WO2004007446A1 - Nouveau derive de l'azetidine ou ses sels - Google Patents

Nouveau derive de l'azetidine ou ses sels Download PDF

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Publication number
WO2004007446A1
WO2004007446A1 PCT/JP2003/008727 JP0308727W WO2004007446A1 WO 2004007446 A1 WO2004007446 A1 WO 2004007446A1 JP 0308727 W JP0308727 W JP 0308727W WO 2004007446 A1 WO2004007446 A1 WO 2004007446A1
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Prior art keywords
optionally substituted
compound according
substituted
compound
amino
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PCT/JP2003/008727
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English (en)
Japanese (ja)
Inventor
Masahiko Hayakawa
Kenji Negoro
Takayuki Suzuki
Tatsuya Maruyama
Ryosuke Nakano
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Yamanouchi Pharmaceutical Co., Ltd.
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Priority to AU2003248259A priority Critical patent/AU2003248259A1/en
Priority to JP2004521166A priority patent/JPWO2004007446A1/ja
Publication of WO2004007446A1 publication Critical patent/WO2004007446A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a medicament, particularly a novel azetidine derivative or a salt thereof, which is useful as a dipeptidyl peptidase IV (hereinafter, referred to as "DPP-IV") inhibitor, and a medicament containing the compound as an active ingredient.
  • DPP-IV dipeptidyl peptidase IV
  • DPP-IV is a sequence containing proline, hydroxyproline or alanine at the second position from the N-terminus (H-Xaa-Pro, H-Xaa-Hyp, or H-Xaa-Ala [Xaa represents an arbitrary amino acid]) )
  • H-Xaa-Pro H-Xaa-Hyp
  • H-Xaa-Ala H-Xaa represents an arbitrary amino acid]
  • Is a serine protease that recognizes and cleaves DPP-IV is widely distributed in vivo and is known to be present in tissues such as kidney, liver, and salivary glands, as well as in body fluids such as serum, urine, and saliva. Although its physiological role has not been completely elucidated, it is thought that cleavage of various bioactive peptides is involved in the regulation of biological functions (Non-Patent Document 1). Above all, attention has been focused on controlling the activity of a hormone called incretin, which is involved in suppressing post
  • Incretin is a hormone that is secreted from the intestinal tract after oral intake of nutrients and acts on Teng3 cells to regulate blood sugar by enhancing insulin secretion. It is known that incretin action is attenuated in patients with type 2 diabetes.
  • Non-Patent Document 2 this reduced action is considered to be one of the onset factors of diabetes. This suggests that postprandial hyperglycemia in diabetic patients is enhanced by enhancing incretin action. Is thought to be able to improve.
  • GLP-1 glucagon-like peptide
  • DPP-IV glucagon-like peptide
  • DPP-IV inhibitors may be a safe therapeutic agent without the side effects such as hypoglycemia seen in existing insulin secreting agents. Be expected.
  • Non-Patent Documents 5 and 6 it has been reported that administration of a DPP-IV inhibitor lowers the blood glucose level of type 2 diabetic patients and diabetic animals.
  • DPP-IV is involved in the control of various physiological phenomena in vivo, and diabetic patients generally have diseases other than diabetes in many cases.
  • Pamphlet discloses a compound represented by the general formula (A), which prevents or treats diabetes and impairs it. It states that it is expected to be effective in the prevention and treatment of other diseases induced or exacerbated by glucose tolerance, hyperinsulinemia, and complications of diabetes.
  • Patent Document 6 discloses a compound represented by the general formula (B), which significantly suppresses an increase in blood glucose level in an oral glucose tolerance test in Zucker Fatty rats. Is described.
  • Patent Document 7 discloses compounds represented by general formulas (C), (D), (E), (F), (G), and (H). It is described as being useful for treating diseases such as diabetes, obesity and the like.
  • Non-Patent Document 2 Nauck M. A., "Diabetologia”, 1986, Vol. 29, p. 46-52
  • Non-Patent Document 5 Ahren B., "Diabetes Care", 2002, Vol. 25, p.869-875
  • Patent Document 1 International Publication No. WO 98/19998 Pamphlet
  • Patent Document 2 International Publication No. WO 01/96295 pamphlet
  • Patent Document 3 International Publication No. WO 00/34241 Pamphlet
  • Patent Document 4 International Publication No. WO 01/55105 Pamphlet
  • Patent Document 5 International Publication No. WO 02/30890 pamphlet
  • Patent Document 6 International Publication No. WO 02/38541 Pamphlet
  • Patent Document ⁇ International Publication No. WO 03/002553 pamphlet Disclosure of the invention
  • the present inventors have further developed a compound having a DPP-IV inhibitory action that is expected to be effective against insulin-dependent diabetes (type 1 diabetes), non-insulin-dependent diabetes (type 2 diabetes), insulin resistance disease, and obesity. After intensive studies, they have found that the novel azetidine derivative of the present invention or a salt thereof has an excellent inhibitory effect on DPP-IV, and completed the present invention.
