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WO1995005372A1 - Derive de cyclopentane a activite antagoniste de l'endotheline - Google Patents

Derive de cyclopentane a activite antagoniste de l'endotheline Download PDF

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Publication number
WO1995005372A1
WO1995005372A1 PCT/JP1994/001316 JP9401316W WO9505372A1 WO 1995005372 A1 WO1995005372 A1 WO 1995005372A1 JP 9401316 W JP9401316 W JP 9401316W WO 9505372 A1 WO9505372 A1 WO 9505372A1
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group
alkoxy
alkyl
mono
amino
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PCT/JP1994/001316
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English (en)
Japanese (ja)
Inventor
Kiyofumi Ishikawa
Takashi Hayama
Toshio Nagase
Toshiaki Mase
Masaki Ihara
Masaru Nishikibe
Mitsuo Yano
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Banyu Pharmaceutical Co., Ltd.
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Priority to AU72765/94A priority Critical patent/AU7276594A/en
Publication of WO1995005372A1 publication Critical patent/WO1995005372A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—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

Definitions

  • the present invention relates to a novel compound having an antagonistic activity against three kinds of endoselins (endoselin-1, endoselin-2 and endoselin-3), which are endogenous powerful bioactive peptides, a process for producing the same and a use thereof. Things.
  • the compounds of the invention have a high affinity for least one of the receptors of Endoserin receptor subtypes ET A and ET B, by inhibiting the binding of Endoserin, vasodilation, bronchodilation It has an action and a smooth muscle relaxing action. It can be used as a therapeutic agent for gastric ulcer, diabetes mellitus, restenosis, prostatic hypertrophy, endotoxin shock, multi-organ failure due to endotoxin, disseminated intravascular coagulation, and Z or cyclosporine-induced renal impairment and high blood age.
  • Endothelin is a polypeptide consisting of 21 amino acids and is produced from human and porcine endothelial cells and has a strong vasoconstrictive action and a sustained and strong pressor action [Nature, 332, 411]. -Pp. 415 (1988)].
  • endoselin-1, endoselin-2, and endoselin-3 three types of endoselins exist in human and other animals as a family of peptides with similar structures. It is known that all peptides have a vasoconstrictive action and a pressor action [Proceding National 'Academy' of Science (Proc. Natl. Acad. Sci. USA), 86, 2863-2867 (1989) ) See].
  • Endothelin is clinically present in patients with essential hypertension, patients with acute myocardial infarction, patients with pulmonary hypertension, patients with Reino's disease, patients with diabetes mellitus, patients with atherosclerosis, blood in patients with asthma, or airway lavage fluid In Japan, it has been reported that the number is clearly higher than that in normal individuals [J. Hypertension), Volume 12, p. 79 (1989), Journal of Vascular Medicine Biology, J. Vascular Medicine Biology, Volume 2, p. 207 (1990) Diabetologia, Vol. 33, pp. 306-310 (1990), Journal of 'American Medical Association (J. Am. Med. Association), Vol. 264, p. 2868 ( 1990) and The Lancet, Vol. 2, pp. 747-748 (1989) and Vol. 2, pp. 1144--1147 (1990)].
  • endothelin has been found to be released not only from vascular endothelial cells but also from tracheal epithelial cells or renal parenchymal cells [Fubes Letters]
  • Endothelin is an endogenous bioactive peptide renin and atrial sodium diuretic hormone, as well as endothelial cell-derived vasorelaxant (EDRF), thromboxane A2, prostacyclin, noradrenaline, angiotensin II and substance. It has also been found that it regulates the release of physiologically active substances such as P [Biochemical 'and' Biophysical 'Research Commun., Vol. 157, Vol. 1164-1168 (1988), Biochemical 'and' Biophysical Research Co., Ltd. (Biochem. Biophys. Res.
  • Endothelin has also been found to promote the proliferation of rat vascular smooth muscle cells, suggesting a relationship with arterial hypertrophy [Atherosclerosis, Vol. 78, pp. 225-228. (1989)]. Furthermore, it is known that endothelin receptors are present in high concentrations not only in peripheral tissues but also in central tissues.Endothelin regulates neuronal function because endothelin administered to the brain causes changes in animal behavior. It is also considered to have an important role in the treatment of neuroscience (see Neuroscience Letters, Vol. 97, pp. 276-279 (1989)). In particular, endothelin has been suggested to be a mediator of pain sensation [Life Sciences, 49, PL-61-PL-65 (1991)].
  • Endotoxin is one of the leading scavengers for endogenous endoselin release. It has been found that when endotoxin is administered exogenously to animals or when added to cultured vascular endothelial cells, the concentration of endoselin in blood or culture supernatant is significantly increased. Is believed to be one of the important mediators involved in endotoxin-induced diseases [Biochem. Biophys. Res. Commun., Vol. 161 1220 (1989) and Acta Physiol. Scand. N, Volume 137, Page 317 (1989)].
  • Endothelin receptors have at least two subtypes from previous studies, and endothelin has a vasoconstrictor effect on these two endothelin receptors. It is known to be caused through body subtypes [Journal of Canolegiopa 'Skyura-ichi' Pharmacology. (J. Cardiovasc. Pharmacol.) S 17 (Suppl. 7), Vol. S119- S121 (1991)].
  • One of these endoselin receptor subtypes is an endoselin receptor (ETJ) that has selectivity for ET-1 over endoselin receptor ET-3, while the other is ET-1 and ET-1.
