JP2021506810A - フッ素化4−(置換アミノ)フェニルカルバメート誘導体 - Google Patents
フッ素化4−(置換アミノ)フェニルカルバメート誘導体 Download PDFInfo
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- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 231100000886 tinnitus Toxicity 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
- 229940035305 topamax Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229960004394 topiramate Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- 210000003901 trigeminal nerve Anatomy 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 229960005066 trisodium edetate Drugs 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- PJDFLNIOAUIZSL-UHFFFAOYSA-N vigabatrin Chemical compound C=CC(N)CCC(O)=O PJDFLNIOAUIZSL-UHFFFAOYSA-N 0.000 description 1
- 229960005318 vigabatrin Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- KAKZBPTYRLMSJV-UHFFFAOYSA-N vinyl-ethylene Natural products C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
- 229940061639 zonegran Drugs 0.000 description 1
- 229960002911 zonisamide Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C233/07—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
- C07C233/42—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/43—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
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- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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Abstract
Description
本出願は、2017年12月13日に出願された米国特許仮出願第62/597,979号の優先権を主張し、当該出願の全内容はここに引用することにより組み込まれる。
てんかんは、最も一般的な慢性神経障害の一つであり、世界中で約5,000万人が罹患している。てんかん患者は、閉鎖頭部損傷、骨折、火傷、歯の損傷、及び軟部組織損傷を含む罹患率が非常に高い。てんかん患者では、記憶力、認知、抑うつ、及び性機能の低下又は悪化、並びにその他の生活スタイルの制限が頻繁に生じる。てんかん患者はまた、一般集団と比較して死亡リスクが高い。
本出願の目的のために、(他に明記されていない限り)以下の定義が使用される。
は互いに互変異性体である。
本出願は下記式Aの化合物、又はその薬学的に許容可能な塩若しくは溶媒和物に関する。
式中、
X1及びX9は、それぞれ独立して、メチル又はエチルであり;
X4は、H、C1〜C4アルキル、C2〜C6アルケニル、又はC2〜C6アルキニルであり;
X5は、フェニル−(CX8X8)mであり、ここで、該フェニルは、重水素、F、SF5、C1〜C4アルキル、一つ又は複数のFで置換されているC1〜C4アルキル、C1〜C4アルコキシ、及び一つ又は複数のFで置換されているC1〜C4アルコキシから独立して選択される一つ又は複数の置換基で置換されていてもよく;又は、