  • the present invention provides an azetidine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof, which is useful as a DPP-IV inhibitor.
  • R 1 a bridged hydrocarbon ring which may be substituted, a bridged non-aromatic hetero ring which may be substituted, a non-aromatic hetero ring which may be substituted, and which may be substituted Cycloalkyl, or optionally substituted lower alkyl.
  • R 2 lower alkyl optionally substituted with -H or -OH, or cycloalkyl optionally substituted with -OH.
  • both R 1 and R 2 do not represent -H.
  • R 1 R 2 may represent a cyclic amino which may be substituted together with an adjacent nitrogen atom and carbon atom.
  • R 3 , R 4 same or different, -H, halogen, cyano, or ethel.
  • R 1 in the above general formula (I) is a bridged hydrocarbon ring, a bridged non-aromatic hetero ring, a non-aromatic hetero ring, or a lower alkyl, each of which may be substituted.
  • R 2 in the above general formula (I) is preferably -H.
  • R 3 in the above general formula (I) is preferably -H.
  • R 4 in the above general formula (I) is preferably -H, fluoro, or cyano; more preferably -H.
  • the azetidine derivative of the present invention has an amino acid derivative at the 1-position of the azetidine ring, has a chemical structural feature at the point of having a cyano group at the 2-position of the azetidine ring, and has a DPP-IV inhibitory action. It has pharmacological characteristics.
  • the compound of the present invention has an azetidine ring which is a 4-membered heterocyclic ring, whereas the compounds described in Patent Documents 1 to 7 differ in structure such as having a 5-membered heterocyclic ring (thiazolidine or pyrrolidine).
  • the compound of the present invention has good oral activity, but its activity is rapidly eliminated in the body as compared with a compound having a conventional DPP-IV inhibitory action. Has features.
  • R 1 is a bridged hydrocarbon ring which may be substituted, a bridged non-aromatic hetero ring which may be substituted, or a group which may be substituted.
  • R ′ is a bridged hydrocarbon ring which may be substituted, a ring may be substituted, a bridged non-aromatic heterocyclic ring, a substituted or unsubstituted heterocyclic ring.
  • R 2 is -H and R 3 is -H, which is an aromatic ring or an optionally substituted lower alkyl;
  • R 1 is a substituted or unsubstituted bridged hydrocarbon ring, substituted or unsubstituted, bridged non-aromatic heterocyclic ring, substituted or unsubstituted or non-aromatic heterocyclic ring. Ring, Or a lower alkyl which may be substituted, wherein R 2 is —H, R 3 is —H, and R 4 is —H, fluoro, or cyano;
  • R 1 is a bridged hydrocarbon ring which may be substituted, may be substituted, may be a bridged non-aromatic heterocyclic ring, may be substituted, or may be a non-aromatic heterocyclic ring.
  • another preferred embodiment is an R 1 -bridging bridged hydrocarbon ring which may be substituted, preferably an optionally substituted adamantane-1-yl
  • Optionally substituted lower alkyl preferably substituted with one or more groups selected from the group consisting of halogen, trifluoromethyl, cyano and nitro, aromatic heterocyclic ring
  • a non-aromatic heterocyclic ring preferably an optionally substituted 8-azabicyclo [3.2.1] octane-3-yl, wherein R 2 is -H, R 3 is -H, Lists compounds where R 4 is —H, fluoro or cyano be able to.
  • R 1 is -H
  • R 2 is lower alkyl optionally substituted with -OH or cycloalkyl optionally substituted with -OH
  • R 3 is- A compound wherein H is and R 4 is --H; preferably, a compound wherein R 1 is --H, R 2 is lower alkyl, R 3 is --H and R 4 is --H be able to.
  • a pharmaceutical composition comprising any one of the above compounds as an active ingredient; in particular, insulin-dependent diabetes (type 1 diabetes), non-insulin-dependent diabetes (type 2 diabetes), insulin resistance disease, A pharmaceutical composition comprising the above compound or an active ingredient as a therapeutic or / and prophylactic agent for obesity; or a pharmaceutical composition comprising the above compound or an active compound as a DPP-IV inhibitor as an active ingredient. Things are provided.
  • lower alkyl means a C 1-6 linear or branched alkyl, and specifically, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl , neopentyl, hexyl and the like to, preferably, Mechinore a C M alkyl, Echiru, propyl, isopropyl, butyl, Isobuchi Le, sec- butyl, tert- butyl.
  • Cycloalkyl means a C 3-8 carbocyclic monovalent group, and these rings may partially have an unsaturated bond. Specific examples include cyclopropyl, cyclopentinole, cyclopenteninole, cyclohexinole, cyclohexeninole, cyclooctyl, and cyclooctenyl.
  • “Bridged hydrocarbon ring” means a monovalent group of a bridged hydrocarbon ring, and specifically includes, for example, adamantyl, bornyl, norbornyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1 Octyl, bicyclo [2.2.1] heptyl and bicyclo [3.1.1] heptyl, preferably adamantyl and bicyclo [2.2.2] octyl, and particularly preferably adamantyl.
