, Pos.):271(M+H)+。
HPLC保持時間(分):1.15;
MS(ESI, Pos.):498(M+H)+;
1H-NMR(CDCl3):δ1.47, 1.66-1.77, 2.11-2.22, 2.35, 2.62-2.74, 3.10, 4.17, 6.60, 7.14, 7.21-7.37, 7.43-7.54, 8.27。
4-ヒドロキシ-2,6-ジメチル安息香酸メチルの代わりに対応するフェノール体を用い、参考例4で製造した化合物の代わりに参考例6で製造した化合物を用いて、参考例26→参考例27→参考例8→実施例1と同様の操作を行うことにより、以下の物性値を有する本発明化合物を得た。
MS(ESI, Pos.):484(M+H)+;
1H-NMR(DMSO-d6):δ0.95-1.02, 1.21-1.29, 1.70-1.79, 2.04-2.13, 2.40, 3.05, 4.24, 6.83-6.89, 7.20-7.27, 7.29-7.43, 7.44-7.52, 9.76。
MS(ESI, Pos.):504(M+H)+;
1H-NMR(DMSO-d6):δ1.36-1.41, 1.51-1.59, 2.07-2.15, 2.64-2.75, 3.05, 4.29, 7.02-7.07, 7.05, 7.21-7.28, 7.29-7.37, 7.42-7.52, 7.65, 10.06, 12.01。
MS(ESI, Pos.):538(M+H)+;
1H-NMR(DMSO-d6):δ1.30-1.38, 1.45-1.56, 2.02-2.13, 2.56-2.69, 3.08, 4.35, 7.20-7.41, 7.55-7.67, 10.19, 12.01。
4-ブロモ-2,6-ジメチル安息香酸メチル(CAS番号:90841-46-6、1g)のDMF(1mL)溶液にアリルベンゼン(CAS番号:300-57-2、0.73g)、酢酸パラジウム(CAS番号:3375-31-3、46mg)、トリ-2-トリルホスフィン(CAS番号:6163-58-2、0.19g)及びDIPEA(1.6g)を加えて、窒素雰囲気下90℃で6時間、120℃で3時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を水及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=7:3→2:3)で精製することにより、以下の物性値を有する表題化合物(1.1g)を得た。
HPLC保持時間(分):1.27;
MS(ESI, Pos.):281(M+H)+。
参考例28で製造した化合物(180mg)の酢酸エチル(1mL)溶液に水酸化パラジウム(45mg)を加え、水素雰囲気下、室温で1.5時間撹拌した。反応液をセライト(商品名)でろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=100:0→95:5)で精製することにより、以下の物性値を有する表題化合物(160mg)を得た。
1H-NMR(CDCl3):δ1.87-1.97, 2.29, 2.57, 2.64, 3.90, 6.85, 7.15-7.23, 7.25-7.32。
参考例29で製造した化合物(160mg)のNMP(2mL)溶液に水(2mL)及び水酸化カリウム(600mg)を加え120℃で21時間撹拌した。反応液に1N塩酸を加えて酸性にして、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後減圧濃縮することにより、以下の物性値を有する表題化合物(210mg)を得た。
1H-NMR(CDCl3):δ1.89-1.97, 2.40, 2.59, 2.65, 6.88, 7.15-7.24, 7.26-7.33。
4-ヒドロキシ-2,6-ジメチル安息香酸(CAS番号:75056-97-2、3g)の酢酸エチル(18mL)懸濁液に、無水酢酸(2mL)及びピリジン(1.8mL)を加え室温で終夜撹拌した。反応液を酢酸エチルで希釈し、希塩酸及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後減圧濃縮した。得られた残渣をヘキサン及び酢酸エチルでスラリー洗浄することにより、以下の物性値を有する表題化合物(2.9g)を得た。
1H-NMR(CDCl3):δ 2.30, 2.45, 6.82。
参考例31で製造した化合物(50g)のDMF(175mL)溶液に炭酸カリウム(50g)及びベンジルブロミド(43g)を加え室温で3時間撹拌した。反応液にメタノール(125mL)及び炭酸カリウム(50g)を加え室温で1時間撹拌した。反応液を5N塩酸及び水で希釈し酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後減圧濃縮した。得られた残渣をヘキサンでスラリー洗浄することにより、以下の物性値を有する表題化合物(57g)を得た。
TLC:Rf 0.60(ヘキサン:酢酸エチル=2:1);
1H-NMR(DMSO-d6):δ2.13, 3.32, 5.27, 6.44, 7.31-7.48, 9.63。
参考例32で製造した化合物(1.6g)のTHF(10mL)溶液に2-(2,4-ジフルオロフェニル)エタノール(CAS番号:81228-02-6、1g)、トリフェニルホスフィン(2.5g)及びジエチルアゾジカルボキシラート(以下、DEADと略記)のトルエン溶液(2.2M,4.3mL)を加え室温で5時間撹拌した。さらにDEADのトルエン溶液(2.2M,2mL)を加え室温で30分撹拌した。反応液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=95:5→75:25)で精製することにより、以下の物性値を有する表題化合物(1.8g)を得た。
TLC:Rf 0.79(ヘキサン:酢酸エチル=3:1)。
参考例33で製造した化合物(1.8g)のメタノール(20mL)溶液に10%パラジウム/カーボン(0.6g)を加え、水素雰囲気下、室温で3.5時間撹拌した。反応液をセライト(商品名)でろ過し、ろ液を減圧濃縮することにより、以下の物性値を有する表題化合物(1.4g)を得た。
1H-NMR(CDCl3):δ2.40, 3.08, 4.15, 6.57, 6.76-6.88, 7.17-7.28。
参考例30で製造した化合物(23mg)のトルエン(1mL)懸濁液に塩化チオニル(0.01mL)を加え80℃で1時間撹拌した。反応液を減圧濃縮し、得られた残渣をアセトニトリル(1mL)に溶解した。反応液に参考例6で製造した化合物(20mg)を加えて室温で21時間撹拌した。反応液を濃縮し次の反応に使用した。
HPLC保持時間(分):1.32;
MS(ESI, Pos.):496(M+H)+;
1H-NMR(CDCl3):δ1.46-1.54, 1.67-1.79, 1.89-2.00, 2.16-2.24, 2.36, 2.56-2.74, 6.90, 7.15-7.23, 7.26-7.32, 7.46-7.57, 8.17。
参考例30で製造した化合物の代わりに参考例34で製造した化合物を用いて参考例35→実施例12と同様の操作を行うことにより、以下の物性値を有する本発明化合物を得た。
MS(ESI, Pos.):534(M+H)+;
1H-NMR(CDCl3):δ1.46-1.56, 1.75, 2.15-2.27, 2.35, 2.66-2.78, 3.09, 4.15, 6.59, 6.76-6.89, 7.16-7.32, 7.46-7.57, 8.23。
1-ブロモ-2,3-ジクロロ-4-フルオロベンゼン(CAS番号:1093092-14-8、200mg)の1,4-ジオキサン(6mL)溶液にエチル 2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)シクロプロパンカルボキシラート(197mg)、2Mリン酸カリウム水溶液(1.2mL)、及び[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド-ジクロロメタン付加物(134mg)を加え、100℃で20時間撹拌した。反応液を酢酸エチルで希釈し水及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=97:3→3:1)で精製することにより、以下の物性値を有する表題化合物を含む混合物(150mg)を得た。
HPLC保持時間(分):1.12, 1.17;
MS(ESI, Pos.):277(M+H)+。
参考例36で製造した混合物(150mg)の濃硫酸(0.15mL)溶液に氷冷下、濃硫酸(0.15mL)と発煙硝酸(0.07mL)の混合物を滴下し、室温で1時間撹拌した。反応液を氷に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後減圧濃縮した。得られた残渣は精製せずそのまま次の反応に使用した。
参考例11で製造した化合物の代わりに参考例37で製造した化合物を用いて参考例12と同様の操作を行うことにより、表題化合物を含む混合物を得た。
参考例30で製造した化合物の代わりに参考例27で製造した化合物を用いて、参考例6で製造した化合物の代わりに参考例38で製造した化合物を用いて参考例35→実施例1と同様の操作を行った後、HPLCで分取精製することにより以下の物性値を有する本発明化合物を得た。
MS(ESI, Pos.):516(M+H)+;
1H-NMR(CDCl3):δ1.53-1.60, 1.69-1.77, 2.23-2.31, 2.34, 2.57-2.66, 3.10, 4.18, 6.60, 7.20-7.37, 7.39-7.43, 8.37。
MS(ESI, Pos.):516 (M+H)+;
1H-NMR(CDCl3):δ1.50-1.62, 1.68-1.81, 1.85-1.94, 2.33, 2.74-2.87, 3.10, 4.18, 6.61, 7.21-7.38, 7.44, 8.25。
参考例27で製造した化合物(8mg)及び参考例7で製造した化合物(6mg)のアセトニトリル(0.5mL)溶液にDIPEA(4mg)及びオキシ塩化リン(3mg)を加え50℃で2時間撹拌した。反応液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=95:5→4:1)で精製することにより、以下の物性値を有する表題化合物(6mg)を得た。
HPLC保持時間(分):1.25;
MS(ESI, Pos.):560(M+H)+。
HPLC保持時間(分):1.12;
MS(ESI, Pos.):532(M+H)+;
1H-NMR(CDCl3:δ1.54-1.62, 1.67-1.76, 2.22-2.37, 2.59-2.66, 3.10, 4.16-4.20, 6.59, 7.18-7.37, 7.45, 7.59, 8.30。
MS(ESI, Pos.):464(M+H)+;
1H-NMR(CDCl3):δ1.21-1.27, 1.30-1.36, 1.42-1.49, 2.00-2.07, 2.28-2.32, 2.99-3.05, 4.19, 6.67, 7.06-7.10, 7.19-7.24, 7.28-7.34, 7.36-7.41, 7.49, 9.90, 11.94。
