WO2011085643A1 - 吡啶并环衍生物 - Google Patents

吡啶并环衍生物 Download PDF

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WO2011085643A1
WO2011085643A1 PCT/CN2011/000068 CN2011000068W WO2011085643A1 WO 2011085643 A1 WO2011085643 A1 WO 2011085643A1 CN 2011000068 W CN2011000068 W CN 2011000068W WO 2011085643 A1 WO2011085643 A1 WO 2011085643A1
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group
methyl
oxo
amino
atom
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PCT/CN2011/000068
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French (fr)
Chinese (zh)
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WO2011085643A8 (zh
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黄振华
张艳
宋运涛
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山东轩竹医药科技有限公司
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Priority to EP11732633.0A priority Critical patent/EP2524917B1/en
Priority to JP2012548326A priority patent/JP5719382B2/ja
Priority to US13/522,304 priority patent/US8680089B2/en
Priority to CN201180006084.4A priority patent/CN102741251B/zh
Publication of WO2011085643A1 publication Critical patent/WO2011085643A1/zh
Publication of WO2011085643A8 publication Critical patent/WO2011085643A8/zh

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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of medical technology, and in particular to a pyridocyclic derivative, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvent compound thereof, a process for preparing the same, a pharmaceutical composition containing the same, and the like Use in the preparation of a medicament for the treatment and/or prevention of non-insulin dependent diabetes, hyperglycemia, hyperlipidemia, insulin resistance. Background technique
  • Diabetes is a systemic chronic metabolic disease caused by uncontrolled blood glucose levels above normal levels. They are basically divided into four categories, including: type I (insulin dependent), type II (non-insulin dependent), other types, and gestational diabetes. Type I and Type II diabetes are primary diabetes and are the two most common forms, caused by the interaction of genetic and environmental factors. The cause of diabetes is complex, but in the final analysis is due to absolute or relative lack of insulin, or insulin resistance. It is characterized by a decrease in the metabolism of carbohydrates, proteins, fats, electrolytes and water due to the absolute or relative deficiency of insulin and the reduced sensitivity of target cells to insulin.
  • Diabetes has become the third after tumor and cardiovascular disease. A chronic disease that seriously threatens human health.
  • more than 40 million people have been diagnosed with diabetes in China, and they are increasing at a rate of 1 million per year.
  • type I diabetes accounted for 10%
  • type II diabetes accounted for 90%. Diabetes has become a public health issue of increasing concern.
  • the treatment of type I diabetes is mainly insulin preparations and their substitutes; for the treatment of type II diabetes, the main drugs are oral hypoglycemic agents, which are roughly classified into sulfonylureas, biguanides, traditional Chinese medicine preparations, other hypoglycemic agents and auxiliary Medication. Although it has a good effect, the drug can not maintain long-term efficacy in reducing hyperglycemia, and can not effectively alleviate the disease. Many antidiabetic drugs initially control blood sugar well, but they do not maintain efficacy with the continuation of medication.
  • Dipeptidase-IV is widely present in the body and is a cell surface protein involved in various biological functions. It can degrade various active enzymes in the body, such as glucagon-like peptide-l (glucagons-like Peptide 1, GLP-1) Glucose-dependent insulinotropic polypeptide (GIP), neuropeptides, substance P and chemokines. and The lack of GLP-K GIP is a major cause of type 2 diabetes (ie, non-insulin dependent diabetes). DPP-IV inhibitors are a new generation of drugs for the treatment of diabetes.
  • GLP-1 and GIP inhibit the activity of GLP-1 and GIP by inhibiting DPP-IV activity, promotes insulin secretion, lowers blood sugar, and does not cause side effects such as hypoglycemia, weight gain, and edema. Its hypoglycemic effect does not continue to exert hypoglycemic effect after reaching normal blood sugar level, and it will not cause hypoglycemia, and it can repair ⁇ -cell function for a long time.
  • Sitagliptin was the first DPP-IV inhibitor to be marketed and quickly became a blockbuster for Merck after its launch in 2006.
  • the FDA approved the listing of saxagliptin developed by AstraZeneca and Bristol-Myers Squibb. Taketa's SYR-322 is superior to sitagliptin and saxagliptin in activity and selectivity and is currently in pre-registration.
  • BI-1356 linagliptin
  • PF-734200 gosogliptin
  • PHX1149 dutogliptin
  • the inventors have provided a new class of DPP-IV inhibitors through extensive experimental research.
  • the present invention provides a compound represented by the formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvent compound thereof:
  • R 1 is unsubstituted or substituted with halogen atom, hydroxy, amino, carboxy, carbamoyl, or sulfamoyl substituted with C ⁇ 3 ⁇ 4 embankment group, C 3 6 alkenyl or C 2 alkynyl group, or.