  • Non-aromatic hetero ring means a monovalent non-aromatic hetero ring containing at least one hetero atom in the ring selected from the group consisting of nitrogen, oxygen and sulfur.
  • azetidur, pyrrolidinyl, piberidiel, azepinyl, tetrahydrofurfuryl, tetrahydrodrobilanyl, tetrahydrothrothiolyl, tetrahydrothiopyranyl, imidazolidinyl, pyrazolidinyl, morpholinyl, and thiomorpholyl are preferred.
  • Rahydropyriel particularly preferably piperidinyl.
  • Cyclic amino refers to a monovalent group of a non-aromatic heterocyclic ring containing at least one nitrogen atom in the ring, and these rings may be condensed with a benzene ring.
  • azetidur, pyrrolidinyl, piberidinyl, azepinyl, imidazolidinyl, pyrazolidinyl, morpholyl, thiomorpholyl, dihydroindolyl, dihydrindazolyl, tetrahydroquinolyl, tetrahydroquinolyl, and benzoxoxilone are preferred. It is.
  • “Bridged non-aromatic heterocycle” means a monovalent group of a crosslinked non-aromatic heterocycle, specifically, for example, quinuclidinyl, 7-azabicyclo [2.2.1] heptyl, 8-azabicyclo [3.2.1] octyl, 8-oxabicyclo [3.2.1] octyl, 8-thiabisic mouth [3.2.1] octyl, preferably quinuclidinyl, 8-azabisic mouth [3.2.1] Otatyl, particularly preferably 8-azabisik mouth [3.2.1] octyl.
  • halogen examples include a funoleo mouth, a black mouth, bromo, and a pseudo, and a fluoro and a black mouth are preferred.
  • the permissible substituent in the term “optionally substituted” may be any substituent that is generally used as a substituent for each group, and one substituent for each group It may have a substituent as described above.
  • R 1 in the general formula (I) may have a substituent on a carbon atom and / or a nitrogen atom, including the carbon atom of R 1 directly bonded to an NH group.
  • R 1 “optionally substituted bridged hydrocarbon ring”, “optionally substituted bridged non-aromatic hetero ring”, “optionally substituted non-aromatic hetero ring”, “ (Optionally substituted cycloalkyl), (optionally substituted lower alkyl), (optionally substituted adamantyl small aryl), (optionally substituted 8-azabicyclo [3.2.
  • Substituents X, -OH, -0-substituents which are allowed on carbon atoms in 1] octane-3-inole "and" optionally substituted piperidin-4-yl " group X, halogen, -CO- substituent group X, -COO- substituent group X, -S0 2 - substituted with a substituent selected from substituent group X, 1 or 2 substituents group X Carbamoyl, one or two substituent groups X may be substituted with a substituent selected from X Bets can be; preferably - OH, methyl, human Dorokishimechiru, phenylene Honoré, a phenoxy.
  • the substituent group X may be each substituted with one or more groups selected from the group consisting of -OH, -0-lower alkyl, phenoxy, halogen, trifluoromethyl, cyano and nitro.
  • aryl or aromatic Indicates a terrorist ring.
  • “Ariru” means a monovalent group of monocyclic to tricyclic aromatic ring of C 6. 14 of carbon atoms, specifically, for example, phenyl, naphthyl, preferably phenyl is there.
  • aromatic heterocycle means a monovalent or tricyclic monovalent group having at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur.
  • substituents that are permissible in the “optionally substituted cyclic amino” of R 1 and R 2 include substituent group X, —OH, —0-substituent group X, halogen, and —CO-substituent group X , -COO- substituent group X, -S0 2 - substituent group X, one or two optionally substituted with a substituent selected from substituent group X force Rubamoiru, one or two substituents Group X And amino which may be substituted with a substituent selected from the group consisting of the following; preferably -OH, one or two substituents X may be substituted with a substituent selected from the group X. Amino.
  • the compound of the present invention includes a mixture of various stereoisomers such as tautomers and optical isomers, and an isolated one.
  • the compound of the present invention may form an acid addition salt.
  • a salt with a base may be formed depending on the type of the substituent.
  • Specific examples of such salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, and succinic acid.
  • Acid addition salts with organic amino acids such as fumaric acid, maleic acid, lactic acid, lingoic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, and P-toluenesulfonic acid, and acidic amino acids such as aspartic acid and glutamic acid;
  • organic amino acids such as fumaric acid, maleic acid, lactic acid, lingoic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, and P-toluenesulfonic acid
  • acidic amino acids such as aspartic acid and glutamic acid
  • examples include inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; organic bases such as methylamine, ethylamine, and ethanolanol; salts with basic amino acids such as lysine and ortin; and ammonium salts.
  • the compounds of the present invention also include hydrates, various pharmaceutically acceptable solvates, polymorphs, and the like. It should be understood that the present invention is not limited to the compounds described in the Examples below, but includes all derivatives represented by the general formula (I) and pharmaceutically acceptable salts thereof. Is what you do.
  • the compounds of the present invention also include all compounds that are metabolized in vivo and converted into the above general formula (I) or compounds converted into salts thereof, so-called prodrugs.