X4及びX5は、それらが結合する窒素原子と共に、N、O、及びSから選択される1つ若しくは2つのヘテロ原子を含む5員〜7員の複素環を形成し、ここで、該複素環は、重水素、F、SF5、C1〜C4アルキル、一つ又は複数のFで置換されているC1〜C4アルキル、C1〜C4アルコキシ、及び一つ又は複数のFで置換されているC1〜C4アルコキシから独立して選択される一つ又は複数の置換基で置換されていてもよく、又は、該複素環上の隣接する炭素原子に結合する二つの置換基は、それらが結合する炭素原子と共にフェニルを形成し、該フェニルは、重水素、F、SF5、C1〜C4アルキル、一つ又は複数のFで置換されているC1〜C4アルキル、C1〜C4アルコキシ、及び一つ又は複数のFで置換されているC1〜C4アルコキシから独立して選択される一つ又は複数の置換基で置換されていてもよく;
各X8は、独立してH、重水素、F、C1〜C4アルキル、又は一つ若しくは複数のFで置換されているC1〜C4アルキルであり;
mは1、2、又は3である。
(式中、窒素原子はX4及びX5に結合する窒素原子である)から選択される複素環を形成する。一態様において、X4及びX5は、それらが結合する窒素原子と共に、
(式中、窒素原子はX4及びX5に結合する窒素原子である)を形成する。
一態様において、フェニルは、F、C1〜C4アルキル(例えば、メチル、エチル、プロピル、i−プロピル、ブチル、i−ブチル、若しくはt−ブチル)、一つ又は複数のFで置換されているC1〜C4アルキル(例えば、それぞれが一つ又は複数のFで置換されている、メチル、エチル、プロピル、i−プロピル、ブチル、i−ブチル、若しくはt−ブチル)、C1〜C4アルコキシ(例えば、メトキシ、エトキシ、プロポキシ、i−プロポキシ、ブトキシ、i−ブトキシ、若しくはt−ブトキシ)、及び一つ又は複数のFで置換されているC1〜C4アルコキシ(例えば、それぞれが一つ又は複数のFで置換されている、メトキシ、エトキシ、プロポキシ、i−プロポキシ、ブトキシ、i−ブトキシ、若しくはt−ブトキシ)から独立して選択される一つ又は複数の置換基で置換されている。一態様において、フェニルは、C1〜C4アルキル(例えば、メチル、エチル、プロピル、i−プロピル、ブチル、i−ブチル、若しくはt−ブチル)、一つ又は複数のFで置換されているC1〜C4アルキル(例えば、それぞれが一つ又は複数のFで置換されている、メチル、エチル、プロピル、i−プロピル、ブチル、i−ブチル、若しくはt−ブチル)、C1〜C4アルコキシ(例えば、メトキシ、エトキシ、プロポキシ、i−プロポキシ、ブトキシ、i−ブトキシ、若しくはt−ブトキシ)、及び一つ又は複数のFで置換されているC1〜C4アルコキシ(例えば、それぞれが一つ又は複数のFで置換されている、メトキシ、エトキシ、プロポキシ、i−プロポキシ、ブトキシ、i−ブトキシ、若しくはt−ブトキシ)から独立して選択される一つ又は複数の置換基で置換されている。一態様において、フェニルは、F、一つ又は複数のFで置換されているC1〜C4アルキル(例えば、それぞれが一つ又は複数のFで置換されている、メチル、エチル、プロピル、i−プロピル、ブチル、i−ブチル、若しくはt−ブチル)、及び一つ又は複数のFで置換されているC1〜C4アルコキシ(例えば、それぞれが一つ又は複数のFで置換されている、メトキシ、エトキシ、プロポキシ、i−プロポキシ、ブトキシ、i−ブトキシ、若しくはt−ブトキシ)から独立して選択される一つ又は複数の置換基で置換されている。一態様において、フェニルは、F、SF5、CF3、CHF2、CH2F、CH2CF3、CH2CHF2、CH2CH2F、OCF3、OCHF2、OCH2F、OCH2CF3、OCH2CHF2、及びOCH2CH2Fから独立して選択される一つ又は複数の置換基で置換されている。一態様において、フェニルは、F、CF3、CHF2、CH2F、CH2CF3、CH2CHF2、CH2CH2F、OCF3、OCHF2、OCH2F、OCH2CF3、OCH2CHF2、及びOCH2CH2Fから独立して選択される一つ又は複数の置換基で置換されている。一態様において、フェニルは、F、CF3、CHF2、CH2F、OCF3、OCHF2、及びOCH2Fから独立して選択される一つ又は複数の基で置換されている。一態様において、フェニルは、F、CF3、及びOCF3から独立して選択される一つ又は複数の置換基で置換されている。