WO2011125011A1 - Novel hypoglycemic compounds - Google Patents

Novel hypoglycemic compounds Download PDF

Info

Publication number
WO2011125011A1
WO2011125011A1 PCT/IB2011/051407 IB2011051407W WO2011125011A1 WO 2011125011 A1 WO2011125011 A1 WO 2011125011A1 IB 2011051407 W IB2011051407 W IB 2011051407W WO 2011125011 A1 WO2011125011 A1 WO 2011125011A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
amino acid
methyl
oxo
amino
Prior art date
Application number
PCT/IB2011/051407
Other languages
French (fr)
Inventor
Bakulesh Mafatlal Khamar
Chandan Singh
Rajiv Indravadan Modi
Original Assignee
Cadila Pharmaceuticals Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cadila Pharmaceuticals Limited filed Critical Cadila Pharmaceuticals Limited
Priority to CN201180022812.0A priority Critical patent/CN102946726B/en
Priority to CA2795514A priority patent/CA2795514A1/en
Priority to EP11765149.7A priority patent/EP2555617A4/en
Priority to US13/639,596 priority patent/US9029567B2/en
Publication of WO2011125011A1 publication Critical patent/WO2011125011A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—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
    • 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
    • C07D471/04—Ortho-condensed systems
    • 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
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention is directed to novel hypoglycemic compounds of formula I and pharmaceutically acceptable salts thereof.
  • the invention relates to novel amino acid derivatives of the formula I,
  • A is amino acid
  • B is peptide bond
  • Diabetes mellitus is a group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both.
  • diabetes mellitus describes a metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism. The metabolism disturbance effect is resulting from defects in insulin secretion, insulin action, or both.
  • the effects of diabetes mellitus include long-term damage, dysfunction and failure of various organs.
  • agents used as monotherapy or in combinations for the treatment of diabetes mellitus. These include metformin, sulphonylureas, meglinitides, alpha-glucosidase inhibitors, thiazolidinediones, glucagon like peptide-1 agonists and insulin. Many conventional agents frequently exhibit reduced efficacy over time, leading to inadequate glycaemic control. Several of these agents are also associated with adverse effects that include weight gain, hypoglycemia and gastrointestinal distress. There is a need therefore, for alternative therapies that can overcome the limitations associated with conventional anti-hyperglycemic medications.
  • Figure 1 In vivo screening results of CPL-2009-030 & CPL-2009-031 .
  • Figure 2 In vivo screening results of CPL-2009-01 1 , CPL-2009-012, CPL-2009-015 & CPL- 2009-020.
  • Figure 3 In vivo screening results of CPL-2010-079, CPL-201 1 -085
  • Figure 4 In vivo screening results (AUC) of CPL-201 0-079, CPL-201 1 -085
  • An object of this invention is to provide novel hypoglycemic compounds of formula I and its pharmaceutically acceptable salts thereof.
  • Another object of this invention is to provide a process for the preparation of the novel hypoglycemic compounds of formula I.
  • Yet another object of the invention is to provide novel hypoglycemic compounds which react with DPP IV enzyme.
  • the synthesized compounds are potential candidates for the treatment of metabolic disorder associated with diabetes mellitus.
  • the invention relates to novel amino acid derivatives of the formula I,
  • A is amino acid
  • B is peptide bond
  • A is an amino acid selected from naturally occurring or synthetic amino acid analogues.
  • the preferred amino acid is selected from glycine, alanine, valine, histidine, serine, leucine, isoleucine, phenylalanine, methionine, tryptophan, lysine, glutamine, glutamic acid, serine, proline, cysteine, tyrosine, histidine, arginine, asparagines, aspartic acid, threonine or mixtures of amino acid thereof.
  • A is amino acid
  • B is peptide bond
  • the process disclosed herein is not limited to the preparation of specific compounds as prepared herein but is described the general state of art in order to prepare the compounds of present invention.
  • the compounds of formula 2-6 are prepared by the process as known in literature.
  • the scope of invention also includes compound which are selected from the group consisting of the compounds of formula 2-6 or its pharmaceutically acceptable salts thereof to prepare similarly set of other compounds.
  • the present invention is directed to the use of the compounds disclosed as hypoglycemic activity.
  • the following synthesized compounds are useful as hypoglycemic compound for a patient such as a mammal in need of such diabetic treatment comprising the administration of an effective amount of the compound.