  • Examples of the group that forms a prodrug of the compound of the present invention include those described in Prog. Med. 5: 2157-2161 (1985), and Hirokawa Shoten 1990, “Development of Pharmaceuticals,” Vol. 7, Molecular Design 163-198. Examples include the groups described on the page. (Manufacturing method)
  • the compounds of the present invention and their pharmaceutically acceptable salts can be produced by applying various known synthetic methods by utilizing the characteristics based on the types of substituents in the basic skeleton.
  • it is effective in production technology to replace the functional group with an appropriate protecting group at the stage of the raw material or intermediate, that is, a group that can be easily converted to the functional group. It may be.
  • the desired compound can be obtained by removing the protecting group as necessary.
  • a functional group include a hydroxyl group, a carboxyl group, and an amino group.
  • Examples of such a protecting group include "Protective Groups in Organic Synthesis J" by Greene and Wuts.
  • the protecting groups described in the third edition can be mentioned, and these may be appropriately used depending on the reaction conditions.
  • R 1 R 2 and RR 4 have the same definitions as above, and X means a leaving group such as a halogen or a sulfonyloxy group. The same applies hereinafter.
  • This reaction is a reaction to obtain the present compound by reacting the Amin compound represented relative to compound (II) in the general formula ⁇ ⁇ ⁇ 2.
  • This reaction can be carried out without a solvent or with a solvent.
  • the solvent used include aromatic hydrocarbons such as toluene and xylene, ketones such as methylethylketone and acetone, dioxane, and tetrahydroquinone.
  • Ethers such as drofuran and diglyme; alcohols such as methanol, ethanol and isopropanol; Examples thereof include methylene chloride, acetonitrile, dimethylformamide, dimethylsulfoxide, water, and a mixed solvent thereof, which is appropriately selected according to the type of the reaction substrate and the reaction conditions.
  • the addition of a base is useful for the smooth progress of the reaction.
  • the base include alkali carbonates such as sodium carbonate and potassium carbonate, alkali hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, and organic amines such as triethylamine, diisopropylethylamine, and pyridine.
  • P means a protecting group such as a tert-butoxycarbyl group, a benzyloxycarbonyl group, or a 0-nitrobenzenebenzenesulfonyl group
  • This reaction is a reaction for removing the protecting group from the compound (III) without or in a solvent to obtain the compound of the present invention.
  • Examples of the protecting group to be used and a method for removing the same include the methods described in “Protective Groups in Organic Synthesis, 3rd Edition”, “Basics and Experiments of Peptide Synthesis” published by Maruzen.
  • X 1 represents a leaving group such as a halogen or a hydroxyl group. The same applies hereinafter.
  • compound (IV) is reacted with compound (V) to perform an acylation reaction.
  • This is a reaction for obtaining a compound (II) by obtaining an intermediate (VI) by subjecting it to a dehydration reaction.
  • the acylation reaction can be carried out by a conventional method.
  • X 1 is a hydroxyl group, ⁇ , ⁇ '-dicyclohexylcarbodiimide, 1-ethyl-3- (3, -dimethylaminopropyl) carbodiimide
  • the reaction can be carried out in the presence of a condensing agent such as 1,1,1-carboerdiimidazole and diphenylphosphoryl azide.
  • X 1 is a halogen atom may solvent
  • a method for the presence of a base reactions apply.
  • the base include alkali carbonates such as sodium carbonate and potassium carbonate, sodium hydrogen carbonate, hydrogen carbonate such as potassium hydrogen carbonate, and organic compounds such as triethylamine, diisopropylethylamine, and pyridine. Examples include amines.
  • the dehydration reaction of the intermediate (VI) can also be carried out according to a conventional method of dehydration of an amide group, and examples of the dehydrating agent include trifluoroacetic anhydride, oxychlorine thyrine, and thionyl chloride.
  • the use of a base as an additive or a solvent may cause the dehydration reaction to proceed rapidly, and the base used in the acylation reaction can be used as the base.
  • the compound (VII) is allowed to react with the compound (VII) for the acylation reaction.
  • a compound (III) by subjecting the compound (VIII) to a dehydration reaction to obtain the compound (III), and a compound (III) by performing an acylation reaction of the compound (IX) with the compound (VII).
  • some compounds contained in the compound of the present invention are generally employed by those skilled in the art, such as alkylation, acylation, oxidation, reduction, hydrolysis, etc., from the compound (I) obtained as described above. It can also be manufactured by arbitrarily combining the steps that can be performed.
  • the compound of the present invention thus produced is isolated or purified as it is, or subjected to a salt-forming treatment by a known method, and as a salt thereof. Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography.
  • optical isomers exist. These optical isomers can be separated by a conventional method such as fractional crystallization by recrystallization with an appropriate salt or column chromatography. Further, the optically active compound can also be produced by using an appropriate optically active raw material.
  • the compound of the present invention has a DPP-IV inhibitory action. That is, it acts on the [knee] 3 cells to enhance insulin secretion, thereby inhibiting blood sugar-regulating hormones, particularly GLP-1, from degrading.
