EP1077960A1 - Derives de l'acide (2-acylaminothiazole-4-yl)acetique - Google Patents

Derives de l'acide (2-acylaminothiazole-4-yl)acetique

Info

Publication number
EP1077960A1
EP1077960A1 EP99920420A EP99920420A EP1077960A1 EP 1077960 A1 EP1077960 A1 EP 1077960A1 EP 99920420 A EP99920420 A EP 99920420A EP 99920420 A EP99920420 A EP 99920420A EP 1077960 A1 EP1077960 A1 EP 1077960A1
Authority
EP
European Patent Office
Prior art keywords
oxo
amino
thiazoleacetic acid
octadecenyl
acid
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP99920420A
Other languages
German (de)
English (en)
Inventor
Kenneth Lewis Kees
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wyeth
Original Assignee
American Home Products Corp
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 American Home Products Corp filed Critical American Home Products Corp
Publication of EP1077960A1 publication Critical patent/EP1077960A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof

Definitions

  • Hyperinsulinemia can be present as a result of insulin resistance, such as is in obese and/or diabetic (NTDDM) subjects and/or glucose intolerant subjects, or in IDDM subjects, as a consequence of over injection of insulin compared with normal physiological release of the hormone by the endocrine pancreas.
  • NTDDM diabetic diabetic
  • insulin resistance is usually the result of a defect in the insulin receptor signaling system, at a site post binding of insulin to the receptor.
  • Accumulated scientific evidence demonstrating insulin resistance in the major tissues which respond to insulin strongly suggests that a defect in insulin signal transduction resides at an early step in this cascade, specifically at the insulin receptor kinase activity, which appears to be diminished (reviewed by Haring, Diabetalogia 1991, 34, 848).
  • PTPases Protein-tyrosine phosphatases play an important role in the regulation of phosphorylation of proteins.
  • the interaction of insulin with its receptor leads to phosphorylation of certain tyrosine molecules within the receptor protein, thus activating the receptor kinase.
  • PTPases dephosphorylate the activated insulin receptor, attenuating the tyrosine kinase activity.
  • PTPases can also modulate post-receptor signaling by catalyzing the dephosphorylation of cellular substrates of the insulin receptor kinase.
  • the enzymes that appear most likely to closely associate with the insulin receptor and therefore, most likely to regulate the insulin receptor kinase activity include PTP1B, LAR, PTP ⁇ and SH-PTP2 (B. J. Goldstein, J. Cellular Biochemistry 1992, 48, 33; B. J. Goldstein, Receptor 1993, 3, 1-15,; F. Ahmad and B. J. Goldstein Biochim. Biophys Acta 1995, 1248,
  • the compounds of this invention have been shown to inhibit rat-derived and human-derived recombinant PTPase- IB (rPTP-lB) in vitro . They are useful in the treatment of insulin resistance associated with obesity, glucose intolerance, diabetes mellitus, hypertension and ischemic diseases of the large and small blood vessels.
  • 2-Aminothiazoleacetic acid derivatives have been used extensively in chemical and patent literature as intermediates for penam and cepham classes of antibiotics, but the long (Ci6, Cl8) unsaturated carboxamide chains at C2 of the thiazoleacetic acid moiety makes these compounds novel.
  • WO 9616650 and JP 07149745 generically claim "lower alkyl" amides of 2-aminothiazoleacetic acid are antibacterial and antiinflammatory (elastase inhibitors) agents, respectively.
  • patent 5,688,821 (1997, to AHP) teaches that some of the same compounds that are in this invention are inhibitors of the enzymes phospholipase A 2 derived from human sources (anti- inflammatory agents), but others are not and vice- versa.
  • Certain long acylhydrocarbon chain derivatives of 2-aminothiazoleacetic acid have been prepared (Toth, Liebigs Ann. Chem. EN, 7, 685, 1994).
  • This invention provides a method of using a compound of formula I having the structure
  • R , R 2 are both hydrogen or form a bond, or are each, independently, alkyl of
  • Pharmaceutically acceptable salts can be formed from organic and inorganic bases, such as alkali metals (sodium, potassium, or lithium), alkaline earth metals (calcium or magnesium), ammonium, primary, secondary alkyl amines, or tertiary alkyl - 4 - amines.
  • alkali metals sodium, potassium, or lithium
  • alkaline earth metals calcium or magnesium
  • ammonium primary, secondary alkyl amines
  • tertiary alkyl - 4 - amines tertiary alkyl - 4 - amines.
  • the compounds of this invention can exhibit E (trans) or Z (cis) stereoisomerism about the double bond, and that this invention covers both the E and Z isomers, at each double bond, and in particular when R 1 and R 2 are both hydrogen, alkyl, or aryl. When R 1 and R 2 are not a bond, it is preferred that they both are hydrogen.