  • An aryl group d. 6 alkyl which is unsubstituted or substituted with 1-5 substituents V, which are independently selected from cyano, C 2 alkynyl, halogen atom, hydroxy group, amino group, carboxyl group, C, alkyl, alkoxy, carbamoyl, cyano Cw alkyl, Cw haloalkyl group, C ⁇ alkyl with hydroxy, amino alkyl with C e, C w embankment carboxy group, a halogenated d.
  • substituents V which are independently selected from cyano, C 2 alkynyl, halogen atom, hydroxy group, amino group, carboxyl group, C, alkyl, alkoxy, carbamoyl, cyano Cw alkyl, Cw haloalkyl group, C ⁇ alkyl with hydroxy, amino alkyl with C e, C w embankment carboxy group, a halogenated d.
  • R 2 and R 3 are each independently a hydrogen atom, a halogen atom, a cyano group, an amino group, a hydroxyl group, a carboxyl group, a C alkylamino group, a bis(C ⁇ alkyl)amino group, a C 3 -6 cyclodecyl group, a C fluorenyl group or a C6 decyloxy group substituted or substituted by a halogen atom, a hydroxyl group, an amino group, a carboxyl group, a cyano group, a carbamoyl group, an aminosulfonyl group, or a R 2 , R 3 linkage to form a phenyl group together with a carbon atom to which it is bonded a 5-6 membered saturated or unsaturated heterocyclic group containing at least one nitrogen atom or a C ⁇ cycloalkyl group;
  • X is 0, S, NR 4 or CR 5 R 6 ,
  • R 4 is selected from hydrogen, C ⁇ alkyl with, halogenated alkyl with C w, C ⁇ alkenyl or C 3. 6 cycloalkyl,
  • R 5 independently selected from a hydrogen atom, a halogen atom, Cw of alkyl, halo.
  • R 7 is a hydrogen atom, a carbamoyl group, C ⁇ alkylcarbonyl, C 3. 6 embankment cycloalkyl group, a substituted or unsubstituted or a halogen atom, a hydroxyl group, an amino group, a carboxyl group or a carbamoyl Acyl substituted C l alkyl, decyloxy, aryl Q). 6 alkyl or aryl C oxime;
  • Q is a 3-8 membered saturated or unsaturated heterocyclic group having at least one nitrogen atom which is unsubstituted or substituted with 1-5 substituents W,
  • the substituent W is independently selected from the group consisting of an amino group, an alkylamino group, a bis(d alkyl)amino group, an amino C 6 fluorenyl group, a hydroxy group .6 alkyl group, a carboxy C oxime group, a carbamoyl group, a Cw fluorenyl group. , halogenated C l-6 fluorenyl, C alkoxy, halo C alkoxy, halogen atom, imine methyl, C alkylcarbonylaminomethyl, decylcarbonyloxy, alkylamine Acyl or
  • R 1 is a Cw alkenyl, C W alkynyl group, a substituted or unsubstituted aromatic group or substituted alkyl with C w V substituent substituted
  • the substituent group V is independently selected from cyano, C 2 Block group, halogen atom, hydroxyl group, amino group, carboxyl group, CL 6 alkyl group, Cw decyloxy group, carbamoyl group, cyano group, 6 fluorenyl group, halogenated Cu6 alkyl group, hydroxy Cue fluorenyl group, amino group C thiol group, a carboxy C oxime group, a halogenated C 6 methoxy group, a C hydrazino group, a C alkoxyamino group or a bis(d decyl)amine group;
  • R 2 and R 3 are each independently a hydrogen atom, a sulfonyl group, a cyano group, an amino group, a hydroxyl group, a carboxyl group, a C fluorenylamino group, a bis(CL 6 alkyl)amino group, which is unsubstituted or substituted by a halogen atom or a hydroxyl group.
  • X is 0, S, NR 4 or CR 5 R 6 ,
  • R 4 is selected from hydrogen, C ⁇ alkyl with, alkyl with halo, C 2. 6 alkenyl or cyclic alkyl with Cw,
  • R 5 and R 6 are independently selected from the group consisting of a hydrogen atom, a halogen atom, a Cw alkyl group, a halogenated C e alkyl group, a d. 6 anthoxy group, a halogenated C 6 alkoxy group or a cycloalkyl group.
  • R 5 , R 6 linkage together with the attached carbon atom to form a C 3 -6 cycloalkyl group
  • Y is 0, S or NR 7
  • R 7 is a hydrogen atom, C ⁇ cycloalkyl group embankment, or unsubstituted or substituted by a halogen atom, a hydroxyl group, an amino group, a carboxyl group or a carbamoyl group substituted embankment.
