JP2019529468A - mGluR2陰性アロステリック調節剤としてのクロマン、イソクロマン及びジヒドロイソベンゾフラン誘導体、組成物、及びそれらの使用 - Google Patents
mGluR2陰性アロステリック調節剤としてのクロマン、イソクロマン及びジヒドロイソベンゾフラン誘導体、組成物、及びそれらの使用 Download PDFInfo
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- JP2019529468A JP2019529468A JP2019516203A JP2019516203A JP2019529468A JP 2019529468 A JP2019529468 A JP 2019529468A JP 2019516203 A JP2019516203 A JP 2019516203A JP 2019516203 A JP2019516203 A JP 2019516203A JP 2019529468 A JP2019529468 A JP 2019529468A
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- compound
- difluorophenyl
- mmol
- pharmaceutically acceptable
- pyridine
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Links
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- XWIXXUJIMCMENH-UHFFFAOYSA-N ethyl 4-[2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl]-2-hydroxybutanoate Chemical compound ClC1=NC(=CC(=C1CCC(C(=O)OCC)O)C1=C(C=C(C=C1)F)F)Cl XWIXXUJIMCMENH-UHFFFAOYSA-N 0.000 description 4
- ZYUBBRUPXKDPFR-UHFFFAOYSA-N ethyl 4-[2,6-dichloro-4-(2,4-difluorophenyl)pyridin-3-yl]-2-oxobutanoate Chemical compound ClC1=NC(=CC(=C1CCC(C(=O)OCC)=O)C1=C(C=C(C=C1)F)F)Cl ZYUBBRUPXKDPFR-UHFFFAOYSA-N 0.000 description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
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Abstract
Description
R2は、H、シクロプロピル、−(C1−C4)アルキル、−(C1−C4)アルキル−OH、−(C1−C4)アルキル−OCH3、−(C1−C4)ハロアルキル、−(C1−C4)アルキル−O−(C1−C4)ハロアルキル、−CH2−O−(C1−C4)ハロアルキル、−CH(CH3)−O−(C1−C4)ハロアルキル、−CH2−NH−(C1−C4)ハロアルキル、及び−CH2−N(CH3)−(C1−C4)ハロアルキルから選択され、
R2Aは、H及びメチルから選択され;
R3は、H及びメチルから選択され;
R3Aは、H及びメチルから選択され;
環Bは、フェニル、ヘテロアリール、−(C5−C6)シクロアルキル、及び−(C5−C6)シクロアルケニルからなる群から選択される部分であり;
nは、0、1、2又は3であり、但し、nの値は環B上の置換可能な水素原子の最大数を超えるものではなく;
各R1(存在する場合)は、ハロゲン、−CN、−OH、−(C1−C6)アルキル,−O−(C1−C6)アルキル、−(C1−C6)ハロアルキル、−O−(C1−C6)ハロアルキル、シクロプロピル、シクロブチル、−NH2、−NH(C1−C6)アルキル、−N(C1−C6アルキル)2、−C(O)O(C1−C6)アルキル、及びフェニルからなる群から独立に選択される。
環B、n及び各R1は式(I)で定義の通りである。
R2は、H、シクロプロピル、−CH3、−CH(CH3)2、−CH2−OH、−CH2−OCH3、−CH2F、−CHF2、−CF3、−CH2CH2F、−CH2CHF2、−CH2CF3、−CH2−O−CH2F、−CH2−O−CHF2、−CH(CH3)−O−CH2F、−CH(CH3)−O−CHF2、−CH2−NH−CH2CF3、及び−CH2−N(CH3)−CH2CF3から選択され;
R2AはH及びメチルから選択され;
