JP5776695B2 - Substituted amide compounds - Google Patents
Substituted amide compounds Download PDFInfo
- Publication number
- JP5776695B2 JP5776695B2 JP2012535071A JP2012535071A JP5776695B2 JP 5776695 B2 JP5776695 B2 JP 5776695B2 JP 2012535071 A JP2012535071 A JP 2012535071A JP 2012535071 A JP2012535071 A JP 2012535071A JP 5776695 B2 JP5776695 B2 JP 5776695B2
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- lpa
- added
- thiazole
- mixture
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- -1 amide compounds Chemical class 0.000 title description 21
- 239000000203 mixture Substances 0.000 claims description 70
- 150000001875 compounds Chemical class 0.000 claims description 68
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 37
- 201000010099 disease Diseases 0.000 claims description 36
- 150000003839 salts Chemical class 0.000 claims description 30
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 11
- 208000004403 Prostatic Hyperplasia Diseases 0.000 claims description 11
- 201000004240 prostatic hypertrophy Diseases 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 230000002265 prevention Effects 0.000 claims description 6
- 206010013990 dysuria Diseases 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 206010016654 Fibrosis Diseases 0.000 claims description 4
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 4
- 230000004761 fibrosis Effects 0.000 claims description 4
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 4
- XIHUJZYNUPKBAN-UHFFFAOYSA-N 2-[[[2-(2-cyano-4-methoxyphenyl)acetyl]-(3-phenylpropyl)amino]methyl]-n-(dimethylsulfamoyl)-5-methyl-1,3-thiazole-4-carboxamide Chemical compound N#CC1=CC(OC)=CC=C1CC(=O)N(CC=1SC(C)=C(C(=O)NS(=O)(=O)N(C)C)N=1)CCCC1=CC=CC=C1 XIHUJZYNUPKBAN-UHFFFAOYSA-N 0.000 claims description 3
- 206010049576 Bladder neck sclerosis Diseases 0.000 claims description 2
- 208000020832 chronic kidney disease Diseases 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 156
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 110
- 230000002829 reductive effect Effects 0.000 description 53
- 238000004519 manufacturing process Methods 0.000 description 52
- 239000011541 reaction mixture Substances 0.000 description 51
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 50
- 102000057248 Lipoprotein(a) Human genes 0.000 description 49
- 239000000243 solution Substances 0.000 description 39
- 239000002904 solvent Substances 0.000 description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 37
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 238000010898 silica gel chromatography Methods 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 239000012044 organic layer Substances 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- 239000012267 brine Substances 0.000 description 25
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- 239000011734 sodium Substances 0.000 description 17
- 102000004137 Lysophosphatidic Acid Receptors Human genes 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 108090000642 Lysophosphatidic Acid Receptors Proteins 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 14
- 101000966782 Homo sapiens Lysophosphatidic acid receptor 1 Proteins 0.000 description 13
- 102100040607 Lysophosphatidic acid receptor 1 Human genes 0.000 description 13
- 239000008213 purified water Substances 0.000 description 13
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 12
- 206010028980 Neoplasm Diseases 0.000 description 12
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 12
- 238000001816 cooling Methods 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 239000005457 ice water Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- 201000011510 cancer Diseases 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 238000001914 filtration Methods 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 230000003042 antagnostic effect Effects 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 208000014001 urinary system disease Diseases 0.000 description 6
- 239000007821 HATU Substances 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 235000019270 ammonium chloride Nutrition 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000006188 syrup Substances 0.000 description 5
- 235000020357 syrup Nutrition 0.000 description 5
- 229940124597 therapeutic agent Drugs 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 210000003932 urinary bladder Anatomy 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- OUVXYXNWSVIOSJ-UHFFFAOYSA-N Fluo-4 Chemical compound CC1=CC=C(N(CC(O)=O)CC(O)=O)C(OCCOC=2C(=CC=C(C=2)C2=C3C=C(F)C(=O)C=C3OC3=CC(O)=C(F)C=C32)N(CC(O)=O)CC(O)=O)=C1 OUVXYXNWSVIOSJ-UHFFFAOYSA-N 0.000 description 4
- 206010027476 Metastases Diseases 0.000 description 4
- 206010033128 Ovarian cancer Diseases 0.000 description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- 206010060862 Prostate cancer Diseases 0.000 description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 208000012931 Urologic disease Diseases 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
- FOMNACSNJGTOCF-UHFFFAOYSA-N ethyl 1-(4-hydroxyphenyl)cyclopropane-1-carboxylate Chemical compound C=1C=C(O)C=CC=1C1(C(=O)OCC)CC1 FOMNACSNJGTOCF-UHFFFAOYSA-N 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000005755 formation reaction Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000002198 insoluble material Substances 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 230000009401 metastasis Effects 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 230000036470 plasma concentration Effects 0.000 description 4
- 229940002612 prodrug Drugs 0.000 description 4
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- 230000002062 proliferating effect Effects 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 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
- JXZSXYQUKONQRG-UHFFFAOYSA-N 2-(2-fluoro-4-methoxyphenyl)-2-hydroxyacetic acid Chemical compound COC1=CC=C(C(O)C(O)=O)C(F)=C1 JXZSXYQUKONQRG-UHFFFAOYSA-N 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
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- QMHAHUAQAJVBIW-UHFFFAOYSA-N [methyl(sulfamoyl)amino]methane Chemical compound CN(C)S(N)(=O)=O QMHAHUAQAJVBIW-UHFFFAOYSA-N 0.000 description 3
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- YXVBEHSZYHOJKC-UHFFFAOYSA-N ethyl 5-methyl-2-[(3-phenylpropylamino)methyl]-1,3-thiazole-4-carboxylate Chemical compound S1C(C)=C(C(=O)OCC)N=C1CNCCCC1=CC=CC=C1 YXVBEHSZYHOJKC-UHFFFAOYSA-N 0.000 description 3
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Description
本発明は医薬組成物、殊に、リゾホスファチジン酸(以下、LPAと略す)により引き起こされる疾患の予防及び/又は治療用医薬組成物の有効成分として有用な置換アミド化合物に関する。 The present invention relates to a pharmaceutical composition, particularly a substituted amide compound useful as an active ingredient of a pharmaceutical composition for preventing and / or treating a disease caused by lysophosphatidic acid (hereinafter abbreviated as LPA).
LPAは、例えば以下の化学式で示されるようなリン脂質で、グリセロール骨格の1位又は2位に脂肪酸を持ち、3位にリン酸基が結合した単純な構造であり、1-アシルLPA、1-アルキルLPA、1-アルケニルLPA、2-アシルLPAなどが含まれる。また、脂肪酸の種類によって多様性があり、炭素鎖の長さと不飽和度により18:1-LPA、18:3-LPA、16:0-LPAなどがある。 LPA is, for example, a phospholipid represented by the following chemical formula, having a fatty acid at the 1- or 2-position of the glycerol skeleton and a simple structure in which a phosphate group is bonded to the 3-position, and 1-acyl LPA, 1 -Alkyl LPA, 1-alkenyl LPA, 2-acyl LPA and the like are included. In addition, there are variations depending on the type of fatty acid, and there are 18: 1-LPA, 18: 3-LPA, 16: 0-LPA, etc. depending on the length of the carbon chain and the degree of unsaturation.
LPAは下部尿路組織においては精液に存在することが報告されており(非特許文献1)、in vitroにおいては摘出尿道標本及び前立腺標本を収縮させ、in vivoでは尿道内圧を上昇させることが示されている(特許文献1)。
またLPAは単離膀胱平滑筋細胞を収縮させることや、LPAが前立腺肥大症由来の前立腺細胞の増殖を促進することが報告されている(非特許文献2、3)。
神経細胞において、LPA1はミエリン形成期のオリゴデンドロサイト及びシュワン細胞に多く発現し、ミエリン形成の時期に一致して発現する(非特許文献4)。
脱髄モデルマウスでは、LPA1のmRNA量が約40%減少することも知られている(非特許文献5)。
LPAはシュワン細胞、オリゴデンドロサイトの細胞死を抑制し、ミエリン形成への関与が示唆されている(非特許文献6)。
また,LPA及びLPA1が神経因性疼痛の発現に関与することが報告されている(非特許文献7)。
LPAは各種の線維化疾患に関与することが示されている。肝線維化においてはLPAが肝線維化の過程で重要な役割を示す星細胞の収縮や増殖を促進することや、慢性C型肝炎患者や各種肝障害動物モデルでLPA濃度が上昇することが報告されている(非特許文献8、9、10、11)。また、腎線維化においては、動物モデルである片側尿管結紮モデルマウスにおいてLPAの産生やLPA1の発現が亢進しており、LPA1欠損マウス及びLPA受容体拮抗薬で線維化進行が抑制されることが報告されている(非特許文献12)。肺線維化に関しては特発性肺線維症患者において肺胞洗浄液中のLPA濃度が上昇していること、またブレオマイシン誘発肺線維症モデルマウスにおいて肺胞洗浄液でLPA濃度が上昇していること、またLPA1欠損マウスでは線維症の進行と死亡が著しく抑制されていることが報告されている(非特許文献13)。
その他、粥状動脈硬化病変においてLPAが集積し酸化LDLによる血小板及び内皮細胞の活性化を仲介することが報告されており、循環器疾患へのLPAの関与が示唆されている(非特許文献14)。
また、増殖性疾患においては、LPAが癌細胞の遊走を促進することが知られている(非特許文献15)。卵巣癌患者の腹水中においてLPA濃度が亢進しており、実際に卵巣癌細胞の増殖を促進することが報告されている(非特許文献16、17)。前立腺癌においても、実際の癌病変においてLPA1受容体の発現が亢進していることやLPA1を過剰発現させた前立腺癌細胞で増殖が亢進することが報告されている(非特許文献18)。また乳癌骨転移モデルにおいてはLPA1の過剰発現による腫瘍増殖・転移能の亢進及びLPA受容体拮抗薬による転移抑制作用が報告されている(非特許文献19)。また、近年癌組織内では癌細胞周辺の様々な細胞が癌細胞の生存、成長、遠隔転移を補助していることが急速に明らかになってきている。ヒト脂肪由来間葉系幹細胞が癌細胞との共移植により腫瘍組織内でLPA1の活性化を介して腫瘍関連線維芽細胞に分化し、腫瘍の生育・血管新生を促進することが明らかになっている(非特許文献20)。
これらのLPA及びLPA受容体に関する様々な研究から得られている知見より、LPAの生理活性を抑制する薬剤、とりわけLPA1のアンタゴニストは前立腺肥大に伴う排尿障害などの泌尿器系疾患、中枢・末梢神経系の疾患及び泌尿器系疾神経疾患、肝炎や腎不全、特発性肺線維症等の線維化を伴う疾患、動脈硬化等の循環器疾患、また前立腺癌、乳癌、卵巣癌などの増殖性疾患等の予防薬ないしは治療薬として有用であると考えられる。
LPA has been reported to be present in semen in the lower urinary tract tissue (Non-Patent Document 1), and it has been shown to contract the isolated urethral specimen and prostate specimen in vitro and increase the urethral pressure in vivo. (Patent Document 1).
In addition, LPA has been reported to contract isolated bladder smooth muscle cells, and LPA promotes the proliferation of prostate cells derived from prostatic hypertrophy (Non-patent Documents 2 and 3).
In neurons, LPA1 is highly expressed in oligodendrocytes and Schwann cells in the myelin formation phase, and is expressed in accordance with the time of myelin formation (Non-patent Document 4).
In demyelination model mice, it is also known that the amount of LPA1 mRNA is reduced by about 40% (Non-patent Document 5).
LPA suppresses cell death of Schwann cells and oligodendrocytes, and is implicated in myelin formation (Non-patent Document 6).
In addition, it has been reported that LPA and LPA1 are involved in the expression of neuropathic pain (Non-patent Document 7).
LPA has been shown to be involved in various fibrotic diseases. In liver fibrosis, LPA promotes the contraction and proliferation of stellate cells, which play an important role in the process of liver fibrosis, and reports that LPA levels increase in patients with chronic hepatitis C and various liver injury animal models (Non-Patent Documents 8, 9, 10, and 11). Moreover, in renal fibrosis, LPA production and LPA1 expression are increased in unilateral ureteral ligation model mice, which are animal models, and progression of fibrosis is suppressed by LPA1-deficient mice and LPA receptor antagonists. Has been reported (Non-Patent Document 12). Regarding lung fibrosis, LPA concentration in alveolar lavage fluid is increased in patients with idiopathic pulmonary fibrosis, LPA concentration is increased in alveolar lavage fluid in bleomycin-induced pulmonary fibrosis model mice, and LPA1 It has been reported that fibrosis progression and death are significantly suppressed in the deficient mice (Non-patent Document 13).
In addition, it has been reported that LPA accumulates in atherosclerotic lesions and mediates activation of platelets and endothelial cells by oxidized LDL, suggesting the involvement of LPA in cardiovascular disease (Non-Patent Document 14). ).
In proliferative diseases, LPA is known to promote migration of cancer cells (Non-patent Document 15). It has been reported that LPA concentration is increased in the ascites of ovarian cancer patients and actually promotes proliferation of ovarian cancer cells (Non-patent Documents 16 and 17). Also in prostate cancer, it has been reported that expression of LPA1 receptor is increased in actual cancer lesions, and that proliferation is increased in prostate cancer cells overexpressing LPA1 (Non-patent Document 18). In breast cancer bone metastasis models, enhancement of tumor growth / metastasis by LPA1 overexpression and metastasis suppression by LPA receptor antagonists have been reported (Non-patent Document 19). In recent years, it has rapidly become clear that various cells around cancer cells assist the survival, growth and distant metastasis of cancer cells in cancer tissues. It became clear that human adipose-derived mesenchymal stem cells differentiated into tumor-related fibroblasts through LPA1 activation in tumor tissues by co-transplantation with cancer cells, and promoted tumor growth and angiogenesis (Non-Patent Document 20).
Based on findings from various studies on these LPA and LPA receptors, drugs that suppress LPA physiological activity, especially LPA1 antagonists, are urological diseases such as dysuria due to prostatic hypertrophy, central / peripheral nervous system Diseases such as urological diseases, hepatitis, renal failure, idiopathic pulmonary fibrosis and other fibrotic diseases, arteriosclerosis and other cardiovascular diseases, and proliferative diseases such as prostate cancer, breast cancer and ovarian cancer It is considered useful as a prophylactic or therapeutic agent.
一方、式(A)で示されるカルボン酸誘導体がLPA受容体拮抗作用を有し、種々の疾患、例えば泌尿器系疾患、癌関連疾患、増殖性疾患、炎症免疫疾患、脳関連疾患、慢性疾患等に有用であることが知られている(特許文献2)。 On the other hand, the carboxylic acid derivative represented by the formula (A) has an LPA receptor antagonistic action, and various diseases such as urological diseases, cancer-related diseases, proliferative diseases, inflammatory immune diseases, brain-related diseases, chronic diseases, etc. (Patent Document 2).
また、式(B)で示される化合物がLPA受容体拮抗作用を有し、種々の疾患、例えば泌尿器系疾患(前立腺肥大症または神経因性膀胱疾患に伴う症状等)、癌関連疾患、増殖性疾患、炎症免疫疾患、脳関連疾患、慢性疾患等に有用であることが知られている(特許文献3)。 In addition, the compound represented by the formula (B) has an LPA receptor antagonistic action, and various diseases such as urological diseases (such as symptoms associated with prostatic hypertrophy or neurogenic bladder disease), cancer-related diseases, proliferative It is known to be useful for diseases, inflammatory immune diseases, brain-related diseases, chronic diseases and the like (Patent Document 3).
いずれの文献においても、本発明化合物に関する具体的な開示はない。 In any document, there is no specific disclosure regarding the compound of the present invention.
【0009】
【非特許文献1】 FEBS Lett. 2002, 523, 187.
【非特許文献2】J. Urol. 1999, 162, 1779.
【非特許文献3】J. Urol. 2000, 163, 1027.
【非特許文献4】Eur. J. Neurosci. 1998, 10, 1045.
【非特許文献5】J. Comp. Neurol. 1998, 398, 587.
【非特許文献6】Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 5233.
【非特許文献7】Nat. Med. 2004, 10, 712.
【非特許文献8】Biochem. Biophys. Res. Commun. 2000, 277, 72.
【非特許文献9】Biochem. Biophys. Res. Commun. 2000, 248,436.
【非特許文献10】J. Clin. Gastroenterol. 2007, 41, 616.
【非特許文献11】Life Sci. 2008, 81, 1009.
【非特許文献12】J. Am. Soc. Nephrol. 2007, 18, 3110.
【非特許文献13】Nat. Med. 2007, 14, 45.
【非特許文献14】Proc. Natl Acad. Sci. U.S.A. 1999, 96, 6931.
【非特許文献15】Biochem. Biophysic. Res. Communic. 1993, 193, 497.
【非特許文献16】JAMA 1998, 280, 719.
【非特許文献17】J. Natl. Cancer. Inst. 2001, 93, 762.
【非特許文献18】Endocrinology 2006, 147, 4883.
【非特許文献19】Proc. Natl. Acad. Sci. U. S. A. 2006, 103, 9643.
【非特許文献20】Bio.chim. Biophys. Acta. 2010, 1801, 1205.
【特許文献】
[0009]
[Non-Patent Document 1] FEBS Lett. 2002, 523, 187.
[Non-Patent Document 2] J. Urol. 1999, 162, 1779.
[Non-Patent Document 3] J. Urol. 2000, 163, 1027.
[Non-Patent Document 4] Eur. J. Neurosci. 1998, 10, 1045.
[Non-Patent Document 5] J. Comp. Neurol. 1998, 398, 587.
[Non-Patent Document 6] Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 5233.
[Non-Patent Document 7] Nat. Med. 2004, 10, 712.