  • Q is a 4-7 membered saturated or unsaturated heterocyclic group having at least one nitrogen atom which is unsubstituted or substituted with 1-3 substituents W,
  • the substituent W is independently selected from a halogen atom, an amino group, a C hydrazino group, a bis(C 6 fluorenyl)amino group, an amino group d. 6 alkyl group, a hydroxy C alkyl group, a carboxy C alkyl group, Carboyl, C decyl, halo Cw alkyl, d. 6 decyloxy, halo Cw decyloxy, imine methyl, fluorenylcarbonylaminomethyl, decylcarbonyloxy, alkylamine Acyl or .6 oxocarbonyl.
  • R 1 is an aryl C 14 fluorenyl group which is unsubstituted or substituted with 1-3 substituents V, and the substituent V is independently selected from cyano group, cyano CM alkyl group, C M alkynyl group, halogen Atom, C 14 mercapto, halo C M alkyl, C M decyloxy, halo CM alkoxy, amino, CM mercaptoamine, hydroxy, hydroxy C M decyl or carbamoyl;
  • R 2 and R 3 are each independently a hydrogen atom, a halogen atom, a cyano group, a carboxyl group, a C 14 alkylamino group, a bis(CM fluorenyl)amino group, a CM which is unsubstituted or substituted by a halogen atom, a hydroxyl group or an amino group.
  • Alkyl or CM methoxy, or R 2 , R 3 are bonded to the attached carbon atom to form phenyl, pyridyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolyl, cyclopentyl Or cyclohexyl sulfhydryl;
  • X is 0, S, NR 4 or CR 5 R 6 , R 4 is selected from a hydrogen atom, a C L 4 fluorenyl group, a halogenated CM fluorenyl group, a C 2 alkenyl group or a cyclodecyl group.
  • R 5 independently selected from a hydrogen atom, a halogen atom, alkyl with CM, CM haloalkyl group, C M alkoxy, halo or C ⁇ alkoxy embankment C 3. 5 embankment cycloalkyl group,
  • R 5 are joined to form C 3 6 cycloalkyl group together with the carbon atoms are attached.
  • Y is 0, S or NR 7 , and R 7 is a hydrogen atom or a CM fluorenyl group;
  • Q is azetidinyl, pyrrolidinyl, pyrrolyl, 4,5-dihydroimidazolyl, imidazolyl, pyrazolyl, pyrazolyl, 4,5 which is unsubstituted or substituted with 1-3 substituents W - dihydropyrazolyl, pyrazolidinyl, piperidinyl, homopiperazinyl, homopiperidinyl, piperazinyl or morpholinyl,
  • the substituent W is independently selected from a halogen atom, an amino group, a CM mercaptoamine group, a bis(CM alkyl)amino group, an amino C M fluorenyl group, a hydroxy CM fluorenyl group, a carboxy CM alkyl group, a carbamoyl group, C L4 fluorenyl, halogenated C M fluorenyl, C M methoxy, imine methyl, CM fluorenylcarbonylaminomethyl, CM alkylcarbonyloxy, C M decyl, C M alkoxy Acyl, acetamido or 2-cyanobenzylamino.
  • R 1 is an aromatic CM fluorenyl group which is unsubstituted or substituted with 1-3 substituents V, which are independently selected from cyano , cyanomethyl, ethynyl, fluorine atom, chlorine atom, methyl, trifluoromethyl, methoxy, trifluoromethoxy, amino, methylamino, hydroxymethyl or carbamoyl;
  • R 2 and R 3 are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a cyano group, a methyl group, an ethyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a hydroxymethyl group, a carboxyl group, and an aminomethyl group. , a methylamino group, a di(methyl)amino group, a methoxy group, a trifluoromethoxy group, or a R 2 , R 3 linkage to form a phenyl or pyridyl group together with the attached carbon atom;
  • X is 0, S, NR 4 or CR 5 R 6 ,
  • R 4 is selected from a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a vinyl group or a cyclopropenyl group.
  • R 5 and R 6 are independently selected from a hydrogen atom, a fluorine atom, a methyl group, an ethyl group, a trifluoromethyl group or a methoxy group.
  • R 5 , R 6 are bonded together with the carbon atom to which they are attached to form a cyclopropyl group, a cyclobutenyl group, a cyclopentyl group or a cyclohexane group;
  • Y is 0, S or NR 7 , and R 7 is a hydrogen atom or a methyl group
  • Q is a pyrrolidinyl, piperazinyl, piperidinyl, homopiperazinyl, homopiperidinyl or azetidinyl group which is unsubstituted or substituted with 1 to 2 substituents W, which are independently selected from the group consisting of Fluorine atom, chlorine atom, amino group, methylamino group, di(methyl)amino group, aminomethyl group, methyl group, ethyl group, methoxy group, methoxy group, hydroxymethyl group, acetamido group or 2-cyano group Alkylamino group.