R3はH及びメチルから選択され;
R3AはH及びメチルから選択され;
環B、n及び各R1は式Iで定義の通りである。
R2は、H、シクロプロピル、−CH3、−CH(CH3)2、−CH2−OH、−CH2−OCH3、−CH2F、−CHF2、−CF3、−CH2CH2F、−CH2CHF2、−CH2CF3、−CH2−O−CH2F、−CH2−O−CHF2、−CH(CH3)−O−CH2F、−CH(CH3)−O−CHF2、−CH2−NH−CH2CF3、及び−CH2−N(CH3)−CH2CF3から選択され;
R2AはH及びメチルから選択され;
R3はH及びメチルから選択され;
R3AはHであり;
環B、n及び各R1は式Iで定義の通りである。
R2及びR2Aは両方ともメチルであり;
R3及びR3Aは両方ともHであり;
環B、n及び各R1は式Iで定義の通りである。
環B、n及び各R1は、式(I)で定義の通りである。
環B、n及び各R1は、式(I)で定義の通りである。
環B、n及び各R1は、式(I)で定義の通りである。
環Bは、フェニル、シクロペンチル、シクロヘキシル、ピリジニル、ピリミジニル、ピラゾリル、チエニル、チアゾリル、チアジアゾリル、イソオキサゾリル、オキサジアゾリル及びオキサゾリルからなる群から選択される部分であり;
nは0、1、2、又は3であり、但し、nの値は、環B上の置換可能な水素原子の最大数を超えるものではなく;
各R1(存在する場合)は、ハロゲン、−CN、−OH、−(C1−C6)アルキル,−O−(C1−C6)アルキル、−(C1−C6)ハロアルキル、−O−(C1−C6)ハロアルキル、シクロプロピル、シクロブチル、−NH2、−NH(C1−C6)アルキル、−N(C1−C6アルキル)2、−C(O)O(C1−C6)アルキル、及びフェニルからなる群から独立に選択される。
環Bは、フェニル、ピラゾリル、ピリジニル、チエニル、イソオキサゾリル、オキサジアゾリル及びオキサゾリルからなる群から選択される部分であり;
nは0、1、2、又は3であり;
各R1(存在する場合)は、フルオロ、クロロ、−CN、−OH、−(C1−C6)アルキル、−O−(C1−C6)アルキル、−(C1−C6)ハロアルキル、−O−(C1−C6)ハロアルキル、シクロプロピル、シクロブチル、−NH2、−NH(C1−C6)アルキル、−N(C1−C6アルキル)2、−C(O)O(C1−C6)アルキル、及びフェニルからなる群から独立に選択される。
環Bは、フェニル、ピラゾリル、ピリジニル、チエニル、イソオキサゾリル、オキサジアゾリル及びオキサゾリルからなる群から選択される部分であり;
nは0、1、2、又は3であり;
各R1(存在する場合)は、フルオロ、クロロ、−CH3、及び−CHCF2からなる群から独立に選択される。
R2は、H、シクロプロピル、−CH3、−CH(CH3)2、−CH2−OH、−CH2−OCH3、−CH2F、−CHF2、−CF3、−CH2CH2F、−CH2CHF2、−CH2CF3、−CH2−O−CH2F、−CH2−O−CHF2、−CH(CH3)−O−CH2F、−CH(CH3)−O−CHF2、−CH2−NH−CH2CF3、及び−CH2−N(CH3)−CH2CF3から選択され;
R2AはH及びCH3から選択され;
R3はH及びCH3から選択され;
R3AはH及びCH3から選択される。
R2がH、シクロプロピル、−CH3、−CH(CH3)2、−CH2−OH、−CH2−OCH3、−CH2F、−CHF2、−CF3、−CH2CH2F、−CH2CHF2、−CH2CF3、−CH2−O−CH2F、−CH2−O−CHF2、−CH(CH3)−O−CH2F、−CH(CH3)−O−CHF2、−CH2−NH−CH2CF3、及び−CH2−N(CH3)−CH2CF3から選択され;
R2AがH及びCH3から選択され;
R3がH及びCH3から選択され;
R3AがHである、式(IA−1)の化合物若しくはそれの立体異性体、又は当該化合物若しくは当該立体異性体の薬学的に許容される塩である。
R2がH、シクロプロピル、−CH3、−CH(CH3)2、−CH2−OH、−CH2−OCH3、−CH2F、−CHF2、−CF3、−CH2CH2F、−CH2CHF2、−CH2CF3、−CH2−O−CH2F、−CH2−O−CHF2、−CH(CH3)−O−CH2F、−CH(CH3)−O−CHF2、−CH2−NH−CH2CF3、及び−CH2−N(CH3)−CH2CF3から選択され;
R2AがHであり;
R3がH及びCH3から選択され:
R3AがHである、
別の実施形態は、
R2がH、シクロプロピル、−CH3、−CH(CH3)2、−CH2−OH、−CH2−OCH3、−CH2F、−CHF2、−CF3、−CH2CH2F、−CH2CHF2、−CH2CF3、−CH2−O−CH2F、−CH2−O−CHF2、−CH(CH3)−O−CH2F、−CH(CH3)−O−CHF2、−CH2−NH−CH2CF3、及び−CH2−N(CH3)−CH2CF3から選択され;
