JP2020519636A - Trpv1モジュレータ化合物 - Google Patents
Trpv1モジュレータ化合物 Download PDFInfo
- Publication number
- JP2020519636A JP2020519636A JP2019562376A JP2019562376A JP2020519636A JP 2020519636 A JP2020519636 A JP 2020519636A JP 2019562376 A JP2019562376 A JP 2019562376A JP 2019562376 A JP2019562376 A JP 2019562376A JP 2020519636 A JP2020519636 A JP 2020519636A
- Authority
- JP
- Japan
- Prior art keywords
- amino
- methoxybenzyl
- hydroxy
- formula
- oxoethyl
- 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.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 169
- 102000003566 TRPV1 Human genes 0.000 title claims abstract description 65
- 101150016206 Trpv1 gene Proteins 0.000 title claims abstract 3
- 239000000203 mixture Substances 0.000 claims abstract description 53
- 150000002430 hydrocarbons Chemical class 0.000 claims abstract description 48
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims abstract description 43
- 229930195733 hydrocarbon Natural products 0.000 claims abstract description 43
- 239000004215 Carbon black (E152) Substances 0.000 claims abstract description 30
- 125000003118 aryl group Chemical group 0.000 claims abstract description 28
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 229910052736 halogen Chemical group 0.000 claims abstract description 21
- 150000002367 halogens Chemical group 0.000 claims abstract description 21
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 14
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 12
- 239000001257 hydrogen Substances 0.000 claims abstract description 6
- -1 Here Chemical group 0.000 claims description 77
- 208000003251 Pruritus Diseases 0.000 claims description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
- 201000010099 disease Diseases 0.000 claims description 16
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 16
- 208000002193 Pain Diseases 0.000 claims description 15
- 238000011282 treatment Methods 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 14
- PTSSSGIPXDLEBI-UHFFFAOYSA-N [2-[(3,4-dimethoxyphenyl)methylamino]-2-oxoethyl] but-3-enoate Chemical compound C(CC=C)(=O)OCC(NCC1=CC(=C(C=C1)OC)OC)=O PTSSSGIPXDLEBI-UHFFFAOYSA-N 0.000 claims description 12
- 230000001404 mediated effect Effects 0.000 claims description 11
- 206010028980 Neoplasm Diseases 0.000 claims description 7
- GWNWJOHXCQELNJ-UHFFFAOYSA-N [2-[(3,4-dimethoxyphenyl)methylamino]-2-oxoethyl] butanoate Chemical compound CCCC(=O)OCC(=O)NCC1=CC=C(OC)C(OC)=C1 GWNWJOHXCQELNJ-UHFFFAOYSA-N 0.000 claims description 7
- 201000011510 cancer Diseases 0.000 claims description 7
- 239000000969 carrier Substances 0.000 claims description 7
- 201000004700 rosacea Diseases 0.000 claims description 7
- 230000037307 sensitive skin Effects 0.000 claims description 7
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 6
- 206010061218 Inflammation Diseases 0.000 claims description 6
- 241001303601 Rosacea Species 0.000 claims description 6
- SAOJILHZIAFXLG-UHFFFAOYSA-N [2-[(3,4-dimethoxyphenyl)methylamino]-2-oxoethyl] 3-methylbut-2-enoate Chemical compound COC1=CC=C(CNC(=O)COC(=O)C=C(C)C)C=C1OC SAOJILHZIAFXLG-UHFFFAOYSA-N 0.000 claims description 6
- FEQMHPZCBKEPLG-UHFFFAOYSA-N [2-[2-(3,4-dimethoxyphenyl)ethylamino]-2-oxoethyl] 3-methylbut-2-enoate Chemical compound COC1=CC=C(CCNC(=O)COC(=O)C=C(C)C)C=C1OC FEQMHPZCBKEPLG-UHFFFAOYSA-N 0.000 claims description 6
- MGBGPYZDLNSTFT-UHFFFAOYSA-N [2-[2-(3,4-dimethoxyphenyl)ethylamino]-2-oxoethyl] but-2-enoate Chemical compound COC1=CC=C(CCNC(=O)COC(=O)C=CC)C=C1OC MGBGPYZDLNSTFT-UHFFFAOYSA-N 0.000 claims description 6
- GTBNGSVISMIIQM-UHFFFAOYSA-N [2-[2-(3,4-dimethoxyphenyl)ethylamino]-2-oxoethyl] hexa-2,4-dienoate Chemical compound COC1=CC=C(CCNC(=O)COC(=O)C=CC=CC)C=C1OC GTBNGSVISMIIQM-UHFFFAOYSA-N 0.000 claims description 6
