NZ726027B2 - Cyclohexyl pyridine derivative - Google Patents
Cyclohexyl pyridine derivative Download PDFInfo
- Publication number
- NZ726027B2 NZ726027B2 NZ726027A NZ72602715A NZ726027B2 NZ 726027 B2 NZ726027 B2 NZ 726027B2 NZ 726027 A NZ726027 A NZ 726027A NZ 72602715 A NZ72602715 A NZ 72602715A NZ 726027 B2 NZ726027 B2 NZ 726027B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- mixture
- added
- bistrifluoromethylphenyl
- methylamino
- ethyl acetate
- Prior art date
Links
- HUTHUTALXJNNRS-UHFFFAOYSA-N 2-cyclohexylpyridine Chemical class C1CCCCC1C1=CC=CC=N1 HUTHUTALXJNNRS-UHFFFAOYSA-N 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 166
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims abstract description 8
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical group 0.000 claims description 2
- 125000004429 atoms Chemical group 0.000 claims 1
- -1 4-fluoro-2-methyl phenyl Chemical group 0.000 abstract description 89
- 102000002002 Neurokinin-1 Receptors Human genes 0.000 abstract description 41
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 abstract description 41
- 239000011780 sodium chloride Substances 0.000 abstract description 35
- 150000003839 salts Chemical class 0.000 abstract description 34
- 206010047700 Vomiting Diseases 0.000 abstract description 23
- 230000002401 inhibitory effect Effects 0.000 abstract description 22
- ATALOFNDEOCMKK-OITMNORJSA-N Aprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 abstract description 17
- 229960001372 aprepitant Drugs 0.000 abstract description 17
- 102100004057 CYP3A4 Human genes 0.000 abstract description 14
- 101710007540 CYP3A4 Proteins 0.000 abstract description 14
- 230000002265 prevention Effects 0.000 abstract description 10
- 239000002246 antineoplastic agent Substances 0.000 abstract description 4
- 230000003042 antagnostic Effects 0.000 abstract description 3
- 229920000089 Cyclic olefin copolymer Polymers 0.000 abstract 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 abstract 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 2
- 230000003292 diminished Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 235
- 239000000203 mixture Substances 0.000 description 146
- 239000000243 solution Substances 0.000 description 80
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 73
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 72
- 239000011541 reaction mixture Substances 0.000 description 66
- 230000002829 reduced Effects 0.000 description 63
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 58
- 239000002904 solvent Substances 0.000 description 53
- 239000012267 brine Substances 0.000 description 49
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 49
- 239000012044 organic layer Substances 0.000 description 45
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 45
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 44
- 210000004027 cells Anatomy 0.000 description 41
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 40
- 239000012043 crude product Substances 0.000 description 37
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 37
- 239000000741 silica gel Substances 0.000 description 37
- 229910002027 silica gel Inorganic materials 0.000 description 37
- 238000004440 column chromatography Methods 0.000 description 33
- 239000003480 eluent Substances 0.000 description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 26
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- 230000000694 effects Effects 0.000 description 24
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 22
- 239000000126 substance Substances 0.000 description 22
- 125000004076 pyridyl group Chemical group 0.000 description 21
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 20
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- 238000001816 cooling Methods 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- 239000003795 chemical substances by application Substances 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- 239000003814 drug Substances 0.000 description 16
- 239000002253 acid Substances 0.000 description 15
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 15
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 15
- 239000000725 suspension Substances 0.000 description 15
- 101700065588 TAC1 Proteins 0.000 description 14
- 102100002996 TAC1 Human genes 0.000 description 14
- 238000002512 chemotherapy Methods 0.000 description 14
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 14
- 238000007792 addition Methods 0.000 description 13
- 239000012298 atmosphere Substances 0.000 description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- 230000027455 binding Effects 0.000 description 12
- 239000002609 media Substances 0.000 description 12
- 239000007858 starting material Substances 0.000 description 12
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 11
- 229940040692 Lithium Hydroxide Monohydrate Drugs 0.000 description 11
- 230000000875 corresponding Effects 0.000 description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- 150000002500 ions Chemical class 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
- 239000012442 inert solvent Substances 0.000 description 10
- 239000002464 receptor antagonist Substances 0.000 description 10
- 238000010079 rubber tapping Methods 0.000 description 10
- 239000001187 sodium carbonate Substances 0.000 description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 description 10
- 239000007789 gas Substances 0.000 description 9
- 102000005962 receptors Human genes 0.000 description 9
- 108020003175 receptors Proteins 0.000 description 9
- ADNPLDHMAVUMIW-CUZNLEPHSA-N (2S)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-N-[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-1-amino-4-methylsulfanyl-1-oxobutan-2-y Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 ADNPLDHMAVUMIW-CUZNLEPHSA-N 0.000 description 8
- XTHFKEDIFFGKHM-UHFFFAOYSA-N dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 7
- QZAYGJVTTNCVMB-UHFFFAOYSA-N Serotonin Natural products C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 7
- 230000001154 acute Effects 0.000 description 7
- 239000007853 buffer solution Substances 0.000 description 7
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 7
- 239000011575 calcium Substances 0.000 description 7
- 229910052791 calcium Inorganic materials 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 229960004316 cisplatin Drugs 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- LXZZYRPGZAFOLE-UHFFFAOYSA-L transplatin Chemical compound [H][N]([H])([H])[Pt](Cl)(Cl)[N]([H])([H])[H] LXZZYRPGZAFOLE-UHFFFAOYSA-L 0.000 description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- XJHCXCQVJFPJIK-UHFFFAOYSA-M Caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
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- 238000004811 liquid chromatography Methods 0.000 description 6
- 229910052763 palladium Inorganic materials 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 230000003449 preventive Effects 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- 241000588724 Escherichia coli Species 0.000 description 5
- 239000012097 Lipofectamine 2000 Substances 0.000 description 5
- 241000282341 Mustela putorius furo Species 0.000 description 5
- 235000019270 ammonium chloride Nutrition 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 229940079593 drugs Drugs 0.000 description 5
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- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- ROOXNKNUYICQNP-UHFFFAOYSA-N Ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 description 4
- 206010002091 Anaesthesia Diseases 0.000 description 4
- 210000004556 Brain Anatomy 0.000 description 4
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N Lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 229920001850 Nucleic acid sequence Polymers 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N Oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 210000002381 Plasma Anatomy 0.000 description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M Potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 4
- 206010038776 Retching Diseases 0.000 description 4
- 229940076279 Serotonin Drugs 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N Triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
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- 230000014759 maintenance of location Effects 0.000 description 4
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- SECXISVLQFMRJM-UHFFFAOYSA-N n-methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/76—Nitrogen atoms to which a second hetero atom is attached
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
-
- Y10S514/872—
Abstract
Provided is a novel compound which has an NK1 receptor antagonistic action and which is useful in the prevention and treatment of nausea and vomiting accompanying the administration of antineoplastic drugs, which have a diminished CYP3A4 inhibitory action compared to aprepitant. That is to say, the present invention pertains to a cyclohexyl-pyridine derivative represented by formula (I), or a pharmacologically acceptable salt thereof. In the formula, ring A is 4-fluoro-2-methyl phenyl or the like, X is a hydrogen atom or the like, R1 is a carboxymethyl or the like, R2 is an alkyl or the like, Y is from 0-2 or the like, U is -N(CH3)COC(CH3)2-3,5-bis(trifluoromethyl)phenyl or the like. present invention pertains to a cyclohexyl-pyridine derivative represented by formula (I), or a pharmacologically acceptable salt thereof. In the formula, ring A is 4-fluoro-2-methyl phenyl or the like, X is a hydrogen atom or the like, R1 is a carboxymethyl or the like, R2 is an alkyl or the like, Y is from 0-2 or the like, U is -N(CH3)COC(CH3)2-3,5-bis(trifluoromethyl)phenyl or the like.
Description
DESCRIPTION
TITLE OF THE INVENTION
CYCLOHEXYL PYRIDINE DERIVATIVE
TECHNICAL FIELD
The present invention relates to cyclohexyl pyridine derivatives useful as
medicaments.
[0002]
More particularly, the present ion relates to cyclohexyl pyridine
derivatives or pharmaceutically able salts thereof which have substance
P/neurokinin 1 (NK1) receptor antagonist activity, and which are useful as agents for the
tion or treatment of cancer-chemotherapy-induced nausea and vomiting (CINV)
and so on.
BACKGROUND ART
CINV occurs when the vomiting center located in the lateral reticular formation
ofthe medulla oblongata receives a us. The area postrema and the solitary nucleus
of the medulla oblongata contain NK1 receptors, and the NK1 receptors are believed to
be closely ed in vomiting.
Administration of an oplastic agent facilitates the serotonin ion
from the enterochromaffin (EC) cells in the digestive tract, and serotonin directly
stimulates the vomiting center through 5-hydroxytryptarnine3 (5-HT3) receptors in the
digestive tract. Also, when serotonin stimulates the vomiting center through the
chemoreceptor trigger zone (CTZ) located in the area postrema of the fourth ventricle,
nausea and vomiting occur. Substance P, like serotonin, is found in the EC cells in the
digestive tract, and its secretion is promoted by stration of an antineoplastic agent.
Recently, it has been revealed that substance P induces vomiting through the NK1
receptors in the CTZ or by binding to the NK1 receptors in the central nervous ,
and therefore NKI receptors have been attracting attention as the target for developing
etic agents atent literature 1).
Aprepitant is the first selective NK1 receptor antagonist in the world which was
approved as a preventive agent for nausea and vomiting associated with administration
of antineoplastic agents. Regarding the mechanism of action of aprepitant, it is believed
that aprepitant selectively ts the binding of substance P and the NK1 receptors in
the central nervous system, which is one of the pathways that induce CINV, and thus
prevents CINV. Aprepitant has been launched as a preventive agent for CINV (Non-
patent ture 2).
[0005]
It is known that aprepitant is metabolized by cytochrome P450 (CYP) 3A4.
Also, aprepitant is known to have a dose—dependent inhibitory effect on CYP3A4, a
CYP3A4-inducing effect and a CYP2C9-inducing effect. Accordingly, aprepitant may
cause the drug-drug interactions with drugs that inhibit or induce CYP3A4 or with
drugs that are metabolized by CYP3A4 or CYP2C9. For example, it is reported that the
inhibitory effect of aprepitant on CYP3A4 sometimes inhibits the metabolism of
dexamethasone and that the dose should be thus adjusted when dexamethasone is
combined with tant (Non-patent literature 3).
Therefore, when tant is used, sufficient care should be ed to the
drug—drug interactions based on the inhibitory effect of aprepitant on CYP3A4.
For the above reasons, a novel NK1 receptor antagonist with fewer rug
interactions is required in the prevention or treatment of CINV.
Compounds with an NK1 receptor antagonist activity such as casopitant,
netupitant, ezlopitant, rolapitant, vestipitant, vofopitant and so on, are known.
However, casopitant is reported to have an inhibitory effect on CYP3A4 and
cause the drug-drug interactions due to the effect Won-patent literature 4). Clinical
trials on casopitant, as a preventive agent for cancer—chemotherapy-induced nausea and
vomiting, had been conducted in the U.S. and Europe; however, its development was
discontinued after the application. Netupitant is currently under development as a
preventive agent for -chemotherapy-induced nausea and vomiting; however,
netupitant is reported to have an inhibitory effect on CYP3A4 and cause the drug-drug
interactions due to the effect (Non-patent literature 5). Clinical trials on tant, as a
tive agent for cancer-chemotherapy-induced nausea and vomiting, had been
conducted in the U.S.; however, its development was discontinued. Clinical trials on
vofopitant, as a preventive agent for cancer-chemotherapy-induced nausea and ng,
had been conducted in Europe; however, its development was discontinued.
Many of the above compounds resulted in the discontinuance. All the above
compounds have not yet on the market.
[0008]
ne derivatives claiming to be having NK1 receptor antagonist activity are
described in Patent literature 1 to ‘16. And, prodrugs of ne derivatives are
described in Patent literature 17 and 18.
However, cyclohexyl pyridine derivatives of the present invention are not
described in the above literatures.
Citation List
Patent literature
Patent ture 1: US. Patent No. 6,479,483
Patent literature 2: US. Patent No. 637
Patent literature 3: US. Patent No. 7,939,533
Patent literature 4: European Patent No. 1,103,545
Patent literature 5: US. Patent No. 7,211,579
Patent literature 6: US Patent Publication No.2006/0030600
Patent literature 7: US. Patent No. 6,576,762
Patent ture 8: US. Patent No. 316
Patent literature 9: US. Patent No. 7,683,056
Patent literature 10: US. Patent No. 8,344,005
Patent literature 11: International ation No. W02011/ 054773
Patent literature 12: US. Patent Publication No. 2007/0071813
Patent literature 13: US. Patent Publication No. 2003/0083345
Patent literature 14: US. Patent Publication No. 2003/0004157
Patent literature 15: US Patent No. 6,849,624
Patent literature 16: US. Patent No. 6,297,375
Patent literature 17: US. Patent No. 6,593,472
Patent literature 18: US. Patent No. 8,426,450
Non-Patent literature
Non-patent literature 1: P. J. Hesketh et al., European Journal of Cancer, 2003,
Vol. 39, pp. 1074-1080
Non-patent literature 2: Toni M. Dando et al., Drugs, 2004, Vol. 64, No. 7, pp.
777-794
tent literature 3: line B. McCrea et al., CLINICAL
PHARMACOLOGY & THERAPEUTICS, 2003, Vol. 74, No. 1, pp. 17-24
Non-patent literature 4: Stefano Zamuner et al., British Journal of Clinical
Pharmacology, 2010, Vol. 70, No. 4, pp. 537-546
Non-patent literature 5: Corinna Lanzarotti et al., Support Care Cancer, 2013,
Vol. 21, No. 10, pp. 2783-2791
SUMMARY OF THE INVENTION
Problem to be solved by the Invention
[0012]
A problem of the present invention is to provide a new nd which has
NK1 or nist activity, whose CYP3A4 inhibitory activity is reduced
compared to aprepitant, and which are useful for the prevention or ent of cancer-
chemotherapy-induced nausea and vomiting. A problem ofthe present invention is
preferably to provide the above compound whose central transportation property and
long-acting medicinal effect is excellent.
Means for solving the Problem
The present invention relates to a compound represented by the following
formula (I) or a pharmaceutically acceptable salt thereof.
That is, the t invention relates to the following [1] to [12] and the like.
A compound represented by the formula (1):
[Chem 1]
N X (1)
R‘ (R1
wherein
ring A is a group represented by the following formula:
[Chem.2]
X is a hydrogen atom, cyano, halogen, C1-6 alkyl or hydroxymethyl;
R1 is a group represented by the following formula:
[Chem.3]
R1b 0
m WM
R111 0r
wherein
R1a and R1b are each ndently any one of a hydrogen atom, a fluorine atom or C1-6
alkyl;
m is 0, l or 2;
when m is 2, these Rla and Rlb are optionally different from each other ;
R2 is C1-6 alkyl, a hydroxy group or CH, alkoxy;
U is a group ented by the following formula:
wherein
R3a and R313 are each independently a hydrogen atom, C1_6 alkyl, hydroxy C1-6 alkyl or
C1_6 alkoxlyC1_6 alkyl;
Y is 0, l or 2;
when Y is 2, two R2 are optionally different from each other;
or a pharmaceutically acceptable salt thereof.
The compound represented by the formula (Ia) according to the above [1]:
[Chem.S]
wherein
ring A and X have the same meaning as described in the above [1];
R” and R1d are each independently a hydrogen atom or methyl;
Ul is a group ented by the ing formula:
[Chem.6]
lec R3d F
X” F
F F
in which
R3c and R3d are each independently a hydrogen atom, methyl or hydroxymethyl;
n is 0, l or 2;
when n is 2, these R10 and R1d are optionally different from each other;
or a pharmaceutically acceptable salt thereof.
The compound represented by the formula (lb) according to the above [2]:
[Chem.7]
wherein
Rlc and R1“l have the same meaning as bed in the above [2];
or a pharmaceutically acceptable salt thereof.
The compound represented by the following a according to the above [1]:
[Chem. 8]
HO F F
or a pharmaceutically acceptable salt thereof.
