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WO2017063564A1 - Dérivé octahydrocyclopenta[c]pyrrole, son procédé de préparation et son utilisation pharmaceutique - Google Patents

Dérivé octahydrocyclopenta[c]pyrrole, son procédé de préparation et son utilisation pharmaceutique Download PDF

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Publication number
WO2017063564A1
WO2017063564A1 PCT/CN2016/101979 CN2016101979W WO2017063564A1 WO 2017063564 A1 WO2017063564 A1 WO 2017063564A1 CN 2016101979 W CN2016101979 W CN 2016101979W WO 2017063564 A1 WO2017063564 A1 WO 2017063564A1
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Prior art keywords
methyl
oxo
amino
group
alkyl
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English (en)
Chinese (zh)
Inventor
郑苏欣
张国彪
张晓波
王文晶
邱关鹏
魏用刚
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Sichuan Haisco Pharmaceutical Co Ltd
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Sichuan Haisco Pharmaceutical Co Ltd
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Priority to CN201680042115.4A priority Critical patent/CN107849009B/zh
Publication of WO2017063564A1 publication Critical patent/WO2017063564A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D209/52—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 condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to an octahydrocyclopenta[c]pyrrole derivative, a preparation method thereof and a medicine application thereof, in particular to a muscarinic receptor (M receptor) antagonist and a ⁇ 2 -adrenal gland
  • M receptor muscarinic receptor
  • Bronchodilators play an important role in the treatment of respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma.
  • Bronchodilators in clinical use include widely muscarinic receptor antagonist and ⁇ 2 - adrenergic agonist.
  • a muscarinic receptor antagonist exerts potency in bronchodilation by reducing the level of vagal cholinergic energy in airway smooth muscle.
  • Inhaled muscarinic receptor antagonists currently used include ipratropium bromide, oxitropium bromide, glycopyrrolate, tiotropium bromide, adiponium bromide and indole bromide.
  • 2 2 -adrenergic agonists bronchodilate by stimulating adrenergic receptors in airway smooth muscle, reversing the response of bronchoconstrictors to various mediators such as acetylcholine.
  • the ⁇ 2 -adrenergic agonists currently used include albuterol, salmeterol, arformoterol, formoterol, vilantrol and indacaterol. In addition to improving lung function, these drugs can improve the quality of life of patients and reduce the deterioration of their condition.
  • the combination of muscarinic receptor antagonists and ⁇ 2 -adrenergic agonists is more effective than the use of one of the therapeutic agents alone
  • the current prion base receptor antagonists And ⁇ 2 -adrenergic agonists are prepared as a combination preparation for the treatment of asthma and moderate to severe COPD.
  • These compound preparations mainly include Anoro Ellipta (Ambroxol/Vylantro) and Ultibro Breezhaler (Glon Brom). Ammonium / indacaterol) and ipratropium bromide / salbutamol.
  • muscarinic receptor antagonist and ⁇ 2 - adrenergic agonists dual-acting drugs drugs with this dual function the advantages of both pharmaceutical ingredient combination, along with a single molecule pharmacokinetics.
  • These compounds are administered as a single therapeutic agent and can provide bronchodilation by two different and possibly synergistic modes of action.
  • compounds with muscarinic receptor antagonism and ⁇ 2 -adrenergic agonistic dual action can also be combined with corticosteroid (ICS) anti-inflammatory drugs to form two therapeutic agents (MABA/ICS) to provide triple Therapeutic effect of action (Expert Opin. Investig. Drugs (2014) 23(4): 453-456).
  • ICS corticosteroid
  • the present invention provides a compound of the formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof:
  • R 1a , R 1b , R 1c , R 1d , R 1e , R 1f and R 1g are each independently selected from H or C 1-4 alkyl;
  • W is selected from -O-, -NH- or -NC 1-4 alkyl-;
  • R' and R" are each independently selected from the group consisting of F, Cl, Br, I, OH, cyano, C 1-4 alkyl or C 1-4 alkoxy;
  • R 3 and R 4 are each independently selected from H or C 1-4 alkyl
  • R 5 is selected from H or OH
  • a 0, 1, 2, 3 or 4;
  • b 0, 1, 2, 3, 4 or 5;
  • c or d is independently selected from 0, 1, 2, 3 or 4;
  • L is selected from The condition is that the number of connected atoms of the L shortest chain is in the range of 6 to 26;
  • R 3a , R 3c , and R 3d are each independently selected from a C 1-6 alkylene group, and the alkylene group is optionally further substituted with 0, 1 , 2, 3, 4 or 5 R 3e ;
  • R 3b is selected from C 1-6 alkylene, phenylene or 5 to 6 membered heteroarylene, said alkylene, phenylene or heteroarylene optionally further 0, 1, 2, 3 Or substituted with four substituents selected from the group consisting of F, Cl, Br, I, cyano, OH, C 1-4 alkyl or C 1-4 alkoxy;
  • R 3e is selected from the group consisting of F, Cl, Br, I, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl-C 1-4 alkylene;
  • two R 3e may form a 3 to 6 membered carbocyclic ring together with the atoms to which they are attached, said carbon ring optionally further being 0, 1, 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br Substituted with a substituent of I, cyano, OH, C 1-4 alkyl or C 1-4 alkoxy;
  • a 1 and A 2 are each independently selected from a C 3-11 carbocyclic ring, a 5 to 11 membered heterocyclic ring, a -OC 3-11 carbocyclic ring, a -O-5 to 11 membered heterocyclic ring, and a C 3-11 carbocyclic ring-O-.