一態様において、フェニルは、F、及び一つ又は複数のFで置換されているC1〜C4アルキル(例えば、それぞれが一つ又は複数のFで置換されている、メチル、エチル、プロピル、i−プロピル、ブチル、i−ブチル、若しくはt−ブチル)から独立して選択される一つ又は複数の置換基で置換されている。一態様において、フェニルは、F、SF5、CF3、CHF2、CH2F、CH2CF3、CH2CHF2、及びCH2CH2Fから独立して選択される一つ又は複数の置換基で置換されている。一態様において、フェニルは、F、CF3、CHF2、CH2F、CH2CF3、CH2CHF2、及びCH2CH2Fから独立して選択される一つ又は複数の置換基で置換されている。一態様において、フェニルは、F、CF3、CHF2、及びCH2Fから独立して選択される一つ又は複数の基で置換されている。一態様において、フェニルは、F、及びCF3から独立して選択される一つ又は複数の置換基で置換されている。一態様において、フェニルは、F、及び一つ又は複数のFで置換されているC1〜C4アルコキシ(例えば、それぞれが一つ又は複数のFで置換されている、メトキシ、エトキシ、プロポキシ、i−プロポキシ、ブトキシ、i−ブトキシ、若しくはt−ブトキシ)から独立して選択される一つ又は複数の置換基で置換されている。一態様において、フェニルは、F、SF5、OCF3、OCHF2、OCH2F、OCH2CF3、OCH2CHF2、及びOCH2CH2Fから独立して選択される一つ又は複数の置換基で置換されている。一態様において、フェニルは、F、OCF3、OCHF2、OCH2F、OCH2CF3、OCH2CHF2、及びOCH2CH2Fから独立して選択される一つ又は複数の置換基で置換されている。一態様において、フェニルは、F、CF3、CHF2、CH2F、OCF3、OCHF2、及びOCH2Fから独立して選択される一つ又は複数の基で置換されている。一態様において、フェニルは、F、及びOCF3から独立して選択される一つ又は複数の置換基で置換されている。一態様において、フェニルは、C1〜C4アルキル(例えば、メチル、エチル、プロピル、i−プロピル、ブチル、i−ブチル、若しくはt−ブチル)、及びC1〜C4アルコキシ(例えば、メトキシ、エトキシ、プロポキシ、i−プロポキシ、ブトキシ、i−ブトキシ、若しくはt−ブトキシ)から独立して選択される一つ又は複数の置換基で置換されている。一態様において、フェニルは、CH3、CH2CH3、OCH3、及びOCH2CH3から独立して選択される一つ又は複数の置換基で置換されている。一態様において、フェニルは、CH3、及びCH2CH3から独立して選択される一つ又は複数の置換基で置換されている。一態様において、フェニルは、一つ又は複数のCH3で置換されている。一態様において、フェニルは、OCH3、及びOCH2CH3から独立して選択される一つ又は複数の置換基で置換されている。一態様において、フェニルは、一つ又は複数のOCH3で置換されている。
の化合物、又はその薬学的に許容可能な塩若しくは溶媒和物であり、
式中、
X4及びmは、それぞれ、式Aにおいて上記に定義されたとおりであり、
t1は、1、2、3、4、又は5であり;並びに、
各Z1は、独立して、重水素、F、SF5、C1〜C4アルキル、一つ又は複数のFで置換されているC1〜C4アルキル、C1〜C4アルコキシ、又は一つ又は複数のFで置換されているC1〜C4アルコキシである。
の化合物、又はその薬学的に許容可能な塩若しくは溶媒和物であり、
式中、
qは、1、2、又は3であり;
t2は、1、2、3、又は4であり;並びに、
各Z2は、独立して、重水素、F、SF5、C1〜C4アルキル、一つ又は複数のFで置換されているC1〜C4アルキル、C1〜C4アルコキシ、又は一つ又は複数のFで置換されているC1〜C4アルコキシである。
の化合物、又はその薬学的に許容可能な塩若しくは溶媒和物であり、
式中、
rは、1、2、又は3であり;
t3は、1、2、3、又は4であり;並びに、
各Z3は、独立して、重水素、F、SF5、C1〜C4アルキル、一つ又は複数のFで置換されているC1〜C4アルキル、C1〜C4アルコキシ、又は一つ又は複数のFで置換されているC1〜C4アルコキシである。
スキーム1Aは、本出願の重水素標識化合物の調製を概説する。この調製は、化合物Aから(本明細書に記載のスキーム1Aから)開始する。工程1では、化合物Aのニトロ基が還元され、次いで、重水素標識が、一つ又は複数の重水素を含むカルバメートの形成を介して導入される。例えば、化合物Aのニトロ基を、亜鉛粉末及び塩化アンモニウムのメタノール溶液を用いて還元することができ、エチル−d5クロロホルメートを用いてカルバメートを形成して重水素標識化合物を得ることができる。