The compound represented by the following a according to the above [1]:
[Chem.9]
l FF
|\ F
N/ 0
HO FFF
or a ceutically acceptable salt thereof.
The compound represented by the following formula according to the above [1]:
[Chem. 1 0]
J. FF
|\ F
o N’ O
HO FFF
or a pharmaceutically acceptable salt thereof.
The compound represented by the following formula according to the above [1]:
[Chem.l 1]
or a pharmaceutically acceptable salt thereof.
The compound represented by the following a according to the above [1]:
[Chem. 12]
.1 FF
|\ F
N/ O
HO F F
or a pharmaceutically acceptable salt thereof.
The compound represented by the following formula according to the above [1]:
[Chem.13]
I F
\ F
o N’ CNO
Hok‘“ F F
.
or a pharmaceutically acceptable salt f.
The compound represented by the following formula according to the above [1]:
[Chem.14]
I FF
|\N F
o N’ CN
HO FF
or a pharmaceutically acceptable salt thereof.
A ceutical composition comprising as an active ingredient a compound
according to any one of the above [1] to [10], or a pharmaceutically acceptable salt
The pharmaceutical composition according to the above [1 l], for use in the
prevention of cancer—chemotherapy—induced nausea and ng.
Effect of the Invention
The compounds of the present invention have an excellent NK1 receptor
antagonist activity. And, CYP3A4 inhibitory activity of the compounds of the present
invention is reduced compared to aprepitant. The preferable compounds of the present
ion excel in central ortation property. The more preferable compounds of
the present invention excel in central transportation property and long-acting medicinal
effect.
Therefore, the compounds of the t invention or pharmaceutically
acceptable salts f are useful as an agent for the prevention or treatment of cancer-
chemotherapy—induced nausea and vomiting.
Brief ption of the Drawings
[Figure 1] Figure 1 shows the effect on cisplatin—induced acute and delayed
emetic response in test example 6. In the figure, each bar chart shows a value of control
group (Control), the group intravenously administered with 0.01 mg/kg of the
compound of Example 13 (Ex. No 13, 0.01 mg/kg, iv) and the group intravenously
administered with 0.1 mg/kg of the compound of Example 13 (Ex. No 13, 0.1 mg/kg,
iv) in the acute phase, and a value of control group, the group intravenously
administered with 0.01 mg/kg of the compound of Example 13 (Ex. No 13, 0.01 mg/kg,
iv) and the group intravenously administered with 0.1 mg/kg of the compound of
e 13 (Ex. No 13, 0.1 mg/kg, iv) in the delayed phase from the left respectively.
The vertical axes show the number of retching and vomiting (Retches + Vomits) (the
mean+standard error of 3 examples of control group, the mean+standard error of 3
examples of the group intravenously administered with 0.01 mg/kg, and the
mean+standard error of 3 examples of the group enously administered with
0.1mg/kg).
Mode for Carrying out the Invention
Hereinafter, embodiments ofthe present invention will be discribed in further
detail.
In the present ion, each term has the following meaning unless otherwise
specified.
[001 9]
The term “C16 alkyl” means a straight-chained or a branched alkyl group
having 1 to 6 carbon atoms, and for example, methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, tyl, tert—butyl and the like can be illustrated.
The term “C1_6 alkoxy” means a straight-chained or a branched alkoxy group
having 1 to 6 carbon atoms, and for example, methoxy, ethoxy, propoxy, isopropoxy
and the like can be illustrated.
The term “hydroxyl C1-6 alkyl” means an C1-6 alkyl group tuted with a
hydroxy group such as a hydroxymethyl group, a l—hydroxyethyl group, a l-hydroxy-
1,1-dimethylmethyl group, a 2-hydroxyethyl group, a 2-hydroxymethylpropyl group,
a 3—hydroxypropyl group and the like.
The term “C1-6 alkoxyC1-6 alkyl” means the above C1-6 alkyl substituted by the
above C1_6 alkoxy.
[002 1 ]
In the case Where the compounds represented by the a (I) of the present
invention contain one or more asymmetric carbon atoms, all stereoisomers in the R- or
S—configuration at each of asymmetric carbons and their mixtures are included in the
present invention. In such cases, racemic compounds, c mixtures, individual
enantiomers and mixtures of diastereomers are included in the scope of the present
invention. In the case where the compounds represented by the formula (I) of the
present invention have the cis-trans isomers, all cis-trans isomers are included in the
t invention.
In the present invention, chemical determination can also be determined
according to well—known methods in the art. For example, see also "Tokuron NMR
rittai kagaku", Kodansha, 2012, p. 59.
A compound represented by the a (I) of the present invention can also be
converted into phannaceutically acceptable salts thereof ing to a general method.
As such salts, acid additive salts and salts with a base can be illustrated.
As the acid additive salt, an acid additive salt with a mineral acid such as
hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid,
phosphoric acid and the like, and an acid additive salt with an organic acid such as
formic acid, acetic acid, roacetic acid, methanesulfonic acid, benzenesulfonic acid,
p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric
acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid,
ic acid, benzoic acid, glutamic acid, aspartic acid and the like can be illustrated.
As the salt with a base, a salt formed with nic base such as a lithium salt,
a sodium salt, a potassium salt, a calcium salt, a magnesium salt and the like, and a salt
formed with organic base such as N—methyl-D—glucamine, N,N'-
dibenzylethylenediamine, triethylamine, piperidine, morpholine, idine, arginine,
lysine, choline and the like.
In the present invention, a pharmaceutically acceptable salt also includes a
solvate thereof with a pharmaceutically acceptable solvent such as water, ethanol or the
like.
In the compounds represented by the formula (I) of the present invention, the
symbol R1 and R2 means a substituent of the cyclohexane ring.
In an embodiment of the compound represented by the formula (I) of the
present invention, as cyclohexane ring having a substituent on the ring, a group
represented by the following formula can be rated.
[Chem.15]
,0/* ”>0* * *
R1 R1 R1 OR:
* R2
* *
R1 R1
R2 R2 R2 R2
U R2
wherein, bonds with (*) are bonding site to the pyridine ring, and R1 and R2
have the same g as bed in the above [1].
A compound represented by the formula (I) of the t invention can also be
prepared, for example, by a method described below or a similar method o, or a
method described in literatures or a similar method thereto.
Scheme 1
[Chem.16]
7 8 (I)
In the formula, L1 and L2 are each ndently a leaving group such as a
chlorine atom, a bromine atom, an iodine atom, a trifluoromethanesulfonyloxy group or
the like and ring A, X, R], R2, R33, R3b and Y have the same meanings as defined above.
Process 1
Compound (4) can also be prepared by conducting coupling reaction of
Compound (2) with Compound (3) in an inert solvent in the presence of a base and a
palladium catalyst.
Process 2
Compound (6) can also be prepared by conducting sation reaction of
nd (4) with Compound (5) in an inert solvent in the presence of a base.
Process 3
Compound (8) can also be prepared by conducting coupling reaction of
Compound (6) with Compound (7) in an inert solvent in the presence of a base and a
palladium catalyst.
As the inert solvent, for e, N, N—dimethylformamide, N-
methylpyrrolidone, dimethylsulfoxide, diethyl ether, tetrahydrofuran, 1, 4-dioxane, 1, 2-
dimethoxyethane, benzene, toluene, xylene, ethanol, water and a mixed solvent thereof
can be illustrated. As the base, for example, potassium carbonate, sodium carbonate,
cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide,
potassium fluoride, cesium fluoride, triethylamine, pyridine, N, N-
diisopropylethylamine, 2, 6-lutidine, and 1, abicyclo[5, 4, 0]undecene can be
illustrated. As the palladium catalyst, [1,1'—bis (diphenylphosphino) ferrocene]-
palladium (II) dichloride oromethane complex (1:1) ,
tetrakis(triphenylphosphine)palladium(0) and the like can be rated. The reaction
temperature is usually at 0°C to reflux temperature. The reaction time is usually from 30
minutes to 7 days, varying based on a used starting al, solvent and reaction
temperature or the like.
The above coupling reaction can also be conducted by using a ave
reactor (Biotage). When a microwave r is used, the reaction is ted at
pressure range: 1 to 30 bar, power range: 1 to 400 W, reaction temperature: room
temperature to 300°C, and reaction time: a minute to 1 day, varying based on a used
starting material, t and model.
In addition, when a protective group is required for functional group of R1 or
R2, the above coupling reaction can also be conducted after introduction of protective
group.
Process 4
A compound represented by the formula (I) can also be prepared by conducting
reduction such as tic ion method of the olefin of Compound (8). The
catalytic reduction method can be conducted, for example, by allowing Compound (8)
to react by using a catalyst under a hydrogen gas atmosphere in an inert solvent. As the
inert solvent, for example, methanol, ethanol, ethyl acetate, tetrahydrofuran and acetic
acid can be rated. As the catalyst, for example, palladium-carbon powder,
m-carbon powder, um-carbon powder, platinum-carbon powder doped with
vanadium can be illustrated. The reaction temperature is usually at room temperature to
reflux temperature. The on time is usually from 30 minutes to 7 days, varying
based on a used starting material, solvent and reaction temperature or the like.
In on, when a protective group was introduced into functional group in
the above step 3, a compound represented by the formula (I) can also be prepared by
conducting deprotection reaction after the above reduction reaction.
Scheme 2
[003 7]
[Chem 17]
1 1 O
o 0 0° é,
process 5 process 6 g 0
—. O‘S\|<F —>F
‘ (R2), R1 (sz F R1 (R2)Y
9 10 7
In the formula, R1, R2 and Y have the same meanings as defined above.
[003 8]
Compound (10) can also be prepared by conducting reaction of nd (9)
with romethanesulfonic anhydride in an inert solvent in the presence of a base. As
the inert solvent, for example, N, N-dimethylformamide, N-methylpyrrolidone,
dimethylsulfoxide, diethyl ether, tetrahydrofuran, 1, 4-dioxane, l, 2-dimethoxyethar1e,
benzene, toluene, xylene, and a mixed solvent thereof can be illustrated. As the base, for
example, ium carbonate, sodium ate, cesium carbonate, sodium hydroxide,
ium hydroxide, lithium hydroxide, potassium e, cesium fluoride,
triethylamine, pyridine, N, N-diisopropylethylamine, 2, 6-lutidine, 2,6-Di-tert-butyl
methylpyridine and l, 8-diazabicyclo[5, 4, 0]undecene can be illustrated. The
reaction temperature is usually at 0°C to reflux temperature. The reaction time is usually
from 30 minutes to 7 days, varying based on a used starting material, solvent and
reaction ature or the like.
[0039]
Process 6
Compound (7) can also be prepared by conducting coupling on of
Compound (10) with Compound (1 1) in an inert solvent in the presence of a base and a
palladium catalyst. As the inert solvent, for example, N, N-dimethylformamide, N-
methylpyrrolidone, dimethylsulfoxide, diethyl ether, tetrahydrofuran, l, 4-dioxane, l, 2-
oxyethane, benzene, toluene, xylene, and a mixed solvent thereof can be
illustrated. As the base, for example, potassium ate, potassium acetate, sodium
carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium
hydroxide, potassium fluoride, cesium fluoride, triethylamine, pyridine, N, N-
diisopropylethylamine, 2, 6—lutidine, and l, 8-diazabicyclo[5, 4, 0]-7—undecene can be
illustrated. As the palladium catalyst, for example, [1,1'-bis (diphenylphosphino)
ferrocene]—palladium (II) dichloride -dich10romethane complex (1 :1),
bis(triphenylphosphine)palladium(ll) dichloride can be illustrated. The reaction
temperature is usually at room temperature to reflux temperature. The reaction time is
usually from 30 minutes to 7 days, varying based on a used starting al, solvent
and reaction ature or the like.
The above-mentioned schemes are exemplary for preparing compounds
ented by the formula (I) of the present invention and synthetic intermediates
thereof. The above schemes can be changed or modified into schemes which a person
ordinarily skilled in the art can easily understand.
[0041]
In the above schemes, when a protective group is necessary based on ion
of functional group, operations of introduction and remove can also be conducted
optionally in combination according to a general method.
Compounds represented by the formula (I) of the present invention and
intermediates thereof can also be ed and purified, if required, according to
conventional isolation and purification techniques well known to a person ordinarily
skilled in the art in the relevant field, such as solvent extraction, crystallization,
recrystallization, chromatography, ative high performance liquid chromatography
or the like.
The compounds of the present invention have an excellent NK1 receptor
nist activity, and thus can also be used as an agent for the prevention or treatment
of various diseases mediated by NK1 receptor. For example, the compounds of the
present invention are useful as antiemetic agent, especially useful as preventive agent of
cancer—chemotherapy (for example, cisplatin)—induced gastrointestinal symptom (for
example, nausea and vomiting). Preferable compounds of the t invention are not
only useful for acute cancer—chemotherapy-induced nausea and vomiting but also
d cancer—chemotherapy-induced-nausea and vomiting.
In an embodiment, the compounds of the present invention have an excellent
NK1 receptor antagonist activity, and thus can also be used as an agent for the
prevention of postoperative nausea and vomiting (PONV), nausea and vomiting
associated with radiotherapy, morphine-induced vomiting or motion sickness, and the
ent of schizophrenia, social phobia, anxiety and depression, alcoholism, irritable
bowel syndrome, ulcerative colitis, coughing, , atopic dermatitis, psoriasis,
pruritus, pain, migraine, tinnitus, benign prostatic hyperplasia, overactive bladder or
urinary incontinence.
Pharmaceutical compositions of the present invention can be administered in
s dosage forms depending on their usages. As such dosage forms, for example,
powders, granules, fine granules, dry syrups, tablets, capsules, injections, liquids,
ointments, suppositories and poultices can be illustrated, which are stered orally
or parenterally.
Pharmaceutical compositions of the present invention can be prepared by using
a compound represented by the formula (I) or a pharmaceutically able salt thereof
and at least one of a pharmaceutical additive. These pharmaceutical itions can
be ated by ng, diluting 0r dissolving with appropriate pharmaceutical
additives such as excipients, disintegrants, binders, lubricants, diluents, buffers, tonicity
agents, preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing
, lizing agents and the like, according to a conventional formulation
procedure depending upon their dosage forms.
When a pharmaceutical composition of the present invention is used in the
prevention or treatment, the dosage of a compound represented by the formula (I) or a
pharmaceutically able salt thereof as the active ingredient is appropriately decided
to depend on the age, sex, body , degree of disorders and treatment of each
patient and the like. The dosage for an adult can be decided within the range of, for
example, 0.1 to 1000 mg per day, 0.1 to 500 mg per day, 0.1 to 100 mg per day, or 0.1
to 50 mg per day in the case of oral administration, and the daily dose can be divided
into one, two, three or four times per day and administered. And, the dosage for an adult
can be decided within the range of, for example, 0.1 to 1000 mg per day, 0.1 to 500 mg
per day, 0.1 to 100 mg per day, or 0.1 to 50 mg per day in the case of parenteral
administration, and the daily dose can be divided into one, two, three or four times per
day and administered.
When a pharmaceutical composition of the present invention is used in the ‘
prevention of cancer-chemotherapy-induced nausea and vomiting, this pharmaceutical
can also be stered before administration of antineoplastic agents. For example,
the pharmaceutical can be administered immediately before administration to before an
hour and a half of the administration in chemotherapy, and after the second day, the
pharmaceutical can also be administered in the morning.
[0049]
In an embodiment, a compound represented by the formula (I) of the present
ion or a ceutically acceptable salt thereof can also be used in combination
with any other medicament other than NK1 receptor antagonists. As such other
medicaments used in combination, for example, corticosteroid and 5-HT3 or
nist antiemetic agent can be illustrated.
When a compound represented by the formula (I) of the present invention or a
pharrnaceutically acceptable salt thereof are used in combination with the other
medicament, it can be administered as a formulation sing together with their
active ients or as formulations each of which is separately formulated from each
active ingredient. When separately formulated, these ations can be administered
separately or concurrently.
[005 1]
Furthermore, the dosage of the compound represented by the formula (I) of the
present invention or a pharmaceutically able salt thereof can be reduced
depending on the dosage of the other medicaments used in combination.