  • the compound of the present invention is useful for the treatment and prevention or prevention of insulin-dependent diabetes (type 1 diabetes), particularly insulin-independent diabetes (type 2 diabetes), insulin resistance disease, and obesity based on these actions. It is.
  • “Treatment” is a concept that also encompasses prevention.
  • the procedure for measuring DPP-IV activity is as follows. The reaction was performed using a 96-well plate. A reaction solution containing various concentrations of test compounds in an aqueous solution consisting of 25 mM Tris-HCl, 140 mM sodium chloride, 10 mM chloride, 1% serum albumin, and 0.01 mM Gly-Pro-AMC (BACHEM) ( To 95 ⁇ 1 / ⁇ ), 5 ⁇ of plasma collected from a healthy adult volunteer was added and incubated at room temperature for 20 minutes. After the reaction, the fluorescence intensity (Exitation 355 nm I Emission 460 nm) of each well was measured (ARVO, PerkinElmer). The measurement results were calculated by averaging the values of 3-well under the same conditions. The inhibition rate for the solvent-added group was calculated, and the IC 50 value was determined by logistic analysis. The results are shown in Table 1.
  • the compound of the present invention exhibited a DPP-IV inhibitory effect.
  • test compound dissolved in distilled water was orally administered at a dose of 10 mg / kg to 5 male ICR mice (Japan SLC) in each group, and distilled water alone was orally administered to the control group.
  • Blood was collected from the orbital venous plexus at 0.5, 2 and 4 hours after administration of the compound. The collected blood was immediately centrifuged, the plasma was collected, and the DPP-IV activity in the plasma was measured.
  • the procedure for measuring DPP-IV activity in plasma is as follows. The reaction was performed using a 96-well plate. 25 mM Tris-HCl, 140 mM sodium chloride, 10 mM potassium salt, 1% serum albumin, 0.01 mM Gly-Pro-AMC (BACHEM) 5 ⁇ l of the collected plasma was added to an aqueous solution (95 ⁇ l / well), incubated at room temperature for 20 minutes, and the fluorescence intensity (Exitation 355 nm I Emission 460 nm) was measured (ARVO, PerkinElmer).
  • the DPP-IV activity in the plasma of mice to which the test compound was administered was calculated based on the fluorescence intensity of the wells to which the plasma collected from the control group was added as 100%, and the difference between the activity and the control group was defined as the inhibition rate of the test compound. .
  • the results are shown in Table 2.
  • Comparative Compound 1 is the compound of Example 36 described in Patent Document 6 above
  • Comparative Compound 2 is the compound of Example 33 described in Patent Document 6 above
  • Comparative Compound 3 Is the compound of Example 1 described in Patent Document 3 above
  • Comparative Compound 4 is the compound of No. 18 described in International Publication WO 95/15309
  • Comparative Compound 5 is the compound of International Publication WO FIG. 14 is the compound of Example 5 described in 02/14271.
  • the structures of Comparative Compounds 1 to 5 are shown below. Comparative compound 3 Comparative compound 4
  • the compound of the present invention had good oral activity.
  • the compound of the present invention showed a rapid disappearance of the activity, while the comparative compound maintained a high activity even 4 hours after administration, indicating that the compound of the present invention was compared with a known DPP-IV inhibitor.
  • DPP-IV is involved in the control of various physiological phenomena in vivo, and diabetic patients generally have diseases other than diabetes in many cases. Therefore, depending on the comorbidities of each patient, it may be desirable to inhibit DPP-IV for a short period of time before and after a meal, rather than to inhibit DPP-IV for a long time, in the treatment of diabetes.
  • DPP-IV inhibitors that show rapid elimination of DPP-IV inhibitory activity, such as the compounds of the present invention, are extremely useful.
  • compositions containing the compound of the present invention or one or more pharmaceutically acceptable salts thereof as an active ingredient can be used as carriers, excipients, and other commonly used pharmaceutical preparations. Tablets, powders, fine granules, granules, capsules, pills, liquids, injections, suppositories, ointments, patches, etc. are prepared using additives and administered orally or parenterally. You.
  • the clinical dose of the compound of the present invention to humans is appropriately determined in consideration of the patient's symptoms, weight, age, sex, etc., and is usually 0.1 to 500 mg orally per adult and 0.01 to parenteral per day. It is preferably 100 mg or less, which is administered once or in several divided doses. Since the dose varies under various conditions, a dose smaller than the above dose range may be sufficient.
  • the one or more active compounds comprise at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polybutylpyrrolidone, It is mixed with magnesium metasilicate aluminate.
  • inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polybutylpyrrolidone, It is mixed with magnesium metasilicate aluminate.
  • composition may be formulated in a conventional manner with additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, stabilizers such as lactose, glutamic acid or A solubilizing agent such as aspartic acid or a solubilizing agent.
  • Tablets or pills may be coated with sugar or a film of a gastric or enteric compound such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylsenorelose phthalate, if necessary.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents such as purified water Including ethyl alcohol.
