WO1996038415A1 - Nouveaux derives de l'acide 2-amino-3-phenylpropionique - Google Patents

Nouveaux derives de l'acide 2-amino-3-phenylpropionique Download PDF

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Publication number
WO1996038415A1
WO1996038415A1 PCT/JP1996/001380 JP9601380W WO9638415A1 WO 1996038415 A1 WO1996038415 A1 WO 1996038415A1 JP 9601380 W JP9601380 W JP 9601380W WO 9638415 A1 WO9638415 A1 WO 9638415A1
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Prior art keywords
phenyl
group
methyl
oxazolyl
ethoxy
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PCT/JP1996/001380
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English (en)
Japanese (ja)
Inventor
Hidekazu Takeno
Tomoyuki Ikemoto
Isao Saitoh
Kazuhiro Watanabe
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Sumitomo Metal Industries, Ltd.
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Priority to AU57791/96A priority Critical patent/AU5779196A/en
Publication of WO1996038415A1 publication Critical patent/WO1996038415A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a novel 2-amino-3-phenylpropionic acid derivative. More specifically, it has a hypoglycemic effect and a hypolipidemic effect, and is useful as a therapeutic agent for diabetes and hyperlipidemia.
  • sulfonylurea agents For the treatment of non-insulin-dependent diabetes mellitus (type I diabetes), insulin, oral hypoglycemic agents (sulfonylurea agents, biguanides) are generally given in addition to diet and exercise. It has been known that administration of a sulfonylurea agent causes severe hypoglycemia due to its potent hypoglycemic effect. In addition, when a sulfonylurea agent is used for a long period of time, its effect gradually becomes weaker, and a phenomenon of secondary ineffectiveness may be observed. In addition, biguanides can cause lactic acidosis, and their administration requires great care.
  • Japanese Patent Application Laid-Open No. 61-853772 discloses [5- [4-1] [2-((5-methyl-12-phenyl-41-kizazolyl)].
  • A is a bicyclic fused ring containing a benzene ring, XI is 0, S, represents a SO or S 0 2
  • compounds showing hypoglycemic action represented by is disclosed.
  • W093Z21166 has the formula
  • a 2 is a benzene ring having a substituent
  • a 3 is one (CH 2 ) m—CHR! —
  • W094 01420 has the formula
  • W094 No 13650 has the formula
  • R! And A 2 are the same as above, and R! And R 2 independently represent hydrogen, or R! And R 2 represent a single bond.
  • R 3 and R 4 independently represent A compound having a hypoglycemic action represented by a nitrile group or 1 C 0 R 5 ) is disclosed.
  • W094 / 29302 has the formula A 1 -X- (CH 2 ) n-0-A2- (CH 2 ) m-CHR 1 (COR 2 )
  • Ai A 2 is as defined above, represents a terrorist 5-membered ring aromatic of bound substituted or unsubstituted with N, including the proviso nitrogen atom of the ring appropriately 1-3
  • a compound having a hypoglycemic action represented by
  • 094-29285 has the formula
  • Ai-X- (CH 2 ) -0-A 2- (CH 2 ) m-CHNR 1 R 2 (COR3) (where A! And A 2 are the same as above and represent a hydrogen or an alkyl group. , R 2 is an aryl group) is disclosed as having a hypoglycemic effect.
  • the present inventors have conducted intensive studies to provide a novel compound useful as a therapeutic agent for diabetes and hyperlipidemia.As a result, the present inventors have found that they have a strong blood glucose lowering action and The present inventors have found a novel 2-amino-3-funinylpropionic acid derivative having extremely high safety, and have completed the present invention.
  • the compound of the present invention is a novel 2-amino-3-phenylpropionic acid derivative represented by the following general formula (I) and a pharmaceutically acceptable salt thereof.
  • R! Is a hydroxyl group, a lower alkoxy group, a fuunoxy group or a phenyl lower alkoxy group, an amino group, a mono- or di-lower alkylamino group, a pyrrolidino group, a pyridino group, a morpholino group, and 3 or less halogen atoms.
  • R 2 and R 3 are independently 5 or 6 members in which one or two atoms selected from hydrogen, lower alkyl group, aryl lower alkyl group, nitrogen, oxygen and sulfur together with carbon constitute a ring
  • R 4 represents hydrogen, nitro group, lower alkoxy group, halogen atom or hydroxyl group substituted at the 2- or 3-position of the benzene ring.
  • W represents an oxygen atom or a carbonyl group, m represents 0, 1 or 2, and A represents the formula (II), (III) or (IV)
  • X represents an oxygen, nitrogen or sulfur atom
  • R 5 and R e each independently represent hydrogen, a lower alkyl group, a phenyl group
  • R 7 represents hydrogen or a lower alkyl group
  • a lower alkoxy group means a linear or branched alkoxy group having 8 or less carbon atoms
  • a fuunyl lower alkoxy group or a lower alkoxy group is a lower alkoxy moiety
  • a phenylalkoxy group or an alkoxycarbonyl group having the same meaning as described above, and is a lower alkenyl sulfonyl group or a lower alkane sulfonyla group which may be substituted with three or less halogen atoms.
  • a mino group is a straight-chain or branched alkyne in which the hydrocarbon moiety has 8 or less carbon atoms, which means that they may be substituted with 3 or less halogen atoms, for example, methanesulfonyl. Trifluoromethanesulfonyl, methanesulfonylamino, trifluoromethanesulfonylamino and the like.