  • a 5- to 11-membered heterocyclic ring-O- said carbocyclic or heterocyclic ring optionally further substituted by 0, 1, 2, 3, 4 or 5 R 6 and said heterocyclic ring containing 1 to 3 a hetero atom selected from N, O or S;
  • R x is each independently selected from H, C 1-6 alkyl or C 3-8 cycloalkyl, and the alkyl or cycloalkyl group is optionally further selected from 0, 1, 2, 3, 4 or 5 Substituted with a substituent of F, Cl, Br, I, C 1-4 alkyl, C 3-6 cycloalkyl or C 1-4 alkoxy;
  • n, p or q are each independently selected from 0 or 1.
  • a preferred embodiment of the invention a compound of the formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:
  • R 1 and R 2 are each independently selected from the group consisting of F, Cl, Br, I, CF 3 , NH 2 , OH, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio , -NHC 1-4 alkyl or -N(C 1-4 alkyl) 2 ;
  • W is selected from -O-, -NH- or -NC 1-4 alkyl-;
  • R' and R" are each independently selected from the group consisting of F, Cl, Br, I, OH, cyano, C 1-4 alkyl or C 1-4 alkoxy;
  • R 3 and R 4 are each independently selected from H or C 1-4 alkyl
  • R 5 is selected from H or OH
  • L is selected from The condition is that the number of connected atoms of the L shortest chain is in the range of 6 to 26;
  • R 3a , R 3c , and R 3d are each independently selected from a C 1-6 alkylene group, and the alkylene group is optionally further substituted with 0, 1 , 2, 3, 4 or 5 R 3e ;
  • R 3b is selected from C 1-6 alkylene, phenylene or 5 to 6 membered heteroarylene, said alkylene, phenylene or heteroarylene optionally further 0, 1, 2, 3 Or substituted with four substituents selected from the group consisting of F, Cl, Br, I, cyano, OH, C 1-4 alkyl or C 1-4 alkoxy;
  • R 3e is selected from the group consisting of F, Cl, Br, I, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl-C 1-4 alkylene;
  • two R 3e may form a 3 to 6 membered carbocyclic ring together with the atoms to which they are attached, said carbon ring optionally further being 0, 1, 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br Substituted with a substituent of I, cyano, OH, C 1-4 alkyl or C 1-4 alkoxy;
  • a 1 and A 2 are each independently selected from a C 3-11 carbocyclic ring, a 5 to 11 membered heterocyclic ring, a -OC 3-11 carbocyclic ring, a -O-5 to 11 membered heterocyclic ring, and a C 3-11 carbocyclic ring-O-.
  • a 5- to 11-membered heterocyclic ring-O- preferably a C 5-11 carbocyclic ring, a 5 to 11 membered heterocyclic ring, a -OC 5-11 carbocyclic ring, a -O-5 to 11 membered heterocyclic ring, a C 5-11 carbocyclic ring.
  • R x is each independently selected from H, C 1-6 alkyl or C 3-8 cycloalkyl, and the alkyl or cycloalkyl group is optionally further selected from 0, 1, 2, 3, 4 or 5 Substituted with a substituent of F, Cl, Br, I, C 1-4 alkyl, C 3-6 cycloalkyl or C 1-4 alkoxy;
  • n, p or q are each independently selected from 0 or 1;
  • a 0, 1, 2, 3 or 4;
  • b 0, 1, 2, 3, 4 or 5;
  • c or d is independently selected from 0, 1, 2, 3 or 4.
  • a preferred embodiment of the invention a compound of the formula (II) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof,
  • R 1 and R 2 are each independently selected from the group consisting of F, Cl, Br, I, CF 3 , NH 2 , OH, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio , -NHC 1-4 alkyl or -N(C 1-4 alkyl) 2 ;
  • W is selected from -O-, -NH- or -NC 1-4 alkyl-, preferably -O-, -NH- or -NCH 3 -;
  • R' and R" are each independently selected from the group consisting of F, Cl, Br, I, OH, cyano, C 1-4 alkyl or C 1-4 alkoxy, preferably F, Cl, Br, I, OH, cyanide Base, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or propoxy;
  • R 3 and R 4 are each independently selected from H or C 1-4 alkyl, preferably H, methyl or ethyl;
  • R 5 is selected from H or OH
  • R 3a and R 3d are each independently selected from a C 1-6 alkylene group, preferably a C 1-5 alkylene group, more preferably a methylene group, an ethylene group, a propylene group, a butylene group or a pentylene group.