  • the composition may contain, in addition to the inert diluent, solubilisers, solubilizing agents, wetting agents, auxiliary agents such as suspending agents, sweetening agents, flavoring agents, flavoring agents, and preservatives.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • a diluent for aqueous solutions and suspensions for example, injection And distilled water and saline.
  • diluents for water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethyl alcohol, and polysorbate 80 (trade name).
  • compositions may further comprise additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizing agents (eg, ratatose), solubilizing agents or solubilizing agents.
  • additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizing agents (eg, ratatose), solubilizing agents or solubilizing agents.
  • the starting compounds used in the examples include novel substances, and a method for producing such starting compounds from known products will be described as a reference example.
  • reaction mixture was concentrated under reduced pressure, and 5.24 ml of trifluoroacetic anhydride was added dropwise to a 20 ml solution of the obtained residue in ice-cold form under ice-cooling.
  • the reaction mixture was warmed to room temperature and stirred for 30 minutes.
  • a saturated aqueous solution of sodium hydrogen carbonate extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate.
  • the drying agent was removed, and the solvent was distilled off under reduced pressure to obtain 0.95 g of (S) -1- (chloroacetyl) azetidine-2-carbonitrile. This was used for the next reaction without further purification.
  • Boc tert-butyloxycarbonyl, Me: methyl.
  • Salt Salt (HC1: hydrochloride, 2HC1: dihydrochloride, not described: free).
  • Example 2 As in Example 1, Examples 2 and 3 shown in Table 4 were produced using the corresponding raw materials.
  • Table 5 shows NMR data of some examples.

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  • Child & Adolescent Psychology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention porte sur un composé de formule (I) présentant une excellente activité d'inhibiteur de la dipeptidyl peptidase IV, et sur un agent thérapeutique présentant ladite activité et hautement efficace pour traiter le diabète insulino-dépendant (de type 1), le diabète non insulino-dépendant (de type 2), les maladies résistant à l'insuline et l'obésité.
PCT/JP2003/008727 2002-07-10 2003-07-09 Nouveau derive de l'azetidine ou ses sels WO2004007446A1 (fr)

Priority Applications (2)

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AU2003248259A AU2003248259A1 (en) 2002-07-10 2003-07-09 Novel azetidine derivative or salt thereof
JP2004521166A JPWO2004007446A1 (ja) 2002-07-10 2003-07-09 新規なアゼチジン誘導体又はその塩

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JP2002-201829 2002-07-10
JP2002201829 2002-07-10

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Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004071454A2 (fr) * 2003-02-13 2004-08-26 Guilford Pharmaceuticals Inc. Composes d'azetidine substitues servant d'inhibiteurs de dipeptidyl peptidase iv
WO2004098591A2 (fr) 2003-05-05 2004-11-18 Probiodrug Ag Inhibiteurs de glutaminyl-cyclase
WO2007120702A2 (fr) 2006-04-11 2007-10-25 Arena Pharmaceuticals, Inc. Agonistes du récepteur de gpr119 dans des procédés d'augmentation de la masse osseuse et de traitement de l'ostéoporose et autres états se caractérisant par une masse osseuse faible, et thérapie de combinaison associée
US7291618B2 (en) 2004-05-12 2007-11-06 Pfizer Inc Therapeutic compounds
JP2008507541A (ja) * 2004-07-23 2008-03-13 ロイヤルティ，スーザン・マリー ペプチダーゼ阻害剤
WO2008055945A1 (fr) 2006-11-09 2008-05-15 Probiodrug Ag Dérivés 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one utiles en tant qu' inhibiteurs de la glutaminyl-cyclase dans le traitement des ulcères, du cancer et d'autres maladies
WO2008065141A1 (fr) 2006-11-30 2008-06-05 Probiodrug Ag Nouveaux inhibiteurs de glutaminylcyclase
US7514571B2 (en) 2004-02-27 2009-04-07 Kyorin Pharmaceutical Co., Ltd. Bicyclo derivative
US7560569B2 (en) 2004-02-18 2009-07-14 Kyorin Pharmaceutical Co., Ltd Bicycloamide derivative
EP2116235A1 (fr) 2005-01-10 2009-11-11 Arena Pharmaceuticals, Inc. Thérapie combinée pour le traitement des diabètes et des conditions associées, et pour le traitement des conditions améliorées par l'augmentation du niveau de sang GLP-1
US7754757B2 (en) 2004-02-05 2010-07-13 Kyorin Pharmaceutical Co., Ltd. Bicycloester derivative
WO2011005929A1 (fr) 2009-07-09 2011-01-13 Arena Pharmaceuticals, Inc. Dérivé de pipéridine et son utilisation pour le traitement du diabète et de l'obésité