  • the residue obtained by removing one hydrogen from the amino group of an amino acid or a lower alkyl ester thereof is the residue obtained by removing one hydrogen from the amino group of various amino acids, particularly amino acids that constitute a living body or their lower alkyl esters.
  • a lower alkyl group or an aryl lower alkyl group means a linear or branched alkyl group in which the lower alkyl moiety has 8 or less carbon atoms, and an aryl group means a fuunyl group or another benzene ring.
  • a 5- or 6-membered aromatic heterocyclic group in which one or two atoms selected from nitrogen, oxygen and sulfur form a ring together with carbon for example, A nyl group, a furyl group, a quinolylmethyl group, It may be substituted with a lower alkyl group or 3 or less halogen atoms! ⁇ , A lower alkyl group is an alkyl group having 8 or less carbon atoms in the lower alkyl group. Means that.
  • Preferred compounds of the present invention include, in the above formula (I), a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms, a benzyloxy group, a phenoxy group, Amino group, alkylamino group having 1 to 4 carbon atoms, dialkylamino group having 1 to 4 carbon atoms, pyrrolidino group, piperidino group, morpholino group, alkanesulfonylamino group having 1 to 2 carbon atoms, benzenesulfonylamino group An amino acid or a residue obtained by removing one hydrogen from the amino group of an alkyl ester having 1 to 3 carbon atoms of an amino acid; X, R 2 and R 3 are each independently hydrogen or an alkyl having 1 to 8 carbon atoms; Group, benzyl group R
  • R 2 and R 3 R 4 is hydrogen, nitro group, alkoxy group having 8 or less carbon atoms, halogen atom, hydroxyl group substituted at the 2- or 3-position of the benzene ring, and R 4 is a phthalimid group or a succinylimido group.
  • R 5 and R 6 are each independently hydrogen, an alkyl group having 1 to 4 carbon atoms, a phenyl group, or a phenyl group. Or a furyl group, and R 7 is hydrogen, a 2-amino-3-phenylpropionic acid derivative which is an alkyl group having 1 to 4 carbon atoms, or a pharmaceutically acceptable salt thereof.
  • A is the formula ( ⁇ )
  • R 5 and R 6 each independently represent hydrogen, a lower alkyl group, a phenyl group, a phenyl group, or a furyl group.
  • a particularly preferred group is a compound group in which X is an oxygen atom, R 5 is a fuunyl group, and R 6 is a methyl group.More preferably, is a lower alkyl group represented by a hydroxyl group or an ethoxy group.
  • R 2 and R 3 are each independently hydrogen, a lower alkyl group having a carbon number of 5 or less or a fuunyl lower alkyl group in the alkyl portion, and R 4 is hydrogen.
  • A is a group represented by the formula (II)
  • R 7 represents hydrogen, a lower alkyl group, particularly an alkyl group having 1 to 4 carbon atoms.
  • a 2-amino-3-phenylpropionic acid derivative or a pharmaceutically acceptable salt thereof is provided.
  • Another preferred group is a compound represented by the general formula (I), wherein A is a group represented by the formula (IV) ⁇ 7
  • R 7 represents hydrogen, a lower alkyl group, particularly an alkyl group having 1 to 4 carbon atoms.
  • a 2-amino-3-funilpropionic acid derivative or a pharmaceutically acceptable salt thereof is provided.
  • the alkoxy group having 1 to 3 carbon atoms is specifically a methoxy group, an ethoxy group, a normal propyloxy group, an isopropyloxy group, or the like, and is preferably an ethoxy group.
  • An alkylamino group having 1 to 4 carbon atoms or a dialkylamino group having 1 to 4 carbon atoms specifically means a methylamino group, an ethylamino group, a normal propylamino group, an isopropylamino group, a normal butylamino group, an isobutylamino group, sec-butylamino group, tert-butylamino group, preferably methylamino group, ethylamino group, and the like, including dimethylamino group, ethylamino group, dinormal propylamino group, diisopropylamino group, dinormalaminobutylamino group, dimethylamino group Examples include a sobutylamino group, a di-sec-butylamino group, a di-tert-butylamino group, preferably a dimethylamino group and a getylamino group.
  • Residues obtained by removing one hydrogen atom from the amino group of an amino acid or an alkyl ester of an amino acid having 1 to 3 carbon atoms include glycine, alanine, valine, leucine, isoloisin, serine, threonine, cysteine, Proline, glutamic acid, histidine, lysine, ordinine, arginine, phenylalanine, tyrosine, etc., preferably glycine, alanine, etc., or an alkyl ester thereof having 1 to 3 carbon atoms, preferably Is a methyl ester or an ethyl ester.
  • C1-C8 alkyl Specific examples of the group include a methyl group, an ethyl group, a normal propyl group, a normal butyl group, a normal pentyl group, a normal hexyl group, a normal heptyl group, a normal octyl group, an isopropyl group, an isobutyl group, a sec-butyl group, It represents an isopentyl group and the like, and is preferably a methyl group, an ethyl group, a normal propyl group, a normal butyl group, a normal pentyl group, an isopropyl group, an isobutyl group or a sec-butyl group.
  • An aryl lower alkyl group is specifically a benzyl group, a phenylethyl group, a phenylpropyl group, a naphthylmethyl group, a naphthylethyl group, or one or two atoms selected from nitrogen, sulfur or oxygen together with carbon.