  • the alkylene, methylene, ethylene, propylene, butylene or pentylene group is optionally further substituted by 0, 1, 2, 3, 4 or 5 R 3e ;
  • R 3b is selected from C 1-6 alkylene, phenylene or 5- to 6-membered heteroarylene, preferably C 1-4 alkylene, phenylene or 5- to 6-membered heteroarylene, more preferably sub- Methyl, ethylene, propylene, butylene, pentylene, phenylene, thienylene, furanyl, thiazolyl, oxazolyl or pyridylene, said alkylene, Methylene, ethylene, propylene, butylene, pentylene, phenylene, heteroarylene, thienylene, furanyl, thiazolyl, oxazolyl or pyridyl Further substituted with 0, 1, 2, 3 or 4 substituents selected from F, Cl, Br, I, cyano, OH, C 1-4 alkyl or C 1-4 alkoxy;
  • R 3e is selected from the group consisting of F, Cl, Br, I, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl-C 1-4 alkylene;
  • two R 3e may form a 3 to 6 membered carbocyclic ring together with the atoms to which they are attached, said carbon ring optionally further being 0, 1, 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br Substituted with a substituent of I, cyano, OH, C 1-4 alkyl or C 1-4 alkoxy;
  • a 1 is selected from a C 5-11 carbocyclic ring, a 5 to 11 membered heterocyclic ring, a -OC 5-11 carbocyclic ring, a -O-5 to 11 membered heterocyclic ring, a C 5-11 carbon ring-O- or a 5 to 11 member.
  • Heterocyclic ring-O- preferably C 5-11 carbocyclic or 5- to 11-membered heterocyclic ring, more preferably benzene ring or 5- to 6-membered heterocyclic ring, further preferably benzene ring, thiophene ring, furan ring, thiazole ring, oxazole ring Or a pyridine ring, said carbocyclic, heterocyclic, benzene ring, thiophene ring, furan ring, thiazole ring, oxazole ring or pyridine ring optionally further substituted by 0, 1, 2, 3, 4 or 5 R 6
  • the heterocyclic ring contains 1 to 3 hetero atoms selected from N, O or S;
  • R x is each independently selected from H, C 1-6 alkyl or C 3-8 cycloalkyl, and the alkyl or cycloalkyl group is optionally further selected from 0, 1, 2, 3, 4 or 5 Substituted with a substituent of F, Cl, Br, I, C 1-4 alkyl, C 3-6 cycloalkyl or C 1-4 alkoxy;
  • R x each independently is preferably H, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, said methyl, ethyl , propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl optionally further selected from 0, 1, 2, 3, 4 or 5 selected from F, Cl, Substituted with Br, I, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy or ethoxy;
  • R 6 is each independently preferably F, Cl, Br, OH, cyano, methyl, ethyl, propyl, isopropyl, ethynyl, propynyl, CHF 2 , CF 3 , methoxy, ethoxy, -OCHF 2 , -OCF 3 , pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl or oxazolyl;
  • the number of linking atoms of the shortest chain of R 3a to R 3d is in the range of 6 to 26;
  • a is 0, 1, 2, 3 or 4, preferably 0 or 1;
  • b is 0, 1, 2, 3, 4 or 5, preferably 0, 1 or 2;
  • c or d is independently selected from 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3.
  • a preferred embodiment of the invention is a compound represented by the formula (II): or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:
  • R 1 and R 2 are each independently selected from the group consisting of F, Cl, Br, I, CF 3 , NH 2 , OH, cyano, methyl, ethyl, methoxy, ethoxy, -NHCH 3 or -N (CH) 3 ) 2 ;
  • W is selected from -O-, -NH- or -NC 1-4 alkyl-, preferably -O-, -NH- or -NCH 3 -;
  • R' and R" are each selected from the group consisting of F, Cl, Br, I, OH, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or propoxy;
  • R 3 and R 4 are each independently selected from H, methyl or ethyl
  • R 5 is selected from H or OH
  • R 3a is selected from methylene, ethylene, propylene, butylene, pentylene or The methylene, ethylene, propylene, butylene, pentylene or Optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from the group consisting of F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;
  • R 3b is selected from the group consisting of methylene, ethylene, propylene, butylene, pentylene, phenylene, thienylene, furanyl, thiazolyl, oxazolyl or pyridylene, Methylene, ethylene, propylene, butylene, pentylene, phenylene, thienylene, furanyl, thiazolyl, oxazolyl or pyridylene optionally further 0, 1 Substituting 2, 3 or 4 substituents selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;
  • R 3d is selected from methylene, ethylene, propylene, butylene or pentylene, and the methylene, ethylene, propylene, butylene or pentylene group is further further 0. 1, 2, 3, 4 or 5 substituents selected from the group consisting of F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;
  • a 1 is selected from a benzene ring, a thiophene ring, a furan ring, a thiazole ring, an oxazole ring or a pyridine ring, and the benzene ring, thiophene ring, furan ring, thiazole ring, oxazole ring or pyridine ring is optionally further 0. 1, 2, 3 or 4 R 6 substitutions;
  • R x is selected from H, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, said methyl, ethyl, propyl
  • the base, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl are optionally further 0, 1, 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br, Substituting I, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy or ethoxy;
  • R 6 is selected from the group consisting of F, Cl, Br, OH, cyano, methyl, ethyl, propyl, isopropyl, ethynyl, propynyl, CHF 2 , CF 3 , methoxy, ethoxy, - OCHF 2 , -OCF 3 , pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl or oxazolyl;
  • the number of linking atoms of the shortest chain of R 3a to R 3d is in the range of 6 to 26;
  • a is 0 or 1
  • b 0, 1 or 2;
  • c or d are each independently selected from 0, 1, 2 or 3.