[Non-Patent Document 8] Biochem. Biophys. Res. Commun. 2000, 277, 72.
[Non-patent document 9] Biochem. Biophys. Res. Commun. 2000, 248, 436.
[Non-Patent Document 10] J. Clin. Gastroenterol. 2007, 41, 616.
[Non-Patent Document 11] Life Sci.2008, 81, 1009.
[Non-Patent Document 12] J. Am. Soc. Nephrol. 2007, 18, 3110.
[Non-Patent Document 13] Nat. Med. 2007, 14, 45.
[Non-Patent Document 14] Proc. Natl Acad. Sci. U.S.A. 1999, 96, 6931.
[Non-patent Document 15] Biochem. Biophysic. Res. Communic. 1993, 193, 497.
[Non-Patent Document 16] JAMA 1998, 280, 719.
[Non-patent document 17] J. Natl. Cancer. Inst. 2001, 93, 762.
[Non-patent document 18] Endocrinology 2006, 147, 4883.
[Non-patent Document 19] Proc. Natl. Acad. Sci. U. S. A. 2006, 103, 9643.
[Non-Patent Document 20] Bio.chim. Biophys. Acta. 2010, 1801, 1205.
[Patent Literature]
本発明は医薬組成物、殊に、LPAにより引き起こされる疾患の予防及び/又は治療医薬組成物の有効成分として有用な置換アミド化合物を提供する。 The present invention provides a substituted amide compound useful as an active ingredient of a pharmaceutical composition, particularly a pharmaceutical composition for preventing and / or treating a disease caused by LPA.
本発明者らは、LPA受容体拮抗作用を有する化合物について鋭意検討した結果、本発明化合物である置換アミド化合物が優れたLPA受容体拮抗作用を有し、LPAにより引き起こされる疾患の予防及び/又は治療剤として有用であることを見出して本発明を完成した。 As a result of intensive studies on compounds having an LPA receptor antagonistic activity, the present inventors have found that the substituted amide compound of the present invention has an excellent LPA receptor antagonistic activity and can prevent diseases caused by LPA and / or The present invention was completed by finding it useful as a therapeutic agent.
本発明は、以下の(I)の群から選択される化合物又はその塩に関する。
ここで、(I)の群とは、
2-{[({1-[4-(2-フルオロエトキシ)フェニル]シクロプロピル}カルボニル)(3-フェニルプロピル)アミノ]メチル}-N-[(2-ヒドロキシプロピル)スルホニル]-5-メチル-1,3-チアゾール-4-カルボキサミド、
N-(ジメチルスルファモイル)-5-メチル-2-{[({1-[4-(メチルスルファニル)フェニル]シクロプロピル}カルボニル)(3-フェニルプロピル)アミノ]メチル}-1,3-チアゾール-4-カルボキサミド、
N-(ジメチルスルファモイル)-2-[({[1-(4-メトキシフェニル)シクロプロピル]カルボニル}[3-(5-メチル-2-フリル)プロピル]アミノ)メチル]-5-メチル-1,3-チアゾール-4-カルボキサミド、
N-(ジメチルスルファモイル)-2-[({[1-(5-メトキシピリジン-2-イル)シクロプロピル]カルボニル}[3-(5-メチル-2-フリル)プロピル]アミノ)メチル]-5-メチル-1,3-チアゾール-4-カルボキサミド、
N-(ジメチルスルファモイル)-2-[([3-(4-フルオロフェニル)プロピル]{[1-(4-メトキシフェニル)シクロプロピル]カルボニル}アミノ)メチル]-5-メチル-1,3-チアゾール-4-カルボキサミド、
2-({[(4-エトキシ-2-フルオロフェニル)(ヒドロキシ)アセチル](3-フェニルプロピル)アミノ}メチル)-5-メチル-N-スルファモイル-1,3-チアゾール-4-カルボキサミド、
2-[([3-(5-クロロ-2-チエニル)プロピル]{[1-(4-メトキシフェニル)シクロプロピル]カルボニル}アミノ)メチル]-N-(ジメチルスルファモイル)-5-メチル-1,3-チアゾール-4-カルボキサミド、
N-(ジメチルスルファモイル)-2-[({[1-(4-メトキシフェニル)シクロプロピル]カルボニル}[3-(5-メチル-2-チエニル)プロピル]アミノ)メチル]-5-メチル-1,3-チアゾール-4-カルボキサミド、
N-(ジメチルスルファモイル)-5-メチル-2-({[(1-{4-[(2H2)メチルオキシ]フェニル}シクロプロピル)カルボニル](3-フェニルプロピル)アミノ}メチル)-1,3-チアゾール-4-カルボキサミド、
2-{[{[4-(2,2-ジフルオロエトキシ)-2-フルオロフェニル](ヒドロキシ)アセチル}(3-フェニルプロピル)アミノ]メチル}-5-メチル-N-スルファモイル-1,3-チアゾール-4-カルボキサミド、
N-(ジメチルスルファモイル)-2-[([3-(3-フルオロフェニル)プロピル]{[1-(5-メトキシピリジン-2-イル)シクロプロピル]カルボニル}アミノ)メチル]-5-メチル-1,3-チアゾール-4-カルボキサミド、
2-[([3-(4,5-ジメチル-2-フリル)プロピル]{[1-(4-メトキシフェニル)シクロプロピル]カルボニル}アミノ)メチル]-5-メチル-N-スルファモイル-1,3-チアゾール-4-カルボキサミド、
2-({[(2R)-2-ヒドロキシ-2-(4-メトキシフェニル)アセチル](3-フェニルプロピル)アミノ}メチル)-5-メチル-N-スルファモイル-1,3-チアゾール-4-カルボキサミド、
N-[(2-ヒドロキシエチル)(メチル)スルファモイル]-2-({[(2R)-2-ヒドロキシ-2-{4-[(2H1)メチルオキシ]フェニル}アセチル](3-フェニルプロピル)アミノ}メチル)-5-メチル-1,3-チアゾール-4-カルボキサミド、
2-({[3-(3-フルオロフェニル)プロピル][(2R)-2-ヒドロキシ-2-(4-メトキシフェニル)アセチル]アミノ}メチル)-5-メチル-N-スルファモイル-1,3-チアゾール-4-カルボキサミド、
5-クロロ-N-(ジメチルスルファモイル)-2-({[(2R)-2-ヒドロキシ-2-(4-メトキシフェニル)アセチル](3-フェニルプロピル)アミノ}メチル)-1,3-チアゾール-4-カルボキサミド、
5-{[{[1-(4-メトキシフェニル)シクロプロピル]カルボニル}(3-フェニルプロピル)アミノ]メチル}-N-スルファモイル-2-フラミド、
5-ブロモ-2-({[(2R)-2-ヒドロキシ-2-(4-メトキシフェニル)アセチル](3-フェニルプロピル)アミノ}メチル)-N-(メチルスルホニル)-1,3-チアゾール-4-カルボキサミド、
2-({[(2-シアノ-4-メトキシフェニル)アセチル](3-フェニルプロピル)アミノ}メチル)-N-(ジメチルスルファモイル)-5-メチル-1,3-チアゾール-4-カルボキサミド、
2-[([3-(3-ブロモフェニル)プロピル]{[1-(5-メトキシピリジン-2-イル)シクロプロピル]カルボニル}アミノ)メチル]-N-(ジメチルスルファモイル)-5-メチル-1,3-チアゾール-4-カルボキサミド、
5-シアノ-N-(ジメチルスルファモイル)-2-{[{[1-(4-メトキシフェニル)シクロプロピル]カルボニル}(3-フェニルプロピル)アミノ]メチル}-1,3-チアゾール-4-カルボキサミド、
2-[({[1-(4-メトキシフェニル)シクロプロピル]カルボニル}[3-(3-チエニル)プロピル]アミノ)メチル]-5-メチル-N-スルファモイル-1,3-チアゾール-4-カルボキサミド、
2-({[3-(2-フルオロフェニル)プロピル][(2R)-2-ヒドロキシ-2-(4-メトキシフェニル)アセチル]アミノ}メチル)-5-メチル-N-(メチルスルホニル)-1,3-チアゾール-4-カルボキサミド、
2-({[(2R)-2-(2-フルオロ-4-メトキシフェニル)-2-ヒドロキシアセチル](3-フェニルプロピル)アミノ}メチル)-5-メチル-N-(メチルスルホニル)-1,3-チアゾール-4-カルボキサミド、
N-(エチルスルホニル)-2-({[(2R)-2-(2-フルオロ-4-メトキシフェニル)-2-ヒドロキシアセチル](3-フェニルプロピル)アミノ}メチル)-5-メチル-1,3-チアゾール-4-カルボキサミド、
N-(エチルスルホニル)-2-[([3-(2-フリル)プロピル]{[1-(4-メトキシフェニル)シクロプロピル]カルボニル}アミノ)メチル]-5-メチル-1,3-チアゾール-4-カルボキサミド、
5-エチル-N-(エチルスルホニル)-2-({[(2R)-2-ヒドロキシ-2-(4-メトキシフェニル)アセチル](3-フェニルプロピル)アミノ}メチル)-1,3-チアゾール-4-カルボキサミド、及び、
2-({[(2R)-2-(2-フルオロ-4-メトキシフェニル)-2-ヒドロキシアセチル](3-フェニルプロピル)アミノ}メチル)-5-メチル-N-(メチルスファモイル)-1,3-チアゾール-4-カルボキサミド、
である。The present invention relates to a compound selected from the following group (I) or a salt thereof.
Here, the group (I) is
2-{[({1- [4- (2-fluoroethoxy) phenyl] cyclopropyl} carbonyl) (3-phenylpropyl) amino] methyl} -N-[(2-hydroxypropyl) sulfonyl] -5-methyl -1,3-thiazole-4-carboxamide,
N- (dimethylsulfamoyl) -5-methyl-2-{[({1- [4- (methylsulfanyl) phenyl] cyclopropyl} carbonyl) (3-phenylpropyl) amino] methyl} -1,3- Thiazole-4-carboxamide,
N- (dimethylsulfamoyl) -2-[({[1- (4-methoxyphenyl) cyclopropyl] carbonyl} [3- (5-methyl-2-furyl) propyl] amino) methyl] -5-methyl -1,3-thiazole-4-carboxamide,
N- (dimethylsulfamoyl) -2-[({{1- (5-methoxypyridin-2-yl) cyclopropyl] carbonyl} [3- (5-methyl-2-furyl) propyl] amino) methyl] -5-methyl-1,3-thiazole-4-carboxamide,
N- (dimethylsulfamoyl) -2-[([3- (4-fluorophenyl) propyl] {[1- (4-methoxyphenyl) cyclopropyl] carbonyl} amino) methyl] -5-methyl-1, 3-thiazole-4-carboxamide,
2-({[(4-ethoxy-2-fluorophenyl) (hydroxy) acetyl] (3-phenylpropyl) amino} methyl) -5-methyl-N-sulfamoyl-1,3-thiazole-4-carboxamide,
2-[([3- (5-Chloro-2-thienyl) propyl] {[1- (4-methoxyphenyl) cyclopropyl] carbonyl} amino) methyl] -N- (dimethylsulfamoyl) -5-methyl -1,3-thiazole-4-carboxamide,
N- (dimethylsulfamoyl) -2-[({[1- (4-methoxyphenyl) cyclopropyl] carbonyl} [3- (5-methyl-2-thienyl) propyl] amino) methyl] -5-methyl -1,3-thiazole-4-carboxamide,
N- (dimethylsulfamoyl) -5-methyl-2-({[(1- {4-[( 2 H 2 ) methyloxy] phenyl} cyclopropyl) carbonyl] (3-phenylpropyl) amino} methyl) -1,3-thiazole-4-carboxamide,
2-{[{[4- (2,2-difluoroethoxy) -2-fluorophenyl] (hydroxy) acetyl} (3-phenylpropyl) amino] methyl} -5-methyl-N-sulfamoyl-1,3- Thiazole-4-carboxamide,
N- (dimethylsulfamoyl) -2-[([3- (3-fluorophenyl) propyl] {[1- (5-methoxypyridin-2-yl) cyclopropyl] carbonyl} amino) methyl] -5- Methyl-1,3-thiazole-4-carboxamide,
2-[([3- (4,5-Dimethyl-2-furyl) propyl] {[1- (4-methoxyphenyl) cyclopropyl] carbonyl} amino) methyl] -5-methyl-N-sulfamoyl-1, 3-thiazole-4-carboxamide,
2-({[(2R) -2-hydroxy-2- (4-methoxyphenyl) acetyl] (3-phenylpropyl) amino} methyl) -5-methyl-N-sulfamoyl-1,3-thiazole-4- Carboxamide,
N-[(2-hydroxyethyl) (methyl) sulfamoyl] -2-({[(2R) -2-hydroxy-2- {4-[( 2 H 1 ) methyloxy] phenyl} acetyl] (3-phenylpropiyl L) amino} methyl) -5-methyl-1,3-thiazole-4-carboxamide,
2-({[3- (3-Fluorophenyl) propyl] [(2R) -2-hydroxy-2- (4-methoxyphenyl) acetyl] amino} methyl) -5-methyl-N-sulfamoyl-1,3 -Thiazole-4-carboxamide,
5-Chloro-N- (dimethylsulfamoyl) -2-({[(2R) -2-hydroxy-2- (4-methoxyphenyl) acetyl] (3-phenylpropyl) amino} methyl) -1,3 -Thiazole-4-carboxamide,
5-{[{[1- (4-methoxyphenyl) cyclopropyl] carbonyl} (3-phenylpropyl) amino] methyl} -N-sulfamoyl-2-furamide,
5-Bromo-2-({[(2R) -2-hydroxy-2- (4-methoxyphenyl) acetyl] (3-phenylpropyl) amino} methyl) -N- (methylsulfonyl) -1,3-thiazole -4-carboxamide,
2-({[(2-Cyano-4-methoxyphenyl) acetyl] (3-phenylpropyl) amino} methyl) -N- (dimethylsulfamoyl) -5-methyl-1,3-thiazole-4-carboxamide ,
2-[([3- (3-Bromophenyl) propyl] {[1- (5-methoxypyridin-2-yl) cyclopropyl] carbonyl} amino) methyl] -N- (dimethylsulfamoyl) -5- Methyl-1,3-thiazole-4-carboxamide,
5-cyano-N- (dimethylsulfamoyl) -2-{[{[1- (4-methoxyphenyl) cyclopropyl] carbonyl} (3-phenylpropyl) amino] methyl} -1,3-thiazole-4 -Carboxamide,
2-[({[1- (4-Methoxyphenyl) cyclopropyl] carbonyl} [3- (3-thienyl) propyl] amino) methyl] -5-methyl-N-sulfamoyl-1,3-thiazole-4- Carboxamide,
2-({[3- (2-fluorophenyl) propyl] [(2R) -2-hydroxy-2- (4-methoxyphenyl) acetyl] amino} methyl) -5-methyl-N- (methylsulfonyl)- 1,3-thiazole-4-carboxamide,
2-({[(2R) -2- (2-fluoro-4-methoxyphenyl) -2-hydroxyacetyl] (3-phenylpropyl) amino} methyl) -5-methyl-N- (methylsulfonyl) -1 , 3-thiazole-4-carboxamide,
N- (ethylsulfonyl) -2-({[(2R) -2- (2-fluoro-4-methoxyphenyl) -2-hydroxyacetyl] (3-phenylpropyl) amino} methyl) -5-methyl-1 , 3-thiazole-4-carboxamide,
N- (ethylsulfonyl) -2-[([3- (2-furyl) propyl] {[1- (4-methoxyphenyl) cyclopropyl] carbonyl} amino) methyl] -5-methyl-1,3-thiazole -4-carboxamide,
5-ethyl-N- (ethylsulfonyl) -2-({[(2R) -2-hydroxy-2- (4-methoxyphenyl) acetyl] (3-phenylpropyl) amino} methyl) -1,3-thiazole -4-carboxamide, and
2-({[(2R) -2- (2-Fluoro-4-methoxyphenyl) -2-hydroxyacetyl] (3-phenylpropyl) amino} methyl) -5-methyl-N- (methylsulfamoyl)- 1,3-thiazole-4-carboxamide,
It is.
本発明は、(I)の群より選択される化合物又はその塩、及び賦形剤を含有する医薬組成物に関する。
また、本発明は、(I)の群より選択される化合物又はその塩、及び賦形剤を含有する医薬組成物、殊に、LPAにより引き起こされる疾患、あるいはLPAにより引き起こされる疾患の予防及び/又は治療用医薬組成物に関する。
更に、本発明は、LPAにより引き起こされる疾患、あるいはLPAにより引き起こされる疾患の予防及び/又は治療用医薬組成物の製造のための(I)の群より選択される化合物又はその塩の使用、LPAにより引き起こされる疾患、あるいはLPAにより引き起こされる疾患の予防及び/又は治療のための(I)の群より選択される化合物又はその塩の使用、LPAにより引き起こされる疾患の予防及び/又は治療のための(I)の群より選択される化合物又はその塩の使用、LPAにより引き起こされる疾患の予防及び/又は治療のための(I)の群より選択される化合物又はその塩、並びに、(I)の群より選択される化合物又はその塩の有効量を患者に投与することからなるLPAにより引き起こされる疾患の予防及び/又は治療方法に関する。The present invention relates to a pharmaceutical composition comprising a compound selected from the group (I) or a salt thereof, and an excipient.
The present invention also relates to a pharmaceutical composition containing a compound selected from the group (I) or a salt thereof, and an excipient, particularly a disease caused by LPA or a disease caused by LPA and / or Alternatively, it relates to a therapeutic pharmaceutical composition.