EXAMPLES
The present invention is r illustrated in more detail by way of the
following Reference Examples, Examples and Test Examples. However, the present
invention is not d o.
Reference Example 1
4-(4,4,5,5-Tetramethyl-[1,3,2]-dioxaboro1anyl)cycloheXenecarboxy1ic acid ethyl
ester
To a solution of 4-oxocyclohexanecarboxylic acid ethyl ester (1.00 g) and 2,6-
di-tert-butylmethylpyridine (1.39 g) in romethane (40 mL) was added
trifluoromethanesulfonic anhydride (1.74 g) at room temperature, and the mixture was
stirred at room temperature for 16 hours. The insoluble material was removed by
filtration, and then washed with dichloromethane (5 mL). The filtrate was concentrated
under reduced pressure, and to the residue was added dichloromethane (5 mL). The
insoluble material was removed by filtration, and then washed with dichloromethane (3
mL). The filtrate was concentrated under reduced pressure, and to the residue was added
dichloromethane (3 mL). The insoluble material was removed by filtration, and then
washed with dichloromethane (2 mL). The filtrate was trated under reduced
pressure to give 4-trifluoromethanesulfonyloxy—cyclohexenecarboxylic acid ethyl
ester (1.57 g). Under an argon gas atmosphere, a suspension of 4-
trifluoromethanesulfonyloxy-cyclohexenecarboxylic acid ethyl ester (1.57 g),
bis(pinacolato)diboran (1.39 g), [l,1'-bis(diphenylphosphino)ferrocene]palladium(II)
ride dichloromethane complex (1:1) (0.13 g) and potassium e (1.53 g) in
dimethyl sulfoxide (26 mL) was stirred at 50°C for 4.5 hours. The reaction mixture was
cooled to room temperature and water was added. The resulting mixture was extracted
with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous
ium sulfate, and the solvent was removed under reduced pressure. The obtained
crude product was purified by column chromatography on aminopropylsilylated silica
gel (eluent: ne/ethyl acetate=100/0-85/15) to give the title compound (0.84 g).
Reference es 2 to 7
The compounds of Reference Examples 2 to 7 were prepared in a similar
manner to that described in Reference Example 1 using the corresponding starting
materials.
[005 5]
Reference Example 8
(6-Chloroiodopyridinyl)carbamic acid tert—butyl ester
Under an argon gas atmosphere, to a solution of oropyridin
yl)carbamic acid tert—butyl ester (5.0 g) and N, N, N', N'—tetramethylethane-l,2-diamine
(7.7 g) in diethyl ether (120 mL) was added se n-butyllithium (2.65 mol/L
tetrahydrofuran solution, 25 mL) at —78°C. After the mixture was stirred at -10°C for 2
hours, to the mixture was added dropwise a solution of iodine (11.4 g) in diethyl ether
(40 mL) at -78°C, and the resulting mixture was stirred at room temperature for 1 day.
To the reaction e was added a ted aqueous ammonium chloride solution,
and the resulting e was extracted with diethyl ether. The organic layer was
washed with 10% aqueous sodium pyrosulphite solution and brine, and dried over
anhydrous ium sulfate, and the solvent was removed under reduced pressure.
The obtained crude product was purified by column chromatography on silica gel
(eluent: n-hexane/ethyl acetate=100/0-60/40) to give the title compound (2.59 g).
Reference Example 9
(6-Chloroiodopyridin—3—yl)methylcarbamic acid tert—butyl ester
To a solution of (6-chloroiodopyridinyl)carbamic acid tert—butyl ester
(2.59 g) in N,N-dimethylformamide (30 mL) was added sodium hydride (60%, 0.32 g)
under ice-cooling, and the mixture was d at room temperature for 30 minutes. To
the mixture was added iodomethane (2.60 g) under ice-cooling and the mixture was
stirred at room temperature overnight. To the reaction mixture was added a saturated
aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted
with ethyl acetate. The organic layer was washed with water and brine, and dried over
anhydrous magnesium sulfate, and the solvent was removed under reduced pressure.
The obtained crude product was d by column chromatography on
aminopropylsilylated silica gel (eluent: n-hexane/ethyl acetate=1 00/0-70/3 0) to give the
title compound (2.66 g).
Reference Example 10
(6-Chloroiodopyridin—3-y1)methylamine
To a on of oroiodopyridinyl)methylcarbamic acid tert-butyl
ester (2.66 g) in dichloromethane (10 mL) was added trifluoroacetic acid (8.23 g) under
ice-cooling, and the mixture was stirred at room ature for 2 hours. The reaction
mixture was concentrated under reduced pressure, and to the residue was added a
saturated aqueous sodium carbonate solution, and the mixture was extracted with ethyl
acetate. The c layer was washed with water and brine, and dried over anhydrous
magnesium sulfate. The solvent was concentrated under reduced pressure to give the
title compound (1.89 g).
nce Example 11
[6-Chloro(4-fluoro—2—methylphenyl)pyridin—3 -yl]methylamine
To a mixture of (6-chloroiodopyridinyl)methylamine (1.89 g), 4—fluoro
methylphenyl boronic acid (1.30 g), 1,2-dimethoxyethane (20 mL) and water (20 mL)
were added palladium (II) acetate (0.16 g), triphenylphosphine (0.37 g) and sodium
carbonate (3.73 g) at room temperature, and the mixture was d at 90°C overnight.
The on mixture was cooled to room temperature and water was added. The
resulting mixture was extracted with ethyl acetate. The organic layer was washed with
water and brine, and dried over anhydrous magnesium e, and the solvent was
removed under reduced pressure. The obtained crude product was purified by column
chromatography on aminopropylsilylated silica gel (eluent: n—hexane/ethyl
acetate=100/0—50/50) to give the title compound (1.56 g).
[005 9]
nce Example 12
(6-Chloro0rth0—tolylpyridin—3—yl)methylamine
To a e of (6-chlor0-4—iodopyridin—3—yl)methylamine (0.70 g), 2—
methylphenyl boronic acid (0.42 g), 1,2-dimethoxyethane (10 mL) and water (10 mL)
were added palladium (II) acetate (0.058 g), triphenylphosphine (0.14 g) and sodium
carbonate (1.38 g) at room temperature, and the mixture was stirred at 90°C overnight.
The reaction mixture was cooled to room temperature and water was added. The
resulting mixture was ted with ethyl acetate. The organic layer was washed with
water and brine, and dried over anhydrous magnesium sulfate, and the solvent was
removed under d pressure. The ed crude product was purified by colunm
chromatography on silica gel (eluent: n-hexane/ethyl acetate=100/O-70/30) to give the
title compound (0.54 g).
Reference Example 13
6—Chloronitropyridinecarbonitrile
To a solution of 2, 6-dichloronitropyridine (2.50 g) in N—methylpyrrolidone
(25 mL) was added copper (I) cyanide (2.32 g) at room temperature, and the mixture
was stirred at 180°C for 1 hour. The reaction mixture was cooled to room temperature,
and to the mixture were added ethyl e and water. The ble material was
removed by filtration. The filtrate was washed with brine, and the separated aqueous
layer was re-extracted with ethyl acetate. The combined organic layer was washed with
water and brine, and dried over anhydrous magnesium sulfate, and the solvent was
removed under d pressure. The ed crude product was purified by column
chromatography on silica gel (eluent: n-hexane/ethyl acetate=90/10-70/3 0) to give the
title compound (0.90 g).
Reference Example 14
3-Aminochloropyridine—2-carbonitrile
To a solution of 6—chloronitropyridinecarbonitrile (0.32 g) and
concentrated hydrochloric acid (1.2 mL) in ethanol (3 .6 mL) was added iron powder
(0.34 g) at room ature, and the mixture was heated at reflux for 30 minutes. The
reaction mixture was cooled to room temperature, and basified by the addition of
saturated aqueous sodium hydrogen carbonate solution. To the reaction mixture was
added ethyl acetate, and the resulting mixture was filtered through a Celite (registered
trademark) pad. The e was extracted with ethyl acetate. The organic layer was
washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent
was concentrated under reduced pressure to give the title compound (0.24 g).
Reference Example 15
3—Aminobromochloropyridine—Z-carbonitrile
To a solution of 3-amino-6—chloropyridinecarbonitrile (0.24 g) in N,N-
dimethylformamide (8 mL) was added N-bromosuccinimide (0.37 g) at room
temperature, and the mixture was stirred at the same temperature overnight. To the
reaction mixture was added saturated aqueous sodium thiosulfate solution, and the
resulting e was extracted with ethyl acetate. The organic layer was washed with
brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under
reduced pressure. The obtained crude product was purified by column chromatography
on aminopropylsilylated silica gel (eluent: ne/ethyl acetate=75/25-50/50) to give
the title nd (0.30 g).
[0063]
Reference Example 16
ochloro(4—fluoro-2—methylphenyl)pyridinecarbonitrile
A mixture of 3-amino—4-bromo-6—chloropyridine—2-carbonitrile (0.15 g), 4—
fluoromethylphenylboronic acid (0.08 g), tetrakis(triphenylphosphine)palladium(0)
(0.07 g), sodium carbonate (0.20 g), 1, 2-dimethoxyethane (3.2 mL) and water (0.8 mL)
was d at 100°C under microwave irradiation for 1 hour. The reaction mixture was
cooled to room temperature and water was added. The resulting mixture was extracted
with ethyl acetate. The organic layer was washed with saturated s sodium
hydrogen ate solution and brine, and dried over anhydrous magnesium sulfate,
and the solvent was removed under reduced pressure. The obtained crude product was
purified by column chromatography on aminopropylsilylated silica gel t: n-
hexane/ethyl acetate=50/50-0/100) to give the title compound (0.14 g).
Reference Example 17
3-Benzyloxy(3,5-bistrifluoromethylphenyl)—2-methylpropionic acid
Under an argon gas atmosphere, to a solution of 2-(3,5-
bistrifluoromethylphenyl)propionic acid methyl ester (0.60 g) in tetrahydrofuran (5 mL)
was added dropwise lithium diisopropylamide (1.09 mol/L tetrahydrofuran/n—hexane
solution, 2 mL) at —78°C, and the e was stirred at the same temperature for 15
minutes. To the reaction mixture was added a solution of benzyl methyl ether
(0.34 g) in tetrahydrofuran (2 mL) at -78°C, and the mixture was stirred at room
temperature for 1 hour. To the reaction mixture was added a saturated aqueous
ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate.
The organic layer was washed with water and brine, and dried over anhydrous
magnesium sulfate, and the solvent was removed under reduced pressure. The obtained
crude product was purified by column chromatography on silica gel (eluent: n-
hexane/ethyl acetate=100/0-70/30) to give 3-benzyloxy-2—(3,5-
bistrifluoromethylphenyl)methylpropionic acid methyl ester (0.78 g). To a solution
of the obtained nd (0.78 g) in l (3 mL) was added 5.0 mol/L s
sodium hydroxide solution (1 mL) at room temperature, and the mixture was stirred at
room temperature for 3 hours. To the reaction mixture was added 2.0 mol/L
hydrochloric acid (3 ml), and the mixture was extracted with ethyl acetate. The organic
layer was washed with water and brine, and dried over anhydrous magnesium e.
The solvent was d under reduced pressure to give the title compound (0.77 g).
Reference Example 18
—Bistrifluoromethylphenyl)-N-[6-chloro(4-fluoromethylphenyl)pyridin
yl]-N-methylisobutylamide
To a solution of -bistrifluoromethylphenyl)methylpr0pionic acid (0.66
g) in dichloromethane (10 mL) were added oxalyl chloride (0.56 g) and N,N-
dimethylformamide (2 drops) at room temperature, and the mixture was stirred at the
same temperature for 1 hour. The reaction e was concentrated under reduced
pressure to give the residue. Under an argon gas atmosphere, to a solution of [6-chloro-
4-(4-fluoromethylphenyl)pyridin-3 -yl]methylamine (0.50 g) in tetrahydrofuran (10
mL) was added dropwise potassium bis(trimethylsily1)amide (0.5 mol/L toluene
solution, 5.0 mL) under ice-cooling, and the mixture was stirred at room temperature for
s. To the reaction mixture was added dropwise a solution of the above residue
in tetrahydrofuran (5 mL) under ice-cooling, and the e was stirred at room
temperature for 2 hours. To the reaction mixture was added 1.0 mol/L aqueous sodium
hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The
organic layer was washed with water and brine, and dried over anhydrous magnesium
sulfate, and the solvent was removed under reduced pressure. The obtained crude
product was d by column chromatography on aminopropylsilylated silica gel
(eluent: n-hexane/ethyl acetate=100/0—60/40) to give the title compound (1.03 g).
nce Examples 19 and 20
The nds of Reference Examples 19 and 20 were prepared in a r
manner to that described in Reference Example 18 using the corresponding starting
materials.
Reference Example 21
2—(3,5—Bistrifluoromethylphenyl)-N-[6-chlorocyano(4-fluor0
methylphenyl)pyridin—3—y1]isobutylamide
To a solution of 2-(3,5—bistrifluoromethylphenyl)methylpropionic acid (0.31
g) in dichloromethane (2.6 mL) were added oxalyl chloride (0.26 g) and N,N—
dimethylformamide (2 drops) at room temperature, and the mixture was stirred at the
same ature for 1 hour. The reaction mixture was concentrated under reduced
pressure to give the residue. To a solution of 3-aminochloro(4-fluoro
methylphenyl)pyridinecarbonitrile (0.14 g) in tetrahydrofuran (5 mL) was added
sodium bis(trimethylsi1yl)amide (1.0 mol/L tetrahydrofuran solution, 1.1 mL) under ice-
cooling, and the mixture was stirred at the same temperature for 30 minutes. To the
reaction mixture was added dropwise a solution of the above residue in tetrahydrofuran
(2.0 mL) under ice~cooling, and the mixture was stirred at room temperature for 30
minutes. To the reaction mixture was added a saturated aqueous sodium hydrogen
carbonate solution, and the resulting mixture was extracted with ethyl acetate. The
organic layer was washed with water and brine, and dried over anhydrous magnesium
sulfate, and the t was removed under reduced pressure. The obtained crude
product was purified by column chromatography on aminopropylsilylated silica gel
t: n-hexane/ethyl acetate=8 5/ 1 0) to give the title compound (0.21 g).
[0068]
Reference Example 22
2-(3,5-Bistrifluoromethylphenyl)-N—[6-chlorocyano(4-fluoro
methylphenyl)pyridinyl]-N—methylisobutylamide
To a solution of -bistrifluoromethylphenyl)-N-[6-chlorocyano(4-
fluoromethy1phenyl)pyridinyl]isobutylamide (0.21 g) in N,N-dimethylformamide
(2.4 mL) was added sodium hydride (60%, 0.018 g) under ice-cooling, and the mixture
was d at the same temperature for 5 minutes. To the reaction mixture was added
iodomethane (0.11 g) under ice-cooling, and the mixture was stirred at room
temperature overnight. To the reaction mixture was added water, and the resulting
mixture was extracted with ethyl e. The organic layer was washed with water and
brine, and dried over ous magnesium sulfate, and the solvent was d under
reduced pressure. The obtained crude product was purified by column chromatography
on silica gel (eluent: ne/ethyl acetate=90/ 10—50/50) to give the title compound
(0.09 g).
Reference Example 23
4- [5- { [2-(3 ,5—Bistrifluoromethylphenyl)methylpropionyl]methylamino } (4-fluoro-
2-methylphenyl)pyridin—2—yl]cyclohex—3—enecarboxy1ic acid ethyl ester
A mixture of 2-(3,5—bistrifluoromethylphenyl)-N-[6-chloro(4-fluoro
methylphenyl)pyridin-3 -y1]-N-methylisobutylamide (0.08 g), 4-(4,4,5,5-tetramethyl-
[1,3,2]-dioxaborolanyl)cyclohexenecarboxylic acid ethyl ester (0.08 g), sodium
carbonate (0.05 g), tetrakis(triphenylphosphine)palladium(0) (0.02 g), 1, 2-
dimethoxyethane (1.0 mL), water (0.2 mL) and ethanol (0.2 mL) was stirred at 120°C
under microwave ation for 1 hour. The reaction mixture was cooled to room
temperature and water was added. The ing mixture was extracted with ethyl
acetate. The organic layer was washed with water and brine, and dried over anhydrous
magnesium sulfate, and the solvent was removed under reduced pressure. The obtained
crude product was purified by column chromatography on aminopropylsilylated silica
gel (eluent: n-hexane/ethyl e=100/O-80/20) to give the title compound (0.03 g).