  • R 1 is an arylmethyl group which is unsubstituted or substituted with 1-3 substituents V, and the substituent V is independently selected from the group consisting of a cyano group, an ethynyl group, a fluorine atom, a chlorine atom, a methyl group, and a trifluoro group.
  • R 2 and R 3 are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a hydroxymethyl group, a carboxyl group, an aminomethyl group, and a methyl group.
  • X is 0, NR 4 or CR 5 R 6 ,
  • R 4 is selected from a hydrogen atom, a methyl group, an ethyl group, an isopropyl group or a trifluoromethyl group.
  • R 5 and R 6 are independently selected from a hydrogen atom, a fluorine atom, a methyl group, an ethyl group or a trifluoromethyl group;
  • Y is 0 or S
  • Q is pyrrolidinyl, piperazinyl, piperidinyl, homopiperazinyl, homopiperidinyl or azetidinyl which is unsubstituted or substituted with 1-2 substituents W, which are independently selected from the group consisting of A fluorine atom, a chlorine atom, an amino group, a methylamino group, an aminomethyl group, a methyl group, a di(methyl)amino group, an acetamide group or a 2-cyanobenzylamino group.
  • R 1 is a phenylmethyl or naphthylmethyl group which is unsubstituted or substituted with 1-3 substituents V, and the substituent V is independently selected from a cyano group, an ethynyl group, a fluorine atom, a chlorine atom or methyl;
  • R 2 and R 3 are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a hydroxymethyl group, a carboxyl group, an aminomethyl group, and a methyl group.
  • An amine group, a di(methyl)amino group, or a R 2 , R 3 linkage to form a phenyl group together with the attached carbon atom;
  • X is 0, NR 4 or CR 5 R 6 ,
  • R 4 is selected from a hydrogen atom, a methyl group, an ethyl group or an isopropyl group.
  • R 5 and R 6 are independently selected from a hydrogen atom, a methyl group or an ethyl group
  • Y is 0 or S
  • Q is pyrrolidinyl, piperazinyl, piperidinyl, homopiperazinyl, homopiperidinyl or azetidinyl which is unsubstituted or substituted with 1-2 substituents W, which are independently selected from the group consisting of Fluorine atom, amino group, methylamino group, methyl group, di(methyl)amino group, acetamido group or 2-cyanobenzylamino group.
  • R 1 is a phenylmethyl or naphthylmethyl group which is unsubstituted or substituted with 1-2 substituents V, and the substituent V is independently selected from a cyano group, an ethynyl group, a fluorine atom or a chlorine atom;
  • R 2 and R 3 are each independently hydrogen atom, chlorine atom, methyl group, ethyl group, hydroxymethyl group, carboxyl group, aminomethyl group, methylamino group, di(methyl)amino group, or R 2 , R 3
  • the linkage forms a phenyl group together with the carbon atom to which it is attached;
  • X is 0, NR 4 or CR 5 R 6 ,
  • R 4 is selected from a hydrogen atom, a methyl group, an ethyl group or an isopropyl group.
  • R 5 and R 6 are independently selected from a hydrogen atom or a methyl group;
  • Y is O or S
  • Q is pyrrolidinyl, piperazinyl, piperidinyl, homopiperazinyl, homopiperidinyl or azetidinyl which is unsubstituted or substituted with one substituent W, and the substituent W is selected from amino group, methylamine A bis(methyl)amino group, an acetamido group or a 2-cyanobenzylamino group.
  • the "halogen atom" as used in the present invention includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • d_ 6 fluorenyl means a straight or branched fluorenyl group derived from a hydrocarbon having 1 to 6 carbon atoms removed by a hydrogen atom, such as methyl, ethyl, n-propyl, isopropyl, n-butyl.
  • CM thiol refers to a specific example containing from 1 to 4 carbon atoms in the above examples.
  • halo in the "halogenated CL 6 alkyl group, halogenated C 14 alkyl group, halogenated C alkoxy group, halogenated C 14 nonyloxy group” in the present invention means a C 1-6 alkyl group, One or more hydrogen atoms on a carbon atom in the CM thiol group, the C methoxy group, and the CM methoxy group are substituted by a halogen atom.
  • the "C ⁇ cycloalkyl” as used in the present invention means a cyclopropyl group, a cyclobutyl group, a 1-methylcyclobutyl group, a cyclopentyl group, a cyclohexyl group and the like.
  • 6 alkoxy refers to the group "C w alkyl” which is bonded to other structures through an oxygen atom, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy Base, tert-butoxy, sec-butoxy, pentyloxy, neopentyloxy, hexyloxy and the like.
  • CM alkoxy refers to a group of the term “CM fluorenyl” attached to other structures through an oxygen atom.
  • the "C 2 . 6 alkenyl group” as used in the present invention means a linear or branched or cyclic alkenyl group having 2 to 6 carbon atoms and having a double bond, such as a 1-propenyl group, a 2-propenyl group, and 1 -butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, cyclopropenyl , cyclopentenyl, cyclohexenyl and the like.