Furthermore, the present invention relates to the use of a compound selected from the group (I) or a salt thereof for the manufacture of a pharmaceutical composition for the prevention and / or treatment of a disease caused by LPA or a disease caused by LPA, LPA Use of a compound selected from the group (I) or a salt thereof for the prevention and / or treatment of a disease caused by LPA or a disease caused by LPA, for the prevention and / or treatment of a disease caused by LPA Use of a compound selected from the group of (I) or a salt thereof, a compound selected from the group of (I) for the prevention and / or treatment of a disease caused by LPA, or a salt thereof, and The present invention relates to a method for preventing and / or treating a disease caused by LPA comprising administering to a patient an effective amount of a compound selected from the group or a salt thereof.
(I)の群より選択される化合物又はその塩は、LPA受容体拮抗作用を有し、LPAにより引き起こされる疾患の予防及び/又は治療剤として使用できる。 The compound selected from the group (I) or a salt thereof has an LPA receptor antagonistic action and can be used as a preventive and / or therapeutic agent for a disease caused by LPA.
以下、本発明を詳細に説明する。尚、以下において「(I)の群より選択される化合物又はその塩」を「本発明化合物(I)」や「化合物(I)」と表記することがある。 Hereinafter, the present invention will be described in detail. In the following, “a compound selected from the group of (I) or a salt thereof” may be referred to as “the present compound (I)” or “compound (I)”.
本明細書において、「LPAにより引き起こされる疾患」とは、例えば泌尿器系疾患(前立腺肥大症(前立腺肥大症に伴う排尿障害など)、過活動膀胱、神経因性膀胱、膀胱頚部硬化症、低活動性膀胱など)、中枢・末梢神経疾患(神経因性疼痛、有痛性末梢糖尿病性神経障害、脳梗塞後の神経細胞変性・神経細胞死など)、癌関連疾患(前立腺癌、乳癌、卵巣癌、肺癌、大腸癌など)、炎症性疾患(関節リウマチ、変形性膝関節症、C型肝炎、非アルコール性脂肪肝炎)、線維化を伴う疾患(慢性腎臓病、特発性肺線維症、、非臓器移植後の慢性拒絶反応)、動脈硬化等の循環器疾患をいう。別の態様としては、例えば泌尿器系疾患(前立腺肥大症(前立腺肥大症に伴う排尿障害など)、過活動膀胱、神経因性膀胱、膀胱頚部硬化症、低活動性膀胱など)をいう。 In this specification, “disease caused by LPA” means, for example, urinary system diseases (prostatic hypertrophy (such as dysuria associated with prostatic hypertrophy)), overactive bladder, neurogenic bladder, bladder cervical sclerosis, low activity Urinary bladder etc.), central / peripheral neurological diseases (neuropathic pain, painful peripheral diabetic neuropathy, neuronal degeneration / neural cell death after cerebral infarction), cancer-related diseases (prostate cancer, breast cancer, ovarian cancer) , Lung cancer, colon cancer, etc.), inflammatory diseases (rheumatoid arthritis, osteoarthritis of the knee, hepatitis C, nonalcoholic steatohepatitis), diseases with fibrosis (chronic kidney disease, idiopathic pulmonary fibrosis, non Chronic rejection after organ transplantation), cardiovascular diseases such as arteriosclerosis. Another embodiment refers to, for example, a urinary system disease (prostatic hypertrophy (such as dysuria associated with prostatic hypertrophy), overactive bladder, neurogenic bladder, bladder neck sclerosis, underactive bladder, etc.).
(I)の群より選択される化合物には、置換基の種類によって、互変異性体や幾何異性体が存在しうる。本明細書中、(I)の群より選択される化合物が異性体の一形態のみで記載されることがあるが、本発明は、それ以外の異性体も包含し、異性体の分離されたもの、あるいはそれらの混合物も包含する。
また、(I)の群より選択される化合物には、不斉炭素原子や軸不斉を有する場合があり、これに基づく光学異性体が存在しうる。本発明は、(I)の群より選択される化合物の光学異性体の分離されたもの、あるいはそれらの混合物も包含する。The compound selected from the group (I) may have a tautomer or a geometric isomer depending on the type of the substituent. In the present specification, a compound selected from the group (I) may be described in only one form of an isomer, but the present invention also includes other isomers, and the isomers are separated. Or a mixture thereof.
In addition, the compound selected from the group (I) may have an asymmetric carbon atom or axial asymmetry, and optical isomers based on this may exist. The present invention also includes separated optical isomers of a compound selected from the group (I) or a mixture thereof.
さらに、本発明は、(I)の群より選択される化合物の製薬学的に許容されるプロドラッグも包含する。製薬学的に許容されるプロドラッグとは、加溶媒分解により又は生理学的条件下で、アミノ基、水酸基、カルボキシル基等に変換されうる基を有する化合物である。プロドラッグを形成する基としては、例えば、Prog. Med., 5, 2157-2161(1985)や、「医薬品の開発」(廣川書店、1990年)第7巻 分子設計163-198に記載の基が挙げられる。 Furthermore, the present invention includes a pharmaceutically acceptable prodrug of a compound selected from the group (I). A pharmaceutically acceptable prodrug is a compound having a group that can be converted to an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions. Examples of groups that form prodrugs include those described in Prog. Med., 5, 2157-2161 (1985) and “Development of Pharmaceuticals” (Yodogawa Shoten, 1990), Volume 7, Molecular Design 163-198. Is mentioned.
また、(I)の群より選択される化合物の塩とは、(I)の群より選択される化合物の製薬学的に許容される塩であり、置換基の種類によって、酸付加塩又は塩基との塩を形成する場合がある。具体的には、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸等の無機酸や、ギ酸、酢酸、プロピオン酸、シュウ酸、マロン酸、コハク酸、フマル酸、マレイン酸、乳酸、リンゴ酸、マンデル酸、酒石酸、ジベンゾイル酒石酸、ジトルオイル酒石酸、クエン酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸、アスパラギン酸、グルタミン酸等の有機酸との酸付加塩、ナトリウム、カリウム、マグネシウム、カルシウム、アルミニウム等の無機塩基、メチルアミン、エチルアミン、エタノールアミン、リシン、オルニチン等の有機塩基との塩、アセチルロイシン等の各種アミノ酸及びアミノ酸誘導体との塩やアンモニウム塩等が挙げられる。 The salt of the compound selected from the group (I) is a pharmaceutically acceptable salt of the compound selected from the group (I), and an acid addition salt or a base depending on the type of substituent. May form a salt with. Specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid Acid addition with organic acids such as lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid Salts, salts with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine and ornithine, salts with various amino acids and amino acid derivatives such as acetylleucine and ammonium salts Etc.
さらに、本発明は、(I)の群より選択される化合物及びその塩の各種の水和物や溶媒和物、及び結晶多形の物質も包含する。また、本発明は、種々の放射性又は非放射性同位体でラベルされた化合物も包含する。 Furthermore, the present invention also includes various hydrates and solvates of compounds selected from the group (I) and salts thereof, and polymorphic substances. The present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.
(製造法)
(I)の群より選択される化合物及びその塩は、その基本構造あるいは置換基の種類に基づく特徴を利用し、種々の公知の合成法を適用して製造することができる。その際、官能基の種類によっては、当該官能基を原料から中間体へ至る段階で適当な保護基(容易に当該官能基に転化可能な基)に置き換えておくことが製造技術上効果的な場合がある。このような保護基としては、例えば、ウッツ(P. G. M. Wuts)及びグリーン(T. W. Greene)著、「Greene’s Protective Groups in Organic Synthesis(第4版、2006年)」に記載の保護基等を挙げることができ、これらの反応条件に応じて適宜選択して用いればよい。このような方法では、当該保護基を導入して反応を行なったあと、必要に応じて保護基を除去することにより、所望の化合物を得ることができる。
また、(I)の群より選択される化合物のプロドラッグは、上記保護基と同様、原料から中間体へ至る段階で特定の基を導入、あるいは得られた(I)の群より選択される化合物を用いてさらに反応を行なうことで製造できる。反応は通常のエステル化、アミド化、脱水等、当業者に公知の方法を適用することにより行うことができる。(Production method)
A compound selected from the group (I) and a salt thereof can be produced by applying various known synthetic methods using characteristics based on the basic structure or the type of substituent. At that time, depending on the type of functional group, it is effective in terms of production technology to replace the functional group with an appropriate protective group (a group that can be easily converted into the functional group) at the stage from the raw material to the intermediate. There is a case. Examples of such protecting groups include protecting groups described in “Greene's Protective Groups in Organic Synthesis (4th edition, 2006)” by PGM Wuts and TW Greene. These may be appropriately selected according to the reaction conditions. In such a method, after carrying out the reaction by introducing the protective group, the desired compound can be obtained by removing the protective group as necessary.
In addition, the prodrug of the compound selected from the group (I) is selected from the group (I) obtained by introducing a specific group at the stage from the raw material to the intermediate, as in the case of the protecting group. It can be produced by further reacting with a compound. The reaction can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.
(I)の群より選択される化合物は、遊離化合物、その塩、水和物、溶媒和物、あるいは結晶多形の物質として単離され、精製される。(I)の群より選択される化合物の塩は、常法の造塩反応に付すことにより製造することもできる。
単離、精製は、抽出、分別結晶化、各種分画クロマトグラフィー等、通常の化学操作を適用して行なわれる。
各種の異性体は、適当な原料化合物を選択することにより製造でき、あるいは異性体間の物理化学的性質の差を利用して分離することができる。例えば、光学異性体は、ラセミ体の一般的な光学分割法(例えば、光学活性な塩基又は酸とのジアステレオマー塩に導く分別結晶化や、キラルカラム等を用いたクロマトグラフィー等)により得られ、また、適当な光学活性な原料化合物から製造することもできる。The compound selected from the group (I) is isolated and purified as a free compound, a salt thereof, a hydrate, a solvate, or a polymorphic substance. A salt of a compound selected from the group (I) can also be produced by subjecting it to a conventional salt formation reaction.
Isolation and purification are performed by applying ordinary chemical operations such as extraction, fractional crystallization, and various fractional chromatography.
Various isomers can be produced by selecting an appropriate raw material compound, or can be separated by utilizing a difference in physicochemical properties between isomers. For example, optical isomers can be obtained by general optical resolution of racemates (for example, fractional crystallization leading to diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.). Further, it can also be produced from a suitable optically active raw material compound.
(I)の群より選択される化合物の薬理活性は、以下の試験により確認した。
試験例1 (I)の群より選択される化合物のヒトLPA1に対するアンタゴニスト作用
ヒトLPA1に対するアンタゴニスト作用は、ヒトLPA1-CHO細胞[CHO(dhfr遺伝子欠損)細胞株にヒトLPA1受容体を安定発現させた細胞]を用いてLPA刺激による細胞内カルシウムイオン濃度上昇に対する抑制作用を指標に評価した。
ヒトLPA1-CHO細胞の作製は基本的な遺伝子工学的手法に基づき作製した。
作製した細胞は核酸不含有α-MEM培地(invitrogen社)に10% FBS、1% penicillin/streptomycin(Invitrogen社)および100 nM Methotrexateを添加した培地にて維持継代し、実験に際しては実験前日にFBS濃度を1%に低下させた上記培地に置換した後、1.5×10e5 cells/100μL/wellとなるよう96穴プレートに播種し、一晩培養した。
実験当日、細胞に0.5μM Fluo-4溶液 [Hanks Balanced Solt Solution (Invitrogen社)に20 mM HEPES (Sigma社)、250 mM probenecid(ナカライテスク)、0.05% BSA、0.5μM Fluo-4 AM (同仁化学)および0.1% pluronic F217(Molecular Probe社)を加えたもの]を添加し,室温にて2時間処置することにより細胞にFluo-4を負荷した。
Fluo-4負荷後、Fluo-4溶液を反応溶液[Hanks Balanced Solt Solution に20 mM HEPES、250 mM probenecidおよび0.05% BSAを添加したもの]に置換し、以後、細胞内カルシウム濃度測定装置(FLIPR tetra、Molecular Devices社)を用いて測定を実施した。
(I)の群より選択される化合物(終濃度0.1 nM〜10μM)を溶解した反応溶液を各ウェルに添加し、4分間経時的にシグナルを測定したのち、LPA (終濃度100 nM)を溶解した反応溶液を添加し、シグナルを2分間経時的に測定した。LPA添加時から1分間の反応の最大値と最小値の差を計算し、LPAのみ添加(化合物を含まない)した時の応答を0%阻害、化合物ならびにLPAのいずれも含まない反応溶液を添加した時の応答を100%阻害として阻害活性を算出し、50%阻害する濃度をIC50値(nM)として算出した。結果を表1に示す。
尚、本試験におけるヒトLPA1-CHO細胞は、国際公開第WO99/19513号パンフレットのSequence NO.1に記載された配列と同一の配列、あるいは、Biochemical and Biophysical Research Communications 1997年231号619-622頁に記載の配列と同一の配列を有する細胞を用いた。尚、Exは、後記実施例番号を示す。The pharmacological activity of the compound selected from the group (I) was confirmed by the following test.
Test Example 1 Antagonism against human LPA1 of a compound selected from group (I) The human LPA1 receptor was stably expressed in human LPA1-CHO cells [CHO (dhfr gene deficient) cell line] Cell] was used to evaluate the inhibitory effect of LPA stimulation on the increase in intracellular calcium ion concentration.
Human LPA1-CHO cells were prepared based on basic genetic engineering techniques.
The prepared cells were maintained and passaged in a medium containing 10% FBS, 1% penicillin / streptomycin (Invitrogen) and 100 nM Methotrexate in α-MEM medium (invitrogen) without nucleic acid. After substituting the above medium with the FBS concentration reduced to 1%, the medium was seeded in a 96-well plate at 1.5 × 10e 5 cells / 100 μL / well and cultured overnight.
On the day of the experiment, 0.5 μM Fluo-4 solution [Hanks Balanced Solt Solution (Invitrogen) in 20 mM HEPES (Sigma), 250 mM probenecid (Nacalai Tesque), 0.05% BSA, 0.5 μM Fluo-4 AM (Dojin Chemical) And 0.1% pluronic F217 (Molecular Probe)] were added, and the cells were loaded with Fluo-4 by treatment at room temperature for 2 hours.
After loading with Fluo-4, the Fluo-4 solution was replaced with the reaction solution [Hanks Balanced Solt Solution with 20 mM HEPES, 250 mM probenecid and 0.05% BSA added], and then the intracellular calcium concentration measuring device (FLIPR tetra , Molecular Devices).
A reaction solution in which a compound selected from the group (I) (final concentration 0.1 nM to 10 μM) is dissolved is added to each well, the signal is measured over time for 4 minutes, and then LPA (final concentration 100 nM) is dissolved. The reaction solution was added and the signal was measured over time for 2 minutes. Calculate the difference between the maximum and minimum reaction values for 1 minute from the addition of LPA, and inhibit 0% of the response when LPA alone is added (without compound). Add reaction solution containing neither compound nor LPA The inhibitory activity was calculated with the response at the time of 100% inhibition, and the concentration at which 50% inhibition was performed was calculated as the IC 50 value (nM). The results are shown in Table 1.
The human LPA1-CHO cells in this test are the same sequences as those described in Sequence No. 1 of International Publication No. WO99 / 19513, or Biochemical and Biophysical Research Communications 1997 No. 231, pages 619-622. Cells having the same sequence as described in 1. were used. Ex represents an example number described later.
雄性Wistarラット(チャールズリバー社、使用時9-12週齡)をウレタン(1.2g/kg ip)により麻酔し、37℃に保温した手術台上に仰臥位に保定する。下腹部を正中切開し膀胱を露出、膀胱頂部に小切開を加えマイクロチップ圧トランスデューサ(Millar)を順行性に挿入し、尿道内に留置して、尿道内圧を連続的に記録する。また、大腿静脈には薬物投与用のカニューレを留置した。約1時間の安定化後、(I)の群より選択される化合物を静脈内投与(0.1 mg/kg)し、5分後にLPA (1-oleoyl) 3mg/kgを静脈内投与し尿道内圧の変化を記録する。(I)の群より選択される化合物の溶媒投与時のLPA刺激による尿道内圧上昇に対する化合物の抑制率(%)を記録する。
試験例3 ex vivoバイオアッセイ法を用いたラットにおける(I)の群より選択される化合物投与後の血漿中濃度の推定(経口投与2時間後)
ラットにおける(I)の群より選択される化合物投与後の血漿中濃度の推定はバイオアッセイ法によって行える。すなわち雄性Wistarラット(チャールズリバー社、6週齡、絶食下)に被試験化合物を経口投与し、一定時間経過後眼窩底静脈叢より採血し血漿を得る。血漿中より化合物を抽出し、抽出した化合物を一定量のDMSOに溶解する。また、検量線作成用として各種濃度の化合物を溶解した血漿を別途調製し同様の抽出操作を行う。
上記のDMSO抽出液のLPA1発現細胞におけるLPA刺激による細胞内カルシウムイオン濃度上昇に対する抑制作用を測定し、作成した検量線から化合物投与個体における投与後の血漿中濃度を推定する。
Male Wistar rats (Charles River, 9-12 weeks old when used) are anesthetized with urethane (1.2 g / kg ip) and kept in a supine position on an operating table kept at 37 ° C. A midline incision is made in the lower abdomen, the bladder is exposed, a small incision is made in the top of the bladder, a microchip pressure transducer (Millar) is inserted antegradely, and it is placed in the urethra, and the intraurethral pressure is continuously recorded. In addition, a cannula for drug administration was placed in the femoral vein. After stabilization for about 1 hour, a compound selected from the group (I) is intravenously administered (0.1 mg / kg), and 5 minutes later, LPA (1-oleoyl) 3 mg / kg is intravenously administered to reduce the urethral pressure. Record changes. Record the inhibition rate (%) of the compound against the increase in intraurethral pressure by LPA stimulation at the time of solvent administration of the compound selected from the group (I).