  • a preferred embodiment of the invention a compound of the formula (II) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:
  • R 1 and R 2 are each independently selected from the group consisting of F, Cl, Br, I, CF 3 , NH 2 , OH, cyano, methyl, ethyl, methoxy, ethoxy, -NHCH 3 or -N (CH) 3 ) 2 ;
  • W is selected from -O-, -NH- or -NC 1-4 alkyl-, preferably -O-, -NH- or -NCH 3 -;
  • R' and R" are each selected from the group consisting of F, Cl, Br, I, OH, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or propoxy;
  • R 3 and R 4 are each independently selected from H, methyl or ethyl
  • R 5 is selected from H or OH
  • R 3a is selected from the group consisting of methylene, ethylene, propylene, -CH 2 CH(CH 3 )-, -CH(CH 3 )CH 2 -, -C(CH 3 ) 2 CH 2 -, -CH 2 C(CH 3 ) 2 -, n-n-butyl, -CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )CH 2 -, Or pentylene;
  • R 3b is selected from the group consisting of methylene, ethylene, propylene, butylene, pentylene, phenylene, thienylene, furanyl, thiazolyl, oxazolyl or pyridylene, Methylene, ethylene, propylene, butylene, pentylene, phenylene, thienylene, furanyl, thiazolyl, oxazolyl or pyridylene optionally further 0, 1 Substituting 2, 3 or 4 substituents selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;
  • R 3d is selected from the group consisting of methylene, ethylene, propylene, -CH 2 CH(CH 3 )-, -CH(CH 3 )CH 2 -, n-butylene, -CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )CH 2 - or pentylene;
  • a 1 is selected from a benzene ring, a thiophene ring, a furan ring, a thiazole ring, an oxazole ring or a pyridine ring, and the benzene ring, thiophene ring, furan ring, thiazole ring, oxazole ring or pyridine ring is optionally further 0. 1, 2, 3, 4 or 5 R 6 substitutions;
  • R 6 is selected from the group consisting of F, Cl, Br, cyano, methyl, ethyl, propyl, isopropyl, ethynyl, CHF 2 , CF 3 , methoxy, ethoxy, -OCHF 2 or -OCF 3 ;
  • R x is selected from the group consisting of H, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, said methyl, ethyl, propyl Base, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl are optionally further from 0 to 5 selected from the group consisting of F, Cl, Br, I, methyl, ethyl, Substituted by cyclopropyl, cyclobutyl, cyclopentyl, methoxy or ethoxy;
  • the number of linking atoms of the shortest chain of R 3a to R 3d is in the range of 6 to 26;
  • the compounds of the invention include, but are not limited to, one of the following compounds:
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of the formula (I) or (II) or a stereoisomer, hydrate or metabolite thereof.
  • said composition may further comprise one or A variety of other therapeutic agents; preferably, wherein the additional therapeutic agent is selected from one or more of a PDE4 inhibitor, a M receptor antagonist, a corticosteroid, and a beta-adrenoreceptor agonist.
  • the present invention also relates to providing a compound of the formula (I) or (II) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, for preparation Use in the treatment of a medicament for an airway obstructive disease, preferably, in the preparation of a medicament for the treatment of asthma, chronic obstructive pulmonary disease or bronchitis.
  • the present invention also provides a method for treating an airway obstructive disease, which comprises administering a compound of the above formula (I) or (II) or a stereoisomer, hydrate, metabolite, solvent thereof. a pharmaceutically acceptable salt, eutectic or prodrug, or a pharmaceutical composition as described above.
  • the present invention also provides a method for treating asthma, chronic obstructive pulmonary disease or bronchitis, which comprises administering a compound of the above formula (I) or (II) or a stereoisomer thereof or a hydrate thereof. , metabolites, solvates, A pharmaceutically acceptable salt, eutectic or prodrug, or a pharmaceutical composition as described above.
  • the present invention provides an intermediate for preparing a compound of the formula (II) or a stereoisomer thereof, which is selected from a compound represented by the formula (III) or a stereoisomer thereof:
  • M is selected from a carboxyl group, -COOC 1-4 alkyl, -X 1 -A 1 -CH 2 OH, -X 1 -A 1 -CHO or -X 1 -A1-1,3-dioxolan-2- base;
  • R 1 and R 2 are each independently selected from the group consisting of F, Cl, Br, I, CF 3 , NH 2 , OH, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio , -NHC 1-4 alkyl or -N(C 1-4 alkyl) 2 ;
  • W is selected from -O-, -NH- or -NC 1-4 alkyl-;
  • R' and R" are each independently selected from the group consisting of F, Cl, Br, I, OH, cyano, C 1-4 alkyl or C 1-4 alkoxy;
  • R 3d is selected from a C 1-6 alkylene group, and the alkylene group is optionally further substituted by 0, 1 , 2, 3, 4 or 5 R 3e ;
  • R 3b is selected from C 1-6 alkylene, phenylene or 5 to 6 membered heteroarylene, said alkylene, phenylene or heteroarylene optionally further 0, 1, 2, 3 Or substituted with four substituents selected from the group consisting of F, Cl, Br, I, cyano, OH, C 1-4 alkyl or C 1-4 alkoxy;
  • R 3e is selected from the group consisting of F, Cl, Br, I, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl-C 1-4 alkylene;
  • two R 3e may form a 3 to 6 membered carbocyclic ring together with the atoms to which they are attached, said carbon ring optionally further being 0, 1, 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br Substituted with a substituent of I, cyano, OH, C 1-4 alkyl or C 1-4 alkoxy;
  • a 1 is selected from a C 5-11 carbocyclic ring, a 5 to 11 membered heterocyclic ring, a -OC 5-11 carbocyclic ring, a -O-5 to 11 membered heterocyclic ring, a C 5-11 carbon ring-O- or a 5 to 11 member.
