WO2010121382A1 - Procédé pour la fabrication de dérivés de cyclopropylamides de l'indole - Google Patents

Procédé pour la fabrication de dérivés de cyclopropylamides de l'indole Download PDF

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Publication number
WO2010121382A1
WO2010121382A1 PCT/CA2010/000626 CA2010000626W WO2010121382A1 WO 2010121382 A1 WO2010121382 A1 WO 2010121382A1 CA 2010000626 W CA2010000626 W CA 2010000626W WO 2010121382 A1 WO2010121382 A1 WO 2010121382A1
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WIPO (PCT)
Prior art keywords
formula
compound
process according
base
group
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Application number
PCT/CA2010/000626
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English (en)
Inventor
Carmela Molinaro
Christian Nadeau
Gregory Hughes
Original Assignee
Merck Frosst Canada Ltd.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Merck Frosst Canada Ltd. filed Critical Merck Frosst Canada Ltd.
Publication of WO2010121382A1 publication Critical patent/WO2010121382A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring

Definitions

  • This invention relates to a process for making indoline cyclopropyl amide derivatives, which are EP4 antagonists useful for treating prostaglandin E mediated diseases, such as acute and chronic pain, osteoarthritis and rheumatoid arthritis.
  • the compounds are antagonists of the pain and inflammatory effects of E-type prostaglandins and are structurally different from NSAIDs and opiates.
  • Three review articles describe the characterization and therapeutic relevance of the prostanoid receptors as well as the most commonly used selective agonists and antagonists: Eicosanoids: From Biotechnology to Therapeutic Applications, Folco, Samuelsson, Maclouf, and VeIo eds, Plenum Press, New York, 1996, chap. 14, 137-154; Journal of Lipid Mediators and Cell Signalling, 1996, 14, 83-87; and Prostaglandins and Other Lipid Mediators, 2002, 69, 557-573.
  • selective prostaglandin ligands, agonists or antagonists have anti-inflammatory, antipyretic and analgesic properties similar to a conventional non-steroidal anti-inflammatory drug, and in addition, have effects on vascular homeostasis, reproduction, gastrointestinal functions and bone metabolism.
  • These compounds may have a diminished ability to induce some of the mechanism- based side effects of NSAIDs which are indiscriminate cyclooxygenase inhibitors.
  • the compounds are believed to have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and a lessened ability to induce asthma attacks in aspirin- sensitive asthmatic subjects.
  • Indoline cyclopropyl derivatives are useful as EP4 antagonists and processes for making such compounds are disclosed in PCT/CA08/000351, filed on February 22, 2008.
  • synthetic method disclosed in the above reference suffices to prepare small quantities of material, they suffer from a variety of safety issues, low yields or lengthy processes that are not amenable to large scale synthesis.
  • the present invention describes an efficient and economical process for the preparation of derivatives that is useful for the production of kilogram quantities of material for preclinical, clinical and commercial use.
  • the invention encompasses a process for making indoline cyclopropyl amide derivatives, which are EP4 antagonists useful for treating pain and inflammation.
  • the invention encompasses a process for making a compound of Formula I
  • alkanol my be a linear or branched Cj.galkanol, preferably ethanol.
  • activating agent is defined to include triazolols, such as 1 -hydroxy-benzotriazole (HOBt) or 1 -hydroxy-7-azabenzotriazole (HOAt).
  • An embodiment of the invention encompasses the process of the invention wherein the activating agent is 1 -hydroxy-benzotriazole (HOBT).
  • first amine base is defined to include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, for example, N-methylmorpholine, diethylamine, triethylamine and dipropylamine.
  • An embodiment of the invention encompasses the process of the invention wherein the first amine base is N-methylmorpholine.
  • first base is defined to include any appropriate strong base such as lithium hydroxide or sodium hydroxide.
  • first base is lithium hydroxide.
  • the term "acidification” is defined to include the addition of an appropriate acid, such as HCl.
  • second base is defined to include an appropriate base which forms a pharmaceutically acceptable salt with the compound of Formula I.
  • An embodiment of the invention encompasses the process of the invention wherein the base is diethylamine.
  • salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, N-methylmorpholine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganese, potassium, sodium, zinc, and the like.