  • Specific examples of the heterocyclic group contained as a constituent include a phenyl group, a phenyl group, a phenyl group, a phenyl group, and a benzyl group.
  • the alkanoyl group having 1 to 6 carbon atoms specifically includes a formyl group, an acetyl group, a propanoyl group, a butanol group, a pentanoyl group, a hexanoyl group, an isopropanol group, an isobutanol group, and the like, preferably a formyl group, an acetyl group. , Propanoyl and butanoyl groups.
  • the halogen atom is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • halogenated lower alkanol group for example, a chloroacetyl group, a trifluoroacetyl group and the like are preferable.
  • alkoxycarbonyl group having 1 to 4 carbon atoms include a methoxycarbonyl group, an ethoxycarbonyl group, a propyloxycarbonyl group, a normal butoxycarbonyl group, and a tert-butoxycarbonyl group.
  • particularly excellent representative compounds are as follows:
  • the pharmaceutically acceptable salt may be any as long as it forms a nontoxic salt with the 2-amino-3-phenylpropionic acid derivative represented by the above general formula (I).
  • examples of the formation of a salt with an acidic functional group of a 2-amino-3-phenylpropionic acid derivative include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium and magnesium, ammonium, and trimethylamate.
  • organic base salts such as min, triethylamine, pyridine salt and picoline salt, and amino acid salts such as lysine salt and arginine salt.
  • examples of the formation of a salt with a basic functional group of a 2-amino-3-phenylpropionic acid derivative include salts of inorganic acids such as hydrochloride, hydrobromide, sulfate, and phosphate, and acetates.
  • organic acid salts such as succinate, citrate, malate, oxalate, maleate and methanesulfonate.
  • any of the above salts is not limited to these.
  • the compound of the present invention represented by the general formula (I) has a strong blood glucose lowering action and a blood lipid lowering action, and is used as a preventive and therapeutic drug for diabetes and hyperlipidemia.
  • a pharmaceutical preparation containing a compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, which is expected to be useful as well as a prophylactic agent for arteriosclerosis, can be prepared by a conventional method.
  • pharmacologically acceptable carriers, excipients, diluents, bulking agents, disintegrants, stabilizers, preservatives, buffers, emulsifiers, fragrances, coloring agents, sweeteners which are generally known per se.
  • Thickeners such as water, vegetable oils, ethanol, or alcohols such as benzyl alcohol, polyethylene glycol, glycerol triacetate, gelatin, lactose, Tablets, pills, powders, granules, suppositories, injections, eye drops, liquids, capsules, troches, etc. using carbohydrates such as starch, magnesium stearate, talc, lanolin, petrolatum, etc.
  • Formulations for oral or parenteral administration such as aerosols, exyls, suspensions, emulsions and capsules can be made.
  • the dose may vary depending on the type and degree of the disease, the compound to be administered and the administration route, the age, sex, weight and the like of the patient.
  • the compound of the present invention (I) It is preferable to administer 0.1 to: L000 mg, especially 1 to 100 mg.
  • the compound of the present invention represented by the general formula (I) has one or more asymmetric carbon atoms, and in the case of one, a pure optically active substance, a mixture thereof in any ratio, Alternatively, when a racemate exists, and when there are two or more, an optically pure diastereomer, a racemate thereof, or a combination thereof, and a mixture having an arbitrary ratio exist, all of which are present invention. It belongs to the range.
  • the compound of the present invention can be produced, for example, by the following routes. However, it goes without saying that the method for producing the compound of the present invention is not limited to these. (Route 1) —General formula (A)
  • hydroxyl group is a hydroxyl group, a lower alkoxy group, a phenoxy group or a phenyl lower alkoxy group, an amino group, a mono- or di-lower alkylamino group, Lysino group, piperidino group, morpholino group, lower alkenyl sulfonylamino group, benzenesulfonylamino group which may be substituted with 3 or less halogen atoms, or amino group of amino acid or its lower alkyl ester. Indicates a residue excluding one hydrogen.
  • R 2 and R 3 are independently 5 or 6 members in which one or two atoms selected from hydrogen, lower alkyl group, aryl lower alkyl group, nitrogen, oxygen and sulfur together with carbon constitute a ring Aromatic heterocyclic group-substituted lower alkyl group, lower alkanol group, benzoyl group, nitro group or benzoyl group substituted with a halogen atom, lower alkanol group optionally substituted with 3 or less halogen atoms, lower alkoxy
  • R 4 represents hydrogen, a nitro group, a lower alkoxy group, a halogen atom, or a hydroxyl group substituted at the 2- or 3-position of the benzene ring.
  • T represents a hydrogen atom or a hydroxyl group
  • W represents an oxygen atom or a carbonyl group
  • m represents 0, 1 or 2
  • A is the formula (II), (III) or (IV)
  • R 5 and R 6 each independently represent hydrogen, a lower alkyl group, a phenyl group, a phenyl group or a furyl group, and R 7 represents a hydrogen or a lower alkyl group.
  • R 8 is a protecting group for an amino group
  • R 9 is a lower alkoxy group
  • T is a hydrogen atom or a hydroxyl group
  • Q is a reactive group in a carboxy group
  • R 1 () and RH are both or any of One is lower alkyl group
  • aryl lower alkyl Represents an aromatic heterocyclic group-substituted lower alkyl group containing one or two atoms selected from nitrogen, oxygen and sulfur together with carbon as a ring constituent, the other being hydrogen, and R! 2 being lower.