  • the "C 3 .4 alkenyl group” as used in the present invention means an example of a linear or branched or cyclic alkenyl group having a double bond and having 3 to 4 carbon atoms.
  • the present invention is "C 2. 6 alkynyl group” refers to the number of carbon atoms containing a triple bond is 2 to 6 straight or branched chain or cyclic alkynyl group such as ethynyl, propynyl, 2-butynyl A group, a 2-pentynyl group, a 3-pentynyl group, a 2-hexynyl group, a 3-hexynyl group, a cyclopropynyl group, a cyclobutynyl group, a cyclopentynyl group, a cyclohexynyl group, and the like.
  • the "C 3 alkynyl group” as used in the present invention means a straight or branched chain having 3 to 4 carbon atoms and containing a double bond. Or an example of a cyclic alkynyl group.
  • aromatic group as used in the present invention means an aromatic ring such as a phenyl group, a naphthyl group, an anthracenyl group or the like.
  • the "3-8 membered saturated or unsaturated heterocyclic group having at least one nitrogen atom” as used in the present invention includes “3-8 member saturated heterocyclic group having at least one nitrogen atom” and “3-8 member unsaturated” a heterocyclic group containing at least one nitrogen atom.”
  • the "3-8 member saturated heterocyclic group having at least one nitrogen atom” are azacyclopropenyl group, diazetidinyl group, azetidinyl group (i.e., azetidinyl group), 1, 2-diazetidine, pyrrolidine, imidazolium, pyrazolidine, piperidine, piperazine, morpholine, azalea, 1,4-diazepane, and the like.
  • Preferable "4-7-membered saturated heterocyclic group containing at least one nitrogen atom” such as azetidinyl (ie azetidinyl), 1,2-diazacyclobutane, pyrrolidine, imidazolium, pyridyl Azathioprine, piperidine, piperazine, morpholine, azepine, 1,4-diazacyclopentane, and the like.
  • it is preferably a "5-6 member saturated heterocyclic group containing at least one nitrogen atom” such as pyrrolidine, imidazolidine, pyrazolium, piperidine, piperazine, morpholine or the like.
  • the "3-8-membered unsaturated heterocyclic group having at least one nitrogen atom” are 2H-azetidinyl, 3H-diazapropenyl, azetidin, 1,2- Diazacyclobutene, pyrrole, dihydropyrrole, imidazole, 4,5-dihydroimidazole, pyrazole, 4,5-dihydropyrazole, 1,2,3-triazole, 1,2,4- Triazole, tetrazole, oxazole, 4,5-dihydrooxazole, isoxazole, 4,5-dihydroisoxazole, 2,3-dihydroisoxazole, 1,2,3-oxo Azole, 1,2,5-oxadiazole, thiazole, 4,5-dihydrothiazole, isothiazole, 1 ,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4 - thiadia
  • Preferable "4-7-membered unsaturated heterocyclic group containing at least one nitrogen atom" such as azetidin, 1,2-diazacyclobutene, pyrrole, dihydropyrrole, imidazole, 4,5 - dihydroimidazole, pyrazole, 4,5-dihydropyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, oxazole, 4,5-dihydrooxazole, Isoxazole, 4,5-dihydroisoxazole, 2,3-dihydroisoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, thiazole, 4,5- Dihydrothiazole, isothiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, pyridine, pyridazine, pyrimidine, pyri
  • a "5-6 membered unsaturated heterocyclic group containing at least one nitrogen atom” such as pyrrole, dihydropyrrole, imidazole, 4,5-dihydroimidazole, pyrazole, 4,5-dihydropyridyl.
  • the following compounds are further preferred:
  • the invention also provides a preparation method of the above compound, and the reaction equation is as follows, but is not limited to the following methods:
  • the compound of the formula A is added, dissolved in butanol, added with a methylamine ethanol solution, stirred at a high temperature, and the reaction solution is dried under reduced pressure to precipitate a yellow solid to obtain a compound of the formula B.
  • the compound of the formula C is a compound of the formula E - 2. Steps 1-3 of the compound are the same as the reaction steps 1-3 when Y is 0.
  • Step 5 is the same as when the Y is 0.
  • the preparation method is prepared by referring to a preparation method in which Y is 0 or Y is S.
  • the pharmaceutically acceptable salt of any of the above compounds of the present invention means a salt prepared from a pharmaceutically acceptable, non-toxic base or acid, including an organic acid salt, a mineral acid salt, an organic base salt, and an inorganic base salt.
  • Organic acids include formic acid, acetic acid, benzenesulfonic acid, benzoic acid, p-toluenesulfonic acid, (2R, 3R)-2,3-dihydroxysuccinic acid, camphorsulfonic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, Propanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, isethionethane, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid, etc., especially Preference is given to benzoic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, maleic acid, fumaric acid, tartaric acid.