  • Example 3 Analogously to example 1 the compound, ⁇ 3-Methyl-1 -[3-oxo-1 -(2,4,5-trifluoro- benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[1 ,2,4]triazolo[4,3-a]pyrazin-7-yl)-propyl- carbamoyl]-butyl ⁇ -carbamic acid tert-butyl ester (Formula 9) is prepared by the reaction of compound having formula 4 (0.59 gm) and 2-tert-Butoxycarbonyl amino-4-methyl pentanoic acid (0.43 gm). The reaction mixture is concentrated under vaccum and purified by column chromatography. (Yields 0.62 gm, 81 %)
  • Hydrochloride (Formula 16) is prepared by saltification of the compound of formula 15 (1 .2 gm) using hydrochloric acid. (Yield: 1 .03 gms, 95%)
  • Hydrochloride (Formula 18) is prepared by saltification of the compound of formula 17 (0.6 gm) using hydrochloric acid. The hydrochloride salt was dissolved in saturated aq. NaHC0 3 and was extracted with EtoAC (50 ml x 3). The combined EtoAC layers were dried over Na 2 S0 4 and were concentrated under vaccum to give the title compound. (Yield: 0.454 gm, 89%)
  • Form 24 is prepared by saltification of the compound of formula 23 (0.89 gm) using hydrochloric acid at room temperature followed concentrated the filtrate under vaccum.
  • reaction mixture was concentrated in vaccum to give Hydrochloride salt of 1 -(2-Amino-3-methyl-butyryl)-pyrrolidine-2-carboxylic acid [3-oxo-1 -(2,4,5-trifluoro-benzyl)-3-(3- trifluoromethyl-5,6-dihydro-8H-[1 ,2,4]triazolo[4,3-a]pyrazin-7-yl)-propyl]-amide.
  • hydrochloric acid salt of compound is treated with sodium bicarbonate to give corresponding free base compound of formula 28. [0.46gm, 93.88% yield]
  • Step A The tert-Butoxycarbonylamino-(3-hydroxy-adamantan-1 -yl)-acetic acid
  • Step B 13 gm of [2-(2-Carbamoyl-3-aza-bicyclo[3.1 .0]hex-3-yl)-1 -(3-hydroxy- adamantan-1 -yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (0.0300moles) was taken into CH 2 CI 2 (30 ml) and trifluoroacetic acid (15 ml) was added to the solution at room temperature. The reaction mixture was stirred for 3 hours. Di-chloromethane was evaporated to give oily residue which on titration with Et 2 0 to afford as the white solid having formula 27a). (Yield
  • Step C 1 .5 gm of ⁇ 1 -[2-(2-Carbamoyl-3-aza-bicyclo[3.1 .0]hex-3-yl)-1 -(3-hydroxy- adamantan-1 -yl)-2-oxo-ethylcarbamoyl]-2-phenyl-ethyl ⁇ -carbamic acid tert-butyl ester of formula 33 (0.0031 moles) in THF was added into the mixture of pyridine (1 .26 ml). Triflouro acetic anhydride (10 ml) was added at 0 °C and stirred for 3 hours at room temperature.
  • Trifluoro acetic acid salt of l-(2-Amino-3- methyl-butyryl)-pyrrolidine-2-carboxylic acid [2-(2-cyano-3-aza-bicyclo[3.1.0]hex- 3-yl)-l-(5-hydroxy-adamantan-2-yl)-2- oxo-ethyl]-amide ⁇ [ o the stirred solution 1 .7 gm (0.00380 moles) of 3-[2-Amino-2-(5-hydroxy-adamantan-2-yl)- acetyl]-3-aza-bicyclo[3.1 .0]hexane-2-carboxylic acid amide trifluoro acetic acid of formula 35 and 1 .19 gm (0.00380 moles) of 1 -(2-tert-Butoxycarbonylamino-3-methyl-butyryl)-pyrrolidine-2- carboxylic acid (Formula 26) in THF was added into HoBT (0.6 gm) and DIPEA
  • the synthesized compound were screened to check their hypoglycemic effect through in vivo screening using Sitagliptin, Saxagliptin and other commercially available compound as control.
  • the structures of some of the compounds prepared as per process described in present invention are as under:
  • novel hypoglycemic compounds according to present invention on reaction with DPP IV enzyme release an entity that inhibits the DPP IV enzyme.