  • Endothelin is an endogenous bioactive substance that directly or indirectly (regulates the release of various endogenous substances) and continuously contracts or relaxes vascular and non-vascular smooth muscles.
  • hypersecretion are one of the causes of hypertension, pulmonary hypertension, Reino's disease, bronchial asthma, gastric ulcer, diabetes, arteriosclerosis, acute renal failure, myocardial infarction, angina, cerebral vasospasm and cerebral infarction Conceivable.
  • endoselin acts as an important mediator for diseases such as restenosis, benign prostatic hyperplasia, endotoxin shock or endotoxin-induced multiple organ failure, disseminated intravascular coagulation, cyclosporine-induced renal impairment and hypertension.
  • the present inventors synthesized various derivatives and examined their endocrine antagonistic activity.
  • Ar 1 and Ar 2 each independently represent a hydrogen atom on an aromatic ring, a halogen atom, a hydroxyl group, an amino group, a carboxy group, a d-C 6 alkoxycarbonyl group, , - ⁇ alkyl ⁇ amino group, a force Rubamoiru group, Te Torazo one Honoré - 5-I group, Mechirenjiokishi group, CI- C 6 alkoxy groups, C 2 - C 6 ⁇ Rukeniruokishi group, Ji mono- or di ⁇ Arukiruamino Group, d-Ce alkyl group, C 2 -C 6 alkenyl group and C 2 -C 6 alkynyl group (provided that the -C 6 alkoxy group, C 2 -C 6 alkenyloxy group, mono- or di-C 6 alkylamino groups, C] - C 6 alkyl groups, C 2 -C 6 alkenyl group and C 2 - C 6 alkyl group
  • R 4 is a hydrogen atom, a hydroxyl group or a d - C 6 alkoxy group, or C, at -C 6 alkoxy-substituted May be, d-C 6 ⁇ alkyl group, C 2 -C 6 alkenyl or C 2 - Kaka showing a C 6 alkynyl group, or substituted with engaged and R s d-C 6 alkoxy group which may be C, - C 6 shows an alkylidene group or Okiso group
  • R 6 is also hydrogen or showing a d-C 6 alkyl group, or combined with R 5 Y represents a formula: -CO-R 7 wherein R 7 is a hydroxyl group, an amino group, a d-C 6 alkoxy group, a mono- or di- ⁇ alkylamino group, a d-C 6 alkyl An arylsulfonylamino group or an aryl group, wherein any hydrogen atom on the aryl ring may be substituted with a CC 6 alkyl group; Ichiru d-C 6 alkylsulfonyl ⁇ amino group show a) a group represented by, S0 3 H, P0 3 H 2, tetrazole - 5- pray group, 2-Okiso - 3H-1, 2, 3, 5- Or a pharmaceutically acceptable salt thereof, which is represented by the formula:
  • halogen atom means fluorine, chlorine, bromine and iodine.
  • the C, -C 6 alkoxycarbonyl group means an alkoxycarbonyl group having a linear or branched alkoxy group having 1 to 6 carbon atoms, such as a methoxycarbonyl group, an ethoxycarbonyl group, Propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutyloxycarbonyl group, tert-butyloxycarbonyl group, pentyloxycarbonyl group, isopentyloxycarbonyl group, hexyloxy And a carbonyl group.
  • Mono- or di-C ⁇ C 6 alkylaminocarbonyl group means an alkylamino group having one or two linear or branched alkyl groups having 1 to 6 carbon atoms on N, For example, a methylaminocarbonyl group, an ethylaminocarbonyl group, a propylaminocarbonyl group, an isopropylaminocarbonyl group, a butylaminocarbonyl group, an isobutylaminocarbonyl group, a tert-butylaminocarbonyl group, a pentylaminocarbonyl group, an isopentylamino group Carbonyl, hexylaminocarbonyl, dimethylaminocarbonyl, ethylmethylaminocarbonyl, acetylamino, isopropylmethylaminocarbonyl, dipropylaminocarbonyl, ethylisopropyl Minocarbonyl group, diis
  • the d-C 6 alkoxy group, carbon atoms means a 1-6 straight-chain or branched an alkoxy group, specifically, main butoxy group, an ethoxy group, a propoxy group, iso-propoxy, Butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.
  • the C 2 -C 6 alkenyloxy group means an alkenyloxy group having a linear or branched alkenyl group having 2 to 6 carbon atoms, for example, a vinyloxy group, a Lyloxy, 1-propenyloxy, isopropenyloxy, 2-butenyloxy, 3-butenyloxy, 2-pentenyloxy, 3-methyl-3-butenyloxy, 2-hexenyloxy, etc. Can be mentioned.
  • the mono- or di-C 6 alkylamino group means an alkylamino group having one or two linear or branched alkyl groups having 1 to 6 carbon atoms on N, such as a methylamino group, an ethylamino group, and the like.
  • the dC 6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and an isobutyl group.
  • the C 2 -C 6 alkenyl group means a linear or branched alkenyl group having 2 to 6 carbon atoms, specifically, a vinyl group, an aryl group, a 1-propenyl group, Isopropanol group, 3-butenyl group, 2-butenyl group, tributeninole group, 1-methynole-2-propyl group, 1-methyl-1-propenyl group, 1-ethyl-1-ethenyl Group, 2-methyl-2-propenyl group, 2-methyl-1-propenyl group, 4-pentenyl group and the like.