  • Heterocyclic-O-, said carbocyclic or heterocyclic ring optionally further substituted by 0, 1, 2, 3, 4 or 5 R 6 and said heterocyclic ring containing 1 to 3 selected from N, O Or a hetero atom of S;
  • R x is each independently selected from H, C 1-6 alkyl or C 3-8 cycloalkyl, and the alkyl or cycloalkyl group is optionally further selected from 0, 1, 2, 3, 4 or 5 Substituted with a substituent of F, Cl, Br, I, C 1-4 alkyl, C 3-6 cycloalkyl or C 1-4 alkoxy;
  • the oxy, cycloalkyl, NH 2 or heteroaryl group is further optionally from 0 to 4 selected from the group consisting of F, Cl, Br, I, CF 3 , C 1-4 alkyl, C 1-4 alkoxy or - Substituted by a
  • a 0, 1, 2, 3 or 4;
  • b 0, 1, 2, 3, 4 or 5;
  • c or d is independently selected from 0, 1, 2, 3 or 4.
  • the compound of the formula (IV) is selected from one of the following structures:
  • the reagent such as saturated sodium bicarbonate solution or saturated sodium carbonate solution
  • an organic solvent such as dichloromethane, ethyl acetate, etc.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, and the groups and compounds involved in the present invention.
  • the nitrogen or halogen is optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C, 13 C, and 14 C, and the hydrogen isotopes include helium (H), helium (D, also known as heavy hydrogen ), tritium (T, also known as tritium), oxygen isotopes include 16 O, 17 O and 18 O, comprising sulfur, 32 S, 33 S, 34 S and 36 S, the nitrogen isotopes 14 N and 15 comprising N, the fluorine isotope 19 F, the chlorine isotope includes 35 Cl and 37 Cl, and the bromine isotopes include 79 Br and 81 Br.
  • Alkyl means a straight-chain and branched monovalent saturated hydrocarbon group, and the main chain includes 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, further preferably 1 to 6 carbon atoms, more preferably 1 Straight and branched groups of up to 4 carbon atoms, most preferably 1 to 2 carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, n-hexyl, n-glycol a base, an n-octyl group, a n-decyl group, a n-decyl group, etc.; the alkyl group may optionally be further from 0 to 5 selected from the alky
  • Alkoxy means a monovalent group of an O-alkyl group, wherein alkyl is as defined herein, and alkoxy embodiments include, but are not limited to, methoxy, ethoxy, 1-propoxy, 2 -propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, 1-pentyloxy, 2-pentyloxy , 3-pentyloxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy, 3-methyl-1-butoxy and 2-methyl-1-butoxy Wait.
  • alkenyl means a straight-chain or branched monovalent unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon double bonds, the main chain comprising 2 to 10 carbon atoms, further preferably 2 Up to 6 carbon atoms, more preferably 2 to 4 carbon atoms in the main chain, and alkenyl examples include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl , 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2- Methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-hep
  • Alkynyl means a straight-chain or branched monovalent unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, the main chain comprising 2 to 10 carbon atoms, further preferably 2 Up to 6 carbon atoms, more preferably 2 to 4 carbon atoms in the main chain
  • alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butyl Alkynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3 -hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-decynyl and 4-decynyl, etc.; the alkynyl group
  • Cycloalkyl means a monovalent saturated carbocyclic hydrocarbon group, usually having from 3 to 10 carbon atoms, and non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • Carbocycle or “carbocyclyl” means a saturated or unsaturated aromatic or non-aromatic ring.
  • the aromatic or non-aromatic ring may be a 3 to 10 membered monocyclic ring, a 4 to 12 membered bicyclic ring or a 10 to 15 membered member.
  • a tricyclic system, a carbocyclic group may be bonded to a bridged ring or a spiro ring, and non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl -2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, cyclohexadienyl , cycloheptyl, cyclooctyl, cyclodecyl, cyclodecyl, cyclodecyl, cyclododecyl, phenyl, naphthyl, benzocyclopropenyl, 2,3-dihydrobenzo ring Propylene
  • the carbocyclic group may be further optional
  • Heterocycle or “heterocyclyl” means a saturated or unsaturated aromatic or non-aromatic ring, and the aromatic or non-aromatic ring may be a 3 to 10 membered monocyclic ring, a 4 to 12 membered bicyclic ring or a 10 to 15 membered member.
  • a tricyclic system comprising 1 to 4 heteroatoms selected from N, O or S, preferably a 3 to 10 membered heterocyclic group, and optionally substituted N, S in the ring of the heterocyclic group can be oxidized to various oxidations state.