Test Example 3 Estimation of plasma concentration after administration of a compound selected from group (I) in rats using ex vivo bioassay (2 hours after oral administration)
The estimation of plasma concentration after administration of a compound selected from the group (I) in rats can be performed by a bioassay method. That is, a test compound is orally administered to male Wistar rats (Charles River, 6 weeks old, fasted), and blood is collected from the orbital venous plexus after a certain period of time to obtain plasma. A compound is extracted from plasma, and the extracted compound is dissolved in a certain amount of DMSO. For the preparation of a calibration curve, plasma in which various concentrations of compounds are dissolved is separately prepared and subjected to the same extraction operation.
The inhibitory effect of the DMSO extract on the increase in intracellular calcium ion concentration by LPA stimulation in LPA1-expressing cells is measured, and the plasma concentration after administration in the compound-administered individual is estimated from the prepared calibration curve.
試験例4 (1)の群より選択される化合物のラット体内動態(PK)試験
実験動物は、投与前日から投与後6時間まで絶食および投与直前から投与後6時間まで絶水させた、雄性SDラットを用いた。
被験物質はN,N-ジメチルホルムアミド, ポリエチレングリコール等を含有する可溶化溶液に溶解して投与した。投与は、経口投与の場合は経口ゾンデを用いて強制経口投与 (1mg/5mL/kg) し、静脈内投与の場合は尾静脈あるいは予めカニュレーションを施した総頚静脈あるいは大腿静脈に投与 (1mg/1mL/kg) した。投与後所定の時点において、抗凝固剤(ヘパリン等)存在下にて全血を各時点最大250μL採取した。採血は経口投与の場合投与後0.25, 0.5, 1, 2, 4, 6, 24時間、静脈内投与の場合は投与後 0.1, 0.25, 0.5, 1, 2, 4, 6, 24時間の時点で行った。採血は眼窩底静脈叢、予め施した大腿動脈カニューレあるいは尾静脈より行った。
採取した血液は氷冷下で保存した後、遠心分離操作により血漿を得た。得られた血漿中の被験物質濃度は、LC/MSにて測定し算出した。その結果、例えば、1 mg/kg経口投与時における、実施例19の化合物のCmax(最高血漿中濃度)は、108 (ng/mL)であり、AUC(血漿中濃度-時間曲線下面積)は、782 (ng・h/mL)であり、BA(バイオアベイラビリティ)は、90 (%)であった。Test Example 4 Rat Pharmacokinetics (PK) Test of a Compound Selected from Group (1) Male SD was fasted from the day before administration to 6 hours after administration, and water was stopped from immediately before administration to 6 hours after administration. Rats were used.
The test substance was administered after being dissolved in a solubilizing solution containing N, N-dimethylformamide, polyethylene glycol and the like. For oral administration, oral gavage is used (1 mg / 5 mL / kg) using an oral sonde, and for intravenous administration, it is administered to the tail vein or the precannulated common jugular vein or femoral vein (1 mg / 1 mL / kg). At predetermined time points after administration, a maximum of 250 μL of whole blood was collected at each time point in the presence of an anticoagulant (such as heparin). Blood sampling is 0.25, 0.5, 1, 2, 4, 6, 24 hours after administration for oral administration, and 0.1, 0.25, 0.5, 1, 2, 4, 6, 24 hours after administration for intravenous administration. went. Blood was collected from the orbital floor venous plexus, the femoral artery cannula or tail vein previously applied.
The collected blood was stored under ice cooling, and then plasma was obtained by centrifugation. The test substance concentration in the obtained plasma was measured and calculated by LC / MS. As a result, for example, the C max (maximum plasma concentration) of the compound of Example 19 at the time of oral administration of 1 mg / kg was 108 (ng / mL), and AUC (area under the plasma concentration-time curve) Was 782 (ng · h / mL), and BA (bioavailability) was 90 (%).
上記試験の結果、(I)の群より選択される化合物は優れたLPA受容体拮抗作用を有することが確認された。また、(I)の群より選択される化合物のうちいくつかは、優れた経口吸収性を有することも確認された。よって、LPAにより引き起こされる疾患の治療等に使用できる。 As a result of the above test, it was confirmed that the compound selected from the group (I) has an excellent LPA receptor antagonistic action. It was also confirmed that some of the compounds selected from the group (I) have excellent oral absorbability. Therefore, it can be used for the treatment of diseases caused by LPA.
(I)の群より選択される化合物又はその塩の1種又は2種以上を有効成分として含有する医薬組成物は、当分野において通常用いられている賦形剤、即ち、薬剤用賦形剤や薬剤用担体等を用いて、通常使用されている方法によって調製することができる。
投与は錠剤、丸剤、カプセル剤、顆粒剤、散剤、液剤等による経口投与、又は、関節内、静脈内、筋肉内等の注射剤、坐剤、点眼剤、眼軟膏、経皮用液剤、軟膏剤、経皮用貼付剤、経粘膜液剤、経粘膜貼付剤、吸入剤等による非経口投与のいずれの形態であってもよい。A pharmaceutical composition containing, as an active ingredient, one or more compounds selected from the group (I) or a salt thereof is an excipient usually used in the art, that is, a pharmaceutical excipient It can be prepared by a commonly used method using a drug carrier or the like.
Administration is orally by tablets, pills, capsules, granules, powders, liquids, etc. Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, and an inhalant may be used.
経口投与のための固体組成物としては、錠剤、散剤、顆粒剤等が用いられる。このような固体組成物においては、1種又は2種以上の有効成分を、少なくとも1種の不活性な賦形剤と混合される。組成物は、常法に従って、不活性な添加剤、例えば滑沢剤や崩壊剤、安定化剤、溶解補助剤を含有していてもよい。錠剤又は丸剤は必要により糖衣又は胃溶性若しくは腸溶性物質のフィルムで被膜してもよい。
経口投与のための液体組成物は、薬剤的に許容される乳濁剤、溶液剤、懸濁剤、シロップ剤又はエリキシル剤等を含み、一般的に用いられる不活性な希釈剤、例えば精製水又はエタノールを含む。当該液体組成物は不活性な希釈剤以外に可溶化剤、湿潤剤、懸濁剤のような補助剤、甘味剤、風味剤、芳香剤、防腐剤を含有していてもよい。As a solid composition for oral administration, tablets, powders, granules and the like are used. In such solid compositions, one or more active ingredients are mixed with at least one inert excipient. The composition may contain an inert additive such as a lubricant, a disintegrant, a stabilizer and a solubilizing agent according to a conventional method. If necessary, tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. Or it contains ethanol. The liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances and preservatives in addition to the inert diluent.
非経口投与のための注射剤は、無菌の水性又は非水性の溶液剤、懸濁剤又は乳濁剤を含有する。水性の溶剤としては、例えば注射用蒸留水又は生理食塩液が含まれる。非水性の溶剤としては、例えばエタノールのようなアルコール類がある。このような組成物は、さらに等張化剤、防腐剤、湿潤剤、乳化剤、分散剤、安定化剤、又は溶解補助剤を含んでもよい。これらは例えばバクテリア保留フィルターを通す濾過、殺菌剤の配合又は照射によって無菌化される。また、これらは無菌の固体組成物を製造し、使用前に無菌水又は無菌の注射用溶媒に溶解又は懸濁して使用することもできる。 Injections for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of the aqueous solvent include distilled water for injection or physiological saline. Non-aqueous solvents include alcohols such as ethanol. Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
外用剤としては、軟膏剤、硬膏剤、クリーム剤、ゼリー剤、パップ剤、噴霧剤、ローション剤、点眼剤、眼軟膏等を包含する。一般に用いられる軟膏基剤、ローション基剤、水性又は非水性の液剤、懸濁剤、乳剤等を含有する。 External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like. Contains commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like.
吸入剤や経鼻剤等の経粘膜剤は固体、液体又は半固体状のものが用いられ、従来公知の方法に従って製造することができる。例えば公知の賦形剤や、更に、pH調整剤、防腐剤、界面活性剤、滑沢剤、安定剤や増粘剤等が適宜添加されていてもよい。投与は、適当な吸入又は吹送のためのデバイスを使用することができる。例えば、計量投与吸入デバイス等の公知のデバイスや噴霧器を使用して、化合物を単独で又は処方された混合物の粉末として、もしくは医薬的に許容し得る担体と組み合わせて溶液又は懸濁液として投与することができる。乾燥粉末吸入器等は、単回又は多数回の投与用のものであってもよく、乾燥粉末又は粉末含有カプセルを利用することができる。あるいは、適当な駆出剤、例えば、クロロフルオロアルカン又は二酸化炭素等の好適な気体を使用した加圧エアゾールスプレー等の形態であってもよい。 Transmucosal agents such as inhalants and nasal agents are used in solid, liquid or semi-solid form and can be produced according to conventionally known methods. For example, known excipients, and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added. For administration, an appropriate device for inhalation or insufflation can be used. For example, using a known device such as a metered dose inhalation device or a nebulizer, the compound is administered alone or as a powder in a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier. be able to. The dry powder inhaler or the like may be for single or multiple administration, and a dry powder or a powder-containing capsule can be used. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as chlorofluoroalkane or carbon dioxide.
通常経口投与の場合、1日の投与量は、体重当たり約0.001〜100 mg/kg、好ましくは0.1〜30 mg/kg、更に好ましくは0.1〜10 mg/kgが適当であり、これを1回であるいは2回〜4回に分けて投与する。静脈内投与される場合は、1日の投与量は、体重当たり約0.0001〜10 mg/kgが適当で、1日1回〜複数回に分けて投与する。また、経粘膜剤としては、体重当たり約0.001〜100 mg/kgを1日1回〜複数回に分けて投与する。投与量は症状、年令、性別等を考慮して個々の場合に応じて適宜決定される。 In general, in the case of oral administration, the appropriate daily dose is about 0.001 to 100 mg / kg, preferably 0.1 to 30 mg / kg, more preferably 0.1 to 10 mg / kg per body weight. Or in 2 to 4 divided doses. In the case of intravenous administration, the daily dose is appropriately about 0.0001 to 10 mg / kg per body weight, and is administered once a day or divided into multiple times. In addition, as a transmucosal agent, about 0.001 to 100 mg / kg per body weight is administered once to several times a day. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.
(I)の群より選択される化合物は、前述の(I)の群より選択される化合物が有効性を示すと考えられる疾患の種々の治療剤又は予防剤と併用することができる。当該併用は、同時投与、或いは別個に連続して、若しくは所望の時間間隔をおいて投与してもよい。同時投与製剤は、配合剤であっても別個に製剤化されていてもよい。 The compound selected from the group (I) can be used in combination with various therapeutic agents or preventive agents for diseases for which the compound selected from the group (I) is considered effective. The combination may be administered simultaneously, separately separately, or at desired time intervals. The simultaneous administration preparation may be a compounding agent or may be separately formulated.
以下、実施例に基づき、(I)の群より選択される化合物の製造法をさらに詳細に説明する。なお、本発明は、以下に示される具体的実施例及び製造例の製造法のみに限定されるものではなく、(I)の群より選択される化合物はこれらの製造法の組み合わせ、あるいは当業者に自明である方法によっても製造されうる。 Hereinafter, based on an Example, the manufacturing method of the compound selected from the group of (I) is demonstrated in detail. The present invention is not limited only to the production methods of the specific examples and production examples shown below, and the compound selected from the group (I) may be a combination of these production methods or a person skilled in the art. It can also be produced by methods that are self-evident.
尚、実施例、製造例及び後記表中において、以下の記号を用いる場合がある。
Rf:製造例番号、
Ex:実施例番号、
Data:物理化学的データ、
ESI+:ESI-MS(陽イオン)におけるm/z値を示し、特に明記する場合を除き[M+H]+ピークを示す、
ESI-:ESI-MS(陰イオン)におけるm/z値を示し、特に明記する場合を除き[M-H]-ピークを示す、
APCI+:APCI-MS(陽イオン)におけるm/z値を示し、特に明記する場合を除き[M+H]+ピークを示す、
FAB+:FAB-MS(陽イオン)におけるm/z値を示し、特に明記する場合を除き[M+H]+ピークを示す、
FAB-:FAB-MS(陰イオン)におけるm/z値を示し、特に明記する場合を除き[M-H]-ピークを示す、
EI+:EI-MS(陽イオン)におけるm/z値を示し、特に明記する場合を除き[M]+ピークを示す、
NMR-DMSO-d6:DMSO-d6中の1H-NMRにおけるδ(ppm)、
NMR-CDCl3:CDCl3中の1H-NMRにおけるδ(ppm)、
Structure:構造式、
Syn:製造法(数字のみの場合は同様に製造した実施例番号を、数字の前にRがある場合は同様に製造した製造例番号をそれぞれ示す。)、
HCl:塩酸塩、
brine:飽和食塩水、
DMSO:ジメチルスルホキシド、
THF:テトラヒドロフラン、
EtOH:エタノール、
DMF:N,N-ジメチルホルムアミド、
MeOH:メタノール、
CHCl3:クロロホルム、
CDI:1,1’-カルボニルジイミダゾール、
DBU:1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エン、
DMAP:4-ジメチルアミノピリジン、
NBS:N-ブロモスクシイミド、
AIBN:2,2'-アゾビス(イソブチロニトリル)、
Pd(PPh3)4:テトラキス(トリフェニルホスフィン)パラジウム(0)、
Zn(CN)2:ジシアノ亜鉛、
HATU:O-(7-アザベンゾトリアゾール-1-イル)-N,N,N',N'-テトラメチルウロニウム ヘキサフルオロホスフェート、
DBAD:ジ-tert-ブチルアゾジカルボキシラート、
MgSO4:無水硫酸マグネシウム、
Na2SO4:無水硫酸ナトリウム、
M:mol/L。Note that the following symbols may be used in Examples, Production Examples, and Tables below.
Rf: Production example number,
Ex: Example number,
Data: Physicochemical data,
ESI +: Shows m / z value in ESI-MS (positive ion), and shows [M + H] + peak unless otherwise specified.
ESI-: ESI-MS showed the m / z value in (anion) Unless otherwise specified [MH] - a peak,
APCI +: Shows the m / z value in APCI-MS (positive ion), showing [M + H] + peak unless otherwise specified,
FAB +: Shows m / z value in FAB-MS (positive ion), and shows [M + H] + peak unless otherwise specified.
FAB-: FAB-MS showed the m / z value in (anion) Unless otherwise specified [MH] - a peak,
EI +: Shows m / z value in EI-MS (positive ion), showing [M] + peak unless otherwise specified,
NMR-DMSO-d 6 : δ (ppm) in 1 H-NMR in DMSO-d 6
NMR-CDCl 3 : δ (ppm) in 1 H-NMR in CDCl 3
Structure:
Syn: Production method (in the case of only numbers, the example number produced in the same manner is indicated, and in the case where R precedes the number, the production example number produced in the same manner is indicated),
HCl: hydrochloride,
brine: saturated saline,
DMSO: dimethyl sulfoxide,
THF: tetrahydrofuran,
EtOH: ethanol,
DMF: N, N-dimethylformamide,
MeOH: methanol,
CHCl 3 : chloroform,
CDI: 1,1′-carbonyldiimidazole,
DBU: 1,8-diazabicyclo [5.4.0] undec-7-ene,
DMAP: 4-dimethylaminopyridine,
NBS: N-bromosuccinimide,
AIBN: 2,2'-azobis (isobutyronitrile),
Pd (PPh 3 ) 4 : tetrakis (triphenylphosphine) palladium (0),
Zn (CN) 2 : dicyanozinc,
HATU: O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate,
DBAD: di-tert-butylazodicarboxylate,
MgSO 4 : anhydrous magnesium sulfate,
Na 2 SO 4 : anhydrous sodium sulfate,
M: mol / L.
製造例1
1-(5-メトキシピリジン-2-イル)シクロプロパンカルボニトリル(100 mg)及び5 M水酸化カリウム水溶液(2 mL)をエチレングリコール(2 mL)に加え、120℃で終夜加熱した。反応混合物に適量の氷水を注ぎ、更に1 M塩酸を加え弱酸性とした後、酢酸エチルで抽出した。有機層をbrineで洗浄し、Na2SO4で乾燥後、減圧下濃縮することより、1-(5-メトキシピリジン-2-イル)シクロプロパンカルボン酸(55 mg)を製造した。Production Example 1
1- (5-Methoxypyridin-2-yl) cyclopropanecarbonitrile (100 mg) and 5 M aqueous potassium hydroxide solution (2 mL) were added to ethylene glycol (2 mL), and the mixture was heated at 120 ° C. overnight. An appropriate amount of ice water was poured into the reaction mixture, and the mixture was made weakly acidic by adding 1 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure to produce 1- (5-methoxypyridin-2-yl) cyclopropanecarboxylic acid (55 mg).
製造例2
2-(クロロメチル)-5-メトキシピリジン(125 mg)をDMSO(5 mL)に加え、続いて、シアン化カリウム水溶液(シアン化カリウム(155 mg)、水(1 mL))を添加し、室温で終夜攪拌した。反応混合物に氷冷下で適量の精製水を注ぎ、酢酸エチルで抽出した。得られた有機層を精製水及びbrineで順次洗浄し、MgSO4で乾燥後、溶媒を減圧留去することより(5-メトキシピリジン-2-イル)アセトニトリル(110 mg)を製造した。Production Example 2
2- (Chloromethyl) -5-methoxypyridine (125 mg) was added to DMSO (5 mL), followed by aqueous potassium cyanide (potassium cyanide (155 mg), water (1 mL)) and stirred at room temperature overnight. did. An appropriate amount of purified water was poured into the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with purified water and brine, dried over MgSO 4 , and the solvent was evaporated under reduced pressure to produce (5-methoxypyridin-2-yl) acetonitrile (110 mg).