  • R 13 represents a hydrogen atom from an amino group of an amino group, a mono- or di-lower alkylamino group, a pyrrolidino group, a piperidino group, a morpholino group, a lower alkanesulfonylamino group, a benzenesulfonylamino group, an amino acid or an amino acid ester.
  • R 1 5, 6 represents a Futaruimi de group or Sukushi two Ruimi de group
  • R 1 7 represents a lower alkyl group which may be substituted with 3 or less halogen atoms
  • R represents a hydroxyl group or a leaving group at the time of a nucleophilic reaction.
  • Step 1 Compound (B) (wherein, R 8 is a t-butyloxycarbonyl group And R 9 represents, for example, an alkoxy group having 1 to 3 carbon atoms. )
  • R 8 is a t-butyloxycarbonyl group
  • R 9 represents, for example, an alkoxy group having 1 to 3 carbon atoms.
  • A— (CH 2 ) m-introduced alkylating reagent represented by A— (CH 2 ) mR, wherein R Represents a hydroxyl group, or represents a functional group which becomes a good leaving group in a nucleophilic reaction such as a halogen atom, a ⁇ -toluenesulfonyloxy group, a methanesulfonyloxy group, etc.
  • R represents a hydroxyl group.
  • the conditions for the Mitsunobu reaction include, for example, the starting compounds methylene chloride, tetrahydrofuran, benzene, toluene, ether, dimethylformamide, dioxane, etc.
  • Each solution contains 1-3 equivalents of triphenylphosphine, dialkyl azobiscarboxylate (dimethyl, getyl, diisopropyl) or azobiscarboxylate amide and While handling alkylation reagent in one 50 ° Celsius to room, the reaction at the boiling point corresponding temperature of the solvent that temperature.
  • R is a leaving functional group
  • water, dimethylformamide, benzene, toluene, or the like is used as a solvent in the presence of a base such as sodium hydroxide, lithium hydroxide, or sodium hydride. It can be obtained by reacting at a temperature between ° C and the boiling point of each solvent.
  • Step 1 A phenylalanine derivative in which T is a hydrogen atom in the general formula (A), which is easily available, is combined with a reactive derivative of carboxylic acid represented by the formula A— (CH 2 ) mCOQ, for example, an acid halide.
  • the reaction is carried out under the conditions used in the Friedel-Crafts reaction to give a 3- (4-alkanoylphenyl) propionic acid derivative represented by the general formula (B).
  • the reaction conditions include, for example, methylene chloride, 1,2-dichloroethane, Lewis acid such as aluminum chloride, ferrous chloride, ferric chloride, titanium tetrachloride, boron trifluoride, tin tetrachloride, zinc chloride, or hydrogen fluoride sulfuric acid, using carbon fluoride, carbon tetrachloride, nitrobenzene, etc.
  • Lewis acid such as aluminum chloride, ferrous chloride, ferric chloride, titanium tetrachloride, boron trifluoride, tin tetrachloride, zinc chloride, or hydrogen fluoride sulfuric acid, using carbon fluoride, carbon tetrachloride, nitrobenzene, etc.
  • Lewis acid such as aluminum chloride, ferrous chloride, ferric chloride, titanium tetrachloride, boron trifluoride, tin tetrachloride, zinc chloride, or hydrogen fluoride sulfuric acid, using carbon flu
  • Step 2 Compound (C) or a salt thereof may be prepared by subjecting compound (B) to an acid treatment under appropriate conditions when N-protecting group R 8 is t-butyloxycarbonyl, for example, dioxane, tetrahydrofuran, or acetic acid.
  • N-protecting group R 8 is t-butyloxycarbonyl, for example, dioxane, tetrahydrofuran, or acetic acid.
  • Ethyl, acetonitrile, etc. as a solvent, or without solvent, introduce hydrogen chloride gas, or react with an appropriate solution of hydrogen chloride (for example, dioxane solution, ethyl acetate solution, etc.) or acid such as trifluoroacetic acid Can be obtained by desorption.
  • Production route 2 (W oxygen atom)
  • Step 3 Compound (C) or a salt thereof is added to dimethylformamide, methanol, ethanol, tetrahydrofuran, dioxane, acetonitrile, ethoxyethanol, etc., and R 10 or R restroomhalide (for example, iodide , Bromide, chloride) in an amount of 1 to 20 equivalents, and triethylamine, pyridine, Obtained by reacting in the presence of 1 to 20 equivalents of a base such as N, N-diisopropylethylamine, sodium hydroxide, rhodium hydroxide, potassium carbonate, sodium hydrogencarbonate at room temperature or under heating. Can be done.
  • a base such as N, N-diisopropylethylamine, sodium hydroxide, rhodium hydroxide, potassium carbonate, sodium hydrogencarbonate at room temperature or under heating.
  • Compound (D) can also be obtained by catalytic reduction under a hydrogen stream at 1 to 50 atm using palladium carbon, platinum oxide, Raney nickel or the like as a catalyst.
  • compound (D) can also be obtained by a method using a reducing agent such as sodium borohydride, sodium cyanoborohydride, diborane or the like instead of the above catalytic reduction.
