WO2005115998A1 - Derives de tyrosine substitues par alcanoyle en tant qu'antagonistes hppar$g(a) et hppar$g(g) - Google Patents

Derives de tyrosine substitues par alcanoyle en tant qu'antagonistes hppar$g(a) et hppar$g(g) Download PDF

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Publication number
WO2005115998A1
WO2005115998A1 PCT/CN2005/000147 CN2005000147W WO2005115998A1 WO 2005115998 A1 WO2005115998 A1 WO 2005115998A1 CN 2005000147 W CN2005000147 W CN 2005000147W WO 2005115998 A1 WO2005115998 A1 WO 2005115998A1
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WO
WIPO (PCT)
Prior art keywords
phenyl
propionic acid
ethoxy
methyl
oxazol
Prior art date
Application number
PCT/CN2005/000147
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English (en)
Chinese (zh)
Inventor
Song Li
Xinbo Zhou
Cuifang Lin
Lili Wang
Cheng Xu
Chengmai Ruan
Junhai Xiao
Zhibing Zheng
Hongying Liu
Yunde Xie
Wu Zhong
Hao Cui
Original Assignee
Beijing Molecule Science And Technology Co., Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beijing Molecule Science And Technology Co., Ltd filed Critical Beijing Molecule Science And Technology Co., Ltd
Publication of WO2005115998A1 publication Critical patent/WO2005115998A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Thiazolidinediones such as troglitazone and rosiglitazone have been clinically shown to enhance insulin action and reduce serum glucose in patients with type II diabetes.
  • Thiazolidinedione has been reported as a potent and selective activator of PPARy and directly binds to the PPAR gamma receptor (J. M. Lehmann et al., J. Biol. Chem. 12953-12956, 270 (1995)).
  • one aspect of the invention relates to a compound of formula I, a racemate, an optical isomer, or a pharmaceutically acceptable salt or solvate thereof,
  • Y is H, halogen
  • a further aspect of the invention relates to the use of a compound of formula I according to the invention for the manufacture of a medicament for the treatment or prevention of a hPPAR Y and / or hPPAR a mediated disease, risk factor or condition.
  • n is an integer from 1-4;
  • the compounds of formula I of the present invention have stereocenters.
  • a single enantiomer of a compound of formula I can be prepared using reactants in all possible steps in the form of a single enantiomer, or Prepared in the presence of a reaction, or It is prepared by resolving a mixture of stereoisomers by a conventional method.
  • Some preferred methods include resolution using microorganisms, resolution of diastereomeric salts with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, etc., or resolution with Diastereomeric salts such as brae ine, cinchona alkaloids and their derivatives.
  • compounds of the general formula I are useful in the treatment or prevention of hPPAR ⁇ and / or hPPAR ct-mediated diseases, risk factors or conditions.
  • the hPPAR v and / or hPPAR oc-mediated diseases, risk factors or conditions include hyperglycemia, dyslipidemia, and type II diabetes including related diabetic dyslipidemia, type I diabetes , Hypertriglyceridemia, syndrome X, insulin resistance, heart failure, hyperlipidemia, hypercholesterolemia, hypertension, cardiovascular diseases including atherosclerosis, suffering from diseases such as obesity, anorexia, greed Regulation of appetite and food absorption in patients with anorexia and anorexia nervosa.
  • the compounds of the present invention are particularly useful in the treatment or prevention of hyperglycemia, dyslipidemia, and type II diabetes, including related diabetic dyslipidemia.
  • compositions of the present invention can be used both by themselves and in the form of their pharmaceutically acceptable salts or solvates.
  • Pharmaceutically acceptable salts of the compounds of formula I include conventional salts with pharmaceutically acceptable inorganic or organic acids or inorganic or organic bases, as well as acid addition salts of quaternary ammonium.
  • suitable acid addition salts include with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, formic acid, lactic acid, maleic acid, tartaric acid , Citric acid, navic acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluene Salts formed from sulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, tannic acid, and the like.