WO2011029920A1 (fr) 2009-09-11 2011-03-17 Probiodrug Ag Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase
JP2011509289A (ja) * 2008-01-10 2011-03-24 サン・ファーマ・アドバンスド・リサーチ・カンパニー・リミテッド 新規なアシルシアノピロリジン誘導体
US7915427B2 (en) 2006-03-08 2011-03-29 Kyorin Pharmaceuticals Co., Ltd. Process for producing aminoacetyl pyrrolidine carbonitrile derivative and intermediate for production thereof
US7960384B2 (en) 2006-03-28 2011-06-14 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
WO2011107530A2 (fr) 2010-03-03 2011-09-09 Probiodrug Ag Nouveaux inhibiteurs
WO2011110613A1 (fr) 2010-03-10 2011-09-15 Probiodrug Ag Inhibiteurs hétérocycliques de la glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011127051A1 (fr) 2010-04-06 2011-10-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur de gpr119 et traitement de troubles associés
WO2011131748A2 (fr) 2010-04-21 2011-10-27 Probiodrug Ag Nouveaux inhibiteurs
US8143427B2 (en) 2007-03-22 2012-03-27 Kyorin Pharmaceutical Co., Ltd. Method for producing aminoacetylpyrrolidinecarbonitrile derivative
WO2012040279A1 (fr) 2010-09-22 2012-03-29 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement des troubles qui lui sont liés
WO2012123563A1 (fr) 2011-03-16 2012-09-20 Probiodrug Ag Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase
WO2012135570A1 (fr) 2011-04-01 2012-10-04 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles qui lui sont associés
WO2012145603A1 (fr) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012145604A1 (fr) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012145361A1 (fr) 2011-04-19 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012170702A1 (fr) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés à celui-ci
WO2013055910A1 (fr) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés
US8476470B2 (en) 2008-08-07 2013-07-02 Kyorin Pharmaceutical Co., Ltd. Process for production of bicyclo[2.2.2]octylamine derivative
WO2014074668A1 (fr) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulateurs de gpr119 et traitement de troubles associés à ceux-ci
US8883714B2 (en) 2008-04-07 2014-11-11 Arena Pharmaceuticals, Inc. Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues
US8906901B2 (en) 2005-09-14 2014-12-09 Takeda Pharmaceutical Company Limited Administration of dipeptidyl peptidase inhibitors
EP2865670A1 (fr) 2007-04-18 2015-04-29 Probiodrug AG Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase
JP2017530955A (ja) * 2014-09-03 2017-10-19 ザ ユニバーシティ オブ バーミンガム 頭蓋内圧上昇の治療
EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase
US10555929B2 (en) 2015-03-09 2020-02-11 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US11253508B2 (en) 2017-04-03 2022-02-22 Coherus Biosciences, Inc. PPARy agonist for treatment of progressive supranuclear palsy

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WO2000034241A1 (fr) * 1998-12-10 2000-06-15 Novartis Ag 2-cyanopyrrolidines n-substitues
WO2001062266A2 (fr) * 2000-02-25 2001-08-30 Novo Nordisk A/S Inhibition de la degenerescence des cellules beta
WO2001096295A2 (fr) * 2000-06-13 2001-12-20 Novartis Ag Composes organiques
WO2002030890A1 (fr) * 2000-10-06 2002-04-18 Tanabe Seiyaku Co., Ltd. Composes azotes a noyau a cinq elements
WO2002038541A1 (fr) * 2000-11-10 2002-05-16 Taisho Pharmaceutical Co., Ltd. Derives de cyanopyrrolidine
WO2003057144A2 (fr) * 2001-12-26 2003-07-17 Guilford Pharmaceuticals Changement d'inhibiteurs de la dipeptidyl peptidase iv
WO2003057666A2 (fr) * 2001-12-26 2003-07-17 Guilford Pharmaceuticals Inhibiteurs de la dipeptidyl peptidase iv

Cited By (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004071454A2 (fr) * 2003-02-13 2004-08-26 Guilford Pharmaceuticals Inc. Composes d'azetidine substitues servant d'inhibiteurs de dipeptidyl peptidase iv
WO2004071454A3 (fr) * 2003-02-13 2004-11-04 Guilford Pharm Inc Composes d'azetidine substitues servant d'inhibiteurs de dipeptidyl peptidase iv
WO2004098591A2 (fr) 2003-05-05 2004-11-18 Probiodrug Ag Inhibiteurs de glutaminyl-cyclase
US8053465B2 (en) 2004-02-05 2011-11-08 Kyorin Pharmaceutical Co., Ltd. Bicycloester derivative
US7754757B2 (en) 2004-02-05 2010-07-13 Kyorin Pharmaceutical Co., Ltd. Bicycloester derivative
US7560569B2 (en) 2004-02-18 2009-07-14 Kyorin Pharmaceutical Co., Ltd Bicycloamide derivative
US7514571B2 (en) 2004-02-27 2009-04-07 Kyorin Pharmaceutical Co., Ltd. Bicyclo derivative
US7291618B2 (en) 2004-05-12 2007-11-06 Pfizer Inc Therapeutic compounds
US7465732B2 (en) 2004-05-12 2008-12-16 Pfizer Inc (2S,4S)-4-(piperazin-1-yl)pyrrolidine-2-methanone derivatives
US7842707B2 (en) 2004-07-23 2010-11-30 Nuada, Llc Peptidase inhibitors
