WO2007142253A1 - Dérivé de 2-cyanopyrrolidine - Google Patents

Dérivé de 2-cyanopyrrolidine Download PDF

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Publication number
WO2007142253A1
WO2007142253A1 PCT/JP2007/061418 JP2007061418W WO2007142253A1 WO 2007142253 A1 WO2007142253 A1 WO 2007142253A1 JP 2007061418 W JP2007061418 W JP 2007061418W WO 2007142253 A1 WO2007142253 A1 WO 2007142253A1
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compound
dppiv
disease
symptom
medicament
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PCT/JP2007/061418
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English (en)
Japanese (ja)
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Yuichi Koga
Saburo Kawanami
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Mitsubishi Tanabe Pharma Corporation
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Publication of WO2007142253A1 publication Critical patent/WO2007142253A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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 novel 2-cyanpyrrolidine derivative having an excellent inhibitory action on dipeptidyl peptidase IV (DPPIV), a method for producing the same, a use thereof, and a pharmaceutical composition containing the 2-cyanopyrolidine derivative. It relates to things.
  • DPPIV Dipeptidyl peptidase IV specifically hydrolyzes a dipeptide of Xaa-Pro or Xaa-Ala (Xaa can be any amino acid) from the N-terminus of the polypeptide chain It is a kind of serine protease.
  • Non-Patent Documents 1 to 4 There are various reports on the role of DPPIV (also referred to as CD26) in vivo and the relationship with diseases (Non-Patent Documents 1 to 4).
  • GLP-1 (glucagon-like peptide 1) is a peptide hormone that has a function of increasing insulin secretion mainly in a glucose-dependent manner, and is secreted mainly after lower small intestinal phagocytosis and acts in the spleen. There are also reports suggesting that GLP-1 has an antifeedant effect. DPPIV hydrolyzes and inactivates GLP-1 to produce a peptide that acts as an antagonist of GLP-1.
  • a substance that inhibits the enzyme activity of DPPIV enhances the insulin secretion response to oral glucose load by enhancing the action of endogenous GLP-1 through its inhibitory action. Improve impaired glucose tolerance).
  • DPPIV inhibitors are considered useful for the prevention and treatment of diabetes (particularly type 2 diabetes).
  • Other diseases induced or exacerbated by impaired glucose tolerance hyperglycemia (e.g., postprandial hyperglycemia), hyperinsulinemia, diabetic complications (e.g., renal disorder, neuropathy), abnormal lipid metabolism, Prevention of obesity, etc.] 'An effect in treatment is expected.
  • DPPIV (CD26) present on the surface of T cells, etc. Expression is induced by cell activation and plays an important role in T cell activation and proliferation. It is known that when this DPPIV (CD26) is blocked with an antibody or an inhibitor, the activity of T cells is suppressed. He is also interested in the relationship between this enzyme and the pathology in disorders of collagen metabolism and immune disorders. For example, DPPIV (CD26) positive rate of peripheral blood T cells is increased in rheumatic patients, and high DPPIV activity is detected in urine of nephritic patients. In addition, DPPIV (CD26) is thought to play an important role in the entry of HIV into lymph cells.
  • substances that inhibit DPPIV can be used for autoimmune diseases (eg, arthritis, rheumatoid arthritis), osteoporosis, acquired immune deficiency syndrome (AIDS), and rejection of transplanted organ tissues. Even a prophylactic or therapeutic effect is expected.
  • Patent Documents 7 to: LO describes N- (substituted glycyl) -2 cyanopyrrolidine derivatives having a bicyclooctane structure.
  • Non-Patent Document 1 Hoist et al., Diabetes, 47th, 1663-1670, 1998
  • Non-Patent Document 2 Augustyns et al., Current Medicinal Chemistry, Vol. 6, pp. 311-327, 19
  • Non-Patent Document 3 Meester et al., Immunol. Today, 20th, 367-375, 1999
  • Non-patent Document 4 Fleicher et al., Immunol. Today, 15th, 180-184, 1994
  • Patent Document 1 US6,011,155
  • Patent Document 2 WO 1998/19998
  • Patent Document 3 WO2000 / 34241
  • Patent Document 4 WO2001 / 96295
  • Patent Document 5 WO2002 / 30890
  • Patent Document 6 WO2002 / 30891
  • Patent Document 7 WO2005 / 075421
  • Patent Document 8 WO2005 / 077900
  • Patent Document 9 WO2005 / 082847 Disclosure of the invention
  • the present invention provides a novel compound having an excellent inhibitory action on dipeptidyl peptidase IV (DPPIV), a method for producing the same, a use thereof, and a pharmaceutical composition containing the compound. .