参考例11で製造した化合物の代わりに3-ブロモ-4,5-ジクロロニトロベンゼンを用い、参考例30で製造した化合物の代わりに参考例27で製造した化合物を用い、エチル 2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)シクロプロパンカルボキシラートの代わりに対応するボロン酸エステルを用いて参考例12→参考例35→参考例10→実施例1と同様の操作を行った後、HPLCで分取精製することにより、下記物性値を有する本発明化合物を得た。
MS(ESI, Pos.):498(M+H)+;
1H-NMR(CDCl3):δ1.44-1.69, 2.32, 2.56-2.70, 3.07-3.12, 4.13-4.19, 6.58, 7.20-7.38, 7.91。
MS(ESI, Pos.):498(M+H)+;
1H-NMR(CDCl3):δ1.39-1.49, 1.67-1.73, 1.81-1.88, 2.32, 2.73-2.90, 3.10, 4.17, 6.59, 7.19-7.42, 7.72。
参考例27で製造した化合物(1g)及び5-ブロモ-2-(トリフルオロメチル)アニリン(1.1g)のアセトニトリル溶液(10mL)にDIPEA(0.72g)及びオキシ塩化リン(0.62g)を加え50℃で12時間撹拌した。反応液にオキシ塩化リン(0.12g)追加し6時間撹拌した。反応液を室温に戻し1N水酸化ナトリウム水溶液(10mL)を加え10分撹拌した。析出した沈殿をろ取し、ヘキサンで洗浄することにより、下記物性値を有する表題化合物(1.5g)を得た。
HPLC保持時間(分):1.26;
MS(ESI, Pos.):492(M+H)+。
参考例40で製造した化合物(500mg)のDME(5mL)溶液にビス(ネオペンチルグリコラート)ジボロン(459mg)および酢酸カリウム(300mg)を加え脱気し、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド-ジクロロメタン付加物(83mg)を加えて88℃で1.5時間撹拌した。反応液をMTBEで希釈し、セライト(商品名)でろ過した。ろ液を水で洗浄し無水硫酸ナトリウムで乾燥後減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=95:5→1:4)で精製することにより、以下の物性値を有する表題化合物(508mg)を得た。
HPLC保持時間(分):1.03。
参考例41で製造した化合物(488mg)の1,4-ジオキサン(5.4mL)溶液にエチル (1S,2S)-2-ヨードシクロプロパンカルボキシラート(185mg)及び2M炭酸セシウム水溶液(1.2mL)を加えて脱気し、XPhos Pd G2(122mg)を加え100℃で1.5時間撹拌した。反応液をMTBEで希釈し、水で洗浄して無水硫酸ナトリウムで乾燥後減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=95:5→0:1)で精製することにより、以下の物性値を有する表題化合物(316mg)を得た。
HPLC保持時間(分):1.20;
MS(ESI, Pos.):526(M+H)+。
HPLC保持時間(分):1.06;
MS(ESI, Pos.):498(M+H)+;
1H-NMR(CDCl3):δ1.39-1.51, 1.64-1.75, 2.09-2.21, 2.34, 2.62-2.73, 3.10, 4.15-4.21, 6.59, 7.11-7.18, 7.22-7.37, 7.45-7.53, 8.24。
HPLC保持時間(分):1.08;
MS(ESI, Pos.):498(M+H)+;
1H-NMR(CDCl3):δ1.43-1.53, 1.68-1.77, 2.10-2.21, 2.34, 2.63-2.76, 3.10, 4.17, 6.59, 7.17, 7.22-7.36, 7.47-7.58, 8.22。
参考例31で製造した化合物(914mg)のトルエン(5mL)懸濁液に塩化チオニル(0.4mL)及びDMF(42mg)を加え75℃で2時間撹拌した。反応液を減圧濃縮し、得られた残渣に参考例6で製造した化合物(1g)のアセトニトリル溶液を加えて55℃で2時間撹拌した。反応液をヘキサン及びMTBEで希釈し1N水酸化ナトリウム水溶液、5N塩酸及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=9:1→1:1)で精製することにより、以下の物性値を有する表題化合物(1.4g)を得た。
HPLC保持時間(分):1.03;
MS(ESI, Pos.):464(M+H)+。
参考例43で製造した化合物(1.4g)のエタノール(40mL)溶液に炭酸カリウム(1.3g)を加え室温で22時間撹拌した。反応液をセライト(商品名)でろ過し、ろ液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=9:1→0:1)で精製することにより、以下の物性値を有する表題化合物(1.1g)を得た。
HPLC保持時間(分):0.94;
MS(ESI, Pos.):422(M+H)+。
HPLC保持時間(分):1.05;
MS(ESI, Pos.):502(M+H)+;
1H-NMR(CDCl3):δ1.45-1.53, 1.71-1.78, 2.15-2.23, 2.36, 2.64-2.76, 2.93, 3.87, 4.04-4.11, 6.61, 7.18, 7.27, 7.40, 7.48, 7.53, 8.29。
2-(1-メチル-1H-ピラゾール-4-イル)エタノールの代わりに対応するアルコール体を用いて、実施例20と同様の操作を行うことにより、以下の物性値を有する本発明化合物を得た。
MS(ESI, Pos.):462(M+H)+;
1H-NMR(CDCl3):δ0.09-0.17, 0.47-0.53, 0.77-0.91, 1.44-1.55, 1.65-1.78, 2.20, 2.36, 2.63-2.75, 4.04, 6.62, 7.20, 7.46-7.58, 8.18。
HPLC保持時間(分):1.19;
MS(ESI, Pos.):436(M+H)+;
1H-NMR(CDCl3):δ1.04, 1.45-1.53, 1.66-1.87, 2.11-2.26, 2.35, 2.62-2.74, 3.93, 6.60, 7.20, 7.44-7.58, 8.17。
HPLC保持時間(分):1.14;
MS(ESI, Pos.):478(M+H)+;
1H-NMR(CDCl3):δ0.86-0.98, 1.04-1.16, 1.03-1.55, 1.72-1.83, 1.84-1.95, 2.19-2.31, 3.95, 6.53, 7.07-7.14, 7.31-7.39, 7.46-7.57, 7.67-7.76。
HPLC保持時間(分):1.22;
MS(ESI, Pos.):484(M+H)+;
1H-NMR(CDCl3):δ1.43-1.55, 1.73, 2.14-2.27, 2.36, 2.65-2.76, 5.07, 6.69, 7.20, 7.31-7.46, 7.49-7.59, 8.17。
HPLC保持時間(分):1.07;
MS(ESI, Pos.):452(M+H)+;
1H-NMR(DMSO-d6):δ1.35-1.43, 1.49-1.59, 2.05-2.15, 2.30, 2.63-2.79, 3.30, 3.60-3.68, 4.08, 6.67, 7.27-7.34, 7.44, 7.58-7.68, 9.95, 12.03。
HPLC保持時間(分):1.21;
MS(ESI, Pos.):506(M+H)+;
1H-NMR(CDCl3):δ1.22-1.76, 1.80-1.96, 2.15-2.24, 2.35, 2.63-2.77, 3.35-3.60, 3.91-4.18, 6.62, 7.19, 7.46-7.57, 8.19。
HPLC保持時間(分):1.20;
MS(ESI, Pos.):488(M+H)+;
1H-NMR(CDCl3):δ1.45-1.55, 1.69-1.76, 2.16-2.23, 2.35, 2.62-2.77, 3.13, 4.22, 6.15, 6.32, 6.61, 7.20, 7.29-7.40, 7.44-7.59, 8.18。
HPLC保持時間(分):1.30;
MS(ESI, Pos.):532(M+H)+;
1H-NMR(CDCl3):δ1.43-1.53, 1.67-1.78, 2.18, 2.34, 2.61-2.74, 3.24, 4.20, 6.61, 7.14-7.26, 7.32-7.42, 7.44-7.50, 7.50-7.56, 8.22。
HPLC保持時間(分):1.30;
MS(ESI, Pos.):532(M+H)+;
1H-NMR(CDCl3):δ1.44-1.55, 1.67-1.77, 2.16-2.24, 2.35, 2.65-2.74, 3.07, 4.17, 6.59, 7.14-7.31, 7.45-7.55, 8.20。
HPLC保持時間(分):0.84;
MS(ESI, Pos.):488(M+H)+;
1H-NMR(CDCl3):δ1.46-1.55, 1.69-1.78, 2.17-2.27, 2.33, 2.65-2.74, 4.28-4.34, 4.52-4.59, 6.55, 7.19-7.30, 7.37, 7.48, 7.53-7.57, 8.18, 8.96。
HPLC保持時間(分):1.26;
MS(ESI, Pos.):534(M+H)+;
1H-NMR(CDCl3):δ1.45-1.56, 1.67-1.79, 2.15-2.26, 2.34, 2.65-2.76, 3.18, 4.16, 6.60, 6.83-6.94, 7.14-7.25, 7.45-7.57, 8.19。
HPLC保持時間(分):1.27;
MS(ESI, Pos.):534(M+H)+;
1H-NMR(CDCl3):δ1.57-1.58, 1.70-1.79, 2.15-2.28, 2.36, 2.68-2.78, 3.07, 4.17, 6.60, 6.65-6.73, 6.78-6.88, 7.17-7.23, 7.50, 7.55, 8.23。
HPLC保持時間(分):1.09;
MS(ESI, Pos.):524(M+H)+;
1H-NMR(DMSO-d6):δ1.35-1.47, 1.51-1.60, 2.32, 2.65-2.74, 5.21, 6.79, 7.31-7.36, 7.40-7.48, 7.54-7.60, 7.65,7.84, 8.09, 9.95, 12.62-13.37。
HPLC保持時間(分):1.33;
MS(ESI, Pos.):538(M+H)+;
1H-NMR(DMSO-d6):δ1.34-1.46, 1.49-1.58, 1.62-2.02, 2.04-2.20, 2.28-2.35, 2.65-2.80, 3.16-3.28, 3.99-4.10, 4.15-4.22, 6.73, 7.07-7.19, 7.29-7.37, 7.46, 7.61-7.70, 9.94, 12.1。
HPLC保持時間(分):0.89;
MS(ESI, Pos.)499:(M+H)+;
