WO2014127745A1 - Composés inhibiteurs de la dpp-iv et leurs intermédiaires - Google Patents

Composés inhibiteurs de la dpp-iv et leurs intermédiaires Download PDF

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WO2014127745A1
WO2014127745A1 PCT/CN2014/072432 CN2014072432W WO2014127745A1 WO 2014127745 A1 WO2014127745 A1 WO 2014127745A1 CN 2014072432 W CN2014072432 W CN 2014072432W WO 2014127745 A1 WO2014127745 A1 WO 2014127745A1
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product
reaction
solvent
compound
substituted
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李进
斯托克斯·迈克尔
窦登峰
万金桥
冯静超
潘飞
宋宏梅
胡晓
易磊
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成都先导药物开发有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/18—Bridged systems
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems

Definitions

  • the present invention relates to a compound which inhibits DPP-IV and an intermediate thereof.
  • DPP-IV Dipeptidyl peptidase-IV
  • DPP-IV also known as the T cell surface antigen CD26
  • CD26 T cell surface antigen
  • DPP-IV is a type II transmembrane glycoprotein composed of 766 amino acid residues.
  • DPP-IV is widely distributed in various tissues and organs in the body, including kidney, liver, lung, small intestine, lymphocytes and vascular endothelial cells (Abbott CA, Baker E, Sutherland GR, McCaughan GW. Genomic organization, exact localization, And tissue expression of the human CD26 (dipeptidyl peptidase IV) gene. Immunogenetics. 1994; 40 (5): 331-8), partially present in the plasma in soluble form ( Mentlein R. Dipeptidyl-peptidase IV (CD26)-role In the inactivation of regulatory peptides.
  • DPP-IV is a specific serine protease, and its substrate is a polypeptide with a proline (Pro) or alanine (Ala) at the second end of the N-terminal, which can be cleaved from the N-terminus of such a polypeptide. Peptide.
  • the pharmacological action of DPP-IV inhibitors is mainly achieved by increasing the concentration of active glucagon-like peptide-1 (GLP-1) in vivo.
  • GLP-1 active glucagon-like peptide-1
  • GLP-1 is synthesized and secreted by small intestinal L cells, and is the most potent intestinal peptide hormone that has been found to promote insulin secretion.
  • GLP-1 can exert hypoglycemic effects in many aspects (Gautier JF, Fetita S, Sobngwi E, Salaun-Martin C. Biological actions of the incretins GIP and GLP-1 and therapeutic perspectives in patients with type 2 diabetes. Diabetes Metab. 2005; 31(3 Pt l):233-42.
  • GLP-1 Promotes glucose-dependent insulin secretion, increases tissue uptake of glucose; 2) Promotes transcription of proinsulin genes and enhances mRNA stability Increased biosynthesis; 3) inhibits glucagon secretion and reduces hepatic glucose release; 4) promotes islet ⁇ cell proliferation and differentiation, inhibits ⁇ cell apoptosis; 5) inhibits gastric emptying, controls appetite, lowers blood sugar, and simultaneously Reduce the risk of weight gain.
  • the above physiological functions of GLP-1 provide an important target for the treatment of type 2 diabetes. However, GLP-1 is easily inactivated by DPP-IV from two amino acid residues in the scorpion, and its plasma half-life is less than 2 minutes, which severely limits its clinical application.
  • DPP-IV is one of the key enzymes that promote the degradation and inactivation of GLP-1 in vivo. Selective inhibition of DPP-IV can increase the plasma level of active GLP-1. Therefore, the development of DPP-IV inhibitors provides a new way to treat diabetes.
  • Sitagl iptin developed by Merck was approved by the US Food and Drug Administration (FDA) to become the first DPP-IV inhibitor to be marketed.
  • currently marketed DPP-IV inhibitors include vildagliptin (vi ldagl iptin), saxagl iptin, alogl iptin, and linagliptin (l inagl iptin). Wait for four.
  • the new DPP-IV inhibitor repagliptin (retagl iptin) was independently developed by Chinese pharmaceutical companies and is currently undergoing a phase III clinical study in China. Clinical studies have shown that DPP-IV inhibitors have good hypoglycemic effects in patients with type 2 diabetes (Argyrakopoulou G, Doupis J. DPP4 inhibitors: from sitagliptin monotherapy to the new alogliptin-pioglitazone combination therapy. Adv Ther. 2009; 26 ( 3): 272-80.), compared with traditional diabetes drugs, has the following advantages [Scheen A ⁇ DPP-4 inhibitors in the management of type 2 diabetes: a critical review of head-to-head trials. Diabetes Metab.