製造例3
(5-メトキシピリジン-2-イル)アセトニトリル(0.11 mg)、1-ブロモ-2-クロロエタン(0.2 mL)及びN-ベンジル-N,N,N-トリエチルアンモニウムクロリド(20 mg)の混合物に、氷冷下で50%水酸化ナトリウム水溶液(2 mL)をゆっくり滴下し、室温で約5時間攪拌した。反応混合物に氷水を注ぎ、ジエチルエーテルで抽出した。有機層をbrineで洗浄し、Na2SO4で乾燥後、減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=1:2)で精製し、白色固体の1-(5-メトキシピリジン-2-イル)シクロプロパンカルボニトリル(100 mg)を製造した。Production Example 3
To a mixture of (5-methoxypyridin-2-yl) acetonitrile (0.11 mg), 1-bromo-2-chloroethane (0.2 mL) and N-benzyl-N, N, N-triethylammonium chloride (20 mg), add ice. A 50% aqueous sodium hydroxide solution (2 mL) was slowly added dropwise under cooling, and the mixture was stirred at room temperature for about 5 hours. Ice water was poured into the reaction mixture and extracted with diethyl ether. The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to produce 1- (5-methoxypyridin-2-yl) cyclopropanecarbonitrile (100 mg) as a white solid.
製造例4
エチル 2-メチル-1,3-チアゾール-4-カルボキシラート(10 g)をアセトニトリル(100 mL)に加え、続いて、NBS (11.4 g)を添加し、加熱還流下で3時間攪拌した。反応混合物にNBS (5.0 g)を加え、加熱還流下で2時間攪拌後、さらにNBS (5.0 g)を加え、同条件下で約12時間攪拌した。反応混合物に冷却下で適量の飽和炭酸水素ナトリウム水溶液をゆっくり注ぎ、酢酸エチルで抽出した。有機層をbrineにて洗浄し、MgSO4で乾燥後、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=3:2)により精製し、エチル 5-ブロモ-2-メチル-1,3-チアゾール-4-カルボキシラート(8.86 g)を製造した。Production Example 4
Ethyl 2-methyl-1,3-thiazole-4-carboxylate (10 g) was added to acetonitrile (100 mL), followed by NBS (11.4 g), and the mixture was stirred for 3 hours under heating to reflux. NBS (5.0 g) was added to the reaction mixture, and the mixture was stirred for 2 hours under heating to reflux, then NBS (5.0 g) was further added, and the mixture was stirred for about 12 hours under the same conditions. An appropriate amount of saturated aqueous sodium hydrogen carbonate solution was slowly poured into the reaction mixture under cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO 4 and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to produce ethyl 5-bromo-2-methyl-1,3-thiazole-4-carboxylate (8.86 g).
製造例5
エチル 5-ブロモ-2-メチル-1,3-チアゾール-4-カルボキシラート(6.84 g)を四塩化炭素(114 mL)に加え、続いて、NBS (5.35 g)及びAIBN (2.25 g)を加えて、約90℃で2時間攪拌後、NBS (5.0 g)及びAIBN (0.9 g)を追加し、更に1時間加熱還流した。反応混合物を放冷後、不溶物をろ去し、ろ液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=3:2)により精製し、エチル 5-ブロモ-2-(ブロモメチル)-1,3-チアゾール-4-カルボキシラート(5.55 g)を製造した。Production Example 5
Ethyl 5-bromo-2-methyl-1,3-thiazole-4-carboxylate (6.84 g) was added to carbon tetrachloride (114 mL), followed by NBS (5.35 g) and AIBN (2.25 g). After stirring at about 90 ° C. for 2 hours, NBS (5.0 g) and AIBN (0.9 g) were added, and the mixture was further heated to reflux for 1 hour. The reaction mixture was allowed to cool, insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to produce ethyl 5-bromo-2- (bromomethyl) -1,3-thiazole-4-carboxylate (5.55 g). did.
製造例6
エチル 2-メチル-1,3-チアゾール-4-カルボキシラート(10 g)を氷冷下でDMF (100 mL)に加え、続いて、トリクロロイソシアヌル酸(13.6 g)を徐々に加えて、室温にて終夜攪拌した。その後、さらに当量のトリクロロイソシアヌル酸を数回に分けて添加しながら1日間室温攪拌した。反応混合物中の不溶物をセライトろ過によりろ去し、ろ液に適量の1 M水酸化ナトリウム水溶液を含む氷水を加え、酢酸エチルで抽出した。有機層をbrineにて洗浄し、MgSO4で乾燥後、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=7:3→1:1)により精製し、エチル 5-クロロ-2-メチル-1,3-チアゾール-4-カルボキシラート(6.7 g)を製造した。Production Example 6
Ethyl 2-methyl-1,3-thiazole-4-carboxylate (10 g) was added to DMF (100 mL) under ice cooling, followed by the slow addition of trichloroisocyanuric acid (13.6 g) to room temperature. And stirred overnight. Thereafter, the mixture was further stirred at room temperature for 1 day while adding an equivalent amount of trichloroisocyanuric acid in several portions. Insoluble matters in the reaction mixture were removed by filtration through Celite, ice water containing an appropriate amount of 1 M aqueous sodium hydroxide solution was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO 4 and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3 → 1: 1), and ethyl 5-chloro-2-methyl-1,3-thiazole-4-carboxylate (6.7 g) Manufactured.
製造例7
エチル 2-(ジエトキシメチル)-5-メチル-1,3-チアゾール-4-カルボキシラート(12.1g)をアセトン(300 mL)に加え、続いて、1 M塩酸(150mL)を加えて、55℃にて約5時間攪拌した。反応混合物を濃縮し、適量の飽和炭酸水素ナトリウム水溶液を加えて中和した後、酢酸エチルで数回抽出した。有機層をMgSO4で乾燥し、溶媒を減圧留去し、エチル 2-ホルミル-5-メチル-1,3-チアゾール-4-カルボキシラート(8.25 g)を製造した。Production Example 7
Ethyl 2- (diethoxymethyl) -5-methyl-1,3-thiazole-4-carboxylate (12.1 g) was added to acetone (300 mL), followed by 1 M hydrochloric acid (150 mL). Stir at about 5 hours. The reaction mixture was concentrated, neutralized with an appropriate amount of saturated aqueous sodium hydrogen carbonate solution, and extracted several times with ethyl acetate. The organic layer was dried over MgSO 4 and the solvent was distilled off under reduced pressure to produce ethyl 2-formyl-5-methyl-1,3-thiazole-4-carboxylate (8.25 g).
製造例8
2,2-ジエトキシエタンチオアミド(9.21 g)、炭酸カルシウム(3.39 g)及び適量の粉末モレキュラーシーブ(4Å、薬さじ2杯程度)をEtOH (220 mL)に加え、続いて、Plouvierらの方法(Heterocycles, 1991 32, 693.)により調製した3-ブロモ-2-オキソブタン酸エチル(13.1 g)を約5分かけて滴下し、室温で約30分間攪拌した。その後、55℃にて更に約6時間加温した。反応混合物を放冷後、不溶物をろ去し、ろ液を減圧下濃縮した。得られた残渣に適量の水を加え、酢酸エチルで2回抽出した。有機層をbrine洗浄し、MgSO4で乾燥後、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=7:3)により精製し、エチル 2-(ジエトキシメチル)-5-メチル-1,3-チアゾール-4-カルボキシラート(12.1 g)を製造した。Production Example 8
2,2-diethoxyethanethioamide (9.21 g), calcium carbonate (3.39 g) and an appropriate amount of powdered molecular sieve (4 kg, about 2 tablespoons) are added to EtOH (220 mL), followed by the method of Plouvier et al. Ethyl 3-bromo-2-oxobutanoate (13.1 g) prepared by (Heterocycles, 1991 32, 693.) was added dropwise over about 5 minutes and stirred at room temperature for about 30 minutes. Thereafter, the mixture was further heated at 55 ° C. for about 6 hours. The reaction mixture was allowed to cool, insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. An appropriate amount of water was added to the resulting residue, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with brine and dried over MgSO 4 , and then the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3), and ethyl 2- (diethoxymethyl) -5-methyl-1,3-thiazole-4-carboxylate (12.1 g) Manufactured.
製造例9
3-フェニルプロパン-1-アミン(1.3 g)を塩化メチレン(30 mL)に加え、続いて、エチル 2-ホルミル-5-メチル-1,3-チアゾール-4-カルボキシラート(1.2 g)及び酢酸(1.5 mL)を順次添加し、室温で約20分間攪拌した。その後、氷冷下で、トリアセトキシ水素化ホウ素ナトリウム(2.69 g)を添加し、約1時間室温攪拌した。反応混合物にCHCl3を加え、さらに適量の飽和炭酸水素ナトリウム水溶液を加えて、攪拌した後、分液した。有機層をMgSO4にて乾燥後、溶媒を減圧留去した。得られた黄色油状物をシリカゲルカラムクロマトグラフィー(CHCl3:MeOH=250:1)にて精製し、エチル 5-メチル-2-{[(3-フェニルプロピル)アミノ]メチル}-1,3-チアゾール-4-カルボキシラート(1.56 g)を製造した。Production Example 9
Add 3-phenylpropan-1-amine (1.3 g) to methylene chloride (30 mL), followed by ethyl 2-formyl-5-methyl-1,3-thiazole-4-carboxylate (1.2 g) and acetic acid. (1.5 mL) was sequentially added, and the mixture was stirred at room temperature for about 20 minutes. Thereafter, sodium triacetoxyborohydride (2.69 g) was added under ice cooling, and the mixture was stirred for about 1 hour at room temperature. CHCl 3 was added to the reaction mixture, and an appropriate amount of saturated aqueous sodium hydrogen carbonate solution was added, followed by stirring and liquid separation. The organic layer was dried over MgSO 4 and the solvent was distilled off under reduced pressure. The obtained yellow oil was purified by silica gel column chromatography (CHCl 3 : MeOH = 250: 1), and ethyl 5-methyl-2-{[(3-phenylpropyl) amino] methyl} -1,3- Thiazole-4-carboxylate (1.56 g) was prepared.
製造例10
2-フルオロ-4-メトキシベンズアルデヒド(1.0 g)、トリエチルアミン(0.2 mL)及びトリメチルシリルシアニド(0.9 mL)を塩化メチレン(10 mL)に加え、室温で3時間攪拌した。反応混合物を減圧下濃縮し、得られた残渣にEtOH (12 mL)及びクロロトリメチルシラン(12 mL)を加え、室温で終夜攪拌した。反応混合物を放冷後、溶媒を留去した。得られた残渣にジクロロエタン(20 mL)、EtOH (10 mL)、飽和炭酸水素ナトリウム水溶液(20 mL)を注ぎ、室温で約3時間激しく攪拌した。この反応混合物を適量のCHCl3で抽出し、有機層をMgSO4で乾燥後、溶媒を減圧留去して、(2-フルオロ-4-メトキシフェニル)(ヒドロキシ)酢酸エチル(0.67 g)を製造した。
続いて、製造例24の方法と同様にして、(2-フルオロ-4-メトキシフェニル)(ヒドロキシ)酢酸エチル(0.67 g)から(2-フルオロ-4-メトキシフェニル)(ヒドロキシ)酢酸(0.35 g)を製造した。Production Example 10
2-Fluoro-4-methoxybenzaldehyde (1.0 g), triethylamine (0.2 mL) and trimethylsilylcyanide (0.9 mL) were added to methylene chloride (10 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, EtOH (12 mL) and chlorotrimethylsilane (12 mL) were added to the resulting residue, and the mixture was stirred at room temperature overnight. After allowing the reaction mixture to cool, the solvent was distilled off. To the obtained residue, dichloroethane (20 mL), EtOH (10 mL) and saturated aqueous sodium hydrogen carbonate solution (20 mL) were poured, and the mixture was vigorously stirred at room temperature for about 3 hours. The reaction mixture was extracted with an appropriate amount of CHCl 3 , the organic layer was dried over MgSO 4 , and the solvent was distilled off under reduced pressure to produce ethyl (2-fluoro-4-methoxyphenyl) (hydroxy) acetate (0.67 g). did.
Subsequently, in the same manner as in Production Example 24, (2-fluoro-4-methoxyphenyl) (hydroxy) acetic acid ethyl (0.67 g) to (2-fluoro-4-methoxyphenyl) (hydroxy) acetic acid (0.35 g ) Was manufactured.
製造例11
1-(4-ヒドロキシフェニル)シクロプロパンカルボン酸(1.07 g)をEtOH (20 mL)に加え、さらに濃硫酸(0.1 mL)を滴下し、70℃で2日間攪拌した。溶媒を減圧留去し、得られた残渣に飽和炭酸水素ナトリウム水溶液を加え、適量の酢酸エチルで抽出した。有機層をbrine洗浄し、Na2SO4にて乾燥後、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=2:1)により精製し、淡黄色固体の1-(4-ヒドロキシフェニル)シクロプロパンカルボン酸エチル(1.15 g)を製造した。
続いて、1-(4-ヒドロキシフェニル)シクロプロパンカルボン酸エチル(200 mg)、トリフェニルホスフィン(382 mg)及び2-フルオロエタノール(93 mg)をTHFに加え、続いて、氷冷下で、DBAD (335 mg)を加えて、室温で終夜攪拌した。溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=2:1)により精製し、無色油状物の1-[4-(2-フルオロエトキシ)フェニル]シクロプロパンカルボン酸エチル(190 mg)を製造した。
更に、1-[4-(2-フルオロエトキシ)フェニル]シクロプロパンカルボン酸エチル(190 mg)をEtOH/THF (1:1)溶液(10 mL)に加え、続いて、1 M水酸化ナトリウム水溶液(2 mL)を滴下し、室温で終夜攪拌した。反応混合物を減圧下濃縮し、精製水及び1 M塩酸を加えて中性とした後、生じた不溶物をろ取し、白色固体の1-[4-(2-フルオロエトキシ)フェニル]シクロプロパンカルボン酸(152 mg)を製造した。Production Example 11
1- (4-Hydroxyphenyl) cyclopropanecarboxylic acid (1.07 g) was added to EtOH (20 mL), concentrated sulfuric acid (0.1 mL) was further added dropwise, and the mixture was stirred at 70 ° C. for 2 days. The solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the mixture was extracted with an appropriate amount of ethyl acetate. The organic layer was washed with brine and dried over Na 2 SO 4 , and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to produce ethyl 1- (4-hydroxyphenyl) cyclopropanecarboxylate (1.15 g) as a pale yellow solid.
Subsequently, ethyl 1- (4-hydroxyphenyl) cyclopropanecarboxylate (200 mg), triphenylphosphine (382 mg) and 2-fluoroethanol (93 mg) were added to THF, followed by ice cooling, DBAD (335 mg) was added and stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 1- [4- (2-fluoroethoxy) phenyl] cyclopropanecarboxylic acid as a colorless oil. Ethyl acid (190 mg) was prepared.
Furthermore, ethyl 1- [4- (2-fluoroethoxy) phenyl] cyclopropanecarboxylate (190 mg) was added to EtOH / THF (1: 1) solution (10 mL), followed by 1 M aqueous sodium hydroxide solution. (2 mL) was added dropwise and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, neutralized with purified water and 1 M hydrochloric acid, and the resulting insoluble material was collected by filtration to give 1- [4- (2-fluoroethoxy) phenyl] cyclopropane as a white solid. Carboxylic acid (152 mg) was prepared.
製造例12
Johnsonらの方法(Tetrahedron Lett., 2004 45, 8483-8487.)を一部改良して、以下、製造した。
N-ベンジルメタンスルホンアミド(2.0 g)をTHF (40 mL)に加え、続いて、-78℃の冷却下で、1.66 M n-ブチルリチウムのn-ヘキサン溶液(13.1 mL)を滴下し、5分攪拌した後、0℃まで昇温した。反応混合物にアセトアルデヒド(2.4 mL)をTHF (20 mL)に加えて調整した混合物をゆっくり滴下し、室温まで昇温しながら2時間攪拌した。反応混合物に塩化アンモニウム水溶液を加え、CHCl3で抽出し、フェーズセパレーターで水層を分離して、有機層の溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(CHCl3:MeOH=20:1)により精製し、白色固体としてN-ベンジル-2-ヒドロキシプロパン-1-スルホンアミド(1.94 g)を製造した。
続いて、N-ベンジル-2-ヒドロキシプロパン-1-スルホンアミド(1.94 g)、DMAP (0.52 g)、トリエチルアミン(1.77 mL)及びtert-ブチルジメチルクロロシラン(1.91 g)を塩化メチレン(50 mL)に加え、室温で終夜攪拌した。反応混合物に塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層をbrineで洗浄し、MgSO4を加えて乾燥し、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=2:1)により精製し、N-ベンジル-2-{[tert-ブチル(ジメチル)シリル]オキシ}プロパン-1-スルホンアミド(1.84 g)を製造した。
更に、N-ベンジル-2-{[tert-ブチル(ジメチル)シリル]オキシ}プロパン-1-スルホンアミド(1.8 g)及び10%水酸化パラジウム(0.5 g)を酢酸エチル(30 mL)に加え、水素雰囲気下、室温で3時間攪拌した。反応混合物をセライトろ過し、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(CHCl3:MeOH=10:1)により精製し、白色固体として2-{[tert-ブチル(ジメチル)シリル]オキシ}プロパン-1-スルホンアミド(1.04 g)を製造した。Production Example 12
The method of Johnson et al. (Tetrahedron Lett., 2004 45, 8483-8487.) Was partially modified and manufactured as follows.