  • a C 2 -C 6 alkynyl group is a straight or branched alkynyl having 2 to 6 carbon atoms.
  • the hydroxy d-Cs alkylcarbonyl group means a straight or branched hydroxyalkyl carbonyl group having 2 to 7 carbon atoms, such as a hydroxymethylcarbonyl group, a 1-hydroxyethylcarbonyl group, 1-hydroxypropyl carbonyl group, 1-hydroxybutyl carbonyl group, 1-hydroxypentyl carbonyl group, 1-hydroxyhexyl carbonyl group, 2-hydroxyethyl carbonyl group, 3-hydroxypropyl carbonyl group, 2- Examples thereof include a hydroxybutylcarbonyl group, a 4-hydroxypentylcarbonyl group, a 3-hydroxyhexylcarbonyl group, and a 2-hydroxy-2-methylpropylcarbonyl group.
  • the C 6 alkyl force Lupo two group refers to a d-C 6 Ashirokishi d-C 6 alkyl force carbonyl group having an aliphatic or aromatic Ryo siloxy groups such Asechiru Oxymethylcarbonyl group, 1-acetyloxyshethylcarbonyl group, 2-acetyloxyshethylcarbonyl group, 1-acetyloxypropylcarbonyl group, 1-acetyloxyloxybutylcarbonyl group, 1 -Acetyloxypentylcarbonyl group, 1-acetyloxyhexylcarboninole group, 2-acetyloxypropylcarbonyl group, propionyloxymethylcarbonyl group, 1-propionyloxyshetylcarbonyl group, butyryloxymethylcarbonyl group, Pentanoyloxymethylcarbonyl group, hexanoyloxymethylcarbonyl group, be
  • the carboxy d-C 6 alkoxycarbonyl group a linear or branched carboxy 3-10 carbon atoms - means Ji 6 alkoxycarbonyl two group, for example the force Rupokishime butoxycarbonyl group, 1-Karubokin Ethoxyquin carbonyl group, 1-force ruboxoxypropoxycarbonyl group, 1-carboxybutoxycarbonyl group, 2-carboxyethoxycarbonyl group, 2-carboxybutoxycarbonyl group, 2- Carboxypentoxycarbonyl group, 3-carboquinpropoxycarbonyl group, 3-carboxybutoxycarbonyl group, 4-carboxypentoxycarbonyl group, 3-carboxyhexyloxycarbonyl group, 2-carboxy-2-methylpropyl pyroxy And a carbonyl group.
  • d-C 6 alkylsulfonylaminocarbonyl group means an alkylsulfonylaminocarbonyl group having a linear or branched alkyl group having 1 to 6 carbon atoms, such as methylsulfonylaminocarbonyl group, ethyl Sulfonylaminocarbonyl group, propylsulfonylaminocarbonyl group, isopropylsulfonylaminocarbonyl group, butylsulfonylaminocarbonyl group, isobutylsulfonylaminocarbonyl group, tert-butylsulfonylaminocarbonyl group, pentylsulfonylamine Examples thereof include a minocarbonyl group, an isopentylsulfonylaminocarbonyl group, and a hexylsulfonylaminocarbonyl group.
  • the d-C 6 alkylidene group means a linear or branched alkylidene group having 1 to 6 carbon atoms, and specifically, a methylene group, an ethylidene group, a propylidene group, an isopropylidene group, a butylidene group Group, 2-methylpropylidene group, 1-methylpropylidene group, pentylidene group and the like.
  • Ci-Cs alkylsulfonylamino group means an alkylsulfonylamino group having a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methylsulfonylamino group, ethylsulfonylamino group Amino group, propylsulfonylamino group, isopropylsulfonylamino group, butylsulfonylamino group, isobutylsulfonylamino group, tert-butylsulfonylamino group, pentylsulfonylamino group, isopentylsulfonylamino group, to Xylsulfonylamino groups and the like can be mentioned.
  • An arylsulfonylamino group is a cyclic hydrocarbon group having 6 to 14 carbon atoms or a complex containing 1 to 4 hetero atoms selected from the group consisting of oxygen, nitrogen and sulfur atoms.
  • An arylsulfonylamino group having a ring system aromatic ring group such as a phenylsulfonylamino group, a naphthylsulfonylamino group, a phenylsulfonylamino group, a pyridylsulfonylamino group, and a furylsulfonylamino group. And the like.
  • Ar 1 and Ar 2 are each independently any hydrogen atom on the aromatic ring represented by a halogen atom, a hydroxyl group, an amino group, a carboxy group, a CC 6 alkoxycarbonyl group, a mono- or di-C, -C 6 alkylamino carbonyl group, a force Rubamoiru group, Tet Razoru - 5-I group, Mechirenjiokishi group, d-C 6 alkoxy groups, C 2 - C 6 Al Keniruokishi group, a mono- or di-Ji ⁇ alkylamino groups, C ⁇ C 6 alkyl group A C 2 -C 6 alkenyl group and a C 2 -C 6 alkynyl group (provided that the CC 6 alkoxy group, C 2 -C 6 alkenyloxy group, mono- or di-CC 6
  • From the group consisting of 1-4 may be substituted with a substituent barrel shown Fuweniru group, thienyl group, a pyridyl group, an indolyl group, a benzofuranyl group or a dihydrobenzofuranyl two Le group.
  • the C, -C 6 alkoxyl group is an alkoxycarbonyl group having a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, and propoxy.