  • DPP-4 inhibitors focus on linagliptin for type 2 diabetes. Diabetes Metab Syndr Obes. 2013; 6:1-9.]: 1) Oral administration; 2) blood glucose-dependent incretin secretion, low risk of hypoglycemia; 2) can protect and improve islet ⁇ -cell function, prevent beta cell degradation, and help to fundamentally undermine the progression of type 2 diabetes 3) Do not increase weight and weight. Therefore, DPP-IV inhibitors play an increasingly important role in the treatment of type 2 diabetes, and have become a research hotspot of current new anti-diabetic drugs.
  • the present invention provides a compound of the formula IA or IB or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from substituted or unsubstituted phenyl
  • R 2 is selected from C1-5 alkyl or substituted alkyl, 1-5 heteroalkyl or substituted heteroalkyl, or 1-5 heteroatoms or Substituting a hetero atom
  • R 3 is selected from H, CN, or Cl-10 alkyl or substituted alkyl
  • X is selected from N or CH
  • Y is selected from N or CR 6 , wherein R 6 is selected from H, CN, carboxyl or Ester group.
  • the substituent of the substituted phenyl group is 1 to 5 R 4 , wherein R 4 is selected from the group consisting of CN, halogen, C1-6 alkyl or halogen-substituted alkyl, or C1-6 Alkoxy or halogen substituted alkoxy;
  • the substituent of the substituted alkyl group is selected from halogen, CN, 0H, R 5 , 0R 5 , NHS0 2 R 5 , S0 2 R 5 , COOH or C0 2 R 7 , substituted hetero atom or substituted hetero
  • the substituent of the alkyl group is halogen, CN, 0H, R 5 , OR 5 , NHS0 2 R 5 , S0 2 R 5 , COOH or C0 2 R 7 ;
  • R 3 the substituent of the substituted alkyl group is selected from 1 to 5 halogens
  • the carboxyl group is COOH, and the ester group is C0 2 R 7 ;
  • hetero atom is 0 or S
  • R 5 is a C1-6 alkyl or substituted alkyl group having a substituent of 1 to 5 halogens, COOH or C0 2 R 7
  • R 7 is a C 1-6 alkyl group.
  • the heteroalkyl group is a C1-4 fluorenyl group containing one hetero atom.
  • R 1 is selected from a halogen-substituted phenyl group
  • R 2 is selected from a heteroalkyl group, 1-2 hetero atoms or a C2-3 alkyl group
  • R 3 is selected from a halogen-substituted alkyl group.
  • the halogen is F or Cl.
  • RR 11 is selected from the group consisting of a substituted phenylphenyl group from a halohalogen;
  • Alkyl fluorenyl group:: RR 66 is selected from the group consisting of HH, CCNN, and carboxycarboxylate. Further, R 6 is selected from C0 2 R 7 .
  • the compound or a pharmaceutically acceptable salt thereof is:
  • the selectivity of DPP9) plays a major role, and the substitution of tetrahydropyrazine therein can modulate the activity and selectivity of the compound.
  • substituents will additionally produce multiple chiral isomers, making it difficult to synthesize and identify compounds.
  • the introduction of a substituent group by bridging can not only reduce the complexity of the chiral compound and increase the controllability of chirality, but also increase the rigidity of the compound, and can change the activity and selectivity of the compound.
  • the substituted five-membered aromatic heterocyclic tetrahydropyrazine was bridged to form a bridge-parallel combination.
  • the material is very challenging in synthesis and needs to solve many technical problems.
  • chiral controlled bridge rings are difficult to form effectively, and bridges and loops cannot be directly formed by corresponding parallel rings (especially for short bridge rings).
  • the construction process of the five-membered aromatic heterocyclic ring is not affected by the tension of the bridged ring, the secondary ammonia of the amino acid and the bridged ring is affected by the steric hindrance, and the intermediate stability of the bridged ring in the formation of the final compound is poor. And other issues.
  • the inventors finally developed an ideal synthetic route, effectively overcoming the difficulties in the synthesis process, successfully synthesizing bridge tetrahydropyrazine and replacing the five-membered aromatic heterocycle. It has been experimentally verified that these compounds have good inhibition and selectivity for DPP4.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof for the preparation of a dipeptidyl peptidase-IV inhibitor.
  • the dipeptidyl peptidase-IV inhibitor is a drug for treating or/and preventing diabetes, hyperglycemia, and insulin resistance.