  • the invention also includes active metabolites of the compounds of the invention.
  • the compounds of the present invention can be used either alone or in the form of pharmaceutical compositions.
  • the pharmaceutical composition of the present invention comprises an effective amount of a compound of formula I of the present invention, a racemate, an optical isomer, or a pharmaceutically acceptable salt or solvate thereof, and one or more suitable pharmaceutically acceptable carriers.
  • the pharmaceutical carriers according to the present invention include, but are not limited to: ion exchangers, alumina, aluminum stearate, zoster ring fat, serum proteins such as human albumin, buffer substances such as phosphate, glycerol, sorbic acid, sorbic acid Potassium acid, a mixture of partially glycerides of saturated plant fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, Polyvinylpyrrolidone, cellulose shield, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax, lanolin.
  • composition of the compound of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal, nasal, buccal, topical, parenteral, such as subcutaneous, intravenous, intramuscular, intraperitoneal, sheath Inner, ventricle, sternum Intracranial and intracranial injection or infusion, or medication with the aid of an explant reservoir.
  • oral, intraperitoneal or intravenous administration is preferred.
  • the compounds of the present invention can be formulated into any orally acceptable formulation including, but not limited to, tablets, capsules, aqueous solutions or aqueous suspensions.
  • the carriers used for tablets generally include lactose and corn starch, and lubricants such as magnesium stearate can also be added.
  • Diluents used in capsule preparations generally include lactose and dried corn starch.
  • Aqueous suspensions are usually prepared by mixing the active ingredient with suitable emulsifying and suspending agents. If desired, some sweeteners, fragrances, or colorants may be added to the above oral preparation forms.
  • Example 5 (2S) -3- ⁇ 4- [2- (5-methyl-2-phenyl-1,3-poxazol-4-yl) -ethoxy] -phenyl ⁇ -2 -[3- (4-trifluoromethyl-phenyl) -propionamido] -propionic acid
  • the 3- (4-methoxy-phenyl) -propane Replace the acid with 3- (4-trifluoromethyl-phenyl) -propionic acid to obtain (2S) -3- ⁇ 4- [2- (5-methyl-2 -phenyl-1, 3 as a white solid) -Oxazolyl-4-yl) -ethoxy] -phenyl ⁇ -2- [3- (4-trifluoromethyl-phenyl) -propionamido] -propionic acid, mp: 159-161 ° C .
  • Example 12 (2S)-3- ⁇ 4- [2- (5-methyl-2 -phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl ⁇ -2- (2-o-trifluoromethyl- Phenyl-acetylamino) -propionic acid was prepared in a similar manner to that in Example 1.
  • Example 38 (28) -3- ⁇ 3-bromo-4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl ⁇ -2- (3-phenyl-butyrylamino) -propionic acid
  • the GAL4DNA binding region was linked to pB4-tk-luc to form PB4-RES-tk-luc (a reporter gene for firefly luciferase containing a GAL4DNA binding site).
  • PRL-CMV-Rluc was used as an internal standard to correct transfection efficiency and endogenous effects.
  • 293-T cells were seeded into a 48-well plate with a cell density of 2-4 x 10 4 cells / well and the culture medium was 10% defatted fetal calf serum (FCS) without phenol red and antibiotic-free 1640 medium. After 48 hours, the culture medium was replaced with 5% defatted FCS without phenol red and antibiotic-free 1640 medium, and then two subtypes of pM-hPPAR / GAL4, pB4-RES-tk-luc, and pRL-CMV- The three Rluc plasmids were co-transfected into 293-T cells and administered after 24 hours. The intensity of luciferase was measured 24 hours after administration. 0.2% 0 DMS0 was used as a blank control.
  • Example 8 8.2 3.9 9.01
  • Example 9 26.9 12.8 10.45
  • Example 10 23.1 11 11.51
  • Example 11 21.7 10.3
  • Example 6 23.9 17.1 0.058
  • Example 7 11.8 8.4
  • Example 8 12.2 8.7 1.19
  • Example 9 12.4 8.9 0.021
  • Example 10 6.2 4.4 0.24
  • Example 11 13.7 9.8