Reference Examples 24 to 26
The compounds of Reference Examples 24 to 26 were prepared in a similar
manner to that described in nce Example 23 using the corresponding starting
als.
[007 l ]
Reference Example 27
2-(3,5-Bistrifluoromethylphenyl)-N-[6-(1,4-dioxaspiro[4.5]decenyl)—4—(4-fluoro-
2-methylpheny1)pyridin—3-yl]-N—methy1isobutylamide
A mixture of 2-(3,5-bistrifluoromethylphenyl)—N-[6—chloro-4—(4-fluoro
methylphenyl)pyridinyl]-N—methylisobutylamide (0.53 g), 8-(4,4,5,5-tetramethyl-
[l,3,2]-dioxaborolanyl)-l,4—dioxaspiro[4.5]decene (0.29 g), sodium ate
(0.32 g), tetrakis(triphenylphosphine)palladium(0) (0.12 g), l, 2-dimethoxyethane (7.5
mL), water (1.5 mL) and ethanol (1.5 mL) was stirred at 120°C under microwave
irradiation for 30 minutes. The reaction mixture was cooled to room ature and
water was added. The ing mixture was extracted with ethyl acetate. The organic
layer was washed with water and brine, and dried over anhydrous magnesium sulfate,
and the solvent was removed under d pressure. The obtained crude product was
purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=90/10-
/90) to give the title compound (0.52 g).
Reference Examples 28 to 30
The compounds of Reference Examples 28 to 30 were prepared in a similar
- manner to that described in Reference Example 23 using the corresponding starting
materials.
Reference Example 31
2-{4-[5- { [2-(3 ,5-Bistrifluoromethylphenyl)—2-methylpropionyl]methylamino} (4-
2-methylphenyl)pyridin—2—yl]cyclohexenyl}methy1pr0pionic acid ethyl
ester
A mixture of -bistrifluoromethylphenyl)-N-[6-chloro(4-fluoro-2—
methylphenyl)pyridin-3 -yl]-N-methylisobutylamide (0.11 g), 2-methyl[4-(4,4,5,5-
tetramethyl[l,3,2]dioxaborolanyl)cyclohexenyl]propionic acid ethyl ester (0.12 g),
sodium carbonate (0.06 g), tetrakis(triphenylphosphine)palladium(0) (0.02 g), 1, 2-
dimethoxyethane (1.5 mL), water (0.3 mL) and ethanol (0.3 mL) was stirred at 120°C
under microwave irradiation for 30 minutes. The on mixture was cooled to room
temperature and water was added. The ing mixture was extracted with ethyl
acetate. The c layer was washed with water and brine, and dried over anhydrous
magnesium sulfate, and the solvent was d under reduced pressure. The obtained
crude product was purified by column chromatography on silica gel (eluent: n-
hexane/ethyl acetate=100/0-60/40) to give the title compound (0.12 g).
Reference Example 32
{4- [5— { [2-(3 ,5 -Bistrifluoromethylphenyl)methylpropionyl]methylamino } (4-
fluoromethylphenyl)pyridin—2-yl]cyclohexeny1}acetic acid methyl ester
A mixture of 2-(3,5-bistrifluoromethylphenyl)-N-[6-chloro—4-(4-fluoro-2—
methylphenyl)pyridiny1]-N-methylisobutylamide (2.00 g), [4-(4,4,5,5-
tetramethyl[1,3,2]dioxaborolanyl)cyclohexenyl]acetic acid methyl ester (1.26 g),
tetrakis(triphenylphosphine)palladium(0) (0.22 g), 2.0 mol/L aqueous sodium carbonate
solution (5.6 mL), 1, 2-dimethoxyethane (22.5 mL) and ethanol (5 .6 mL) was stirred at
120°C under microwave irradiation for 30 minutes. The reaction mixture was cooled to
room temperature and water was added. The resulting mixture was extracted with ethyl
acetate. The organic layer was washed with brine, and dried over anhydrous magnesium
sulfate, and the solvent was removed under d pressure. The obtained crude
product was purified by column chromatography on aminopropylsilylated silica gel
t: n—hexane/ethyl acetate=1 0/50) to give the title compound (2.14 g).
Reference Example 33
2-(3 ,5—Bistrifluoromethylphenyl)-N-[4-(4-fluoromethylphenyl)(l -methyl-3 -
oxocyclohexyl)pyridin—3—yl]-N-methylisobutylamide
To a suspension of copper (I) iodide (0.05 g) in diethyl ether (2 mL) was added
methyllthium (1.13 mol/L diethyl ether solution, 0.45 mL) under ice-cooling, and the
e was stirred at the same temperature for 15 minutes. To the reaction mixture
was added dropwise 2-(3,5-bistrifluoromethylphenyl)-N-[4-(4-fluoromethylphenyl)—
6-(3 -oxocyclohex-l—enyl)pyridinyl]—N—methylisobutylamide (0.10 g) in diethyl ether
(1 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hour.
To the reaction mixture was added a saturated s ammonium chloride solution,
and the resulting mixture was extracted with ethyl acetate. The organic layer was
washed with brine, and dried over anhydrous magnesium sulfate, and the solvent was
d under reduced pressure. The ed crude product was purified by column
chromatography on silica gel t: n-hexane/ethyl acetate=85/ l 5-50/5 0) to give the
title compound (0.50 g).
[0076]
Reference Example 34
{3 - [5 -{ [2-(3 ,5-Bistrifluoromethylphenyl)methylpropionyl]methylamino } (4-
fluoromethylphenyl)pyridinyl]cyclohex—2-enylidene}acetic acid ethyl ester
To a suspension of sodium hydride (60%, 0.012 g) in tetrahydrofuran (2 mL)
was added diethyl phosphonoacetate (0.08 g) under ice-cooling, and the mixture was
stirred at the same ature for 30 minutes. To the reaction mixture was added 2-
(3 ,5 -bistrifluoromethylphenyl)—N—[4-(4-fluoromethylphenyl)-6—(3-oxocyclohex
enyl)pyridinyl]-N—methy1isobutylamide (0.10 g) in tetrahydrofuran(1 mL) at room
temperature, and the mixture was stirred at the same temperature overnight and at 50°C
for 24 hours. The reaction mixture was cooled to room temperature and water was
added. The resulting mixture was extracted with ethyl acetate. The organic layer was
washed with brine, and dried over anhydrous magnesium e, and the solvent was
removed under reduced pressure. The obtained crude product was purified by column
chromatography on silica gel (eluent: n-hexane/ethyl acetate=8 5/ 1 5-40/60) to give the
title compound (0.05 g).
Reference Example 35
The compound of Reference Example 35 was prepared in a r manner to
that described in Reference Example 34 using the corresponding ng material.
Reference Example 36
~Bistrifluoromethylphenyl)-N—[6-(1,4-dioxaspiro[4.5]decyl)(4-fluoro-2—
methylphenyl)pyridinyl]-N—methy1isobutylamide
Under a hydrogen gas atmosphere, a suspension of -
bistrifluoromethylphenyl)-N-[6-(1,4-dioxaspiro[4.5]decen—8-yl)(4-fluoro
methylphenyl)pyridin-3—yl]-N-methylisobutylamide (0.52 g) and 10% palladium on
carbon (0.10 g, wet) in methanol (10 mL) was stirred at room temperature ght.
The reaction mixture was filtered through a Celite (registered ark) pad, and the
filtrate was concentrated under reduced pressure to give the title compound (0.50 g).
Reference Example 37
2-(3,5-Bistrifluoromethylphenyl)-N-[4-(4-fluoromethylphenyl)(4-
lohexyl)pyridin—3-yl]-N-methylisobutylamide
To a solution of 2-(3,5-bistrifluoromethylphenyl)—N-[6-(l,4-
dioxaspiro[4.5]decyl)(4—fluoro-2—methy1phenyl)pyridinyl]-N—
methylisobutylamide (0.50 g) in acetone was added 1.0 mol/L hydrochloric acid (3.0
mL) at room temperature, and the mixture was stirred at 50°C for 2 hours. The reaction
mixture was cooled to room temperature and water was added. The resulting mixture
was extracted with ethyl acetate. The organic layer was washed with brine, and dried
over anhydrous magnesium sulfate, and the solvent was removed under reduced
pressure. The obtained crude product was purified by column chromatography on silica
gel (eluent: n-hexane/ethyl acetate=90/10-10/90) to give the title compound (0.41 g).
Reference Example 38
{ [2-(3 ,5—Bistrifluoromethylphenyl)methylpropionyl]methylamino } (4-
fluoromethylphenyl)pyridin—2—yl]— l -hydroxycyclohexyl}acetic acid ethyl ester
Under an argon gas phere, to a solution of ethyl acetate (0.021 g) in
tetrahydrofuran (1 mL) was added dropwise lithium diisopropylamide solution (1.09
mol/L tetrahydrofuran/n-hexane solution, 0.20 mL) at -78°C, and the e was
stirred at the same temperature for 20 minutes. To the reaction mixture was added a
solution of 2-(3,5—bistrifluoromethylphenyl)-N-[4-(4-fluoromethylphenyl)—6-(4—
oxocyclohexyl)pyridinyl]-N-methylisobutylamide (0.10 g) in tetrahydrofuran (1 mL)
at -78°C, and the mixture was stirred at room ature for 2 hours. To the reaction
mixture was added a saturated aqueous ammonium de solution, and the resulting
e was extracted with ethyl acetate. The organic layer was washed with water and
brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under
reduced pressure. The obtained crude product was purified by column tography
on silica gel (eluent: n-hexane/ethyl e=90/10-10/90) to give the title compound
(0.10 g).
[008 1]
Reference Example 39
2—{4-[5-{ [2-(3,5-Bistrifluoromethylphenyl)methylpropionyl]methylamino}(4-
fluoromethylphenyl)pyridinyl]cyclohexylidene}propionic acid ethyl ester
To a suspension of sodium hydride (60%, 0.017 g) in tetrahydrofuran (2 mL)
was added 2-phosphonopropionic acid triethyl ester (0.11 g) under ice—cooling, and the
mixture was stirred at the same ature for 30 minutes. To the reaction mixture was
added a solution of 2—(3,5-bistrifluoromethylphenyl)—N-[4-(4-fluoromethylphenyl)
(4-oxocyclohexyl)pyridin-3—yl]-N-methylisobutylamide (0.14 g) in tetrahydrofuran (1
mL) at room temperature, and the mixture was stirred at 50°C overnight. The reaction
mixture was cooled to room temperature and a saturated aqueous ammonium chloride
solution was added. The resulting mixture was extracted with ethyl acetate. The organic
layer was washed with water and brine, and dried over anhydrous ium sulfate,
and the solvent was removed under reduced pressure. The ed crude t was
purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=100/0-
50/50) to give the title compound (0.13 g).
Reference e 40
{3 -[5-{ [2—(3 ,5 ifluoromethylphenyl)—2-methylpropionyl]methylamino } (4-
fluoromethylphenyl)pyridinyl]cyclohexyl}acetic acid ethyl ester
Under a hydrogen gas atmosphere, a suspension of {3-[5-{ 5—
'10 bistrifluoromethylphenyl)—2-methylpropionyl]methylamino} fluoro
methylphenyl)pyridin—2-yl]cyclohexenylidene}acetic acid ethyl ester (0.03 g) and
% palladium on carbon (0.01 g, wet) in methanol (1 mL) was stirred at room
temperature overnight. The reaction mixture was filtered through a Celite (registered
trademark) pad, and the filtrate was concentrated under reduced pressure. The obtained
crude product was purified by column chromatography on silica gel (eluent: n-
hexane/ethyl acetate=85/15-40/60) to give the title compound (0.02 g).
Reference Example 41
The compound of Reference Example 41 was prepared in a similar manner to
that described in Reference Example 40 using the corresponding starting material.
Reference Example 42
2-{4-[5—{ [2-(3,5-Bistrifluoromethylphenyl)methylpropionyl]methylamino}(4-
fluoromethylphenyl)pyridin—2-yl]cyclohexyl}propionic acid ethyl ester
Under a hydrogen gas atmosphere, a suspension of 2-{4-[5-{[2-(3,5-
bistrifluoromethylphenyl)methylpropionyl]methylamino}—4—(4-fluor0
methylphenyl)pyridinyl]cyclohexylidene}propionic acid ethyl ester (0.13 g) and 10%
palladium on carbon (0.025 g, wet) in methanol (5 mL) was stirred at room temperature
overnight. The reaction mixture was filtered through a Celite (registered trademark) pad,
and the filtrate was trated under d pressure to give the title compound
(0.11 g).
Reference Example 43
4~ [5 -{ [2-(3 ,5-Bistrifluoromethylphenyl)-2—methylpropionyl]methylamino} (4-fluoro-
ylphenyl)pyridinyl]cyclohexanecarboxylic acid ethyl ester
Under a hydrogen gas atmosphere, a suspension of 4-[5-{ [2—(3,5-
bistrifluoromethylphenyl)methylpropionyl]methylamino} (4—fluoro
methylphenyl)pyridin—2-yl]cyclohexenecarboxylic acid ethyl ester (0.03 g) and 10%
palladium on carbon (0.010 g, wet) in l (1 mL) was stirred at room ature
for 14 hours. The reaction mixture was filtered through a Celite (registered trademark)
pad, and the filtrate was concentrated under reduced pressure. The obtained crude
product was purified by column chromatography on silica gel (eluent: n—hexane/ethyl
acetate=70/30-50/5 0) to give the title compound (0.02 g).
Reference Examples 44 to 47
The nds of Reference Examples 44 to 47 were prepared in a similar
manner to that described in Reference Example 43 using the corresponding starting
materials.
Reference Example 48
{4-[5-{ [3-Benzyloxy(3,5-bistrifluoromethylphenyl)
methylpropionyl]methylamino}(4-fluoromethylphenyl)pyridinyl]cyclohex
enyl}acetic acid
To a e of {4-[5-{[3-benzyloxy(3,5—bistrifluoromethylphenyl)—2-
methylpropionyl]methylamino} (4-fluoromethylphenyl)pyridin—2—yl]cyclohex-3 -
enyl}acetic acid ethyl ester (0.11 g), tetrahydrofuran (1 mL), methanol (0.5 mL) and
water (0.5 mL) was added lithium hydroxide monohydrate (0.03 g) at room temperature,
and the mixture was stirred at the same temperature overnight. To the reaction mixture
was added 2.0 mol/L hydrochloric acid (0.4 mL), and the solvent was removed under
reduced re. To the residue was added water, and extracted with ethyl acetate. The
organic layer was washed with water and brine, and dried over anhydrous magnesium
sulfate, and the solvent was removed under reduced pressure. The obtained crude
product was purified by column chromatography on silica gel (eluent: ethyl
e/methanol=1 00/0-90/10) to give the title compound (0.05 g).
Reference Examples 49 and 50
trans{4-[5-{ [2-(3,5-Bistrifluoromethylphenyl)-2—methylpropionyl]methylamino}
(4-fluoromethylphenyl)pyridinyl]cyclohexyl}methylpropionic acid ethyl ester
(Reference Example 49), and cis{4-[5-{[2-(3,5-bistrifluor0methylphenyl)
methylpropionyl]methylamino}(4—fluoromethylphenyl)pyridinyl]cyclohexyl}-
2-methy1propionic acid ethyl ester (Reference Example 50)
Under a hydrogen gas atmosphere, a mixture of 2-{4-[5—{[2-(3,5-
bistrifluoromethylphenyl)-2—methylpropionyl]methylamino}(4-fluoro
methylphenyl)pyridinyl]cyclohexenyl}methylpropionic acid ethyl ester (0.11
g), 10% palladium on carbon (0.03 g, wet), methanol (2 mL) and tetrahydrofuran (1
mL) was stirred at room temperature ght. The reaction mixture was filtered
through a Celite (registered trademark) pad, and the filtrate was concentrated under
reduced pressure. The obtained crude product was d by column chromatography
on silica gel (eluent: n—hexane/ethyl acetate=100/0-60/40) to give nce es
49 (0.05 g) and Reference Examples 50 (0.04 g). In the above chromatography, the
compound of Reference Examples 49 was in the high polarity side, and the compound
of Reference Examples 50 was in the low polarity side.