N-benzylmethanesulfonamide (2.0 g) was added to THF (40 mL), followed by dropwise addition of 1.66 M n-butyllithium in n-hexane (13.1 mL) under cooling at −78 ° C. After stirring for minutes, the temperature was raised to 0 ° C. A mixture prepared by adding acetaldehyde (2.4 mL) to THF (20 mL) was slowly added dropwise to the reaction mixture, and the mixture was stirred for 2 hours while warming to room temperature. An aqueous ammonium chloride solution was added to the reaction mixture, extraction was performed with CHCl 3 , the aqueous layer was separated with a phase separator, and the solvent of the organic layer was distilled off. The obtained residue was purified by silica gel column chromatography (CHCl 3 : MeOH = 20: 1) to produce N-benzyl-2-hydroxypropane-1-sulfonamide (1.94 g) as a white solid.
Subsequently, N-benzyl-2-hydroxypropane-1-sulfonamide (1.94 g), DMAP (0.52 g), triethylamine (1.77 mL) and tert-butyldimethylchlorosilane (1.91 g) were added to methylene chloride (50 mL). In addition, the mixture was stirred overnight at room temperature. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried by adding MgSO 4 and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give N-benzyl-2-{[tert-butyl (dimethyl) silyl] oxy} propane-1-sulfonamide (1.84 g ) Was manufactured.
Further, N-benzyl-2-{[tert-butyl (dimethyl) silyl] oxy} propane-1-sulfonamide (1.8 g) and 10% palladium hydroxide (0.5 g) were added to ethyl acetate (30 mL). The mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (CHCl 3 : MeOH = 10: 1) to give 2-{[tert-butyl (dimethyl) silyl] oxy} propane-1-sulfonamide (1.04 g) as a white solid. Manufactured.
製造例13
tert-ブチル [(4-{[(ジメチルアミノ)スルホニル]カルバモイル}-5-メチル-1,3-チアゾール-2-イル)メチル](3-フェニルプロピル)カルバマート(4.12 g)をジオキサン(30 mL)に加え、続いて、4 M塩酸/ジオキサン溶液(30 mL)を注ぎ、アルゴンガス雰囲気密封下にて、室温で約12時間攪拌した。反応混合物を減圧下濃縮することにより、白色固体のN-(ジメチルスルファモイル)-5-メチル-2-{[(3-フェニルプロピル)アミノ]メチル}-1,3-チアゾール-4-カルボキサミド 塩酸塩(3.4 g)を製造した。Production Example 13
tert-Butyl [(4-{[(dimethylamino) sulfonyl] carbamoyl} -5-methyl-1,3-thiazol-2-yl) methyl] (3-phenylpropyl) carbamate (4.12 g) was added to dioxane (30 mL Then, 4 M hydrochloric acid / dioxane solution (30 mL) was poured, and the mixture was stirred at room temperature for about 12 hours under a sealed argon gas atmosphere. The reaction mixture was concentrated under reduced pressure to give N- (dimethylsulfamoyl) -5-methyl-2-{[(3-phenylpropyl) amino] methyl} -1,3-thiazole-4-carboxamide as a white solid. The hydrochloride (3.4 g) was prepared.
製造例17
2-{[(tert-ブトキシカルボニル)(3-フェニルプロピル)アミノ]メチル}-5-メチル-1,3-チアゾール-4-カルボン酸(4.0 g)を無水THF (120 mL)に加え、続いて、CDI (2.49 g)を加えて、アルゴン雰囲気下、約60℃で1.5時間攪拌した。反応混合物を氷冷し、N,N-ジメチルスルファミド(2.54 g)及びDBU (2.34 g)を順次加え、室温で約13時間攪拌した。反応混合物に適量の1 M塩酸及び氷水を加え、酢酸エチルで数回抽出した。有機層をbrineで洗浄し、MgSO4で乾燥後、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=1:3)で精製し、無色シロップのtert-ブチル [(4-{[(ジメチルアミノ)スルホニル]カルバモイル}-5-メチル-1,3-チアゾール-2-イル)メチル](3-フェニルプロピル)カルバマート(4.12 g)を製造した。
Production Example 17
2-{[(tert-butoxycarbonyl) (3-phenylpropyl) amino ] methyl } -5-methyl-1,3-thiazole-4-carboxylic acid (4.0 g) was added to anhydrous THF (120 mL) followed by Then, CDI (2.49 g) was added, and the mixture was stirred at about 60 ° C. for 1.5 hours under an argon atmosphere. The reaction mixture was ice-cooled, N, N-dimethylsulfamide (2.54 g) and DBU (2.34 g) were sequentially added, and the mixture was stirred at room temperature for about 13 hours. Appropriate amounts of 1 M hydrochloric acid and ice water were added to the reaction mixture, and the mixture was extracted several times with ethyl acetate. The organic layer was washed with brine and dried over MgSO4, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 3), and colorless syrup tert-butyl [(4-{[(dimethylamino) sulfonyl] carbamoyl} -5-methyl-1, 3-Thiazol-2-yl) methyl] (3-phenylpropyl) carbamate (4.12 g) was prepared.
製造例19
エチル 5-メチル-2-{[(3-フェニルプロピル)アミノ]メチル}-1,3-チアゾール-4-カルボキシラート(6.7 g)をTHF (67 mL)に加え、続いて、氷冷下でジ-tert-ブチル-ジカルボナート(4.59 g)を徐々に添加し、約14時間室温で攪拌した。反応混合物を減圧下で濃縮し、得られた無色油状物をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=3:2)にて精製して、エチル 2-{[(tert-ブトキシカルボニル)(3-フェニルプロピル)アミノメチル]メチル}-5-メチル-1,3-チアゾール-4-カルボキシラート(8.34 g)を製造した。Production Example 19
Ethyl 5-methyl-2-{[(3-phenylpropyl) amino] methyl} -1,3-thiazole-4-carboxylate (6.7 g) was added to THF (67 mL) followed by ice cooling. Di-tert-butyl-dicarbonate (4.59 g) was gradually added and stirred at room temperature for about 14 hours. The reaction mixture was concentrated under reduced pressure, and the resulting colorless oil was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to give ethyl 2-{[(tert-butoxycarbonyl) (3- Phenylpropyl) aminomethyl] methyl} -5-methyl-1,3-thiazole-4-carboxylate (8.34 g) was prepared.
製造例24
エチル 2-[([3-(4-フルオロフェニル)プロピル]{[1-(4-メトキシフェニル)シクロプロピル]カルボニル}アミノ)メチル]-5-メチル-1,3-チアゾール-4-カルボキシラート(0.25 g)をTHF/EtOH (2:1)溶液(3 mL)に加え、更に1 M水酸化ナトリウム水溶液(1 mL)を滴下し、室温で約4時間攪拌した。反応混合物中に1 M塩酸(2.5 mL)を含む適量の飽和塩化アンモニウム水溶液及び氷水を注ぎ、酢酸エチルにて2回抽出した。得られた有機層をbrineで洗浄し、MgSO4で乾燥し、溶媒を減圧留去して、白色残渣(0.21 g)を得た。これを少量のジエチルエーテル−ジイソプロピルエーテル(1:1)で固化させ、同溶媒で希釈・洗浄しながら濾取することにより、白色固体の2-[([3-(4-フルオロフェニル)プロピル]{[1-(4-メトキシフェニル)シクロプロピル]カルボニル}アミノ)メチル]-5-メチル-1,3-チアゾール-4-カルボン酸を製造した。Production Example 24
Ethyl 2-[([3- (4-fluorophenyl) propyl] {[1- (4-methoxyphenyl) cyclopropyl] carbonyl} amino) methyl] -5-methyl-1,3-thiazole-4-carboxylate (0.25 g) was added to a THF / EtOH (2: 1) solution (3 mL), a 1 M aqueous sodium hydroxide solution (1 mL) was further added dropwise, and the mixture was stirred at room temperature for about 4 hours. An appropriate amount of saturated aqueous ammonium chloride solution and ice water containing 1 M hydrochloric acid (2.5 mL) were poured into the reaction mixture, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed with brine, dried over MgSO 4 , and the solvent was distilled off under reduced pressure to obtain a white residue (0.21 g). This was solidified with a small amount of diethyl ether-diisopropyl ether (1: 1) and filtered while diluting and washing with the same solvent to give 2-[([3- (4-fluorophenyl) propyl] {[1- (4-Methoxyphenyl) cyclopropyl] carbonyl} amino) methyl] -5-methyl-1,3-thiazole-4-carboxylic acid was prepared.
製造例49
tert-ブチル {[(2-ヒドロキシエチル)(メチル)アミノ]スルホニル}カルバマート(1.1 g)及びトリフルオロ酢酸(2.3 mL)を塩化メチレン(10 mL)に加え、室温で約15時間攪拌した後、溶媒を減圧留去し、淡黄色油状物のN-(2-ヒドロキシエチル)-N-メチルスルファミド(0.66 g)を製造した。Production Example 49
After adding tert-butyl {[(2-hydroxyethyl) (methyl) amino] sulfonyl} carbamate (1.1 g) and trifluoroacetic acid (2.3 mL) to methylene chloride (10 mL) and stirring at room temperature for about 15 hours, The solvent was distilled off under reduced pressure to produce N- (2-hydroxyethyl) -N-methylsulfamide (0.66 g) as a pale yellow oil.
製造例51
エチル 5-ブロモ-2-{[{[1-(4-メトキシフェニル)シクロプロピル]カルボニル}(3-フェニルプロピル)アミノ]メチル}-1,3-チアゾール-4-カルボキシレート(415 mg)をDMF (5.2 mL)に加え、続いて、Pd(PPh3)4 (430 mg)及びZn(CN)2 (110 mg)を順次添加し、120℃で終夜攪拌した。反応混合物を放冷後、適量の氷水を注ぎ酢酸エチルで抽出した。有機層をbrine洗浄しNa2SO4で乾燥後、減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン〜ヘキサン:酢酸エチル=1:1)で精製、これを再度繰り返し精製して、無色油状物のエチル 5-シアノ-2-{[{[1-(4-メトキシフェニル)シクロプロピル]カルボニル}(3-フェニルプロピル)アミノ]メチル}-1,3-チアゾール-4-カルボキシレート(65 mg)を製造した。Production Example 51
Ethyl 5-bromo-2-{[{[1- (4-methoxyphenyl) cyclopropyl] carbonyl} (3-phenylpropyl) amino] methyl} -1,3-thiazole-4-carboxylate (415 mg) In addition to DMF (5.2 mL), Pd (PPh 3 ) 4 (430 mg) and Zn (CN) 2 (110 mg) were sequentially added, and the mixture was stirred at 120 ° C. overnight. After allowing the reaction mixture to cool, an appropriate amount of ice water was poured and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na 2 SO 4 and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane to hexane: ethyl acetate = 1: 1). Colorless oily ethyl 5-cyano-2-{[{[1- (4-methoxyphenyl) cyclopropyl] carbonyl} (3-phenylpropyl) amino] methyl} -1,3-thiazole-4-carboxylate (65 mg) was produced.
製造例53
3-フェニルプロパン-1-アミン(1.46 g)及び炭酸カリウム(1.64 g)をアセトニトリル(55 mL)に加え、MeOH氷浴中で、エチル 2-(ブロモメチル)-5-クロロ-1,3-チアゾール-4-カルボキシラート(2.79 g)のアセトニトリル(30 mL)溶液を徐々に滴下し、室温で約4.5時間攪拌した。反応混合物に適量の氷水を加え、酢酸エチルで数回抽出した。有機層をbrineで洗浄し、Na2SO4で乾燥後、溶媒を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(CHCl3:MeOH=100:0〜95:5)にて精製し、エチル 5-クロロ-2-{[(3-フェニルプロピル)アミノ]メチル}-1,3-チアゾール-4-カルボキシラート(3.04 g)を製造した。Production Example 53
Add 3-phenylpropan-1-amine (1.46 g) and potassium carbonate (1.64 g) to acetonitrile (55 mL) and add ethyl 2- (bromomethyl) -5-chloro-1,3-thiazole in a MeOH ice bath. A solution of -4-carboxylate (2.79 g) in acetonitrile (30 mL) was gradually added dropwise, and the mixture was stirred at room temperature for about 4.5 hours. An appropriate amount of ice water was added to the reaction mixture, and the mixture was extracted several times with ethyl acetate. The organic layer was washed with brine and dried over Na 2 SO 4 , and then the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl 3 : MeOH = 100: 0 to 95: 5), and ethyl 5-chloro-2-{[(3-phenylpropyl) amino] methyl} -1, 3-thiazole-4-carboxylate (3.04 g) was prepared.
製造例72
アルゴン雰囲気下、クロロスルホニルイソシアナート(0.52 mL)を塩化メチレン(10 mL)に加えて、MeOH/氷浴で約-10℃まで冷却した。続いて、tert-ブタノール(0.44 g)を滴下し、冷却下で約30分間攪拌した。別途、トリエチルアミン(1.4 mL)および2-(メチルアミノ)エタノール(0.4 mL)を含む適量の塩化メチレン溶液を調製して氷浴中で冷却させ、前記の冷却塩化メチレン溶液を徐々に滴下した後、約30分間室温攪拌した。反応混合物に適量の冷却0.5M塩酸を注ぎ、適量のCHCl3で抽出した。得られた有機層をMgSO4で乾燥させ、溶媒を減圧留去することにより、無色シロップのtert-ブチル {[(2-ヒドロキシエチル)(メチル)アミノ]スルホニル}カルバマート(1.15 g)を製造した。Production Example 72
Under an argon atmosphere, chlorosulfonyl isocyanate (0.52 mL) was added to methylene chloride (10 mL) and cooled to about −10 ° C. in a MeOH / ice bath. Subsequently, tert-butanol (0.44 g) was added dropwise and stirred for about 30 minutes under cooling. Separately, an appropriate amount of methylene chloride solution containing triethylamine (1.4 mL) and 2- (methylamino) ethanol (0.4 mL) was prepared and cooled in an ice bath, and the cooled methylene chloride solution was gradually added dropwise. Stir at room temperature for about 30 minutes. An appropriate amount of cooled 0.5 M hydrochloric acid was poured into the reaction mixture, and the mixture was extracted with an appropriate amount of CHCl 3 . The obtained organic layer was dried over MgSO 4 and the solvent was distilled off under reduced pressure to produce colorless syrup tert-butyl {[(2-hydroxyethyl) (methyl) amino] sulfonyl} carbamate (1.15 g). .
製造例75
エチル 2-({[3-(4-フルオロフェニル)プロピル]アミノ}メチル)-5-メチル-1,3-チアゾール-4-カルボキシレート(200 mg)、1-(4-メトキシフェニル)シクロプロパンカルボン酸 (130 mg)、トリエチルアミン(0.17 mL)及びHATU (280 mg)をDMF (3 mL)に加え、室温で約15時間攪拌した。反応混合物に冷却した塩化アンモニウム水溶液を注ぎ、適量の酢酸エチルで抽出した。有機層を重曹水およびbrineで順次洗浄し、MgSO4で乾燥させた。溶媒を減圧留去して生じた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=3:2)により精製し、黄色油状物のエチル 2-[([3-(4-フルオロフェニル)プロピル]{[1-(4-メトキシフェニル)シクロプロピル]カルボニル}アミノ)メチル]-5-メチル-1,3-チアゾール-4-カルボキシレート(260 mg)を製造した。Production Example 75
Ethyl 2-({[3- (4-fluorophenyl) propyl] amino} methyl) -5-methyl-1,3-thiazole-4-carboxylate (200 mg), 1- (4-methoxyphenyl) cyclopropane Carboxylic acid (130 mg), triethylamine (0.17 mL) and HATU (280 mg) were added to DMF (3 mL), and the mixture was stirred at room temperature for about 15 hours. A cooled aqueous ammonium chloride solution was poured into the reaction mixture, and the mixture was extracted with an appropriate amount of ethyl acetate. The organic layer was washed sequentially with aqueous sodium hydrogen carbonate and brine and dried over MgSO 4 . The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to give ethyl 2-[([3- (4-fluorophenyl) propyl] { [1- (4-Methoxyphenyl) cyclopropyl] carbonyl} amino) methyl] -5-methyl-1,3-thiazole-4-carboxylate (260 mg) was prepared.
製造例93
[4-(メチルスルファニル)フェニル]アセトニトリル(2.5 g)およびN-ベンジル-N,N,N-トリエチルアンモニウムクロリド(0.38 g)をブロモクロロエタン(2.8 mL)に加え、氷冷下で50%水酸化ナトリウム水溶液(15 mL)をゆっくり加えた。反応混合物を40℃で18時間攪拌した。反応混合物に適量の氷水を加え、トルエンで抽出し、有機層をbrineで洗浄、Na2SO4で乾燥後、減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=4:1)により精製し、無色油状物質として1-[4-(メチルスルファニル)フェニル]シクロプロパンカルボニトリル(2.82 g)を製造した。
次に、1-[4-(メチルスルファニル)フェニル]シクロプロパンカルボニトリル(2.82 g)および水酸化カリウム(2.4 g)を精製水(15 mL)およびエチレングリコール(15 mL)の混合溶液に加え、140℃で4時間攪拌した。反応混合物を氷水(100 mL)と6M塩酸(50 mL)の混合溶液に注ぎ、析出した固体をろ取し、減圧下で乾燥して白色固体の1-[4-(メチルスルファニル)フェニル]シクロプロパンカルボン酸(1.09 g)を製造した。Production Example 93
[4- (Methylsulfanyl) phenyl] acetonitrile (2.5 g) and N-benzyl-N, N, N-triethylammonium chloride (0.38 g) were added to bromochloroethane (2.8 mL) and 50% hydroxylated under ice cooling. Aqueous sodium solution (15 mL) was added slowly. The reaction mixture was stirred at 40 ° C. for 18 hours. An appropriate amount of ice water was added to the reaction mixture, and the mixture was extracted with toluene. The organic layer was washed with brine, dried over Na 2 SO 4 and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to produce 1- [4- (methylsulfanyl) phenyl] cyclopropanecarbonitrile (2.82 g) as a colorless oil.