  • DPPIV dipeptidyl peptidase IV
  • the present inventors have found a novel 2-cyanpyrrolidine derivative having an excellent inhibitory action on DPPIV, and have completed the present invention. That is, the present invention relates to the general formula [I]:
  • the present invention also relates to a method for producing a 2-cyanopyrrolidine derivative represented by the above general formula [I] (hereinafter referred to as compound [I]) or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound [I] or a pharmacologically acceptable salt thereof as an active ingredient.
  • the present invention also relates to a therapeutic or prophylactic method comprising administering to a patient an effective amount of the compound [I] or a pharmacologically acceptable salt thereof.
  • the present invention also relates to the use of the compound [I] or a pharmaceutically acceptable salt thereof for the manufacture of a medicament.
  • the present invention also relates to the use of the aforementioned compound [I] or a pharmaceutically acceptable salt thereof for inhibiting the activity of DPPIV.
  • the compound [I] of the present invention or a pharmaceutically acceptable salt thereof is an excellent inhibitor against DPPIV. Has harmful effects.
  • the pharmaceutical composition containing the target compound of the present invention as an active ingredient is useful as an active ingredient in a medicament for treating or preventing a disease or symptom (such as diabetes) that is expected to be improved by inhibiting DPPIV.
  • examples of the lower alkyl group, the lower alkylsulfonyl group, and the lower alkoxy group include linear or branched ones having 1 to 6 carbon atoms (C), Charcoal
  • examples of the lower alkanoyl group include those having 2 to 7 carbon atoms (C).
  • Examples include those having 2 to 5 carbon atoms (C).
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • a preferred example of the “optionally substituted piperazine-1-yl” represented by R is “substituent substituted at the 4-position nitrogen atom”.
  • piperazin 1 yl is “substituent substituted at the 4-position nitrogen atom”.
  • Substituted with lower alkoxy may be lower alkoxy carbo
  • a preferred compound group includes compounds wherein R is morpholino.
  • Specific examples of the compound of the present invention include free forms of each compound shown in the examples and the pharmacologically acceptable salts thereof shown in the Examples of the specification.
  • the compound of the present invention may be in a free form or a pharmacologically acceptable salt form! ⁇ .
  • Pharmacological Examples of acceptable salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate or hydrobromide, acetate, fumarate, oxalate, kenate, and methanesulfonic acid. Examples include salts, organic acid salts such as benzenesulfonate, p-toluenesulfonate, and maleate.
  • the compound of the present invention includes an internal salt or an adduct thereof, a solvate or a hydrate thereof, and the like.
  • the compound [I] of the present invention or a pharmacologically acceptable salt thereof has an excellent inhibitory action on the enzyme activity of DPPIV. Its action is also highly selective for DPPIV.
  • the compound [I] of the present invention or a pharmacologically acceptable salt thereof includes various serine proteases other than DPPIV (for example, plasmin, thrombin, prolyl endopeptidase, trypsin, dipeptidyl peptidase II). Compared with the inhibition against dipeptidyl peptidase 8 etc.), it shows a strong selective inhibitory activity especially against DPPIV.
  • various serine proteases other than DPPIV for example, plasmin, thrombin, prolyl endopeptidase, trypsin, dipeptidyl peptidase II.
  • the compound [I] of the present invention or a pharmacologically acceptable salt thereof exhibits excellent sustained action when administered in vivo.
  • the compound [I] of the present invention or a pharmacologically acceptable salt thereof has various pharmacological effects through its DPPIV inhibition action, such as improving the insulin secretion response to oral glucose load. Demonstrate.
  • the compound [I] of the present invention or a pharmacologically acceptable salt thereof, or a pharmaceutical composition containing this as an active ingredient can be used for the inhibition of DPPIV.
  • the compound or a pharmacologically acceptable salt thereof or the pharmaceutical composition can be used for the treatment or prevention of diseases or symptoms that are expected to be improved by inhibiting DPPIV.
  • diabetes eg. type 1 diabetes, type 2 diabetes
  • hyperglycemia eg, postprandial hyperglycemia
  • hyperinsulinemia e.g., diabetic complications (eg, Nephropathy, neuropathy, etc.)
  • diabetes e.g. type 1 diabetes, type 2 diabetes
  • hyperglycemia e.g, postprandial hyperglycemia
  • hyperinsulinemia e.g., diabetic complications
  • diabetic complications eg, Nephropathy, neuropathy, etc.