R2AがHであり;
R3がHであり;
R3AがHである、式(IA−1)の化合物若しくはそれの立体異性体、又は当該化合物若しくは当該立体異性体の薬学的に許容される塩である。
式中、
R2はH、シクロプロピル、−CH3、−CH(CH3)2、−CH2−OH、−CH2−OCH3、−CH2F、−CHF2、−CF3、−CH2CH2F、−CH2CHF2、−CH2CF3、−CH2−O−CH2F、−CH2−O−CHF2、−CH(CH3)−O−CH2F、−CH(CH3)−O−CHF2、−CH2−NH−CH2CF3、及び−CH2−N(CH3)−CH2CF3から選択され;
R3はHであり;
R3AはCH3である。
R2がH、シクロプロピル、−CH3、−CH(CH3)2、−CH2−OH、−CH2−OCH3、−CH2F、−CHF2、−CF3、−CH2CH2F、−CH2CHF2、−CH2CF3、−CH2−O−CH2F、−CH2−O−CHF2、−CH(CH3)−O−CH2F、−CH(CH3)−O−CHF2、−CH2−NH−CH2CF3、及び−CH2−N(CH3)−CH2CF3から選択され;
R3がCH3であり;
R3AがHである、式(IA−1a)の化合物若しくはそれの立体異性体、又は当該化合物若しくは当該立体異性体の薬学的に許容される塩である。
R2がH、シクロプロピル、−CH3、−CH(CH3)2、−CH2−OH、−CH2−OCH3、−CH2F、−CHF2、−CF3、−CH2CH2F、−CH2CHF2、−CH2CF3、−CH2−O−CH2F、−CH2−O−CHF2、−CH(CH3)−O−CH2F、−CH(CH3)−O−CHF2、−CH2−NH−CH2CF3、及び−CH2−N(CH3)−CH2CF3から選択され;
R3がHであり;
R3AがHである、式(IA−1a)の化合物若しくはそれの立体異性体、又は当該化合物若しくは当該立体異性体の薬学的に許容される塩である。
式中、
R2はH、シクロプロピル、−CH3、−CH(CH3)2、−CH2−OH、−CH2−OCH3、−CH2F、−CHF2、−CF3、−CH2CH2F、−CH2CHF2、−CH2CF3、−CH2−O−CH2F、−CH2−O−CHF2、−CH(CH3)−O−CH2F、−CH(CH3)−O−CHF2、−CH2−NH−CH2CF3、及び−CH2−N(CH3)−CH2CF3から選択され;
R3はHであり;
R3AはCH3である。
R2がH、シクロプロピル、−CH3、−CH(CH3)2、−CH2−OH、−CH2−OCH3、−CH2F、−CHF2、−CF3、−CH2CH2F、−CH2CHF2、−CH2CF3、−CH2−O−CH2F、−CH2−O−CHF2、−CH(CH3)−O−CH2F、−CH(CH3)−O−CHF2、−CH2−NH−CH2CF3、及び−CH2−N(CH3)−CH2CF3から選択され;
R3がCH3であり;
R3AがHである、式(IA−1b)の化合物若しくはそれの立体異性体、又は当該化合物若しくは当該立体異性体の薬学的に許容される塩である。
R2がH、シクロプロピル、−CH3、−CH(CH3)2、−CH2−OH、−CH2−OCH3、−CH2F、−CHF2、−CF3、−CH2CH2F、−CH2CHF2、−CH2CF3、−CH2−O−CH2F、−CH2−O−CHF2、−CH(CH3)−O−CH2F、−CH(CH3)−O−CHF2、−CH2−NH−CH2CF3、及び−CH2−N(CH3)−CH2CF3から選択され;
R3がHであり;
R3AがHである、式(IA−1b)の化合物若しくはそれの立体異性体、又は当該化合物若しくは当該立体異性体の薬学的に許容される塩である。
本明細書で用いられる用語はその通常の意味を有し、そのような用語の意味は各場合において独立している。それにもかかわらず、別段の記述がある場合を除き、以下の定義が本明細書全体及び特許請求の範囲に適用される。化学名、一般名及び化学構造は、同じ構造を説明するのに互換的に用いられることがあり得る。これらの定義は、別段の断りがない限り、用語が単独で使用されているか、他の用語と組み合わせて使用されているかに関係なく適用される。従って、「アルキル」の定義は、「アルキル」並びに「ヒドロキシアルキル」、「ハロアルキル」、アリールアルキル−、アルキルアリール−、「アルコキシ」などの「アルキル」部分に適用される。
本発明の化合物の個々の立体異性体は、例えば、実質的に他の異性体を含まないものであってもよく、例えば、ラセミ化合物として、又は全ての他の、若しくは他の選択された立体異性体と混合されたものであってもよい。本発明のキラル中心は、IUPAC 1974 Recommendationsによって定義されるS配置又はR配置を有するものであり得る。「塩」、「溶媒和物」、「エステル」、「プロドラッグ」などの用語の使用は、本発明の化合物のエナンチオマー、立体異性体、回転異性体、互変異性体、ラセミ化合物又はプロドラッグの塩、溶媒和物、エステル及びプロドラッグにも等しく適用されることが意図される。