  • Step 4 Compound (E) is obtained by converting compound (D) to methanol, ethanol, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, acetic acid, trifluoroacetic acid, ethyl acetate, chloroform, methylene chloride, water, etc.
  • a base such as sodium hydroxide, potassium hydroxide or potassium carbonate or an acid such as hydrochloric acid, sulfuric acid, trifluoroacetic acid or the like to a mixture thereof as a solvent and reacting the mixture at room temperature or under heating. .
  • Step 5 Compound (E) (when R 10 and Ru both represent hydrogen) can be obtained from compound (C) in the same procedure as in the above step 4.
  • Step 6 Compound (F) is obtained by adding compound (C) or a salt thereof to chloroform-methylene chloride, tetrahydrofuran, dioxane, dimethylformamide, acetone, pyridine, water and a mixture thereof, and adding triethylamine, pyridine, N, N-diisopropyl E chill ⁇ Min, sodium hydroxide, water oxidizing power helium, carbonic force potassium, active form for introducing R 12 in the presence of a base such as sodium hydrogen carbonate, for example, corresponds to R 12
  • a base such as sodium hydrogen carbonate
  • Step 7 Compound (G) can be obtained from compound (F) in the same procedure as in Step 4 above.
  • Production route 4 (W oxygen atom)
  • Step 8 Compound (H) can be obtained from compound (B) in the same procedure as in Step 4 above.
  • Step 9 The compound (N) is converted into an N-hydroxysuccinate derivative by a conventional method for amidating a carboxylic acid such as the compound (H), and is reacted with an amine component corresponding to R13. Or a mixture of carboxylic acid and reagents such as isobutyl chlorocarbonate with a base such as N-methylmorpholine It can be obtained by producing an acid anhydride and reacting the acid anhydride with a corresponding amine. In addition, a general method for amidating a carboxylic acid can be applied.
  • Step 10 Compound (J) can be obtained by the above step 2, followed by acid treatment of compound (N).
  • Production route 6 oxygen atom
  • Step 11 In the compound (F), when R 12 is a trifluoroacetyl group, the compound (K) (R 14 represents a lower alkyl group or an aralkyl group) is obtained by converting the compound (F) into the compound of the above step 3. Can be obtained in the same procedure as
  • Step 12 Compound (L) can be obtained by the same procedure as in Step 4 described above.
  • the compound obtained in each of these steps can be isolated and purified by a conventional separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization or chromatography.
  • a conventional separation and purification means for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization or chromatography.
  • Example 3 To a solution of the product of Example 3 (4.56 g) in ethanol (50 ml) was added a 1 M sodium monohydroxide solution (18 ml), and the mixture was heated and stirred at 60 ° C. for 1 hour. The reaction solution is concentrated under reduced pressure, distilled water is added to the residue, and the mixture is neutralized with 3% hydrochloric acid. The resulting precipitate is collected by filtration, washed thoroughly with water, and dried to give the title compound (2.95) having the following properties.
  • Example 2 The compound of Example 2 (1.077 g) and isopropyl iodide were treated in the same manner as in Example 5 to obtain the title compound (0.51 g) having the following properties.
  • Example 2 The compound of Example 2 (1.077 g) and n-propyl iodide were treated in the same manner as in Example 5 to obtain the title compound (0.644 g) having the following properties and the compound of Example 12 (0.412).
  • 1 HNMR (CDC1 3, ppm) 0.86 (3H, t, J 7.3 Hz) 1.1
  • Example 2 The compound of Example 2 (2.154 g) and n-butyl iodide were treated in the same manner as in Example 5 to obtain the title compound (1.384 g) having the following properties and the compound of Example 16 (0.556).
  • Example 22 The title compound (1.754 g) and the compound of Example 22 (0.535 g) having the following properties were obtained from the compound of Example 2 (2.154 g) and n-pentyl iodide in the same manner as in Example 5.
  • Example 2 The compound (1.077) of Example 2 and benzyl bromide were treated in the same manner as in Example 5 to obtain the title compound (0.428 g) having the following properties and the compound of Example 26 (0.688).
  • Example 2 The compound of Example 2 (0.861 g) was dissolved in THF (20 ml), and formalin (10 ml), triethylamine (0.404 g), and 10% palladium charcoal were dissolved. Element (0.5 g) and catalytic reduction under a hydrogen stream of about 3 kgZcm 2 . The residue is treated as usual and purified on a silica gel column to give the title compound (0.344) having the following properties.
  • Example 32 To the compound of Example 32 (0.59 g) was added trifluoroacetic acid (8 ml), and the mixture was allowed to stand at room temperature for 2 hours. The reaction solution is concentrated, and methylene chloride (20 ml), triethylamine (0.43 g) and trifluoroacetic anhydride (0.335 g) are added to the residue, and the mixture is stirred at room temperature for 2 hours. Methylene chloride (50 ml) is added to the reaction mixture, which is washed sequentially with dilute hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over sodium sulfate, and concentrated to dryness. Diisopropyl ether is added to the concentrated residue for crystallization, and the crystals are collected by filtration to give the title compound (0.44 g) having the following properties.
  • Trifluoroacetic acid (10 ml) was added to the compound of Example 1 (0.99 g), and the mixture was allowed to stand at room temperature for 2 hours.
