JP5989253B2 - mGluR5受容体活性のモジュレータとしてのエチニル誘導体 - Google Patents
mGluR5受容体活性のモジュレータとしてのエチニル誘導体 Download PDFInfo
- Publication number
- JP5989253B2 JP5989253B2 JP2015537221A JP2015537221A JP5989253B2 JP 5989253 B2 JP5989253 B2 JP 5989253B2 JP 2015537221 A JP2015537221 A JP 2015537221A JP 2015537221 A JP2015537221 A JP 2015537221A JP 5989253 B2 JP5989253 B2 JP 5989253B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- formula
- pyridine
- compounds
- disease
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Psychology (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Epidemiology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
[式中、
YはN又はCHである]
で示されるエチニル誘導体もしくは薬学的に許容しうる酸付加塩、ラセミ混合物、又はその対応する鏡像異性体及び/もしくは光学異性体及び/もしくはその立体異性体に関する。
5−(2−クロロ−ピリジン−4−イルエチニル)−ピリジン−2−カルボン酸tert−ブチル−メチル−アミド
である。
5−(3−クロロ−フェニルエチニル)−ピリジン−2−カルボン酸tert−ブチル−メチル−アミド
である。
本発明の特定の実施形態は、次の化合物からなる:
5−(2−クロロ−ピリジン−4−イルエチニル)−ピリジン−2−カルボン酸tert−ブチル−メチル−アミド、
5−(3−クロロ−フェニルエチニル)−ピリジン−2−カルボン酸tert−ブチル−メチル−アミド。
細胞内Ca2+動員アッセイ法
ヒトmGlu5a受容体をコードするcDNAで安定にトランスフェクトされたモノクローナルHEK−293細胞株を生成した。mGlu5ポジティブアロステリックモジュレータ(PAM)を用いた試験については、低受容体発現レベル及び低構成的受容体活性を有する細胞株を選択し、アゴニスト活性対PAM活性の差別化を可能にした。細胞を、標準プロトコル(Freshney, 2000)に従い、1mMグルタミン、10%(vol/vol)加熱不活性化子ウシ血清、ペニシリン/ストレプトマイシン、50μg/mLハイグロマイシン及び15μg/mLブラストサイジンを補充した、高グルコースのダルベッコ変法イーグル培地で培養した(細胞培養試薬及び抗生物質は全てInvitrogen(Basel, Switzerland)製である)。
結合実験については、Schlaeger及びChristensen[Cytotechnology 15:1-13 (1998)]によって記載された手順を用いて、ヒトmGlu5a受容体をコードするcDNAを、EBNA細胞に一時的にトランスフェクトした。細胞膜ホモジェネートをアッセイ当日まで−80℃で保存し、アッセイ当日、その細胞膜ホモジェネートを解凍し、pH7.4の結合バッファー(15mM Tris−HCl、120mM NaCl、100mM KCl、25mM CaCl2、25mM MgCl2)に再懸濁し、ポリトロナイズ(polytronise)し、20μgのタンパク質/ウェルの最終アッセイ濃度とした。
以下の表から分かるように、本発明の化合物(NAM)は、構造上類似した対照化合物1、2及び3(PAM)と比較して、明らかに異なるプロファイルを示す。
a)式
で示される化合物を化合物CH3Iと反応させ、式
[式中、置換基は上述したものである]で示される化合物とすること、又は
b)式
で示される化合物を、式
で示される化合物と反応させ、式
[式中、置換基は上述したものである]で示される化合物とすることを含む。
5−(2−クロロ−ピリジン−4−イルエチニル)−ピリジン−2−カルボン酸tert−ブチル−メチル−アミド
5−(3−クロロ−フェニルエチニル)−ピリジン−2−カルボン酸tert−ブチル−メチル−アミド
Claims (11)
- 式I
[式中、
YはN又はCHである]
で示される化合物もしくは薬学的に許容しうる酸付加塩、ラセミ混合物、又はその対応する鏡像異性体及び/もしくは光学異性体及び/もしくはその立体異性体。 - YがNである、請求項1に記載の式Iで示される化合物。
- 前記化合物が、
5−(2−クロロ−ピリジン−4−イルエチニル)−ピリジン−2−カルボン酸tert−ブチル−メチル−アミド
である、請求項2に記載の式Iで示される化合物。 - YがCHである、請求項1に記載の式Iで示される化合物。
- 前記化合物が、
5−(3−クロロ−フェニルエチニル)−ピリジン−2−カルボン酸tert−ブチル−メチル−アミド
である、請求項4に記載の式Iで示される化合物。 - 治療上有効な物質としての使用のための、請求項1〜5のいずれか一項に記載の化合物。
- 請求項1に記載の式Iで示される化合物の調製のための方法であって、以下のバリアント:
a)式
で示される化合物を化合物CH3Iと反応させ、式
[式中、置換基は請求項1に記載される]で示される化合物とすること、又は
b)式
で示される化合物を、式
で示される化合物と反応させ、式
[式中、置換基は請求項1に記載される]で示される化合物とすることを含む、方法。 - 請求項1〜5のいずれか一項に記載の化合物及び治療上有効な担体を含有する医薬組成物。
- 不安及び疼痛、うつ病、脆弱X症候群、自閉性障害、パーキンソン病、ならびに胃食道逆流疾患(GERD)の処置のための、請求項8に記載の医薬組成物。