  • Preferred salts derived from inorganic bases include sodium, potassium and calcium.
  • the invention also encompasses the process described in steps (al) to (cl) above further comprising making the compound of Formula 4a by
  • step (dl) the following amounts of the reagents may be used relative to compound 4, 1 -(4-trifluoromethyl -benzyl)- lH-indole-7-carboxylic acid: 1 to 1.5 equivalents of the second amine base, 1 to 15L of alkanoate per kg of compound 4.
  • the alkanoate solvent is defined to include isopropylacetate, ethylacetate and methylacetate. Isopropylacetate is preferred.
  • second amine base is defined to include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, for example, N-methylmorpholine, diethylamine, triethylamine and dipropylamine, diisopropylamine.
  • An embodiment of the invention encompasses the process of the invention wherein the second amine base is diisopropylamine.
  • the invention also encompasses the process described in steps (al) to (dl) above further comprising making the compound of Formula 4 by
  • the following amounts of the reagents may be used relative to compound 1, lH-indole-7-carboxylic acid methyl ester: 1 to 1.5 equivalent of compound 2, 1 to 1.5 equivalents of the third base, 5 to 2OL of N,N-dialkylformamide per kg of compound 1, 1 to 10 equivalents of the of the acid used in the acidification step, and 2 to 15L of methanol per kg of compound 1.
  • alkanol is defined as C ⁇ alkanol.
  • Methanol is preferred.
  • the N,N-dialkylformamide is defined to include N,N-diethylformamide and N,N-dimethylformamide.
  • the term "third base” is defined to include any appropriate strong base such as potassium tert-butoxide or sodium hydride. In an embodiment of the invention, the third base is potassium tert-butoxide.
  • the term "fourth base” is defined to include any appropriate strong base such as lithium hydroxide or sodium hydroxide. In an embodiment of the invention, the fourth base is lithium hydroxide.
  • the term "acidification” is defined to include the addition of an appropriate acid, such as HCl.
  • the invention also encompasses the process described in steps (al) to (fl) above further comprising making the compound of Formula 6
  • the Lewis acid is defined to include organotitanium, such as titaniumisopropoxide, chlorotriisopropoxytitanium, and triisopropoxymethyltitaniummethane, as well as boron trihalide and titanium tetrachloride.
  • boron trihalide is defined to include BX3, wherein X is F, Cl or Br, or an adduct thereof such as with an ether.
  • the boron trihalide is boron trifluoride diethyl ether. Titaniumisopropoxide, followed by the addition of boron trihalide is preferred.
  • the following amounts of the reagents may be used relative to compound 5, methyl 4-cyanobenzoate: 2 to 4 equivalents of the ethyl Grignard reagent, and 2 to 6 equivalents Lewis acid (for example, 1 to 2 equivalents of titaniumisopropoxide, and 1 to 4 equivalents of boron trihalide).
  • the term "ethyl Grignard reagent” is defined to include ethyl magnesium bromide and ethyl magnesium chloride.
  • the Grignard reagent is EtMgBr.
  • the term "boron trihalide” is defined to include BX3, wherein X is F, Cl or Br, or an adduct thereof such as with an ether.
  • the boron trihalide is boron trifluoride diethyl ether.
  • the invention also encompasses the diethylamine salt of the compound of Formula I
  • H 2 O (1.9 L) was added at 15 0 C in order to precipitate the product.
  • the slurry was filtered and rinsed with H 2 O (4 X IL) and the product dried under a flow of N 2 under vacuum. 411.1 g of material was obtained at 82 A%.
  • the mixture was aged at -20 0 C for 30 minutes and borontrifluoride diethyl ether (4.09 L) was added over 40 minutes keeping the reaction mixture between -24 0 C and -8 0 C.
  • the mixture was aged at -20 0 C for 30 minutes and the reaction was quenched by the slow addition of 3N HCl (40 L) over 30 minutes.
  • the mixture was transferred into an extractor and the layers were separated.
  • the aqueous layer was washed with toluene (13 L) and extracted with 2-Me-THF (2 x 26 L) and (2 x 13 L).
  • the combined Me-THF layers were washed with 4N NaOH (26 L) and with brine (13 L).
  • the intermediate 7 can be obtained using a combination of the following coupling partners : the indole-acid diisopropylamine salt 4a with the cyclopropylamine mesylate salt 6a, or the indole-acid 4 with either the cyclopropylamine 6 or cyclopropylamine mesylate salt 6a following the same experimental procedure.
  • Benzylic ester 7 492.49 222.5 g 0.452 1.00 4N LiOH 565 mL 2.259 5.00 4N HC1 565 mL 2.259 5.00 IN HCl 111.3 mL 0.10 0.22