  • the present invention also provides a process for the preparation of the above formula or a compound of the formula, characterized in that the reaction comprises the following steps:
  • Step 1 using (l S,5R)-3,8-diazabicyclo[3.2.1]heptan-2-one (Tetrahedron, 1992, 23, 4985) as raw material, with di-tert-butyl dicarbonate The ester is reacted under basic conditions to obtain a product which is retained as the next reactant;
  • Step 2 The product obtained in the previous step is subjected to a thiolation reaction with a Lawson reagent to obtain a product which is left as a next reaction;
  • Step 3 The product obtained in the previous step is added to a strong acid solution to obtain a product which is left as a next reaction.
  • Step 4 The product obtained in Step 3 is reacted with R 3 -substituted acetyl hydrazine under the action of activating reagent R 3 instead of sodium acetate to obtain a product which is left as the next reactant;
  • Step 5 reacting the product obtained in Step 4, R 1 -substituted protected ⁇ -aminobutyric acid, and a condensation reagent to obtain a product which is reserved as a next step;
  • Step 6 reacting the product obtained in Step 3, R 1 -substituted protected ⁇ -aminobutyric acid, and a condensation reagent to obtain a product which is reserved as a next step;
  • Step 7 reacting the product obtained in Step 6 with R 3 -substituted acetohydrazide under the action of activating reagent R 3 in place of sodium acetate, thereby obtaining a product which is left as the next reactant;
  • Step 8 Take the product of Step 5 or Step 7 and add a strong acid for deprotection to obtain a product of the formula; or, (lR, 5S)-3,8-diazabicyclo[3.2.1]heptane-2 - the ketone is used as a raw material and the same synthetic method is used to obtain the compound hydrazine; or the racemic starting material is used, and after synthesizing according to the above method, the optical isomer is resolved to obtain a compound.
  • the solvent used in Step 1 is an aprotic solvent
  • the aprotic solvent is preferably dichloromethane.
  • the reaction temperature is 0 ° C to 30 ° C
  • the reaction time is 2 to 16 hours;
  • the solvent used in Step 2 is a polar aprotic solvent, and the aprotic solvent is preferably tetrahydrofuran, diethyl ether, diisopropyl ether or toluene, the reaction temperature is 0 ° C to 30 ° C, and the reaction time is 0.5-3 hours; It is also possible to use a toluene as a solvent to heat the reaction.
  • the acid used in Step 3 is a proton strong acid, and the proton strong acid is preferably trifluoroacetic acid or hydrochloric acid, the solvent used is preferably dichloromethane or ethyl acetate, the reaction temperature is 0 ° C to 30 ° C, and the reaction time is 0.5 to 4 hours. ;
  • the solvent used in Step 4 is a polar protic solvent, and the polar protic solvent is preferably n-butanol, the reaction temperature is 110 to 130 ° C, preferably 118 ° C, and the reaction time is 2 to 12 hours;
  • the solvent used in Step 5 is an aprotic solvent, and the aprotic solvent is preferably dichloromethane, tetrahydrofuran or N, N-dimethylformamide, the base used is diisopropylethylamine or other organic base, and the condensing agent is 1_ (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole, or 2-(7-azobenzotriazole)-ruthenium, osmium, iridium ', ⁇ '-tetramethylurea hexafluorophosphate, the reaction temperature used is 0 ° C to 30 ° C, the reaction time is 0.5 to 2 hours;
  • the solvent used in Step 6 is an aprotic solvent, and the aprotic solvent is preferably dichloromethane, tetrahydrofuran or N, N-dimethylformamide, the base used is diisopropylethylamine or other organic base, and the condensing agent is 1_ (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole or 2-(7-azobenzotriazole)- ⁇ , ⁇ , ⁇ ' , ⁇ '-tetramethylurea hexafluorophosphate, the reaction temperature is from 0 ° C to 30 ° C, and the reaction time is from 0.5 to 2 hours.
  • the aprotic solvent is preferably dichloromethane, tetrahydrofuran or N, N-dimethylformamide
  • the base used is diisopropylethylamine or other organic base
  • the condensing agent is 1_ (3-dimethyla
  • the solvent used in Step 7 is a polar protic solvent, and the polar protic solvent is preferably n-butanol, the reaction temperature is in the range of 110 to 130 ° C, and the reaction time is 2 to 12 hours;
  • the acid used in Step 8 is a proton strong acid, and the proton strong acid is preferably trifluoroacetic acid or hydrochloric acid, and the solvent used is preferably dichloromethane, ethyl acetate or none, the reaction temperature is 0 ° C to 30 ° C, and the reaction time is 0.5 to 4 hours.
  • the proton strong acid is preferably trifluoroacetic acid or hydrochloric acid
  • the solvent used is preferably dichloromethane, ethyl acetate or none
  • the reaction temperature is 0 ° C to 30 ° C
  • the reaction time is 0.5 to 4 hours.