  • the inhibition of DPP IV enzyme by compound of formula 1 is attributed to the particular amino acid analogues synthesized as per present invention. These are evaluated by the in vivo screening of the compounds of present invention.
  • the efficacy compound CPL-2009-0030 and CPL-2009-0031 were prepared as per present invention. They were evaluated through Oral Glucose Tolerance Test in animals. Each group consist of 10-12 weeks old Wistar female rats. The animals were divided into 4 different groups of 6 animals per group. The group I received vehical (WFI Placebo), Group II received Sitagliptin as positive control, Group III received CPL-2009-0030 and Group IV received CPL-2009-0031 . All animals had over night fasting.
  • the drug was administrated as per table 01 at 0 hour to all the study group animals with 10 mL/kg of dose volume.
  • the compounds were administered orally.
  • the glucose (2 gm / Kg body weight) was administered 3 hrs after the administration of compounds.
  • Blood glucose was measured at the time of administration of compound, glucose and 30 min, 1 hr, 2 hr, 3 hr and 4 hr after the glucose administration.
  • the change in glucose levels over time is shown in figure 1 . All animals showed rise in blood glucose level following administration of glucose. The rise was maximum at 30 min after glucose administration. The rise in glucose is significantly lower when compound of present invention were administered compared to no treatment group. The difference between no treatment group and other three groups is maximum at 30 min and it decreases over time (Figure 01 ).
  • the compound of present invention does not alter the fasting glucose levels from 0 to 3 Hrs.
  • the compound of present invention reduces hyperglycaemic effect of glucose without inducing hypoglycaemia.
  • compounds of present invention provide hypoglycaemic effect only to reduce post-prandial hyperglycaemia without inducing fasting hypoglycaemia.
  • the above results indicate that the newly synthesized compounds are showing hypoglycemic activity as compared to standard.
  • the novel hypoglycemic compounds according to present invention on reaction with DPP IV enzyme release an entity that inhibits the DPP IV enzyme. This is further evaluated by following analytical method.
  • Analytical Method to analyze the DPP IV compounds of present invention Reagents and Solvents: The reagents, solvents, standards and equipments to analyze the DPP IV compounds of present invention are as under:
  • Sample Preparation Extracted samples (after removing proteneous matter) were provided from different organs (Liver, Kidney and Pancreas) and serum samples which were directly injected on to HPLC system.
  • the liquid chromatography is equipped with variable wavelength UV detector, Auto sampler and Data processor
  • Inject blank (diluent) and blank extraction samples inject standard preparation of varying concentration from 0.025 ⁇ to 100 ⁇ and plot a graph of Area under curve against concentration in ⁇ . Inject sample preparation and record the chromatogram. Disregard any peak due to blank and calculate concentration of an entity which is released from the extracted samples collected at different time intervals.
  • the retention time of Sitagliptine is about 5.0 to 6.0 minutes.
  • novel hypoglycemic compounds of formula I and its pharmaceutically acceptable salts thereof according to present invention are showing hypoglycemic activity in vivo model comprising the pharmaceutical composition combining a compound of the present invention with a pharmaceutical carrier or diluent.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The present invention relates to novel hypoglycemic compounds of formula (1) and pharmaceutically acceptable salts thereof. The invention relates to novel amino acid derivatives of the formula (1), wherein, A is amino acid B is peptide bond R-NH- wherein R is defined in the specification

Description

TITLE: NOVEL HYPOGLYCEMIC COMPOUNDS
FIELD OF INVENTION
The present invention is directed to novel hypoglycemic compounds of formula I and pharmaceutically acceptable salts thereof. The invention relates to novel amino acid derivatives of the formula I,
Figure imgf000002_0001
Formu la 1
wherein,
A is amino acid, B is peptide bond
R-NH- wherein R is defined in the specification.
BACKGROND OF INVENTION
Diabetes mellitus (DM) is a group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both. The term diabetes mellitus describes a metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism. The metabolism disturbance effect is resulting from defects in insulin secretion, insulin action, or both. The effects of diabetes mellitus include long-term damage, dysfunction and failure of various organs.
