WO2014127747A1 - Composés inhibant dpp-iv et leurs intermédiaires - Google Patents

Composés inhibant dpp-iv et leurs intermédiaires Download PDF

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WO2014127747A1
WO2014127747A1 PCT/CN2014/072443 CN2014072443W WO2014127747A1 WO 2014127747 A1 WO2014127747 A1 WO 2014127747A1 CN 2014072443 W CN2014072443 W CN 2014072443W WO 2014127747 A1 WO2014127747 A1 WO 2014127747A1
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reaction
solvent
product
compound
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PCT/CN2014/072443
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Chinese (zh)
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李进
斯托克斯⋅迈克尔
窦登峰
万金桥
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

Definitions

  • the present invention relates to a compound which inhibits DPP-IV and an intermediate thereof.
  • Diabetes is a metabolic disorder caused by a combination of genetic and environmental factors that poses a serious threat to human health and life.
  • the prevalence of diabetes has increased dramatically with the improvement of quality of life and lifestyle changes.
  • IDF International Diabetes Federation
  • the number of adult diabetes patients in China has reached 98.4 million, ranking first in the world, and the situation of prevention and control is grim.
  • Dipeptidyl peptidase-IV (DPP-IV) inhibitors are an important research object in this field.
  • 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 soluble form in plasma ( 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 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 glyce-glucan-like peptide-1 (GLP-1) in vivo.
  • GLP-1 active glyce-glucan-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 have the highest 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 pre-insulin genes and enhances mR A stability Increase biosynthesis; 3) inhibit glucagon secretion and reduce hepatic glucose release; 4) promote pancreatic ⁇ -cell proliferation and differentiation, inhibit ⁇ -cell apoptosis; 5) control gastric appetite, control appetite, lower blood sugar by inhibiting gastric emptying, At the same time 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 in vivo, 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.
  • Sitagliptin developed by Merck was approved by the US Food and Drug Administration (FDA) to become the first DPP-IV inhibitor to be marketed.
  • the currently marketed DPP-IV inhibitors include vildagliptin, saxagliptin, alogliptin, and linagliptin.
  • the new DPP-IV inhibitor repagliptin was independently developed by Chinese pharmaceutical companies.
  • 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.), which has the following advantages compared to traditional diabetes drugs [ScheenAJ. DPP-4 inhibitors in the management of type 2 diabetes: a critical review of head-to-head trials. Diabetes Metab. 2012 ;38(2):89-101.; Gallwitz B. Emerging DPP-4 inhibitors: focus on linagliptin for type 2 diabetes.
  • the present invention provides a compound shown below, 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.
  • R 1 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 alkane An alkoxy group substituted with an oxy group or a halogen;
  • 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 , substituted hetero atom or substituted hetero
  • the substituent of the alkyl group is halogen, CN, OH, 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 alkyl group having 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 C1-2 alkyl group
  • R 3 is selected from a halogen-substituted alkyl group
  • R 6 is selected from C0. 2 R 7 .
  • halogen is F or Cl.
  • R 2 is selected from alkyl or substituted alkyl of Cl-5 or 1-5 heteroalkyl-containing or substituted heteroalkyl or 1-5 heteroatoms or substituted heteroatoms;
  • R 3 is selected from H, CN Or a C-10 alkyl or substituted alkyl group;
  • 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 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 , the hetero
  • the substituent N, S or 0, substituted hetero atom or substituted heteroalkyl containing substituent is halogen, CN, 0H, R 5 , 0R 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, C00H or C0 2 R 7 ; and R 7 is a C1-6 alkyl group.
  • 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 create multiple chiral isomers, adding to the difficulty of compound synthesis and identification.
  • introduction of a substituent group by bridging not only reduces the complexity of the chiral compound and increases the controllability of chirality, but also increases the rigidity of the compound, and can change the activity and selectivity of the compound.
  • 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-like compound.
  • the dipeptidyl peptidase-IV inhibitor is a drug for treating or/and preventing diabetes, hyperglycemia, and insulin resistance.
