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WO2014079850A1 - Dérivés hétérocycliques substitués - Google Patents

Dérivés hétérocycliques substitués Download PDF

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Publication number
WO2014079850A1
WO2014079850A1 PCT/EP2013/074211 EP2013074211W WO2014079850A1 WO 2014079850 A1 WO2014079850 A1 WO 2014079850A1 EP 2013074211 W EP2013074211 W EP 2013074211W WO 2014079850 A1 WO2014079850 A1 WO 2014079850A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
methoxy
oxazol
acetamide
lower alkyl
Prior art date
Application number
PCT/EP2013/074211
Other languages
English (en)
Inventor
Simona M. Ceccarelli
Ravi Jagasia
Roland Jakob-Roetne
Jens-Uwe Peters
Juergen Wichmann
Original Assignee
F. Hoffmann-La Roche Ag
Hoffmann-La Roche Inc.
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 F. Hoffmann-La Roche Ag, Hoffmann-La Roche Inc. filed Critical F. Hoffmann-La Roche Ag
Publication of WO2014079850A1 publication Critical patent/WO2014079850A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/08—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • cycloalkyl denotes a cyclic alkyl group, containing from 3 to 6 ring carbon atoms.
  • R is lower alkyl, -C(0)0-lower alkyl, C3_6-cycloalkyl optionally substituted by lower
  • One further object of the present invention are compounds of formula
  • both R 1 and R 1 may be simultaneously hydrogen, but only one of R 1 and R 1 is lower alkyl, lower alkoxy, halogen, 0(CH 2 ) 2 -lower akoxy, 0(CH 2 ) 2 N(CH 3 ) 2 , or 0(CH 2 )-morpholinyl;
  • both R 1 and R 1 may be simultaneously hydrogen, but only one of R 1 and R 1 is lower alkyl, lower alkoxy, halogen, 0(CH 2 ) 2 -lower akoxy, 0(CH 2 ) 2 N(CH 3 ) 2 , or 0(CH 2 )-morpholinyl;
  • Het is a 5-or 6 membered heteroaryl group, wherein the heteroatoms are selected from N, O or S;
  • Compounds of general formula I-l can be prepared by coupling the amine of general formula 15 to carboxylic acids of general 4, as described above.
  • Amines of general formula 15 can be prepared from the corresponding nitro derivatives 14, which are generated by reaction of the fluoro derivatives 13 with lH-1, 2, 4-triazole in the presence of a base.
  • Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick- layer chromatography, preparative low or high-pressure liquid chromatography or a combination of these procedures.
  • suitable separation and isolation procedures can be had by reference to the preparations and examples herein below. However, other equivalent separation or isolation procedures could, of course, also be used. Racemic mixtures of chiral compounds of formula I can be separated using chiral HPLC.
  • the value of negative (neutral) control is determined for each assay plate by taking the average of 16 negative control wells.
  • the neurogenic compound response is calculated for each compound as (compound/Negative Control)* 100.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof can be used as medicaments, e.g. in the form of pharmaceutical preparations.
  • the pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions.
  • the administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention porte sur des composés représentés par la formule générale (I-1) ou (I-2), dans laquelle R1 représente l'atome d'hydrogène ou un groupe alkyle inférieur, alcoxy inférieur, halogéno, O(CH2)2-(alcoxy inférieur), O(CH2)2N(CH3)2 ou O(CH2)-morpholinyle ; R1' représente l'atome d'hydrogène ou un groupe alkyle inférieur, alcoxy inférieur, halogéno, O(CH2)2-(alcoxy inférieur), O(CH2)2N(CH3)2 ou O(CH2)-morpholinyle ; à condition que R1 et R1' puissent représenter tous deux simultanément l'atome d'hydrogène, mais que seul l'un de R1 et R1' représente un groupe alkyle inférieur, alcoxy inférieur, halogéno, O(CH2)2-(alcoxy inférieur), O(CH2)2N(CH3)2 ou O(CH2)-morpholinyle ; Het représente un groupe hétéroaryle à 5 ou 6 chaînons, l'hétéroatome étant choisi parmi N, O ou S ; X représente -CRR'-, -CRR'-NR'-, -C(O)-, -CH2-S-, -CH2-S(O)2-, -CH2-O- ou -CH2-CRR'-, R/R' représentant chacun indépendamment de l'autre l'atome d'hydrogène ou un groupe alkyle inférieur, hydroxy ou phényle ou R et R' pouvant former conjointement avec l'atome de carbone auquel ils sont attachés un noyau cycloproplyle ; R2 représente un groupe alkyle inférieur, -C(O)O-(alkyle inférieur), cycloalkyle en C3-6 éventuellement substitué par alkyle inférieur ou =O, cyclohexyle ponté ou cycloalcényle en C3-6, ou il représente un groupe hétéroaryle à 5 chaînons, l'hétéroatome étant choisi parmi N, O ou S, qui est éventuellement substitué par un ou plusieurs substituants alkyle inférieur, ou il représente un groupe pyridinyle, éventuellement substitué par halogéno ou alcoxy inférieur, ou il représente un groupe phényle, éventuellement substitué par un ou plusieurs groupes R2', choisis parmi les groupes halogéno, cyano, S(O)2-(alkyle inférieur), alkyle inférieur, alkyle inférieur substitué par halogéno, alcoxy inférieur, alcoxy inférieur substitué par halogéno ou amino, ou il représente un groupe benzo[1,3]dioxolyle, naphtyle, indolyle, benzoisoxazolyle, 2,3-dihydro-1H-indényle, éventuellement substitué par alcoxy inférieur ou par un groupe oxo, ou il représente un groupe 3,4-dihydro-2H-[1,4]oxazinyle, éventuellement substitué par un groupe oxo, ou il représente un groupe hétérocycloalkyle à cinq ou six chaînons ; ou sur un sel d'addition d'acide pharmaceutiquement acceptable de ceux-ci, sur un mélange racémique de ceux-ci ou sur leurs énantiomères et/ou isomères optiques correspondants. Les composés peuvent être utilisés pour le traitement ou la prophylaxie de la schizophrénie, d'un trouble de la personnalité obsessionnel-compulsif, de la dépression majeure, de troubles bipolaires, de troubles anxieux, du vieillissement normal, de l'épilepsie, d'une dégénérescence rétinienne, d'une lésion cérébrale traumatique, d'une lésion médullaire, d'un état de stress post-traumatique, d'un trouble panique, de la maladie de Parkinson, de la démence, de la maladie d'Alzheimer, d'un trouble cognitif léger, d'un dysfonctionnement cognitif induit par chimiothérapie, de la trisomie 21, de troubles du spectre de l'autisme, d'une perte auditive, d'acouphènes, de l'ataxie spinocérébelleuse, de la sclérose latérale amyotrophique, de la sclérose en plaques, de la maladie de Huntington, d'un accident vasculaire cérébral, d'une radiothérapie, d'un stress chronique ou de l'abus de drogues neuro-actives telles que l'alcool, les opiacés, la méthamphétamine, la phencyclidine et la cocaïne.
PCT/EP2013/074211 2012-11-23 2013-11-20 Dérivés hétérocycliques substitués WO2014079850A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP12193945.8 2012-11-23
EP12193945 2012-11-23