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- LIMOTGGDSTZJRY-YTXTXJHMSA-N [2-[(3,4-dimethoxyphenyl)methylamino]-2-oxoethyl] (2e,4e)-hexa-2,4-dienoate Chemical compound COC1=CC=C(CNC(=O)COC(=O)\C=C\C=C\C)C=C1OC LIMOTGGDSTZJRY-YTXTXJHMSA-N 0.000 claims description 5
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- NJQHFSGNPIGSJH-UHFFFAOYSA-N [2-[(3,4-dimethoxyphenyl)methylamino]-2-oxoethyl] but-2-enoate Chemical compound COC1=CC=C(CNC(=O)COC(=O)C=CC)C=C1OC NJQHFSGNPIGSJH-UHFFFAOYSA-N 0.000 claims description 5
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
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- NCFSNMIWTMPUHQ-UHFFFAOYSA-N [2-[2-(3,4-dimethoxyphenyl)ethylamino]-2-oxoethyl] 2-ethylbutanoate Chemical compound CCC(CC)C(=O)OCC(=O)NCCC1=CC=C(OC)C(OC)=C1 NCFSNMIWTMPUHQ-UHFFFAOYSA-N 0.000 claims description 4
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- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 claims description 4
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- DUKYGGYDSJNGMM-UHFFFAOYSA-N [1-[2-(3,4-dimethoxyphenyl)ethylamino]-2-methyl-1-oxopropan-2-yl] pentanoate Chemical compound C(CCCC)(=O)OC(C)(C)C(NCCC1=CC(=C(C=C1)OC)OC)=O DUKYGGYDSJNGMM-UHFFFAOYSA-N 0.000 claims 1
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- DERUVJAAKIKQPZ-AXBXZHNYSA-N [2-[(3,4-dihydroxyphenyl)methylamino]-2-oxoethyl] (4E,8E,12E,16E)-4,8,13,17,21-pentamethyldocosa-4,8,12,16,20-pentaenoate Chemical compound C/C(/CCC(=O)OCC(=O)NCC1=CC(=C(C=C1)O)O)=C\CC\C(=C\CC\C=C(\CC\C=C(\CCC=C(C)C)/C)/C)\C DERUVJAAKIKQPZ-AXBXZHNYSA-N 0.000 claims 1
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- XOZYXXGYXQZQTP-FFAVVIEKSA-N [2-[(4-hydroxy-2-iodo-5-methoxyphenyl)methylamino]-2-oxoethyl] (4E,8E,12E,16E)-4,8,13,17,21-pentamethyldocosa-4,8,12,16,20-pentaenoate Chemical compound C/C(/CCC(=O)OCC(=O)NCC1=C(C=C(C(=C1)OC)O)I)=C\CC\C(=C\CC\C=C(\CC\C=C(\CCC=C(C)C)/C)/C)\C XOZYXXGYXQZQTP-FFAVVIEKSA-N 0.000 claims 1
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/08—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/231—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having one or two double bonds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
Description
mは1〜3から選択される整数であり、
R1、R2、R6及びR6´は、H、(C1−C8)アルキル、不飽和(C2−C8)炭化水素及び(C3−C6)シクロアルキルからなる群から独立して選択され、
ここで(C1−C8)アルキル、不飽和(C2−C8)炭化水素、及び(C3−C6)シクロアルキルは、ハロゲン、−COOH、−OH、−NH2、−COOR6、−NO2、−CF3、−OCF3、−CN、
−OR6、−CONH2、−CONHR6、−CONR6R7、−NHR6、−NR6R7、−NHCOR6、−NHSO2R6及び
−SO2NHR6からなる群から選択される1つ以上の置換基で任意に置換され、
R3は、水素又はハロゲンであり、
R4は、H、(C1−C8)アルキル、不飽和(C2−C8)炭化水素、(C3−C6)シクロアルキル、(C6−C12)アリール及び(C5−C12)ヘテロアリールからなる群から選択され;
ここで(C1−C8)アルキル、不飽和(C2−C8)炭化水素、(C3−C6)シクロアルキル、(C6−C12)アリール及び(C5−C12)ヘテロアリールは、ハロゲン、−COOH、−OH、−NH2、−COOR6、
−NO2、−CF3、−OCF3、−CN、−OR6、−CONH2、−CONHR6、−CONR6R7、−NHR6、−NR6R7、
−NHCOR6、−NHSO2R6及び−SO2NHR6からなる群から選択される1つ以上の置換基で任意に置換され、
R5は、(C3−C28)アルキル、不飽和(C3−C28)炭化水素、(C6−C12)アリール及び(C5−C12)ヘテロアリールであり、
ここで(C1−C8)アルキル、不飽和(C2−C8)炭化水素、(C6−C12)アリール及び(C5−C12)ヘテロアリールは、ハロゲン、−COOH、−OH、−NH2、−COOR6、−NO2、−CF3、
−OCF3、−CN、−OR6、−CONH2、−CONHR6、−CONR6R7、−NHR6、−NR6R7、−NHCOR6、
−NHSO2R6及び−SO2NHR6からなる群から選択される1つ以上の置換基で任意に置換され、
ただし、式(I)の化合物は、
(3,4−ジメトキシフェネチルカルバモイル)メチル−ブタ−2−エノエート、(3,4−ジメトキシフェネチル−カルバモイル)メチル4−メチルペンタノエート、(3,4−ジメトキシベンジルカルバモイル)メチル3,3−ジメチルブタノエート、(3,4−ジメトキシフェネチルカルバモイル)メチル3,3−ジメチルブタノエート、(3,4−ジメトキシフェネチルカルバモイル)メチル3−メチルブタ−2−エノエート、(3,4−ジメトキシベンジルカルバモイル)メチル4−メチルペンタノエート、(3,4−ジメトキシベンジルカルバモイル)−メチル3−メチルブタ−2−エノエート、(2E,4E)−(3,4−ジメトキシベンジルカルバモイル)メチルヘキサ−2,4−ジエノエート、(3,4−ジメトキシベンジルカルバモイル)メチルブチレート、(3,4−ジメトキシベンジルカルバモイル)メチルブチレート、(3,4−ジメトキシフェネチルカルバモイル)メチルヘキサ−2,4−ジエノエート、(3,4−ジメトキシフェネチルカルバモイル)メチル2−エチルブタノエート、(3,4−ジメトキシベンジルカルバモイル)メチルブタ−2−エノエート、(3,4−ジメトキシベンジルカルバモイル)メチルブタ−3−エノエート、