  • the heterocyclic group may be bonded to a hetero atom or a carbon atom, and the heterocyclic group may be bonded to a bridged or spiro ring, and non-limiting examples include an epoxyethyl group, a glycidyl group, an azacyclopropyl group, and an oxocyclic ring.
  • ⁇ -adrenergic receptor binding group refers to a group capable of binding to a ⁇ -adrenergic receptor; for example, see review article “ ⁇ -adrenergic receptors in Comprehensive Medicinal Chemistry, 1990, BEMain, p187 (Pergamon Press) ".
  • the above-mentioned groups are also described, for example, in WO/2005092841, US/20050215542, WO/2005070872, WO/2006023460, WO/2006051373, WO/2006087315 and WO/2006032627.
  • alkyl group optionally substituted by F means that the alkyl group may, but need not, be substituted by F, indicating a case where the alkyl group is substituted by F and a case where the alkyl group is not substituted by F.
  • “Pharmaceutical composition” means a mixture of one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt thereof, with other components, wherein the other components comprise physiologically/pharmaceutically acceptable carriers and excipients.
  • Carrier refers to a carrier or diluent that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
  • Excipient refers to an inert substance that is added to a pharmaceutical composition to further depend on the administration of the compound.
  • excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, Granules, lubricants, binders, disintegrators, and the like.
  • Prodrug means a compound that can be converted to a biologically active compound of the invention under physiological conditions or by solvolysis. Prodrugs of the invention are prepared by modifying functional groups in the compounds of the invention which can be removed by conventional procedures or in vivo to provide the parent compound.
  • Stepoisomer refers to isomers resulting from the spatial arrangement of atoms in a molecule, including cis and trans isomers, enantiomers and conformational isomers.
  • Effective dose refers to an amount of a compound that causes a physiological or medical translation of a tissue, system or subject, which amount is sought, and includes one or more of the conditions or conditions sufficient to prevent treatment when administered to a subject. The amount of a compound that occurs or reduces it to some extent.
  • Solvate means a compound of the invention or a salt thereof, which also includes a stoichiometric or non-stoichiometric amount of solvent bound by intermolecular non-covalent forces.
  • solvent is water, it is a hydrate.
  • IC 50 refers to the half-inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) NMR instrument and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD).
  • the internal standard is tetramethylsilane (TMS).
  • the HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm).
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.20mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anheji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies.
  • the nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • reaction was carried out under a nitrogen atmosphere.
  • the solution means an aqueous solution.
  • M is mol/L.
  • reaction temperature is room temperature.
  • the room temperature is an optimum reaction temperature of 20 ° C to 30 ° C.
  • TBS is tert-butyldimethylsilyl.
  • Boc is a tert-butyloxycarbonyl group.
  • Bn is a benzyl group.
  • HATU is 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (CAS: 148893-10-1)
  • EtOAcjjjjjjjjjjjjjjjjjjj Methane 40 mL
  • triethylamine was adjusted to basic.
  • EtOAc EtOAc
  • EtOAc EtOAc
  • EtOAc EtOAc
  • EtOAc EtOAc
  • EtOAc EtOAc
  • the organic layer was concentrated under reduced EtOAcqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH
  • Step 5 N-(2-Chloro-4-carbaldehydel-5-methoxy-phenyl)-4-methylamino-butanamide trifluoroacetate (Intermediate 3)
  • Step 6 N-(2-Chloro-4-formyl-5-methoxy-phenyl)-5(methyl(acryloyl)amino)-pentanamide (Intermediate 4)
  • Example 1 [(3aR, 5s, 6aS)-2-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-) 1,4-Benzoxazine-8-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-3 ,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl N-(2-phenylphenyl)carbamate (Compound 1)
  • EtOAc EtOAc m.
  • 5-[2-amino-1-(tert-butyl(dimethyl)silyl)oxy-ethyl]-8-hydroxyl was added sequentially -1H-quinolin-2-one (2B) (0.34 g, 1.0 mmol), methanol (10 mL) and dichloromethane (10 mL). 3.0 mmol), the reaction was continued for 3 hours.
  • tert-Butyl 3-(methylammonium)propionate (1.3 g, 8.2 mmol) was placed in a 50 mL round bottom flask at 0 ° C under nitrogen, and dichloromethane (30 mL) and acrylic acid were added sequentially. (0.72g, 10mmol), stir evenly and then add three Ethylamine (2.02 g, 20 mmol) and HATU (5.7 g, 15 mmol) were warmed to room temperature for 20 min.
  • the third step [(3aR, 5s, 6aS)-2-[3-[[3-[4-(hydroxymethyl)anilino]-3-oxo-propyl]-methyl-amino]-3 -oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)amino Formate (5D)
  • Step 5 [(3aR, 5s, 6aS)-2-[3-[[3-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-) Quinoline-5-yl)ethyl] Amino]methyl]anilino]-3-oxo-propyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H- Cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 5)
  • Methyl 4-(methylammonium)butanoate (6A) (prepared by reference to WO2015028850) (0.66 g, 5 mmol) was placed in a 50 mL round bottom flask at 0 ° C under nitrogen and dichloromethane (30 mL) And acrylic acid (0.36 g, 5 mmol), and after stirring, triethylamine (1.01 g, 10 mmol) and HATU (2.28 g, 6 mmol) were successively added, and the mixture was allowed to react at room temperature for 20 minutes.