Landscapes

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

Abstract

La présente invention concerne des composés de la formule générale (I), des mélanges racémiques, des isomères optiques, des sels, solvates pharmaceutiquement acceptables et des compositions pharmaceutiques de ceux-ci. Les définitions des substituants dans la formule générale (I) sont les mêmes que les définitions des revendications. La présente invention concerne également la préparation des composés de la formule générale (I) ainsi que leur utilisation dans la préparation d'un médicament utilisé pour traiter l'hyperglycémie, la dyslipidémie lipémique et le diabète non insulino-dépendant (type II).
PCT/CN2005/000147 2004-05-24 2005-02-02 Derives de tyrosine substitues par alcanoyle en tant qu'antagonistes hppar$g(a) et hppar$g(g) WO2005115998A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNB2004100425722A CN100436430C (zh) 2004-05-24 2004-05-24 作为hPPARα和hPPARγ激动剂的烷酰基取代的酪氨酸衍生物
CN200410042572.2 2004-05-24

Publications (1)

Publication Number Publication Date
WO2005115998A1 true WO2005115998A1 (fr) 2005-12-08

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CN (1) CN100436430C (fr)
WO (1) WO2005115998A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101805308B (zh) * 2009-02-13 2011-10-19 天津药物研究院 一类含酪氨酸和异噁唑骨架的化合物、其制备方法和用途
CN101805336B (zh) * 2009-02-13 2012-05-30 天津药物研究院 一类含色氨酸和异恶唑骨架的化合物、其制备方法和用途

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000344748A (ja) * 1999-03-29 2000-12-12 Welfide Corp ３−芳香族置換プロピオン酸またはアクリル酸化合物
US6194446B1 (en) * 1996-07-01 2001-02-27 Eli Lilly And Company Hypoglycemic and hypolipidemic compounds
CN1321152A (zh) * 1998-08-07 2001-11-07 葛兰素集团有限公司 作为hPPARγ和hPPARα激活剂的取代的噁唑和噻唑衍生物
WO2002100403A1 (fr) * 2001-06-07 2002-12-19 Eli Lilly And Company Modulateurs des recepteurs actives par les proliferateurs du peroxisome (ppar)
US6506781B1 (en) * 1999-09-08 2003-01-14 Smithkline Beecham Corporation Oxazole PPAR antagonist
WO2003059895A1 (fr) * 2002-01-17 2003-07-24 Toaeiyo Ltd. Derives d'acide halogenobenzylaminopropionique
WO2003066574A1 (fr) * 2002-02-07 2003-08-14 Hitoshi Endo Derives d'amino-acides aromatiques et compositions medicamenteuses
WO2004067495A1 (fr) * 2003-01-28 2004-08-12 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Composes d'alanine, leur procede de preparation et leur utilisation

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08325263A (ja) * 1995-05-31 1996-12-10 Sumitomo Metal Ind Ltd 新規２−アミノ−３−フェニルプロピオン酸誘導体
EE03765B1 (et) * 1996-08-19 2002-06-17 Japan Tobacco Inc. Propioonhappe derivaadid ja nende kasutamine
SI1392295T1 (sl) * 2001-05-15 2006-10-31 Hoffmann La Roche Derivati oksazola, substituirani s karboksilno kislino, za uporabo kot ppar -alfa in -gama aktivatorji pri zdravljenju diabetesa

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6194446B1 (en) * 1996-07-01 2001-02-27 Eli Lilly And Company Hypoglycemic and hypolipidemic compounds
CN1321152A (zh) * 1998-08-07 2001-11-07 葛兰素集团有限公司 作为hPPARγ和hPPARα激活剂的取代的噁唑和噻唑衍生物
JP2000344748A (ja) * 1999-03-29 2000-12-12 Welfide Corp ３−芳香族置換プロピオン酸またはアクリル酸化合物
US6506781B1 (en) * 1999-09-08 2003-01-14 Smithkline Beecham Corporation Oxazole PPAR antagonist
WO2002100403A1 (fr) * 2001-06-07 2002-12-19 Eli Lilly And Company Modulateurs des recepteurs actives par les proliferateurs du peroxisome (ppar)
WO2003059895A1 (fr) * 2002-01-17 2003-07-24 Toaeiyo Ltd. Derives d'acide halogenobenzylaminopropionique
WO2003066574A1 (fr) * 2002-02-07 2003-08-14 Hitoshi Endo Derives d'amino-acides aromatiques et compositions medicamenteuses
WO2004067495A1 (fr) * 2003-01-28 2004-08-12 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Composes d'alanine, leur procede de preparation et leur utilisation

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CAI Z-F. AND GUO Z-R.: "Peroxisome poliferator-activates receptors and their modulators", ACTA PHARMACEUTICA SINICA (CHINA), vol. 39, no. 2, 2004, pages 158 - 160 *
CHENG F. ET AL: "Research progress in PPARgama agonists", CHINESE JOURNAL OF MEDICINAL CHEMISTRY, vol. 13, no. 2, April 2003 (2003-04-01), pages 110 *
LIU K.G. ET AL: "Synthesis and Biological Activity of L-Tyrsine-based PPARgama Agonists With Reduced Molecular Weight", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 11, 2001, pages 3111 - 3113 *
REYNOLDS D.J. AND HERMITAGE S.A.: "The synthesis of GW710936X to support the development of L-tyrosine-based PPARgammaAgonist with Reduced Molecular Weight", TETRAHEDRON, vol. 57, 2001, pages 7765 - 7770 *
YI X. AND GUO Z-R.: "Study on 3D-qsar of PPARgama Agonists with Thiazolodinedione and Arylketo-Acid Moieties", ACTA PHARMACEUTICA SINICA (CHINA), vol. 36, no. 4, 2001, pages 262 - 268 *

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CN100436430C (zh) 2008-11-26
CN1702068A (zh) 2005-11-30

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