There are at least seven different classes of agents used as monotherapy, or in combinations for the treatment of diabetes mellitus. These include metformin, sulphonylureas, meglinitides, alpha-glucosidase inhibitors, thiazolidinediones, glucagon like peptide-1 agonists and insulin. Many conventional agents frequently exhibit reduced efficacy over time, leading to inadequate glycaemic control. Several of these agents are also associated with adverse effects that include weight gain, hypoglycemia and gastrointestinal distress. There is a need therefore, for alternative therapies that can overcome the limitations associated with conventional anti-hyperglycemic medications.
The conventional agents used to treat type 2 diabetes frequently exhibit reduced efficacy over time leading to inadequate glycaemic control and are also associated with adverse effects. Hence, there is a need for alternative therapies that can overcome the limitations associated with conventional antidiabetic agents.
DESCRIPTION OF DRAWING
Figure 1 : In vivo screening results of CPL-2009-030 & CPL-2009-031 .
Figure 2: In vivo screening results of CPL-2009-01 1 , CPL-2009-012, CPL-2009-015 & CPL- 2009-020.
Figure 3: In vivo screening results of CPL-2010-079, CPL-201 1 -085 Figure 4: In vivo screening results (AUC) of CPL-201 0-079, CPL-201 1 -085
OBJECT OF THE INVENTION
An object of this invention is to provide novel hypoglycemic compounds of formula I and its pharmaceutically acceptable salts thereof.
Another object of this invention is to provide a process for the preparation of the novel hypoglycemic compounds of formula I.
Yet another object of the invention is to provide novel hypoglycemic compounds which react with DPP IV enzyme.
DESCRIPTION OF INVENTION
The synthesized compounds are potential candidates for the treatment of metabolic disorder associated with diabetes mellitus. We disclose herein a series of novel compounds that are potential hypoglycemic compounds. The invention relates to novel amino acid derivatives of the formula I,
K N I
R
Formula 1
Wherein,
A is amino acid, B is peptide bond
R-NH- wherein R-NH- is together having group of formula 2 to 6
Figure imgf000003_0001
The compound of formula 2-6 are chemically named as,
• 2-({6-[(3R)-3-substituted-aminopiperidin-1 -yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin- 1 (2H)-yl}methyl)-benzonitrile (formula 2);
• 1 -[2-substitutedamino-3,3-bis-(4-fluoro-phenyl)-propionyl]-4-fluoro-pyrrolidine-2- carbonitrile (formula 3);
• (2R)-2-substituted-amino-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1 ,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl]-1 -(2,4,5-trifluorophenyl)butan (formula 4); • 8-[(3R)-3-2-substituted-aminopiperidin-1 -yl]-7-(but-2-yn-1 -yl)-3-methyl-1 -[(4- methylquinazolin-2-yl)methyl]-3,7-dihydro-1 H-purine-2,6-dione (formula 5);
• (1 S,3S,5S)-2-[(2S)-2-2-substituted-amino-2-(3-hydroxy-1 -adamantyl)acetyl]-2- azabicyclo-[3.1 .0]-hexane-3-carbonitrile (formula 6); and salts thereof.
A is an amino acid selected from naturally occurring or synthetic amino acid analogues. The preferred amino acid is selected from glycine, alanine, valine, histidine, serine, leucine, isoleucine, phenylalanine, methionine, tryptophan, lysine, glutamine, glutamic acid, serine, proline, cysteine, tyrosine, histidine, arginine, asparagines, aspartic acid, threonine or mixtures of amino acid thereof.
The title compounds were synthesized by reaction of carboxylic group of an amino acid (A-OH) and the amino group of R-NH2 wherein R-NH is having formula 2-6 by the scheme 1 .
- H20 A/B-N-H
A - OH + NH2 - R ► A I
Ri
Formula 1
Wherein,
A is amino acid, B is peptide bond
R-NH- wherein R-NH- is together having group of formula 2 to 6
The process disclosed herein is not limited to the preparation of specific compounds as prepared herein but is described the general state of art in order to prepare the compounds of present invention. The compounds of formula 2-6 are prepared by the process as known in literature. The scope of invention also includes compound which are selected from the group consisting of the compounds of formula 2-6 or its pharmaceutically acceptable salts thereof to prepare similarly set of other compounds.
The present invention is directed to the use of the compounds disclosed as hypoglycemic activity. The following synthesized compounds are useful as hypoglycemic compound for a patient such as a mammal in need of such diabetic treatment comprising the administration of an effective amount of the compound.