別の実施形態は、治療上有効量の本発明の化合物、又はそれの立体異性体、又は当該化合物若しくは当該立体異性体の薬学的に許容される塩、並びに薬学的に許容される担体を含む医薬組成物を提供する。
別の実施形態は、mGluR2受容体が関与する疾患若しくは障害について患者(例えば、ヒト患者又は研究動物)を治療する方法を提供する。これらの方法は、有効量の本発明の化合物又は本発明の化合物(又はそれの立体異性体、又は前記化合物若しくは前記立体異性体の薬学的に許容される塩)を含む組成物を、処置を必要とする患者に対して投与して、mGluR2受容体が関与する疾患又は障害を治療することを含む。
本発明の化合物及び組成物は、本発明の化合物が有用性を有する疾患又は状態の治療において1以上の他の薬剤と組み合わせて用いることができ、その場合、薬剤組み合わせが望まれるものであり、例えば、その組み合わせが、いずれかの薬剤単独の場合よる安全性が高いか効果が高い。本発明の化合物は、本発明の化合物の副作用又は毒性を治療、予防、制御、改善又はリスク低下する1以上の他の薬剤と組み合わせて使用することができる。そのような他薬剤は、本発明の化合物と同時に、又は順次に、そのために一般的に使用される経路及び量で投与することができる。従って、本発明の医薬組成物には、本発明の化合物に加えて、1以上の他の有効成分を含むものなどがある。その組み合わせは、単位製剤組み合わせ製品の一部として、又は1以上の別の薬剤を治療法の一部として別個の製剤で投与するキット若しくは治療プロトコールとして投与しても良い。1実施形態において、前記組み合わせで有用な本発明の化合物は、本明細書に記載の式(I)、(IA)、(IA−1)、(IA−1a)、(IA−1b)、(IB)、(IC)及び(ID)のいずれか一つによる化合物、又は本明細書に記載の各種実施形態のいずれかによる化合物、又はそれの立体異性体、又は前記化合物の薬学的に許容される塩又は前記立体異性体、又はそれの薬学的に許容される組成物を含む。別の実施形態において、前記組み合わせで有用な本発明の化合物は、例えば本発明の実施例化合物として記載されている実施例の化合物を含む。別の実施形態において、前記組み合わせで有用な本発明の化合物は、実施例2−5の化合物又は前記化合物の薬学的に許容される塩、又はそれの薬学的に許容される組成物を含む。別の実施形態において、前記組み合わせで有用な本発明の化合物は、実施例2−3Aの化合物又は前記化合物の薬学的に許容される塩、又はそれの薬学的に許容される組成物を含む。別の実施形態において、前記組み合わせで有用な本発明の化合物は、実施例2−3Bの化合物又は前記化合物の薬学的に許容される塩、又はそれの薬学的に許容される組成物を含む。別の実施形態において、前記組み合わせで有用な本発明の化合物は、実施例3−1Aの化合物又は前記化合物の薬学的に許容される塩、又はそれの薬学的に許容される組成物を含む。別の実施形態において、前記組み合わせで有用な本発明の化合物は、実施例3−1Bの化合物又は前記化合物の薬学的に許容される塩、又はそれの薬学的に許容される組成物を含む。別の実施形態において、前記組み合わせで有用な本発明の化合物は、実施例3−7Aの化合物又は前記化合物の薬学的に許容される塩、又はそれの薬学的に許容される組成物を含む。別の実施形態において、前記組み合わせで有用な本発明の化合物は、実施例3−7Bの化合物又は前記化合物の薬学的に許容される塩、又はそれの薬学的に許容される組成物を含む。
概して、本発明における化合物は、当業者に公知の各種方法により、又はその方法に類似の公知の方法によって製造することができる。本明細書に開示の発明は、下記の製造及び実施例によって例示されるが、それらは本開示の範囲を限定するものと解釈すべきではない。別途機構的経路及び類似の構造は、当業者には明らかであろう。実施者はこれらの方法に制限されるものではない。
実施例2−1A及び2−1B、段階1の手順を参照する。
実施例2−1A及び2−1B、段階2の手順を参照する。
実施例2−1A及び2−1B、段階5の手順を参照する。
実施例2−2A、2−2B、2−2C及び2−2D、段階8の手順を参照する。
実施例2−3A及び2−3B、段階3の手順を参照する。
実施例2−3A及び2−3B、段階5の手順を参照する。
実施例3−7A及び3−7B、段階1の手順を参照する。
実施例2−9A、2−9B、2−9C及び2−9D、段階1の手順を参照する。
段階1:メチル5−(3−メトキシ−3−オキソプロピル)フラン−2−カルボキシレート
段階1:(2−(エトキシカルボニル)−6,7,8,9−テトラヒドロ−5H−6,9−エポキシシクロヘプタ[b]ピリジン−4−イル)ボロン酸