Next, 1- [4- (methylsulfanyl) phenyl] cyclopropanecarbonitrile (2.82 g) and potassium hydroxide (2.4 g) were added to a mixed solution of purified water (15 mL) and ethylene glycol (15 mL). Stir at 140 ° C. for 4 hours. The reaction mixture was poured into a mixed solution of ice water (100 mL) and 6M hydrochloric acid (50 mL), and the precipitated solid was collected by filtration, dried under reduced pressure, and dried as a white solid 1- [4- (methylsulfanyl) phenyl] cyclohexane. Propanecarboxylic acid (1.09 g) was prepared.
製造例95
2-フルオロ-4-ヒドロキシベンズアルデヒド(1.25 g)、トリフェニルホスフィン(3.51 g)および2,2-ジフルオロエタノール(1.1 g)をTHF (25 mL)に加え、氷冷下にてジイソプロピル (E)-ジアゼン-1,2-ジカルボキシレート(2.7 g)を添加した後、室温で終夜攪拌した。反応混合物を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン〜ヘキサン:酢酸エチル=10:1)により精製し、無色油状物の4-(2,2-ジフルオロエトキシ)-2-フルオロベンズアルデヒド(0.5 g)を製造した。Production Example 95
2-Fluoro-4-hydroxybenzaldehyde (1.25 g), triphenylphosphine (3.51 g) and 2,2-difluoroethanol (1.1 g) were added to THF (25 mL), and diisopropyl (E)- Diazene-1,2-dicarboxylate (2.7 g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane to hexane: ethyl acetate = 10: 1) to give 4- (2,2-difluoroethoxy) -2-fluorobenzaldehyde ( 0.5 g) was produced.
製造例96
4-エトキシ-2-フルオロベンズアルデヒド(1.6 g)、トリエチルアミン(0.2 mL)およびトリメチルシランカルボニトリル(1.5 mL)を塩化メチレン(17 mL)に順次加え、室温で終夜攪拌した。反応混合物を減圧下濃縮し、残渣にEtOH (16 mL)、クロロトリメチルシラン(3.6 mL)を加え、室温で終夜攪拌した。反応混合物に適量の飽和炭酸水素ナトリウム水溶液を加え、室温で3時間攪拌した。溶媒を減圧留去し、生じた残渣を適量の酢酸エチルで抽出し、brine洗浄後、Na2SO4で乾燥した。、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン〜ヘキサン:酢酸エチル=2:1)により精製し、白色固体のエチル [4-エトキシ-2-フルオロフェニル](ヒドロキシ)アセテート(1.55 g)を製造した。Production Example 96
4-Ethoxy-2-fluorobenzaldehyde (1.6 g), triethylamine (0.2 mL) and trimethylsilanecarbonitrile (1.5 mL) were sequentially added to methylene chloride (17 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, EtOH (16 mL) and chlorotrimethylsilane (3.6 mL) were added to the residue, and the mixture was stirred at room temperature overnight. An appropriate amount of saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the resulting residue was extracted with an appropriate amount of ethyl acetate, washed with brine, and dried over Na 2 SO 4 . The residue was purified by silica gel column chromatography (hexane to hexane: ethyl acetate = 2: 1) to produce ethyl [4-ethoxy-2-fluorophenyl] (hydroxy) acetate (1.55 g) as a white solid.
製造例99
エチル [4-エトキシ-2-フルオロフェニル](ヒドロキシ)アセテート(1.55 g)、[2-(クロロメトキシ)エチル](トリメチル)シラン(2.3 mL)、ヒューニッヒ塩基(2.2 mL)及びテトラ−n−ブチルアンモニウム ヨージド(4.73 g)を塩化メチレン(15.5 mL)に順次加え、室温で終夜攪拌した。反応混合物を減圧下濃縮し、適量の精製水を加え、酢酸エチルで抽出後、brineで洗浄し、Na2SO4で乾燥させた。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン〜ヘキサン:酢酸エチル=5:1)により精製し、無色油状物のエチル (4-エトキシ-2-フルオロフェニル){[2-(トリメチルシリル)エトキシ]メトキシ}アセテート(1.55 g)を製造した。Production Example 99
Ethyl [4-ethoxy-2-fluorophenyl] (hydroxy) acetate (1.55 g), [2- (chloromethoxy) ethyl] (trimethyl) silane (2.3 mL), Hunig base (2.2 mL) and tetra-n-butyl Ammonium iodide (4.73 g) was sequentially added to methylene chloride (15.5 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, an appropriate amount of purified water was added, extracted with ethyl acetate, washed with brine, and dried over Na 2 SO 4 . The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-hexane: ethyl acetate = 5: 1) to give colorless oily ethyl (4-ethoxy-2-fluorophenyl) {[2- (trimethylsilyl ) Ethoxy] methoxy} acetate (1.55 g) was prepared.
製造例103
エチル 5-メチル-2-{[(3-フェニルプロピル)アミノ]メチル}-1,3-チアゾール-4-カルボキシレート(0.8 g)、ヒューニッヒ塩基(0.15 mL)、(4-エトキシ-2-フルオロフェニル){[2-(トリメチルシリル)エトキシ]メトキシ}酢酸(0.95 g)およびHATU (1.1 g)をアセトニトリル(53 mL)に順次加え、室温で3時間攪拌した。反応混合物を減圧留去し、残渣に適量の精製水および1M塩酸を加え、CHCl3で抽出した。有機層をNa2SO4で乾燥及び減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン〜ヘキサン:酢酸エチル=1:1)により精製し、無色油状物のエチル 2-[4-(4-エトキシ-2-フルオロフェニル)-10,10-ジメチル-3-オキソ-2-(3-フェニルプロピル)-5,7-ジオキサ-2-アザ-10-シラウンデク-1-イル]-5-メチル-1,3-チアゾール-4-カルボキシレート(1.45 g)を製造した。
次に、エチル 2-[4-(4-エトキシ-2-フルオロフェニル)-10,10-ジメチル-3-オキソ-2-(3-フェニルプロピル)-5,7-ジオキサ-2-アザ-10-シラウンデク-1-イル]-5-メチル-1,3-チアゾール-4-カルボキシレート(1.45 g)および1M水酸化ナトリウム水溶液(5 mL)をTHF/EtOH(1:1)溶液(20 mL)に加え、室温で終夜攪拌した。反応混合物を減圧留去し、残渣に適量の精製水および1M塩酸を加えて中性とした後、酢酸エチルで抽出した。有機層をbrine洗浄し、Na2SO4で乾燥した後、溶媒を減圧留去して、2-[4-(4-エトキシ-2-フルオロフェニル)-10,10-ジメチル-3-オキソ-2-(3-フェニルプロピル)-5,7-ジオキサ-2-アザ-10-シラウンデク-1-イル]-5-メチル-1,3-チアゾール-4-カルボン酸(1.35 g)を製造した。Production Example 103
Ethyl 5-methyl-2-{[(3-phenylpropyl) amino] methyl} -1,3-thiazole-4-carboxylate (0.8 g), Hunig base (0.15 mL), (4-ethoxy-2-fluoro Phenyl) {[2- (trimethylsilyl) ethoxy] methoxy} acetic acid (0.95 g) and HATU (1.1 g) were sequentially added to acetonitrile (53 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was evaporated under reduced pressure, an appropriate amount of purified water and 1M hydrochloric acid were added to the residue, and the mixture was extracted with CHCl 3 . The organic layer was dried over Na 2 SO 4 and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane to hexane: ethyl acetate = 1: 1) to give colorless oily ethyl 2- [4- (4-ethoxy-2-fluorophenyl) -10,10-dimethyl-3 -Oxo-2- (3-phenylpropyl) -5,7-dioxa-2-aza-10-silaundec-1-yl] -5-methyl-1,3-thiazole-4-carboxylate (1.45 g) Manufactured.
Next, ethyl 2- [4- (4-ethoxy-2-fluorophenyl) -10,10-dimethyl-3-oxo-2- (3-phenylpropyl) -5,7-dioxa-2-aza-10 -Silaundec-1-yl] -5-methyl-1,3-thiazole-4-carboxylate (1.45 g) and 1M aqueous sodium hydroxide solution (5 mL) in THF / EtOH (1: 1) solution (20 mL) And stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure, the residue was neutralized with appropriate amounts of purified water and 1M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine and dried over Na 2 SO 4 , and then the solvent was distilled off under reduced pressure to give 2- [4- (4-ethoxy-2-fluorophenyl) -10,10-dimethyl-3-oxo- 2- (3-Phenylpropyl) -5,7-dioxa-2-aza-10-silaundec-1-yl] -5-methyl-1,3-thiazole-4-carboxylic acid (1.35 g) was prepared.
製造例104
1-(4-ヒドロキシフェニル)シクロプロパンカルボン酸(4.5 g)および濃硫酸(0.2 mL)をEtOH (60 mL)に加え、70℃で2日間攪拌した。反応混合物を減圧留去し、残渣に適量の飽和重曹水を加え、酢酸エチルで抽出した。有機層をbrine洗浄およびNa2SO4で乾燥後、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン〜ヘキサン:酢酸エチル=2:1)により精製し、淡黄色固体のエチル1-(4-ヒドロキシフェニル)シクロプロパンカルボキシレート(5.0 g)を製造した。Production Example 104
1- (4-Hydroxyphenyl) cyclopropanecarboxylic acid (4.5 g) and concentrated sulfuric acid (0.2 mL) were added to EtOH (60 mL), and the mixture was stirred at 70 ° C. for 2 days. The reaction mixture was evaporated under reduced pressure, an appropriate amount of saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over Na 2 SO 4 , and then the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane to hexane: ethyl acetate = 2: 1) to produce ethyl 1- (4-hydroxyphenyl) cyclopropanecarboxylate (5.0 g) as a pale yellow solid.
製造例105
エチル 1-(4-ヒドロキシフェニル)シクロプロパンカルボキシレート(0.7 g)、炭酸カリウム(0.7 g)およびヨードメタン−d2をDMF (7 mL)に順次加え、終夜室温攪拌した。反応混合物に適量の氷水を加え、酢酸エチルで抽出した。有機層をbrineで洗浄し、Na2SO4で乾燥させ、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン〜ヘキサン:酢酸エチル=5:1)により精製し、無色油状物のエチル 1-{4-[(2H2)メチルオキシ]フェニル}シクロプロパンカルボキシラート(0.705 g)を製造した。Production Example 105
Ethyl 1- (4-hydroxyphenyl) cyclopropanecarboxylate (0.7 g), potassium carbonate (0.7 g) and iodomethane-d 2 were sequentially added to DMF (7 mL), and the mixture was stirred overnight at room temperature. An appropriate amount of ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na 2 SO 4 and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane to hexane: ethyl acetate = 5: 1) to give ethyl 1- {4-[( 2 H 2 ) methyloxy] phenyl} cyclopropanecarboxylate as a colorless oil. (0.705 g) was produced.
製造例106
N-(2-ヒドロキシエチル)-N-メチルスルフリック ジアミド(780 mg)、DMAP(309 mg)、トリエチルアミン(0.85 mL)およびtert-ブチル(クロロ)ジメチルシラン(915 mg)をDMF (8 mL)に順次加え、室温で終夜攪拌した。反応混合物に適量の飽和塩化アンモニウム水溶液を加え、CHCl3で抽出、有機層をbrineで洗浄し、MgSO4で乾燥させた。溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=1:1)により精製し、白色固体のN-(2-{[tert-ブチル(ジメチル)シリル]オキシ}エチル)-N-メチルスルフリック ジアミド(801 mg)を製造した。Production Example 106
N- (2-hydroxyethyl) -N-methylsulfuric diamide (780 mg), DMAP (309 mg), triethylamine (0.85 mL) and tert-butyl (chloro) dimethylsilane (915 mg) in DMF (8 mL) And stirred at room temperature overnight. An appropriate amount of saturated aqueous ammonium chloride solution was added to the reaction mixture, extracted with CHCl 3 , the organic layer was washed with brine, and dried over MgSO 4 . The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give N- (2-{[tert-butyl (dimethyl) silyl] oxy} as a white solid. Ethyl) -N-methylsulfuric diamide (801 mg) was prepared.
製造例107
エチル (2R)-[4-(ベンジルオキシ)フェニル]{[2-(トリメチルシリル)エトキシ]メトキシ}アセテート(2.65 g)、シクロヘキセン(20 mL)および10%パラジウム炭素(530 mg)をEtOH(40 mL)に順次加え、100℃で2時間攪拌した。不溶物をセライトろ過し、得られたろ液を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン〜ヘキサン:酢酸エチル=2:1)により精製し、無色油状物のエチル (2R)-(4-ヒドロキシフェニル){[ 2-(トリメチルシリル)エトキシ]メトキシ}アセテート(2.0 g)を製造した。Production Example 107
Ethyl (2R)-[4- (benzyloxy) phenyl] {[2- (trimethylsilyl) ethoxy] methoxy} acetate (2.65 g), cyclohexene (20 mL) and 10% palladium on carbon (530 mg) were added to EtOH (40 mL). ) And stirred at 100 ° C. for 2 hours. The insoluble material was filtered through Celite, and the resulting filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane to hexane: ethyl acetate = 2: 1) to give colorless oily ethyl (2R)-(4-hydroxyphenyl) {[2- (trimethylsilyl) ethoxy] methoxy. } Acetate (2.0 g) was prepared.
製造例108
エチル 2-[(4R)-4-(4-メトキシフェニル)-10,10-ジメチル-3-オキソ-2-(3-フェニルプロピル)-5,7-ジオキサ-2-アザ-10-シラウンデク-1-イル]-5-ビニル-1,3-チアゾール-4-カルボキシレート (319 mg)および10%パラジウム炭素(60 mg)をEtOH(40 mL)に順次加え、水素ガス雰囲気下、常温常圧下で約2時間攪拌した。触媒をセライト濾過し、得られたろ液を減圧留去して生じた残渣に再度適量のEtOHを注ぎ、10%パラジウム炭素(100 mg)添加後、同様に水素ガス雰囲気下にて2時間室温攪拌した。これを再度繰り返して(触媒量:200 mg)、同様の後処理で得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン〜ヘキサン:酢酸エチル=2:1)で精製し、無色油状物のエチル 5-エチル-2-[(4R)-4-(4-メトキシフェニル)-10,10-ジメチル-3-オキソ-2-(3-フェニルプロピル)-5,7-ジオキサ-2-アザ-10-シラウンデク-1-イル]-1,3-チアゾール-4-カルボキシレート(150 mg)を製造した。Production Example 108
Ethyl 2-[(4R) -4- (4-methoxyphenyl) -10,10-dimethyl-3-oxo-2- (3-phenylpropyl) -5,7-dioxa-2-aza-10-silaundec- 1-yl] -5-vinyl-1,3-thiazole-4-carboxylate (319 mg) and 10% palladium on carbon (60 mg) were added to EtOH (40 mL) in this order, under a hydrogen gas atmosphere at room temperature and normal pressure. For about 2 hours. The catalyst was filtered through Celite, and the resulting filtrate was distilled off under reduced pressure. To the resulting residue, a suitable amount of EtOH was poured again, 10% palladium on carbon (100 mg) was added, and the mixture was similarly stirred at room temperature under a hydrogen gas atmosphere for 2 hours. did. This was repeated again (catalyst amount: 200 mg), and the residue obtained by the same post-treatment was purified by silica gel column chromatography (hexane to hexane: ethyl acetate = 2: 1) to give a colorless oily ethyl 5- Ethyl-2-[(4R) -4- (4-methoxyphenyl) -10,10-dimethyl-3-oxo-2- (3-phenylpropyl) -5,7-dioxa-2-aza-10-silaundec 1-yl] -1,3-thiazole-4-carboxylate (150 mg) was prepared.
製造例109
(2-フルオロ-4-メトキシフェニル)(ヒドロキシ)酢酸(1.25 g)および(1R)-1-(1-ナフチル)エタンアミン(1.07 g)をイソプロピルアルコール(15 mL)に順次加え、室温で5時間攪拌した。析出した固体をろ取し、これを予熱させたイソプロピルアルコール(20 mL)に添加し溶解させた後、放冷して再結晶化させた。ろ取して得られた析出物(0.55 g)を適量の精製水中に加え、1M塩酸で弱酸性溶液とし、酢酸エチルで抽出した。有機層をbrine洗浄、続いてNa2SO4で乾燥させ、溶媒を減圧留去して白色固体の(2R)- (2-フルオロ-4-メトキシフェニル)(ヒドロキシ)酢酸(0.28 g)を製造した。Production Example 109
(2-Fluoro-4-methoxyphenyl) (hydroxy) acetic acid (1.25 g) and (1R) -1- (1-naphthyl) ethanamine (1.07 g) were sequentially added to isopropyl alcohol (15 mL) and stirred at room temperature for 5 hours. Stir. The precipitated solid was collected by filtration, dissolved in preheated isopropyl alcohol (20 mL), allowed to cool and recrystallized. The precipitate (0.55 g) obtained by filtration was added to an appropriate amount of purified water, made into a weakly acidic solution with 1M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine, then dried over Na 2 SO 4 and the solvent was distilled off under reduced pressure to produce (2R)-(2-fluoro-4-methoxyphenyl) (hydroxy) acetic acid (0.28 g) as a white solid. did.