The following examples serve to illustrate the present invention directed to provide novel hypoglycemic compounds of formula I and its pharmaceutically acceptable salts thereof having hypoglycemic activity in humans and animals comprising the pharmaceutical composition combining a compound of the present invention with a pharmaceutical carrier or diluent.
Example 1 :
Tert-Butoxycarbonylamino-acetic acid (0.33 gms, 0.0018 mole) was dissolved in dichloromethane (20 ml) and added in dicyclohexyl dicarbodiimide (0.51 gm, 0.0025 M) at 0 0C. The reaction mixture was stirred for 10 minutes. 3-Amino-1 -(3-trifluoromethyl-5, 6,7,8- tetrahydro-[1 ,2,4]triazolo[4,3-a]pyridin-7-yl)-4-(2,4,5-trifluoro-phenyl)-butan-1 -one (Formula 4) (0.59 gm, 0.00123 M) was added at 0 OC and stirred, dicyclohexyl urea was removed After the reaction mixture being stirred. The reaction mixture was filtered and filtrate was concentrated under vaccum. The residue was purified by column chromatography to yield {[3-Oxo-l -(2,4, 5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[1 ,2,4]triazolo[4,3- a]pyrazin-7-yl)-propylcarbamoyl]-methyl}-carbamic acid tert-butyl ester (Formula 7). (Yield: 0.
Figure imgf000005_0001
{ [3-Oxo-l-(2,4,5-trifluoro-benzyl)-3-(3- Hydrochloride salt of 2-Amino-A^-[3-oxo-l-(2,4,5- trifluoromethyl-5,6-dihydro-8//-[l,2,4]triazolo[4,3- trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8//- a]pyrazin-7-yl)-propylcarbamoyl]-methyl}-carbamic [l,2,4]triazolo[4,3-a]pyrazin-7-yl)-propyl]-acetamide acid ferf-butyl ester
{[3-Oxo-l -(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[1 ,2,4]triazolo-
[4,3-a]-pyrazin-7-yl)-propylcarbamoyl]-methyl}-carbamic acid tert-butyl ester (Formula 7) (0.52 gms, 0.0009 mole) was dissolved in EtoAc and stirred at room temperature.3M HCI- EtoAc (3 ml) was added to the reaction mixture and stirred at room temperature. The reaction mass was concentrated under vaccum to yield 2-Amino-N-[3-oxo-1 -(2,4,5-trifluoro- benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[1 ,2,4]triazolo[4,3-a]pyrazin-7-yl)-propyl]- acetamide Hydrochloride (Formula 8). (0.447 gm, 96%)
Example 3: Analogously to example 1 the compound, {3-Methyl-1 -[3-oxo-1 -(2,4,5-trifluoro- benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[1 ,2,4]triazolo[4,3-a]pyrazin-7-yl)-propyl- carbamoyl]-butyl}-carbamic acid tert-butyl ester (Formula 9) is prepared by the reaction of compound having formula 4 (0.59 gm) and 2-tert-Butoxycarbonyl amino-4-methyl pentanoic acid (0.43 gm). The reaction mixture is concentrated under vaccum and purified by column chromatography. (Yields 0.62 gm, 81 %)
Figure imgf000006_0001
{3-Methyl-l-[3-oxo-l-(2,4,5-trifluoro-benzyl)-3-(3- 2-Amino-4-methyl-pentanoic acid [3-oxo-l-(2,4,5- trifluoromethyl-5,6-dihydro-8ff-[l,2,4]triazolo[4,3- trifluoro-benzyl)-3-(3-triiluoromethyl-5,6-dihydro-8if- a]pyrazin-7-yl)-propylcarbamoyl] -butyl } -carbamic [ 1 ,2,4]triazolo [4,3-a]pyrazin-7-yl)-propyl] -amide acid fert-butyl ester Hydrochloride
Example 4:
Analogously to example 2 the compound, [3-oxo-1 -(2,4,5-trifluoro-benzyl)-3-(3- trifluoromethyl-5,6-dihydro-8H-[1 ,2,4]triazolo[4,3-a]pyrazin-7-yl)-propyl]-amide Hydrochloride (Formula 10) is prepared by saltification of the compound of formula 9 (0.52 gm) using hydrochloric acid. (Yield: 0.45 gm, 96%).