  • obesity overeating
  • lipid metabolism abnormalities e.g. hyperlipidemia such as hypertriglyceridemia
  • autoimmune diseases e.g. arthritis, rheumatoid arthritis, etc.
  • osteoporosis e.g. arthritis, rheumatoid arthritis, etc.
  • osteoporosis e.g. arthritis, rheumatoid arthritis, etc.
  • osteoporosis e.g. arthritis, rheum
  • the compound [I] of the present invention or a pharmacologically acceptable salt thereof, or a pharmaceutical composition containing this as an active ingredient is particularly for the treatment or prevention of diabetes (especially type 2 diabetes). Useful.
  • a therapeutic or prophylactic method in which an effective amount of the compound [I] of the present invention or a pharmacologically acceptable salt thereof is administered to a patient or the like is also applied to the above purpose and is included in the present invention.
  • the use of the compound [I] of the present invention or a pharmacologically acceptable salt thereof for the manufacture of a medicament is also applied to the above purpose and is included in the present invention.
  • DPPIV inhibitory action of the compound of the present invention and the pharmacological effects are known methods or equivalent methods (WO98 / 19998; WO00 / 34241; H. lst et al., Diabetes, 47, 1663-1670, 1998; Augustyns et al., Current Medicinal Chemistry, 6, 311-327, 1999; Meester et al., Immunol. ⁇ , 367-375, 1999; Fleicher et al., Immunol. Today, ⁇ 15, 180-184, 1994).
  • the compound [I] of the present invention or a pharmacologically acceptable salt thereof is used as an active ingredient for a pharmaceutical use, it is used together with an inert carrier according to the administration method, and a conventional pharmaceutical preparation (tablet) , Granules, capsules, powders, solutions, suspensions, emulsions, injections, drops, etc.).
  • a conventional pharmaceutical preparation tablettes, Granules, capsules, powders, solutions, suspensions, emulsions, injections, drops, etc.
  • strong carriers include binders (eg, gum arabic, gelatin, sorbit, polybulurpyrrolidone, etc.), excipients (lactose, sugar, corn starch, sorbit, etc.), lubricants that are acceptable in general medicine.
  • disintegrants potato starch, etc.
  • an injection or infusion it can be formulated using distilled water for injection, physiological saline, aqueous glucose solution, or the like.
  • the method of administration when the compound [I] of the present invention or a pharmacologically acceptable salt thereof is used for pharmaceutical use is not particularly limited, and a general oral or parenteral method (intravenous) Intramuscular, subcutaneous, transdermal, nasal, other transmucosal, enteral, etc.) can be applied.
  • the dose is expressed according to the potency characteristics of the compound as the active ingredient. May be appropriately set within the range of the effective amount sufficient for the above.
  • the dose varies depending on the method of administration and the age, weight and condition of the administration subject (patient, etc.), but a general dose, for example, an appropriate dose within the range of 0.001 to 300 mgZkg per day. Set to quantity.
  • examples of DPPIV include DPPIV of human or non-human warm-blooded animals.
  • the target of application of the medicine, the pharmaceutical composition, and the treatment or prevention method includes humans or warm-blooded animals other than humans (particularly preferably humans).
  • the target compound [I] of the present invention can be produced by the following method, but is not limited thereto.
  • the desired compound [I] can be produced by reacting with the compound represented by the formula (1) or a salt thereof to produce a pharmacologically acceptable salt if desired.
  • an inorganic acid salt such as hydrochloride or sulfate
  • an organic acid salt such as methanesulfonate or p-toluenesulfonate
  • a conventional reactive residue such as a halogen atom, a lower alkylsulfonyloxy group, and an arylsulfonyloxy group can be preferably used. Atoms are preferred.
  • reaction of compound [2] with compound [3] or a salt thereof can be carried out in the presence or absence of a deoxidizer, in a suitable solvent or without solvent.
  • Examples of the deoxidizer include inorganic bases (eg, alkali metal hydrides such as sodium hydride, alkali metals such as sodium carbonate and potassium carbonate, and alkali metals such as sodium methoxide).
  • inorganic bases eg, alkali metal hydrides such as sodium hydride, alkali metals such as sodium carbonate and potassium carbonate, and alkali metals such as sodium methoxide.
  • organic bases eg, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, dimethylamine, dimethyl
  • Aminopyridine etc. can be preferably used.
  • This reaction suitably proceeds at 0 to 120 ° C, particularly at room temperature to 80 ° C.