(3,4−ジメトキシベンジルカルバモイル)メチルブタ−3−エノエート、(3,4−ジメトキシベンジルカルバモイル)メチルウンデカ−10−エノエート、(3,4−ジメトキシベンジルカルバモイル)メチル2−メチルペンタノエート及び2−(3,4−ジメトキシフェネチルカルバモイル)プロパン−2−イルペンタノエート以外である。
a)ホルムアルデヒドの存在下で、式(II)の化合物を、式(III)の化合物(式中、R1、R2、R3、R5、R6、R6´及びmは、上で定義した通りである)と反応させて、式(I)の化合物を生じる工程;
c)任意に、工程a)又はb)のいずれかで得られた前記式(I)の化合物を塩基又は酸と反応させて、対応する塩を得る工程;
を含む方法に関する。
TBDMSCl:tert−ブチルジメチルシリルクロリド
TEA:トリエチルアミン
(4−ヒドロキシ−3−メトキシフェニル)メタンアミニウムクロリド(2.30g、15mmol)を飽和Na2CO3水溶液に溶解させ、THFで(3回)抽出する。収集した有機層を蒸発させる。次いで、4−(アミノメチル)−2−メトキシフェノールをTHF(70mL)に溶解させ、メチルホルメート(1.12mL、18mmol)を添加する。反応物を室温にて一晩撹拌する。次いで、メチルホルメート1.8当量(1.68mL、27mmol)を添加して、反応物をさらに6時間撹拌する。揮発物を真空下で除去すると、中間体1が褐色油として得られた(2.61g、14.4mmol、96%)。分析データ: 1H−NMR(300MHz,CDCl3):δ8.87(s,1H),8.38(br s,1H),8.08(s,1H),6.82(s,1H),6.72−6.64(m,2H),4.17(d,J5.8Hz,2H),3.73(s,3H).MS:M+1 182
N−(4−ヒドロキシ−3−メトキシベンジル)ホルムアミド(3.29g、18.17mmol)の無水DMF(35mL)溶液に、TBDMSCl(3.29g、21.80mmol)、N,N−ジメチル−アミノピリジン(44mg、0.36mmol)及びイミダゾール(1.36g、19.99mmol)を順に窒素下で添加する。反応物を室温で2時間撹拌し、次に水で(1回)洗浄し、ジエチルエーテルで(1回)抽出する。有機層をナトリウムサルフェートで脱水し、揮発物を真空下で除去する。粗物質によって、溶離液として石油エーテル/エチルアセテート6:4、次いで石油エーテル/エチルアセテート4:6を使用したカラムクロマトグラフィーによる精製後、中間体2(2.90 g、9.83mmol、54%)を暗黄色油として得た。分析データ: 1H−NMR(300MHz,CDCl3):δ8.04(s,1H),6.92(br s,1H),6.68(d,J8.0Hz,1H),6.65(d,J1.9Hz,1H),6.60(dd,J8.0,1.9Hz,1H),4.22(d,J6.1Hz,2H),3.66(s,3H),0.91(s,9H),0.06(s,6H).MS:M+1 296
N−(4−((tert−ブチルジメチルシリル)オキシ)−3−メトキシベンジル)ホルムアミド(200mg、0.68mmol)を0℃にて無水CH2Cl2(2mL)に溶解させ、TEA(343mg、3.39mmol)を窒素下で添加する。POCl3(93μL、1mmol)の無水CH2Cl2(2mL)溶液を滴加し、反応物を1時間撹拌する。次いで、飽和NaHCO3水溶液を添加して、混合物を10分間撹拌する。次いで、反応物をCH2Cl2で抽出し、ナトリウムサルフェート上で脱水し、蒸発させる。粗物質を、溶離液として石油エーテル/エチルアセテート4:6を使用するカラムクロマトグラフィーにより精製し、中間体3(164mg、0.59mmol、87%)を暗黄色油として得る。分析データ: 1H−NMR(300MHz,CDCl3):δ6.83−6.73(m,3H),4.52(s,2H),3.78(s,3H),0.97(s,9H),0.13(s,6H).MS:M+1 279
N−(4−((tert−ブチルジメチルシリル)オキシ)−3−メトキシベンジル)ホルムアミド(1.65g、5.59mmol)のCHCl3(17mL)溶液に、銀トリフルオロアセテート(1.23g、5.59mmol)及びヨウ素(1.42g、5.59mmol)のCHCl3(14mL)溶液を添加する。反応物を1時間撹拌し、真空下にてセライトのパッドで濾過する。濾液をCH2Cl2で希釈し、NaHCO3の飽和水溶液(1回)及び飽和Na2S2O3水溶液(1回)で洗浄する。有機層をナトリウムサルフェートで脱水し、蒸発させて、黄色固体(1.98g、4.70mmol、84%)を得る。分析データ: 1H−NMR(300MHz,CDCl3):δ8.12(s,1H),7.16(s,1H),6.78(s,1H),6.74(br t,1H),4.31(d,J6.0Hz,2H),0.91(s,9H),0.07(s,6H).MS:M+1422
この中間体は、実施例3に記載の方法によって調製したが、出発材料としてN−(4−((tert−ブチルジメチルシリル)オキシ)−2−ヨード−5−メトキシベンジル)ホルムアミドを使用した。黄色固体を得た(84%)。分析データ: 1H−NMR(300MHz,CDCl3):δ7.25(s,1H),6.96(s,1H),4.52(s,2H),3.79(s,3H),0.96(s,9H),0.14(s, 6H).MS:M+1 404
(3,4−ジヒドロキシフェニル)メタナミニウムブロミド(4.50g、20.44mmol)及びイミダゾール(4.18g、61.33mmol)の無水CH2Cl2(50mL)溶液に、TBDMSCl(6.16g、40.89mmol)の無水CH2Cl2溶液(25 mL)を窒素下で滴加する。反応物を室温にて一晩撹拌する。揮発物を減圧下で蒸発させる。エチルアセテートを添加し、有機相を水で(4回)洗浄し、ナトリウムサルフェートで脱水し、蒸発させる。粗物質を、溶離液として石油エーテル/エチルアセテート2:8、次いでエチルアセテート/メタノール8:2を使用するカラムクロマトグラフィーにより精製し、中間体6(5.69g、14.37mmol、76%)を暗黄色油として得る。分析データ: 1H−NMR(300MHz;CDCl3):δ6.79−6.76(m,3H),3.78(s,2H),1.01−0.93(m,18H),0.19−0.15(m,12H).MS:M+1 369
(3,4−ビス((tert−ブチルジメチルシリル)オキシ)フェニル)メタンアミン(4.95g、13.47mmol)のエチルホルメート(50mL)溶液を還流下で28時間加熱する。揮発物を真空下で除去して、中間体7(5.17g、13.06mmol、97%)を深黄色油として得る。分析データ:1H−NMR(300MHz;CDCl3):主回転異性体を参照;δ8.22(s,1H),6.78−6.72(m,3H),4.34(d,J3.2Hz,2H),0.97−0.87(m,18H),0.21−0.18(m,12H).MS:M+1 397
この中間体は、実施例3に記載の方法によって調製したが、出発材料としてN−(3,4−ビス((tert−ブチルジメチルシリル)オキシ)ベンジル)ホルムアミドを使用した。黄色固体を得た(61%)。分析データ: 1H−NMR(300MHz,CDCl3):δ6.83−6.81(m,2H),6.76(d,J8.2Hz,1H),4.50(s,2H),1.04−0.92(m,18H),0.26−0.19(m,12H).
この中間体は、実施例4に記載の方法によって調製しが、出発材料としてN−(3,4−ビス((tert−ブチルジメチルシリル)オキシ)ベンジル)ホルムアミドを使用した。非晶質オレンジ色固体を得た(66%)。分析データ:1H−NMR(300MHz,CDCl3):主回転異性体を参照;δ8.22(s,1H),7.23(s,1H),6.89(s,1H),5.90(br s,1H),4.39(d,J6.1Hz,2H),1.04−0.90(m,18H),0.24−0.18(m,12H).MS:M+1 523
この中間体は、実施例3に記載の方法によって調製したが、出発材料としてN−(4,5−ビス((tert−ブチルジメチルシリル)オキシ)−2−ヨードベンジル)ホルムアミドを使用した。深黄色固体を得た(87%)。分析データ: 1H−NMR(300MHz;CDCl3):δ7.28(s,1H),7.03(s,1H),4.54(s,2H),1.08−0.98(m,18H),0.22−0.19(m,12H).