Reference Example 51
{4- [5-{ [2-(3 ,5-Bistrifluoromethylphenyl)methylpropionyl]methylamino } —4-(4-
fluoromethylphenyl)pyridin—2-yl]cyclohexyl}acetic acid methyl ester
Under a hydrogen gas atmosphere, a suspension of {4-[5-{[2-(3,5-
bistrifluoromethylphenyl)methylpropionyl]methylamino}-4—(4-fluoro
phenyl)pyridinyl]cyclohexeny1}acetic acid methyl ester (2.14 g) and 10%
palladium on carbon (E101 NE/W type (EVONIK))(0.21 g) in ol (96 mL) was
stirred at room temperature overnight. The reaction mixture was filtered through a
Celite (registered trademark) pad, and the filtrate was concentrated under reduced
pressure. The obtained crude product was purified by column chromatography on
aminopropylsilylated silica gel t: n-hexane/ethyl acetate=100/0-40/60) to give the
title compound (2.13 g).
Reference e 52
{4- [5-{ [2-(3 ,5-Bistrifluoromethylpheny1)methy1propionyl]methylamino}(4-
fluoromethylphenyl)pyridinyl] methylcyclohexyl } acetic acid methyl ester
To a suspension of sodium hydride (60%, 0.020 g) in tetrahydrofuran (2 mL)
was added dimethyl phosphonoacetic acid methyl ester (0.09 g) under ice-cooling, and
the mixture was stirred at room temperature for 1 hour. To the reaction mixture was
added a solution of 2-(3,5-bistrifluoromethylphenyl)-N—[4-(4-fluoromethylphenyl)
(4-oxocyclohexyl)pyridin—3-yl]-N-methylisobuty1amide (0.15 g) in tetrahydrofuran (1
mL) at room temperature, and the mixture was stirred at 50°C for 30 minutes. The
reactiOn mixture was cooled to room temperature and a saturated s um
chloride solution was added. The resulting e was extracted with ethyl acetate. The
organic layer was washed with water and brine, and dried over ous magnesium
sulfate, and the t was d under reduced pressure. The obtained crude
product was purified by column chromatography on silica gel (eluent: n—hexane/ethyl
acetate=90/10-30/70) to give {4-[5-{[2-(3,5-bistrifluoromethylphenyl)
methylpropionyl]methylamino}(4-fluoromethy1phenyl)pyridin
yl]cyclohexy1idene}acetic acid methyl ester (0.15 g).
To a suspension of copper (I) iodide (0.05 g) in diethyl ether (0.40 mL) was
added methyllithium (1.13 mol/L diethyl ether solution, 0.50 mL) under ice-cooling,
and the mixture was stirred at the same temperature for 10 minutes, and the solvent was
concentrated under reduced pressure. Under an argon gas atmosphere, to the residue
was added dichloromethane (0.40 mL) under ice-cooling, and the e was stirred
for 5 minutes, and the solvent was concentrated under reduced pressure. To the residue
was added dichloromethane (0.40 mL), and cooled to —78°C. To the mixture was added
trimethylsilyl chloride (0.03 g), and to the resulting mixture was added dropwise a
solution of {4-[5-{[2-(3,5-bistrifluoromethylphenyl)methylpropionyl]methylamino}-
4-(4-fluoromethylphenyl)pyridiny1]cyclohexylidene}acetic acid methyl ester (0.09
g) in romethane (1.0 mL). The resulting e was d under ice-cooling for
1 hour and at room temperature overnight. To the reaction mixture was added a
saturated aqueous ammonium chloride solution, and the resulting mixture was ted
with ethyl acetate. The c layer was washed with brine, and dried over anhydrous
magnesium sulfate, and the solvent was removed under reduced pressure. The obtained
crude product was purified by column chromatography on silica gel (eluent: n—
hexane/ethyl acetate=90/10-40/60) to give the title compound (0.08 g).
[009 1 ]
Reference Example 53
The compound of Reference Example 53 was prepared in a r manner to
that described in Reference Example 16 using the corresponding starting material.
Reference Example 54
The compound of nce Example 54 was prepared in a similar manner to
that described in Reference Example 21 using the corresponding ng material.
Reference Example 55
The compound of Reference Example 55 was prepared in a similar manner to
that described in Reference Example 22 using the ponding starting material.
Reference Examples 56 and 57
The compounds of Reference Examples 56 and 57 were ed in a similar
manner to that described in nce Example 23 using the corresponding starting
materials.
Reference Examples 58 and 59
The compounds of Reference Examples 58 and 59 were prepared in a similar
manner to that described in Reference Example 43 using the corresponding starting
materials.
Reference Example 60
{4-[5- { [2-(3 ,5—Bistrifluoromethylphenyl)methylpropionyl]methylamino } —4-(4-
fluoro—2-methylphenyl)- l -oxypyridinyl]cyclohexyl}acetic acid ethyl ester
To a solution of {4—[5-{[2-(3,5—bistrifluoromethylphenyl)
methylpropionyl]methylamino}(4-fluoromethylphenyl)pyridin
yl]cyclohexyl}acetic acid ethyl ester (0.37 g) in dichloromethane was added m-
chloroperoxybenzoic acid (purity 70%, 0.55 g) under ice-cooling, and the mixture was
stirred at room ature overnight. The reaction mixture was cooled with ice, and to
the mixture was added 1.0 mol/L s sodium hydroxide on. The resulting
mixture was extracted with ethyl acetate. The organic layer was washed with brine, and
dried over anhydrous magnesium sulfate, and the solvent was removed under reduced
pressure. The obtained crude product was purified by column tography on silica
gel (eluent: n-hexane/ethyl acetate=40/60—0/100) to give the title compound (0.35 g).
Reference Example 61
{4-[5 - { [2-(3 trifluoromethylphenyl)—2-methy1propiony1]methylamino}chloro
(4-fluoromethylphenyl)pyridinyl]cyclohexyl}acetic acid ethyl ester
A mixture of {4-[5-{ [2-(3,5-bistrifluoromethylphenyl)
methylpropionyl]methylamino }—4—(4—fluoro-2—methylphenyl)oxypyridin
yl]cyclohexyl}acetic acid ethyl ester (0.20 g) and phosphoryl chloride (0.60 mL) was
stirred at 120°C for 2 hours. The reaction mixture was cooled with ice, and basified by
the addition of water and aqueous ammonia. The resulting mixture was extracted with
ethyl e. The organic layer was washed with brine, and dried over anhydrous
magnesium sulfate, and the solvent was d under reduced pressure. The obtained
crude product was purified by column chromatography on silica gel (eluent: n-
hexane/ethyl acetate=90/ 1 0-50/5 0) to give the title compound (0.16 g).
Reference Example 62
{4- [5-{ [2-(3 ,5-Bistrifluoromethylphenyl)methylpropionyl]methylamino } (4—
2-methylphenyl)methylpyridinyl]cyclohexyl}acetic acid ethyl ester
A mixture of {4-[5-{[2-(3,5-bistrifluoromethylphenyl)~2-
methylpropionyl]methylamino} -6—chloro(4—fluoro—2-methylphenyl)pyridin
yl]cyclohexyl}acetic acid ethyl ester (0.04 g), 2,4,6—trimethylcyclotriboroxane (0.014 g),
tetrakis(triphenylphosphine)palladium(0) (0.007 g), sodium ate (0.016 g) and 1,
2-dimethoxyethane (2.9 mL) was stirred at 120°C under microwave irradiation for 1
hour. The reaction mixture was cooled to room temperature and water was added. The
resulting mixture was ted with ethyl acetate. The organic layer was washed with
water and brine, and dried over anhydrous magnesium sulfate, and the t was
removed under reduced pressure. The obtained crude product was purified by column
chromatography on silica gel (eluent: n-hexane/ethyl acetate=80/20-20/80) to give the
title compound (0.019 g).
Reference Example 63
{4-[5- { [2-(3 trifluoromethylphenyl)methylpropionyl]methylamino } (4-
2-methylphenyl)hydroxymethylpyridinyl]cyclohexyl}acetic acid ethyl ester
To a solution of {4-[5—{[2-(3,5-bistrifluoromethylphenyl)-2—
propionyl]methylamino} (4-fluoro-2—methylphenyl)— 1 -oxypyridin-2—
yl]cyclohexyl}acetic acid ethyl ester (0.15 g) in dichloromethane (2.0 mL) was added
trimethyloxonium tetrafluoroborate (0.04 g) at room temperature, and the mixture was
stirred at the same temperature for 2 hours. The reaction mixture was concentrated
under reduced pressure, and to the residue was added methanol (2.0 mL). To the
mixture was added a on of ammonium persulfate (0.01 g) in water (0.02 mL) at
65°C, and the mixture was stirred at the same temperature for 1 hour. To the reaction
mixture was added a solution of ammonium persulfate (0.01 g) in water (0.02 mL) at
65°C, and the mixture was stirred at the same temperature for 13 hours. After the
reaction mixture was cooled to room temperature, the solvent was concentrated under
reduced pressure. To the residue was added an aqueous solution of sodium carbonate,
and the mixture was extracted with ethyl acetate. The organic layer was washed with
brine, and dried over anhydrous magnesium sulfate. The t was concentrated under
d pressure to give a mixture of the title compound and {4-[5-{[2-(3,5-
bistrifluoromethylphenyl)methylpropionyl]methylamino}(4-fluoro—2-
methylphenyl)hydroxymethylpyridiny1]cyclohexyl}acetic acid methyl ester (0.06
[01 00]
Example 1
4-[5 -{ [2-(3 ,5-Bistrifluoromethylphenyl)—2-methylpropionyl]methylamino } (4-fluoro—
2-methylphenyl)pyridinyl]cyclohexanecarboxylic acid
To a mixture of 4-[5-{ [2-(3,5-bistrifluoromethylphenyl)
methylpropionyl]methylamino}(4-fluoromethy1phenyl)pyridin
yl]cyclohexanecarboxylic acid ethyl ester (0.022 g), tetrahydrofuran (0.375 mL),
methanol (0.375 mL) and water (0.150 mL) was added lithium ide monohydrate
(0.014 g) at room ature, and the mixture was stirred at the same temperature for
72 hours. To the reaction mixture were added 2.0 mol/L hydrochloric acid (0.170 mL)
and water, and the resulting mixture was extracted with ethyl acetate. The organic layer
was washed with water and brine, and dried over ous sodium sulfate. The t
was concentrated under reduced pressure to give the title compound (0.018 g).
[01 01]
Example 2
3- { 4- [5 -{ [2-(3 ,5-Bistrifluoromethylphenyl)-2—methylpropionyl]methylamino} (4-
fluoromethylphenyl)pyridinyl]cyclohexyl}propi0nic acid
To a mixture of 3-{4-[5-{[2-(3,5-bistrifluoromethylphenyl)—2-
methylpropionyl]methylamino} —4-(4-fluoromethylphenyl)pyridin
y1]cyclohexyl}propionic acid ethyl ester (0.019 g), tetrahydrofuran (0.375 mL),
methanol (0.375 mL) and water (0.150 mL) was added lithium hydroxide drate
(0.012 g) at room temperature, and the mixture was stirred at the same temperature for 6
hours. To the reaction mixture was added 2.0 mol& hydrochloric acid (0.140 mL) and
water, and the resulting mixture was extracted with ethyl acetate. The organic layer was
washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was
concentrated under reduced pressure to give the title compound (0.017 g).
[0 1 02]
Example 3
{3 - [5 -{ [2-(3 ,5-Bistrifluoromethylphenyl)methylpropionyl]methylamino } (4-
fluoro—2-methylphenyl)pyridinyl]cyclohexyl} acetic acid
To a mixture of {3-[5-{[2-(3,5-bistrifluoromethylphenyl)
methylpropionyl]methylamino}(4-fluoromethylphenyl)pyridin-2—
lohexyl}acetic acid ethyl ester (0.023 g), tetrahydrofuran (0.50 mL), methanol
(0.25 mL) and water (0.25 mL) was added lithium hydroxide monohydrate (0.007 g) at
room temperature, and the mixture was stirred at the same temperature overnight. The
reaction mixture was neutralized by the addition of acetic acid. The resulting mixture
was extracted with ethyl acetate. The organic layer was washed with brine, and dried
over anhydrous magnesium sulfate, and the solvent was removed under d
pressure. The ed crude product was purified by column chromatography on silica
gel (eluent: n-hexane/ethyl acetate/methanol=5 0/50/0-0/ 1 00/0-0/90/10) to give the title
compound (0.003 g).
[01 03]
Example 4
{3- [5- { [2-(3 ,5—Bistrifluoromethylphenyl)methylpropionyl]methylamino } (4-
2-methylphenyl)pyridinyl]methylcyclohexyl}acetic acid
To a mixture of {3-[5-{[2-(3,5-bistrifluoromethylphenyl)
methylpropionyl]methylamino}(4-fluoromethylphenyl)pyridinyl]—3-
cyclohexyl}acetic acid ethyl ester (0.022 g), tetrahydrofuran (0.40 mL),
methanol (0.20 mL) and water (0.20 mL) was added lithium hydroxide monohydrate
(0.006 g) at room ature, and the mixture was stirred at the same temperature
overnight. The reaction mixture was lized by the addition of acetic acid. The
resulting e was ted with ethyl acetate. The organic layer was washed with
brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under
reduced pressure. The obtained crude product was purified by colurrm chromatography
on silica gel (eluent: n-hexane/ethyl acetate/methanol=50/50/0-0/100/0-0/90/10) to give
the title compound (0.007 g).
[01 04]
Example 5
{4-[5-{ [2-(3 ,5 -Bistrifluoromethylphenyl)hydr0xymethylpropionyl]methylamino } -
4-(4-fluoromethylphenyl)pyridiny1]cyclohexyl}acetic acid
Under a hydrogen gas here, a suspension of {4-[5-{ [3-benzyloxy
(3,5-bistrifluoromethylphenyl)methylpropionyl]methylamino}-4—(4-fluoro
methylphenyl)pyridin-2—yl]cyclohexeny1}acetic acid (0.045 g) and 10% palladium on
carbon (0.03 g, wet) in methanol (1.5 mL) was stirred at room temperature for 5 hours.
To the reaction mixture was added 10% palladium on carbon (0.03 g, wet). Under a
hydrogen gas atmosphere, the resulting mixture was stirred at room temperature
overnight. The reaction mixture was filtered h a Celite (registered trademark) pad,
and the filtrate was concentrated under d pressure to give the title compound
(0.04 g).
[01 05]
Example 6
{4- [5-{ [2-(3 ,5-Bistrifiuoromethylphenyl)methylpropionyl]methylamino } (4-
fluoromethylphenyl)pyridinyl] hydroxycyclohexyl } acetic acid
To a mixture of {4-[5-{ 5-bistrifluoromethylphenyl)
methylpropionyl]methylamino } (4-fluoromethylphenyl)pyridin—2—yl]
hydroxycyclohexyl}acetic acid ethyl ester (0.05 g), tetrahydrofuran (1.00 mL),
methanol (0.50 mL) and water (0.50 mL) was added lithium hydroxide monohydrate
(0.015 g) at room temperature, and the mixture was stirred at the same temperature
overnight. To the reaction mixture was added 2.0 mol/L hydrochloric acid (0.20 mL),
and the solvent was removed under reduced pressure. To the residue was added water,
and the resulting mixture was extracted with ethyl e. The organic layer was
washed with brine, and dried over anhydrous ium sulfate. The solvent was
concentrated under reduced pressure to give the title compound (0.046 g).