  • the solvent may be any solvent that does not adversely influence the reaction.
  • acetonitrile, ethanol, isopropyl alcohol, propyl alcohol, acetone, N, N-dimethylacetamide, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, ether, Dioxane, ethyl acetate, toluene, methylene chloride, dichloroethane, chloroform, or a mixed solvent thereof can be appropriately used.
  • the target compound [I] produced by the above production method is further converted into another target compound [I] by the method described in the examples and the Z or known methods or combinations thereof described later in the specification. can do.
  • the starting compound in the above method can be produced by a known method and a method described in Z or a reference example described later in the specification or a combination thereof.
  • the raw material compound [2] is described in Villhauer et al. (Villhauer et al., Journal of Medicinal Chemistry, 2003, Vol. 46, pp. 2774-2789), International Patent Publication W098Zl9998, W
  • the compound [3a] which is R force morpholino can be produced as follows.
  • Q 1 represents an amino group-protecting group.
  • a force capable of suitably using a conventional reactive residue such as a halogen atom, a lower alkylsulfonyloxy group, an arylsulfo-loxy group, etc.
  • a rogen atom is preferred.
  • the salts of the compounds [11], [13] and [3a] include, for example, inorganic acid salts such as hydrochloride and sulfate, or organic acids such as methanesulfonate and p-toluenesulfonate. Salt can be used.
  • reaction of the compound [11] or a salt thereof and the compound [12a] can be carried out in a suitable solvent or without a solvent in the presence or absence of a deoxidizer.
  • Examples of the deoxidizer include inorganic bases (for example, alkali metal hydrides such as sodium hydride, alkali metals such as sodium carbonate and potassium carbonate, alkali metal alkoxides such as sodium methoxide, sodium hydroxide, water Hydroxyl-alkali metal such as potassium carbonate, etc.) or organic base (for example, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, dimethylamine, dimethylaminopyridine, etc.) are preferably used. be able to.
  • inorganic bases for example, alkali metal hydrides such as sodium hydride, alkali metals such as sodium carbonate and potassium carbonate, alkali metal alkoxides such as sodium methoxide, sodium hydroxide, water Hydroxyl-alkali metal such as potassium carbonate, etc.
  • organic base for example, triethylamine, diisopropylethylamine, N-methylmorpholine,
  • This reaction suitably proceeds at 0 to 120 ° C, particularly at room temperature to 80 ° C.
  • the solvent may be any solvent that does not adversely affect the reaction.
  • Removal of the amino group protecting group (Q 1 ) of compound [13] or a salt thereof can be carried out by a conventional method.
  • a conventional method for example, an acid using trifluoroacetic acid, hydrochloric acid or the like in a suitable solvent or without solvent.
  • the treatment can be carried out by treatment with a thiol alkali metal salt or the like, or catalytic reduction.
  • compound [3b] which is piperazine 1-yl optionally substituted at the 4-position nitrogen atom in R force among compound [3] can be produced as follows.
  • Q 1 represents an amino group-protecting group.
  • R 1 represents a piperazine 1yl which may be substituted at the 4-position nitrogen atom.
  • amino protecting group represented by Q 2 is preferable to use those which differ from the Q 1,.
  • the amino-protecting group represented by Q 2 includes a conventional amino-protecting group such as 2-trobenzenesulfol group, t-butoxycarbonyl group, benzyloxycarbonyl group, etc. Can also be suitably used.
  • a force capable of suitably using a conventional reactive residue such as a halogen atom, a lower alkyl sulfo-oxy group, an aryl sulfo-oxy group, etc.
  • a no and a rogen atom are preferred.
  • Examples of the salts of the compounds [14], [15] and [3b] include inorganic acid salts such as hydrochloride and sulfate, or organic acid salts such as methanesulfonate and p-toluenesulfonate. Etc. can be used.
  • reaction of compound [11] or a salt thereof and compound [12b] can be carried out in the same manner as the reaction of compound [11] or a salt thereof and compound [12a].
  • the compound [I] of the present invention or the starting material compound produced as described above is isolated and purified as it is or as a salt thereof.
  • the salt can be produced by subjecting it to a commonly used salt formation treatment. Isolation and purification can be performed by applying ordinary chemical operations such as extraction, concentration, crystallization, filtration, recrystallization, and various types of chromatography.
  • optical isomers such as racemates, optically active isomers, diastereomers and the like may exist alone or as a mixture.
  • Stereosterically pure isomers can be derived by using stereosterically pure raw materials or by separating optical isomers by a general racemic resolution method. .