この中間体は、実施例6に記載の方法によって調製したが、出発材料として2−(3,4−ジヒドロキシフェニル)エタンアミニウムクロリドを使用した。白色固体を得た(59%)。分析データ: 1H−NMR(300MHz,CDCl3):δ8.34(brs,2H),6.74−6.67(m,3H),3.19(t,J6.8Hz,2H),2.99(t,J6.8Hz,2H),1.04−0.76(m,18H),0.25−0.17(m,12H).MS:M+1 383
2−(3,4−ビス((tert−ブチルジメチルシリル)オキシ)フェニル)エタンアミン(2.72g、7.14mmol)を、窒素下で1:1メチルホルメート及びメタノール(115mL)の溶液に溶解させた。K2CO3(9.87g、71.39mmol)を上記混合物に添加し、反応物を還流下で2時間撹拌する。次いで、反応物を濾過し、揮発物を蒸発させた後、水を添加する。水層をCH2Cl2で(2回)抽出し、有機相をナトリウムサルフェートで脱水し、真空下で蒸発させて、淡黄色油(2.55g、6.22mmol、87%)を得る。分析データ: 1H−NMR(300MHz,CDCl3):主回転異性体を参照;δ8.12(s,1H),6.76(d,J3.1Hz,1H),6.64−6.61(m,2H),5.48(br s,1H),3.51(q,J6.3Hz,2H),2.70(t,J6.3Hz,2H),1.02−0.98(m,18H),0.26−0.14(m,12H).MS:M+1 411
この中間体は、実施例3に記載の方法によって調製したが、出発材料としてN−(3,4−ビス((tert−ブチルジメチルシリル)オキシ)フェネチル)ホルムアミドを使用した。淡黄色油を得た(77%)。分析データ: 1H−NMR(300MHz,CDCl3):δ6.78(d,J3.1Hz,1H),6.69−6.67(m,2H),3.54(t,J6.2Hz,2H),2.86(t,J6.2Hz,2H),1.00−0.99(m,18H),0.24−0.20(m,12H).
この中間体は、実施例4に記載の方法によって調製したが、出発材料としてN−(3,4−ビス((tert−ブチルジメチルシリル)オキシ)フェネチル)ホルムアミドを使用した。。深黄色油を得た(86%)。分析データ: 1H−NMR(300MHz,CDCl3):主回転異性体を参照;δ8.15(s,1H),7.25(s,1H),6.67(s,1H),5.58(br s,1H),3.50(q,J6.2Hz,2H),2.82(t,J6.2Hz,2H),1.07−0.90(m,18H),1.18−0.08(m,12H).MS:M+1 537
この中間体は、実施例3に記載の方法によって調製したが、出発材料としてN−(4,5−ビス((tert−ブチルジメチルシリル)オキシ)−2−ヨードフェネチル)ホルムアミドを使用した。白色固体を得た(82%)。分析データ: 1H−NMR(300MHz,CDCl3):δ7.25(s,1H),6.77(s,1H),3.57(t,J6.1Hz,2H),2.96(t,J6.1Hz,2H),1.03−0.93(m,18H),0.21−0.19(m,12H).
tert−ブチル(4−(イソシアノメチル)−2−メトキシフェノキシ)ジメチルシラン(中間体3)(200mg、0.72mmol)のCH2Cl2(6.2mL)溶液に、37%ホルムアルデヒド水溶液(215μL、2.88mmol)及び酪酸(スキーム1の化合物R5−COOH)(63mg、0.72mmol)を添加し、得られた混合物を還流下で3時間撹拌し、次いで室温に達するまで放置し、一晩撹拌する。次いで、揮発物を真空下で除去し、生成物をTHF(2mL)に溶解させ、0℃まで冷却する。この温度にて、酢酸(49μL、0.86mmol)及びTBAF(0.86mL、0.86mmol)を添加する。反応物を30分間撹拌する。揮発物を蒸発させ、エチルアセテートを添加し、水(1回)及び飽和NaHCO3水溶液(1回)で洗浄する。収集した有機層をナトリウムサルフェートで脱水し、蒸発させた。溶離液として石油エーテル/エチルアセテート9:1、次いで石油エーテル/エチルアセテート6:4を使用したカラムクロマトグラフィーによる精製により、化合物16を黄色がかった固体として得た。(120mg、0.43mmol、59%)分析データ: 1H−NMR(300MHz,CDCl3):δ6.85−6.65(m,3H),6.59(br t,1H),6.14(br s,1H),4.54(s,2H),4.33(d,J5.8Hz,2H),3.80(s,3H),2.31(t,J7.4Hz,2H),1.60(m,J7.4Hz,2H),0.89(t,J7.4Hz,3H).MS:M+1 280.
((4−(イソシアノメチル)−1,2−フェニレン)ビス(オキシ))ビス(tert−ブチルジメチルシラン)(中間体8)(272mg、0.72mmol)のCH2Cl2(6.2mL)溶液に、37%ホルムアルデヒド水溶液(215μL、2.88mmol)及び(E)−3,7−ジメチルオクタ−2,6−ジエン酸(スキーム1の化合物R5−COOH)(121mg、0.72mmol)を添加し、得られた混合物を還流下で3時間撹拌する。次いで、揮発物を真空下で除去し、生成物をTHF(6.5mL)に溶解させ、0℃まで冷却する。この温度にて、酢酸(140μL、2.45mmol)及びTBAF(2.45mL、2.45mmol)を添加する。反応物を3時間撹拌する。揮発物を蒸発させ、エチルアセテートを添加し、水で(2回)洗浄し、ナトリウムサルフェートで脱水し、蒸発させてオレンジ色固体を得る。粗物質を、石油エーテル/エチルアセテート9:1、次いで石油エーテル/エチルアセテート7:3を溶離液としてクロマトグラフィーカラムに加え、化合物54を白色固体(47%)として得る。分析データ: 1H−NMR(300MHz,CDCl3):δ6.86−6.78(m,2H),6.66(br s,1H),6.63(d,J7.7Hz,1H),5.70(s,1H),5.04(t,J6.2Hz,1H),4.63(s,2H),4.36(d,J 5.8Hz,2H),2.20−2.15(m,7H),1.67(s,3H),1.59(s,3H).MS:M−1 346.