  • the present invention also provides a process for the preparation of the above formula or a ruthenium compound, the reaction steps being as follows:
  • Step 1 N-Boc-3-amino-1,2-propanediol is reacted with methyl (-1-nitrobenzyloxycarbonyl-2-aziridinecarboxylate) under Lewis acid catalysis to obtain a product Reserved as the next reactant;
  • Step 2 The product obtained in the previous step is subjected to an oxidation reaction, and the product is obtained as a reactant for the next step;
  • Step 3 hydrogenating the product obtained in the previous step to obtain a product which is reserved for the next step;
  • Step 4 The product obtained in the previous step is deprotected by adding a strong acid solution, and the product is obtained as the next step.
  • Step 5 The product obtained in the previous step is added to a strong basic organic solvent to obtain a product which is reserved for the next step;
  • Step 6 The product obtained in the previous step is reacted with di-tert-butyl dicarbonate under basic conditions to obtain a product which is left as the next reaction;
  • Step 7 The product obtained in the previous step is added to the Lawson reagent to obtain a product which is left as the next reaction;
  • Step 8 The product obtained in the previous step is added to a strongly acidic solution, and the reaction is obtained, and the product is obtained as the next step. Reactant;
  • Step 9 reacting the product obtained in the previous step, R 1 -substituted protected ⁇ -aminobutyric acid, and a condensation reagent to obtain a product which is reserved as a next step;
  • Step 10 reacting the product obtained in the previous step with R 3 -substituted acetyl hydrazine under the activation of R 3 -substituted sodium acetate to obtain a product which is left as the next reactant;
  • Step 11 adding the product obtained in the previous step to a strong acid reaction to obtain a product of the formula
  • the starting material is replaced by (R)-l-p-nitrobenzyloxycarbonyl-2-aziridinecarboxylic acid methyl ester, and the compound oxime is prepared according to the above synthesis method; or, the racemic N-Boc-serine is used.
  • Methyl ester after synthesis according to the above method, the optical isomer is resolved to obtain the compound hydrazine or hydrazine.
  • the solvent used in Step 1 is a non-polar solvent
  • the non-polar solvent is preferably toluene or xylene
  • the Lewis acid is preferably boron trifluoride etherate
  • the reaction temperature is 20 to 30 ° C
  • the reaction time is 0.5 to 2 hours;
  • the solvent used in Step 2 is a polar aprotic solvent, and the polar aprotic solvent is preferably dichloromethane or tetrahydrofuran, the reaction temperature is 0 ° C to 30 ° C, and the reaction time is 1 to 2 hours;
  • the solvent used in Step 3 is a polar solvent, the polar solvent is preferably ethyl acetate or methanol, the catalyst used is a metal catalyst, the metal catalyst is preferably palladium carbon, the reaction temperature is 20 to 30 ° C, and the reaction time is 2 Up to 4 hours;
  • the solvent used in Step 4 is a polar aprotic solvent, and the polar aprotic solvent is preferably dichloromethane or ethyl acetate.
  • the acid used is a strong acid, preferably trifluoroacetic acid or hydrochloric acid, and the reaction temperature is 0 ° C to 30 ° C. °C, the reaction time is 2 to 4 hours;
  • the solvent used in Step 5 is a polar protic solvent, preferably methanol, and the strong base used is preferably sodium methoxide, the reaction temperature is 20 to 30 ° C, and the reaction time is 4 to 16 hours;
  • Step 6 The solvent is a polar protic solvent, preferably methanol, and the base is preferably a tertiary amine, and the reaction time is 2 to 10 hours;
  • the solvent used in Step 7 is a polar aprotic solvent, and the aprotic solvent is preferably tetrahydrofuran, diethyl ether or diisopropyl ether, the reaction temperature is 0 ° C to 30 ° C, and the reaction time is 0.5 to 3 hours;
  • the solvent used in Step 8 is a polar aprotic solvent, and the polar aprotic solvent is preferably dichloromethane or ethyl acetate.
  • the acid used is a strong acid, preferably trifluoroacetic acid, and the reaction temperature is 0 ° C to 30 ° C. , the reaction time is 2 to 4 hours;
  • the solvent used in Step 9 is an aprotic solvent, and the aprotic solvent is preferably dichloromethane, N, N to dimethylformate.