KCNQ2/3チャネル活性化活動の評価
本出願の化合物の生物学的活動を、当該分野で公知の様々な方法を用いて評価することができる。例えば、本出願の化合物のKCNQ2/3チャネル活性化活動を、以下に記載のインビトロアッセイによって評価することができる。
MES試験では、麻酔薬/電解質溶液の滴下で薬物刺激された角膜電極を介して送達される、電気刺激によって誘発される発作を防止することに関して、試験化合物の様々な用量の能力を試験する。マウスは拘束され、全発作症状の発現の観察を可能にする角膜刺激の直後に解放される。試験動物の最大限の発作は、後肢屈筋部分の強直フェーズ(第Iフェーズ)、後肢伸筋部分の強直フェーズ(第IIフェーズ)、断続的な全身クローヌス(第IIIフェーズ)、及び筋弛緩(第IVフェーズ)の四つの異なるフェーズがあり、続いて発作終了を含む(Woodbury&Davenport,1952;Racine et al.,1972)。試験化合物を、MES誘発発作伝播を阻害する化合物の能力を示す後肢強直伸筋部分を排除する能力について試験する。化合物を予め投与し(i.p)、電気刺激後の後肢強直伸筋部分の排除について様々な時点で試験する。
角膜キンドリング発作モデルでは、5回の連続したステージV発作が誘発されるまで、毎日二回、マウスに塩酸テトラカインの生理食塩水溶液で薬物刺激された角膜電極を介して伝送される刺激で、電気的にキンドリングを起こさせる。口と顔面のクローヌス(ステージI)、ステージIに加えて点頭痙攣(ステージII)、ステージIIに加えて前肢クローヌス(ステージIII)、ステージIIIに加えてリアリング(rearing)(ステージIV)、ステージIVに加えてリアリング及び転倒(ステージV)を含むRacineスケール(Racine et al.,1972)に従う少なくとも5回の連続したステージVの発作をマウスが示した場合、マウスはキンドリングを起こしたと見なされる(Racine et al.,1972)。キンドリング獲得が完了した時点で、マウスには薬物検査前に3日間の無刺激期間が与えられる。実験の日に、充分にキンドリングを起こしたマウスに、試験化合物の漸増用量を事前投与(i.p)し、角膜キンドリング刺激を受けさせる。Racineスコアリング(Racine et al.,1972)に基づいて、マウスは保護された(発作スコア<3)又は保護されていない(発作スコア≧4)としてスコア化される。
本出願は、本出願の化合物を有効成分として含む薬学的組成物に関する。一実施形態では、本出願は、本出願に記載の式のいずれかの少なくとも一つの化合物又はその薬学的に許容可能な塩若しくは溶媒和物と、一つ若しくは複数の薬学的に許容可能な担体若しくは賦形剤とを含む、薬学的組成物を提供する。一実施形態では、本出願は、表1から選択される少なくとも一つの化合物を含む薬学的組成物を提供する。
本出願は、本出願の化合物の使用方法に関する。本出願の化合物は有用な薬理活性範囲を有し、したがって疾患又は障害の予防及び/又は治療に特に適している。
6−フルオロ−1,2,3,4−テトラヒドロイソキノリンの代わりに、対応する市販の4−メトキシピペリジンを用いて、化合物1と同様の方法で化合物3を合成する。
メチルトリフェニルホスホニウムブロミドの代わりに、対応する市販のエチルトリフェニルホスホニウムブロミドを用いて、化合物1と同様の方法で化合物4を合成する。
メチルトリフェニルホスホニウムブロミドの代わりに、対応する市販のエチルトリフェニルホスホニウムブロミドを用いて、化合物2と同様の方法で化合物5を合成する。
メチルトリフェニルホスホニウムブロミドの代わりに、対応する市販のエチルトリフェニルホスホニウムブロミドを用いて、化合物3と同様の方法で化合物6を合成する。
本出願の化合物の、組換え発現されたヒトKv7.2/7.3チャネルのインビトロ効果を、Syncropatchハイスループット電気生理学プラットフォームで評価する。
当業者は、日常的な実験のみを用いて、本明細書に具体的に記載された特定の実施形態に対する多数の等価物を認識し、又は確認することができるであろう。そのような均等物は、以下の特許請求の範囲に包含されることが意図される。
Claims (50)
- 式A:
(式中、
X1及びX9は、それぞれ独立して、メチル又はエチルであり;
X4は、H、C1〜C4アルキル、C2〜C6アルケニル、又はC2〜C6アルキニルであり;