1H-NMR(DMSO-d6):δ1.35-1.46, 1.50-1.58, 2.04-2.20, 2.31, 2.62-2.77, 3.21, 4.29, 6.68, 7.31-7.39, 7.45, 7.66, 7.81, 8.27-8.30, 8.70, 8.80 9.93, 11.48-12.44。
HPLC保持時間(分):0.88;
MS(ESI, Pos.):499(M+H)+;
1H-NMR(DMSO-d6):δ1.38-1.43, 1.50-1.59, 2.07-2.18, 2.31, 2.66-2.75, 3.16-3.19, 4.31, 6.68, 7.34 ,7.45, 7.60, 7.66, 8.63, 9.94, 11.70-12.35。
HPLC保持時間(分):0.90;
MS(ESI, Pos.):499(M+H)+;
1H-NMR(DMSO-d6):δ1.34-1.44, 1.49-1.59, 2.05-2.17, 2.31, 2.66-2.79, 3.36, 4.40, 6.67, 7.30-7.38, 7.45, 7.66, 7.73-7.85, 8.09-8.36, 8.73, 9.93, 12.03。
HPLC保持時間(分):1.05;
MS(ESI, Pos.):522(M+H)+;
1H-NMR(DMSO-d6):δ1.33-1.47, 1.50-1.59, 2.05-2.18, 2.31, 2.67-2.75, 4.25-4.31, 4.33-4.39, 6.66, 6.91-6.96, 7.30-7.37, 7.38-7.41, 7.44-7.48, 7.65, 9.95。
HPLC保持時間(分):1.25;
MS(ESI, Pos.):516(M+H)+;
1H-NMR(DMSO-d6):δ1.33-1.45, 1.48-1.59, 2.10-2.16, 2.31, 2.63-2.77, 3.08, 4.21, 6.68, 7.12-7.23, 7.25-7.38, 7.39-7.49, 7.65, 9.95, 12.10。
HPLC保持時間(分):1.24;
MS(ESI, Pos.):516(M+H)+;
1H-NMR(DMSO-d6):δ1.34-1.46, 1.48-1.60, 2.05-2.19, 2.31, 2.64-2.78, 3.07, 4.22, 6.69, 7.02-7.10, 7.15-7.24, 7.30-7.40, 7.45, 7.65, 9.95, 12.10。
HPLC保持時間(分):1.23;
MS(ESI, Pos.):516(M+H)+;
1H-NMR(DMSO-d6):δ1.38-1.45, 1.50-1.61, 2.08-2.17, 2.31, 2.64-2.73, 3.03, 4.19, 6.68, 7.11-7.19, 7.29-7.42, 7.45, 7.65, 9.94, 12.06。
HPLC保持時間(分):1.17;
MS(ESI, Pos.):490(M+H)+;
1H-NMR(DMSO-d6):δ1.38-1.46, 1.50-1.58, 2.07-2.17, 2.33, 2.68-2.74, 2.74-2.85, 4.22, 6.72, 7.34, 7.46, 7.66, 9.98, 12.02。
HPLC保持時間(分):1.20;
MS(ESI, Pos.):504(M+H)+;
1H-NMR(DMSO-d6):δ1.21, 1.36-1.48, 1.50-1.62, 2.07-2.18, 2.33, 2.64-2.74, 2.82-3.02, 4.03-4.19, 6.72, 7.30-7.37, 7.46, 7.66, 9.97, 11.99。
参考例44で製造した化合物(50mg)のDMF(1mL)溶液に2,6-ジクロロピラジン(CAS番号:4774-14-5、21mg)及び炭酸カリウム(25mg)を加え50℃で2時間撹拌した。反応液をMTBEで希釈し、水及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後減圧濃縮した。得られた残渣は精製せず次反応に用いた。
HPLC保持時間(分):1.16;
MS(ESI, Pos.):506(M+H)+;
1H-NMR(CDCl3):δ1.46-1.55, 1.70-1.77, 2.16-2.24, 2.41, 2.66-2.76, 6.89, 7.21, 7.53-7.59, 8.20, 8.31, 8.32。
2,6-ジクロロピラジンの代わりに対応するクロル体を用いて、参考例45→実施例21と同様の操作を行うことにより、以下の物性値を有する本発明化合物を得た。
MS(ESI, Pos.):539(M+H)+;
1H-NMR(DMSO-d6):δ1.37-1.47, 1.52-1.61, 2.09-2.19, 2.37, 2.66-2.80, 6.98, 7.27-7.43, 7.48, 7.68, 8.02-8.27, 10.22, 12.05。
MS(ESI, Pos.):511(M+H)+;
1H-NMR(DMSO-d6):δ1.39-1.46, 1.52-1.59, 2.10-2.17, 2.39, 2.69-2.81, 6.38, 6.83, 7.03, 7.36, 7.49, 7.68, 8.08, 9.08, 10.27, 12.16。
参考例44で製造した化合物(100mg)のTHF(3mL)溶液に1,1,1-トリフルオロ-N-(トリフルオロメチルスルホニル)メタンスルホンアミド(CAS番号:37595-74-7、127mg)及びトリエチルアミン(72mg)を加え、室温で88時間撹拌した。反応液を酢酸エチルで希釈し、水で洗浄し、無水硫酸ナトリウムで乾燥後減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=97:3→1:1)で精製することにより、以下の物性値を有する表題化合物(120mg)を得た。
HPLC保持時間(分):1.14;
MS(ESI, Pos.):554(M+H)+。
参考例46で製造した化合物(30mg)の1,4-ジオキサン溶液(3mL)に2-フルオロ-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ピリジン(CAS番号:444120-95-0、127mg)、2M炭酸セシウム水溶液(0.08mL)及びXPhos Pd G2(8mg)を加え100℃で2.5時間撹拌した。反応液を酢酸エチルで希釈し、水で洗浄し、無水硫酸ナトリウムで乾燥後減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=9:1→1:1)で精製することにより、以下の物性値を有する表題化合物を得た。
HPLC保持時間(分):1.07;
MS(ESI, Pos.):501(M+H)+。
HPLC保持時間(分):1.13;
MS(ESI, Pos.):473(M+H)+;
1H-NMR(CDCl3):δ1.46-1.58, 1.71-1.80, 2.16-2.28, 2.47, 2.66-2.78, 7.01-7.09, 7.18-7.27, 7.52-7.61, 7.94-8.03, 8.21, 8.43。
4-(2-ヒドロキシエチル)フェノール(CAS番号:501-94-0、2g)のDMF(10mL)溶液に炭酸カリウム(3g)及び4-メトキシベンジルクロリド(CAS番号:824-94-2、2.5g)を加え50℃で14時間撹拌した。反応液に水を加え、析出した沈殿をろ取した。得られた粗生成物を酢酸エチルに溶解し、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後減圧濃縮することにより、以下の物性値を有する表題化合物(3.4g)を得た。
1H-NMR(CDCl3):δ2.81, 3.75-3.90, 4.97, 6.85-6.98, 7.11-7.19, 7.33-7.38。
参考例44で製造した化合物(20mg)のトルエン(0.5mL)溶液に参考例48で製造した化合物(25mg)及びCMBP(17mg)を加え80℃で27時間撹拌した。反応液を減圧濃縮し、残渣にメタノール(0.3mL)、THF(0.3mL)及び5N水酸化ナトリウム水溶液(0.05mL)を加え、50℃で2時間撹拌し、さらに室温で21時間撹拌した。反応液を5N塩酸で中和し酢酸エチルで抽出した。有機層を減圧濃縮し、得られた残渣は精製することなく次反応に使用した。
HPLC保持時間(分):1.13;
MS(ESI, Pos.):514(M+H)+;
1H-NMR(CDCl3):δ1.43-1.51, 1.64-1.75, 2.17, 2.34, 2.63-2.72, 3.02, 4.13, 6.59, 6.75-6.82, 7.08-7.20, 7.45-7.49, 7.50-7.55, 8.16-8.24。
参考例40で製造した化合物(30mg)の1,4-ジオキサン溶液(1mL)にアクリル酸エチル(18mg)、DIPEA(24mg)、テトラキス(トリフェニルホスフィン)パラジウム(0)(CAS番号:14221-01-3、14mg)を加えて100℃で終夜撹拌した。反応液をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=9:1→0:1)で精製し、得られた表題化合物を次反応に使用した。
参考例50で製造した化合物のTHF/メタノール(1mL)溶液に2N水酸化ナトリウム水溶液(0.5mL)を加え室温で2時間撹拌した。反応液を2N塩酸で中和し酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後減圧濃縮した。得られた残渣は精製せずそのまま次反応に使用した。
HPLC保持時間(分):1.20;
MS(ESI, Pos.):486(M+H)+;
1H-NMR(DMSO-d6):δ2.30, 2.56-2.62, 2.92, 3.02, 4.19, 6.66, 7.19-7.25, 7.28-7.34, 7.34-7.37, 7.41, 7.67, 9.92, 12.11-12.32。
アクリル酸エチルの代わりに、クロトン酸エチルまたはメタクリル酸エチルを用いて、参考例50→参考例51→実施例24と同様の操作を行うことにより、以下の物性値を有する本発明化合物を得た。
MS(ESI, Pos.):500(M+H)+;
1H-NMR(DMSO-d6):δ1.24, 2.30, 2.55-2.63, 2.96-3.05, 3.20-3.29, 4.19, 6.66, 7.17-7.25, 7.28-7.35, 7.38-7.43, 7.66-7.69, 9.91, 12.06-12.24。
MS(ESI, Pos.):500(M+H)+;
1H-NMR(DMSO-d6):δ1.08, 2.29, 2.64-2.78, 2.94-3.04, 4.15-4.23, 6.66, 7.18-7.25, 7.27-7.36, 7.39, 7.67, 9.92, 12.25。
参考例31で製造した化合物の代わりに参考例27で製造した化合物を用い、参考例6で製造した化合物の代わりに5-ヨード-2-(トリフルオロメチル)アニリン(CAS番号:1544-89-4)を用いて、参考例43と同様の操作を行うことにより、以下の物性値を有する表題化合物(1.45g)を得た。
HPLC保持時間(分):1.25;
MS(ESI, Pos.):540(M+H)+。