  • Aryl is defined as an organic radical derived from an aromatic hydrocarbon by the removal of a hydrogen (i.e., phenyl from benzene). It is preferred that the aryl moiety is a phenyl or naphthyl group; with phenyl being most preferred.
  • the aryl moiety may be optionally mono-, di-, or tri- substituted with a substituent selected from the group consisting of alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoromethyl, halogen, alkoxycarbonyl of 2-7 carbon atoms, alkylamino of 1-6 carbon atoms, and dialkylamino in which each of the alkyl groups is of 1-6 carbon atoms, nitro, cyano, -CO2H, alkylcarbonyloxy of 2-7 carbon atoms, and alkylcarbonyl of 2-7 carbon atoms.
  • the compounds of this invention can be synthesized by saponification of the corresponding 2-fatty acylaminothiazole-4-acetic acid ethyl esters, followed by acidification of the reaction mixture.
  • Basic salts of these acids are prepared also in a conventional manner as is known in the art.
  • the tromethamine salts of this invention provide water soluble derivatives for improved bioavailability.
  • the fatty acylaminothiazoleacetic acid esters are prepared in one of two ways: condensation of ethyl-2-aminothiazoleacetate with a fatty acid chloride in the presence of a tertiary amine base such as triethyla ine or diisopropylethylamine in an aprotic solvent (e.g.
  • fatty acyl starting materials are either prepared according to standard chemical methodology (such as Wittig or Peterson olefination reactions and or modifications thereof, or by reductive dicarbonyl coupling reactions, such as those procedures of McMurry, Corey and Mukiyama), or from commercially available starting materials
  • Standard chemical methodology such as Wittig or Peterson olefination reactions and or modifications thereof, or by reductive dicarbonyl coupling reactions, such as those procedures of McMurry, Corey and Mukiyama
  • General procedures to prepare representative compounds of this invention are disclosed in U.S. Patent 5,688,821, which is hereby incorporated by reference, and the preparation of specific representative compounds of this invention are provided in Examples which follow.
  • the compounds of this invention are useful in treating metabolic disorders related to insulin resistance or hyperglycemia, typically associated with obesity or glucose intolerance.
  • the compounds of this invention are therefore, particularly useful in the treatment or inhibition of type II diabetes.
  • the compounds of this invention are also useful in modulating glucose levels in disorders such as type I diabetes. Additionally, because an association exists between insulin resistance and hypertension and between insulin resistance, hypertension and coronary artery disease, the compounds of this invention are also useful for the treatment of primary (essential) hypertension and atherosclerosis.
  • the incubation mixture contains in a final volume of 0.24 ml: 50 mM HEPES (pH 7.4), 6.33 mM p-nitrophenyl phosphate and 5/25/100 ⁇ M compound suspended in 1.25% DMSO.
  • rPTPlB obtained from the laboratory of Dr. Barry Goldstein of Thomas Jefferson University. The enzyme (see Goldstein et al. Mol. Cell. Biochem. 109, 107, 1992), in microvials containing 500-700 ⁇ g/ml protein in - 6 -
  • a representative compound (Example 8) of this invention was also evaluated for inhibition of recombinant human PTP1B.
  • Human recombinant PTP1B was prepared as described by Goldstein (see Goldstein et al. Mol. Cell. Biochem. 109, 107, 1992). The enzyme preparation used was in microtubes containing 500-700 ⁇ g/ml protein in 33 mM Tris-HCl, 2 mM EDTA,
  • the malachite green-ammonium molybdate method as described (Lanzetta et al. Anal. Biochem. 100, 95, 1979) and adapted for a platereader, is used for the nanomolar detection of liberated phosphate by recombinant PTP1B.
  • the assay uses, as substrate, a dodecaphosphopeptide custom synthesized by AnaSpec, Inc. (San Jose, CA).
  • the peptide, TRDIYETDYYRK corresponding to the 1142-1153 catalytic domain of the insulin receptor, is tyrosine phosphorylated on the 1146, 1150, and 1151 tyrosine residues.
  • the recombinant rPTPlB is diluted with buffer (pH 7.4, containing 33 mM Tris-HCl, 2 mM EDTA and
  • the stopping reagent consists of 3 parts 0.45% malachite green hydrochloride, 1 part 4.2% ammonium molybdate tetrahydrate in 4 N HC1 and 0.5% Tween 20.