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Publication Number Publication Date
WO2014079850A1 true WO2014079850A1 (fr) 2014-05-30

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AR (1) AR093576A1 (fr)
TW (1) TW201425296A (fr)
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US20160016910A1 (en) * 2013-02-28 2016-01-21 Bristol-Meyers Squibb Company Phenylpyrazole derivatives as potent rock1 and rock2 inhibitors
US9828345B2 (en) 2013-02-28 2017-11-28 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
JP2017538678A (ja) * 2014-11-05 2017-12-28 フレクサス・バイオサイエンシーズ・インコーポレイテッドＦｌｅｘｕｓ Ｂｉｏｓｃｉｅｎｃｅｓ， Ｉｎｃ． 免疫調節剤
US9902702B2 (en) 2014-07-15 2018-02-27 Bristol-Myers Squibb Company Spirocycloheptanes as inhibitors of rock
US10106546B2 (en) 2014-11-05 2018-10-23 Flexus Biosciences, Inc. Immunoregulatory agents
WO2018158256A3 (fr) * 2017-02-28 2018-12-13 Acousia Therapeutics Gmbh Nouveaux composés utiles en tant qu'agents d'ouverture des canaux potassiques
EP3368509A4 (fr) * 2015-10-30 2019-05-01 Trillium Therapeutics Inc. Dérivés amides fluorés et leurs utilisations comme agents thérapeutiques
WO2020140043A1 (fr) 2018-12-28 2020-07-02 Endogena Therapeutics, Inc. Composés destinés à être utilisés en tant que substances thérapeutiquement actives dans le traitement et/ou la prévention de maladies neurorétiniennes
WO2020140050A1 (fr) 2018-12-28 2020-07-02 Endogena Therapeutics, Inc. Dérivés de n-(4-(oxazol-5-yl) phényl)chromane-3-carboxamide et composés apparentés en tant que stimulateurs de la production de cellules précurseurs rétiniennes pour le traitement de maladies neurorétiniennes
US20220089547A1 (en) * 2007-05-23 2022-03-24 Endogena Therapeutics, Inc. Compounds for use as therapeutically active substances in the treatment and/or prevention of neuroretinal diseases
RU2779131C2 (ru) * 2017-02-28 2022-09-01 Акусия Терапьютикс Гмбх Новые соединения, используемые в качестве открывателей калиевых каналов