  • Amide or tetrahydrofuran the base used is diisopropylethylamine or other organic base, and the condensing agent is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriene Oxazole, or 2-(7-azobenzotriazole)-ruthenium, osmium, iridium, ⁇ '-tetramethylurea hexafluorophosphate, reaction temperature of 0 ° C to 30 ° C, reaction time 0.5 to 2 hours;
  • the solvent used in Step 10 is a polar protic solvent, and the polar protic solvent is preferably n-butanol, the reaction temperature is 110 to 130 ° C, preferably 118 ° C, and the reaction time is 2 to 12 hours;
  • the solvent used in Step 11 is a polar aprotic solvent, and the polar aprotic solvent is preferably dichloromethane or ethyl acetate.
  • the acid used is a strong acid, preferably trifluoroacetic acid, and the reaction temperature is 0 ° C to 30 ° C. , the reaction time is 0.5 to 2 hours;
  • R 2 ' is selected from C1-5 alkyl or substituted alkyl;
  • R 2 " is selected from 1 to 5 heteroalkyl- or substituted heteroalkyl, 1-5 heteroatoms or substituted heteroatoms;
  • 3 is selected from H, CN, or Cl-10 alkyl or substituted alkyl;
  • X is selected from N or CH; and
  • R 6 is selected from H, CN, carboxyl or ester groups.
  • the substituent of the substituted alkyl group is selected from halogen, CN, OH, R 5 , OR 5 , NHS0 2 R 5 , S0 2 R 5 , COOH or C0 2 R 7 ;
  • R 5 is an alkyl group or a substituted alkyl group of Cl-6, and the substituent is 1-5 halogens, COOH or C0 2 R 7 ; and R 7 is a C1-6 alkyl group.
  • the intermediate is:
  • Step 1 Using (lS,5R)-3,8-diazabicyclo[3.2.1]heptan-2-one (re ra/ ⁇ i raw, 1992, 23, 4985) as raw material and di-dicarbonate Butyl ester is reacted in an alkaline solution to obtain a product which is left as the next reactant;
  • Step 2 The product obtained in the previous step is added to the Lawson reagent to obtain a product which is left as the next reactant;
  • Step 3 The product obtained in the previous step is added to a strong acid solution to obtain a product which is reserved for the next step.
  • Step 4 reacting the product obtained in the previous step, R 3 -substituted acetohydrazide with sodium acetate or R 3 -substituted sodium acetate to obtain a product which is left as the next reactant;
  • the starting material is replaced by (lR,5S)-3,8-diazabicyclo[3.2.1]heptan-2-one, and the compound oxime is prepared according to the above method; or, using the racemic starting material, After the above method is synthesized, the optical isomer is resolved to obtain the compound IIAA or hydrazine.
  • reaction steps are as follows:
  • the reaction process includes the following steps:
  • Step 1 reacting N-Boc-3-amino-1,2-propanediol with methyl (-1-nitrobenzyloxycarbonyl-2-aziridinecarboxylate) in a solvent to obtain a product for the next step. Reactant;
  • Step 2 The product obtained in the previous step is reacted with a Dess-Martin reagent to obtain a product which is reserved for the next step;
  • Step 3 The product obtained in the previous step is subjected to hydrogenation reaction to obtain a product which is left as a next step;
  • 4 The product obtained in the previous step is added to a strong acid solution, and the reaction is carried out to obtain a product which is left as the next step;
  • Step 5 The product obtained in the previous step is reacted by adding sodium methoxide in a solvent to obtain a product for the next step. Reactant;
  • Step 6 The product obtained in the previous step is added to di-tert-butyl dicarbonate and a tertiary amine to obtain a product which is left as the next reaction;
  • Step 7 The product obtained in the previous step is added to the Lawson reagent to obtain a product which is left as the next reactant;
  • Step 8 The product obtained in the previous step is added to a strong acid solution, and the reaction is carried out to obtain a product for the next reaction.
  • the starting material is replaced by (R)-l-p-nitrobenzyloxycarbonyl-2-aziridinecarboxylic acid methyl ester, and the compound hydrazine is prepared according to the above method; or, using the racemic amino acid methyl ester, After synthesis according to the above method, the optical isomer is resolved to obtain the compound ruthenium or osmium.
  • the compounds and derivatives provided herein may be based on IUPAC (International Union of Pure and Applied Chemistry) or
  • substitution means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
  • the minimum and maximum values of the carbon atom content in the hydrocarbon group are indicated by a prefix, for example, the prefix (Ca-b)alkyl group indicates any alkyl group having "a" to "b” carbon atoms.
  • (C1-4)alkyl means an alkyl group containing from 1 to 4 carbon atoms.
  • pharmaceutically acceptable means that a carrier, carrier, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients that constitute a pharmaceutical dosage form, and is physiologically Compatible with the receptor.