  • the mono- or di-C 6 alkylaminocarbonyl group means an alkylamino group having 1 or 2 linear or branched alkyl groups having 1 to 6 carbon atoms on N, for example, Methylaminocarbonyl group, ethylaminocarbonyl group, propylaminocarbonyl group, isopropylaminocarbonyl group, butylamino group, isobutylamino group, tert-butylaminocarbonyl group, pentylaminocarbonyl group, Sopentylaminocarbonyl, hexylaminocarbonyl, dimethylaminocarbonyl, ethylmethylaminocarbonyl, dimethylaminocarbonyl, isopropylmethylaminocarbonyl, dipropylaminocarbonyl , Ethyl isopropylamino carbonyl group, diisopropyl To minocarbonyl group, dibutylaminocarbonyl
  • the d-C 6 alkoxy group, carbon atoms means a 1-6 straight-chain or branched an alkoxy group, specifically, main butoxy group, Etokin group, a propoxy group, iso-propoxy, Butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, hexyloxy group and the like.
  • the C 2 -C 6 alkenyloxy group means an alkenyloxy group having a linear or branched alkenyl group having 2 to 6 carbon atoms, such as a vinyloxy group, an aryloxy group, and a 1-pro-oxy group.
  • Phenoxy group, isopropyloxy group, 2-butenyloxy group, 3-butenyloxy group, 2-pentenyloxy group, 3-methyl-3-butenyloxy group, 2-hexenyloxy group and the like can be mentioned.
  • the mono- or di-alkylamino group means an alkylamino group having 1 or 2 linear or branched alkyl groups having 1 to 6 carbon atoms on N, for example, a methylamino group, an ethylamino group, Propylamino group, isopropylamino group, butylamino group, isobutylamino group, tert-butylamino group, pentylamino group, isopentylamino group, hexylamino group, dimethylamino group, ethylmethylamino group, getylamino group, diphenylamino group Propylamino group, propylmethylamino group, ethylpropylamino group, diisopropylamino group, diisopropylamino group
  • Examples thereof include an isoptylamino group, an ethylisobutylamino group, a ditert-butylamino
  • the d-C 6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, and specifically, methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl Group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group Butyl group, 1-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-2-methylpropyl group,
  • the C 2 -C 6 alkenyl group means a linear or branched alkenyl group having 2 to 6 carbon atoms, specifically, a vinyl group, an aryl group, a 1-propenyl group, Isopropanol group, 3-butenyl group, 2-butenyl group, 1-butenyl group, 1-methynole-2-propanol group, 1-methyl-1-propenyl group, 1-ethyl-1 Examples include an ethenyl group, a 2-methyl-2-propenyl group, a 2-methyl-1-propenyl group, and a 4-pentenyl group.
  • C 2 - A C 6 alkynyl group, carbon atoms means a 2-6 straight-chain or branched Arukini Honoré groups, specifically, Echiniru group, 1 - propynyl, 2-propynyl group, Examples thereof include a 1-butynyl group, a 2-butynyl group, a 3-butynyl group, a 1-methyl-2-propynyl group, and a 1-pentynyl group.
  • the hydroxy Ci-Cs alkylcarbonyl group means a linear or branched hydroxyalkyl carbonyl group having 2 to 7 carbon atoms, such as a hydroxymethylcarbonyl group, a 1-hydroxyethylcarbonyl group, 1-hydroxypropyl carbonyl group, 1-hydroxybutylcarbonyl group, 1-hydroxypentylcarbonyl group, 1-hydroxyhexylcarbonyl group, 2-hydroxyethylcarbonyl group, 3-hydroxypropylcarbonyl group, 2-hydroquine Butylcarbonyl, 4-hydroxypentylcarbonyl, 3-hydroxyhexylcarbo And a 2-hydroxy-2-methylpropylcarbonyl group.
  • C 6 acyloxy dC 6 alkylcarbonyl group refers to d-C 6 acyloxy C having a aliphatic or aromatic acyloxy group, and a C 6 alkyl alkyl group, for example, acetyloxymethyl.
  • Carbonyl group 1-acetyloxetylcarbonyl group, 2-acetyloxyshetylcarbonyl group, 1-acetyloxypropylcarbonyl group, 1-acetyloxybutylcarbonyl group, 1-acetyloxy group Carbonyl group, 1-acetyloxyhexylcarbonyl group, 2-acetyloxypropylcarbonyl group, propionyloxymethylcarbonyl group, 1-propionyloxyshetylcarbonyl group, ptyryloxymethylcarbonyl group, pentanoyloxy group Methylcarbonyl group, hexanoyloxymethylcarbonyl group, benzoyloxymethylcarbonyl group 1-benzoyloxycarbonyl group, 2-benzoyloxyethyl group, phenylcarbonyloxymethylcarbonyl group, furfuryloxymethylcarbonyl group, pyridylcarbonyloxymethylcarbonyl group, imidazolyl And
  • C-alkoxy C 6 alkoxy carbonyl group means a straight-chain or branched carboxy C Ce alkoxycarbonyl group having 3 to 10 carbon atoms, for example, carbonyl carbonyl group, 1-carboxy group.