2−ブロモ−3,5−ジフルオロピリジンに代えて2−ブロモ−5−クロロ−3−フルオロピリジンを用い、実施例1−6A及び1−6Bと同じ手順に従って、標題化合物を製造した。
段階1:エチル(E)−4−(2,6−ジクロロ−4−(2,4−ジフルオロフェニル)ピリジン−3−イル)−2−オキソブタ−3−エノエート(中間体2−2)
段階1:エチル4−(2,6−ジクロロ−4−(2,4−ジフルオロフェニル)ピリジン−3−イル)−2−オキソブタノエート
段階1:(E)−メチル3−(4−ブロモ−2,6−ジクロロピリジン−3−イル)アクリレート
段階1:(E)−エチル3−(2,6−ジクロロ−4−(2,4−ジフルオロフェニル)ピリジン−3−イル)アクリレート
段階1:4−(2,6−ジクロロ−4−(2,4−ジフルオロフェニル)ピリジン−3−イル)−2−メチルブタン−2−オール
段階1:4−(2,6−ジクロロ−4−(2,4−ジフルオロフェニル)ピリジン−3−イル)ブタン−2−オール
段階1:メチル3−(2,6−ジクロロ−4−(2,4−ジフルオロフェニル)ピリジン−3−イル)−3−ヒドロキシ−2,2−ジメチルプロパノエート
段階1:エチル4−(2,6−ジクロロ−4−(2,4−ジフルオロフェニル)ピリジン−3−イル)−2−オキソブタノエート
段階1:7−クロロ−5−(2,4−ジフルオロフェニル)−3,4−ジヒドロ−2H−ピラノ[2,3−b]ピリジン−2−カルボン酸(中間体3−2)
段階1:エチル2−((ジフルオロメトキシ)メチル)−5−(2,4−ジフルオロフェニル)−3,4−ジヒドロ−2H−ピラノ[2,3−b]ピリジン−7−カルボキシレート
段階1:エチル5−(2,4−ジフルオロフェニル)−2−(メトキシメチル)−3,4−ジヒドロ−2H−ピラノ[2,3−b]ピリジン−7−カルボキシレート
段階1:エチル5−(2,4−ジフルオロフェニル)−2−(フルオロメチル)−3,4−ジヒドロ−2H−ピラノ[2,3−b]ピリジン−7−カルボキシレート
段階1:エチル5−(2,4−ジフルオロフェニル)−2−ホルミル−3,4−ジヒドロ−2H−ピラノ[2,3−b]ピリジン−7−カルボキシレート(中間体3−1)
段階1:エチル5−(2,4−ジフルオロフェニル)−2−(2,2,2−トリフルオロ−1−ヒドロキシエチル)−3,4−ジヒドロ−2H−ピラノ[2,3−b]ピリジン−7−カルボキシレート及び5−(2,4−ジフルオロフェニル)−2−(2,2,2−トリフルオロ−1−((トリメチルシリル)オキシ)エチル)−3,4−ジヒドロ−2H−ピラノ[2,3−b]ピリジン−7−カルボキシレート
段階1:エチル(2S,3R)−、(2S,3S)−、(2R,3R)又は(2R,3S)−2−((ジフルオロメトキシ)メチル)−5−(2,4−ジフルオロフェニル)−3−メチル−3,4−ジヒドロ−2H−ピラノ[2,3−b]ピリジン−7−カルボキシレート
段階1:7−クロロ−5−(2,4−ジフルオロフェニル)−N−(2,2,2−トリフルオロエチル)−3,4−ジヒドロ−2H−ピラノ[2,3−b]ピリジン−2−カルボキサミド
段階1:tert−ブチル((7−クロロ−5−(2,4−ジフルオロフェニル)−3,4−ジヒドロ−2H−ピラノ[2,3−b]ピリジン−2−イル)メチル)(2,2,2−トリフルオロエチル)カーバメート
段階1:3−(トリメチルシリル)ピリジン−2−オール
代謝型グルタミン酸受容体活性、特にはmGluR2活性の阻害剤としての本発明の化合物の有用性を、当業界で公知の方法によって、そして下記に記載の方法で示すことができる。阻害定数(IC50;最大活性の50%を提供するのに必要な化合物の濃度)を、次のように求める。本発明の化合物を、蛍光レーザー画像プレートリーダーに基づくアッセイ(fluorescence laser imaging plate reader based assay)で調べた。このアッセイは、広宿主域(promiscuous)G−タンパク質と結合した組換え受容体を発現する全細胞におけるCa2+動員をモニタリングする一般的な機能アッセイである。Fluo−4AM(Invitrogen, Carlsbad California, USA)を負荷した組換えヒトmGluR2及びGα16を安定に発現するCHO(チャイニーズハムスター卵巣)dhfr細胞を、各種濃度の本発明の各試験化合物で処理し、FLIPR384装置(Molecular Devices, Sunnydale California, USA)でCa2+応答をモニタリングした。2,500nMグルタミン酸存在下に、最大作動薬活性を測定し、グルタミン酸依存性応答を最小阻害及び最大阻害するだけの化合物濃度範囲によって提供される阻害を経時的にモニタリングした。作動薬又は拮抗薬に関する化合物の各濃度での最大カルシウム応答を、用量応答としてプロットし、その曲線を、4パラメータロジスティック方程式に適合させて、反復非線形曲線適合ソフトウェアADA(Merck & Co., Inc.)を用いてIC50及びヒル係数を得た。下記の表中のデータは、この細胞アッセイでのグルタミン酸依存性mGluR2活性を阻害する各化合物の活性を列記したものである。