2-({[(2-メチル-2-プロパニル)オキシ]カルボニル}アミノ)-3-フェニルプロパン酸(CAS番号:13734-34-4、6.6g)、1-ヒドロキシベンゾトリアゾール(CAS番号:2592-95-2、3.4g)及びジメチルアミン塩酸塩(CAS番号:506-59-2、4.5g)のジクロロメタン(200mL)溶液に氷冷下1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩(CAS番号:25952-53-8、5.7g)及びDIPEA(10mL)を加えて室温で1時間撹拌した。反応液を10%クエン酸水溶液及び飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後減圧濃縮した。得られた残渣は精製せず次反応に用いた。
参考例53で製造した粗生成物を4N 塩酸の酢酸エチル溶液(25mL)に溶解し、室温で5分撹拌した。4N 塩酸の酢酸エチル溶液(10mL)を追加し室温で3時間撹拌した。析出物をろ取することにより、以下の物性値を有する表題化合物(1.45g)を得た。
HPLC保持時間(分):0.49;
1H-NMR(DMSO-d6):δ2.63, 2.79, 2.88-3.00, 3.00-3.10, 4.50-4.61, 7.14-7.24, 7.27-7.42, 8.24。
水素化リチウムアルミニウム(0.94g)のTHF(20mL)懸濁液に、氷冷下、参考例54で製造した化合物(3g)のTHF(30mL)懸濁液を滴下し、50℃で2時間撹拌した。反応液を氷冷し、精製水(1mL)、4N 水酸化ナトリウム水溶液(1mL)及び精製水(3mL)を加え室温で30分撹拌した。反応液に無水硫酸マグネシウムを加え室温で15分撹拌し、セライト(商品名)でろ過し、減圧濃縮することにより、以下の物性値を有する表題化合物(2.2g)を得た。
HPLC保持時間(分):0.34;
MS(ESI, Pos.):179(M+H)+;
参考例55で製造した化合物(2.1g)のジクロロメタン(20mL)に、氷冷下、塩化アセチル(1mL)を加え、室温で5分撹拌し、反応液を減圧濃縮した。得られた残渣をMTBEに溶解し、5N 水酸化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後減圧濃縮した。得られた残渣をヘキサンでスラリー洗浄することにより、以下の物性値を有する表題化合物(1.5g)を得た。
HPLC保持時間(分):0.50;
MS(ESI, Pos.):221(M+H)+;
1H-NMR(CDCl3):δ1.97, 2.12-2.23, 2.26-2.36, 2.72-2.90, 2.93-3.04, 4.08-4.27, 5.50-5.65, 7.11-7.40。
HPLC保持時間(分):1.12;
MS(ESI, Pos.):512(M+H)+;
1H-NMR(CDCl3):δ2.22-2.48, 2.58-2.74, 3.10, 3.58-3.70, 4.03-4.24, 6.60, 7.18, 7.23-7.39, 7.47, 7.57, 8.14。
HPLC保持時間(分):1.30;
MS(ESI, Pos.):512(M+H)+;
1H-NMR(CDCl3):δ1.23-1.30, 1.52, 1.92-2.00, 2.35, 2.41-2.49, 3.10, 4.18, 6.60, 7.12-7.20, 7.20-7.37, 7.44-7.54, 8.13。
HPLC保持時間(分):2.19(条件B);
MS(ESI, Pos.):444(M+H)+;
1H-NMR(DMSO-d6):δ1.20-1.45, 1.75-2.02, 2.21, 2.31, 3.03, 4.20, 6.68, 6.94-6.99, 7.05-7.11, 7.20-7.37, 9.65。
2-ブロモ-4-ヒドロキシ安息香酸メチル(CAS番号:101085-03-4、4.0g)のDMF溶液(20mL)に、炭酸カリウム(4.78g)、ベンジルブロミド(2.1mL)を加えて70℃で3時間撹拌した。反応液を水で希釈し酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣は精製することなく次反応に使用した。
HPLC保持時間(分):2.38;(条件E)
MS(ESI, Pos.):321(M+H)+。
参考例57で製造した化合物のエタノール(15mL)、水(3.6mL)溶液を脱気し、2-イソプロペニル-4,4,5,5-テトラメチル-1,3,2-ジオキサボラン(CAS番号:126726-62-3、2.64g)、2,6-ジ-tert-ブチル-4-メチルフェノール(CAS番号:128-37-0、0.58g)、酢酸パラジウム(0.44g)、トリシクロヘキシルホスフィン(CAS番号:2622-14-2、0.37g)、リン酸カリウム(8.32g)を加えて90℃で16時間撹拌した。反応液を水で希釈し酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにより精製し、以下の物性値を有する表題化合物(3g)を得た。
HPLC保持時間(分):2.46;(条件E)
MS(ESI, Pos.):283(M+H)+。
参考例58で製造した化合物のメタノール(2.4mL)溶液に酸化白金(CAS番号:1314-15-4、10mg)を加え、水素雰囲気下室温で16時間撹拌した。反応液をセライトでろ過し、ろ液を減圧濃縮した。得られた残渣は精製することなく次反応に使用した。
HPLC保持時間(分):2.56;(条件E)
MS(ESI, Pos.):285(M+H)+。
参考例59で製造した化合物のメタノール(0.5mL)、THF(0.5mL)、水(0.5mL)溶液に水酸化リチウム 水和物(CAS番号:1310-66-3、88mg)を加え、60℃で16時間撹拌した。反応液を濃縮し塩酸で酸性とし、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣は精製することなく次反応に使用した。
HPLC保持時間(分):2.20;(条件E)
MS(ESI, Pos.):271(M+H)+。
HPLC保持時間(分):2.36(条件C);
MS(ESI, Pos.):498(M+H)+;
1H-NMR(DMSO-d6):δ1.20, 1.31-1.40, 1.51-1.59, 2.03-2.12, 2.62-2.71, 3.33-3.45, 5.17, 6.93-6.96, 7.01, 7.30-7.51, 7.63, 9.91, 12.02。
ベンジルブロミドの代わりに対応するブロモ化合物を用いて参考例57→参考例58→参考例59→参考例60→参考例8→実施例1と同様の操作を行うことにより以下の物性値を有する本発明化合物を得た。
MS(ESI, Pos.):512(M+H)+;
1H-NMR(DMSO-d6):δ1.20, 1.30-1.38, 1.49-1.56, 2.01-2.13, 2.55-2.66, 3.06, 3.33-3.45, 4.25, 6.83-6.94, 7.20-7.27, 7.29-7.45, 7.62, 9.89。
MS(ESI, Pos.):526(M+H)+;
1H-NMR(DMSO-d6):δ1.19, 1.32-1.41, 1.51-1.59, 1.99-2.14, 2.60-2.72, 2.77, 3.34-3.49, 4.04, 6-83-6.89, 6.93, 7.16-7.46, 7.64, 9.91, 11.83。
2-ブロモ-4-ヒドロキシ安息香酸メチルの代わりに2-ブロモ-3-ヒドロキシ安息香酸メチル(CAS番号:1260783-82-1)を用い、ベンジルブロミドまたはベンジルブロミドの代わりに対応するブロモ化合物を用いて参考例57→参考例58→参考例59→参考例60→参考例8→実施例1と同様の操作を行うことにより以下の物性値を有する本発明化合物を得た。
MS(ESI, Pos.):498(M+H)+;
1H-NMR(DMSO-d6):δ1.17-1.55, 1.91-2.04, 2.40-2.59, 3.11-3.25, 5.18, 6.97, 7.15, 7.21-7.53, 7.59, 10.02。
MS(ESI, Pos.):512(M+H)+;
1H-NMR(DMSO-d6):δ1.21, 1.25-1.34, 1.45-1.53, 2.00-2.09, 2.51-2.62, 3.07-3.27, 4.26, 6.93, 7.08, 7.19-7.43, 7.60, 8.47, 9.97。
MS(ESI, Pos.):526(M+H)+;
1H-NMR(DMSO-d6):δ1.33-1.42, 1.51-1.62, 2.03-2.15, 2.61-2.87, 3.22-3.30, 4.00, 6.95, 7.03, 7.18-7.36, 7.44, 7.64, 10.02, 11.73。
2,3,6-トリメチルフェノール(CAS番号:2416-94-6、4.0g)のジクロロメタン(60mL)溶液に、臭素(1.6mL)のジクロロメタン(30mL)溶液を加えて室温で5時間撹拌した。反応液を減圧濃縮し、チオ硫酸ナトリウム溶液を加えて酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮することで、以下の物性値を有する表題化合物(5.9g)を得た。
1H-NMR(CDCl3):δ2.19, 2.21, 2.34, 4.56, 7.18。
参考例61で製造した化合物(2.0g)のTHF(20mL)溶液に2-フェニルエタノール(1.36g)、トリフェニルホスフィン(4.87g)を加えた。その後、DEAD(3.23g、40%トルエン溶液)を滴下し、室温で16時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(石油エーテル:酢酸エチル=9:1)で精製することにより、以下の物性値を有する表題化合物(1.5g)を得た。
1H-NMR(CDCl3):δ2.11, 2.14, 2.30, 3.09, 3.89, 7.20-7.22, 7.27-7.32。
参考例62で製造した化合物(0.3g)のTHF(6mL)溶液に、-78℃でn-ブチルリチウムのヘキサン溶液(2.5mol/L、0.46mL)を加え、-78℃で15分間撹拌した。反応液に-78℃で二酸化炭素ガスを5分間通気し、-78℃で20分間撹拌した。 反応液に塩酸を加えて反応を停止し、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣は精製することなく次反応に使用した。
HPLC保持時間(分):2.59(条件F);
MS(ESI, Pos.):285(M+H)+。
HPLC保持時間(分):2.42(条件C);
MS(ESI, Pos.):512(M+H)+;
1H-NMR(DMSO-d6):δ1.31-1.36, 1.50-1.56, 2.04-2.13, 2.23, 2.55-2.66, 3.07, 3.93, 7.12, 7.22-7.26, 7.30-7.39, 7.42, 7.62, 9.90。
メチル 3-イソプロピル-1H-ピラゾール-4-カルボキシラート(CAS番号:1186537-97-2、0.4g)のDMF(5mL)溶液に炭酸カリウム(0.985g)、1-ブロモ-3-フェニルプロパン(1.42g)を加え、60℃で16時間撹拌した。反応液を室温に冷却し、氷水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(石油エーテル:酢酸エチル=88:12)で精製することにより、以下の物性値を有する表題化合物(0.41g、混合物)を得た。