  • Step l fl is reacted with diphenyl azide, diisopropyl azodicarboxylate or triphenylphosphine, and the obtained product is used as a next reaction;
  • Step 2 The product of the previous step is de-esterified under alkaline conditions to obtain the next reaction product;
  • Step 3 The product of the previous step is deprotected under acidic conditions to obtain the next product;
  • Step 4 The product of the previous step is reacted with fluorenylmethoxycarbonyl chloride under neutral conditions to obtain an amino-protected product;
  • Step 5 the product of the previous step and the R 3 substituted formylhydrazine and the condensing agent are reacted in a solvent, and the obtained product is used as a next reaction;
  • Step 6 The product of the previous step, phosphorus oxychloride is reacted in a solvent, and the obtained product is used as a next reaction;
  • Step 7 The hydrogenation reaction of the previous product is carried out, and the obtained product is used as a next reaction;
  • Step 8 The product of the previous step is intramolecularly reacted in a solvent, and the obtained product is used as a next reaction product;
  • Step 9 The product of the previous step is reacted with an alkaline solution, and the obtained product is used as a next reaction;
  • Step 10 The product of the previous step is reacted with the protected ⁇ -aminobutyric acid substituted by R 1 , and the obtained product is used as a next reaction;
  • Step 11 adding the acid reaction to the product of the previous step to obtain the product hydrazine
  • a compound oxime is prepared by using two chiral centers simultaneously inverted starting materials; or, using a racemate starting material, after reacting according to the above steps, the optical isomers are resolved.
  • Compound ⁇ or ⁇ is prepared by using two chiral centers simultaneously inverted starting materials; or, using a racemate starting material, after reacting according to the above steps, the optical isomers are resolved.
  • the solvent used in Step 1 is an aprotic solvent
  • the aprotic solvent is preferably tetrahydrofuran
  • the reaction temperature is 0 ° C to 30 ° C
  • the reaction time is preferably 6 to 18 hours
  • the solvent used in Step 2 is a mixed solvent of water and tetrahydrofuran
  • the base used is an inorganic strong base
  • the inorganic strong base is preferably lithium hydroxide or sodium hydroxide
  • the reaction temperature is 20 ° C to 30 ° C
  • the reaction time is 2 to 12 hours;
  • the solvent used in Step 3 is a polar solvent, and the polar solvent is preferably dichloromethane, ethyl acetate or methanol.
  • the acid used is an organic strong acid, preferably trifluoroacetic acid or hydrochloric acid, and the reaction temperature is 20 ° C to 30 °. C, the reaction time is 0.5-2 hours;
  • the solvent in the step 4 is preferably a mixed solvent of tetrahydrofuran and water, the base used is a weak base, the weak base is preferably triethylamine, the reaction temperature is 0 ° C to 30 ° C, and the reaction time is 4 to 12 hours;
  • the solvent described in Step 5 is an aprotic solvent, the aprotic solvent is preferably dichloromethane, the base used is an organic base, and the organic base is preferably N,N-diisopropylethylamine, the condensation
  • the agent is preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole, or 2-(7-azobenzotriazole)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethylurea hexafluorophosphate, the temperature is 20 ° C to 30 ° C, the reaction time is 2 to 12 hours;
  • the solvent used in Step 6 is a polar solvent, the polar solvent is preferably acetonitrile, the reaction temperature is 70 ° C to 90 ° C, and the reaction time is 12 to 24 hours;
  • the solvent described in Step 7 is a polar solvent, the polar solvent is preferably methanol, the hydrogenation catalyst used is 10% palladium carbon, and the hydrogenation time is 2 to 4 hours;
  • the solvent described in Step 8 is preferably acetic acid, the reaction temperature is from 110 ° C to 120 ° C, and the reaction time is from 18 to 24 hours;
  • the solvent used in Step 9 is a mixed solvent of tetrahydrofuran and water
  • the base is an inorganic base or an organic base
  • the inorganic base is preferably sodium hydroxide or lithium hydroxide
  • the organic base is preferably piperidine
  • the reaction temperature is 20°. C to 30 ° C, the reaction time is 0.5 to 2 hours;
  • the solvent used in Step 10 is an aprotic solvent, and the aprotic solvent is preferably dichloromethane, N, N-di Methylformamide or tetrahydrofuran, the base used is an organic base, the organic base is preferably N,N-diisopropylethylamine, and the condensing agent is 1-(3-dimethylaminopropyl)-3-ethyl carbon Diimine hydrochloride and 1-hydroxybenzotriazole, or 2-(7-azobenzotriazole)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethylurea hexafluorophosphate, used
  • the reaction temperature is from 0 ° C to 30 ° C, and the reaction time is from 0.5 to 2 hours;
  • the acid in Step 11 is a proton strong acid, and the proton strong acid is preferably hydrochloric acid or trifluoroacetic acid, the solvent used is an aprotic solvent, and the aprotic solvent is preferably dichloromethane or ethyl acetate, and the reaction temperature is 0.