  • Sample blanks are prepared by the addition of 200 mL MG/AM/Tw to substrate and followed by 39.5 ml of the preincubated recombinant enzyme with or without drug. The color is allowed to develop at room temperature for 30 min. and the sample absorbances are determined at 650 nm using a platereader (Molecular Devices). Sample and blanks are prepared in quadruplicates.
  • PTPase activities based on a potassium phosphate standard curve, are expressed as nmoles of phosphate released/min/mg protein. Inhibition of recombinant PTPIB by test compounds is calculated as percent of phosphatase control.
  • PROC NLIN is used for determining IC50 values of test compounds. Representative results are given in Table 2 .
  • representative compounds of this invention have been shown to inhibit PTPase activity, and are therefore useful in treating metabolic disorders related to insulin resistance or hyperglycemia, typically associated with obesity or glucose intolerance. More particularly, the compounds of this invention are useful in the treatment or inhibition of type U diabetes, and in modulating glucose levels in disorders such as type I diabetes. The compounds of this invention are also useful in the treatment of primary (essential) hypertension and atherosclerosis. As used herein, the term modulating means maintaining glucose levels within clinically normal ranges.
  • Effective administration of these compounds may be given at a daily dosage of from about 1 mg/kg to about 250 mg/kg, and may given in a single dose or in two or more divided doses. Such doses may be administered in any manner useful in directing the active compounds herein to the recipient's bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, and transdermally.
  • transdermal administrations are understood to include all administrations across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues.
  • Such administrations may be carried out using the present compounds, or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).
  • Compounds of this invention may be administered neat or with a pharmaceutical carrier to a patient in need thereof.
  • the pharmaceutical carrier may be solid or liquid.
  • Oral formulations containing the active compounds of this invention may comprise any conventionally used oral forms, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions.
  • Capsules may contain mixtures of the active compound(s) with inert fillers and/or diluents such as the pharmaceutically acceptable starches (e.g. corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc.
  • Useful tablet formulations may be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, carboxymethyl- cellulose calcium, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starches and powdered sugar.
  • pharmaceutically acceptable diluents including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, micro
  • Oral formulations herein may utilize standard delay or time release formulations to alter the absorption of the active compound(s).
  • Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin.
  • Water soluble suppository bases such as polyethylene glycols of various molecular weights, may also be used.
  • the dosage, regimen and mode of administration of these compounds will vary according to the malady and the individual being treated and will be subject to the judgment of the medical practitioner involved. It is preferred that the administration of one or more of the compounds herein begin at a low dose and be increased until the desired effects are achieved.
  • Example 3 2-[((E)-l-Oxo-9-octadecenyl)amino]-4-thiazoleacetic acid, tromethamine (2-amino-2-hydroxymethyl)-l,3-propanediol) salt
  • the title compound was prepared by the method of procedure B (example 2).
  • the crude product was recrystallized from heptane on a steam bath to provide white crystals, mp 104.5-105.5°C.
  • the title compound was prepared by the method of procedure B.
  • the crude product was treated with hot heptane (steam bath) cooled to room temperature and collected on a Buchner funnel. The material was air dried for several hours, then in an
  • the title compound was prepared by the method of procedure B.
  • the crude acid was recrystallized from hot heptane to give the product as white crystals, mp 117- 118°C.
  • the title compound was prepared according to the method of procedure B.
  • the crude product was crystallized from hot heptane to give white crystals, mp 115.8- 117.1°C.
  • the title compound was prepared by procedure B and precipitated from heptane as a hygroscopic yellow wax.
  • the title compound was prepared according to procedure B.
  • the crude product was chromatographed on Si ⁇ 2 (flash column, 40 wt. eq., elution with hexane (70%), ethyl acetate (30%), acetic acid (1%)) to give the title compound as a pale yellow wax.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)