MS(ESI, Pos.):287(M+H)+。
参考例26で製造した化合物の代わりに参考例64で製造した化合物を用いて参考例27→実施例11と同様の操作を行うことにより以下の物性値を有する本発明化合物を得た。
MS(ESI, Pos.):500(M+H)+;
1H-NMR(DMSO-d6):δ1.15-1.21, 1.31-1.42, 1.50-1.58, 2.04-2.13, 2.55-2.73, 3.44-3.53, 4.09, 7.16-7.41, 7.62, 8.26, 9.37, 12.00。
MS(ESI, Pos.):500(M+H)+;
1H-NMR(DMSO-d6):δ1.16-1.32, 1.38-1.48, 1.90-2.09, 2.38-2.51, 2.59-2.68, 4.15, 7.15-7.25, 7.26-7.37, 7.56, 7.95, 9.53。
参考例42で製造した化合物(50mg)のベンゼン(CAS番号:71-43-2,2mL)溶液に5硫化リン(CAS番号:1314-80-3,42mg)を0℃で加え、60℃で16時間撹拌した。反応液を室温に冷却し、氷水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣は精製することなく次反応に使用した。
HPLC保持時間(分):2.93(条件F);
MS(ESI, Pos.):542(M+H)+;
HPLC保持時間(分):2.39(条件F);
MS(ESI, Pos.):514(M+H)+;
1H-NMR(DMSO-d6):δ1.21-1.34, 1.66-1.82, 2.28, 2.32-2.61, 3.01, 4.13, 6.45, 6.81-6.92, 7.05-7.14, 7.19-7.27, 7.29-7.36。
HPLC保持時間(分):2.36(条件F);
MS(ESI, Pos.):478(M+H)+;
1H-NMR(DMSO-d6):δ0.10-0.15, 0.41-0.47, 0.78-0.89, 1.37-1.44, 1.51-1.56, 1.59-1.66, 2.10-2.15, 2.34, 2.35, 2.67-2.75, 4.03, 6.68, 7.38-7.44, 7.68-7.73, 11.73, 12.02。
エチル 4-メチル-3-オキソヘキサノアート(CAS番号:98192-72-4,1.0g)および2-クロロアセトアルデヒド水溶液(CAS番号:107-20-0,50wt%、0.815mL)の混合液にアンモニア水(28%NH3水溶液、3.2mL)および水(3.2mL)を加え、70℃で20時間撹拌した。反応混合物を室温に冷却し、水および酢酸エチルで希釈した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=9:1)で精製することにより、以下の物性値を有する表題化合物(300mg)を得た。
LC-MS m/z 196(M+H)+;
1H-NMR(CDCl3):δ0.91, 1.28, 1.37, 1.58-1.70, 3.65-3.73, 4.24-4.33, 6.58-6.61, 6.61-6.63, 8.19。
参考例66で製造した化合物(110mg)および(3-ブロモプロピル)ベンゼン(123mg)のDMF(1mL)溶液に炭酸セシウム(0.184g)を加え、80℃で20時間撹拌した。反応液を室温に冷却し、シリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=8:2)で精製することにより、以下の物性値を有する表題化合物(98mg)を得た。
LC-MS m/z 314(M+H)+;
1H-NMR(CDCl3):δ0.82, 1.32-1.40, 1.74, 1.88, 2.00-2.12, 2.68, 3.23, 3.84-3.97, 4.25, 6.46, 6.59, 7.16-7.21, 7.21-7.27, 7.31-7.36。
参考例67で製造した化合物(126mg)のTHF/メタノール(1:1、1mL)溶液に10N NaOH水溶液(0.1mL)を加え、80℃で20時間撹拌した。反応液を室温に冷却し、酢酸(0.2mL)を加えた。続いてジクロロメタン(5mL)および水(5mL)を加えた。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=1:1)で精製することにより、以下の物性値を有する表題化合物(90mg)を得た。
LC-MS m/z 286(M+H)+;
1H-NMR(DMSO-d6):δ0.71, 1.25, 1.63, 1.80, 1.89-2.06, 2.61, 3.20-3.39, 3.93, 6.37, 6.66, 7.18-7.26, 7.31。
LC-MS m/z 513(M+H)+;
1H-NMR(DMSO-d6):δ0.72, 1.16-1.31, 1.38, 1.47-1.58, 1.58-1.69, 1.78, 1.88-2.03, 2.03-2.20, 2.59-2.75, 3.32, 3.94, 6.54, 6.73, 7.19-7.28, 7.28-7.34, 7.50, 7.60, 8.94。
エチル 4-メチル-3-オキソヘキサノアートの代わりに対応する化合物を用いて参考例66→参考例67→参考例68→参考例8→実施例1と同様の操作を行うことにより以下の物性値を有する本発明化合物を得た。
1H-NMR(DMSO-d6):δ1.27, 1.38, 1.51-1.56, 1.97, 2.07-2.13, 2.58-2.71, 3.35-3.59, 3.95, 6.52, 6.70, 7.18-7.28, 7.28-7.34, 7.51, 7.60, 8.95。
1H-NMR(DMSO-d6):δ1.30-1.35, 1.38, 1.49, 1.98-2.16, 2.57-2.63, 2.70, 3.99-4.16, 6.09, 6.76, 7.20-7.25, 7.25-7.31, 7.31-7.37, 7.42, 7.60, 9.39。
薬理実験例1:プロスタノイドレセプター発現細胞を用いたEP 2 拮抗活性測定実験
ニシガキ(Nishigaki)らの方法(FEBS Letters、第364巻、339-341ページ、1995年)に準じて、ヒトEP2受容体を発現させたCHO細胞を調製し,CELLBANKER2(日本全薬工業株式会社製)中で1.5x107cells/mL/vialとなるように凍結保存したものを実験に供した。細胞を解凍し,5x105cells/mLとなるようにアッセイミディアム(assay medium)(D-PBS containing 1mmol/L IBMX,2μmol/L Diclofenac)に懸濁した。細胞懸濁液(10μL)を終濃度10nmol/LのPGE2単独、またはこれと試験化合物を共に含む溶液(10μL)を添加して反応を開始し、室温で1時間反応した後、cAMP Gs Dynamic kit(CISBIO社製)に記載されている方法に準じ、細胞内のcAMP量を定量した。
マウス大腸がん細胞株であるCT26の同種移植モデルにて、本発明化合物の抗腫瘍効果を評価した。CT26は、10vol%の非働化済ウシ胎児血清(Fetal Bovine Serum;FBS)、100units/mLのPenicillinおよび100μg/mLのStreptomycinを含むRPMI-1640培地でCO2インキュベーター内にて培養した。移植当日、培養上清を取り除き、CT26をリン酸緩衝液(以下、PBSと略す。)で洗浄したのち、回収した。回収したCT26をPBSに懸濁し、移植用細胞とした。麻酔下で雌性Balb/Cマウス(日本チャールスリバー株式会社)の右側背部に、30万個の移植用細胞を皮下移植した。移植4日後に当該マウスを媒体群および化合物A群の2群に10例ずつ割り当てた。媒体および化合物Aとして10mg/kgの本発明化合物を、移植4日目は1回、移植5日から移植25日目までは1日2回、マウスに反復投与した。腫瘍体積(mm3)は、電子ノギスを用いて、腫瘍の短径および長径を測定し、以下の数式1にて腫瘍体積を算出した。なお、投与期間中において腫瘍に潰瘍が形成されたマウスはその時点以降の評価から除外した。
(1)被験物質溶液の調製
被験物質のDMSO溶液(10mmol/L;5μL)を50%アセトニトリル水溶液(195μL)で希釈して、250μmol/Lの被験物質溶液を調製した。
ウォーターバスであらかじめ37℃に加温した反応用容器に、NADPH-Co-Factor(BD-Bioscience社)および1mg/mLラットおよびヒト肝ミクロソームを含む0.1mol/Lリン酸緩衝液(pH7.4)245μLを添加して、5分間プレインキュベーションした。そこに先の被験物質溶液5μLを添加して、反応を開始した(最終濃度1μmol/L)。反応開始直後に反応溶液20μLを採取して、この溶液をアセトニトリル(内部標準物質カンデサルタン含有)180μLに添加して反応を停止した。この反応が停止した溶液(20μL;反応開始直後のサンプル溶液)を除蛋白用フィルタープレート上で50%アセトニトリル(180μL)と撹拌した後、吸引ろ過して、ろ液を標準サンプルとした。
(3)反応サンプル(反応60分後のサンプル)調製
先の反応溶液を37℃で60分間インキュベーションした後、この反応溶液20μLを採取して、アセトニトリル(内部標準物質カンデサルタン含有)180μLに添加して、反応を停止した。この反応が停止した溶液(20μL;60分間反応させたサンプル溶液)を除蛋白用フィルタープレート上で50%アセトニトリル(180μL)と撹拌した後、吸引ろ過して、ろ液を反応サンプルとした。
(4)評価方法
LC-MS/MSで得られたピーク面積を用いて、標準サンプルの被験物質量(X)および反応サンプルの被験物質量(Y)から、次式に従い、被験物質の残存率(%)を算出した。
X:標準サンプルの被験物質量(Ratio=被験物質のピーク面積/内部標準物質のピーク面積)
Y:反応サンプルの被験物質量(Ratio=被験物質のピーク面積/内部標準物質のピーク面積)
(5)結果
本発明化合物は、ヒト肝ミクロソームに対する安定性が高いことが分かった。
(1)検量線溶液の調製
検量線溶液は、被験物質のDMSO溶液(10mmol/L)をアセトニトリルで希釈し、内標準物質(ニカルジピン)を含むアセトニトリルを添加して5、20及び100nmol/Lに調製した.
(2)試料溶液の調製
試料溶液は,局法II液495μLに被験物質のDMSO溶液(10mmol/L;5μL)を添加し,室温で5時間攪拌した後,溶液を溶解度用フィルタープレートに移し吸引ろ過してろ液10μLをアセトニトリルで希釈し,内標準物質(ニカルジピン)を含むアセトニトリルを添加して調製した.
(3)評価
検量線溶液および試料溶液5μLをLC-MS(Thermo Scientific社製 Q Exactive Focus)に注入し定量した(定量範囲5~100nmol/L).溶解度は定量値を1000倍して算出した.定量範囲以下の値が得られた場合の溶解度は<5μmol/L,定量範囲以上の値が得られた場合の溶解度は100μmol/Lとする.