  • a carboxy group for example, a carboxymethoxycarbonylmethoxycarbonyl group, a 1-carboquinethoxycarbonylmethoxycarbonyl group, a 1-carboxypropoxycarbonylmethoxycarbonyl group, a 1-carboxybutoxycarbonylmethoxycarbonyl group, 2-carboquinet Xycarbonylmethoxycarbonyl group, 2-carboxybutoxycarbonylethoxycarbonyl group, 2-carboxypentoxycarbonylethoxycarbonyl group, 3-carboxypropoxycarbonylethoxycarbonyl group, 3-carboxybutoxycarbonylethoxycarbonyl group, Examples thereof include a 4-carbox
  • the C 6 alkylsulfonyl ⁇ amino group means an alkylsulfonyl ⁇ amino carbonyl group having a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl sulfonyl ⁇ amino group, Ethylsulfonylaminocarbonyl group, propylsulfonylaminocarbonyl group, isopropylsulfonylaminocarbonyl group, butylsulfonylaminocarbonyl group, isopropylbutylsulfonylaminocarbonyl group, tert-butylsulfonylaminocarbonyl group, pentyl Examples include a sulfonylaminocarbonyl group, an isopentylsulfonylaminocarbonyl group, a hexylsulfonylaminocarbonyl group, and the like.
  • Ar 1 and Ar 2 are each independently any hydrogen atom on the aromatic ring represented by a halogen atom, a hydroxyl group, an amino group, a methylenedioxy group, a d-Cs alkoxy group, a C 2 -C 6 Arukeniruokishi group, Ji mono- or di - ⁇ Arukiruamino group, d-C e alkyl group, C 2 -C 6 alkenyl group and C 2 - C 6 alkynyl group (provided that the - ⁇ alkoxy, C 2 - C 6 alkenyloxy, mono- or di-alkylamino, dC 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl are phenyl, pyridyl, imidazolyl, hydroxyl , C, - C 6 alkoxy group, an amino group, a mono- or di-CC 6 alkylamin
  • R ′, R 2 and R 3 specific examples of the CC 6 alkyl group include a methyl group, an ethyl group, and a propyl group.
  • specific examples of the d-Ce alkoxy optionally substituted d-C 6 alkyl group can be methyl, Echiru group, a propyl group, an isopropyl group, blanking butyl group, an isobutyl group, a pentyl group, Isopentyl, hexyl, isohexyl, methoxymethyl, methoxyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyquinpropyl, ethoxybutyl, propoxymethyl, propoxyshethyl And a propoxypropyl group.
  • C 2 -C 6 alkenyl group which may be substituted with a C, -C 6 alkoxy group
  • examples include ethenyl group, propenyl group, butenyl group, methoxethenyl group, methoxypropenyl group
  • Examples include a toxic butenyl group, an ethoxyhetenyl group, an ethoxypropenyl group, an ethoxyquinbutenyl group, a propoxyshethenyl group, and a propoxypropenyl group.
  • c 6 alkylidene group a methylene group, Echiriden group, propylidene group, isopropylidene group, butylidene group, iso-butylidene Group, pentylidene group, isopentylidene group, hexylidene group, isohexylidene group, methoxypropylidene group, ethoxypropylidene group, hydroxypropylidene group, methoxybutylidene group, ethoxyquinbutylidene group, etc. Is mentioned.
  • CC 6 alkyl groups include methyl group, Echiru group and the like.
  • R 6 specific examples of dC 6 alkyl group, a methyl group, Echiru group and the like.
  • Y is a compound represented by the formula: -CO-R 7 (wherein R 7 is a hydroxyl group, an amino group, a dC 6 alkoxy group, a mono- or di-alkylamino group, a dC 6 alkylsulfonylamino group, or an aryl group)
  • S0 represents an arylsulfonylamino group or an aryl ⁇ , -C 6 alkylsulfonylamino group in which any hydrogen atom may be substituted by a -Ce alkyl group; 3 H, P0 3 H 2, tetrazole Ichiru 5-I group, 2-Okiso-3H-1, 2, 3, 5-Okisachiajiazo Ichiru - 4-I group or 5-Okiso - 4H-1, It represents a 2,4-oxaziazol-3-yl group.
  • the C ⁇ C 6 alkoxy group, carbon atoms means a 1-6 linear or branched alkoxy group, specifically, main butoxy group, an ethoxy group, a propoxy group, isopropoxy Group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, hexyloxy group and the like.
  • the alkylamino group means a one or two with Arukiruamino group a linear or branched alkyl group having 1 to 6 carbon atoms on the N, eg if Mechiruamino group, Echiruamino Group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, tert-butylamino group, pentylamino group, isopentylamino group, hexylamino group, dimethylamino group, ethylmethylamino group, getylamino group, diethylamino group Propylamino group, propylmethylamino group, ethylpropylamino group, diisopropylamino group, disobutylamino group, ethylisobutylamino group, ditert-butylamino group, dipentylamin
  • the d-C 6 alkylsulfonylamino group means an alkylsulfonylamino group having a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methylsulfonylamino group and an ethylsulfonyl group.
  • Any hydrogen atom on the aryl ring may be substituted with a d-C 6 alkyl group.
  • An arylsulfonylamino group is a group in which any hydrogen atom on the aryl ring is C,-
  • C 6 -alkyl group which may be substituted by alkyl group, having 6 to 14 carbon atoms, or 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms Means an arylsulfonylamino group having a heterocyclic aromatic ring group containing, for example, phenylsulfonylamino group, naphthylsulfonylamino group, chenylsulfonylamino group, pyridylsulfonylamino group.
  • amino group, Furirusuruho Niruamino group, or on their aromatic ring C, - C 6 alkyl group include substituents with.