((4−ヨード−5−(イソシアノメチル)−1,2−フェニレン)ビス(オキシ))ビス(tert−ブチルジメチルシラン)(中間体9)(252mg、0.50mmol)のCH2Cl2(4.5mL)溶液に、37%ホルムアルデヒド水溶液(150μL、2mmol)及び(E)−3,7−ジメチルオクタ−2,6−ジエン酸(スキーム1の化合物R5−COOH)(84mg、0.50mmol)を添加し、得られた混合物を還流下で3.30時間撹拌した。次に、揮発物を減圧下で除去し、生成物をTHF(4.5mL)に溶解させ、0℃まで冷却する。この温度にて、酢酸(97μL、1.70 mmol)及びTBAF(1.70mL、1.70mmol)を添加する。反応物を2時間撹拌する。揮発物を蒸発させ、エチルアセテートを添加し、水で(2回)洗浄し、ナトリウムサルフェートで脱水し、蒸発させてオレンジ色固体を得る。粗物質を、石油エーテル/エチルアセテート8:2、次いで石油エーテル/エチルアセテート7:3を溶離液としてクロマトグラフィーカラムに加え、化合物55を粘着性オレンジ色固体(91mg、192mmol、39%)として得る。分析データ: 1H−NMR(300MHz;CDCl3):δ7.26(s,1H),7.08(br t,J6.0Hz,1H),6.98(s,1H),5.73(s,1H),5.05(t,J5.4Hz,1H),4.62(s,2H),4.40(d,J6.0Hz,2H),2.17−2.15(m,7H),1.70(s,3H),1.60(s,3H).MS:M−1 472
((4−(2−イソシアノエチル)−1,2−フェニレン)ビス(オキシ))ビス(tert−ブチルジメチルシラン)(中間体13)(283mg、0.72mmol)のCH2Cl2(6.2mL)溶液に、37%ホルムアルデヒド水溶液(215μL、2.88mmol)及び(E)−3,7−ジメチルオクタ−2,6−ジエン酸(スキーム1の化合物R5−COOH)(121mg、0.72mmol)を添加し、得られた混合物を還流下で3時間撹拌する。次に、揮発物を減圧下で除去し、生成物をTHF(6.5mL)に溶解させ、0℃まで冷却する。この温度にて、酢酸(140μL、2.45mmol)及びTBAF(2.45mL、2.45mmol)を添加する。反応物を2時間撹拌する。揮発物を蒸発させ、エチルアセテートを添加し、水で(2回)洗浄し、ナトリウムサルフェートで脱水し、蒸発させてオレンジ色固体を得る。粗生成物を、溶離液として石油エーテル/エチルアセテート7:3、次いで石油エーテル/エチルアセテート5:5を用いたクロマトグラフィーカラムに加え、化合物58を無色油(138mg、0.38mmol、53%)として得る。分析データ:1H−NMR(300MHz;CDCl3):δ6.75(d,J7.6Hz,1H),6.69(s,1H),6.56(br s,1H),6.49(d,J7.6Hz,1H),5.66(s,1H),5.04(t,J6.2Hz,1H),4.54(s,2H),3.44(t,J6.5Hz,2H),2.63(t,J6.5Hz,2H),2.15−2.03(m,7H),1.66(s,3H),1.58(s,3H).MS:M−1 360.
化合物の活性は、カルシウム・マイクロフルオロメトリー・アッセイにより、TRPV1発現細胞(TRPV1−SH−SY5Y)で測定した。より強力な化合物の効力も求めた。
5%CO2及び37°Cの湿度制御インキュベータ内において、ラットTRPV1チャネル(SH−SY5Y−TRPV1)を安定発現するSH−SY5Y細胞を、10%(v/v)FCS、1%非必須アミノ酸、2mM L−グルタミン、100μg/mlストレプトマイシン、100U/mlペニシリン及び0.4μg/mlピューロマイシンを含有する、Earleの最小必須培地(Earle´s minimum essential medium(MEM))中で培養した。蛍光アッセイの場合、TRPV1チャネルを発現する細胞(TRPV1−SH−SY5Y)を96ウェルプレート(コーニング社(Corning Incorporated)、コーニング、ニューヨーク)に、処置2日前に細胞密度40,000個で播種した。処置日に、培地をプロベネシド2.5mMを添加した色素添加溶液Fluo−4NW100μLで置き換えた。5%CO2の加湿雰囲気中で37℃にて60分間インキュベートした後、プレートを蛍光プレートリーダ(Polastar Omega BMG Labtech)に移した。Fluo−4色素のベースライン蛍光(発光485nm/励起520nm)を4サイクル記録した。次に、媒体(DMSO)1μL又は最終濃度10μMの化合物をウェルに添加し、アゴニスト(TRPV1では10μMカプサイシン)による刺激する前の10サイクルの間に蛍光強度を記録した。アンタゴニスト(TRPV1では10μMルテニウムレッド)を遮断のために添加した。蛍光強度の変化を更に10サイクルの間に記録した。結果を以下の表2に示す。
最も強力な化合物を選択して、EC50及びIC50を計算した。正規化反応(%)対log[μM]を、可変勾配を用いる非線形適合である、4パラメータ用量応答曲線Y=100/(1+10^((LogEC50−X)*HillSlope))(式中、X=%正規化反応、Y=log [μM])、又は単なる用量応答曲線Y=100/(1+10^((LogEC50−X)))に調整した。EC50は、95%の信頼区間と、後続の回帰調整のためのr2で表される。データはすべて、平均±平均の標準誤差(SD)として表す。各条件は、3種類の独立した実験(N=3)にて3通り(n=3)評価した。表3に結果を示す。
炎症性疼痛のモデル
炎症性疼痛のモデルで試験を行うために、より高い効力を有する化合物の1つ(実施例37)を選択した。C57マウス(約30g)を研究に使用した。C57BL/6は、フランスのJanvierから入手した。完全フロイントアジュバント(CFA)エマルジョン(1:1油/生理食塩水、0.5mg/ml)(10μl)を右後足の足底表面に注射した(Garcia−Martinez et al.,2006)。CFA注射の24時間後、化合物実施例37を右後足に、静脈内(1mg/kg、3mg/kg又は10 mg/kg)又は足底内(10mg/kg、30mg/kg又は100mg/kg)投与した。熱痛覚過敏を、CFA注射後の24時間及び化合物投与の2時間後まで、左記に報告したようなウゴ・バジレ・ダイナミック・プランター・エステシオメータ(Ugo Basile Dynamic Plantar Aesthesiometer)(Garcia−Martinez et al.,2006)によって監視した。簡潔には、マウスは、高架ガラステーブル上の個々のパースペックス(Perspex)ボックスからなる装置に馴化させた。可動式放射熱源がテーブルの下に位置し、後足に焦点を合わせた。足引っ込め潜時は、マウスが後足を熱源から除去するのにかかる時間として定義した。組織の損傷を防止するために、25秒の遮断ポイントを設定した。化合物実施例37は、静脈内投与時(図1)及び足底内投与時(図2)の両方で、熱痛覚過敏試験における抗侵害受容効果を示した。