本発明は一態様において、以下を提供する。
[項目1]
下記式(I)の化合物若しくは該化合物の立体異性体、又は当該化合物若しくは当該立体異性体の薬学的に許容される塩。
[式中、
環Aは、
から選択される部分であり、
R 2 は、H、シクロプロピル、−(C 1 −C 4 )アルキル、−(C 1 −C 4 )アルキル−OH、−(C 1 −C 4 )アルキル−OCH 3 、−(C 1 −C 4 )ハロアルキル、−(C 1 −C 4 )アルキル−O−(C 1 −C 4 )ハロアルキル、−CH(CH 3 ) 2 、−CH 2 −O−(C 1 −C 4 )ハロアルキル、−CH(CH 3 )−O−(C 1 −C 4 )ハロアルキル、−CH 2 −NH−(C 1 −C 4 )ハロアルキル、及び−CH 2 −N(CH 3 )−(C 1 −C 4 )ハロアルキルから選択され、
R 2A は、H及びメチルから選択され;
R 3 は、H及びメチルから選択され;
R 3A は、H及びメチルから選択され;
環Bは、フェニル、ヘテロアリール、−(C 5 −C 6 )シクロアルキル、及び−(C 5 −C 6 )シクロアルケニルからなる群から選択される部分であり;
nは、0、1、2又は3であり、但し、nの値は環B上の置換可能な水素原子の最大数を超えるものではなく;
各R 1 (存在する場合)は、ハロゲン、−CN、−OH、−(C 1 −C 6 )アルキル,−O−(C 1 −C 6 )アルキル、−(C 1 −C 6 )ハロアルキル、−O−(C 1 −C 6 )ハロアルキル、シクロプロピル、シクロブチル、−NH 2 、−NH(C 1 −C 6 )アルキル、−N(C 1 −C 6 アルキル) 2 、−C(O)O(C 1 −C 6 )アルキル、及びフェニルからなる群から独立に選択される。][項目2]
環Aが下記の部分:
であり、式(I)が下記式(IA):
の形態を取る、項目1に記載の化合物又は該化合物の薬学的に許容される塩。
[項目3]
R 2 が、H、シクロプロピル、−CH 3、 −CH(CH 3 ) 2 、−CH 2 −OH、−CH 2 −OCH 3 、−CH 2 F、−CHF 2 、−CF 3 、−CH 2 CH 2 F、−CH 2 CHF 2 、−CH 2 CF 3 、−CH 2 −O−CH 2 F、−CH 2 −O−CHF 2 、−CH(CH 3 )−O−CH 2 F、−CH(CH 3 )−O−CHF 2 、−CH 2 −NH−CH 2 CF 3 、及び−CH 2 −N(CH 3 )−CH 2 CF 3 から選択され;
R 2A が、H及びメチルから選択され;
R 3 が、H及びメチルから選択され;
R 3A が、H及びメチルから選択される、項目2に記載の化合物又は該化合物の薬学的に許容される塩。
[項目4]
R 2 及びR 2A が両方ともメチルであり;
R 3 及びR 3A が両方ともHである、項目2に記載の化合物又は該化合物の薬学的に許容される塩。
[項目5]
環Aが下記部分:
であり、式(I)が下記式(IB):
の形態を取る、項目1に記載の化合物又は該化合物の薬学的に許容される塩。
[項目6]
環Aが下記部分:
であり、式(I)が下記式(IC):
の形態を取る、項目1に記載の化合物又は該化合物の薬学的に許容される塩。
[項目7]
環Aが下記部分:
であり、式(I)が下記式(ID):
の形態を取る、項目1に記載の化合物又は該化合物の薬学的に許容される塩。
[項目8]
環Bが、フェニル、シクロペンチル、シクロヘキシル、ピリジニル、ピリミジニル、ピラゾリル、チエニル、チアゾリル、チアジアゾリル、イソオキサゾリル、オキサジアゾリル及びオキサゾリルからなる群から選択される部分であり;
nが、0、1、2、又は3であり、但し、nの値は、環B上の置換可能な水素原子の最大数を超えるものではなく;
各R 1 (存在する場合)が、ハロゲン、−CN、−OH、−(C 1 −C 6 )アルキル、−O−(C 1 −C 6 )アルキル、−(C 1 −C 6 )ハロアルキル、−O−(C 1 −C 6 )ハロアルキル、シクロプロピル、シクロブチル、−NH 2 、−NH(C 1 −C 6 )アルキル、−N(C 1 −C 6 アルキル) 2 、−C(O)O(C 1 −C 6 )アルキル、及びフェニルからなる群から独立に選択される、項目1〜7のいずれか1項に記載の化合物又は該化合物の薬学的に許容される塩。
[項目9]