  • Aromatic ring of a cyclic hydrocarbon system having 6 to 14 carbon atoms on the alkyl of the sulfonylamino group, or a heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms Means an arylalkylsulfonylamino group having a group, such as benzylsulfonylamino group, phenylethylsulfonylamino group, phenylpropylsulfonylamino group, 1-methyl-2-phenylethylsulfonylamino group, 2-butylsulfonylamino group, phenylpentylsul
  • novel cyclopentane derivative represented by the general formula [I] of the present invention is as follows: Can be produced by the method described in (1).
  • R 41 is a hydrogen atom, a hydroxyl group or a d - C 6 alkoxy group, or Ci one C 6 alkoxy group may be substituted, d - C 6 alkyl group, C 2 - C 6 alkenyl or Represents a C 2 -C 6 alkynyl group, or a C, 1-C 6 alkylidene group or an oxo group which may be substituted with d-C 6 alkoxy group in combination with R 51 , or a synthetic equivalent thereof
  • R 31 represents a hydrogen atom or a C, -C 6 alkyl group
  • R 51 represents a hydrogen atom or a C, -C 6 alkyl group
  • L represents C, or shows a C 6 alkoxy group optionally substituted by d-C 6 alkylidene group or Okiso group, a single bond combined with R 61
  • R 61 is a hydrogen atom or a d - or shows a C 6 alkyl group Or
  • R 71 represents an alkyl group or an aralkyl group, and X represents a leaving group.
  • organometallic reagent [III] an appropriate one is selected from an organic magnesium reagent such as an organic lithium reagent, a Grignard reagent, and an organic copper reagent. It is also possible to use these metal reagents in combination with other metal salts. Further, in the reaction between the reagent [ ⁇ ] and the compound [II], a solvent having an excellent metal coordination ability such as HMPA can be used as an adjuvant if necessary. As the ester derivative [IV], cyanoformate, chloroformate, ester anhydride and the like are selected.
  • P represents a scavenging group for oxygen anion
  • Ar 21 , R 31 , R 41 , R 51 and R 61 have the meaning described above.
  • Ar ′ 1 represents Ar 1 or a synthetic equivalent thereof, and Met has the meaning described above]. Then, if necessary, i) a desired synthetic equivalent ), Deprotection of the protecting group, iii) hydrolysis of the ester moiety, etc.
  • R 11 represents a CC 6 alkyl group
  • Met has the meaning described above, and thereafter, if necessary, i) adding a desired synthetic equivalent.
  • R 21 represents a CC 6 alkyl group
  • X represents a leaving group
  • Compound [V] can be produced by the method shown in 1) or 2), but can also be produced by the following method.
  • the reaction is preferably carried out in an anhydrous solvent such as THF or ether at -100 ° C to around room temperature.
  • anhydrous solvent such as THF or ether
  • the reaction is carried out in a solvent such as methylene chloride. Reactions around 20 ° C to 50 ° C are preferred.
  • a phenylsulfenyl group instead of a phenylselenenyl group.
  • a combination of the functional group conversion reaction, protection and deprotection reactions described in the examples may be used as necessary. Can be manufactured.
  • the reaction intermediate and the target substance in the above-mentioned production method can be purified by a known purification method (for example, recrystallization, reprecipitation, distribution operation, normal phase or reverse phase chromatography or ion exchange chromatography).
  • a known purification method for example, recrystallization, reprecipitation, distribution operation, normal phase or reverse phase chromatography or ion exchange chromatography.
  • Porcine aortic smooth muscle tissue was homogenized with polytron in 10 mM MOPS pH 7.4 buffer at 4 ° C. Sucrose was added to the homogenate to a concentration of 20%, centrifuged at 1000 xg for 15 minutes, and the supernatant was further centrifuged at 10,000 xg for 15 minutes. The supernatant was further centrifuged at 90,000 ⁇ g for 40 minutes, and the obtained precipitate was suspended in 5 mM HEPES / Tris pH 7.4 buffer to prepare a membrane fraction so as to have a concentration of 25 mgZmU.
  • 16 zl of this membrane fraction was added to 50 mM Tris / HCl pH 7.4 buffer A (10 ⁇ chloride power, 10 // magnesium chloride, O.lmM PMSF, 1 / z M epstatin k, 2 M , ImM 1, 10-phenanthroline, containing 0.1% bovine serum albumin).
  • the suspension may contain (A) unlabeled endoselin-1 (for nonspecific binding) at a final concentration of 0.2 aM, (B) buffer A (for total binding), or (C) a final concentration of 1.1 aM. / M to become the test compound each 4 // example 1 pressurized, further each '25 1- Endoserin - 1.
  • Compound 5 is a representative compound of this invention was 86% inhibition at a concentration of 1.1 to binding of Endoserin to ET A receptors.
  • the porcine cerebellum was homogenized at 4 ° C. with a polytron in 10 mM MOPS pH 7.4 buffer. Sucrose was added to the homogenate to a concentration of 20%, centrifuged at lOOOXg for 15 minutes, and the supernatant was centrifuged at lOOOOOXg for 15 minutes. The supernatant was further centrifuged at 90,000 ⁇ g for 40 minutes, and the obtained precipitate was suspended in 5 mM HEPES / Tris pH 7.4 buffer to prepare a membrane fraction to 3.3 mgZml.