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Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220089547A1 (en) * 2007-05-23 2022-03-24 Endogena Therapeutics, Inc. Compounds for use as therapeutically active substances in the treatment and/or prevention of neuroretinal diseases
US20160016910A1 (en) * 2013-02-28 2016-01-21 Bristol-Meyers Squibb Company Phenylpyrazole derivatives as potent rock1 and rock2 inhibitors
US9458110B2 (en) * 2013-02-28 2016-10-04 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US9828345B2 (en) 2013-02-28 2017-11-28 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US9902702B2 (en) 2014-07-15 2018-02-27 Bristol-Myers Squibb Company Spirocycloheptanes as inhibitors of rock
US11242319B2 (en) 2014-11-05 2022-02-08 Flexus Biosciences, Inc. Immunoregulatory agents
EP3215141A4 (fr) * 2014-11-05 2018-06-06 Flexus Biosciences, Inc. Agents immunorégulateurs
US11932601B2 (en) 2014-11-05 2024-03-19 Flexus Biosciences, Inc. Immunoregulatory agents
US10533014B2 (en) 2014-11-05 2020-01-14 Flexus Biosciences, Inc. Immunoregulatory agents
US10106546B2 (en) 2014-11-05 2018-10-23 Flexus Biosciences, Inc. Immunoregulatory agents
JP2017538678A (ja) * 2014-11-05 2017-12-28 フレクサス・バイオサイエンシーズ・インコーポレイテッドＦｌｅｘｕｓ Ｂｉｏｓｃｉｅｎｃｅｓ， Ｉｎｃ． 免疫調節剤
EP3368509A4 (fr) * 2015-10-30 2019-05-01 Trillium Therapeutics Inc. Dérivés amides fluorés et leurs utilisations comme agents thérapeutiques
JP2020510694A (ja) * 2017-02-28 2020-04-09 アコージア セラピューティクス ゲゼルシャフト ミット ベシュレンクテル ハフツング カリウムチャンネル開口薬としての有用な新規化合物
US11034665B2 (en) 2017-02-28 2021-06-15 Acousia Therapeutics Gmbh Compounds useful as potassium channel openers
CN114105942A (zh) * 2017-02-28 2022-03-01 阿库西亚医疗有限责任公司 可用作钾通道开放剂的新化合物
RU2779131C2 (ru) * 2017-02-28 2022-09-01 Акусия Терапьютикс Гмбх Новые соединения, используемые в качестве открывателей калиевых каналов
WO2018158256A3 (fr) * 2017-02-28 2018-12-13 Acousia Therapeutics Gmbh Nouveaux composés utiles en tant qu'agents d'ouverture des canaux potassiques
US10752593B2 (en) 2018-12-28 2020-08-25 Endogena Therapeutics, Inc. Compounds for use as therapeutically active substances in the treatment of retinal diseases
US10807973B2 (en) 2018-12-28 2020-10-20 Endogena Therapeutics, Inc. Compounds for use as therapeutically active substances in the treatment of retinal diseases
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JP2022516087A (ja) * 2018-12-28 2022-02-24 エンドジーナ セラペウティクス インコーポレーテッド 神経網膜疾患の治療及び／又は予防において治療活性物質として使用する化合物
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JP7492964B2 (ja) 2018-12-28 2024-05-30 エンドジーナ セラペウティクス インコーポレーテッド 神経網膜疾患の治療及び／又は予防において治療活性物質として使用する化合物

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