環Bが、フェニル、ピラゾリル、ピリジニル、チエニル、イソオキサゾリル、オキサジアゾリル及びオキサゾリルからなる群から選択される部分であり;
nが、0、1、又は2であり;
各R 1 (存在する場合)が、フルオロ、クロロ、−CH 3 及び−CHCF 2 からなる群から独立に選択される、項目1〜7のいずれか1項に記載の化合物又は該化合物の薬学的に許容される塩。
[項目10]
下記式(IA−1)を有する項目1に記載の化合物若しくは該化合物の立体異性体、又は当該化合物若しくは当該立体異性体の薬学的に許容される塩。
[式中、
R 2 は、H、シクロプロピル、−CH 3 、−CH(CH 3 ) 2 、−CH 2 −OH、−CH 2 −OCH 3 、−CH 2 F、−CHF 2 、−CF 3 、−CH 2 CH 2 F、−CH 2 CHF 2 、−CH 2 CF 3 、−CH 2 −O−CH 2 F、−CH 2 −O−CHF 2 、−CH(CH 3 )−O−CH 2 F、−CH(CH 3 )−O−CHF 2 、−CH 2 −NH−CH 2 CF 3 、及び−CH 2 −N(CH 3 )−CH 2 CF 3 から選択され;
R 2A は、H及びCH 3 から選択され;
R 3 は、H及びCH 3 から選択され;
R 3A は、H及びCH 3 から選択される。]
[項目11]
前記化合物が、下記のものからなる群から選択される、項目1に記載の化合物又は該化合物の薬学的に許容される塩。
[項目12]
前記化合物が下記構造を有する、項目1に記載の化合物。
[項目13]
前記化合物が下記構造:
を有し、当該化合物が薬学的に許容される塩の形態である、項目1に記載の化合物。
[項目14]
前記化合物が下記構造を有する、項目1に記載の化合物。
[項目15]
前記化合物が下記構造:
を有し、当該化合物が薬学的に許容される塩の形態である、項目1に記載の化合物。
[項目16]
前記化合物が下記構造を有する、項目1に記載の化合物。
[項目17]
前記化合物が下記構造:
を有し、当該化合物が薬学的に許容される塩の形態である、項目1に記載の化合物。
[項目18]
前記化合物が下記構造を有する、項目1に記載の化合物。
[項目19]
前記化合物が下記構造:
を有し、当該化合物が薬学的に許容される塩の形態である、項目1に記載の化合物。
[項目20]
前記化合物が下記構造を有する、項目1に記載の化合物。
[項目21]
前記化合物が下記構造:
を有し、当該化合物が薬学的に許容される塩の形態である、項目1に記載の化合物。
[項目22]
前記化合物が下記構造を有する、項目1に記載の化合物。
[項目23]
前記化合物が下記構造:
を有し、当該化合物が薬学的に許容される塩の形態である、項目1に記載の化合物。
[項目24]
前記化合物が下記構造を有する、項目1に記載の化合物。
[項目25]
前記化合物が下記構造:
を有し、当該化合物が薬学的に許容される塩の形態である、項目1に記載の化合物。
[項目26]
治療上有効量の項目1〜12、14、16、18、20、22若しくは24のいずれか1項に記載の化合物又は該化合物の薬学的に許容される塩、及び薬学的に許容される担体を含む医薬組成物。
[項目27]
項目1〜12、14、16、18、20、22若しくは24のいずれか1項に記載の化合物又は該化合物の薬学的に許容される塩若しくは溶媒和物、及び1、2、3若しくはそれ以上の他の治療薬を含む組み合わせ。
[項目28]
アルツハイマー病、軽度認識機能障害、統合失調症、気分障害、又は睡眠障害の治療方法であって、有効量の項目1〜12、14、16、18、20、22若しくは24のいずれか1項に記載の化合物又は該化合物の薬学的に許容される塩を、処置を必要とする人に投与することを含む方法。
[項目29]
アルツハイマー病、軽度認識機能障害、統合失調症、気分障害、又は睡眠障害の治療のための、項目1〜12、14、16、18、20、22若しくは24のいずれか1項に記載の化合物又は該化合物の薬学的に許容される塩、及び薬学的に許容される担体の使用。
[項目30]
治療法で使用される、項目1〜12、14、16、18、20、22又は24のいずれか1項に記載の化合物。
Claims (30)
- 下記式(I)の化合物若しくは該化合物の立体異性体、又は当該化合物若しくは当該立体異性体の薬学的に許容される塩。
環Aは、
R2は、H、シクロプロピル、−(C1−C4)アルキル、−(C1−C4)アルキル−OH、−(C1−C4)アルキル−OCH3、−(C1−C4)ハロアルキル、−(C1−C4)アルキル−O−(C1−C4)ハロアルキル、−CH(CH3)2、−CH2−O−(C1−C4)ハロアルキル、−CH(CH3)−O−(C1−C4)ハロアルキル、−CH2−NH−(C1−C4)ハロアルキル、及び−CH2−N(CH3)−(C1−C4)ハロアルキルから選択され、
R2Aは、H及びメチルから選択され;