  • Second step 4-[3-[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a-hexahydro -1H-cyclopentadienyl[c]pyrrol-2-yl]propionyl-methyl-amino]butyric acid methyl ester (6C)
  • Step 5 [(3aR,5s,6aS)-2-[3-[[4-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-) Quinoline-5-yl)ethyl]amino]methyl]anilino]-4-oxo-butyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5 ,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (Compound 6)
  • Example 7 [(3aR,5s,6aS)-2-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-) Quinoline-5-yl)ethyl]amino]methyl]-N-methyl-anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-3 ,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 7)
  • Example 8 [(3aR,5s,6aS)-2-[3-[[5-[4-[[2-(5-hydroxy-3-oxo-4H-1,4-benzoxazine)- 8-yl)ethylamino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a -Hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 8)
  • Example 10 [(3aR,5r,6aS)-2-[3-[[5-[4-[[2-(5-hydroxy-3-oxo-4H-1,4-benzoxazine)- 8-yl)ethylamino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a -Hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (Compound 10)
  • EtOAc EtOAc m. Add 8-(2-aminoethyl)-5-hydroxy-4H-1,4-benzoxazin-3-one acetate (8A) (0.27 g, 1.0 mmol), methanol (10 mL) After stirring with N-methylpyrrolidone (10 mL) at room temperature for 1 hour, sodium triacetoxyborohydride (0.62 g, 3.0 mmol) was added and the reaction was continued for 5 hours.
  • Example 11 [(3aR,5s,6aS)-2-[3-[[4-[4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-) 1,4-Benzoxazine-8-yl)ethyl]amino]methyl]anilino]-4-oxo-butyl]-methyl-amino]-3-oxo-propyl]-3 ,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 11)
  • Example 12 [(3aR,5s,6aS)-2-[3-[[4-[4-[[2-(5-hydroxy-3-oxo-4H-1,4-benzoxazine)- 8-yl)ethylamino]methyl]anilino]-4-oxo-butyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a -Hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 12)
  • Example 13 [(3aR,5r,6aS)-2-[3-[[4-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-) Quinoline-5-yl)ethyl]amino]methyl]anilino]-4-oxo-butyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5 ,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate
  • the oxidizing agent (0.28 g, 0.66 mmol) was reacted at room temperature for 30 minutes, then a saturated sodium thiosulfate solution (10 mL) and a saturated sodium hydrogen carbonate solution (10 mL) were added to the system, and stirred for 10 minutes, dichloromethane (30 mL ⁇ 2) The organic phase was combined and washed with a saturated sodium hydrogen carbonate solution (30 mL ⁇ 1), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure.
  • Example 14 [(3aR,5r,6aS)-2-[3-[[4-[4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-) 1,4-Benzoxazine-8-yl)ethyl]amino]methyl]anilino]-4-oxo-butyl]-methyl-amino]-3-oxo-propyl]-3 ,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 14)
  • EtOAc (EtOAc m.) Acyloxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]propionic acid (15C) (3.9 g, yield 100%) .
  • the fifth step [(3aR, 5s, 6aS)-2-[3-[[4-[[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-) Oxo-1hydroquinolin-5-yl)ethyl]amino]methyl]-5-methoxy-phenyl]amino]-4-oxo-butyl]-methyl-amino]-3- Oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate Acid ester (compound 15)
  • Example 16 [(3aR,5s,6aS)-2-[3-[[5-[3-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-) 1,4-Benzoxazine-8-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-3 ,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (Compound 16)
  • the third step [(3aR, 5s, 6aS)-2-[3-[[5-[3-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-) 1,4-benzoxazine-8- Ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a- Hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (Compound 16)
  • Example 17 [(3aR,5s,6aS)-2-[3-[[5-[3-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-) Quinoline-5-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5 ,6,6a-hexahydro-1H-ring Pentadieno[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (Compound 17)
  • Test Example 1 Inhibitory activity against human muscarinic M3 receptor
  • CHO cells PerkinElmer, ES-212-AF stably expressing human muscarinic receptor 3 (hM3) and apo-Aequorin were cultured in 10% fetal bovine serum (FBS) (Gibico 10099-141), 400 ⁇ g/mL G418 (sigma G5013) and 250 ⁇ g/mL Zeocin (invivogen ant-zn-5p) in Ham'S F12 medium (Invitrogen 12500-062), cultured at 37 ° C, 5% CO 2 to achieve 90-100% confluence.
  • FBS fetal bovine serum
  • G418 Sigma G5013
  • Zeocin invivogen ant-zn-5p
  • the cells were washed with PBS/5 mM EDTA, collected by centrifugation, resuspended in 0.1% BSA (BOVOGEN BSAS 100) phenol red-free Ham's F12 medium (Invitrogen 11039-021) and counted, and the cell concentration was adjusted to 1 ⁇ 10 6 cells/mL. . 15 ml of the cell suspension was added to a 50 mL centrifuge tube and Coelenterazine-h (promega S2011) was added to a final concentration of 5 ⁇ M. It was wrapped in tin foil and protected from light and incubated for 4 hours at 20 ° C in a rotary shaker.
  • the cells were diluted with 0.1% BSA/phenol red-free Ham's F12 medium to a final concentration of 5.0 ⁇ 10 5 cells/mL, and the cells were placed on a rotary shaker at low speed and incubated at room temperature for at least 1 hour.