  • the inorganic acid includes hydrobromic acid, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, etc., particularly preferably hydrobromic acid, hydrogen Chloric acid, sulfuric acid, phosphoric acid.
  • the organic base includes primary, secondary and tertiary amines, and the substituted amine includes a naturally occurring substituted amine, a cyclic amine and an alkali ion exchange resin selected from the group consisting of arginine, betaine, caffeine, choline, guanidine, ⁇ '-dibenzyl.
  • the inorganic base includes a hinge and a basic compound of lithium, sodium, potassium, calcium, magnesium, zinc, bismuth, aluminum, iron, ketone, ferrous iron, manganese, divalent manganese, etc., particularly preferably ammonium and lithium, sodium, potassium, calcium , alkaline compounds of magnesium, zinc and strontium.
  • the salt in solid form may exist in more than one crystal structure or in the form of a solvent compound, such as a hydrate.
  • the compounds of the invention contain one or more asymmetric centers and are thus useful as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and single diastereomers.
  • the compounds of the invention have asymmetric centers, each of which will independently produce two optical isomers, and the scope of the invention includes all possible optical isomers and mixtures of diastereomers and pure or partially Pure compound.
  • the invention includes all stereoisomeric forms of these compounds.
  • the present invention includes a cis isomer and a trans isomer unless otherwise specified.
  • the compounds of the present invention may exist in tautomeric forms which have different points of attachment of hydrogen by displacement of one or more double bonds.
  • a ketone and its enol form are ketone-'alcoholic tautomers.
  • Each tautomer and mixtures thereof are included in the compounds of the invention.
  • the compound represented by the formula (I), a pharmaceutically acceptable salt thereof, and a stereoisomer thereof may be in the form of a solvent compound.
  • the solvent compound is a hydrate
  • the hydration can be carried out during the preparation process or can be gradually carried out by utilizing the hygroscopicity of the original anhydrous product.
  • the compounds of the invention may be combined with one or more other drugs to be safer or more effective than a single drug.
  • These other drugs may be administered to the compound of formula (I) simultaneously or sequentially through one route and in their usual amounts.
  • a pharmaceutical composition in unit dosage form containing the other drug and a compound of formula (I) is preferred.
  • Other active ingredients which may be administered in combination with the compound of formula (I) or administered separately or in the same pharmaceutical composition include, but are not limited to -
  • Insulin sensitizers include: ( ⁇ ) ⁇ ⁇ agonists, such as glitazones (such as troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, etc.) and other PPAR ligands, including PPARo/gamma double-acting agonists, such as KRP-297, and PPARa agonists such as fenofibric acid derivatives (gefibrozil, clofibrate, fenofibrate and bezafibrate); (ii) biguanide class, Such as metformin and phenformin; (iii) protein tyrosine phosphatase-IB (PTP-IB) inhibitor;
  • glitazones such as troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, etc.
  • PPAR ligands including PPARo
  • a-glucosidase inhibitors eg acarbose
  • PACAP PACAP, PACAP mimetic and PACAP receptor 3 agonists
  • Cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, ivavastatin, rosuvastatin) And other statins), (ii) chelates (cholestyramine, colestipol and didecylaminoalkyl derivatives of cross-linked dextran), (Hi) nicotinic alcohol, niacin or other salts, (iv) PPARa agonists, such as fenofibric acid derivatives (gebfizil, clofibrate, fenofibrate and bezafibrate), (v) PPARa/y double-acting agonists, such as KRP- 297; (vi) Cholesterol absorption inhibitors, such as ⁇ -sitosterol and ezetimibe, (vii) acetyl Co
  • anti-obesity compounds such as fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Y5 inhibitors and ⁇ 3 adrenergic receptor agonists;
  • Drugs for inflammation such as aspirin, non-steroidal anti-inflammatory drugs, glucocorticosteroids, sulfasalazine and cyclooxygenase II selective inhibitors.
  • the above combinations include combinations of the compounds of the invention not only with one other active compound but also with two or more other active compounds.
  • Non-limiting examples include compounds having formula (I) and two or more selected from the group consisting of biguanides, sulfonylureas, HMG-CoA reductase inhibitors, PPAR agonists, PTP-1B inhibitors, other DPP-IV Combination of an inhibitor and an active compound of an anti-obesity compound.
  • the weight ratio of the compound of the invention to the second active ingredient can vary depending on the effective dose of the various ingredients. In general, the respective effective dose will be used. Thus, for example, when the compound of the invention is administered in combination with other drugs, the weight ratio of the compound of the invention to the other drug is generally between about 1000:1 and about 1:1000, preferably between about 200:1 and about 1:200. . Combinations of the compounds of the present invention with other active ingredients will generally also be within the above range, but in each case, an effective amount of each active ingredient should be employed.