  • the reaction time is from 0.5 to 4 hours at °C to 30 °C.
  • the present invention also provides a process for the preparation of the above formula or a ruthenium compound, the reaction steps being as follows:
  • Stepl gl is reacted with diphenyl azide, diisopropyl azodicarboxylate or triphenylphosphine, and the obtained product is used as a next reaction;
  • Step 2 The product of the previous step and HR 6 are reacted under a strong base, and the obtained product is used as a next reaction;
  • Step 3 The product of the previous step is reacted with an acid, and the obtained product is used as a next reaction;
  • Step 4 The product of the previous step is reacted with fluorenylmethoxycarbonyl chloride under weakly basic conditions, and the obtained product is used as the next reaction;
  • Step 5 The product of the previous step is hydrogenated and reacted with di-tert-butyl dicarbonate, and the obtained product is used as the next reaction.
  • Step 6 The product of the previous step and the sodium nitrite solution are reacted under acidic conditions, and the obtained product is used as the next reaction.
  • Step 7 The product of the previous step is reacted with zinc powder and an acid anhydride, and the obtained product is used as a next reaction product;
  • Step 8 The product of the previous step is reacted under acidic conditions, and the obtained product is used as the next reactant;
  • Step 9 The product of the previous step is reacted with hexamethyldisilazide and ammonium sulfate under acidic conditions, and the obtained product is used as the next reaction;
  • Step 10 The product of the previous step and the protected ⁇ -aminobutyric acid substituted by R 1 are subjected to a condensation reaction under basic conditions, and the obtained product is used as a next reaction;
  • Step 11 The product of the previous step is added under strong acidic conditions to obtain a product
  • a compound oxime is prepared by using two chiral centers simultaneously inverted starting materials; or, using a racemate starting material, after reacting according to the above steps, the optical isomers are resolved.
  • the solvent in Step 1 is an aprotic solvent, preferably tetrahydrofuran, the reaction temperature is 0 ° C to 30 ° C, and the reaction time is 8 to 12 hours;
  • the solvent used in Step 2 is an aprotic solvent, the aprotic solvent is preferably tetrahydrofuran, the base is a non-nucleophilic organic strong base, and the non-nucleophilic organic strong base is preferably a diisopropylamino group.
  • Lithium the reaction temperature is from minus 70 degrees to minus 20 degrees, and the reaction time is 2 hours;
  • 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 solvent, preferably dichloromethane or water, the base used is a weak base, preferably triethylamine, the reaction temperature is 0 ° C to 30 ° C, and the reaction time is 2 to 8 hours;
  • the catalyst used in Step 5 is a metal catalyst optimized to 10% palladium carbon, the solvent is a protic solvent, preferably methanol, the reaction temperature is 20 ° C to 30 ° C, and the reaction time is 1 to 2 hours;
  • the solvent used in Step 6 is water and acetic acid, the reaction temperature is 0 to 30 ° C, and the reaction time is 12 hours;
  • the solvent described in Step 7 is acetic acid, the reaction temperature is 30 ° C, and the reaction time is 2 hours;
  • the acid used in Step 8 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 9 is a high-boiling aprotic solvent
  • the high-boiling aprotic solvent is preferably toluene
  • the catalyst used is ammonium sulfate
  • the reaction temperature is 110 ° C to 130 ° C
  • the reaction time is 4 to 12 hours;
  • the solvent used in Step 10 is an aprotic solvent, and the aprotic solvent is preferably dichloromethane, tetrahydrofuran or N, N-dimethylformamide, the base used is an organic base, and the organic base is preferably divalent.
  • the condensing agent used is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole, or 2-(7-azobenzene) And triazole)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethylurea hexafluorophosphate
  • the reaction temperature range is from 0 ° C to 30 ° C
  • the reaction time is 0.5 to 2 hours;
  • the acid used in Step 11 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. .