(4)結果
本発明化合物は、良好な溶解度を有することが分かった。
製剤例
以下の各成分を常法により混合した後打錠して、一錠中に10mgの活性成分を含有する錠剤約1万錠が得られる。
・(1R,2S)-2-{3-[({1-[(2S)-2-ブタニル]-5-(3-フェニルプロピル)-1H-ピロール-2-イル}カルボニル)アミノ]-4-クロロフェニル}シクロプロパンカルボン酸 ……100g
・カルボキシメチルセルロースカルシウム(崩壊剤) …… 20g
・ステアリン酸マグネシウム(潤滑剤) …… 10g
・微結晶セルロース ……870g
Claims (19)
- 一般式(I-A):
L1は-(CR38R39)-(CR40R41)-を表し、
R38、R39、R40およびR41は、それぞれ独立して、(1)水素原子、(2)ハロゲン原子、または(3)C1-4アルキル基を表し、
R38、R39、R40およびR41中のC1-4アルキル基は、それぞれ独立して、ハロゲン原子で置換されていてもよく、
R38、R39、R40およびR41から選択される2個の置換基がC1-4アルキル基の時、結合する炭素原子と一緒になってC3-6飽和炭素環を形成してもよく、
L2は、(1)結合手、(2)C1-8アルキレン基、(3)C2-8アルケニレン基、または(4)C2-8アルキニレン基を表し、該C1-8アルキレン基、C2-8アルケニレン基、およびC2-8アルキニレン基中の1~2個の炭素原子は、酸素原子または酸化されていてもよい硫黄原子で置き換わっていてもよく、該C1-8アルキレン基、C2-8アルケニレン基、およびC2-8アルキニレン基は1~8個のハロゲン原子で置換されていてもよく、
Yは、(1)結合手、(2)酸素原子、または(3)酸化されていてもよい硫黄原子を表し、
R1は、(1)COOR10、(2)SO3H、(3)SO2NHR11、(4)CONHSO2R12、(5)SO2NHCOR13、(6)CONR14R15、(7)テトラゾリル基、または(8)ヒドロキサム酸を表し、
R10、R11、R12、R13、R14およびR15は、それぞれ独立して(1)水素原子または(2)C1-4アルキル基を表し、
R2は、(1)水素原子または(2)C1-4アルキル基を表し、
R3は、(1)ハロゲン原子、(2)C1-6アルキル基、(3)C2-6アルケニル基、(4)C2-6アルキニル基、(5)C1-6アルコキシ基、(6)3-6員環状基、(7)(3-6員環状基)-O-、または(8)(3-6員環状基)-(C1-4アルキレン)-を表し、
R3中の(2)~(8)は1~9個のR16で置換されていてもよく、
R3が複数の場合、複数のR3は、それぞれ同じでも異なっていてもよく、
R16は、(1)ハロゲン原子、(2)C1-4アルキル基、(3)C1-4アルコキシ基、(4)C2-6アシル基、(5)C3-6シクロアルキル基、(6)水酸基、または(7)-NR17R18を表し、
R16が複数の場合、複数のR16は、それぞれ同じでも異なっていてもよく、
R17およびR18は、それぞれ独立して、(1)水素原子または(2)C1-4アルキル基を表し、
R4は、(1)ハロゲン原子、(2)C1-6アルキル基、(3)C2-6アルケニル基、(4)C2-6アルキニル基、(5)C1-6アルコキシ基、(6)3-6員環状基、(7)(3-6員環状基)-O-、または(8)(3-6員環状基)-(C1-4アルキレン)-を表し、
R4中の(2)~(8)は1~9個のR19で置換されていてもよく、
R4が複数の場合、複数のR4は、それぞれ同じでも異なっていてもよく、
R19は、(1)ハロゲン原子、(2)C1-4アルキル基、(3)C1-4アルコキシ基、(4)C2-6アシル基、(5)C3-6シクロアルキル基、(6)水酸基、または(7)-NR20R21を表し、
R20およびR21は、それぞれ独立して、(1)水素原子または(2)C1-4アルキル基を表し、
R19が複数の場合、複数のR19は、それぞれ同じでも異なっていてもよく、
R5は、(1)水素原子、(2)C3-10炭素環、または(3)3-10員複素環を表し、該C3-10炭素環および3-10員複素環は、1~5個のR22で置換されていてもよく、
但し、L2が結合手の場合は、R5は水素原子でなく、
R22は、(1)C1-6アルキル基、(2)C2-6アルケニル基、(3)C2-6アルキニル基、(4)C3-6シクロアルキル基、(5)C1-6アルコキシ基、(6)C3-6シクロアルキルオキシ基、(7)C2-6アシル基、(8)C2-6アシルオキシ基、(9)C1-6アルキルチオ基、(10)C3-6シクロアルキルチオ基、(11)C1-6アルキルスルフィニル基、(12)C3-6シクロアルキルスルフィニル基、(13)C1-6アルキルスルホニル基、(14)C3-6シクロアルキルスルホニル基、(15)C1-6アルコキシカルボニル基、(16)5-6員環状基、(17)(5-6員環状基)-(C1-4アルキレン)-、(18)(5-6員環状基)-(C1-4アルキレン)-O-基、(19)(5-6員環状基)-C1-4アシル基、(20)ハロゲン原子、(21)水酸基、(22)ニトロ基、(23)シアノ基、(24)-NR23R24、(25)-CONR25R26または(26)-SO2NR27R28を表し、
R23、R24、R25、R26、R27およびR28は、それぞれ独立して、(1)水素原子、(2)C1-6アルキル基、(3)C2-6アシル基または(4)C1-6アルキルスルホニル基を表し、
R22のうち(1)~(19)の基は、1~9個のR29で置換されていてもよく、
R22が複数の場合、複数のR22は、それぞれ同じでも異なっていてもよく、
R29は、(1)C1-4アルキル基、(2)C1-4アルコキシ基、(3)C2-6アシル基、(4)C3-6シクロアルキル基、(5)水酸基、(6)-NR30R31または(7)ハロゲン原子を表し、
R30およびR31は、それぞれ独立して、(1)水素原子または(2)C1-4アルキル基を表し、
R29が複数の場合、複数のR29は、それぞれ同じでも異なっていてもよく、
Qは(1)酸素原子または(2)硫黄原子を表し、
Xは(1)CR6または(2)NR7を表し、
R6は、(1)ハロゲン原子、(2)C1-6アルキル基、(3)C2-6アルケニル基、(4)C2-6アルキニル基、(5)C1-6アルコキシ基、(6)3-6員環状基、(7)(3-6員環状基)-O-、または(8)(3-6員環状基)-(C1-4アルキレン)-を表し、
R6中の(2)~(8)は1~9個のR32で置換されていてもよく、
R32は、(1)ハロゲン原子、(2)C1-4アルキル基、(3)C1-4アルコキシ基、(4)C2-6アシル基、(5)C3-6シクロアルキル基、(6)水酸基、または(7)-NR33R34を表し、
R33およびR34は、それぞれ独立して、(1)水素原子または(2)C1-4アルキル基を表し、
R32が複数の場合、複数のR32は、それぞれ同じでも異なっていてもよく、
R7は、(1)C1-6アルキル基、(2)C2-6アルケニル基、(3)C2-6アルキニル基、(4)3-6員環状基、または(5)(3-6員環状基)-(C1-4アルキレン)-を表し、
R7は1~9個のR35で置換されていてもよく、
R35は、(1)ハロゲン原子、(2)C1-4アルキル基、(3)C1-4アルコキシ基、(4)C2-6アシル基、(5)C3-6シクロアルキル基、(6)水酸基、または(7)-NR36R37を表し、
R36およびR37は、それぞれ独立して、(1)水素原子または(2)C1-4アルキル基を表し、
R35が複数の場合、複数のR35は、それぞれ同じでも異なっていてもよく、
環Aは、(1)ベンゼン環、または(2)5-6員含窒素芳香族複素環を表し、
環A中の
nは1~4の整数を表し、
mは0~3の整数を表し、
ただし、3-[3-[(2,6-ジメトキシベンゾイル)アミノ]-4-プロポキシフェニル]プロパン酸、
3-[5-({[1-tert-ブチル-5-(4-フルオロフェニル-1H-ピラゾール-4-イル]カルボニル}アミノ-2-クロロフェニル]プロパン酸メチル、
3-[5-({[1-tert-ブチル-5-(4-フルオロフェニル-1H-ピラゾール-4-イル]カルボニル}アミノ-2-クロロフェニル]プロパン酸、
α-エチル-3-[N-(1’-フェニル-5’-メチル-1’,2’,3’-トリアゾールカルボニル)]アミノ-2,4,6-トリヨードヒドロシンナム酸、および
α-エチル-3-{N-(1’-(4”-ヨードフェニル)-5’-メチル-1,2,3-トリアゾールカルボニル]}アミノ-2,4,6-トリヨードヒドロシンナム酸は除外される。)で示される化合物、またはその薬学的に許容される塩。 - 一般式(I-B):
R6aは、(1)ハロゲン原子、(2)C1-6アルキル基、(3)C2-6アルケニル基、(4)C2-6アルキニル基、(5)C1-6アルコキシ基、(6)(3-6員環状基)-O-、または(7)(3-6員環状基)-(C1-4アルキレン)-を表し、
R6a中の(2)~(7)は1~9個のR32で置換されていてもよく、
R7aは、(1)C1-6アルキル基、(2)C2-6アルケニル基、(3)C2-6アルキニル基、(4)3-6員環状基、または(5)(3-6員環状基)-(C1-4アルキレン)-を表し、
R7aは1~9個のR35で置換されていてもよく、
R3a、R3bおよびR3cはそれぞれ独立して(1)水素原子(2)ハロゲン原子、(3)C1-6アルキル基、(4)C2-6アルケニル基、(5)C2-6アルキニル基、(6)C1-6アルコキシ基、(7)3-6員環状基、(8)(3-6員環状基)-O-、または(9)(3-6員環状基)-(C1-4アルキレン)-を表し、
R3a、R3bおよびR3c中の(3)~(9)は1~9個のR16で置換されていてもよく、
ただし、R3a、R3bおよびR3cのうち少なくとも一つは水素原子以外の置換基を表し、
請求項1記載の記号と同じ記号は請求項1記載の記号と同じ意味を表し、
ただし、3-[3-[(2,6-ジメトキシベンゾイル)アミノ]-4-プロポキシフェニル]プロパン酸は除外される。)で示される請求項1記載の化合物、またはその薬学的に許容される塩。 - 一般式(I-C):
R6aは、(1)ハロゲン原子、(2)C1-6アルキル基、(3)C2-6アルケニル基、(4)C2-6アルキニル基、(5)C1-6アルコキシ基、(6)(3-6員環状基)-O-、または(7)(3-6員環状基)-(C1-4アルキレン)-を表し、
R6a中の(2)~(7)は1~9個のR32で置換されていてもよく、
R7aは、(1)C1-6アルキル基、(2)C2-6アルケニル基、(3)C2-6アルキニル基、(4)3-6員環状基、または(5)(3-6員環状基)-(C1-4アルキレン)-を表し、
R7aは1~9個のR35で置換されていてもよく、
R3a、R3bおよびR3cはそれぞれ独立して(1)水素原子(2)ハロゲン原子、(3)C1-6アルキル基、(4)C2-6アルケニル基、(5)C2-6アルキニル基、(6)C1-6アルコキシ基、(7)3-6員環状基、(8)(3-6員環状基)-O-、または(9)(3-6員環状基)-(C1-4アルキレン)-を表し、
R3a、R3bおよびR3c中の(3)~(9)は1~9個のR16で置換されていてもよく、
ただし、R3a、R3bおよびR3cのうち少なくとも一つは水素原子以外の置換基を表し、
pは1~4の整数を表し、
請求項1記載の記号と同じ記号は請求項1記載の記号と同じ意味を表す。)で示される請求項1~4のいずれか1項に記載の化合物、またはその薬学的に許容される塩。 - 環Aがベンゼン環または5員含窒素芳香族複素環である、請求項1~5のいずれか1項に記載の化合物、またはその薬学的に許容される塩。
- 環Aがピロール環であり、Yが結合手である、請求項1~6のいずれか1項に記載の化合物、またはその薬学的に許容される塩。
- 環Aがベンゼン環であり、Yが酸素原子である、請求項1~6のいずれか1項に記載の化合物、またはその薬学的に許容される塩。
- (1)rel-(1R,2S)-2-[3-({[1-sec-ブチル-5-(3-フェニルプロピル)-1H-ピロール-2-カルボニル]アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(2)rel-(1R,2S)-2-{3-[({1-[(2S)-2-ブタニル]-5-(3-フェニルプロピル)-1H-ピロール-2-イル}カルボニル)アミノ]-4-(トリフルオロメチル)フェニル}シクロプロパンカルボン酸、
(3)rel-(1R,2S)-2-{3-[({1-[(2S)-2-ブタニル]-5-(3-フェニルプロピル)-1H-ピロール-2-イル}カルボニル)アミノ]-5-メチルフェニル}シクロプロパンカルボン酸、
(4)rel-(1R,2R)-2-{3-[({1-[(2S)-2-ブタニル]-5-(3-フェニルプロピル)-1H-ピロール-2-イル}カルボニル)アミノ]-5-メチルフェニル}シクロプロパンカルボン酸、
(5)rel-(1R,2S)-2-{5-[({1-[(2S)-2-ブタニル]-5-(3-フェニルプロピル)-1H-ピロール-2-イル}カルボニル)アミノ]-2-(トリフルオロメチル)フェニル}シクロプロパンカルボン酸、
(6)rel-(1R,2R)-2-{5-[({1-[(2S)-2-ブタニル]-5-(3-フェニルプロピル)-1H-ピロール-2-イル}カルボニル)アミノ]-2-(トリフルオロメチル)フェニル}シクロプロパンカルボン酸、
(7)(1S,2R)-2-[3-({[1-イソプロピル-5-(3-フェニルプロピル)-1H-ピロール-2-イル]カルボニル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(8)(1R,2R)-2-[3-({[1-イソプロピル-5-(3-フェニルプロピル)-1H-ピロール-2-イル]カルボニル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(9)(1R,2S)-2-{3-[({1-[(2S)-2-ブタニル]-5-(3-フェニルプロピル)-1H-ピロール-2-イル}カルボニル)アミノ]-4-メトキシフェニル}シクロプロパンカルボン酸、