X5は、フェニル−(CX8X8)mであり[ここで、該フェニルは、重水素、F、SF5、C1〜C4アルキル、一つ又は複数のFで置換されているC1〜C4アルキル、C1〜C4アルコキシ、及び一つ又は複数のFで置換されているC1〜C4アルコキシから独立して選択される一つ又は複数の置換基で置換されていてもよい。];又は、
X4及びX5は、それらが結合する窒素原子と共に、N、O、及びSから選択される1つ若しくは2つのヘテロ原子を含む5員〜7員の複素環を形成し[ここで、該複素環は、重水素、F、SF5、C1〜C4アルキル、一つ又は複数のFで置換されているC1〜C4アルキル、C1〜C4アルコキシ、及び一つ又は複数のFで置換されているC1〜C4アルコキシから独立して選択される一つ又は複数の置換基で置換されていてもよく、又は、該複素環上の隣接する炭素原子に結合する二つの置換基は、それらが結合する炭素原子と共にフェニルを形成し、該フェニルは、重水素、F、SF5、C1〜C4アルキル、一つ又は複数のFで置換されているC1〜C4アルキル、C1〜C4アルコキシ、及び一つ又は複数のFで置換されているC1〜C4アルコキシから独立して選択される一つ又は複数の置換基で置換されていてもよい。];
各X8は、独立してH、重水素、F、C1〜C4アルキル、又は一つ若しくは複数のFで置換されているC1〜C4アルキルであり;
mは1、2、又は3である。)の化合物、又はその薬学的に許容可能な塩若しくは溶媒和物。 - X4がHである、請求項1〜3のいずれか一項に記載の化合物。
- X4が、C1〜C4アルキル、C2〜C6アルケニル、又はC2〜C6アルキニルである、請求項1〜3のいずれか一項に記載の化合物。
- X5が、フェニル−(CX8X8)、フェニル−(CX8X8)2、又はフェニル−(CX8X8)3であり、ここで、フェニルは、重水素、F、SF5、C1〜C4アルキル、一つ又は複数のFで置換されているC1〜C4アルキル、C1〜C4アルコキシ、及び一つ又は複数のFで置換されているC1〜C4アルコキシから独立して選択される一つ又は複数の置換基で置換されていてもよい、請求項1〜3のいずれか一項に記載の化合物。
- X5が、フェニル−(CX8X8)である、請求項6に記載の化合物。
- 前記フェニルが、F及びCF3から独立して選択される一つ又は複数の置換基で置換されている、請求項6に記載の化合物。
- 前記フェニルが、F及びOCF3から独立して選択される一つ又は複数の置換基で置換されている、請求項6に記載の化合物。
- 前記フェニルが、CH3及びOCH3から独立して選択される一つ又は複数の置換基で置換されている、請求項6に記載の化合物。
- 各X8がHである、請求項6に記載の化合物。
- 少なくとも一つのX8が、重水素、F、C1〜C4アルキル、又は一つ若しくは複数のFで置換されているC1〜C4アルキルである、請求項6に記載の化合物。
- X4及びX5が、それらが結合する窒素原子と共に、N、O、及びSから選択される1つ若しくは2つのヘテロ原子を含む5員〜7員の複素環を形成し、ここで、該複素環は、重水素、F、SF5、C1〜C4アルキル、一つ又は複数のFで置換されているC1〜C4アルキル、C1〜C4アルコキシ、及び一つ又は複数のFで置換されているC1〜C4アルコキシから独立して選択される一つ又は複数の置換基で置換されていてもよい、請求項1〜3のいずれか一項に記載の化合物。
- 前記複素環が、F及びCF3から独立して選択される一つ又は複数の置換基で置換されている、請求項13に記載の化合物。
- 前記複素環が、F及びOCF3から独立して選択される一つ又は複数の置換基で置換されている、請求項13に記載の化合物。
- 前記複素環が、CH3及びOCH3から独立して選択される一つ又は複数の置換基で置換されている、請求項13に記載の化合物。
- 前記複素環が、ピロリジニル、テトラヒドロフラニル、テトラヒドロチオフェニル、オキサゾリジニル、イソオキサゾリジニル、チアゾリジニル、イソチアゾリジニル、ピペリジニル、ピペラジニル、テトラヒドロピラニル、テトラヒドロチアピラニル、ジオキサニル、モルフォリニル、オキサジナニル、チアジナニル、又はオキサチアニルである、請求項13に記載の化合物。
- 前記複素環が、ピペリジニルである、請求項13に記載の化合物。
- X4及びX5が、それらが結合する窒素原子と共に、二つ以上の置換基で置換されている5員〜7員の複素環を形成し、ここで、該複素環上の隣接する炭素原子に結合する二つの置換基が、それらが結合する炭素原子と共にフェニルを形成し、該フェニルは、重水素、F、SF5、C1〜C4アルキル、一つ又は複数のFで置換されているC1〜C4アルキル、C1〜C4アルコキシ、及び一つ又は複数のFで置換されているC1〜C4アルコキシから独立して選択される一つ又は複数の置換基で置換されていてもよい、請求項1〜3のいずれか一項に記載の化合物。