  • Step 12 hi is subjected to a sulfonylation reaction under alkaline conditions, and the obtained product is used as a next reactant;
  • Step 13 The reaction product of the previous step is hydrolyzed under alkaline conditions, and the obtained product is used as a next reaction;
  • Step 14 The reaction product of the previous step is reacted with oxalyl chloride, and the obtained compound is reacted with trimethylsilylated diazomethane. Then adding a hydrobromic acid solution to react, and the obtained product is used as a next reaction;
  • Step 15 The reaction product of the previous step is reacted with R 3 substituted formazan, and the obtained product is used as a next reaction;
  • Step 16 The reaction product of the previous step is itself closed under strong alkaline conditions, and the obtained product is used as the next reactant;
  • Step 17 The reaction product of the previous step is subjected to catalytic hydrogenation reaction, and the obtained product is used as the next reaction;
  • Step 18 The product of the previous step is subjected to a condensation reaction with the R 1 -substituted protected ⁇ -aminobutyric acid under basic conditions, and the obtained product is used as a next reaction;
  • Step 19 The reaction product of the previous step is deprotected under strong acidic conditions, and the product is obtained after purification;
  • the optical isomer can be resolved to obtain the compound hydrazine or hydrazine.
  • the solvent used in Step 12 is an aprotic solvent
  • the aprotic solvent is preferably tetrahydrofuran or pyridine
  • the base used is an organic base
  • the organic base is preferably N-methylimidazole
  • the reaction temperature is 20 ° C. By 30 ° C, the reaction time is 4 to 24 hours;
  • the solvent used in Step 13 is a mixed solvent of water and tetrahydrofuran, the ratio of the mixed solvent of water and tetrahydrofuran is 1:1 (V/V), the base used is an inorganic base, and the inorganic base is preferably lithium hydroxide or sodium hydroxide.
  • the reaction temperature is from 20 ° C to 30 ° C, and the reaction time is from 2 to 4 hours;
  • the solvent used in step 14 is preferably a mixed system of acetonitrile, tetrahydrofuran, n-hexane or the like, the reaction temperature is from 0 ° C to 30 ° C, and the reaction time is from 8 to 12 hours;
  • the solvent used in Step 15 is a protic solvent
  • the aprotic solvent is preferably ethanol
  • the reaction temperature is 70 to 90 ° C
  • the reaction time is 3 to 6 hours;
  • the solvent used in Step 16 is an aprotic solvent, the aprotic solvent is preferably DMF, the base is an inorganic strong base, and the inorganic strong base is preferably sodium hydride or potassium hydride at a temperature of 70 ° C to 80 °. C, the reaction time is 3 to 6 hours;
  • the catalyst used in Step 17 is a metal catalyst, optimized to palladium carbon, the solvent is a protic solvent, preferably methanol, the reaction temperature is 20 ° C to 30 ° C, and the reaction time is 1 to 2 hours;
  • the solvent used in Step 18 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)-oxime, ⁇ , ⁇ ', ⁇ '- tetramethyl urea hexafluorophosphate, the reaction temperature used is 0 ° C to 30 ° C, the reaction time is 0.5 to 2 hours;
  • the acid used in Step 19 is a proton strong acid, and the proton strong acid is preferably trifluoroacetic acid or hydrochloric acid, and 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 present invention also provides an intermediate of the above compound of the formula IA and IB, which has the following structural formula:
  • R 2 is selected from C 2-5 alkyl or substituted alkyl or 2-5 heteroatoms or substituted heteroatoms or 2-5 heteroalkyl or substituted heteroalkyl;
  • R 3 is selected from H, CN Or a C-10 alkyl or substituted alkyl group;
  • 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 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 , the hetero atom a substituent selected from N, S or 0, a substituted hetero atom or a substituted heteroalkyl group is 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 invention also provides an intermediate compound, the intermediate being:
  • the present invention also provides a process for the preparation of the above formulas of ruthenium and osmium compounds, the reaction steps being as follows:
  • the compound ⁇ is obtained using two chiral centers simultaneously inverted starting materials; the compounds ⁇ and ⁇ can also be prepared and isolated using the corresponding racemic starting materials and the same synthetic method.