  • the mixture of diastereomers can be separated by a conventional method such as fractional crystallization or chromatography.
  • Table 1 and the reference example table at the end show chemical structural formulas and physical property values of the compounds of the examples and reference examples.
  • MS'APCI (mZz) represents a mass spectrometry value.
  • rphj represents a phenyl group
  • Ns represents a 2-trobenzenesulfol group.
  • the black mouth form solution was extracted with a 5% aqueous citrate solution adjusted to pH 4.5 with potassium carbonate, and the aqueous layer was washed three times with black mouth form. Potassium carbonate was added to the aqueous layer to adjust to PH 8.5, and the mixture was extracted 3 times with black mouth form. The resulting residue was triturated in jetyl ether and collected by filtration to give 166 mg of (S) 2 cyanone 1 [2— (4 morpholine-4-ylbicyclo [2.2.2] otato 1 ylamino) acetyl] pyrrolidine. Obtained as a crystalline powder.
  • the buffer solution 1501 and the sample solution 251 were added to an enzyme solution 25 ⁇ 1 containing human serum 25 ⁇ 1 or recombinant human DPPIV (0.89 ⁇ g / mL), and incubated at 37 ° C. for 10 minutes. After that, 50 ⁇ l of glycyl-L proline p-trore-lidotosylate [Gly-Pro-pNA'Tos manufactured by Peptide Research Institute] solution was added as a substrate (final substrate concentration: 0.234 mM) to initiate the reaction. The reaction was carried out by incubating at 37 ° C for 20 minutes, and during that time, the change in absorbance at 405 nm was monitored to measure DPPIV activity. 50% inhibitory concentration (IC) as DPPIV inhibitory activity
  • the reaction mixture is allowed to cool to room temperature, water is added to the reaction mixture, and the organic layer is washed successively with saturated aqueous sodium hydrogen carbonate, water, 2 mol ZL hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. Left.
  • the obtained residue was dissolved in 10 mL of methanol, and after adding an ImolZL sodium hydroxide aqueous solution, the mixture was heated and stirred at 50 ° C. for 2 hours.
  • reaction solution is allowed to cool to room temperature, methanol is distilled off under reduced pressure, the aqueous layer is washed 4 times with jetyl ether, the aqueous layer is acidified with concentrated hydrochloric acid under ice cooling, and the precipitated solid is collected by filtration and washed with water.
  • 4.15 g of 4 monobenzyloxycarbonylaminobicyclo [2.2.2] octane 1 carboxylic acid was obtained as a colorless powder.
  • reaction mixture was allowed to cool to room temperature, washed 3 times with jetyl ether, the aqueous layer was basified with 2 mol / L aqueous sodium hydroxide and extracted with black mouth form.
  • the extract is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure (4 aminobicyclo [2. 2. 2] otato 1 yl) rubamic acid benzyl ester (table below, reference example 1. 0 1) 2.12 g was obtained as a pale yellow oil.
  • reaction solution was allowed to cool to room temperature, and ethyl acetate and water were added to the reaction solution and stirred to dissolve insolubles. After separation of the aqueous layer, the organic layer was washed 5 times with water and once with saturated brine, and then dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography (solvent: 0 ⁇ 5% chloroform methanol) and the resulting solid was triturated in jetyl ether to give ⁇ 4 [4-— (2-trobenzene Sulfo-l) piperazine-1-yl] bicyclo [2. 2. 2] otato 1-yl ⁇ rubamic acid benzyl ester 2.77 g was obtained as a crystalline powder.
  • the aqueous layer was basified with 2 mol ZL sodium hydroxide aqueous solution and extracted three times with black mouth form. The combined extracts were washed with saturated brine and concentrated under reduced pressure. The obtained residue was diluted again with black mouth form, washed with saturated brine, dried over anhydrous magnesium sulfate and anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • a novel 2-cyanopyrrolidine derivative having an excellent inhibitory action on dipeptidyl peptidase IV (DPPIV), a method for producing the same, a use thereof, and a medicament containing the 2-cyanopyrrolidine derivative A composition or the like can be obtained.
  • the compound [I] of the present invention or a pharmacologically acceptable salt thereof has an excellent inhibitory action on DPPIV.
  • a pharmaceutical composition containing the target compound of the present invention as an active ingredient is DPPIV. It is useful as an active ingredient in medicines for the treatment or prevention of diseases or symptoms (such as diabetes) that are expected to improve due to inhibition of the drug.