実施例37をかゆみのモデルで試験した(図3)。C57マウス(約30g)を透明プラスチックケージに入れ、10分間の馴化期間の後、生理食塩水25μL中のヒスタミン125μgを足底内注射した。ヒスタミンの注射直後に、動物を観察ケージに戻し、30分間に注射した足のリッキングに費やした時間を記録し、クロノメーターを用いて手動で測定した(図3、白棒)。実施例37(100μg)を投与する動物には、ヒスタミン注射の30分前に化合物を注射した(図3、黒棒、****p<0.001)。
実施例37を非ヒスタミン作動性掻痒症のモデルで評価した(図4)。C57マウス(約30g)を透明なプラスチックケージに入れ、10分間馴化させた後、生理食塩水25μL中クロロキン200μgを足底内注射した。クロロキン注射の直後に、動物を観察ケージに戻した。30分間の期間、注射した足のリッキングに費した時間を記録し、クロノメーターを用いて測定した(図4、白棒)。実施例37を、クロロキン注射の30分前に100μg/足にて足底内投与した(図4、黒棒、*p<0.05、***p<0.001)。
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Claims (15)
- 式(I)の化合物又はその医薬的、獣医学的若しくは化粧品的に許容される塩、又は式(I)の化合物又はその医薬的、獣医学的若しくは化粧品的に許容可能な塩のいずれかのどちらかの、立体異性体若しくは混合物:
式中、
mが1〜3から選択される整数であり;
R1、R2、R6及びR6´が、H、(C1−C8)アルキル、不飽和(C2−C8)炭化水素及び(C3−C6)シクロアルキルからなる群から独立して選択され;
ここで(C1−C8)アルキル、不飽和(C2−C8)炭化水素、及び(C3−C6)シクロアルキルが、ハロゲン、−COOH、−OH、−NH2、−COOR6、−NO2、−CF3、−OCF3、−CN、−OR6、−CONH2、−CONHR6、−CONR6R7、−NHR6、−NR6R7、−NHCOR6、−NHSO2R6、及び−SO2NHR6からなる群から選択される1つ以上の置換基で任意に置換され;
R3が、水素又はハロゲンであり;
R4が、H、(C1−C8)アルキル、不飽和(C2−C8)炭化水素、(C3−C6)シクロアルキル、(C6−C12)アリール及び(C5−C12)ヘテロアリールからなる群から選択され;
ここで(C1−C8)アルキル、不飽和(C2−C8)炭化水素、(C3−C6)シクロアルキル、(C6−C12)アリール及び(C5−C12)ヘテロアリールが、ハロゲン、−COOH、−OH、−NH2、−COOR6、−NO2、−CF3、−OCF3、−CN、−OR6、−CONH2、−CONHR6、−CONR6R7、−NHR6、−NR6R7、−NHCOR6、−NHSO2R6、及び−SO2NHR6からなる群から選択される1つ以上の置換基で任意に置換され;
R5が、(C3−C28)アルキル、不飽和(C3−C28)炭化水素、(C6−C12)アリール及び(C5−C12)ヘテロアリールであり、
ここで(C1−C8)アルキル、不飽和(C3−C28)炭化水素、(C6−C12)アリール及び(C5−C12)ヘテロアリールが、ハロゲン、−COOH、−OH、−NH2、−COOR6、−NO2、−CF3、−OCF3、−CN、−OR6、−CONH2、−CONHR6、−CONR6R7、−NHR6、−NR6R7、−NHCOR6、−NHSO2R6、及び−SO2NHR6からなる群から選択される1つ以上の置換基で任意に置換され、
但し、前記式(I)の化合物が、
(3,4−ジメトキシフェネチルカルバモイル)メチル−ブタ−2−エノエート、
(3,4−ジメトキシフェネチル−カルバモイル)メチル4−メチルペンタノエート、
(3,4−ジメトキシベンジルカルバモイル)メチル3,3−ジメチルブタノエート、
(3,4−ジメトキシフェネチルカルバモイル)メチル3,3−ジメチルブタノエート、
(3,4−ジメトキシフェネチルカルバモイル)メチル3−メチルブタ−2−エノエート、
(3,4−ジメトキシベンジルカルバモイル)メチル4−メチルペンタノエート、
(3,4−ジメトキシベンジルカルバモイル)−メチル3−メチルブタ−2−エノエート、
(2E,4E)−(3,4−ジメトキシベンジルカルバモイル)メチルヘキサ−2,4−ジエノエート、(3,4−ジメトキシベンジルカルバモイル)メチルブチレート、
(3,4−ジメトキシベンジルカルバモイル)メチルブチレート、
(3,4−ジメトキシフェネチルカルバモイル)メチルヘキサ−2,4−ジエノエート、
(3,4−ジメトキシフェネチルカルバモイル)メチル2−エチルブタノエート、(3,4−ジメトキシベンジルカルバモイル)メチルブタ−2−エノエート、(3,4−ジメトキシベンジルカルバモイル)メチルブタ−3−エノエート、
(3,4−ジメトキシベンジルカルバモイル)メチルブタ−3−エノエート、
(3,4−ジメトキシベンジルカルバモイル)メチルウンデカ−10−エノエート、
(3,4−ジメトキシベンジルカルバモイル)メチル2−メチルペンタノエート及び
2−(3,4−ジメトキシフェネチルカルバモイル)プロパン−2−イルペンタノエート以外である。 - mが1〜2から選択される整数である、請求項1に記載の式(I)の化合物。
- R1が、H、任意に置換された(C1−C8)アルキル及び任意に置換された不飽和(C2−C8)炭化水素からなる群から選択される、請求項1〜2のいずれかに記載の式(I)の化合物。
- R2が、H、任意に置換された(C1−C8)アルキル及び任意に置換された不飽和(C2−C8)炭化水素からなる群から選択される、請求項1〜3のいずれかに記載の式(I)の化合物。
- R3がHである、請求項1〜4のいずれかに記載の式(I)の化合物。
- R3がハロゲンである、請求項1〜5のいずれかに記載の式(I)の化合物。
- R4が、H、任意に置換された(C1−C8)アルキル及び任意に置換された不飽和(C2−C8)炭化水素からなる群から選択される、請求項1〜6のいずれかに記載の式(I)の化合物。
- R5が、任意に置換された(C3−C28)アルキル及び任意に置換された不飽和(C3−C28)炭化水素からなる群から選択される、請求項1〜7のいずれかに記載の式(I)の化合物。