  • the present invention also provides a process for the preparation of the above formulas of ruthenium and osmium compounds, the reaction steps being as follows:
  • the compound ⁇ is obtained using two chiral centers simultaneously inverting the starting materials; the compounds ⁇ and ⁇ can also be prepared and isolated by the corresponding racemic starting materials and the same synthetic method.
  • the present invention also provides a method for preparing the above-mentioned salts of the hydrazine and IB compounds, the steps are as follows:
  • 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 indicates any alkyl group having "a" to "b” carbon atoms.
  • (C1-4)alkyl means a fluorenyl group containing from 1 to 4 carbon atoms.
  • pharmaceutically acceptable means that a carrier, carrier, diluent, excipient, and I or salt formed are generally chemically or physically compatible with the other ingredients that constitute a pharmaceutical dosage form, and are physiologically Compatible with the receptor.
  • salts and “pharmaceutically acceptable salts” are the acid and/or basic salts of the compounds or their stereoisomers with inorganic and I or organic acids and bases, as well as 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 compound. 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 A fluoro-labeled compound refers to the same as the compounds listed herein, but one or more of the atoms are replaced by another atom whose atomic mass or mass number 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, g ⁇ 2 H, 3 H, 13 C, 14 C, 15 N, 17 0, 18 0, 35 S o
  • Compounds of formula (I) and stereoisomers thereof containing the above isotopes and I or other atomic isotopes, as well as pharmaceutically acceptable salts of such compounds, stereoisomers, are intended to be encompassed within the scope of the invention.
  • the key intermediates and compounds of the present invention are isolated and purified in a manner that is commonly used in organic chemistry for separation and purification and that is extracted, dried, spin dried, 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, these compounds can be simultaneously, separately or sequentially administered to the test compounds to effectively inhibit DPP-IV activity, and compound 1 inhibits DPP4 compared to the commercially available drug Jenovi. The effect is equivalent, but the inhibitory activity against other DPP family members (DPP2, DPP8, DPP9) is lower than that of quetiavir, indicating that the compound of the present invention can not only effectively inhibit the pharmacological activity of DPP4, but also reduce the inhibitory activity against other DPP families. , reduce toxic side effects, and medicinal safety is better.
  • the compounds of the present invention are useful for the treatment of various DPP-4 related diseases such as diabetes and provide better medication safety.
  • Step 1 N-tert-Butyloxy-yl-cis-4-azido-L-proline methyl ester (compound lb)
  • Step 2 N-tert-Butyloxy-yl-cis-4-azido-L-proline (compound lc)
  • Step 4 N-9-fluorenylmethoxycarbonyl--cis 4-azido-L-proline (compound le)
  • Step 5 (25,45)-4-#m-2-(2-Trifluoroacetyl)indolylpyrrolidine-1-carboxylic acid 9-fluorenylmethyl ester (Compound If) Stir at room temperature to le (0.6 N,N-diisopropylethylamine (0.8 g, 6.4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbazone was added sequentially to a solution of g, 1.6 mmol) in dichloromethane. Amine hydrochloride (0.46 g, 2.4 mmol) and 1-hydroxybenzotriazole (0.32 g, 2, 4 mmol).
  • Step 6 (2S,4S)-4-azido-2-(5-trifluoromethyl-1,3,4-oxazole-2-indenyl)pyrroles and 9-oxime methyl formate (compound lg )
  • Step 7 (2S,4S)-4-amino-2-(5-trifluoromethyl-1,3,4-oxazole-2-indenyl) B-pyrrolidine-9-indole methyl ester (compound) Lh )
  • Step 8 (5S,8S)-3-(Trifluoromethyl)-5,6-dihydro-5,8-methyl[1,2,4]triazolo[4,3-a]B Bis-7(8H)-formic acid 9-anthracene methyl ester (compound li)
  • Step 10 ((R)-4-Oxo-4-((5S,8S)-3-(trifluoromethyl)-5,6-dihydro-5, 8-methyl[1,2,4] Triazolo[4,3-a]Bpyrazine-7(8H)alkyl) tert-butyl (2,4,5-trifluorophenyl)butan-2-ylcarbamate (compound lk )
  • Step 11 (R) -3-Amino-1-((5S,8S)-3-(trifluoromethyl)-5-6-dihydro-5 8-bromomethyl[1,2,4]triazole And [4,3-a]pyrazine-7(8H)-alkyl)-4-(2,4 5-trifluorophenyl)-1-butanone hydrochloride (Compound 1) Dissolve lk in 2 In a solution of mL 2N hydrochloric acid in ethyl acetate, stirred at room temperature for 0.5 h. After concentration under reduced pressure, the crude material was purified by preparative HPLC to afford title compound 1 as a white solid.