製造例110
(2R)-(2-フルオロ-4-メトキシフェニル)(ヒドロキシ)酢酸(1.1 g)、炭酸カリウム(0.9 g)およびヨウ化エチル(0.6 mL)をDMF (30 mL)に順次加え、室温で3時間攪拌した。反応混合物に適量の精製水を加え、酢酸エチルで抽出した。有機層をbrineで洗浄し、Na2SO4で乾燥させた後、溶媒を減圧留去して、エチル (2R)-(2-フルオロ-4-メトキシフェニル)(ヒドロキシ)アセテート(1.2 g)を製造した。
次に、エチル (2R)-(2-フルオロ-4-メトキシフェニル)(ヒドロキシ)アセテート(270 mg)、[2-(クロロメトキシ)エチル](トリメチル)シラン(0.42 mL)、ヒューニッヒ塩基(0.42 mL)、及び、テトラ-n-ブチルアンモニウム ヨージド(440 mg)を塩化メチレン(10 mL)に順次加え、室温にて終夜攪拌した。反応混合物を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン〜ヘキサン:酢酸エチル=5:1)により精製し、無色油状物のエチル(2R)-(2-フルオロ-4-メトキシフェニル){[2-(トリメチルシリル)エトキシ]メトキシ}アセテート(325 mg)を製造した。Production Example 110
(2R)-(2-Fluoro-4-methoxyphenyl) (hydroxy) acetic acid (1.1 g), potassium carbonate (0.9 g) and ethyl iodide (0.6 mL) were added sequentially to DMF (30 mL), and Stir for hours. An appropriate amount of purified water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over Na 2 SO 4 , and then the solvent was distilled off under reduced pressure to obtain ethyl (2R)-(2-fluoro-4-methoxyphenyl) (hydroxy) acetate (1.2 g). Manufactured.
Next, ethyl (2R)-(2-fluoro-4-methoxyphenyl) (hydroxy) acetate (270 mg), [2- (chloromethoxy) ethyl] (trimethyl) silane (0.42 mL), Hunig base (0.42 mL) ) And tetra-n-butylammonium iodide (440 mg) were sequentially added to methylene chloride (10 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-hexane: ethyl acetate = 5: 1) to give colorless oily ethyl (2R)-(2-fluoro-4-methoxyphenyl) { [2- (Trimethylsilyl) ethoxy] methoxy} acetate (325 mg) was prepared.
製造例111
エチル 5-ブロモ-2-[(4R)-4-(4-メトキシフェニル)-10,10-ジメチル-3-オキソ-2-(3-フェニルプロピル)-5,7-ジオキサ-2-アザ-10-シラウンデク-1-イル]-1,3-チアゾール-4-カルボキシレート(420 mg)、トリブチル(ビニル)スズ(0.27 mL)、(1E,4E)-1,5-ジフェニルペンタ-1,4-ジエン-3-オン・パラジウム(3:2) (60 mg)、及び、トリス(2-メチルフェニル)ホスフィン(75 mg)をトルエン(10 mL)に順次加え、80℃で2時間攪拌した。溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン〜ヘキサン:酢酸エチル=1:1)により精製し、無色油状物のエチル 2-[(4R)-4-(4-メトキシフェニル)-10,10-ジメチル-3-オキソ-2-(3-フェニルプロピル)-5,7-ジオキサ-2-アザ-10-シラウンデク-1-イル]-5-ビニル-1,3-チアゾール-4-カルボキシレート(319 mg)を製造した。Production Example 111
Ethyl 5-bromo-2-[(4R) -4- (4-methoxyphenyl) -10,10-dimethyl-3-oxo-2- (3-phenylpropyl) -5,7-dioxa-2-aza- 10-Silaundec-1-yl] -1,3-thiazole-4-carboxylate (420 mg), tributyl (vinyl) tin (0.27 mL), (1E, 4E) -1,5-diphenylpenta-1,4 -Dien-3-one palladium (3: 2) (60 mg) and tris (2-methylphenyl) phosphine (75 mg) were sequentially added to toluene (10 mL), and the mixture was stirred at 80 ° C. for 2 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane to hexane: ethyl acetate = 1: 1) to give ethyl 2-[(4R) -4- (4-methoxy) as a colorless oil. Phenyl) -10,10-dimethyl-3-oxo-2- (3-phenylpropyl) -5,7-dioxa-2-aza-10-silaundec-1-yl] -5-vinyl-1,3-thiazole -4-carboxylate (319 mg) was prepared.
上記製造例の方法と同様にして、下記表に示す製造例化合物をそれぞれ対応する原料を使用して製造した。後記表に製造例化合物の構造、製造法及び物理化学的データを示す。 It carried out similarly to the method of the said manufacture example, and manufactured the manufacture example compound shown in the following table | surface using the corresponding raw material, respectively. The following table shows the structure, production method and physicochemical data of the production example compounds.
実施例5
2-[([3-(4-フルオロフェニル)プロピル]{[1-(4-メトキシフェニル)シクロプロピル]カルボニル}アミノ)メチル]-5-メチル-1,3-チアゾール-4-カルボン酸(100 mg)及びCDI(50 mg)を無水THF(4 mL)に加え、60℃で約1時間加熱した。反応混合物に氷冷下で、N,N-ジメチルスルファミド(51 mg)及びDBU (38 mg)をそれぞれ添加し、室温にて終夜攪拌した。反応混合物に適量の精製水および1M塩酸を加えて中性とした後、酢酸エチルで数回抽出した。得られた有機層をbrineで洗浄しMgSO4で乾燥させ、溶媒を減圧留去した。生じた残渣をシリカゲルカラムクロマトグラフィー(CHCl3:MeOH=250:1)で精製し、得られた無色シロップを少量の酢酸エチル/ヘキサン(1:1)およびジエチルエーテルで固化させて白色固体のN-(ジメチルスルファモイル)-2-[([3-(4-フルオロフェニル)プロピル]{[1-(4-メトキシフェニル)シクロプロピル]カルボニル}アミノ)メチル]-5-メチル-1,3-チアゾール-4-カルボキサミド (67 mg)を製造した。Example 5
2-[([3- (4-Fluorophenyl) propyl] {[1- (4-methoxyphenyl) cyclopropyl] carbonyl} amino) methyl] -5-methyl-1,3-thiazole-4-carboxylic acid ( 100 mg) and CDI (50 mg) were added to anhydrous THF (4 mL) and heated at 60 ° C. for about 1 hour. Under ice-cooling, N, N-dimethylsulfamide (51 mg) and DBU (38 mg) were added to the reaction mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with appropriate amounts of purified water and 1M hydrochloric acid, and extracted several times with ethyl acetate. The obtained organic layer was washed with brine, dried over MgSO 4 , and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (CHCl 3 : MeOH = 250: 1), and the resulting colorless syrup was solidified with a small amount of ethyl acetate / hexane (1: 1) and diethyl ether to give a white solid N -(Dimethylsulfamoyl) -2-[([3- (4-fluorophenyl) propyl] {[1- (4-methoxyphenyl) cyclopropyl] carbonyl} amino) methyl] -5-methyl-1,3 -Thiazole-4-carboxamide (67 mg) was prepared.
実施例13
2-[(4R)-4-(4-メトキシフェニル)-10,10-ジメチル-3-オキソ-2-(3-フェニルプロピル)-5,7-ジオキサ-2-アザ-10-シラウンデク-1-イル]-5-メチル-チアゾール-4-カルボン酸(200 mg)及びCDI (83 mg)をTHF(6 mL)に加え、70℃で約1時間加熱した。反応混合物にスルファミド(66 mg)及びDBU (104 mg)を順次加え、室温で終夜攪拌した。反応混合物に4 M塩酸/ジオキサン溶液(2 mL)を加えて2時間室温攪拌した。反応混合物を減圧濃縮し、得られた残渣に精製水を加え、適量のCHCl3で抽出した。有機層をMgSO4で乾燥させ、溶媒を減圧留去して生じた残渣をシリカゲルカラムクロマトグラフィー(CHCl3〜CHCl3:MeOH=20:1)により精製し、この精製物を少量の酢酸エチル/ヘキサン(1:1)で固化させて、白色固体の2-({[(2R)-2-ヒドロキシ-2-(4-メトキシフェニル)アセチル](3-フェニルプロピル)アミノ}メチル)-5-メチル-N-スルファモイル-1,3-チアゾール-4-カルボキサミド(138 mg)を製造した。Example 13
2-[(4R) -4- (4-Methoxyphenyl) -10,10-dimethyl-3-oxo-2- (3-phenylpropyl) -5,7-dioxa-2-aza-10-silaundec-1 -Il] -5-methyl-thiazole-4-carboxylic acid (200 mg) and CDI (83 mg) were added to THF (6 mL) and heated at 70 ° C. for about 1 hour. To the reaction mixture, sulfamide (66 mg) and DBU (104 mg) were sequentially added, and the mixture was stirred overnight at room temperature. A 4 M hydrochloric acid / dioxane solution (2 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, purified water was added to the resulting residue, and the mixture was extracted with an appropriate amount of CHCl 3 . The organic layer was dried over MgSO 4 , the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (CHCl 3 to CHCl 3 : MeOH = 20: 1). The purified product was purified with a small amount of ethyl acetate / Solidify with hexane (1: 1) to give 2-({[(2R) -2-hydroxy-2- (4-methoxyphenyl) acetyl] (3-phenylpropyl) amino} methyl) -5- Methyl-N-sulfamoyl-1,3-thiazole-4-carboxamide (138 mg) was prepared.
実施例16
5-クロロ-N-(ジメチルスルファモイル)-2-{[(3-フェニルプロピル)アミノ]メチル}-1,3-チアゾール-4-カルボキサミド塩酸塩(1: 1) (150 mg)、ヒューニッヒ塩基(0.19 mL)、(2R)-(4-メトキシフェニル){[2-(トリメチルシリル)エトキシ]メトキシ}酢酸(114 mg)およびHATU(151 mg)をアセトニトリル(6 mL)に順次加え、終夜室温攪拌した。反応混合物を減圧留去し、残渣をTHF(6 mL)に溶解させ、4M塩酸/ジオキサン溶液(3 mL)を加えて2時間室温攪拌した。反応混合物を減圧留去して、得られた残渣に精製水を加え、適量のCHCl3で抽出した。有機層をMgSO4で乾燥させ、溶媒を減圧留去して生じた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム〜クロロホルム/メタノール=20:1)により精製し、濃縮物を適量のジイソプロピルエーテルで固化させて白色固体の5-クロロ-N-(ジメチルスルファモイル)-2-({[(2R)-2-ヒドロキシ-2-(4-メトキシフェニル)アセチル](3-フェニルプロピル)アミノ}メチル)-1,3-チアゾール-4-カルボキサミド(73 mg)を製造した。Example 16
5-Chloro-N- (dimethylsulfamoyl) -2-{[(3-phenylpropyl) amino] methyl} -1,3-thiazole-4-carboxamide hydrochloride (1: 1) (150 mg), Hunig Base (0.19 mL), (2R)-(4-methoxyphenyl) {[2- (trimethylsilyl) ethoxy] methoxy} acetic acid (114 mg) and HATU (151 mg) were added sequentially to acetonitrile (6 mL) and overnight at room temperature. Stir. The reaction mixture was evaporated under reduced pressure, the residue was dissolved in THF (6 mL), 4M hydrochloric acid / dioxane solution (3 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was evaporated under reduced pressure, purified water was added to the resulting residue, and the mixture was extracted with an appropriate amount of CHCl 3 . The organic layer was dried over MgSO 4 , the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform to chloroform / methanol = 20: 1), and the concentrate was solidified with an appropriate amount of diisopropyl ether. White solid 5-chloro-N- (dimethylsulfamoyl) -2-({[(2R) -2-hydroxy-2- (4-methoxyphenyl) acetyl] (3-phenylpropyl) amino} methyl)- 1,3-thiazole-4-carboxamide (73 mg) was prepared.
実施例19
N-[(ジメチルアミノ)スルホニル]-2-{[(3-フェニルプロピル)アミノ]メチル}-5-メチル-1,3-チアゾール-4-カルボキサミド 塩酸塩(150 mg)、(2-シアノ-4-メトキシフェニル)酢酸(80 mg)、ヒューニッヒ塩基(0.2 mL)及びHATU(150 mg)をTHF(10 mL)に加え、室温で終夜攪拌した。反応混合物を減圧下濃縮し、生じた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン〜酢酸エチル)により精製し、適量のヘキサン/酢酸エチル(2:1)溶液で固化させて、白色固体の2-({[(2-シアノ-4-メトキシフェニル)アセチル](3-フェニルプロピル)アミノ}メチル)-N-(ジメチルスルファモイル)-5-メチル-1,3-チアゾール-4-カルボキサミド(73 mg)を製造した。Example 19
N-[(dimethylamino) sulfonyl] -2-{[(3-phenylpropyl) amino] methyl} -5-methyl-1,3-thiazole-4-carboxamide hydrochloride (150 mg), (2-cyano- 4-Methoxyphenyl) acetic acid (80 mg), Hunig's base (0.2 mL) and HATU (150 mg) were added to THF (10 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane to ethyl acetate) and solidified with an appropriate amount of hexane / ethyl acetate (2: 1) solution to give 2-({ [(2-Cyano-4-methoxyphenyl) acetyl] (3-phenylpropyl) amino} methyl) -N- (dimethylsulfamoyl) -5-methyl-1,3-thiazole-4-carboxamide (73 mg) Manufactured.
実施例20
2-[([3-(3-ブロモフェニルプロピル]{[1-(5-メトキシピリジン-2-イル)シクロプロピル]カルボニル}アミノ)メチル]-5-メチル-1,3-チアゾール-4-カルボン酸(156 mg)およびCDI (67 mg)を無水THF(4 mL)に加え、60℃にて1時間加熱した。反応混合物を放冷後、N,N-ジメチルスルファミド(68 mg)およびDBU (50 mg)を順次加え、室温にて終夜攪拌した。反応混合物に1M塩酸1.5 mLを含む氷水約15 gを注ぎ、適量の酢酸エチルで数回抽出、得られた有機層をbrineで洗浄後をMgSO4で乾燥させた。溶媒を減圧留去し、生じた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=1:1)で精製し、無色シロップ(120 mg)を得た。これを少量のEtOHに溶解させ、アルゴンガス雰囲気下、適量の4M塩酸−酢酸エチル溶液を滴下し、しばらく攪拌させた後、生じた沈殿物をジエチルエーテル/ジイソプロピルエーテル(1:1)で希釈・洗浄しながらろ取することにより、白色固体の2-[([3-(3-ブロモフェニル)プロピル]{[1-(5-メトキシピリジン-2-イル)シクロプロピル]カルボニル}アミノ)メチル]-N-(ジメチルスルファモイル)-5-メチル-1,3-チアゾール-4-カルボキサミド塩酸塩(65 mg)を製造した。Example 20
2-[([3- (3-Bromophenylpropyl] {[1- (5-methoxypyridin-2-yl) cyclopropyl] carbonyl} amino) methyl] -5-methyl-1,3-thiazole-4- Carboxylic acid (156 mg) and CDI (67 mg) were added to anhydrous THF (4 mL) and heated for 1 hour at 60 ° C. The reaction mixture was allowed to cool, and then N, N-dimethylsulfamide (68 mg) And DBU (50 mg) were added successively, and the mixture was stirred overnight at room temperature.About 15 g of ice water containing 1.5 mL of 1M hydrochloric acid was poured into the reaction mixture, extracted several times with an appropriate amount of ethyl acetate, and the resulting organic layer was washed with brine. After washing, the residue was dried with MgSO 4. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1: 1) to obtain a colorless syrup (120 mg). Was dissolved in a small amount of EtOH, and an appropriate amount of 4M hydrochloric acid-ethyl acetate solution was added dropwise under an argon gas atmosphere. After stirring for a while, the resulting precipitate was dissolved in diethyl ether. By diluting and washing with ether / diisopropyl ether (1: 1) and filtering, white solid 2-[([3- (3-bromophenyl) propyl] {[1- (5-methoxypyridine-2 -Iyl) cyclopropyl] carbonyl} amino) methyl] -N- (dimethylsulfamoyl) -5-methyl-1,3-thiazole-4-carboxamide hydrochloride (65 mg) was prepared.
上記実施例の方法と同様にして、下記表に示す実施例化合物をそれぞれ対応する原料を使用して製造した。後記表に実施例化合物の構造、製造法及び物理化学的データを示す。 In the same manner as in the above Examples, the Example compounds shown in the following table were produced using the corresponding raw materials. The following table shows the structures, production methods and physicochemical data of the example compounds.
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PCT/JP2011/071635 WO2012039460A1 (en) | 2010-09-24 | 2011-09-22 | Substituted amide compound |
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WO2004031118A1 (en) * | 2002-10-03 | 2004-04-15 | Ono Pharmaceutical Co., Ltd. | Lpa receptor antagonists |
WO2005058790A1 (en) * | 2003-12-19 | 2005-06-30 | Ono Pharmaceutical Co., Ltd. | Compounds having lysophosphatidic acid receptor antagonism and uses thereof |
JP2009523774A (en) * | 2006-01-17 | 2009-06-25 | アストラゼネカ アクチボラグ | Compound |
JP2011513418A (en) * | 2008-03-03 | 2011-04-28 | アールエックスバイオ インコーポレイテッド | LPA receptor agonists and antagonists |
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WO2004031118A1 (en) * | 2002-10-03 | 2004-04-15 | Ono Pharmaceutical Co., Ltd. | Lpa receptor antagonists |
WO2005058790A1 (en) * | 2003-12-19 | 2005-06-30 | Ono Pharmaceutical Co., Ltd. | Compounds having lysophosphatidic acid receptor antagonism and uses thereof |
JP2009523774A (en) * | 2006-01-17 | 2009-06-25 | アストラゼネカ アクチボラグ | Compound |
JP2011513418A (en) * | 2008-03-03 | 2011-04-28 | アールエックスバイオ インコーポレイテッド | LPA receptor agonists and antagonists |
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