- R6及びR6´が、H、任意に置換された(C1−C8)アルキル及び任意に置換された不飽和(C2−C8)炭化水素からなる群から独立して選択される、請求項1〜8のいずれかに記載の式(I)の化合物。
- 2−((4−ヒドロキシ−3−メトキシベンジル)アミノ)−2−オキソエチルブチレート;
2−((4−ヒドロキシ−2−ヨード−5−メトキシベンジル)アミノ)−2−オキソエチルブチレート;
2−((4−ヒドロキシ−3−メトキシベンジル)アミノ)−2−オキソエチルペンタノエート;
2−((4−ヒドロキシ−2−ヨード−5−メトキシベンジル)アミノ)−2−オキソエチルペンタノエート;
2−((4−ヒドロキシ−3−メトキシベンジル)アミノ)−2−オキソエチル3−メチルブタノエート;
2−((4−ヒドロキシ−2−ヨード−5−メトキシベンジル)アミノ)−2−オキソエチル3−メチル−ブタノエート;
2−((4−ヒドロキシ−3−メトキシベンジル)アミノ)−2−オキソエチルヘキサノエート;
2−((4−ヒドロキシ−2−ヨード−5−メトキシベンジル)アミノ)−2−オキソエチルヘキサノエート;
(2E,4E)−2−((4−ヒドロキシ−3−メトキシベンジル)アミノ)−2−オキソエチルヘキサ−2,4−ジエノエート;
(2E,4E)−2−((4−ヒドロキシ−2−ヨード−5−メトキシベンジル)アミノ)−2−オキソエチルヘキサ−2,4−ジエノエート;
2−((4−ヒドロキシ−3−メトキシベンジル)アミノ)−2−オキソエチルヘプタノエート;
2−((4−ヒドロキシ−2−ヨード−5−メトキシベンジル)アミノ)−2−オキソエチルヘプタノエート;
2−((4−ヒドロキシ−3−メトキシベンジル)アミノ)−2−オキソエチルオクタノエート;
2−((4−ヒドロキシ−2−ヨード−5−メトキシベンジル)アミノ)−2−オキソエチルオクタノエート;
2−((4−ヒドロキシ−3−メトキシベンジル)アミノ)−2−オキソエチルノナノエート;
2−((4−ヒドロキシ−2−ヨード−5−メトキシベンジル)アミノ)−2−オキソエチルノナノエート;
(E)−2−((4−ヒドロキシ−3−メトキシベンジル)アミノ)−2−オキソエチル3,7−ジメチルオクタ−2,6−ジエノエート;
(E)−2−((4−ヒドロキシ−2−ヨード−5−メトキシベンジル)アミノ)−2−オキソエチル3,7−ジメチルオクタ−2,6−ジエノエート;
2−((4−ヒドロキシ−3−メトキシベンジル)アミノ)−2−オキソエチルデカノエート;
2−((4−ヒドロキシ−2−ヨード−5−メトキシベンジル)アミノ)−2−オキソエチルデカノエート;
2−((4−ヒドロキシ−3−メトキシベンジル)アミノ)−2−オキソエチルドデカノエート;
2−((4−ヒドロキシ−2−ヨード−5−メトキシベンジル)アミノ)−2−オキソエチルドデカノエート;
2−((4−ヒドロキシ−3−メトキシベンジル)アミノ)−2−オキソエチルペンタデカノエート;
2−((4−ヒドロキシ−2−ヨード−5−メトキシベンジル)アミノ)−2−オキソエチルペンタデカノエート;
2−((4−ヒドロキシ−3−メトキシベンジル)アミノ)−2−オキソエチルステアレート;
2−((4−ヒドロキシ−2−ヨード−5−メトキシベンジル)アミノ)−2−オキソエチルステアレート;
2−((4−ヒドロキシ−3−メトキシベンジル)アミノ)−2−オキソエチルオレエート;
2−((4−ヒドロキシ−2−ヨード−5−メトキシベンジル)アミノ)−2−オキソエチルオレエート;
(R,Z)−2−((4−ヒドロキシ−3−メトキシベンジル)アミノ)−2−オキソエチル12−ヒドロキシオクタデカ−9−エノエート;
(R,Z)−2−((4−ヒドロキシ−2−ヨード−5−メトキシベンジル)アミノ)−2−オキソエチル12−ヒドロキシオクタデカ−9−エノエート;
(Z)−2−((4−ヒドロキシ−3−メトキシベンジル)アミノ)−2−オキソエチル12−(2−フェニルアセトキシ)オクタデカ−9−エノエート;
(Z)−2−((4−ヒドロキシ−2−ヨード−5−メトキシベンジル)アミノ)−2−オキソエチル12−(2−フェニルアセトキシ)オクタデカ−9−エノエート;
(Z)−2−((4−ヒドロキシ−3−メトキシベンジル)アミノ)−2−オキソエチルドコサ−13−エノエート;
(Z)−2−((4−ヒドロキシ−2−ヨード−5−メトキシベンジル)アミノ)−2−オキソエチルドコサ−13−エノエート;
(5Z,8Z,11Z,14Z)−2−((4−ヒドロキシ−3−メトキシベンジル)アミノ)−2−オキソエチルイコサ−5,8,11,14−テトラエノエート;
(5Z,8Z,11Z,14Z)−2−((4−ヒドロキシ−2−ヨード−5−メトキシベンジル)アミノ)−2−オキソエチルイコサ−5,8,11,14−テトラエノエート;
(4E,8E,12E,16E)−2−((4−ヒドロキシ−3−メトキシベンジル)−アミノ)−2−オキソエチル4,8,13,17,21−ペンタメチルドコサ−4,8,12,16,20−ペンタエノエート;
(4E,8E,12E,16E)−2−((4−ヒドロキシ−2−ヨード−5−メトキシベンジル)アミノ)−2−オキソエチル4,8,13,17,21−ペンタメチル−ドコサ−4,8,12,16,20−ペンタエノエート;
(E)−2−((3,4−ジヒドロキシベンジル)−アミノ)−2−オキソエチル3,7−ジメチルオクタ−2,6−ジエノエート;
(E)−2−((4,5−ジヒドロキシ−2−ヨード−ベンジル)アミノ)−2−オキソエチル3,7−ジメチルオクタ−2,6−ジエノエート;
(4E,8E,12E,16E)−2−((3,4−ジヒドロキシベンジル)アミノ)−2−オキソエチル4,8,13,17,21−ペンタメチルドコサ−4,8,12,16,20−ペンタエノエート;
(4E,8E,12E,16E)−2−((4,5−ジヒドロキシ−2−ヨードベンジル)−アミノ)−2−オキソエチル4,8,13,17,21−ペンタメチル−ドコサ−4,8,12,16,20−ペンタノエート;
(E)−2−((3,4−ジヒドロキシフェネチル)アミノ)−2−オキソエチル3,7−ジメチルオクタ−2,6−ジエノエート;
(E)−2−((4,5−ジヒドロキシ−2−ヨードフェネチル)アミノ)−2−オキソエチル3,7−ジメチルオクタ−2,6−ジエノエート;
(4E,8E,12E,16E)−2−((3,4−ジヒドロキシフェネチル)アミノ)−2−オキソエチル4,8,13,17,21−ペンタメチルドコサ−4,8,12,16,20−ペンタエノエート;