  • salts and “pharmaceutically acceptable salt” are the acid and I or basic salts which form the compound or its stereoisomers with inorganic and/or organic acids and bases, and also include zwitterionic salts (internal salts). Also included are quaternary ammonium salts such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. It may also be obtained by mixing a compound, or a stereoisomer thereof, with a suitable amount (e.g., equivalent) of a certain amount of an acid or a base.
  • suitable amount e.g., equivalent
  • the salt in the present invention may be a hydrochloride, a sulfate, a citrate, a besylate, a hydrobromide, a hydrofluoride, a phosphate, an acetate, a propionate or a dibutyl compound. Acid, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.
  • the invention includes isotopically-labeled compounds of formula (IA) or (IB), said isotopically-labeled compound being the same as the compounds listed herein, but one or more of the atoms are Another atom is substituted, the atomic mass or mass of which is different from the atomic mass or mass number that is common in nature.
  • Isotopes which may be introduced into the compound of formula (IA) or (IB) include hydrogen, carbon, nitrogen, oxygen, sulfur, ie 2 H, 3 H, 13 C, 14 C, 15 N, 17 0, 18 0, 35 S o
  • Compounds of formula (IA) or (IB) containing the above isotopes and I or other atomic isotopes, and stereoisomers thereof, and pharmaceutically acceptable salts of the compounds, stereoisomers, are intended to be encompassed within the scope of the invention .
  • the key intermediates and compounds in the present invention are isolated and purified in a manner which is commonly used in organic chemistry for separation and purification and examples of such methods include filtration, extraction, drying, spin drying, and various types of chromatography. Alternatively, the intermediate can be subjected to the next reaction without purification.
  • one or more compounds of the invention may be used in combination with one another.
  • the compounds of the present invention can be used in combination with any other active agent for the preparation of a medicament or pharmaceutical composition for modulating cellular function or treating a disease. If a group of compounds is used, the compounds can be administered simultaneously, separately or sequentially to the subject.
  • the compound of the present invention is effective for inhibiting DPP-IV activity, and is a member of the DPP family, DPP2, DPP8,
  • DPP9 has reasonable selectivity. These compounds can be used to treat a variety of DPP-4-related diseases such as diabetes, providing new options for clinical use.
  • Step 4 Small benzyl -2-(methoxycarbonyl)-5-(methylthio)-3,4-dihydro-2H-pyrrole small iodinating gun (combination le)
  • Step 5 trans-Wl-benzyl-(nitroalkenyl)-pyrrole-2-carboxylic acid methyl ester (Compound If)
  • Compound le 8 g, 20.5 mmol
  • nitromethane was added.
  • triethylamine 4 mL, 29 mmol
  • the solvent was evaporated under reduced pressure and then purified tolululululululu
  • the compound lf (2.1 g, 7.6 mmol) was hydrogenated in a mixed solution of ethyl acetate and acetic acid (10 mL + 10 mL) for 4 hours under catalysis of 10% palladium carbon.
  • the palladium carbon catalyst was filtered off with diatomaceous earth and concentrated to dryness.
  • the residue (1.8 g, 7.3 mmol) was dissolved in 15 mL of methanol, and then evaporated.
  • the palladium carbon catalyst was filtered off with celite, and then concentrated to dryness to give compound lg, white solid, 0.9 g, yield 94%.
  • Step 7 (M,5R)-8-tert-Butoxycarbonyl-3,8-azabicyclobicyclo[3.2.1]octan-2-one (compound lh) to an lg (2 g, To a solution of 15.9 mmol) in 40 mL of dichloromethane was added di-tert-butyl dicarbonate ( 5.19 g, 23.8 mmol) and triethylamine (0.66 mL, 4.8 mmol) and allowed to warm to room temperature overnight. After the solvent was evaporated under reduced pressure, EtOAc mjjjjjjjjjjjjjjjjjj
  • Step 8 (M,5R)-8-tert-Butoxycarbonyl-3,8-azabicyclobicyclo[3.2.1]octanoyl-2-thioketone (Compound li)
  • Compound lh (40 mg, 0.18 mmol) Dissolved in 5 mL of tetrahydrofuran and added Lawson's reagent (43 mg, 0.1 mmol) with vigorous stirring. After the reaction mixture was stirred for 3 hours, the reaction mixture was evaporated to dryness and then evaporated and evaporated.