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur un procédé efficace et économique pour la synthèse de quantités de l'ordre de kilogramme d'un dérivé de cyclopropylamides de l'indole de formule I, ou d'un sel pharmaceutiquement acceptable de celui-ci. Le procédé comprend le couplage du dérivé de l'acide indolocarboxylique 4, ou de son sel de diéthylamine, avec de la cyclopropylamine 6 ou son sel d'acide méthanesulfonique. Le composé I est un antagoniste d'EP4 utile pour le traitement de maladies à médiation par la prostaglandine E telles que la douleur aiguë et chronique, l'arthrose et la polyarthrite rhumatoïde.
PCT/CA2010/000626 2009-04-21 2010-04-21 Procédé pour la fabrication de dérivés de cyclopropylamides de l'indole WO2010121382A1 (fr)

Applications Claiming Priority (2)

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US17121209P 2009-04-21 2009-04-21
US61/171,212 2009-04-21

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WO2010121382A1 true WO2010121382A1 (fr) 2010-10-28

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Cited By (10)

* Cited by examiner, † Cited by third party
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WO2015048553A1 (fr) * 2013-09-27 2015-04-02 Allergan, Inc. Composés et méthodes de réparation cutanée
CN108003085A (zh) * 2017-12-19 2018-05-08 张开良 一种药物中间体芳甲酰基吲哚衍生物的合成方法
WO2018195123A1 (fr) * 2017-04-18 2018-10-25 Tempest Therapeutics, Inc. Composés bicycliques et leur utilisation dans le traitement du cancer
WO2019166022A1 (fr) * 2018-03-02 2019-09-06 Shenzhen Ionova Life Science Co., Ltd. Acides carboxyliques hétérobicycliques et leurs sels
WO2019204523A1 (fr) * 2018-04-17 2019-10-24 Tempest Therapeutics, Inc. Carboxamides bicycliques et leurs procédés d'utilisation
WO2020012305A1 (fr) * 2018-07-12 2020-01-16 Rottapharm Biotech S.R.L. Acide (r)-4-(1-(1-(4-(trifluorométhyl)benzyl)pyrrolidine-2-carboxamide)cyclopropyl)-benzoïque en tant qu'antagoniste du récepteur ep4
CN111936138A (zh) * 2018-02-05 2020-11-13 深圳市原力生命科学有限公司 作为ep4受体拮抗剂的杂二环化合物
CN112707831A (zh) * 2021-02-05 2021-04-27 阿里生物新材料（常州）有限公司 一种3-（1-氨基环丙基）苯甲酸甲酯的合成方法
US11066405B2 (en) 2017-04-18 2021-07-20 Tempest Therapeutics, Inc. Bicyclic compounds and their use in the treatment of cancer
WO2022257960A1 (fr) * 2021-06-08 2022-12-15 武汉人福创新药物研发中心有限公司 Composé bicyclique pour traiter des maladies médiées par le récepteur ep2 et ep4

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008104055A1 (fr) * 2007-02-26 2008-09-04 Merck Frosst Canada Ltd. Dérivés d'indole et indoline cyclopropyl amide comme antagonistes du récepteur ep4

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008104055A1 (fr) * 2007-02-26 2008-09-04 Merck Frosst Canada Ltd. Dérivés d'indole et indoline cyclopropyl amide comme antagonistes du récepteur ep4