(4E,8E,12E,16E)−2−((4,5−ジヒドロキシ−2−ヨードフェネチル)−アミノ)−2−オキソエチル4,8,13,17,21−ペンタメチル−ドコサ−4,8,12,16,20−ペンタノエート;
2−((3,4−ジヒドロキシフェネチル)−アミノ)−2−オキソエチルオレエート;
2−((4,5−ジヒドロキシ−2−ヨードフェネチル)アミノ)−2−オキソエチルオレエート;
(5Z,8Z,11Z,14Z)−2−((3,4−ジヒドロキシフェネチル)アミノ)−2−オキソエチルイコサ−5,8,11,14−テトラエノエート;及び
(5Z,8Z,11Z,14Z)−2−((4,5−ジヒドロキシ−2−ヨードフェネチル)−アミノ)−2−オキソエチルイコサ−5,8,11,14−テトラエノエート
からなる群から選択される、請求項1に記載の式(I)の化合物。 - a)ホルムアルデヒドの存在下で、式(II)の化合物と式(III)の化合物(式中、R1、R2、R3、R5、R6、R6´及びmは、上で定義した通りである)とを反応させて、式(I)の化合物を生じる工程;
b)任意に、このように得た前記式(I)の化合物を、式(I)の別の化合物に変換する1つ又は複数の工程;及び
c)任意に、工程a)又はb)のいずれかで得られた前記式(I)の化合物を塩基又は酸と反応させて、対応する塩を得る工程;
を含む、請求項1〜10のいずれかに定義される式(I)の化合物の調製方法。 - 式(I)の化合物又はその医薬的、獣医学的若しくは化粧品的に許容される塩、又は式(I)の化合物又はその医薬的、獣医学的若しくは化粧品的に許容される塩のどちらかの、任意の立体異性体の有効量を、1つ以上の医薬的又は獣医学的に許容される賦形剤又は担体と共に含む、組成物:
式中、
mは1〜3から選択される整数であり;
R1、R2、R6及びR6´は、H、(C1−C8)アルキル、不飽和(C2−C8)炭化水素及び(C3−C6)シクロアルキルからなる群から独立して選択され;
ここで(C1−C8)アルキル、不飽和(C2−C8)炭化水素、及び(C3−C6)シクロアルキルは、ハロゲン、−COOH、−OH、−NH2、−COOR6、−NO2、−CF3、−OCF3、−CN、−OR6、−CONH2、−CONHR6、−CONR6R7、−NHR6、−NR6R7、−NHCOR6、−NHSO2R6、及び−SO2NHR6からなる群から選択される1つ以上の置換基で任意に置換され;
R3は、水素又はハロゲンであり;
R4は、H、(C1−C8)アルキル、不飽和(C2−C8)炭化水素、(C3−C6)シクロアルキル、(C6−C12)アリール及び(C5−C12)ヘテロアリールからなる群から選択され;
ここで(C1−C8)アルキル、不飽和(C2−C8)炭化水素、(C3−C6)シクロアルキル、(C6−C12)アリール及び(C5−C12)ヘテロアリールは、ハロゲン、−COOH、−OH、−NH2、−COOR6、−NO2、−CF3、−OCF3、−CN、−OR6、−CONH2、−CONHR6、−CONR6R7、−NHR6、−NR6R7、−NHCOR6、−NHSO2R6、及び−SO2NHR6からなる群から選択される1つ以上の置換基で任意に置換され、
R5は、(C3−C28)アルキル、不飽和(C3−C28)炭化水素、(C6−C12)アリール及び(C5−C12)ヘテロアリールであり;
ここで(C1−C8)アルキル、不飽和(C3−C28)炭化水素、(C6−C12)アリール及び(C5−C12)ヘテロアリールは、ハロゲン、−COOH、−OH、−NH2、−COOR6、−NO2、−CF3、−OCF3、−CN、−OR6、−CONH2、−CONHR6、−CONR6R7、−NHR6、−NR6R7、−NHCOR6、−NHSO2R6、及び−SO2NHR6からなる群から選択される1つ以上の置換基で任意に置換される。 - TRPV1により媒介される状態及び/又は疾患の治療及び/又は予防への使用のための、式(I)の化合物又はその医薬的、獣医学的若しくは化粧品的に許容される塩、式(I)の化合物又はその医薬的、獣医学的若しくは化粧品的に許容される塩のいずれかのどちらかの、任意の立体異性体若しくは混合物、又は請求項11に記載の組成物。
式中、
mは1〜3から選択される整数であり;
R1、R2、R6及びR6´は、H、(C1−C8)アルキル、不飽和(C2−C8)炭化水素及び(C3−C6)シクロアルキルからなる群から独立して選択され;
ここで(C1−C8)アルキル、不飽和(C2−C8)炭化水素、及び(C3−C6)シクロアルキルは、ハロゲン、−COOH、−OH、−NH2、−COOR6、−NO2、−CF3、−OCF3、−CN、−OR6、−CONH2、−CONHR6、−CONR6R7、−NHR6、−NR6R7、−NHCOR6、−NHSO2R6、及び−SO2NHR6からなる群から選択される1つ以上の置換基で任意に置換され;
R3は、水素又はハロゲンであり;
R4は、H、(C1−C8)アルキル、不飽和(C2−C8)炭化水素、(C3−C6)シクロアルキル、(C6−C12)アリール及び(C5−C12)ヘテロアリールからなる群から選択され;
ここで(C1−C8)アルキル、不飽和(C2−C8)炭化水素、(C3−C6)シクロアルキル、(C6−C12)アリール及び(C5−C12)ヘテロアリールは、ハロゲン、−COOH、−OH、−NH2、−COOR6、−NO2、−CF3、−OCF3、−CN、−OR6、−CONH2、−CONHR6、−CONR6R7、−NHR6、−NR6R7、−NHCOR6、−NHSO2R6、及び−SO2NHR6からなる群から選択される1つ以上の置換基で任意に置換され;
R5は、(C3−C28)アルキル、不飽和(C3−C28)炭化水素、(C6−C12)アリール及び(C5−C12)ヘテロアリールであり;
ここで(C1−C8)アルキル、不飽和(C3−C28)炭化水素、(C6−C12)アリール及び(C5−C12)ヘテロアリールは、ハロゲン、−COOH、−OH、−NH2、−COOR6、−NO2、−CF3、−OCF3、−CN、−OR6、−CONH2、−CONHR6、−CONR6R7、−NHR6、−NR6R7、−NHCOR6、−NHSO2R6、及び−SO2NHR6からなる群から選択される1つ以上の置換基で任意に置換される。 - 前記状態及び/又は疾患が疼痛、炎症及び癌から選択される、請求項13に記載の使用のための式(I)の化合物又は医薬組成物。
- 前記状態及び/又は疾患が、敏感肌、かゆみ(掻痒)、酒さ、尋常性ざ瘡、アトピー性皮膚炎、乾癬及び乾癬性関節炎から選択される、請求項13に記載の使用のための式(I)の化合物又は医薬組成物。
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