  • the present invention claims to include any of the compounds described above, pharmaceutically acceptable salts thereof, and stereoisomers thereof.
  • the pharmaceutical composition of the compound or its solvent compound, with one or more pharmaceutically acceptable carriers and/or diluents, is either a clinically or pharmaceutically acceptable dosage form, preferably an oral preparation or an injection.
  • the physiologically effective amount of the compound represented by the formula (I) is 1 mg to 100 mg, and may be the active ingredient as described in 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg or the like.
  • the compound can be administered in an amount of from 1 to 4 times per day, preferably from 1 to 2 times per day.
  • Any of the compounds of the present invention, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvent compound thereof can be administered orally to a patient in need of such treatment.
  • any of the compounds of the present invention, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvent compound thereof can be prepared into a conventional solid preparation such as a tablet, a capsule, a pill, a granule, etc.; Formulations, such as oral solutions, oral suspensions, syrups, and the like.
  • Tablet refers to a solid preparation of a round or shaped tablet which is prepared by mixing a drug with a suitable excipient, and is mainly composed of an oral plain tablet, and a tablet, a sublingual tablet, a mouth patch, a chewable tablet, and a dispersion. Tablets, soluble tablets, effervescent tablets, sustained release tablets, controlled release tablets and enteric coated tablets.
  • Capsule refers to a solid preparation filled with a drug or an auxiliary material filled in a hollow capsule or sealed in a soft capsule. According to its dissolution and release characteristics, it can be divided into a hard capsule (commonly known as a capsule) and a soft capsule (a capsule). Sustained-release capsules, controlled-release capsules and enteric-coated capsules. Pellets are spherical or spheroidal solid preparations which are uniformly mixed with a suitable excipient and are prepared by a suitable method, including dropping pills, sugar pills, pellets and the like. Granule refers to a dry granular preparation with a certain particle size and a suitable excipient.
  • Oral solution means a clear liquid preparation in which the drug is dissolved in a suitable solvent for oral administration.
  • Oral suspension refers to a poorly soluble solid drug which is dispersed in a liquid medium to prepare a suspension liquid preparation for oral administration, and also includes a dry suspension or a concentrated suspension.
  • a syrup is a concentrated aqueous solution of sucrose containing a drug.
  • a suitable filler, a binder, a disintegrant, a lubricant or the like may be added.
  • Commonly used fillers include starch, powdered sugar, calcium phosphate, calcium sulfate dihydrate, dextrin, microcrystalline cellulose, lactose, pregelatinized starch, mannitol, etc.
  • commonly used binders include sodium carboxymethyl cellulose, PVP - K30, hydroxypropyl cellulose, starch syrup, methyl cellulose, ethyl cellulose, hypromellose, gelatinized starch, etc.
  • commonly used disintegrating agents include dry starch, crospovidone, cross-linked carboxylate Methylcellulose sodium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, etc.
  • commonly used lubricants include magnesium stearate, talc, sodium decyl sulfate, micronized silica gel, and the like.
  • Dipeptidase-IV is a cell surface protein involved in a variety of biological functions. It has a wide distribution of tissues (intestine, kidney, liver, pancreas, placenta, thymus, spleen, epithelial cells, vascular endothelium, lymphoid and myeloid cells, serum) and clear tissue and cell type expression levels. DPP-IV was identified as a T-cell activation marker, CD26, which cleaves a large number of immunoregulatory, endocrine and neurological peptides in vitro. This indicates that this peptidase has a latent effect in various diseases of human or other animals.
  • DPP-IV inhibitors can significantly inhibit DPP-IV activity, protect GLP-1 activity, and promote insulin Secretion, lowering postprandial glucagon, lowering blood sugar, increasing sugar tolerance; and protecting GIP activity, increasing GIP concentration and enhancing insulin secretion; DPP-IV inhibitor can also improve glycolipid metabolism , to prevent weight gain.
  • the present invention also provides the use of a novel DPP-IV inhibitor for the preparation of a medicament for the treatment and/or prevention of the following diseases.
  • Type II diabetes and related diseases it is now fully confirmed that GLP-1 and GIP can be rapidly inactivated by DPP-IV in vivo, so the DPP-IV inhibitor of the present invention can be used for treating type II diabetes and treating and preventing concomitant type II diabetes.
  • DPP-IV inhibitor of the present invention can be used for treating type II diabetes and treating and preventing concomitant type II diabetes.
  • a number of conditions including metabolic syndrome X, reactive hypoglycemia, and diabetes dyslipidemia.