  • the compound of the example was prepared as a 10 mM mother liquor in DMSO, diluted with 0.1% BSA/phenol red free Ham's F12 medium (log (M): -7, -8, -9, -10, -11), and added to a 96-well plate. 50 ⁇ L per well. An additional 50 ⁇ L of cell suspension (25,000 cells/well) was added to each well and incubated for 15 minutes at room temperature.
  • the 96-well plate was placed in a microplate reader (Perkin Elmer, Envision), and 50 ⁇ L of acetylcholine chloride (Sigma A6625) solution was added to each well of the microplate reader at a concentration of 112.92 nM (hM3), and the luminescence was recorded for 20 seconds.
  • the IC 50 was calculated and analyzed using origin 7.5.
  • the inhibitory activity of the muscarinic receptor of the compound of the present invention was measured by the above experiment, and the measured IC 50 values are shown in Table 1 below.
  • Compound number hM3 receptor IC 50 (nM) Compound number hM3 receptor IC 50 (nM) 1 0.74 10 8.65 2 0.67 11 0.69 3 4.43 12 0.76 4 4.40 13 4.6 5 1.08 14 4.01 6 0.72 15 0.99 7 2.49 16 0.69 8 1.36 17 1.13 9 1.17
  • the compounds of the present invention have significant inhibitory activity against the human muscarinic M3 receptor.
  • Test Example 2 Agonistic activity on human adrenergic ⁇ 2 receptor
  • the agonistic activity of the example compounds on human adrenergic receptors was determined by LANCE Ultra cAMP Assay.
  • CHO cells PerkinElmer, ES-034-CF stably expressing human adrenergic receptor (h ⁇ 2) were cultured in 10% fetal bovine serum (FBS) (Gibico 10099-141) and 250 ⁇ g/mL Zeocin (InvivoGen ant-zn) -5p) MEM-alpha medium (Invitrogen 12561-056), cultured at 37 ° C, 5% CO 2 , 90-100% confluence, and assayed with LANCE Ultra cAMP Assay kit (PerkinElmer TRF0263) The agonistic effect of cAMP.
  • FBS fetal bovine serum
  • MEM-alpha medium Invitrogen 12561-056
  • the cells were separated by PBS/5 mM EDTA, collected by centrifugation, and the cells were resuspended with Stimulation Buffer (1 x HBSS, 5 mM HEPES, 0.5 mM IBMX, 0.1% BSA, pH 7.4), and the cell concentration was adjusted to 6 ⁇ 10 5 cells/ml.
  • Stimulation Buffer (1 x HBSS, 5 mM HEPES, 0.5 mM IBMX, 0.1% BSA, pH 7.4
  • the compound of the Example was prepared as a 10 mM stock solution in DMSO, diluted with a Stimulation Buffer gradient, and added to a 384-well plate at 5 ⁇ l per well.
  • the compounds of the invention have significant agonistic activity on the ⁇ 2 adrenergic receptor.
  • Test Example 3 Methotrexate-induced inhibition of bronchial contraction in guinea pigs
  • test compound was formulated into a 0.6 mM stock solution using 83% absolute ethanol + 17% Tween 80. Dilute to the desired concentration with water prior to administration. Prior to administration, the animals were anesthetized with 5% isoflurane using a small animal anesthesia machine (Matrx; VME2) for an anesthesia time of 1.5 to 2 minutes.
  • the guinea pigs were fixed on an tracheal intubation operating platform and intratracheally administered using a rat liquid aerosol administration kit (penn-century; MSA-250-R), and each guinea pig was administered with a volume of 250 ⁇ l.
  • the guinea pig enhanced exhalation pause (PenH) value was measured using a full volume oximeter (DSI; GS220A12-R7B) at 4 hours and 24 hours.
  • 3 mg/ml methacholine (Mch) was administered by nebulization, the atomization time was 36 seconds, and the recording time was 7 minutes. Calculate the PenH average. (Reference J Pharmacol Exp Ther 345: 260-270.).
  • the experimental results are shown in Table 3.
  • the compounds of the present invention have significant inhibition of methacholine-induced bronchial contraction in guinea pigs, and some compounds still have good bronchoconstriction inhibition effects after 24 hours of administration.

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Abstract

L'invention concerne un composé de formule (I), ou un stéréoisomère, un hydrate, un produit métabolique, un solvate, un sel pharmaceutiquement acceptable, un co-cristal ou un promédicament correspondant, un procédé de préparation, et une application pour la préparation d'un médicament utilisé pour le traitement de maladies obstructives des voies respiratoires. La définition de chaque substituant dans le composé de formule (I) est conforme à la description.
PCT/CN2016/101979 2015-10-13 2016-10-13 Dérivé octahydrocyclopenta[c]pyrrole, son procédé de préparation et son utilisation pharmaceutique Ceased WO2017063564A1 (fr)

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WO2022204337A1 (fr) * 2021-03-26 2022-09-29 Novartis Ag Nouveaux modulateurs allostériques négatifs à base de cyclopenta[c]pyrrol de nr2b

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CN107849008B (zh) 2021-04-09
CN106565674A (zh) 2017-04-19
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