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CN105579438A (zh) * 2013-09-27 2016-05-11 阿勒根公司 用于皮肤修复的化合物和方法
US9546162B2 (en) 2013-09-27 2017-01-17 Allergan, Inc. Compounds and methods for skin repair
WO2015048553A1 (fr) * 2013-09-27 2015-04-02 Allergan, Inc. Composés et méthodes de réparation cutanée
JP2020196731A (ja) * 2013-09-27 2020-12-10 アラーガン、インコーポレイテッドＡｌｌｅｒｇａｎ，Ｉｎｃｏｒｐｏｒａｔｅｄ 皮膚修復のための化合物及び方法
US11066405B2 (en) 2017-04-18 2021-07-20 Tempest Therapeutics, Inc. Bicyclic compounds and their use in the treatment of cancer
JP7264060B2 (ja) 2017-04-18 2023-04-25 テンペスト セラピューティクス，インク． 二環式化合物および癌の処置におけるそれらの使用
CN110891935B (zh) * 2017-04-18 2023-12-01 泰普斯特医疗公司 双环化合物及其在癌症治疗中的用途
KR102588955B1 (ko) 2017-04-18 2023-10-13 템페스트 테라퓨틱스, 인크. 이환식 화합물 및 암의 치료에서의 이의 용도
KR20200017387A (ko) * 2017-04-18 2020-02-18 템페스트 테라퓨틱스, 인크. 이환식 화합물 및 암의 치료에서의 이의 용도
CN110891935A (zh) * 2017-04-18 2020-03-17 泰普斯特医疗公司 双环化合物及其在癌症治疗中的用途
JP2020517616A (ja) * 2017-04-18 2020-06-18 テンペスト セラピューティクス，インク． 二環式化合物および癌の処置におけるそれらの使用
US11738009B2 (en) 2017-04-18 2023-08-29 Tempest Therapeutics, Inc. Bicyclic compounds and their use in the treatment of cancer
US11638704B2 (en) 2017-04-18 2023-05-02 Tempest Therapeutics, Inc. Bicyclic compounds and their use in the treatment of cancer
WO2018195123A1 (fr) * 2017-04-18 2018-10-25 Tempest Therapeutics, Inc. Composés bicycliques et leur utilisation dans le traitement du cancer
IL270021B (en) * 2017-04-18 2022-08-01 Tempest Therapeutics Inc Bicyclic compounds and their use in cancer treatment
AU2018255300B2 (en) * 2017-04-18 2021-10-28 Tempest Therapeutics, Inc. Bicyclic compounds and their use in the treatment of cancer
EA038381B1 (ru) * 2017-04-18 2021-08-18 Темпест Терапьютикс, Инк. Бициклические соединения и их применение в лечении рака
CN108003085A (zh) * 2017-12-19 2018-05-08 张开良 一种药物中间体芳甲酰基吲哚衍生物的合成方法
CN111936138A (zh) * 2018-02-05 2020-11-13 深圳市原力生命科学有限公司 作为ep4受体拮抗剂的杂二环化合物
CN111936138B (zh) * 2018-02-05 2024-03-08 深圳市原力生命科学有限公司 作为ep4受体拮抗剂的杂二环化合物
JP2021514939A (ja) * 2018-03-02 2021-06-17 シェンチェン イオノヴァ ライフ サイエンス カンパニー リミテッドＳｈｅｎｚｈｅｎ Ｉｏｎｏｖａ Ｌｉｆｅ Ｓｃｉｅｎｃｅ Ｃｏ．， Ｌｔｄ． ヘテロ二環式有機酸およびその塩類
CN111936502B (zh) * 2018-03-02 2024-05-31 深圳市原力生命科学有限公司 杂二环羧酸及其盐
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US10968201B2 (en) 2018-04-17 2021-04-06 Tempest Therapeutics, Inc. Bicyclic carboxamides and methods of use thereof
CN112313208B (zh) * 2018-04-17 2024-04-19 泰普斯特医疗公司 双环羧酰胺及其使用方法
JP2021521128A (ja) * 2018-04-17 2021-08-26 テンペスト セラピューティクス，インク． 二環式カルボキサミドおよびその使用方法
WO2019204523A1 (fr) * 2018-04-17 2019-10-24 Tempest Therapeutics, Inc. Carboxamides bicycliques et leurs procédés d'utilisation
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JP7361713B2 (ja) 2018-04-17 2023-10-16 テンペスト セラピューティクス，インク． 二環式カルボキサミドおよびその使用方法
WO2020012305A1 (fr) * 2018-07-12 2020-01-16 Rottapharm Biotech S.R.L. Acide (r)-4-(1-(1-(4-(trifluorométhyl)benzyl)pyrrolidine-2-carboxamide)cyclopropyl)-benzoïque en tant qu'antagoniste du récepteur ep4
US11718582B2 (en) 2018-07-12 2023-08-08 Rottapharm Biotech S.R.L. (R)-4-(1-(1-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamide)cyclopropyl)-benzoic acid as EP4 receptor antagonist
JP2021524494A (ja) * 2018-07-12 2021-09-13 ロッタファーム・バイオテック・エッセ・エッレ・エッレ Ｅｐ４受容体アンタゴニストとしての（ｒ）−４−（１−（１−（４−（トリフルオロメチル）ベンジル）ピロジリン−２−カルボキサミド）シクロプロピル）安息香酸
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CN112707831A (zh) * 2021-02-05 2021-04-27 阿里生物新材料（常州）有限公司 一种3-（1-氨基环丙基）苯甲酸甲酯的合成方法
WO2022257960A1 (fr) * 2021-06-08 2022-12-15 武汉人福创新药物研发中心有限公司 Composé bicyclique pour traiter des maladies médiées par le récepteur ep2 et ep4

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