  • Step 7 6-sulfanyl-3-oxo-7,9-diazabicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester
  • Lawson's reagent (367 mg, 0.91 mmol) was added to The compound 2g (220 mg, 0.91 mmol), EtOAc (EtOAc, m. (20 mL). The organic phase was dried, filtered, concentrated and purified tolululululululululululululu
  • Trifluoroacetic acid (3 mL) was added dropwise to a solution of EtOAc (3 mL). The yield is 100%.
  • Step 9 ((2R)-4-carbonyl-4-(6-thioindol-3-oxo-7,9-diazabicyclo[3.3.1] ⁇ -9-fluorenyl) small (2, Benzyl 4,5-trifluorophenyl)butan-2-ylcarbamate (Compound 2j)
  • Step 10 ((2R)-4-carbonyl-4-(3-trifluoromethyl-6,7,9,10-tetrahydro-5H-6,10-cycloimine[1,2,4]3 Benzazo[3,4-d][l,5]oxazolyl-11-fluorenyl)-1-(2,4,5-trifluorophenyl)-2-butyl)carbamate (compound) 2k )
  • Step 11 (3R)-3-Amino-l-(3-trifluoromethyl-6,7,9,10-tetrahydro-5H-6,10-cycloimine[1,2,4]triazole And [3,4-d][l,5]oxazolyl-11-fluorenyl)-4-(2,4,5-trifluorophenyl)-1-butanone trifluoroacetate (Compound 2 )
  • Step 1 ((R)-4-carbonyl-4-((lS,5R)-2-thiocarbonyl-3,8-diazabicyclo[3.2.1]-8-octyl) small (2,4, tert-Butyl 5-trifluorophenyl)-2-butyl)carbamate (Compound 3a)
  • Step 3 (R ) -3-amino-1-(( 6R,9S ) -3-methyl-6,7,8,9-tetrahydro-5H-6,9-cyclic imine [1,2,4 Triazolo[4,3-a]azepine-10-alkyl)-4-(2,4,5-trifluorophenyl)-1-butanone trifluoroacetate (compound 3)
  • Step 1 ((R)-4-carbonyl-4-((lS,5R)-2-thiol-3,8-diazabicyclo[3.2.1]-8-octyl) small (2 -methylphenyl)-2-butyl)carbamic acid tert-butyl ester (compound 4a)
  • Step 2 ((R)-4-((6R,9S)-3-trifluoromethyl-6,7,8,9-tetrahydro-5H-6,9-cycloimine [1,2,4 Triazolo[4,3-a]azepine-10-yl)-4-yl-1-(2-methylphenyl)-2-butyl)carbamic acid tert-butyl ester (compound 4b)
  • Step 3 (R)-3-Amino-1-((6R,95)-3-trifluoromethyl-6,7,8,9-tetrahydro-5H-6,9-cycloimine [1, 2,4] Triazolo[4,3-a]azepine-10-indole)-4-(2-methylphenyl)butanone trifluoroacetate (compound 4)
  • Step 1 ((R)-4-((6R,9S)-3-trifluoromethyl-6,7,8,9-tetrahydro-5H-6,9-cycloimine [1,2,4 Triazolo[4,3-a]azepine-10-yl)-4-yl(t-fluorophenyl)-2-butyl)carbamic acid tert-butyl ester (compound 5a)
  • reaction solution was added to 10 mL of saturated brine, and extracted with dichloromethane (15mIX3).
  • Step 2 (R) -3-Amino-1-((6R,9S -3-trifluoromethyl-6,7,8,9-tetrahydro-5H-6,9-cycloimine [1,2 , 4] triazolo[4,3-a]azepine-10-alkyl)-4-(2-fluorophenyl)butanone trifluoroacetate (compound 5)
  • Step 1 ((R)-4-Methyl-4-((lS,5R)-2-thiolcyl-3,8-diazabicyclo[3.2.1]-8-octyl) Small (3- Chlorophenyl)-2-butyl)carbamic acid tert-butyl ester (compound 6a)
  • Step 2 ((R)-4-((6R,9S)-3-trifluoromethyl-6,7,8,9-tetrahydro-5H-6,9-cycloimine [1,2,4 Triazolo[4,3-a]azepine-10-yl)-4-yl-small (3-chlorophenyl)-2-butyl)carbamic acid tert-butyl ester (compound 6b)
  • Step 3 (R)-3-Amino-1-((6R,9S)-3-trifluoromethyl-6,7,8,9-tetrahydro-5H-6,9-cycloimine [1, 2,4]triazolo[4,3-a]azepine-10-mercapto)-4-(3-chlorophenyl)butanone trifluoroacetate (compound 6)
  • DPP-4, DPP-2, DPP-8, and DPP-9 are members of the DPP family.