  • the reaction mixture was concentrated, and methylene chloride (15 ml), triethylamine (0.44 g) and trifluoroacetic anhydride (0.504 g) were added to the residue, and the mixture was stirred at room temperature for 2 hours.
  • Methylene chloride (50 ml) is added to the reaction mixture, which is washed sequentially with dilute hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over sodium sulfate, and concentrated to dryness.
  • Diisopropyl ether is added to the concentrated residue for crystallization, and the crystals are collected by filtration to give the title compound (0.63 g) having the following properties.
  • Example 1 The compound of Example 1 (0.8 lg) was replaced with 4 parts of trifluoroacetic anhydride. —The title compound (0.60) having the following properties was obtained in the same procedure as in Example 35 using nitrobenzoic acid chloride.
  • Example 1 The title compound (0.56 g) having the following properties was obtained from the compound of Example 1 (0.86 g) in the same procedure as in Example 34, except that a mixed acid of formic acid and acetic anhydride was used instead of acetic anhydride.
  • Example 1 The compound of Example 1 (0.43 g) was replaced with trifluoromethane in place of acetic anhydride. Using tansulfonyl chloride, the title compound (0.1 lg) having the following properties is obtained in the same procedure as in Example 34.
  • Triethylamine (0.142 g) and ethoxycarbonylphthalimid (0.154 g) are added to a solution of the compound of Example 2 (0.303 g) in ethanol (10 ml), and the mixture is heated under reflux. After confirming that the raw materials have disappeared, the reaction solution is concentrated, and the residue is extracted with ethyl acetate. The residue is treated as usual and purified on a silica gel column to give the title compound (0.163) having the following properties.
  • aqueous ammonia (0.3 g) is added to a solution of the active ester (0.650 g) in dioxane (20 ml), and the mixture is stirred at room temperature for 4 hours. After concentrating the reaction mixture, ethyl acetate and water are added to the residue, the organic layer is separated, washed with water, dried and concentrated to dryness under reduced pressure. Diisopropyl ether is added to the crystalline residue, which is collected by filtration and dried to obtain an amide (0.51 lg).
  • Trifluoroacetic acid (3 ml) is added to the amide (0.472) and left at room temperature for 3 hours.
  • the reaction mixture was concentrated to dryness under reduced pressure, dissolved in methylene chloride (10 ml), added with triethylamine (0.225 g) and trifluoroacetic anhydride (0.255 g), and stirred at room temperature for 24 hours.
  • the residue is treated as usual to give the title compound (0.322 g) having the following properties as crystals.
  • Example 11 The product of Example 11 (0.3 g) was treated in the same manner as in Example 53 to obtain the title hydrochloride (0.24 g) having the following properties.
  • Example 9 The product of Example 9 (0.1 Og) was treated in the same manner as in Example 53 to obtain the title hydrochloride (0.09 g) having the following properties.
  • Example 19 The title compound (0.36 g) having the following properties was obtained from the resulting compound of Example 19 (0.45 g) in the same manner as in Example 53.
  • the product hydrochloride (0.14 g) having the following properties was obtained by treating the product of Example 25 (0.32 g) in the same manner as in Example 53.
  • Example 6 The product of Example 6 (1.00 g) was treated in the same manner as in Example 53 to obtain the title hydrochloride (0.57 g) having the following properties.
  • the mice were bred with powdered feed “CE-2” (Clea Japan) five days before the start of the test. Fasting was performed from 9:00 am to 1:00 pm on the first day of the test, and then heparin was collected (50 L) from the tail vein and weighed. Blood was kept in ice, and after centrifugation (10000 rpm, 5 minutes), the glucose and triglyceride concentrations in the obtained plasma were measured using glucose C-II Test Co. and triglyceride E Test Co. (Wako Pure Chemical Industries, Ltd.).
  • a group bred on a feed not containing the compound of the present invention was used as a control group, and pioglitazone represented by the formula (0) (mixing ratio: 0.020%) was used as a positive control compound.
  • the rate of change (%) in blood glucose and blood triglyceride value in each group was calculated by the following formula. The results are as shown in Table 1.
  • SSOmgZkg The compound of the present invention, shown in Table 1 was intraperitoneally administered and observed for one week. All of them survived.
  • the compound of the present invention showed an excellent blood glucose lowering effect and blood triglyceride lowering effect even when compared with the positive control compound.
  • the compound of the present invention did not cause lactic acidosis and did not cause excessive hypoglycemia. From this, the compound of the present invention is useful not only for the treatment of diabetes but also for various complications of diabetes and as a blood lipid lowering agent. In addition, all of these compounds are less toxic and safer than the effective dose.

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

Abstract

L'invention concerne de nouveaux dérivés de l'acide 2-amino-3-phénylpropionique représentés par la formule générale (I), ainsi que leurs sels lorsqu'il sont sans risque. Ces composés sont d'excellents hypoglycémiants et ils sont très efficaces pour diminuer la concentration de lipides dans le sang. L'invention concerne également des préparations à usage médical contenant ces composés et des procédés pour les préparer. Dans la formule (I), A représente un hétérocycle azoté, W représente un oxygène ou un carbonyle, R1 représente un groupe hydroxy, ester ou imide substitué et R2 et R3 représentent chacun un hydrogène, un alkyle, un aralkyle, un alcanoyle, un benzoyle, etc.
