Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
  • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids

Definitions

• the present invention relates to compounds useful in the field of pharmaceuticals and uses thereof, and more particularly to endoselin receptor pig containing a triterpene derivative useful for prevention or treatment of diseases caused by endocrine hypersecretion. And novel triterpene derivatives.
• Endoserin (M. Yanagisawa et al., Nature, 332, 411, 1988 :) is a vasoconstrictive peptide derived from endothelial cells consisting of 21 amino acids. Its oversecretion is thought to be involved in a variety of pathological conditions, such as blood pressure, screening for ischemic heart disease, cerebral circulatory disorders, renal disorders, insufficiency in organ circulation, and asthma. End-cell as a re-emission hypersecretory by intracellular calcium ion concentration on the substance that inhibits Pingtung, the JP 2 2 7 3 6 2 5 No.
• the present invention provides a compound represented by the formula (II):
• R 1 is hydrogen or a metabolic ester residue
• R 3 is an optionally substituted maleyl or an optionally substituted aromatic heterocycle
• one of X and Y is a hydroxy group.
• & represents hydrogen, or X and Y together represent oxo, and Z represents oxygen or two hydrogens.
• the present invention provides an endoserine receptor pig antagonist containing a triterpene derivative or a salt thereof. Things.
• R 1 is hydrogen or a metabolic ester residue
• R 2 is an optionally substituted aryl or an optionally substituted aromatic heterocycle
• one of X and Y is hydroxy.
• the other is hydrogen, or oxo together with X and Y, and Z represents oxygen or two hydrogens, provided that if R 1 is hydrogen and one of X and Y is hydroxy, R 2 is not 3,4-dihydroxyphenyl.
• the terbene derivative represented by the formula or a salt thereof is a novel compound, and the present invention also provides these compounds.
• the term “metabolic ester residue” means an ester residue that is decomposed in vivo to reproduce a carboxylic acid.
• Aryl means phenyl or ( ⁇ - or / 3 — :) naphthyl.
• Aromatic heterocyclic ring refers to an aromatic ring containing one or more arbitrarily selected oxygen, sulfur and / or nitrogen atoms and optionally condensed with a carbocycle or another heterocycle. Means a 5- or 6-membered ring, and includes a ⁇ - or S-oxoside of the aromatic heterocyclic ring.
• Substituents that mean “optionally substituted” include, for example, halogen (F, C 1, Br, I), hydroxy, amino, lower alkanoylamino, mono- or di- Mono-lower alkyl-substituted amino, carboxy, cyano, nitro, lower alkyl, lower alkoxy or lower alkanoloxy.
• halogen F, C 1, Br, I
• hydroxy amino, lower alkanoylamino
• mono- or di- Mono-lower alkyl-substituted amino, carboxy, cyano, nitro, lower alkyl, lower alkoxy or lower alkanoloxy.
• the compound of the present invention may be an alkali metal (sodium, calcium, etc.), an alkaline earth metal (calcium, magnesium, etc.), ammonium or an organic base (triethyl ammonium). And the like).
• the triterpene derivative of the present invention can be separated from white peach by, for example, the following method. That is, the branch of the plant is subjected to a polar solvent (eg, methanol)
• a water-immiscible organic solvent eg, chloroform, chlorinated hydrocarbons such as dichloromethane, ethyl acetate or n-butanol.
• the compound of the present invention can be obtained by separating the obtained extract by silica gel chromatography.
• various compounds represented by R 2 are produced using the compound thus obtained as a raw material.
• the compound of the present invention Since the compound of the present invention has an endothelin receptor antagonistic effect, it is effective in preventing and treating cardiovascular diseases such as vasoconstriction and hypertension.
• the compound of the present invention can be prepared in a conventional manner. It can be made into injections, oral preparations, suppositories, etc. together with various carriers, diluents and excipients.
• the dose varies depending on the target therapeutic effect, administration method, age, body weight, etc., and cannot be unconditionally specified.However, the daily dose is usually 10 mg to 2 g per adult, preferably 5 mg / day. 0111 £ ⁇ 1 ⁇ .