  • DPP-8, DPP When the -9 enzyme is active, it will cause a series of toxic side effects such as dormant T cell death, gastrointestinal toxicity and immune function. Therefore, in the development of DPP-4 (DPP-IV) enzyme inhibitor, it is required to increase the inhibitor pair.
  • DPP-4 (DPP-IV) enzyme inhibitor it is required to increase the inhibitor pair.
  • the present invention determines the inhibitory effect of the compound of the present invention on the DPP family by the following test.
  • test compound was dissolved in dimethyl sulfoxide, followed by a buffer solution (DPP4: 100 mM HEPES, pH 7.5, 0.1 mg/mL BSA; DPP2: 100 mM HEPES, pH 5. 5, 0.1 mg /mL BSA; DPP8: 50 mM Tris-HC1, pH 7.5, 0.1 mg/mL BSA; DPP9: 25 mM Tris-HCl, pH 7.5, 0.1 mg/mL BSA) A series of working solutions.
  • DPP4 100 mM HEPES, pH 7.5, 0.1 mg/mL BSA
  • DPP2 100 mM HEPES, pH 5. 5
  • DPP8 50 mM Tris-HC1, pH 7.5, 0.1 mg/mL BSA
  • DPP9 25 mM Tris-HCl, pH 7.5, 0.1 mg/mL BSA
  • Recombinant human DPP-4 (final concentration approximately 180 ng/mL) or DPP-2 (final concentration approximately 100 ng/mL) or DPP-8 (final concentration approximately 200 ng/mL) or DPP-9 (final Concentration of approximately 50 ng/mL) mixed with the above series of compound working solutions, then added to Gly-Pro-AMC (final concentration DPP4 is 50 ⁇ , DPP2/8/9 is 20 ⁇ ) (total reaction volume is ⁇ immediately continuous
  • the released AMC (excitation wavelength 360 nm, emission wavelength 460 nm) was detected for 15 minutes.
  • the IC50 of the half inhibition concentration was calculated using SigmaPlot software, and the results are shown in the table below.
  • the compound of the present invention can effectively inhibit DPP-IV activity and has good selectivity to members of the DPP family, DPP-2, DPP-8, and DPP-9. These compounds can be used to treat a variety of DPP-4-related diseases such as diabetes, providing new options for clinical use.

Abstract

L'invention concerne des composés tels que présentés dans les formules IA et IB ou des sels pharmaceutiquement acceptables de ceux-ci, le procédé de préparation associé, et des utilisations de ceux-ci, ainsi que les intermédiaires de ces composés et le procédé de préparation approprié. Les composés tels que présentés dans les formules IA et IB peuvent inhiber efficacement l'activité de la DPP-4, présentent une bonne sélectivité et peuvent être transformés en d'éventuels nouveaux médicaments pour traiter le diabète.
PCT/CN2014/072432 2013-02-22 2014-02-24 Composés inhibiteurs de la dpp-iv et leurs intermédiaires WO2014127745A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003082817A2 (fr) * 2002-03-25 2003-10-09 Merck & Co., Inc. Inhibiteurs de la dipeptidyl peptidase beta-amino heterocycliques pour le traitement ou la prevention du diabete
WO2004058266A1 (fr) * 2002-12-20 2004-07-15 Merck & Co., Inc. Derives de 3-amino-4-phenylbutanoique acide utilises en tant qu'inhibiteurs de dipeptidyl peptidase pour le traitement ou la prevention du diabete
CN1882551A (zh) * 2003-07-31 2006-12-20 麦克公司 用作用于治疗或预防糖尿病的二肽基肽酶－iv酶抑制剂的六氢二氮杂吖庚因酮

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA74912C2 (en) * 2001-07-06 2006-02-15 Merck & Co Inc Beta-aminotetrahydroimidazo-(1,2-a)-pyrazines and tetratriazolo-(4,3-a)-pyrazines as inhibitors of dipeptylpeptidase for the treatment or prevention of diabetes

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003082817A2 (fr) * 2002-03-25 2003-10-09 Merck & Co., Inc. Inhibiteurs de la dipeptidyl peptidase beta-amino heterocycliques pour le traitement ou la prevention du diabete
WO2004058266A1 (fr) * 2002-12-20 2004-07-15 Merck & Co., Inc. Derives de 3-amino-4-phenylbutanoique acide utilises en tant qu'inhibiteurs de dipeptidyl peptidase pour le traitement ou la prevention du diabete
CN1882551A (zh) * 2003-07-31 2006-12-20 麦克公司 用作用于治疗或预防糖尿病的二肽基肽酶－iv酶抑制剂的六氢二氮杂吖庚因酮

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