PCT/JP1996/001380 1995-05-31 1996-05-24 Nouveaux derives de l'acide 2-amino-3-phenylpropionique WO1996038415A1 (fr)

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AU57791/96A AU5779196A (en) 1995-05-31 1996-05-24 Novel 2-amino-3-phenylpropionic acid derivatives

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JP7133460A JPH08325263A (ja) 1995-05-31 1995-05-31 新規２−アミノ−３−フェニルプロピオン酸誘導体
JP7/133460 1995-05-31

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Cited By (18)

* Cited by examiner, † Cited by third party
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WO1997031907A1 (fr) * 1996-02-28 1997-09-04 Glaxo Group Limited Derives d'acide 4-hydroxy-phenylalcanoique substitue possedant une activite agoniste envers ppar-gamma
WO1998007699A1 (fr) * 1996-08-19 1998-02-26 Japan Tobacco Inc. Derives d'acide propionique et applications de ces derives
WO1999011606A2 (fr) * 1997-08-28 1999-03-11 Pharmacia & Upjohn Company Inhibiteurs de la proteine tyrosine phosphatase
EP0925063A1 (fr) * 1996-07-01 1999-06-30 Eli Lilly And Company Composes hypoglycemiants et hypolipidemiants
WO2000008002A1 (fr) * 1998-08-07 2000-02-17 Glaxo Group Limited OXAZOLES SUBSTITUES ET DERIVES DE THIAZOLES COMME ACTIVATEURS DE ALPHA hPPAR ET DE GAMMA hPPAR
EP1026149A1 (fr) * 1997-10-02 2000-08-09 Sankyo Company Limited Derives d'acide amidocarboxylique
WO2000053583A1 (fr) * 1999-03-10 2000-09-14 Biovitrum Ab Inhibiteurs de la tyrosine phosphatase
WO2001017959A3 (fr) * 1999-09-07 2001-05-10 Smithkline Beecham Corp Antagonistes du recepteur de la vitronectine
WO2001057001A1 (fr) * 2000-02-04 2001-08-09 Glaxo Group Limited Medicament du diabete sucre non insulinodependant a base de derive d'acide oxazolethoxyphenylpropanoique
US6414002B1 (en) 1999-09-22 2002-07-02 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
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
US6716842B2 (en) 2002-04-05 2004-04-06 Warner-Lambert Company, Llc Antidiabetic agents
WO2004046119A1 (fr) * 2002-11-15 2004-06-03 Cadila Healthcare Limited Derives d'aralkyle substitues
WO2004101560A1 (fr) * 2003-05-13 2004-11-25 Synthon B.V. Procedes de fabrication de derives de thiazolidinedione et composes associes
US7375231B2 (en) * 2003-05-09 2008-05-20 Medichem S.A. Intermediate compound which is used for the preparation of pioglitazone
US7579479B2 (en) 1999-09-22 2009-08-25 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US7951793B2 (en) 2002-07-09 2011-05-31 Bristol-Myers Squibb Company Substituted heterocyclic derivatives useful as antidiabetic and antiobesity agents and method

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GB9914977D0 (en) * 1999-06-25 1999-08-25 Glaxo Group Ltd Chemical compounds
CN100436430C (zh) * 2004-05-24 2008-11-26 北京摩力克科技有限公司 作为hPPARα和hPPARγ激动剂的烷酰基取代的酪氨酸衍生物
JPWO2008081537A1 (ja) * 2006-12-28 2010-04-30 株式会社ヒューマンセルシステムズ Ｌａｔ１阻害活性を有する芳香族アミノ酸誘導体、それを含有するｌａｔ１阻害活性剤及びその製造方法

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EP0655461A1 (fr) * 1993-11-16 1995-05-31 Ciba-Geigy Ag Dérivés d'amino acide cycliques ayant une activité inhibante d'ACE et NEP
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WO1989010355A1 (fr) * 1988-04-05 1989-11-02 Abbott Laboratories Derives de tryptophan utilises comme antagonistes cck
WO1991000725A2 (fr) * 1989-07-07 1991-01-24 Abbott Laboratories Antagonistes cck analogues d'acides amines
WO1994029285A1 (fr) * 1993-06-05 1994-12-22 Smithkline Beecham P.L.C. Derives heterocycliques et leur utilisation dans des produits pharmaceutiques
EP0655461A1 (fr) * 1993-11-16 1995-05-31 Ciba-Geigy Ag Dérivés d'amino acide cycliques ayant une activité inhibante d'ACE et NEP
JPH07196592A (ja) * 1993-12-03 1995-08-01 F Hoffmann La Roche Ag 新規な酢酸誘導体

Cited By (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997031907A1 (fr) * 1996-02-28 1997-09-04 Glaxo Group Limited Derives d'acide 4-hydroxy-phenylalcanoique substitue possedant une activite agoniste envers ppar-gamma
US6294580B1 (en) 1996-02-28 2001-09-25 Glaxo Wellcome Inc. Substituted 4-hydroxy-phenylalcanoic acid derivatives with agonist activity to PPAR-gamma
EP0888317A1 (fr) * 1996-02-28 1999-01-07 Glaxo Group Limited Derives d'acide 4-hydroxy-phenylalcanoique substitue possedant une activite agoniste envers ppar-gamma
EP0925063A4 (fr) * 1996-07-01 2000-12-27 Lilly Co Eli Composes hypoglycemiants et hypolipidemiants