- 不安及び疼痛、うつ病、脆弱X症候群、自閉性障害、パーキンソン病、ならびに胃食道逆流疾患(GERD)を処置するための薬品の製造のための、請求項1〜5のいずれか一項に記載の化合物の使用。
- 不安及び疼痛、うつ病、脆弱X症候群、自閉性障害、パーキンソン病、ならびに胃食道逆流疾患(GERD)の処置のための、請求項1〜5のいずれか一項に記載の化合物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP12189015 | 2012-10-18 | ||
EP12189015.6 | 2012-10-18 | ||
PCT/EP2013/071493 WO2014060394A1 (en) | 2012-10-18 | 2013-10-15 | Ethynyl derivatives as modulators of mglur5 receptor activity |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2015534965A JP2015534965A (ja) | 2015-12-07 |
JP5989253B2 true JP5989253B2 (ja) | 2016-09-07 |
Family
ID=47049073
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2015537221A Expired - Fee Related JP5989253B2 (ja) | 2012-10-18 | 2013-10-15 | mGluR5受容体活性のモジュレータとしてのエチニル誘導体 |
Country Status (25)
Country | Link |
---|---|
US (1) | US9328070B2 (ja) |
EP (1) | EP2909179B1 (ja) |
JP (1) | JP5989253B2 (ja) |
KR (1) | KR101656634B1 (ja) |
CN (1) | CN104718191B (ja) |
AR (1) | AR093043A1 (ja) |
AU (1) | AU2013333984B2 (ja) |
BR (1) | BR112015007991A2 (ja) |
CA (1) | CA2882484A1 (ja) |
CL (1) | CL2015000708A1 (ja) |
CR (1) | CR20150143A (ja) |
EA (1) | EA025668B1 (ja) |
ES (1) | ES2599509T3 (ja) |
HK (1) | HK1208032A1 (ja) |
IL (1) | IL237116A (ja) |
MA (1) | MA38011B1 (ja) |
MX (1) | MX2015004086A (ja) |
MY (1) | MY170152A (ja) |
PE (1) | PE20150628A1 (ja) |
PH (1) | PH12015500496A1 (ja) |
SG (1) | SG11201501375YA (ja) |
TW (1) | TWI468393B (ja) |
UA (1) | UA114934C2 (ja) |
WO (1) | WO2014060394A1 (ja) |
ZA (1) | ZA201500896B (ja) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PE20150733A1 (es) * | 2012-10-18 | 2015-05-17 | Hoffmann La Roche | Derivados de etinilo como moduladores de la actividad del receptor mglur5 |
LT3322701T (lt) | 2015-07-15 | 2019-07-10 | F. Hoffmann-La Roche Ag | Etinilo dariniai kaip metabotropinių glutamato receptorių moduliatoriai |
DK3484889T3 (da) | 2016-07-18 | 2020-10-26 | Hoffmann La Roche | Ethynylderivater |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW544448B (en) * | 1997-07-11 | 2003-08-01 | Novartis Ag | Pyridine derivatives |
SG185285A1 (en) * | 2007-06-03 | 2012-11-29 | Univ Vanderbilt | Benzamide mglur5 positive allosteric modulators and methods of making and using same |
US8853392B2 (en) * | 2007-06-03 | 2014-10-07 | Vanderbilt University | Benzamide mGluR5 positive allosteric modulators and methods of making and using same |
CN101970018A (zh) * | 2007-09-28 | 2011-02-09 | 纳幕尔杜邦公司 | 离子液体稳定剂组合物 |
TW201124391A (en) * | 2009-10-20 | 2011-07-16 | Lundbeck & Co As H | 2-substituted-ethynylthiazole derivatives and uses of same |
US8389536B2 (en) * | 2009-10-27 | 2013-03-05 | Hoffmann-La Roche Inc. | Positive allosteric modulators (PAM) |