  • This membrane fraction 16 ⁇ 1 was treated with 50 mM Tris / HCl pH 7.4 buffer A (10 ⁇ , salted calcium, 10 ⁇ magnesium chloride, O.lmM PMSF, 1 fi M ⁇ pstatin, 2 ⁇ Sanchez, ImM 1,10-fannanthroline, containing 0.1% bovine serum albumin) was suspended in 340 / zl.
  • the suspension may contain (A) unlabeled endoselin-1 (for non-specific binding) at a final concentration of 0.2 uM, (B) buffer A (for total binding), or (C) a final concentration of 1.1 ⁇ M.
  • Compound 5 is a representative compound of the invention, binding of Endoserin to ET B receptors was inhibited 78% at a concentration of 1.1 M.
  • the effect of the compound of the present invention on the dose-response curve obtained by cumulatively adding endoselin-1 to a Magnus tube was examined.
  • the compound of the present invention was added to the Magnus tube 20 minutes before the addition of endoselin-1 so that the final concentration was 10 ⁇ M.
  • compound 5 a representative compound of the present invention, significantly shifted the dose response curve of endothelin-1 to the right without affecting its maximal response. In addition, this compound alone did not show any effect on the above vascular specimen. As described above, the compound of the present invention showed a remarkable antagonistic effect on endothelin contraction in the above-mentioned blood vessel specimen.
  • the compound of the present invention has an excellent endothelin antagonism against the endothelin receptor, is useful as a vasodilator and a bronchodilator in the field of pharmaceuticals, and has hypertension, pulmonary hypertension, Reino-disease, Acute renal failure, myocardial infarction, angina pectoris, cerebral infarction, cerebral vasospasm, arteriosclerosis, bronchial asthma, gastric ulcer, diabetes, endotoxin shock, multi-organ failure due to endotoxin, disseminated intravascular coagulation and Z Alternatively, it can be used as a therapeutic agent for cyclosporine-induced renal disorder and hypertension. When used as a therapeutic agent for such diseases, the compounds of the present invention can be used alone or in combination with other therapeutic agents.
  • the compound of the present invention can be mixed with a solid or liquid excipient carrier known in the art and used in the form of a pharmaceutical preparation suitable for parenteral administration, oral administration or external administration.
  • a pharmaceutical preparation suitable for parenteral administration, oral administration or external administration.
  • the pharmaceutical preparation include liquid preparations such as injections, inhalants, syrups and emulsions, solid preparations such as tablets, capsules and granules, and external preparations such as ointments and suppositories.
  • these preparations may contain additives which are usually used, such as auxiliaries, stabilizers, wetting agents, emulsifiers, absorption promoters or surfactants, if necessary.
  • Additives include distilled water for injection, Ringer's solution, Rucose, sucrose syrup, gelatin, edible oil, cocoa butter, ethylene glycol, sucrose, corn starch, magnesium stearate or talc.
  • the dosage of the compound of the present invention as an endothelin antagonist varies depending on the administration method, the age and weight of the patient, the condition of the patient to be treated, and the like.
  • a typical administration method for an adult is oral administration or parenteral administration. Yes, for oral administration to adult patients 0.1 to 100 mg / kg body weight per day for parenteral administration, 0.01 to 100 mg / kg body weight per day for parenteral administration.
  • reaction solution was diluted with methylene chloride (20 ml), washed with a 10% aqueous solution of citric acid (2 ml), the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Example 1- (3) After the temperature of the reaction solution was raised to ⁇ 40 ° C., it was cooled again to ⁇ 78 ° C., and the 2- (trifluoromethanesulfonyloxy) -5- (3,4-methylene) obtained in Example 1- (3) was obtained. A solution of dioxyphenyl) cyclopentene carboxylate methyl ester (393 mg, l.OO mmol) in tetrahydrofuran (2.0 ml) was added. After the temperature of the reaction solution was raised to ⁇ 30 ° C. over about 1.5 hours, a saturated aqueous solution of ammonium chloride and ethyl acetate were added to terminate the reaction.
  • the cyclopentane derivative of the present invention has a strong anti-antagonistic action against endogen, an endogenous bioactive peptide, it is useful as a drug that antagonizes the vaso- and tracheal muscle contractile action involving endoselin. It is useful as a remedy for hypertension, pulmonary hypertension, Reino's disease, bronchial asthma, arteriosclerosis, acute renal failure, myocardial infarction, angina pectoris, cerebral infarction, cerebral vasospasm, gastric ulcer and diabetes.