(10)(1S,2R)-2-{3-[({1-[(2S)-2-ブタニル]-5-(3-フェニルプロピル)-1H-ピロール-2-イル}カルボニル)アミノ]-4-(トリフルオロメチル)フェニル}シクロプロパンカルボン酸、
(11)(1R,2S)-2-{3-[({1-[(2S)-2-ブタニル]-5-(3-フェニルプロピル)-1H-ピロール-2-イル}カルボニル)アミノ]-4-(トリフルオロメチル)フェニル}シクロプロパンカルボン酸、
(12)(1R,2S)-2-{3-[({1-[(2S)-2-ブタニル]-5-(3-フェニルプロピル)-1H-ピロール-2-イル}カルボニル)アミノ]-4-クロロフェニル}シクロプロパンカルボン酸、
(13)(1R,2S)-2-{3-[({5-[2-(ベンジルオキシ)エチル]-1-[(2S)-2-ブタニル]-1H-ピロール-2-イル}カルボニル)アミノ]-4-(トリフルオロメチル)フェニル}シクロプロパンカルボン酸、
(14)rel-(1R,2S)-2-[3-{[(1-[(2S)-2-ブタニル]-5-{2-[(2-フルオロ-4-ピリジニル)オキシ]エチル}-1H-ピロール-2-イル)カルボニル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(15)(1R,2S)-2-[3-{[(1-[(2S)-2-ブタニル]-5-{2-[(2-クロロ-6-フルオロ-4-ピリジニル)オキシ]エチル}-1H-ピロール-2-イル)カルボニル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(16)(1R,2S)-2-{3-[({1-[(2S)-2-ブタニル]-5-[2-(2-クロロ-3,5-ジフルオロフェノキシ)エチル]-1H-ピロール-2-イル}カルボニル)アミノ]-4-(トリフルオロメチル)フェニル}シクロプロパンカルボン酸、
(17)(1R,2S)-2-{3-[({1-[(2S)-2-ブタニル]-5-[2-(2,4-ジフルオロフェノキシ)エチル]-1H-ピロール-2-イル}カルボニル)アミノ]-4-(トリフルオロメチル)フェニル}シクロプロパンカルボン酸、
(18)(1R,2S)-2-[3-{[(1-[(2S)-2-ブタニル]-5-{2-[(1-メチル-1H-ピラゾール-4-イル)オキシ]エチル}-1H-ピロール-2-イル)カルボニル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(19)rel-(1R,2S)-2-[3-{[2,6-ジメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(20)(1R,2S)-2-[3-{[2,6-ジメチル-4-(3-フェニルプロピル)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(21)(1R,2S)-2-[3-({4-[2-(2,4-ジフルオロフェニル)エトキシ]-2,6-ジメチルベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(22)rel-(1R,2S)-2-(2,3-ジクロロ-5-{[2,6-ジメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-フルオロフェニル)シクロプロパンカルボン酸、
(23)rel-(1R,2R)-2-(2,3-ジクロロ-5-{[2,6-ジメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-フルオロフェニル)シクロプロパンカルボン酸、
(24)(1R,2S)-2-[2-クロロ-5-{[2,6-ジメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(25)(1R,2S)-2-(4-クロロ-3-{[2,6-ジメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}フェニル)シクロプロパンカルボン酸、
(26)rel-(1R,2S)-2-(2,3-ジクロロ-5-{[2,6-ジメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}フェニル)シクロプロパンカルボン酸、
(27)rel-(1R,2R)-2-(2,3-ジクロロ-5-{[2,6-ジメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}フェニル)シクロプロパンカルボン酸、
(28)(1R,2S)-2-[3-{[2,6-ジメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(29)(1S,2R)-2-[3-{[2,6-ジメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(30)(1R,2S)-2-[3-({2,6-ジメチル-4-[2-(1-メチル-1H-ピラゾール-4-イル)エトキシ]ベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(31)(1R,2S)-2-[3-{[4-(2-シクロプロピルエトキシ)-2,6-ジメチルベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(32)(1R,2S)-2-{3-[(2,6-ジメチル-4-プロポキシベンゾイル)アミノ]-4-(トリフルオロメチル)フェニル}シクロプロパンカルボン酸、
(33)(1R,2S)-2-[3-{[4-(ヘキシルオキシ)-2,6-ジメチルベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(34)(1R,2S)-2-[3-{[4-(ベンジルオキシ)-2,6-ジメチルベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(35)(1R,2S)-2-[3-{[4-(2-メトキシエトキシ)-2,6-ジメチルベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(36)(1R,2S)-2-[3-({2,6-ジメチル-4-[2-(テトラヒドロ-2H-ピラン-2-イル)エトキシ]ベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(37)(1R,2S)-2-[3-({4-[2-(2-フリル)エトキシ]-2,6-ジメチルベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(38)(1R,2S)-2-[3-({4-[2-(2-クロロフェニル)エトキシ]-2,6-ジメチルベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(39)(1R,2S)-2-[3-({4-[2-(3-クロロフェニル)エトキシ]-2,6-ジメチルベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(40)(1R,2S)-2-[3-({4-[2-(1H-イミダゾール-1-イル)エトキシ]-2,6-ジメチルベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(41)(1R,2S)-2-[3-({4-[2-(2,6-ジフルオロフェニル)エトキシ]-2,6-ジメチルベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(42)(1R,2S)-2-[3-({4-[2-(3,5-ジフルオロフェニル)エトキシ]-2,6-ジメチルベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(43)(1R,2S)-2-[3-({4-[(6-クロロ-2-ピラジニル)オキシ]-2,6-ジメチルベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(44)(1R,2S)-2-[3-{[4-(6-フルオロ-3-ピリジニル)-2,6-ジメチルベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(45)(1R,2S)-2-[3-({4-[2-(4-ヒドロキシフェニル)エトキシ]-2,6-ジメチルベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(46)3-[3-{[2,6-ジメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]プロパン酸、
(47)3-[3-{[2,6-ジメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]ブタン酸、
(48)3-[3-{[2,6-ジメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]-2-メチルプロパン酸、
(49)(1R,2S)-2-[3-{[2,6-ジメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロブタンカルボン酸、または
(50)(1R,2R)-2-[3-{[2,6-ジメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]-1-メチルシクロプロパンカルボン酸である請求項1記載の化合物、またはその薬学的に許容される塩。 - (1)(1R,2S)-2-[3-{[2-メチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(2)(1R,2S)-2-[3-{[2-クロロ-4-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(3)(1R,2S)-2-[3-{[4-(2-フェニルエトキシ)-2-(トリフルオロメチル)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(4)(1R,2S)-2-[3-{[4-(1H-インダゾール-5-イルメトキシ)-2,6-ジメチルベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(5)(1R,2S)-2-[3-{[2,6-ジメチル-4-(1,2,3,4-テトラヒドロ-1-ナフタレニルメトキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(6)(1R,2S)-2-[3-({2,6-ジメチル-4-[2-(3-ピリジニル)エトキシ]ベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(7)(1R,2S)-2-[3-({2,6-ジメチル-4-[2-(4-ピリジニル)エトキシ]ベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(8)(1R,2S)-2-[3-({2,6-ジメチル-4-[2-(2-ピリジニル)エトキシ]ベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(9)(1R,2S)-2-[3-({4-[2-(2-クロロ-1H-イミダゾール-1-イル)エトキシ]-2,6-ジメチルベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(10)(1R,2S)-2-[3-({4-[2-(2-フルオロフェニル)エトキシ]-2,6-ジメチルベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(11)(1R,2S)-2-[3-({4-[2-(3-フルオロフェニル)エトキシ]-2,6-ジメチルベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(12)(1R,2S)-2-[3-({4-[2-(4-フルオロフェニル)エトキシ]-2,6-ジメチルベンゾイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(13)(1R,2S)-2-[3-{[2,6-ジメチル-4-(3,3,3-トリフルオロプロポキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(14)(1R,2S)-2-[3-{[2,6-ジメチル-4-(3,3,3-トリフルオロ-2-メチルプロポキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(15)(1R,2S)-2-{3-[(2,6-ジメチル-4-{[6-(トリフルオロメチル)-2-ピリジニル]オキシ}ベンゾイル)アミノ]-4-(トリフルオロメチル)フェニル}シクロプロパンカルボン酸、
(16)(1R,2S)-2-[3-{[2,6-ジメチル-4-(ピラゾロ[1,5-a]ピリミジン-5-イルオキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(17)rel-(1R,2S)-2-(3-{[2,6-ジメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-メチルフェニル)シクロプロパンカルボン酸、