Abstract

La présente invention concerne des composés de formule (I) de structure (I), dans laquelle R1, R2 sont tous les deux des hydrogènes ou forment une liaison, ou sont chacun, de manière indépendante, un alkyle en C¿1?-C6 ou un aryle en C6-C12; m prend la valeur de 0 à 10, n prend la valeur de 1 à 3, et p prend la valeur de 0 à 10 ; avec la condition que la somme m+p soit inférieure ou égale à 15. Ces composés ou leurs sels acceptables sur le plan pharmaceutique sont utiles dans le traitement de la résistance insulinique et de l'hyperglycémie.
EP99920420A 1998-05-12 1999-05-10 Derives de l'acide (2-acylaminothiazole-4-yl)acetique Withdrawn EP1077960A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US7670898A 1998-05-12 1998-05-12
US76708 1998-05-12
PCT/US1999/010212 WO1999058514A1 (fr) 1998-05-12 1999-05-10 Derives de l'acide (2-acylaminothiazole-4-yl)acetique

Publications (1)

Publication Number Publication Date
EP1077960A1 true EP1077960A1 (fr) 2001-02-28

Family

ID=22133723

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99920420A Withdrawn EP1077960A1 (fr) 1998-05-12 1999-05-10 Derives de l'acide (2-acylaminothiazole-4-yl)acetique

Country Status (6)

Country Link
EP (1) EP1077960A1 (fr)
JP (1) JP2002514633A (fr)
CN (1) CN1308619A (fr)
AU (1) AU3791899A (fr)
CA (1) CA2330558A1 (fr)
WO (1) WO1999058514A1 (fr)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1331327A (zh) * 2000-06-26 2002-01-16 上海博德基因开发有限公司 一种新的多肽——人纹状体富集磷酸酶14.85和编码这种多肽的多核苷酸
AU2002349705A1 (en) 2001-12-03 2003-06-17 Japan Tobacco Inc. Azole compound and medicinal use thereof
WO2004089918A1 (fr) * 2003-04-09 2004-10-21 Japan Tobacco Inc. Compose pentacyclique heteroaromatique et son usage medical
CN1794989A (zh) * 2003-04-14 2006-06-28 药物研发有限责任公司 用于治疗糖尿病的n－(((((1,3－噻唑－2－基)氨基)羰基)苯基)磺酰基)苯丙氨酸衍生物及相关化合物
WO2004099168A2 (fr) 2003-04-30 2004-11-18 The Institutes For Pharmaceutical Discovery, Llc Acides carboxyliques substitues
WO2005035551A2 (fr) 2003-10-08 2005-04-21 Incyte Corporation Inhibiteurs de proteines se liant a des molecules phosphorylees
EP1753735A1 (fr) 2004-04-20 2007-02-21 Transtech Pharma, Inc. Derives de thiazole et de pyrimidine substitues, modulateurs des recepteurs de la melanocortine
CN101260086B (zh) * 2007-03-06 2011-08-10 中国科学院上海药物研究所 蛋白酪氨酸磷酸酯酶1b抑制剂及其制备方法和用途
EP2320738A4 (fr) 2008-08-29 2011-08-24 Transtech Pharma Inc Dérivés d'aminothiazole substitués, compositions pharmaceutiques et leurs procédés d'utilisation
CN102408417B (zh) * 2011-09-26 2015-03-11 上海交通大学 2-取代乙烯磺酸酯类化合物及其制备方法和应用

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2206315A1 (fr) * 1994-11-29 1996-06-06 Hisamitsu Pharmaceutical Co., Inc. Utilisation de .beta.-carbolines halogenees en tant substances experimentales servant a provoquer des affections degeneratives
US5688821A (en) * 1995-12-12 1997-11-18 American Home Products Corporation Unsaturated fatty acyl derivatives of 2-aminothiazoleacetic acid and their salts as inhibitors of phospholipase A2 derived from human sources
TW513418B (en) * 1996-07-31 2002-12-11 Otsuka Pharma Co Ltd Thiazole derivatives, their production and use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9958514A1 *

Also Published As

Publication number Publication date
CA2330558A1 (fr) 1999-11-18
JP2002514633A (ja) 2002-05-21
CN1308619A (zh) 2001-08-15
AU3791899A (en) 1999-11-29
WO1999058514A1 (fr) 1999-11-18

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