- 前記フェニルが、F及びCF3から独立して選択される一つ又は複数の置換基で置換されている、請求項19に記載の化合物。
- 前記フェニルが、F及びOCF3から独立して選択される一つ又は複数の置換基で置換されている、請求項19に記載の化合物。
- 前記フェニルが、CH3及びOCH3から独立して選択される一つ又は複数の置換基で置換されている、請求項19に記載の化合物。
- Z1が、F及びCF3から独立して選択される、請求項24に記載の化合物。
- Z1が、F及びOCF3から独立して選択される、請求項24に記載の化合物。
- Z1が、CH3及びOCH3から独立して選択される、請求項24に記載の化合物。
- mが1である、請求項24に記載の化合物。
- X4がHである、請求項24に記載の化合物。
- t1が1である、請求項24に記載の化合物。
- Z2が、F及びCF3から独立して選択される、請求項31に記載の化合物。
- Z2が、F及びOCF3から独立して選択される、請求項31に記載の化合物。
- Z2が、CH3及びOCH3から独立して選択される、請求項31に記載の化合物。
- qが2である、請求項31に記載の化合物。
- t2が1である、請求項31に記載の化合物。
- Z3が、F及びCF3から独立して選択される、請求項37に記載の化合物。
- Z3が、F及びOCF3から独立して選択される、請求項37に記載の化合物。
- Z3が、CH3及びOCH3から独立して選択される、請求項37に記載の化合物。
- rが2である、請求項37に記載の化合物。
- t3が1である、請求項37に記載に化合物。
- 請求項1〜43のいずれか一項に記載の少なくとも一つの化合物又はその薬学的に許容可能な塩若しくは溶媒和物と、一つ若しくは複数の薬学的に許容可能な担体若しくは賦形剤とを含む、薬学的組成物。
- 請求項1〜43のいずれか一項に記載の化合物、又はその薬学的に許容可能な塩若しくは溶媒和物を対象に投与する工程を含む、それを必要とする対象におけるKCNQ2/3チャネルを調節する方法。
- 請求項1〜43のいずれか一項に記載の化合物、又はその薬学的に許容可能な塩若しくは溶媒和物を、それを必要とする対象に投与する工程を含む、KCNQ2/3カリウムチャネル開口によって緩和することができる疾患若しくは障害を治療又は予防する方法。
- 請求項1〜43のいずれか一項に記載の化合物、又はその薬学的に許容可能な塩若しくは溶媒和物を、それを必要とする対象に投与する工程を含む、てんかんを治療又は予防する方法。
- それを必要とする対象における、KCNQ2/3チャネルの調節、KCNQ2/3カリウムチャネル開口によって緩和することができる疾患若しくは障害の治療若しくは予防、又はてんかんの治療若しくは予防における使用のための、請求項1〜43のいずれか一項に記載の化合物、又はその薬学的に許容可能な塩若しくは溶媒和物。
- それを必要とする対象における、KCNQ2/3チャネルを調節するための、KCNQ2/3カリウムチャネル開口によって緩和することができる疾患若しくは障害を治療若しくは予防するための、又はてんかんを治療若しくは予防するための医薬の製造における使用のための、請求項1〜43のいずれか一項に記載の化合物、又はその薬学的に許容可能な塩若しくは溶媒和物。
- それを必要とする対象における、KCNQ2/3チャネルを調節するための、KCNQ2/3カリウムチャネル開口によって緩和することができる疾患若しくは障害を治療若しくは予防するための、又はてんかんを治療若しくは予防するための医薬の製造における、請求項1〜43のいずれか一項に記載の化合物、又はその薬学的に許容可能な塩若しくは溶媒和物の使用。
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CN111954663A (zh) | 2020-11-17 |
EP3724163A4 (en) | 2021-07-28 |
WO2019118657A1 (en) | 2019-06-20 |
CA3085450A1 (en) | 2019-06-20 |
US20190177274A1 (en) | 2019-06-13 |
EP3724163A1 (en) | 2020-10-21 |
US10676437B2 (en) | 2020-06-09 |
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