[0 1 06]
Example 7
6—[5- { [2-(3 ,5 -Bistrifluoromethylphenyl)—2-methylpropionyl]methylamino} (4-fluoro-
2-methylphenyl)pyridinyl] spiro [2.5]octane— 1 -carboxylic acid
A mixture of 6-[5-{ [2-(3,5—bistrifluoromethylphenyl)
methylpropionyl]methylamino}(4-fluoromethylphenyl)pyridin
yl]spiro[2.5]0ctane-1—carboxylic acid ethyl ester (0.020 g), 1.0 mol/L aqueous sodium
hydroxide solution (0.09 mL), tetrahydrofuran (0.60 mL) and ol (0.30 mL) was
stirred at 140°C under microwave irradiation for 1 hour and a half. The reaction mixture
was cooled to room temperature and water was added. The resulting e was
extracted with ethyl acetate. The organic layer was washed with water and brine, and
dried over anhydrous magnesium sulfate, and the solvent was removed under reduced
pressure. The obtained crude product was purified by column chromatography on silica
gel (eluent: n-hexane/ethyl e/methanol=40/60/0-0/100/0-0/90/10) to give the title
compound (0.005 g).
[01 07]
Example 8
{4- [5 —{ [2-(3 ,5-Bistrifluoromethylphenyl)methylpropionyl]methylamino} cyano
(4-fluoro—2-methylphenyl)pyridinyl]cyclohexyl}acetic acid
To a mixture of {4-[5-{[2-(3,5-bistrifluoromethylphenyl)
methylpropionyl]methylamino}-6—cyano(4-fluoromethylphenyl)pyridin-2—
yl]cyclohexyl}acetic acid methyl ester (0.017 g), ydrofuran (0.30 mL), methanol
(0.15 mL) and water (0.15 mL) was added lithium hydroxide monohydrate (0.005 g) at
room temperature, and the mixture was stirred at the same ature for 2 days. The
reaction mixture was neutralized by the addition of acetic acid. The resulting mixture
was extracted with ethyl acetate. The organic layer was washed with brine, and dried
over anhydrous magnesium sulfate, and the solvent was d under d
pressure. The obtained crude product was purified by column chromatography on silica
gel (eluent: n-hexane/ethyl acetate=5 0/5 0-0/ 100) to give the title compound (0.008 g).
[01 08]
Example 9
{4-[5 — { [2-(3 ,5-Bistrifluoromethylphenyl)methylpropionyl]methylamino } ortho-
tolylpyridin-Z-yl]-cyclohexyl}acetic acid
To a mixture of {4-[5-{[2—(3,5-bistrifluoromethylphenyl)~2-
methylpropionyl]methylamino } -4—0rtho-tolylpyridin—2-yl]-cyclohexyl } acetic acid
methyl ester (0.08 g), tetrahydrofuran (1.00 mL), methanol (0.50 mL) and water (0.50
mL) was added lithium hydroxide drate (0.021 g) at room temperature, and the
mixture was stirred at the same temperature for 3 hours. To the reaction mixture was
added 2.0 mol/L hydrochloric acid (0.28 mL), and the solvent was removed under
reduced pressure. To the residue was added water, and the resulting mixture was
extracted with ethyl acetate. The organic layer was washed with brine, and dried over
anhydrous magnesium sulfate. The t was trated under reduced pressure to
give the title compound (0.071 g).
Example 10
2-{4- [5 - { [2—(3 ,5—Bistrifluoromethylphenyl)methylpropionyl]methylamino} (4-
fluoromethylphenyl)pyridiny1]cyclohexyl}pr0pionic acid
A e of 2-{4—[5—{ [2-(3,5-bistrifluoromethylphenyl)
methylpropionyl]methylamino}-4—(4-fluoromethylphenyl)pyridin
yl]cyclohexyl}propionic acid ethyl ester (0.11 g), 1.0 mol/L aqueous sodium hydroxide
solution (0.50 mL), tetrahydrofuran (0.50 mL) and methanol (1.50 mL) was stirred at
140°C under microwave irradiation for 1 hour and a half. The reaction mixture was
cooled to room temperature and 1.0 mol/L hydrochloric acid (0.60 mL) was added. The
resulting mixture was extracted with ethyl acetate. The organic layer was washed with
water and brine, and dried over anhydrous magnesium e. The solvent was
concentrated under reduced pressure to give the title compound (0.10 g).
[0 1 1 0]
Example 11
2- {4- [5 - { [2-(3 ,5-Bistrifluoromethylphenyl)methylpropionyl]methylamino}
(4-fluoro-2—methylphenyl)pyridin—2-yl]cyclohexyl} —2-methylpropionic acid
A mixture of trans{4-[5-{ [2-(3,5—bistrifluoromethylphenyl)
methylpropionyl]methylamino} fluoromethy1phenyl)pyridin—2-yl]cyclohexyl} -
2-methylpropionic acid ethyl ester (0.054 g), 1.0 mol/L aqueous sodium hydroxide
solution (0.25 mL), tetrahydrofuran (0.25 mL) and methanol (0.75 mL) was stirred at
140°C under microwave irradiation for 1 hour and a half. The reaction mixture was
cooled to room temperature and 1.0 mol/L aqueous sodium ide solution (0.25
mL) was added. The ing mixture was stirred at 140°C under microwave
irradiation for 1 hour and a half. The reaction mixture was cooled to room temperature
and 1.0 mol/L hydrochloric acid (0.60 mL) was added. The ing mixture was
extracted with ethyl acetate. The organic layer was washed with water and brine, and
dried over anhydrous magnesium sulfate. The t was concentrated under reduced
pressure to give the title compound (0.022 g).
[01 1 1]
Example 12
cis—2- {4— [5 - { [2-(3 ,5-Bistrifluoromethylphenyl)—2-methylpropionyl]methylamino} (4-
fluoromethylpheny1)pyridin—2-yl]cyclohexyl}methylpropionic acid
A mixture of cis{4-[5-{ [2-(3,5-bistrifluoromethylphenyl)
methylpropionyl]methylamino } (4—fluoromethylphenyl)pyridinyl]cyclohexyl} -
2-methylpropionic acid ethyl ester (0.044 g), 1.0 mol/L aqueous sodium hydroxide
on (0.20 mL), ydrofuran (0.20 mL) and methanol (0.60 mL) was stirred at
140°C under microwave irradiation for 1 hour and a half. The reaction mixture was
cooled to room temperature and 1.0 mol/L aqueous sodium hydroxide solution (0.20
mL) was added. The ing mixture was stirred at 140°C under microwave
irradiation for 1 hour and a half. The reaction mixture was cooled to room temperature
and 1.0 mol/L hydrochloric acid (0.50 mL) was added. The resulting mixture was
ted with ethyl acetate. The organic layer was washed with water and brine, and
dried over anhydrous magnesium sulfate, and the solvent was removed under reduced
pressure. The obtained crude product was purified by column chromatography on silica
gel (eluent: n-hexane/ethyl e=90/10-10/90) to give the title compound (0.014 g).
[0 1 1 2]
Example 13 and 14
trans- {4— [5-{ [2—(3 ,5—Bistrifluoromethylphenyl)—2-methy1propiony1]methylamino } (4—
2-methylpheny1)pyridiny1]cyclohexyl}acetic acid (Example 13), and cis-{4-
[5 - { [2-(3 ,5-bistrifluoromethylphenyl)methy1propionyl]methylamino} (4-fluoro
methylpheny1)pyridinyl]cyclohexyl}acetic acid (Example 14)
(1) Synthesis of a mixture of trans and cis s
To a mixed solution of {4-[5-{[2-(3,5-bistrifluoromethylphenyl)
methylpropionyl]methylamino} —4-(4-fluoromethylphenyl)pyridinyl]cyclohexyl} -
acetic acid methyl ester (2.13 g) in tetrahydrofuran (32 mL)-methanol (16 mL)-water
(16 mL) was added lithium hydroxide monohydrate (0.41 g) at room temperature and
the mixture was stirred at the same temperature for 17 hours. To the reaction mixture
was added 2.0 mol/L hloric acid (4.9 mL), and the solvent was removed under
reduced pressure. To the residue was added water, and the resulting mixture was
extracted with ethyl e. The organic layer was washed with brine, and dried over
anhydrous magnesium sulfate. The solvent was trated under reduced pressure to
give a crude product (a mixture of trans- and cis-{4-[5-{[2-(3,5—
bistrifluoromethylphenyl)—2-methy1propionyl]methylamino}(4-fluoro—2-
methylphenyl)pyridinyl]cyclohexyl}acetic acid) (2.08 g).
(2) Separation of trans and cis isomers
A mixture of trans- and cis—{4-[5-{ [2-(3,5-bistrifluoromethylphenyl)~2-
methylpropionyl]methylamino} (4-fluoromethy1phenyl)pyridin—2-
yl]cyclohexyl}acetic acid (36.6 g) was separated by liquid chromatography under the
ing conditions to give Example 13 (17.0 g) and Example 14 (16.2 g) respectively.
[Separation ions of the liquid chromatography]
(A) Preparative isolation system
Device name: K-Prep (KYOTO CHROMATO Co., Ltd.) ;
(B) Separation conditions
Column: CHIRALPAK (registered trademark) IA ;
Size: 5 cm ID. x 25 cmL. ;
Particle size: 5 um ;
Mobile phase: n-hexane/ethanol/acetic 5/15/0.l<v/v/v>
Flow rate: 35 mL/min ;
Temperature: 30°C ;
Detection wavelength: 254 nm ;
Injection method: Loop injection ;
Injection volume: 10-20 mL (20 g/L solution)
(C) Retention time
Example 13: approximately 21 min, Example 14: approximately 17 min
Example 13 and 14 were analyzed under the following analytical conditions.
[Analytical ions of the liquid chromatography]
(A) Analytical System
Pump: LC-20AD (Shimadzu Corporation) ;
Detector: SPD-20A (Shimadzu Corporation) ;
Auto Sampler: SIL-20A (Shimadzu Corporation)
(B) Analytical Conditions
Column: CHIRALPAK (registered trademark) IA ;
Size:0.46 ch.D. X 25 cmL. ;
Mobile phase: n-hexane/ethanol/acetic acid=85/15/0.l<V/V/V>
Flow rate: 1.0 mL/min;
Temperature: 40°C ;
Detection wavelength: 254 nm ;
ion volume: 10 uL
(C) Retention time
e 13 : 6.164 min, Example 14 : 5.016 min
[01 14]
e 15
{4- [5- { [2-(3 ,5 -Bistrifluoromethylphenyl)methylpropionyl]methylamino } (4-
2-methylphenyl)pyridinyl] — 1 -methylcyclohexyl } acetic acid
To a mixture of {4-[5-{[2-(3,5-bistrifluoromethylphenyl)—2-
methylpropionyl]methylamino } (4-fluoromethylphenyl)pyridin—2-yl] - l -
methylcyclohexyl}acetic acid methyl ester (0.078 g), tetrahydrofuran (0.60 mL),
methanol (0.30 mL) and water (0.30 mL) was added lithium hydroxide monohydrate
(0.022 g) at room ature, and the mixture was stirred at the same temperature for 1
hour and at 50°C for 3 hours. The reaction mixture was neutralized by the addition of
acetic acid. The resulting mixture was extracted with ethyl acetate. The organic layer
was washed with brine, and dried over anhydrous magnesium sulfate, and the solvent
was d under d pressure. The obtained crude product was purified by
column chromatography on silica gel (eluent: n—hexane/ethyl acetate/methanol=20/80/0-
0/100/0-0/90/10) to give the title compound (0.069 g).
[01 1 5]
Example 16
[4—(5-{ [2-(3 ,5—Bistrifluoromethylphenyl)—2-methy1propionyl]methylamino}cyano—4-
0rtho—tolylpyridin—2-yl)cyclohexyl]acetic acid
To a mixture of [4-(5-{[2-(3,5-bistrifluoromethylphenyl)—2-
methylpropionyl]methylamino}cyanoortho-tolylpyridin-Z-yl)cyclohexyl]acetic
acid ethyl ester (0.018 g), tetrahydrofuran (0.40 mL), ol (0.20 mL) and water
(0.20 mL) was added lithium hydroxide monohydrate (0.005 g) at room temperature,
and the mixture was d at the same temperature overnight. The reaction mixture was
neutralized by the addition of acetic acid. The resulting mixture was extracted with
ethyl acetate. The organic layer was washed with water and brine, and dried over
anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to
give the title compound (0.016 g).
[01 16]
Example 17
{4— [5— { [2-(3 , 5-Bistrifluoromethylphenyl)methylpropionyl]methylamino } chloro
(4—fluoro—2—methylphenyl)pyridinyl]cyclohexyl } acetic acid
To a mixture of {4-[5-{[2-(3,5—bistrifluoromethylphenyl)
methylpropionyl]methylamino} —6—chloro(4-fluoromethylphenyl)pyridin—2-
lohexyl}acetic acid ethyl ester (0.020 g), tetrahydrofuran (0.50 mL), methanol
(0.25 mL) and water (0.25 mL) was added lithium hydroxide monohydrate (0.005 g) at
room ature, and the mixture was stirred at the same temperature for 2 hours. The
on mixture was neutralized by the addition of acetic acid. The resulting mixture
was extracted with ethyl acetate. The organic layer was washed with water and brine,
and dried over anhydrous magnesium sulfate. The solvent was concentrated under
reduced pressure to give the title compound (0.018 g).
[0 1 l 7]
Example 18
{4— [5-{ [2-(3 ,5-Bistrifluoromethylphenyl)methylpropionyl]methylamino } (4-
fluoromethylphenyl)methylpyridin—2-yl]cyclohexyl}acetic acid
To a mixture of {4-[5-{[2-(3,5-bistrifluoromethylphenyl)—2-
methylpropionyl]methylamino}(4—fluoromethylphenyl)methylpyridin
yl]cyclohexyl}acetic acid ethyl ester (0.019 g), ydrofuran (0.50 mL), methanol
(0.25 mL) and water (0.25 mL) was added lithium hydroxide monohydrate (0.005 g) at
room temperature, and the mixture was stirred at the same temperature overnight. The
reaction e was neutralized by the addition of acetic acid. The resulting mixture
was extracted with ethyl acetate. The organic layer was washed with water and brine,
and dried over anhydrous magnesium sulfate. The solvent was concentrated under
d pressure to give the title compound (0.018 g).
[01 18]
Example 19
{4- [5-{ [2-(3 ,5 ifluoromethylphenyl)methylpropionyl]methylamino } —4-(4-
' 2-methylphenyl)hydroxymethylpyridin-2—yl]cyclohexyl}acetic acid
To a e of a mixture of {4-[5-{ [2-(3,5—bistrifluoromethylphenyl)
methylpropionyl]methylamino}(4-fluoromethylphenyl)—6-hydroxymethylpyridin-
2-yl]cyclohexyl}acetic acid ethyl ester and {4-[5-{[2—(3,5-bistrifluoromethylphenyl)
methylpropionyl]methylamino} (4-fluoromethylphenyl)hydroxymethylpyridin-
2-yl]cyclohexyl}acetic acid methyl ester (0.025 g), tetrahydrofuran (0.50 mL), methanol
(0.25 mL) and water (0.25 mL) was added lithium hydroxide monohydrate (0.007 g) at
room temperature, and the mixture was stirred at same temperature overnight. The
reaction mixture was neutralized by the addition of acetic acid. The resulting mixture
was extracted with ethyl acetate. The organic layer was washed with water and brine,
and dried over anhydrous magnesium sulfate. The solvent was concentrated under
reduced pressure to give the title compound (0.023 g).
[01' 1 9]
Example 20 and 21
trans- {4— [5 — { [2-(3 trifluoromethylphenyl)methylpropionyl]methylamino}
cyano(4-fluoromethylphenyl)pyridin—2-yl]cyclohexyl}acetic acid (Example 20)
and cis— {4— [5 - { [2-(3 ,5-bistrifluoromethylphenyl)methylpropionyl]methylamino }
cyano(4-fluoromethylphenyl)pyridinyl]cyclohexyl}acetic acid le 21)
A mixture of trans— and cis—{4-[5—{[2—(3,5-bistrifluoromethylphenyl)
methylpropionyl]methylamino}cyano(4-fluoromethylphenyl)pyridin—2-
yl]cyclohexyl}acetic acid (Example 8) (0.18 g) was isolated by liquid chromatography
under the following conditions to give Example 20 (0.035 g) and e 21 (0.037 g)
respectively.