  • the preparation of the oxime was carried out using two chiral centers simultaneously reversed la as the starting material, using exactly the same experimental procedure.
  • Step 1 (2, )-4-Azido-2-(3-methoxy-3-propionylpropionyl)pyrroles of tert-butyl formate (Compound 2b) Methyl acetate (26.1 g 296.0) at room temperature Methyl) was dissolved in anhydrous tetrahydrofuran (300 mL), cooled with nitrogen and then cooled to -70[deg.] C. While maintaining the temperature, a solution of the compound 2a (20 g of 74 mmol) in tetrahydrofuran (20 mL) was slowly added dropwise to the reaction mixture, and then the reaction mixture was slowly warmed to -20° and stirred at this temperature for 1 hour. Then the reaction solution was quenched with saturated ammonium chloride solution (100 mL) and concentrated under reduced pressure.
  • Compound 2b Methyl acetate (26.1 g 296.0) at room temperature Methyl) was dissolved in anhydrous tetrahydrofur
  • Step 7 (2)-4-Amino-2-(3-methoxy-3-carbonyl-2-(2,2,2-trifluoroacetamido)-propionyl)pyrrole-1-carboxylic acid (9H - ⁇ -9 ) methyl ester (compound 2h)
  • Trifluoroacetic acid (2 mL) was added dropwise to a solution of compound 2g (150 mg, 0.24 mmol) in dichloromethane (3 mL), and the mixture was stirred for 1 hr. The yield was 100% and used directly in the next reaction without further purification.
  • Step 8 (5S,8S)-3-trifluoromethyl-5,6,7,8-tetrahydro-5,8-bridged methylene-imidazo[1,5-a]pyrazine-pyrrole - 1-methyl formate (Compound 2i)
  • Step 10 (5S,SS)- 7-((R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl)-3-(trifluoromethyl)-5,6 , 7,8-tetrahydrogen -5,8-bridge methylene-imidazo[1,5-a]pyrazine small methyl formate trifluoroacetate (compound 2)
  • Trifluoroacetic acid (2 mL) was added dropwise to a solution of Compound 3b (150 mg, 0.27 mmol) in dichloromethane (3 mL), and the mixture was stirred for 1 hr. 100%, used in the next step without further purification.
  • Step 5 ((5S,8S)-7-((R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl)-3-methyl-5,6,7, 8-tetrahydro-5,8-bridged methylene-imidazo[1 ,5-a]pyrazine small methyl formate trifluoroacetate (compound 3)
  • Trifluoroacetic acid (1 mL) was added dropwise to a solution of Compound 3e (15 mg, 0.028 mmol) in dichloromethane (2 mL), and the mixture was stirred for 1 hour and then concentrated.
  • Compound 3 colorless oil 8 mg, yield 48.5%.
  • Step 1 (2S,4R)-4-p-toluenesulfonyloxy-pyrrole-1,2-dicarboxylic acid small benz-2-methyl ester (compound 4b) Under ice bath to compound p-toluenesulfonyl imidazole (10 g Methyl trifluoromethanesulfonate (7.9 g, 48.2 mmol) was slowly added dropwise to a solution of 45.2 mmol of tetrahydrofuran (5 mL).
  • Step 2 (2S,4R)-1-Benzyloxycarbonylacyl-4-p-toluenesulfonyloxypyrrole-2-carboxylic acid (Compound 4c) aqueous lithium hydroxide solution (20 mL, 0.8 g, 20 mmol) Compound 4b (7.3 g, 16.9 mmol) in MeOH (10 mL) and EtOAc (EtOAc) The reaction solution was concentrated to remove the solvent, then 20 mL of water was added, and the mixture was acidified to pH 3 with 2N hydrochloric acid in an ice bath and extracted with ethyl acetate.
  • Step 3 (2 4RH-Benzyloxycarbonyl-2-(2-bromoacetyl)-4-p-toluenesulfonyloxypyrrolidine (Compound 4d) was applied to compound 4c (2.0 g, 4.8 mmol).