(18)(1R,2S)-2-[3-{[4-(ベンジルオキシ)-2-イソプロピルベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(19)(1R,2S)-2-[3-{[2-イソプロピル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(20)(1R,2S)-2-[3-{[2-イソプロピル-4-(3-フェニルプロポキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(21)(1R,2S)-2-[3-{[3-(ベンジルオキシ)-2-イソプロピルベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(22)(1R,2S)-2-[3-{[2-イソプロピル-3-(2-フェニルエトキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(23)(1R,2S)-2-[3-{[2-イソプロピル-3-(3-フェニルプロポキシ)ベンゾイル]アミノ}-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(24)(1R,2S)-2-[4-(トリフルオロメチル)-3-{[2,3,5-トリメチル-4-(2-フェニルエトキシ)ベンゾイル]アミノ}フェニル]シクロプロパンカルボン酸、
(25)(1R,2S)-2-[3-({[3-イソプロピル-1-(3-フェニルプロピル)-1H-ピラゾール-4-イル]カルボニル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(26)(1R,2S)-2-[3-({[5-イソプロピル-1-(3-フェニルプロピル)-1H-ピラゾール-4-イル]カルボニル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(27)(1R,2S)-2-[3-({[2,6-ジメチル-4-(2-フェニルエトキシ)フェニル]カルボノチオイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(28)(1R,2S)-2-[3-({[4-(2-シクロプロピルエトキシ)-2,6-ジメチルフェニル]カルボノチオイル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(29)(1R,2S)-2-[3-({[2-sec-ブチル-1-(3-フェニルプロピル)-1H-ピロール-3-イル]カルボニル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、
(30)(1R,2S)-2-[3-({[2-イソプロピル-1-(3-フェニルプロピル)-1H-ピロール-3-イル]カルボニル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸、または
(31)(1R,2S)-2-[3-({[2-(2-メチル-2-プロパニル)-1-(3-フェニルプロピル)-1H-ピロール-3-イル]カルボニル}アミノ)-4-(トリフルオロメチル)フェニル]シクロプロパンカルボン酸である請求項1記載の化合物、またはその薬学的に許容される塩。 - 請求項1~10のいずれか1項に記載の化合物、またはその薬学的に許容される塩を有効成分として含有し、さらに薬学的に許容される担体を含有する医薬組成物。
- EP2受容体拮抗剤である、請求項11記載の医薬組成物。
- EP2受容体の活性化に起因する疾患の治療および/または予防剤である、請求項11または12記載の医薬組成物。
- EP2受容体の活性化に起因する疾患が、子宮内膜症、子宮筋腫、月経過多、腺筋症、月経困難症、慢性骨盤痛症候群、がん、炎症性疼痛、神経因性疼痛、頭痛、片頭痛、術後の痛み、間質性膀胱炎、平滑筋腫、過敏性大腸症候群、アルツハイマー病、パーキンソン病、筋萎縮性側索硬化症、多発性硬化症、リウマチ、骨関節炎、痛風、アレルギー性疾患、高血圧、脳障害、虚血、脳卒中、腎疾患、移植拒絶反応、アテローム性動脈硬化症、虚血性心疾患、尋常性ざ瘡、喘息、前立腺炎、糸球体腎炎、サルコイドーシス、血管炎、または、自己免疫疾患である、請求項13記載の医薬組成物。
- EP2受容体の活性化に起因する疾患ががんであり、がんが、乳がん、卵巣がん、大腸がん、肺がん、前立腺がん、頭頸部がん、リンパ腫、ぶどう膜悪性黒色腫、胸腺腫、中皮腫、食道がん、胃がん、十二指腸がん、肝細胞がん、胆管がん、胆のうがん、膵臓がん、腎細胞がん、腎盂・尿管がん、膀胱がん、陰茎がん、精巣がん、子宮がん、膣がん、外陰がん、皮膚がん、悪性骨腫瘍、軟部肉腫、軟骨肉腫、白血病、骨髄異形成症候群、脳腫瘍または多発性骨髄腫である、請求項13または14記載の医薬組成物。
- アルキル化剤、代謝拮抗剤、抗癌性抗生物質、植物性製剤、ホルモン剤、白金化合物、トポイソメラーゼ阻害剤、キナーゼ阻害剤、抗CD20抗体、抗HER2抗体、抗EGFR抗体、抗VEGF抗体、プロテアソーム阻害剤、HDAC阻害剤、および免疫調整薬から選ばれる少なくとも1種以上と組み合わせて投与されることを特徴とする、請求項11~15のいずれか1項に記載の医薬組成物。
- 請求項1~10のいずれか1項に記載の化合物、または薬学的に許容されるその塩を、EP2受容体の活性化に起因する疾患の予防および/または治療を必要とする患者に投与することを特徴とする、EP2受容体の活性化に起因する疾患の予防および/または治療方法。
- EP2受容体の活性化に起因する疾患の予防および/または治療に使用される、請求項1~10のいずれか1項に記載の化合物、またはその薬学的に許容される塩。
- EP2受容体の活性化に起因する疾患の予防および/または治療剤を製造するための、請求項1~10のいずれか1項に記載の化合物、またはその薬学的に許容される塩の使用。
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA3144201A CA3144201A1 (en) | 2019-06-28 | 2020-06-26 | Ep2 antagonist |
AU2020306387A AU2020306387A1 (en) | 2019-06-28 | 2020-06-26 | EP2 antagonist |
KR1020217042562A KR20220030219A (ko) | 2019-06-28 | 2020-06-26 | Ep2 안타고니스트 |
MX2021015654A MX2021015654A (es) | 2019-06-28 | 2020-06-26 | Antagonista del receptor 2 de prostaglandina e2 (ep2). |
US17/621,137 US20220388955A1 (en) | 2019-06-28 | 2020-06-26 | Ep2 antagonist |
JP2021527768A JPWO2020262603A1 (ja) | 2019-06-28 | 2020-06-26 | |
CN202080047042.4A CN114026068A (zh) | 2019-06-28 | 2020-06-26 | Ep2拮抗剂 |
EP20832376.6A EP3992176A4 (en) | 2019-06-28 | 2020-06-26 | EP2 ANTAGONIST |
BR112021026397A BR112021026397A2 (pt) | 2019-06-28 | 2020-06-26 | Antagonista de ep2 |
IL289252A IL289252A (en) | 2019-06-28 | 2021-12-22 | Bispecific antibody |
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US (1) | US20220388955A1 (ja) |
EP (1) | EP3992176A4 (ja) |
JP (1) | JPWO2020262603A1 (ja) |
KR (1) | KR20220030219A (ja) |
CN (1) | CN114026068A (ja) |
AU (1) | AU2020306387A1 (ja) |
BR (1) | BR112021026397A2 (ja) |
CA (1) | CA3144201A1 (ja) |
IL (1) | IL289252A (ja) |
MX (1) | MX2021015654A (ja) |
TW (1) | TW202114985A (ja) |
WO (1) | WO2020262603A1 (ja) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022138792A1 (ja) * | 2020-12-24 | 2022-06-30 | 小野薬品工業株式会社 | Ep2拮抗活性を有する化合物の塩、溶媒和物および結晶 |
WO2022138791A1 (ja) * | 2020-12-24 | 2022-06-30 | 小野薬品工業株式会社 | Ep2アンタゴニスト |
WO2022138793A1 (ja) * | 2020-12-24 | 2022-06-30 | 小野薬品工業株式会社 | Ep2受容体拮抗薬と免疫チェックポイント阻害薬および/またはep4受容体拮抗薬との組み合わせ |
CN115417772A (zh) * | 2022-09-26 | 2022-12-02 | 无锡双启科技有限公司 | 一种3-硝基-4-氟苯甲醚的制备方法 |
JP7205657B1 (ja) | 2021-08-10 | 2023-01-17 | 小野薬品工業株式会社 | Ep4アンタゴニストの製造方法 |
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- 2020-06-24 TW TW109121578A patent/TW202114985A/zh unknown
- 2020-06-26 WO PCT/JP2020/025187 patent/WO2020262603A1/ja active Application Filing
- 2020-06-26 CN CN202080047042.4A patent/CN114026068A/zh active Pending
- 2020-06-26 AU AU2020306387A patent/AU2020306387A1/en active Pending
- 2020-06-26 JP JP2021527768A patent/JPWO2020262603A1/ja active Pending
- 2020-06-26 BR BR112021026397A patent/BR112021026397A2/pt not_active Application Discontinuation
- 2020-06-26 MX MX2021015654A patent/MX2021015654A/es unknown
- 2020-06-26 EP EP20832376.6A patent/EP3992176A4/en active Pending
- 2020-06-26 CA CA3144201A patent/CA3144201A1/en active Pending
- 2020-06-26 US US17/621,137 patent/US20220388955A1/en active Pending
- 2020-06-26 KR KR1020217042562A patent/KR20220030219A/ko unknown
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Cited By (7)
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WO2022138792A1 (ja) * | 2020-12-24 | 2022-06-30 | 小野薬品工業株式会社 | Ep2拮抗活性を有する化合物の塩、溶媒和物および結晶 |
WO2022138791A1 (ja) * | 2020-12-24 | 2022-06-30 | 小野薬品工業株式会社 | Ep2アンタゴニスト |
WO2022138793A1 (ja) * | 2020-12-24 | 2022-06-30 | 小野薬品工業株式会社 | Ep2受容体拮抗薬と免疫チェックポイント阻害薬および/またはep4受容体拮抗薬との組み合わせ |
JP7205657B1 (ja) | 2021-08-10 | 2023-01-17 | 小野薬品工業株式会社 | Ep4アンタゴニストの製造方法 |
WO2023017813A1 (en) * | 2021-08-10 | 2023-02-16 | Ono Pharmaceutical Co., Ltd. | Process for making an ep4 antagonist |
JP2023025693A (ja) * | 2021-08-10 | 2023-02-22 | 小野薬品工業株式会社 | Ep4アンタゴニストの製造方法 |
CN115417772A (zh) * | 2022-09-26 | 2022-12-02 | 无锡双启科技有限公司 | 一种3-硝基-4-氟苯甲醚的制备方法 |
Also Published As
Publication number | Publication date |
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EP3992176A1 (en) | 2022-05-04 |
CN114026068A (zh) | 2022-02-08 |
KR20220030219A (ko) | 2022-03-10 |
CA3144201A1 (en) | 2020-12-30 |
TW202114985A (zh) | 2021-04-16 |
JPWO2020262603A1 (ja) | 2020-12-30 |
AU2020306387A1 (en) | 2022-01-27 |
BR112021026397A2 (pt) | 2022-02-08 |
EP3992176A4 (en) | 2022-08-24 |
MX2021015654A (es) | 2022-02-03 |
IL289252A (en) | 2022-02-01 |
US20220388955A1 (en) | 2022-12-08 |
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