[Separation conditions of the liquid chromatography]
(A) Preparative isolation system
Device name: Preparative HPLC System (Gilson, Inc.)
(B) Separation conditions
Column: ustain tered trademark) C18 ;
Size: 20 mmI.D. x 50 mmL. ;
Particle size: 5 um
Mobile phase: acetonitrile/ 10 mM aqueous ammonium acetate solution=45/55<v/v> ;
Flow rate: 30 mL/min ;
Temperature: room temperature ;
Detection wavelength: 220 nm
(C) Retention time
Example 20: approximately 10.4 min, Example 21: imately 9 min
Example 20 and 21 were analyzed under the following analytical conditions.
[Analytical ions of the liquid chromatography]
(A) Analytical System
PumszC-IOAT dzu Corporation) ;
Detector: SPD-lOA (Shimadzu Corporation) ;
Auto Sampler: SIL—lOA (Shimadzu Corporation)
(B) Analytical Conditions
Column: il (registered trademark) ODS-3 ;
Size: 4.6 mmI.D. x 250 mL. ;
Mobile phase: acetonitrile/ 10 mM s ammonium acetate solution=40/60-
80/20<v/v>
Flow rate: 1.0 mL/min;
Temperature: 40°C ;
Detection wavelength: 225 nm ;
Injection volume:5 uL
(C) Retention time
Example 20: 16.786 min, Example 21: 17.286 min
[0 12 1]
Tables 1 to 11 show the chemical structures of the above compounds of
Reference Examples 1 to 63, and the chemical structures and the physical properties of
the above compounds of es 1 to 21. The abbreviations in these Tables: “Ref
No.”, “Ex No.”, “Str.”, “Physical data”, “lH-NMR”, “DMSO-d6” and “CDC13”
ent Reference Example number, Example , chemical structure, physical
property, hydrogen nuclear magnetic resonance spectrum, dimethylsulfoxide-d6 and
form-d1, respectively. And, “MS” and “ESI_APCI” represent mass spectrometry
and measurement of Electrospray ionization-Atmospheric pressure chemical ionization,
respectively.
[Table 1]
Ref. Ref.
Str.
11 12
13 14
[Table 2]
[Table 3]
8131‘. Str.
[Table 4]
[Table 5]
[Table 6]
[Table 7]
Physical data
1H-NMR 5 ppm (DMSO—dfi) 2 1.00-
3.00 (22H, m), 6.80-7.30 (4H,
m), 7.50—7.90 (2H, m), 8.04
(1H, s), 8.30 (1H, s), 12.17
(1H, brs)
MS PCI, m/z) : 625 (M+H)+
lH—NMR 5 ppm (DMSO-d6) : 0 90—
2.90 (26H, m), 6.80-7.30 (4H,
m), 7.55-7 95 (2H, m), 8.04
(1H, s), 8.20-8.40 (1H, m),
12.03 (1H, brs)
MS (ESI_APCI, m/Z) : 653 (M+H)+
1H—NMR 5 ppm (CDC13) Z 0.80-
3.10 (24H, m), 6 75—7 30 (4H,
m), 7.65 (2H, brs), 7.77 (1H,
brs), 8.37 (1H, brs)
MS (ESI_APCI, m/z) 2 639(M+H)+
1H-NMR 5 ppm (CD013) 3 0.80—
2. 80 , m), 6.80‘7.35 (4H,
m), 7.67 (2H, brs), 7.78 (1H,
brs), 8.39 (1H, brs)
MS (ESI_APCI, 10/2) 3 653 (M+H)+
‘H-NMR 5 Inm1(DMSO-d6) :1.00—
2.90 (21H, m), 3.20—3.90 (2H,
m), 4.40~5.00 (1H, m), 6.90—
7.35 (4H, m), 7 40-8 15 (3H,
m), 8.20-8.45 (1H, m), 12.11
(1H, brs)
MS (ESI_APCI, m/z) : 655 (M+H)+
[Table 8]
Physical data
lH-NMR 5 ppm (DMSO-d6) :1.10-
2.90 (24H, m), 6.90—7.35 (4H,
m), 7.65—7.85 (2H, m), 8.04
(1H, 8), 8.30 (1H, S)
MS (ESI_APCI, m/Z) 3 655 (M+H)+
1H-NMR 5 ppm (CD013) 1 0.90-
2.95 (24H, m), 6.75—7.35 (4H,
m), 7.65 (2H, brs), 7.77 (1H,
s), 8.30—8.60 (1H, m)
MS (ESI_APC1, m/z) : 651(M+H)+
1H-NMR 5 ppm (CDC13) I 1.05—
2.95 (24H, m), 6.80-7.35 (4H,
m), 7.50-7.80(3H, m)
MS (ESI_APCI, m/z) : 664 (M+H)+
1H—NMR 5 ppm d6) $1.00—
2.90 (24H, m), 7 00—7.40 (5H,
m), 7.70—7 90 (2H, m), 8.04
(1H, s), 8 25-8 35 (1H, m),
12.00 (1H, brs)
MS (ESI_APCI, m/z) : 621 (M+H>+
1H-NMR 5 ppm (DMSO-d6) 31.00-
3.00 (26H, m), 6.90—7.30 (4H,
m), 7.65—7.85 (2H, m), 8.04
(1H, s), .35 (1H, m),
12.03 (1H, brs)
MS (ESI_APCI, m/z) I 653 (M+H)+
[Table 9]
EX.NQ Physical data
1H—NMR 6 ppm (DMSO-d6) 21.05
(s, 6H), 1.10—2.80 (22H, m),
6.90—7.30 (4H, m), 7.65—7.85
(2H, m), 8.03 (1H, s), 8.30
r—-‘ ._.
(1H, s), 12.07 (1H, brs)
MS (ESI_APCI, m/z) : 667 (M+H)+
1H—NMR 5 ppm (DMso—d6) :0.95
(s, 6H), 1.00~3.20 (22H, m),
6.90-7.30 (4H, m), 7.66—7.85
(2H, m), 8.04 (1H, s), 8.36
1—- 2
(1H, s), 12.01 (1H, brs)
0 MS (ESI_APCI, m/z) : 667 (M+H)+
1H-NMR 6 ppm (DMSO-d6) I 0.90-
2.80 (24H, m), .30 (4H,
m), 7.60-7.90 (2H, m), 8.04
(1H, s), 8.30 (1H, s), 12.01
1—4 3
(1H, brs)
MS (ESI_APCI, m/z) : 639 (M+H)+
1H—NMR 5 ppm (DMSO—d6) Z 0.90-
2.90 (24H, m), 6 80—7 40 (4H,
m), 7.60—7.90 (2H, m), 8.04
(1H, s), 8.31 (1H, s), 11.99
>——- 4
(1H, brs)
MS (ESI_APCI, m/z) 2 639 (M+H)+
1H—NMR 5 ppm ) I 1.16
(3H, s), 1 20—2 80 (28H, m),
6.80—7.35 (4H, m), 7.66 (2H,
brs), 7.78 (1H, s), 8.46 (1H,
brs)
MS (ESI_APCI, m/z) : 653 (M+H)+
[Table 10]
Physical data
1H—NMR 6 rmm1<CDCIQ :
0.90—2.95 (24H, m), 6 85-
7.40 (4H, no, 7.62 (1H,
m), 7.72 (2H, m), 7.75
(1H, brs)
MS PCI, m/z) : 646
<M+H)+
lH—NMR 5 ppm (CDClB) I
1.05-2.95 (24H, no, 6.80-
7.25 (4H, m), 7.68 (1H,
m), 7.74 (1H, no, 7.78
(1H, brs)
MS (ESI_APCI, m/z) : 674
(M+H)+
1H—NMR 5 ppm (CDClB) I
1 05—2 95 (27H, m), 6.90-
7.25 (4H, m), 7.65 (1H,
m), 7.69 (1H, m), 7.78
(1H, brs)
MS (ESI_APCI, m/z) : 653
(M+H)+
1H—NMR 6 ppm (CD013) I
1. 05-2. 95 (25H, m), 4. 40-
4.50(1H, m), 4. 60-4. 75
(1H, m), 6. 90-7. 25 (4H,
m), 7.61 (1H, m), 7.66
(1H, m), 7.79 (1H, brs)
MS (ESLAPCI, m/z) I 669
(M+H)+
[Table 11]
Physical data
1H-NMR 5 ppm (CDClQ 2
1.10—2.90 (24H, m), 6.85—
7.25 (4H, m), 7.61 (1H, m),
7.69 (1H, HO, 7.77 (1H,
brs)
MS (ESI_APCI, m/Z) I 664
(M+H) +
1H-NMR 5 ppm (CDClQ I
1.20—2.95 (24H, m), 6.85—
7.25 (4H, m), 7.62 (1H, m),
7.69 (1H, m), 7.77 (1H,
brs)
MS (ESI_APCI, m/Z) I 664
(M+H) +
Test Example 1
Affinity for human NK1 receptor
(1) Preparation of human NK1 receptor expression vector
PCR was performed using human adult normal tissue-derived brain cDNA
(BioChain) as the te, with the forward primer of SEQ ID NO:1 and the reverse
primer of SEQ ID NO:2, using a PCR enzyme, PrimeSTAR Max DNA Polymerase or
PrimeSTAR GXL DNA Polymerase (registered trademark, Takara Bio). The amplified
product was inserted into a plasmid luntII-TOPO tered trademark), Life
Technologies) using Zero Blunt PCR Cloning Kit (registered trademark, Life
Technologies). By a l method, Escherichia coli (One Shot TOP10 competent
cells, Life Technologies) was ormed by the plasmid into which the amplified
product had been inserted. The Escherichia coli cells were cultured on an LB agar
medium containing 50 ug/mL kanamycin for a day. After the culture, a colony was
selected and cultured in an LB medium containing 50 ug/mL of kanamycin. After the
culture, the d was purified using Quantum Prep Plasmid Miniprep Kit ad).
The plasmid was double digested for about two hours using restriction enzymes, XhoI
and HindIII (New England Biolabs). Then, ophoresis using 1% agarose gel was
performed, and the fragment that was cleaved was collected and purified using TaKaRa
RICOCHIP (Takara Bio). Separately, a plasmid was also purified from Escherichia coli
that had been transformed by a vector (pcDNA3.1(—) (registered trademark), Life
Technologies), and the plasmid was double digested for about two hours using
restriction enzymes, XhoI and HindIII (New England Biolabs). Then, electrophoresis
using 1% agarose gel was performed, and the vector that was cleaved was ted and
purified using TaKaRa RICOCHIP (Takara Bio). The fragment cut out of unt-II
and the pcDNA3.1(-) vector d with the restriction enzymes were ligated using
DNA Ligation Kit <Mighty Mix> (Takara Bio). By a general method, Escherichia coli
(One Shot TOPl O competent cells, Life Technologies) was transformed by the plasmid
obtained by the ligation. The Escherichia coli cells were cultured on an LB agar
medium containing 50 ug/mL of ampicillin for a day. After the e, a colony was
selected and ed in an LB medium containing 50 ug/mL of ampicillin, and then the
plasmid was purified using Quantum Prep Plasmid ep Kit (Bio-Rad). The
protein—encoding nucleotide sequence (SEQ ID NO:3) of the obtained plasmid was
completely identical to the nucleotide sequence (NM_001 058.3) of human tachykinin
receptor 1 (TACRl , NKlR) registered on a known database (NCBI). Therefore, it was
confirmed that the cloned gene sequence was the nucleotide sequence ofhuman NK1
receptor and that the amino acid sequence which would be translated was human NK1
or. The .1(-) (registered trademark) into which the nucleotide sequence
of SEQ ID NO:3 was inserted was used as the human NK1 receptor expression plasmid.
[01 34]
(2) ation of human NK1 receptor—expressing cells
(2-1) Culture of 293T cells
Using a liquid D-MEM (Dulbecco’s Modified Eagle Medium) medium (low
glucose, containing L-glutamine, Wako Pure al Industries) mented with
an antibiotic penicillin—streptomycin solution (Life Technologies, final penicillin
concentration of 100 U/mL and final streptomycin concentration of 100 ug/mL) and
fetal bovine serum (final concentration of 10%), 293T cells (RIKEN) were cultured in
an tor under the condition of 5% C02 gas at 37°C.
' (2-2) Subculture of 293T cells
Almost nt cells were washed with PBS (Phosphate Buffered Saline,
Wako Pure Chemical Industries), detached using 0.05% trypsin-EDTA (Life
Technologies) and suspended in the liquid medium. The cell suspension was diluted .
with the above liquid medium in such a manner that the spread ratio became 1:10, and
then the cells were cultured.
(2-3) Preparation for human NK1 receptor—expressing cells
Confluent cells were washed with PBS, detached using 0.05% trypsin-EDTA
(Life Technologies) and suspended in a liquid D-MEM medium (low glucose,
containing L—glutamine, Wako Pure Chemical ries) supplemented with fetal
bovine serum (final concentration of 10%). The cell suspension was diluted with the
liquid medium, and the cells were seeded into the wells of a poly-D-lysine-coated 96-
well microplate (BD Biocoat (registered trademark), Nippon Becton Dickinson) at a
density of 5x104 cells/well and a liquid medium volume of 100 uL/well. After seeding,
the cells were cultured in an tor under the condition of 5% C02 gas at 37°C for
about four to five hours, and the cells to be transfected with the human NK1 receptor
expression plasmid were thus prepared.
(2-4) Transfection of human NK1 receptor expression plasmid into 293T cells
For the transfection of the human NK1 receptor expression plasmid,
Lipofectamine 2000 (registered trademark, Life logies) was used. The human
NK1 receptor expression plasmid was diluted with Opti-MEM (registered trademark) I
Reduced-Serum Medium (Life Technologies) to a concentration resulting in 0.2 ug/25
uL/well. At the same time, Lipofectamine 2000 (registered trademark, Life
Technologies) was diluted with Opti-MEM (registered ark) I Reduced-Serum
Medium (Life Technologies) to a concentration resulting in 0.4 uL/25 uL/well and
incubated at room temperature for five minutes. After five minutes, to form a complex
ofhuman NK1 receptor expression plasmid/Lipofectamine 2000, the diluted human NK1
receptor expression d and the d Lipofectamine 2000 were mixed and
incubated at room temperature for 20 to 25 minutes. After the incubation, 50 uL/well of
the complex solution was added to the cells to be transfected with the human NK1
receptor expression plasmid, and the cells were cultured in an incubator under the
condition of 5% C02 gas at 37°C for about 48 hours. The cells that were cultured for 48
hours were used for the assays as the human NK1 receptor-expressing cells.
[0 1 3 5]
(3) Measurement of binding y to human NKI receptor
(3-1) Preparation of membrane fraction from human NKI or-expressing cells
Human NK1 receptor—expressing cells were prepared in a 1750m2 culture flask
(Nippon Becton Dickinson). The formation of a complex of the human NK1 receptor
sion plasmid and Lipofectamine 2000 was performed by calculating the culture
area ratio and increasing the scale of the method described in the above 2-4 by the ratio.
The human NK1 receptor-expressing cells were ted in a buffer solution for the
membrane on preparation (50 mM Tris (Wako Pure Chemical), 120 mM sodium
de (Wako Pure Chemical Industries), 5 mM potassium chloride (Wako Pure
Chemical Industries), 1 mM ethylenediaminetetraacetic acid (Sigma), 0.002 mg/rnL
tatin (Peptide Institute), 0.04 mg/ bacitracin (Wako Pure Chemical Industries),
0.005 mg/mL phosphoramidon (Peptide Institute) and 0.5 mM phenylmethylsulfonyl
fluoride (Wako Pure Chemical Industries), pH7.4) and centrifuged at 1,880 g for 10
s, and the cell sediment was ded in the buffer solution for the membrane
fraction ation. After freezing and g the cells once, the cells were
homogenized using a Dounce-type homogenizer (cooled on ice, 1000 rpm, 20 times).