Abstract

La présente invention concerne une dérivé de 2-cyanopyrrolidine représenté par la formule générale [I] ci-dessous ou un sel pharmacologiquement acceptable de celui-ci. L'invention concerne également un procédé de production de dérivé de 2-cyanopyrrolidine, d'une composition pharmaceutique contenant ce composé sous forme d'ingrédient actif, l'utilisation du composé pour l'inhibition de l'activité de DPPIV et similaire. [I] [Dans la formule, R représente (1) un morpholino, ou (2) un pipérazin-1-yle éventuellement substitué.]
PCT/JP2007/061418 2006-06-06 2007-06-06 Dérivé de 2-cyanopyrrolidine WO2007142253A1 (fr)

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JP2006157309A JP2009190971A (ja) 2006-06-06 2006-06-06 ２−シアノピロリジン誘導体
JP2006-157309 2006-06-06

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WO2010016584A1 (fr) * 2008-08-07 2010-02-11 杏林製薬株式会社 Procédé de fabrication d'un dérivé de bicyclo[2.2.2]octylamine
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
JP2012514630A (ja) * 2009-01-09 2012-06-28 オーキッド リサーチ ラボラトリーズ リミテッド ジペプチジルペプチダーゼｉｖ阻害剤
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2014064215A1 (fr) 2012-10-24 2014-05-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de la kinase tpl2 pour prévenir ou traiter le diabète et favoriser la survie de cellules β
WO2016151018A1 (fr) 2015-03-24 2016-09-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthode et composition pharmaceutique destinées à être utilisées dans le traitement du diabète
WO2019008506A1 (fr) * 2017-07-03 2019-01-10 Glaxosmithkline Intellectual Property Development Limited Dérivés de n-(3-(2-(4-chlorophénoxy)acétamido)bicyclo[1.1.1]pentan-1-yl)-2-cyclobutane-1-carboxamide et composés apparentés en tant qu'inhibiteurs atf4 pour le traitement du cancer et d'autres maladies
US11939320B2 (en) 2017-11-02 2024-03-26 Abbvie Inc. Modulators of the integrated stress pathway

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JP2004002368A (ja) * 2002-04-04 2004-01-08 Tanabe Seiyaku Co Ltd 医薬組成物
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WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2010016584A1 (fr) * 2008-08-07 2010-02-11 杏林製薬株式会社 Procédé de fabrication d'un dérivé de bicyclo[2.2.2]octylamine
CN102119139A (zh) * 2008-08-07 2011-07-06 杏林制药株式会社 二环[2.2.2]辛胺衍生物的制造方法
JP5476305B2 (ja) * 2008-08-07 2014-04-23 杏林製薬株式会社 ビシクロ［２．２．２］オクチルアミン誘導体の製造方法
US8476470B2 (en) 2008-08-07 2013-07-02 Kyorin Pharmaceutical Co., Ltd. Process for production of bicyclo[2.2.2]octylamine derivative
JP2012514630A (ja) * 2009-01-09 2012-06-28 オーキッド リサーチ ラボラトリーズ リミテッド ジペプチジルペプチダーゼｉｖ阻害剤
JP2015091889A (ja) * 2009-01-09 2015-05-14 オーキッド ケミカルズ アンド ファーマシューティカルズ リミテッド ジペプチジルペプチダーゼｉｖ阻害剤
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2014064215A1 (fr) 2012-10-24 2014-05-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de la kinase tpl2 pour prévenir ou traiter le diabète et favoriser la survie de cellules β
WO2016151018A1 (fr) 2015-03-24 2016-09-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthode et composition pharmaceutique destinées à être utilisées dans le traitement du diabète
WO2019008506A1 (fr) * 2017-07-03 2019-01-10 Glaxosmithkline Intellectual Property Development Limited Dérivés de n-(3-(2-(4-chlorophénoxy)acétamido)bicyclo[1.1.1]pentan-1-yl)-2-cyclobutane-1-carboxamide et composés apparentés en tant qu'inhibiteurs atf4 pour le traitement du cancer et d'autres maladies
CN111164069A (zh) * 2017-07-03 2020-05-15 葛兰素史密斯克莱知识产权发展有限公司 作为atf4抑制剂用于治疗癌症和其它疾病的n-(3-(2-(4-氯苯氧基)乙酰胺基)双环[1.1.1]戊-1-基)-2-环丁烷-1-甲酰胺衍生物以及相关化合物
US11939320B2 (en) 2017-11-02 2024-03-26 Abbvie Inc. Modulators of the integrated stress pathway

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