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Abstract

Dérivé de cyclopentane de formule générale (I), ou sel pharmaceutiquement acceptable dudit dérivé, dans laquelle Ar?1 et Ar2¿ représentent chacun indépendamment phényle, thiényle, pyridol, indolyle, benzofuranyle ou dihydrobenzofuranyle dont chacun peut être substitué à des sites d'atome(s) d'hydrogène arbitraire(s) sur le cycle aromatique par un à quatre substituants choisis dans le groupe constitué d'halogène, hydroxy, amino, carboxy, alcoxycarbonyle C¿1?-C6, mono- ou di(C1-C6 alkyl)aminocarbonyle, carbamoyle tétrazol-5-yle, méthylènedioxy, alcoxy C1-C6, alcényloxy C2-C6, mono- ou di(C1-C6 alkyl)amino, alkyle C1-C6, alcényle C2-C6 et alcynyle C2-C6; R?1, R2 et R3¿ représentent chacun indépendamment hydrogène ou alkyle C¿1?-C6, ou une combinaison de R?1 avec R2¿ ou de R?2 avec R3¿ représente une liaison unique; R4 représente hydrogène, hydroxy ou alcoxy C¿1?-C6, ou alkyle C1-C6, alcényle C2-C6 ou alcynyle C2-C6, chacun pouvant être substitué par alcoxy C1-C6, ou alternativemement R?4¿ peut être combiné avec R5 pour représenter alkylidène C¿1?-C6 qui peut être substitué par alcoxy C1-C6, ou oxo; R?5¿ représente hydrogène ou alkyle C¿1?-C6, ou alternativement R?5¿ est combiné avec R4 pour représenter alkylidène C¿1?-C6 qui peut être substitué par alcoxy C1-C6, ou oxo, ou est combiné avec R?6¿ pour représenter une liaison unique; R6 représente hydrogène ou alkyle C¿1?-C6, ou est combiné avec R?5¿ pour représenter une liaison unique; et Y représente -CO-R7, SO3H, PO3H2, tétrazol-5-yle, 2-oxo-3H-1,2,3,5-oxathiadiazol-4-yle, ou 5-oxo-4H-1,2,4-oxadiazol-3-yle.
PCT/JP1994/001316 1993-08-13 1994-08-09 Derive de cyclopentane a activite antagoniste de l'endotheline WO1995005372A1 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5622971A (en) * 1994-08-19 1997-04-22 Abbott Laboratories Endothelin antagonists
US6162927A (en) * 1994-08-19 2000-12-19 Abbott Laboratories Endothelin antagonists
US7208517B1 (en) 1994-08-19 2007-04-24 Abbott Labortories Endothelin antagonists
US7232821B2 (en) 2002-04-08 2007-06-19 Glaxo Group Limited (2-((2-alkoxy)-phenyl) -cyclopent-1enyl) aromatic carbo and heterocyclic acid and derivatives
US7332472B2 (en) 2001-10-19 2008-02-19 Isotechnika Inc. Cyclosporine analogue mixtures and their use as immunomodulating agents
US7358229B2 (en) 1997-10-08 2008-04-15 Isotechnika Inc. Deuterated cyclosporin analogs and their use as immunomodulating agents
US7446222B2 (en) 2002-11-01 2008-11-04 Glaxo Group Limited Phenyl compounds
WO2012163264A1 (fr) * 2011-05-27 2012-12-06 中国医学科学院药物研究所 Substance de saucernétine de structure simplifiée et son procédé de préparation et sa composition pharmaceutique et son utilisation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59190956A (ja) * 1983-04-15 1984-10-29 金　明儒 ロカグラマイド化合物
US4845129A (en) * 1988-03-14 1989-07-04 Sandoz Pharm. Corp. Diaryl substituted cyclopentane and cyclopentene derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59190956A (ja) * 1983-04-15 1984-10-29 金　明儒 ロカグラマイド化合物
US4845129A (en) * 1988-03-14 1989-07-04 Sandoz Pharm. Corp. Diaryl substituted cyclopentane and cyclopentene derivatives

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5622971A (en) * 1994-08-19 1997-04-22 Abbott Laboratories Endothelin antagonists
US5731434A (en) * 1994-08-19 1998-03-24 Abbott Laboratories Endothelin antagonists
US5767144A (en) * 1994-08-19 1998-06-16 Abbott Laboratories Endothelin antagonists
US6162927A (en) * 1994-08-19 2000-12-19 Abbott Laboratories Endothelin antagonists
US6380241B1 (en) 1994-08-19 2002-04-30 Abbott Laboratories Treatment of diseases using endothelin antagonists
US6462194B1 (en) 1994-08-19 2002-10-08 Abbott Laboratories Endothelin antagonists
US7208517B1 (en) 1994-08-19 2007-04-24 Abbott Labortories Endothelin antagonists
US7538189B2 (en) 1997-10-08 2009-05-26 Isotechnika Inc. Methods of making deuterated cyclosporin analogs
US7358229B2 (en) 1997-10-08 2008-04-15 Isotechnika Inc. Deuterated cyclosporin analogs and their use as immunomodulating agents
US7521421B2 (en) 1997-10-08 2009-04-21 Isotechnika Inc. Deuterated cyclosporine analogs and methods of making the same
US7332472B2 (en) 2001-10-19 2008-02-19 Isotechnika Inc. Cyclosporine analogue mixtures and their use as immunomodulating agents
US9765119B2 (en) 2001-10-19 2017-09-19 Aurinia Pharmaceuticals Inc. Cyclosporine analogue mixtures and their use as immunomodulating agents
US10472394B2 (en) 2001-10-19 2019-11-12 Aurinia Pharmaceuticals Inc. Cyclosporine analogue mixtures and their use as immunomodulating agents
USRE48226E1 (en) 2001-10-19 2020-09-29 Aurinia Pharmaceuticals Inc. Cyclosporine analogue mixtures and their use as immunomodulating agents
US7232821B2 (en) 2002-04-08 2007-06-19 Glaxo Group Limited (2-((2-alkoxy)-phenyl) -cyclopent-1enyl) aromatic carbo and heterocyclic acid and derivatives
US7446222B2 (en) 2002-11-01 2008-11-04 Glaxo Group Limited Phenyl compounds
WO2012163264A1 (fr) * 2011-05-27 2012-12-06 中国医学科学院药物研究所 Substance de saucernétine de structure simplifiée et son procédé de préparation et sa composition pharmaceutique et son utilisation

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