The homogenized cell suspension was centrifuged at 20,000 rpm for 10 minutes, and
the supernatant was removed to obtain cell sediment. The cell sediment was suspended
again in the buffer solution for the membrane fraction preparation and homogenized
using a Dounce—type homogenizer (cooled on ice, 1000 rpm, 30 times). The cell
sion was centrifuged at 20,000 rpm for 10 minutes, and the supernatant was
removed to obtain cell sediment. The same homogenization and centrifugation were
repeated again, and final cell sediment was obtained. The final cell sediment was
suspended in a buffer solution for the receptor binding test (50 mM Tris (Wako Pure
Chemical Industries), 3 mM manganese chloride (Wako Pure Chemical Industries),
0.002 Ing/mL chymostatin (Peptide Institute), 0.04 mg/ bacitracin (Wako Pure Chemical
Industries) and 0.02% bovine serum n (Sigma), pH 7.4), and the protein
concentration was measured using BCA Protein Assay Kit e).
(3 -2) Receptor binding test
The buffer on for the receptor binding test was dispensed to the wells of a
96-well assay plate (Greiner) at 22.5 uL/well. DMSO solutions of a test compound,
which were prepared at an 80-time higher concentration using 100% dimethyl sulfoxide
(DMSO), were added to the wells at 2.5 uL/well (final concentrations of 1 nM to 100
nM), and the solutions were mixed. As a radiolabeled ligand, 125I-substance P
ance P, [1251]Tyr8-, PerkinElmer) was used. 125I-substance P was diluted with the
buffer solution for the receptor binding test to a concentration ing in 125 pmol/25
uL/well and added to the 96—well assay plate, and the solutions were mixed. The
membrane fraction prepared from the human NK1 receptor-expressing cells was diluted
with the buffer solution for the receptor binding test to a concentration resulting in 8 to
rig/well, suspended until the suspension became in such a homogenous state that the
suspension could flow through a 27G injection needle smoothly and then added to the
96-well assay plate at 150 uL/well. Then, the plate was incubated at room temperature
for 60 minutes while shaking the plate. The reaction solutions were n-filtered
through a multiscreen 96-well filter plate (Millipore) which had been pre—treated with
0.3% polyethyleneimine, and the on was terminated by washing with a washing
solution (50 mM Tris and 0.02% bovine serum albumin, pH 7.4) four times. The bottom
of the microplate was dried at 60°C, and then 100 uL/well of MicroScint 20
(PerkinElmer) was dispensed to the wells. The top of the plate was sealed with TopSeal
A (PerkinElmer), and the plate was shaken for 5 to 10 minutes. Then, the
radioactivities were measured with nt NXT (registered ark)
(PerkinElmer). The radioactivity of each well was calculated by subtracting the
radioactivity of the well to which 10 14M aprepitant was added (non-specific binding).
The g rate (%) of 125I-substance P = (the radioactivity of the group to which the
test compound was added) / (the radioactivity of the group to which the vehicle was
added) x100 was calculated. Using analysis re, GraphPad Prism (GraphPad
Software), the binding rate (%) was plotted against the concentration of the test
compound andlinearly approximated, and the tration required for 50% inhibition,
ICso, was calculated. These results were shown in Table 12 and 13. In the table, Ex. No.
means the Example number, and IC50 (nM) is the tration required for 50%
inhibition.
(4) Results
[01 3 6]
[Table 12]
[013 7]
[Table 13]
As shown in Table 12 and 13, it was demonstrated that the compounds of the
t invention t a high binding affinity for human NK1 receptor.
[0 1 3 8]
Test Example 2
Inhibitory effect on human NKl receptor
(1) Preparation of human NK1 receptor-expressing cells
Human NK1 receptor-expressing cells were prepared by the same methods as
those described in 2-3 of Test Example 1.
(2) Study on inhibitory effect on increase in intracellular calcium concentration
The human NK1 receptor-expressing cells were washed with 300 uL/well of a
washing solution (20 mM HEPES/Hank’s Balanced Salt on (HBSS) pH 7.3). A
fluorescent calcium indicator (Fluo-4 Direct Calcium Assay Kit, Life logies,
containing 0.42 mM probenecid and 0.1% bovine serum albumin, prepared according to
the protocol of the product) was added to the wells at 150 uL/well, and the plate was
ted at 37°C for 30 s in an incubator. Then, DMSO ons of a test
compound, which were prepared at an e higher concentration using 100%
dimethyl sulfoxide (DMSO), were added to the wells at 2.5 uL/well (final
concentrations of 0.1, 1 and 10 uM), and the solutions were mixed. Then, the plate was
further incubated at 37°C for 30 minutes in an incubator. After 30 minutes, the
ellular calcium concentrations were measured immediately.
The intracellular calcium concentrations were each measured as a fluorescent
signal using FDSS (registered trademark) 7000 (Hamamatsu Photonics). A substance P
(Peptide Institute, Inc.) solution which was prepared at 0.4 uM or 4 uM using an assay
buffer (20 mM HEPES/Hank’s Balanced Salt Solution (HBSS) pH 7.3, containing 0.1%
bovine serum albumin) was added automatically to each well at 50 uL/well (final
concentration of 0.1 or 1 uM) 10 seconds after starting reading, and the fluorescent
signal was measured up to 120 seconds.
The intracellular calcium concentration (%) of the cells to which a test
compound was added was calculated by the equation below, where the fluorescent
signal of the group to which the vehicle (DMSO) was added was regarded as 100%, and
the fluorescent signal before the addition of substance P was regarded as 0%.
Intracellular calcium concentration (%) = (Fluorescent signal of test compound addition
group) / (Fluorescent signal of vehicle addition group) X100
The intracellular calcium tration (%) calculated was regarded as the
remaining agonist activity of substance P ance P—Response Remaining: SPRR).
These results were shown in Table 14 and 15. In the table, Ex. No. means the Example
number. SPRR (%) is the value obtained when the concentration of substance P was 1
”M and the concentration of the compound was 0.1 uM.
(3) Results
[Table 14]
[Table '15]
As shown in Table 14 and 15, it was demonstrated that the compounds of the
present invention exhibit a potent human NK1 or antagonist activity.
[0 1 42]
Test Example 3
Inhibitory effect on CYP3A4
A dimethyl sulfoxide (DMSO) solution of a test compound with a
concentration 1000 times higher than the evaluation concentration was prepared, and a
reaction solution was prepared by diluting the solution. Enzyme reaction was performed
by incubating in a potassium ate buffer solution (pH 7.4) ning 1 nM to 20
uM test compound, 3.2 mM magnesium chloride, 0.2 pmol human CYP3A4 (BD
Biosciences), 0.5 mM reduced nicotinamide adenine dinucleotide phosphate (NADPH)
and 3 uM Luciferin—IPA ga) at 37°C for 10 minutes. The volume of the reaction
solution was 50 uL/well. The 30-minute pre-incubation group was incubated at 37°C for
minutes before adding the substrate, the Luciferin—IPA on (12.5 uL/well). At
the end of the enzyme reaction, 50 uL/well of a Luciferin detection reagent (Promega)
was added to the wells, and the plate was left at room temperature for 20 minutes. Then,
the emission intensities were measured with te M1000 (TECAN). The enzyme
activities (%) relative to the value of the group to which the test compound was not
added were calculated. A dose-response curve was drawn using analysis software,
GraphPad Prism (GraphPad Software), and the concentration of each compound that
exhibited 50% inhibition, IC50, was calculated. As a ative example, aprepitant,
which is an NK1 or antagonist, was tested in the same .
IC50 values of the 30-minute pre-incubation groups using the test compounds
were measured by the above measurement method, and the s are shown in Table
16 and 17. In the table, EX. No. means the Example number, and IC50 (uM) is the
concentration required for 50% inhibition.
[Table 16]
Aprepitant
[Table 17]
As shown in Table 16 and 17, it was demonstrated that the CYP3A4-inhibitory
activities of the compounds of the present invention are reduced as compared to that of
aprepitant. Therefore, it is ed that the compounds of the t invention have
fewer drug—drug interactions based on the inhibitory effect on CYP3A4 than aprepitant.
[0145]
Test Example 4
Effect on foot-tapping
(1) Effect on foot-tapping
The test compound solution was prepared by dissolving the test compound in a
vehicle (a mixture of 50% N,N—dimethylacetamide (Wako Pure Chemical Industries),
% propylene glycol (Wako Pure Chemical Industries), 4% 2-hydroxypropyl-B-
cyclodextrin (Wako Pure Chemical Industries) and 16% distilled water).
A male gerbil (Japan SLC) was anesthetized with isoflurane, and 0.1 mg/kg of
a test compound was administered from the jugular vein. After four hours, GR73632 (5
pmol/S ul saline), which is an NK1 receptor t, was administered into the cerebral
ventricle at the part 1 mm lateral to and 4.5 mm below the bregma in the head, under
anesthesia with isoflurane. After the administration, the gerbil was moved to an
observation cage, and the foot-tapping period during 30 minutes after the recovery of
the righting reflex was ed. The foot-tapping tion rate (%) of each test
nd was calculated by the following equation.
Foot-tapping inhibition rate (%) = {1 - (Foot-tapping period when test nd was
stered) / (Foot-tapping period when t was administered)} x100
[0146]
(2) Measurement of drug concentrations
After foot-tapping was finished, laparotomy was performed ately under
anesthesia with ether, and a blood sample was taken from the abdominal vena cava. At
the same time, the brain was extracted. Through a quantitative analysis using liquid
chromatography-mass spectrometry (LC/MS), the concentrations of the test compound
in the plasma and the brain were measured.
(3) Results
The effects on foot-tapping were measured by the above test method, and the
results are shown in Table 18 and 19. In the table, Ex. No. means the Example number.
Inhibition (%) is the foot-tapping inhibition rate, and Conc. (nM) is the drug
concentration in the brain.
[Table 18]
Cone. (nM)
[Table 19]
Inhibition(/)00
As shown in Table 18 and 19, the compounds of the t invention were
penetrated into the central s system and exhibited an excellent NK1 receptor
antagonist activity also in vivo.
[0 l 49]
Test Example 5
Ferret pharmacokinetic test
(1) Methods
The test compound solution for intravenous administration was prepared by
dissolving the test compound in a vehicle (a mixture of 50% N,N-dimethy1acetamide
(Wako Pure Chemical Industries), 30% propylene glycol (Wako Pure Chemical
Industries), 4% 2-hydroxypropyl-B-cyclodextrin (Wako Pure al Industries) and
16% distilled water). As an oral administration on, the suspension (0.5%
methylcellulose ) was used.
Under anesthesia with isoflurane, 0.1 mg/kg of the test compound was
intravenously administered to a male ferret (Marshall BioResources Japan) from the
l vein. In the case of oral administration, 1 mg/kg of the test compound was
orally administered to an awake animal. After the administration of the test compound,
blood samples were taken sequentially from the brachial cephalic vein up to 7 days after
the administration. Through a quantitative analysis using liquid chromatography-mass
spectrometry (LC/MS), the concentrations of the test compound in the plasma were
ed.
(2) Results
The pharmacokinetic test in a ferret was tested by the above test method, and
the results are shown in Table 20 and Table 21. In the tables, Ex. No. means the
e number. t1/2, CLtot and Vss are the half-life, the total body clearance and the
steady-state volume of distribution, based on the plasma concentrations in the case of
intravenous administration, respectively. Cmax, AUC and BA are the maximum plasma
test compound concentration, the area under the plasma test compound tration-
time curve within 7days after the administration and the bioavailability, in the case of
oral administration, respectively.
[01 5 0]
[Table 20]
Ex.No. CLtot(mL/min/kg) Vs s (mL/kg)
1 3 2. 4 8 9
[Table 21]
Ex. No. Cmax (ng/mL) AUC (ng - mi n/mL) BA (%)
13 1,258 5,294,066 m
As shown in Table 20 and Table 21, the compound of the present invention
exhibited an excellent oral absorbability with low clearance.
[0 1 52]
Test Example 6
Effect on Cisplatin-induced acute and delayed emetic response
(1) Methods
The test compound solution was prepared by dissolving the test compound in a
vehicle (a mixture of 50% N,N—dimethylacetamide (Wako Pure Chemical Industries),
% propylene glycol (Wako Pure Chemical ries), 4% 2-hydroxypropyl-B-
cyclodextrin (Wako Pure Chemical Industries) and 16% distilled water). The vehicle
only was administered to the control group.
Under anesthesia with isoflurane, 0.01 mg/kg or 0.1mg/kg of the test
compound was intravenously administered to a male ferret (Marshall ources
Japan) from the jugular vein. tin in , which was heated to 40-50°C, was
intraperitoneally administered at 5 mg/kg one hour after the drug administration. The
ferret was observed for 72 hours from immediately after the Cisplatin administration,
and the number of retching (periodic abdominal contraction without vomiting of the
gastric t) and vomiting was counted.
(2) s
The results are shown in Figure 1. In the control group, an increase in the
number of retching and vomiting was ed in the acute phase (up to 24 hours after
the Cisplatin administration) and in the delayed phase (24 hours to 72 hours after the
Cisplatin administration). In the group to which the compound of Example 13 was
intravenously administered, the inhibition of the number of retching and vomiting was
observed in the acute phase and in the delayed phase.
It was demonstrated that the compound of the present invention has a long-
acting medicinal effect and an inhibitory effect on the cisplatin—induced acute and
delayed emetic responses.
Test Example 7
Evaluation ofhERG current
( l ) Methods
A dimethyl sulfoxide (DMSO) solution of the test compound with a
concentration 1000 times higher than the evaluation concentration (10 HM) was
ed, and a solution with a final ation concentration was prepared by diluting
the solution. The hERG current was measured by a whole-cell method using a patch
clamp system, where a cover glass on which hERG channel-expressing human
embryonic kidney (HEK) 293 cells were seeded was placed on a perfiasion bath and a
perfusion solution was caused to flow. The change in the hERG channel-derived current
caused by a pulse protocol (holding potential of -80 mV, depolarization pulse of +20
mV for 1.9 seconds, repolarization pulse of —50 mV for 2 seconds, stimulated at
intervals of 15 seconds) of data acquisition/analysis re, pCLAMP9 (Axon
Instruments, Inc.), was measured. The measurement conditions were a flow rate of
about 1.5 mL/min and a temperature of about 33°C. Two wave forms immediately
before applying the test compound and two wave forms immediately after the
application for 10 minutes were analyzed, and the statistical analysis was performed.
The value before the ation of the test compound was ed as 100%, and the
change rate based on the value was ined.
(2) Results
The effect of the test compound on hERG t was evaluated by the above
method (the result is shown in Table 22). In the table, Ex. No. means the Example
number, and the change rate is the average at the standard error.
[Table 22]
Ex.No. % (n=3)
1 3 8 1. 1 i 5 . 6
l 4 8 O. 3 i" 3 . 9
The compound of the present ion did not cause any change in the hERG
current with a statistical significance compared to the vehicle control (0.1% DMSO).
INDUSTRIAL APPLICABILITY
The compounds of the present invention or pharmaceutically acceptable salts
thereof have an excellent NK1 receptor antagonist activity, and thus are also useful as an
agent for the prevention or treatment of cancer-chemotherapy—induced nausea and
vomiting.
SEQUENCE LISTING FREE TEXT
[0 1 5 6]
<Sequence listing 1>
SEQ ID NO:1 is the sequence of forward primer which was used for DNA amplification
of SEQ ID NO:3.
nce listing 2>
SEQ ID NO:2 is the ce of reverse primer which was used for DNA amplification
of SEQ ID NO:3.
Claims (1)
1. A compound represented by the formula (1): [Chem. 1] N X ( I ) R‘ (R1 5 n ring A is a group represented by the following formula: [Chem.2] or)? X is a hydrogen atom, cyano, halogen, C1_6 alkyl or hydroxymethyl; 10 R1 is a group represented by the following formula: [Chem.3] 0 R11: R1a 0!" wherein R1a and R11) are each independently any one of a en atom, a fluorine atom or C1
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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JP2014095776 | 2014-05-07 | ||
JP2014-095776 | 2014-05-07 | ||
PCT/JP2015/063154 WO2015170693A1 (en) | 2014-05-07 | 2015-05-07 | Cyclohexyl-pyridine derivative |
Publications (2)
Publication Number | Publication Date |
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NZ726027A NZ726027A (en) | 2021-11-26 |
NZ726027B2 true NZ726027B2 (en) | 2022-03-01 |
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