• Compound 1 Compound 1 (111.O mg) was dissolved in 4 mj2 of a 3% K0H methanol solution and heated under reflux for 3 hours. Water is added, methanol is distilled off under reduced pressure, acidified with IN sulfuric acid, extracted with ethyl acetate (15 ml ⁇ 3 times), washed with water and the solvent is distilled off. The residue was subjected to silica gel column chromatography to obtain 14.6 mg of Compound A from a 2% methanol Z-form form outlet. [ ⁇ ] D + 91.3 with a melting point of 226-227. (C. L. 0, CHC £ 3), m / e 47 0 (C 3 0 H 4).
• the various substituted compounds at the 27-position are produced by a) a method of directly substituting compound A, b) a compound A by applying the Horner-Emmons method.
• Dimethylphosphonoacetic acid and dimethylphosphonoacetic anhydride synthesized from disuccinic hexyl carposamide (DCC) are reacted with compound A in the presence of DMAP to form a dimethylphosphonoacetate ester of compound A (compound B).
• the compound is condensed with aldehyde (R 2 CHO) in the presence of cesium carbonate or lithium carbonate and triethylamine to produce compound (I).
• Endoselin acts on many organs such as blood vessels and trachea, and exerts various actions such as smooth muscle contraction through activation of specific receptors on the cell membrane. It is thought to be involved in cardiovascular diseases.
• the following test examples show the anti-endoselin effect of the present compound.
• Test Example 1 Inhibitory Effect of 125 I-Labeled Endoselin 1 on Receptor Binding (Method)
• a membrane component was prepared from porcine aortic media and heart, rat aorta and heart, and in the presence or absence of Compound 1 of the present invention. for 1 hour incubated preparative 25 pM 125 I one labeled e down Doseri down 1 and 3 7 e C in the presence. After the completion of the reaction, 125 I-labeled endoselin 1 bound to the membrane component was separated using glass fiber paper, and the radioactivity was measured using a gamma counter.
• Type 50% inhibitory concentration porcine aortic 3 membrane components 2 X 1 0 one 8 porcine heart 8. 3 X 1 0 rat aorta 5. 6 X 1 0 "in the cell according to 8 Test Example 2-ene Doserin 1 Karushiumu Inhibitory effect on increase in concentration (Method) A cell suspension of rat aorta-derived smooth muscle cells A7r5 (Dainippon Pharmaceutical Co., Ltd.) loaded with 2M Hula 2 (Dojindo Laboratories) was cuvetted. The change in fluorescence was measured using a calcium analyzer CAF 100 manufactured by Nihon Bunko Co., Ltd.
• the fluorescence measurement was excited at 340 nm and 380 nm, and recorded at 510 nm. Intracellular force
• the concentration of lucidum was determined in accordance with the method of Grikki-Witt et al. (J. Biol. Chem. Vol. 260, pp. 3440-3450, 1985). was added to the cells suspension in the preparative, after incubation bets 1 minute, the ene Doserin 1 1 0 - 8 M was added, and observed changes in fluorescence intensity.
• the concentration of the compound of the present invention that inhibit the increase in intracellular calcium by down Doseri down 1 50% are shown in Table 2. [Table 2]
• the compound of the present invention binds to endoselin receptor and specifically suppresses the endoselin action. Therefore, the compound of the present invention is expected to have a preventive or therapeutic effect on diseases such as blood pressure elevation, ischemic heart disease, cerebral circulatory disorder, ⁇ disorder, circulatory insufficiency of various organs, and asthma based on endocrine secretion.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Steroid Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Medicines Containing Plant Substances (AREA)
• Compositions Of Macromolecular Compounds (AREA)

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• 1991
  • 1991-12-13 JP JP4501761A patent/JP2950616B2/ja not_active Expired - Fee Related
  • 1991-12-13 US US07/867,683 patent/US5248807A/en not_active Expired - Lifetime
  • 1991-12-13 DK DK92900597T patent/DK0526642T3/da active
  • 1991-12-13 WO PCT/JP1991/001707 patent/WO1992012991A1/ja not_active Ceased
  • 1991-12-13 DE DE69129193T patent/DE69129193T2/de not_active Expired - Lifetime
  • 1991-12-13 EP EP92900597A patent/EP0526642B1/en not_active Expired - Lifetime
  • 1991-12-13 ES ES92900597T patent/ES2115665T3/es not_active Expired - Lifetime
  • 1991-12-13 AT AT92900597T patent/ATE164588T1/de not_active IP Right Cessation

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