R3は、H及びメチルから選択され;
R3Aは、H及びメチルから選択され;
環Bは、フェニル、ヘテロアリール、−(C5−C6)シクロアルキル、及び−(C5−C6)シクロアルケニルからなる群から選択される部分であり;
nは、0、1、2又は3であり、但し、nの値は環B上の置換可能な水素原子の最大数を超えるものではなく;
各R1(存在する場合)は、ハロゲン、−CN、−OH、−(C1−C6)アルキル,−O−(C1−C6)アルキル、−(C1−C6)ハロアルキル、−O−(C1−C6)ハロアルキル、シクロプロピル、シクロブチル、−NH2、−NH(C1−C6)アルキル、−N(C1−C6アルキル)2、−C(O)O(C1−C6)アルキル、及びフェニルからなる群から独立に選択される。] - R2が、H、シクロプロピル、−CH3、−CH(CH3)2、−CH2−OH、−CH2−OCH3、−CH2F、−CHF2、−CF3、−CH2CH2F、−CH2CHF2、−CH2CF3、−CH2−O−CH2F、−CH2−O−CHF2、−CH(CH3)−O−CH2F、−CH(CH3)−O−CHF2、−CH2−NH−CH2CF3、及び−CH2−N(CH3)−CH2CF3から選択され;
R2Aが、H及びメチルから選択され;
R3が、H及びメチルから選択され;
R3Aが、H及びメチルから選択される、請求項2に記載の化合物又は該化合物の薬学的に許容される塩。 - R2及びR2Aが両方ともメチルであり;
R3及びR3Aが両方ともHである、請求項2に記載の化合物又は該化合物の薬学的に許容される塩。 - 環Bが、フェニル、シクロペンチル、シクロヘキシル、ピリジニル、ピリミジニル、ピラゾリル、チエニル、チアゾリル、チアジアゾリル、イソオキサゾリル、オキサジアゾリル及びオキサゾリルからなる群から選択される部分であり;
nが、0、1、2、又は3であり、但し、nの値は、環B上の置換可能な水素原子の最大数を超えるものではなく;
各R1(存在する場合)が、ハロゲン、−CN、−OH、−(C1−C6)アルキル、−O−(C1−C6)アルキル、−(C1−C6)ハロアルキル、−O−(C1−C6)ハロアルキル、シクロプロピル、シクロブチル、−NH2、−NH(C1−C6)アルキル、−N(C1−C6アルキル)2、−C(O)O(C1−C6)アルキル、及びフェニルからなる群から独立に選択される、請求項1〜7のいずれか1項に記載の化合物又は該化合物の薬学的に許容される塩。 - 環Bが、フェニル、ピラゾリル、ピリジニル、チエニル、イソオキサゾリル、オキサジアゾリル及びオキサゾリルからなる群から選択される部分であり;
nが、0、1、又は2であり;
各R1(存在する場合)が、フルオロ、クロロ、−CH3及び−CHCF2からなる群から独立に選択される、請求項1〜7のいずれか1項に記載の化合物又は該化合物の薬学的に許容される塩。 - 下記式(IA−1)を有する請求項1に記載の化合物若しくは該化合物の立体異性体、又は当該化合物若しくは当該立体異性体の薬学的に許容される塩。
R2は、H、シクロプロピル、−CH3、−CH(CH3)2、−CH2−OH、−CH2−OCH3、−CH2F、−CHF2、−CF3、−CH2CH2F、−CH2CHF2、−CH2CF3、−CH2−O−CH2F、−CH2−O−CHF2、−CH(CH3)−O−CH2F、−CH(CH3)−O−CHF2、−CH2−NH−CH2CF3、及び−CH2−N(CH3)−CH2CF3から選択され;
R2Aは、H及びCH3から選択され;
R3は、H及びCH3から選択され;
R3Aは、H及びCH3から選択される。] - 治療上有効量の請求項1〜12、14、16、18、20、22若しくは24のいずれか1項に記載の化合物又は該化合物の薬学的に許容される塩、及び薬学的に許容される担体を含む医薬組成物。
- 請求項1〜12、14、16、18、20、22若しくは24のいずれか1項に記載の化合物又は該化合物の薬学的に許容される塩若しくは溶媒和物、及び1、2、3若しくはそれ以上の他の治療薬を含む組み合わせ。
- アルツハイマー病、軽度認識機能障害、統合失調症、気分障害、又は睡眠障害の治療方法であって、有効量の請求項1〜12、14、16、18、20、22若しくは24のいずれか1項に記載の化合物又は該化合物の薬学的に許容される塩を、処置を必要とする人に投与することを含む方法。
- アルツハイマー病、軽度認識機能障害、統合失調症、気分障害、又は睡眠障害の治療のための、請求項1〜12、14、16、18、20、22若しくは24のいずれか1項に記載の化合物又は該化合物の薬学的に許容される塩、及び薬学的に許容される担体の使用。
- 治療法で使用される、請求項1〜12、14、16、18、20、22又は24のいずれか1項に記載の化合物。
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