JP2008507541A (ja) * 2004-07-23 2008-03-13 ロイヤルティ，スーザン・マリー ペプチダーゼ阻害剤
EP2116235A1 (fr) 2005-01-10 2009-11-11 Arena Pharmaceuticals, Inc. Thérapie combinée pour le traitement des diabètes et des conditions associées, et pour le traitement des conditions améliorées par l'augmentation du niveau de sang GLP-1
US8906901B2 (en) 2005-09-14 2014-12-09 Takeda Pharmaceutical Company Limited Administration of dipeptidyl peptidase inhibitors
US7915427B2 (en) 2006-03-08 2011-03-29 Kyorin Pharmaceuticals Co., Ltd. Process for producing aminoacetyl pyrrolidine carbonitrile derivative and intermediate for production thereof
US7960384B2 (en) 2006-03-28 2011-06-14 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
EP2253311A2 (fr) 2006-04-11 2010-11-24 Arena Pharmaceuticals, Inc. Utilisation d'agonistes du récepteur de GPR119 dans des procédés d'augmentation de la masse osseuse et de traitement de l'ostéoporose, et thérapie de combinaison associée
WO2007120702A2 (fr) 2006-04-11 2007-10-25 Arena Pharmaceuticals, Inc. Agonistes du récepteur de gpr119 dans des procédés d'augmentation de la masse osseuse et de traitement de l'ostéoporose et autres états se caractérisant par une masse osseuse faible, et thérapie de combinaison associée
WO2008055945A1 (fr) 2006-11-09 2008-05-15 Probiodrug Ag Dérivés 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one utiles en tant qu' inhibiteurs de la glutaminyl-cyclase dans le traitement des ulcères, du cancer et d'autres maladies
WO2008065141A1 (fr) 2006-11-30 2008-06-05 Probiodrug Ag Nouveaux inhibiteurs de glutaminylcyclase
US8143427B2 (en) 2007-03-22 2012-03-27 Kyorin Pharmaceutical Co., Ltd. Method for producing aminoacetylpyrrolidinecarbonitrile derivative
EP2865670A1 (fr) 2007-04-18 2015-04-29 Probiodrug AG Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase
JP2011509289A (ja) * 2008-01-10 2011-03-24 サン・ファーマ・アドバンスド・リサーチ・カンパニー・リミテッド 新規なアシルシアノピロリジン誘導体
US8883714B2 (en) 2008-04-07 2014-11-11 Arena Pharmaceuticals, Inc. Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues
US8476470B2 (en) 2008-08-07 2013-07-02 Kyorin Pharmaceutical Co., Ltd. Process for production of bicyclo[2.2.2]octylamine derivative
WO2011005929A1 (fr) 2009-07-09 2011-01-13 Arena Pharmaceuticals, Inc. Dérivé de pipéridine et son utilisation pour le traitement du diabète et de l'obésité
WO2011029920A1 (fr) 2009-09-11 2011-03-17 Probiodrug Ag Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase
WO2011107530A2 (fr) 2010-03-03 2011-09-09 Probiodrug Ag Nouveaux inhibiteurs
WO2011110613A1 (fr) 2010-03-10 2011-09-15 Probiodrug Ag Inhibiteurs hétérocycliques de la glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011127051A1 (fr) 2010-04-06 2011-10-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur de gpr119 et traitement de troubles associés
WO2011131748A2 (fr) 2010-04-21 2011-10-27 Probiodrug Ag Nouveaux inhibiteurs
WO2012040279A1 (fr) 2010-09-22 2012-03-29 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement des troubles qui lui sont liés
EP3323818A1 (fr) 2010-09-22 2018-05-23 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés
WO2012123563A1 (fr) 2011-03-16 2012-09-20 Probiodrug Ag Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase
WO2012135570A1 (fr) 2011-04-01 2012-10-04 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles qui lui sont associés
WO2012145361A1 (fr) 2011-04-19 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012145604A1 (fr) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012145603A1 (fr) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012170702A1 (fr) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés à celui-ci
WO2013055910A1 (fr) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés
WO2014074668A1 (fr) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulateurs de gpr119 et traitement de troubles associés à ceux-ci
JP2017530955A (ja) * 2014-09-03 2017-10-19 ザ ユニバーシティ オブ バーミンガム 頭蓋内圧上昇の治療
US10835579B2 (en) 2014-09-03 2020-11-17 Invex Therapeutics Ltd. Elevated intracranial pressure treatment
US11738067B2 (en) 2014-09-03 2023-08-29 Invex Therapeutics Ltd. Elevated intracranial pressure treatment
US10555929B2 (en) 2015-03-09 2020-02-11 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US10772865B2 (en) 2015-03-09 2020-09-15 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US11400072B2 (en) 2015-03-09 2022-08-02 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US11253508B2 (en) 2017-04-03 2022-02-22 Coherus Biosciences, Inc. PPARy agonist for treatment of progressive supranuclear palsy
EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase

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