  • Step 7 (R)-3-tert-Butoxycarbonylamino-1-((5 8 -3-trifluoromethyl-5,6-dihydro-5,8-hypo-methylidene-imidazo[l , 5 -a]pyrazine- 7 ( 8 H)-alkyl) - 4 -( 2 , 4 , 5 -trifluorophenyl)-1-butanone (compound 4 h)
  • Step 8 (R)-3-Amino-1-((5 8 -3-trifluoromethyl-5,6-dihydro-5,8-bridgedmethylene-imidazo[1,5-a] Pyrazin-7(8H)-alkyl)-4-(2,4,5-trifluorophenyl)-1-butanone trifluoroacetate (Compound 4)
  • Trifluoroacetic acid (1 mL) was added dropwise to a solution of compound 4h (21 mg) in dichloromethane (3 mL), and the mixture was stirred for 1 hour, then the reaction mixture was concentrated. Trifluoroacetate, colorless oil 18 mg, yield 45%.
  • Step 2 (2S,4R)-1-Benzyloxycarbonyl-2-carbamoyl-4-p-toluenesulfonyloxy-pyrrole (Compound 5b)
  • the crude product 5a (14 g) from the above step was dissolved in dry Tetrahydrofuran (30 mL) was added dropwise with aqueous ammonia (100 mL). After 1 hour, the reaction mixture was extracted with EtOAc (EtOAc)EtOAc. The yield was 78%. MS (ESI n/z: 419 (M+H).
  • Step 8 (R)-3-Benzyloxycarbonylamido-l-((5S,8S)-3-methyl-5,6-dihydro-5,8-bromomethylene-imidazo[1,2 -a] pyrazin - 7
  • Step 9 (R)-3-Amino-l-((5S,8S)-3-methyl-5,6-dihydro-5,8-bromomethylene-imidazo[1,2-a]pyridin Oxazide-7(8H)-alkyl)-4-(2,4,5-trifluorophenyl)-1-butanone trifluoroacetate (compound 5)
  • DPP-4, DPP-2 DPP-8, and DPP-9 are members of the DPP family.
  • DPP-4 may cause side effects on the body, such as inhibition of DPP-8, DPP- 9
  • DPP-4 (DPP-IV) enzyme inhibitor it is required to increase the inhibitor to DPP.
  • the selectivity of -4 reduces the selectivity to other DPP families, thereby reducing the toxic side effects of the inhibitor.
  • 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) Dilute it into a series of working solutions.
  • 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
  • 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 above compounds provided by the present invention are useful for the treatment of various DPP-4-related diseases such as diabetes, and provide better drug safety.

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Abstract

Cette invention concerne des composés répondant aux formules IA ou IB ou des sels pharmaceutiquement acceptables de ceux-ci, leur procédé de préparation, et leurs utilisations. Des intermédiaires des composés selon l'invention et leur procédé de préparation sont en outre décrits. Les composés selon l'invention peuvent efficacement inhiber l'activité DPP-IV. Comparé au médicament en vente dans le commerce, le Januvia, le composé 1 manifeste une forte inhibition contre DPP4, mais a une plus faible inhibition de l'activité contre d'autres membres de la famille DDP (DPP2, DPP8, et DPP9). De ce fait, le composé selon l'invention peut non seulement empêcher efficacement DPP4 de manifester une activité médicale, mais aussi abaisser l'inhibition de l'activité contre d'autres membres de la famille DPP, réduire les effets secondaires toxiques, et offrir une meilleure innocuité médicale.
PCT/CN2014/072443 2013-02-22 2014-02-24 Composés inhibant dpp-iv et leurs intermédiaires WO2014127747A1 (fr)

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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
CN101899047A (zh) * 2009-05-26 2010-12-01 北京翔宇恒天医药技术有限公司 作为二肽基肽酶抑制剂用于治疗或预防糖尿病的β-氨基四氢吡嗪、四氢嘧啶和四氢吡啶

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CN101899047A (zh) * 2009-05-26 2010-12-01 北京翔宇恒天医药技术有限公司 作为二肽基肽酶抑制剂用于治疗或预防糖尿病的β-氨基四氢吡嗪、四氢嘧啶和四氢吡啶

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