US8772300B2 (en) * | 2011-04-19 | 2014-07-08 | Hoffmann-La Roche Inc. | Phenyl or pyridinyl-ethynyl derivatives |
-
2013
- 2013-10-15 CA CA2882484A patent/CA2882484A1/en not_active Abandoned
- 2013-10-15 ES ES13776810.7T patent/ES2599509T3/es active Active
- 2013-10-15 EP EP13776810.7A patent/EP2909179B1/en not_active Not-in-force
- 2013-10-15 PE PE2015000395A patent/PE20150628A1/es not_active Application Discontinuation
- 2013-10-15 KR KR1020157009546A patent/KR101656634B1/ko active IP Right Grant
- 2013-10-15 EA EA201590722A patent/EA025668B1/ru not_active IP Right Cessation
- 2013-10-15 CN CN201380053650.6A patent/CN104718191B/zh not_active Expired - Fee Related
- 2013-10-15 BR BR112015007991A patent/BR112015007991A2/pt active Search and Examination
- 2013-10-15 SG SG11201501375YA patent/SG11201501375YA/en unknown
- 2013-10-15 JP JP2015537221A patent/JP5989253B2/ja not_active Expired - Fee Related
- 2013-10-15 MX MX2015004086A patent/MX2015004086A/es unknown
- 2013-10-15 WO PCT/EP2013/071493 patent/WO2014060394A1/en active Application Filing
- 2013-10-15 UA UAA201504379A patent/UA114934C2/uk unknown
- 2013-10-15 MY MYPI2015000492A patent/MY170152A/en unknown
- 2013-10-15 AU AU2013333984A patent/AU2013333984B2/en not_active Ceased
- 2013-10-17 AR ARP130103765A patent/AR093043A1/es unknown
- 2013-10-17 TW TW102137557A patent/TWI468393B/zh not_active IP Right Cessation
-
2015
- 2015-02-05 IL IL237116A patent/IL237116A/en not_active IP Right Cessation
- 2015-02-06 ZA ZA2015/00896A patent/ZA201500896B/en unknown
- 2015-03-06 PH PH12015500496A patent/PH12015500496A1/en unknown
- 2015-03-18 CR CR20150143A patent/CR20150143A/es unknown
- 2015-03-20 CL CL2015000708A patent/CL2015000708A1/es unknown
- 2015-04-17 US US14/689,366 patent/US9328070B2/en not_active Expired - Fee Related
- 2015-04-17 MA MA38011A patent/MA38011B1/fr unknown
- 2015-09-08 HK HK15108720.3A patent/HK1208032A1/zh not_active IP Right Cessation
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5989250B2 (ja) | Mglur5受容体活性のモジュレーターとしてのエチニル誘導体 | |
KR101767348B1 (ko) | 대사형 글루타메이트 수용체 길항제로서의 에틴일 유도체 | |
JP5753626B2 (ja) | ピラゾリジン−3−オン誘導体 | |
JP6263542B2 (ja) | Mglur5受容体活性のモジュレーターとしてのエチニル誘導体 | |
JP5989253B2 (ja) | mGluR5受容体活性のモジュレータとしてのエチニル誘導体 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20160405 |
|
A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20160622 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20160802 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20160809 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5989253 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
LAPS | Cancellation because of no payment of annual fees |