  • the following diseases, conditions and symptoms are associated with type 2 diabetes and can therefore be treated, controlled or, in some cases, prevented by treatment with the compounds of the invention: (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disease, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) high Cholesterolemia, (10) low HDL levels, (11) high HDL 7K level, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) irritable bowel syndrome, (15) Enteritis, including Crohn's disease and ulcerative colitis, (16) Retinopathy, (21) Nephropathy, (22) Neuropathy, (23) Syndrome X, (24) Ovarian hyperandrogenism (polycystic ovary) Syndrome) and other insulin-resistant diseases; and auxin deficiency, intestinal damage, immunosuppression, HIV infection, hematopoiesis, neuronal diseases, brain tumor invasion and metastasis, benign prostatic
  • the DPP-IV inhibitor of the invention has the following advantages:
  • the compound of the present invention can better inhibit the activity of DPP-IV and make the level of GLP-1 in the body more stable;
  • the DPP-IV inhibitor of the invention has good safety and tolerance in vivo, and the incidence of adverse reactions is further reduced;
  • the DPP-IV inhibitor of the invention has simple preparation process, high drug purity, high yield and stable quality, and is easy to carry out large-scale industrial production.
  • Test sample Part of the compound of the present invention, self-made, and its chemical name and structural formula are as described above.
  • reaction solution containing 50 mL of fluorescein DPPIV-Glo TM buffer to obtain a reaction solution.
  • the reaction solution needs to be stored in a refrigerator at -20 °C.
  • Example 29 Compound 13.5 > 100000 > 100000
  • Example 30 Compound 7.9 ⁇ 100000 > 100000
  • Operation (5) in Reference Example 1 was carried out by administering (?)-1-(3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-7.
  • the product was obtained in 230 mg, yield 50.5%.
  • Example 2 For the specific operation, refer to (1) in Example 1, 2.72 g (16.0 mmol) of 2,4-dichloro-3-nitropyridine, and 1.75 g (17.5 mmol) of homopiperazine to obtain the product 2.873 g, yield 70. ,1 %.
  • 6-Methyl-3-nitropyridine-2,4-diol (1.7 g, 10 mmol) was dissolved in 10 mL POCl 3, was heated to 95. C, stirring for 1.5 hours, spinning off excess POCl 3 , carefully adding 100 mL of ice water, extracting with ethyl acetate (80 mL ⁇ 3), combining the organic phases, washing with saturated brine, drying with anhydrous Na 2 SO 4 , spinning dry 1.773 g of yellow powder, yield 85.7%.
  • triphosgene 197 mg 1.65 mmol
  • triethylamine 0.37 mL, 2.65 mmol
  • triphosgene 197 mg 1.65 mmol
  • triethylamine 0.37 mL, 2.65 mmol
  • a constant pressure dropping funnel at -10 °C (i? -l-[3-Amino-2-(methylamino)quinolin-4-yl]piperidin-3-yl-tert-butylcarbamate (224 mg 0.603 mmol) in 10 mL of THF, stirring 0.5
  • the pH was adjusted with a saturated sodium carbonate solution and then extracted with ethyl acetate (100 mL EtOAc).
  • 6-Methyl-3-nitropyridine-2,4-diol (1.7 g, 10 mM) was dissolved in 10 mL of POCl 3 , heated to 95 ° C, stirred for 1.5 hours, spun off excess POCl 3 , carefully added quenched with ice-water, extracted with ethyl acetate, the combined organic phases were washed with brine, dried over anhydrous Na 2 S0 4, spin done as a yellow powder 1.34 g, 64.7% yield.
  • 2,6-Dichloropyridin-4-amine (2.18 g, 13.4 mmol) was added to 11 mL of concentrated sulfuric acid under ice bath. After cooling to 0 °C, 4.4 mL of 90% nitric acid was added dropwise, and the reaction was carried out at room temperature. After stirring for 1 hour, the reaction liquid was poured into ice water, and a solid was precipitated, suction filtered, washed with water, and dried to give the product 2.28 g, yield 81.8%.

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CN101397300A (zh) * 2007-09-04 2009-04-01 山东轩竹医药科技有限公司 二肽酶-ⅳ抑制剂衍生物
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WO2013007167A1 (zh) * 2011-07-09 2013-01-17 山东轩竹医药科技有限公司 二肽基肽酶-iv抑制剂的盐的晶型i及其制备方法和应用
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CN102863440B (zh) * 2011-07-09 2015-05-27 山东轩竹医药科技有限公司 二肽基肽酶-iv抑制剂的盐的晶型
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CN108602817B (zh) * 2015-12-24 2020-12-25 吉林惠升生物制药有限公司 二肽基肽酶-iv抑制剂的苯甲酸盐的晶型

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JP5719382B2 (ja) 2015-05-20
WO2011085643A8 (zh) 2012-07-05
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CN102127072A (zh) 2011-07-20
CN102127071A (zh) 2011-07-20
US8680089B2 (en) 2014-03-25
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