EP0925063A1 (fr) * 1996-07-01 1999-06-30 Eli Lilly And Company Composes hypoglycemiants et hypolipidemiants
US6353027B1 (en) 1996-07-01 2002-03-05 Eli Lilly And Company Hypoglycemic and hypolipidemic compounds
US6194446B1 (en) 1996-07-01 2001-02-27 Eli Lilly And Company Hypoglycemic and hypolipidemic compounds
US6541497B1 (en) 1996-07-01 2003-04-01 Eli Lilly And Company Hypoglycemic and hypolipidemic compounds
WO1998007699A1 (fr) * 1996-08-19 1998-02-26 Japan Tobacco Inc. Derives d'acide propionique et applications de ces derives
US6204277B1 (en) 1996-08-19 2001-03-20 Japan Tobacco Inc. Propionic acid derivatives and applications thereof
WO1999011606A3 (fr) * 1997-08-28 1999-07-08 Upjohn Co Inhibiteurs de la proteine tyrosine phosphatase
WO1999011606A2 (fr) * 1997-08-28 1999-03-11 Pharmacia & Upjohn Company Inhibiteurs de la proteine tyrosine phosphatase
US6410585B1 (en) 1997-08-28 2002-06-25 Scott D. Larsen Inhibitors of protein tyrosine phosphatase
US6353023B1 (en) 1997-08-28 2002-03-05 Pharmacia & Upjohn Company Inhibitors of protein tyrosine phosphatase
EP1026149A4 (fr) * 1997-10-02 2004-12-01 Sankyo Co Derives d'acide amidocarboxylique
EP1026149A1 (fr) * 1997-10-02 2000-08-09 Sankyo Company Limited Derives d'acide amidocarboxylique
US6498174B1 (en) 1998-08-07 2002-12-24 Smithkline Beecham Corporation Substituted oxazoles and thiazoles derivatives as hPPARγ and hPPARα activators
WO2000008002A1 (fr) * 1998-08-07 2000-02-17 Glaxo Group Limited OXAZOLES SUBSTITUES ET DERIVES DE THIAZOLES COMME ACTIVATEURS DE ALPHA hPPAR ET DE GAMMA hPPAR
WO2000053583A1 (fr) * 1999-03-10 2000-09-14 Biovitrum Ab Inhibiteurs de la tyrosine phosphatase
JP2003508516A (ja) * 1999-09-07 2003-03-04 スミスクライン・ビーチャム・コーポレイション ビトロネクチン受容体アンタゴニスト
WO2001017959A3 (fr) * 1999-09-07 2001-05-10 Smithkline Beecham Corp Antagonistes du recepteur de la vitronectine
JP4685307B2 (ja) * 1999-09-07 2011-05-18 グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー ビトロネクチン受容体アンタゴニスト
US6653314B2 (en) 1999-09-22 2003-11-25 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US7579479B2 (en) 1999-09-22 2009-08-25 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US6727271B2 (en) 1999-09-22 2004-04-27 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US7241780B2 (en) 1999-09-22 2007-07-10 Bristols-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US6414002B1 (en) 1999-09-22 2002-07-02 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US7053106B2 (en) 1999-09-22 2006-05-30 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US7084162B2 (en) 1999-09-22 2006-08-01 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US6919358B2 (en) 1999-09-22 2005-07-19 Bristol-Meyers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
WO2001057001A1 (fr) * 2000-02-04 2001-08-09 Glaxo Group Limited Medicament du diabete sucre non insulinodependant a base de derive d'acide oxazolethoxyphenylpropanoique
WO2003059895A1 (fr) * 2002-01-17 2003-07-24 Toaeiyo Ltd. Derives d'acide halogenobenzylaminopropionique
US6933309B2 (en) 2002-01-17 2005-08-23 Toaeiyo Ltd. Halogenobenzyl aminopropionic acid derivatives
CN1293042C (zh) * 2002-02-07 2007-01-03 远藤仁 芳香族氨基酸衍生物及其药物组合物
JPWO2003066574A1 (ja) * 2002-02-07 2005-05-26 仁 遠藤 芳香族アミノ酸誘導体及び医薬組成物
US7345068B2 (en) 2002-02-07 2008-03-18 Hitoshi Endou Aromatic amino acid derivatives and medicinal compositions
WO2003066574A1 (fr) * 2002-02-07 2003-08-14 Hitoshi Endo Derives d'amino-acides aromatiques et compositions medicamenteuses
JP4705756B2 (ja) * 2002-02-07 2011-06-22 仁 遠藤 芳香族アミノ酸誘導体及び医薬組成物
US6716842B2 (en) 2002-04-05 2004-04-06 Warner-Lambert Company, Llc Antidiabetic agents
US7951793B2 (en) 2002-07-09 2011-05-31 Bristol-Myers Squibb Company Substituted heterocyclic derivatives useful as antidiabetic and antiobesity agents and method
WO2004046119A1 (fr) * 2002-11-15 2004-06-03 Cadila Healthcare Limited Derives d'aralkyle substitues
US7375231B2 (en) * 2003-05-09 2008-05-20 Medichem S.A. Intermediate compound which is used for the preparation of pioglitazone
WO2004101560A1 (fr) * 2003-05-13 2004-11-25 Synthon B.V. Procedes de fabrication de derives de thiazolidinedione et composes associes

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AU5779196A (en) 1996-12-18

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