Example 5:
Analogously to example 1 the compound, {2-Methyl-1 -[3-oxo-1 -(2,4,5-trifluoro- benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[1 ,2,4]triazolo[4,3-a]pyrazin-7-yl)-propyl- carbamoyl]-butyl}-carbamic acid tert-butyl ester (Formula 1 1 ) is prepared by the reaction of compound having formula 4 (0.5 gm) and 2-tert-Butoxycarbonyl amino-3-methyl pentanoic acid (0.283 gm). The residue is purified by column chromatography. (Yields 0.47 gm, 62.7%)
Figure imgf000007_0001
{2-Methyl- l-[3-oxo-l-(2,4,5-trifluoro-benzyl)-3-(3- 2-Amino-3-methyl-pentanoic acid [3-oxo-l-(2,4,5- trifluoromethyl-5,6-dihydro-8 i-[l,2,4]triazolo[4,3- trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro- a]pyrazin-7-yl)-propylcarbamoyl] -butyl } -carbamic 8H- [ 1 ,2,4] triazolo [4,3-a]pyrazin-7-yl)-propyl] - acid iert-butyl ester amide Hydrochloride
Example 6:
Analogously to example 2, 2-Amino-3-methyl-pentanoic acid [3-oxo-1 -(2,4,5-trifluoro- benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[1 ,2,4]triazolo[4,3-a]pyrazin-7-yl)-propyl]-amide Hydrochloride (Formula 12) is prepared by saltification of the compound of formula 1 1 (0.44 gm) using hydrochloric acid at room temperature. (Yield = 0.39 gm, 98.73%).
Example 7:
Analogously to example 1 the compound, 2-[3-Oxo-1 -(2,4,5-trifluoro-benzyl)-3-(3- trifluoromethyl-5,6-dihydro-8H-[1 ,2,4]triazolo[4,3-a]pyrazin-7-yl)-propylcarbamoyl]- pyrrolidine-1 -carboxylic acid tert-butyl ester (Formula 13) is prepared by the reaction of compound having formula 4 (0.5 gm) and Pyrrolidine-1 ,2-dicarboxylic acid 1 -tert-butyl ester (0.464 gm). The residue was purified by column. (Yield = 0.42 gm, 89%)
Figure imgf000007_0002
2-[3-Oxo- l-(2,4,5-trifluoro-benzyl)-3-(3- Pyrrolidine-2-carboxylic acid [3-oxo-l-(2,4,5-trifluoro- trifluoromethyl-5,6-dihydro-8ii-[l,2,4]triazolo[4,3- benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8i7- a]pyrazin-7-yl)-propylcarbamoyl] -pyrrolidine- 1- [l,2,4]triazolo[4,3-a]pyrazin-7-yl)-propyl]-amide carboxylic acid ferf-butyl ester
Example 8: Analogously to example 2, Pyrrolidine-2-carboxylic acid [3-oxo-1 -(2,4,5-trifluoro- benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[1 ,2,4]triazolo[4,3-a]pyrazin-7-yl)-propyl]-amide Hydrochloride (Formula 14) is prepared by saltification of the compound of formula 13 (0.55 gm) using hydrochloric acid. (0.49gm, Yield = 81 %)
Example 9:
Analogously to example 1 the compound, {2-Methyl-1 -[3-oxo-1 -(2,4,5-trifluoro- benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[1 ,2,4]triazolo[4,3-a]pyrazin-7-yl)- propylcarbamoyl]-propyl}-carbamic acid tert-butyl ester (Formula 15) is prepared by the reaction of compound having formula 4 (1 gm) and 2-tert-Butoxycarbonylamino-3-methyl- butyric acid (0.59 gm). (Yield: 1 .2 gm, 82%)
Figure imgf000008_0001
{2-Methyl-l-[3-oxo-l-(2,4,5-trifluoro-benzyl)-3- 2-Amino-3-methyl-^-[3-oxo-l-(2,4,5-trifluoro-
(3-trifluoromethyl-5,6-dihydro-8/i- benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8/i-
[l,2,4]triazolo[4,3-a]pyrazin-7-yl)- [l,2,4]triazolo[4,3-a]pyrazin-7-yl)-propyi]- propylcarbamoyl] -propyl }-carbamic acid ten- butyramide Hydrochloride
butyl ester
Example 10:
Analogously to example 2, 2-Amino-3-methyl-N-[3-oxo-1 -(2,4,5-trifluoro-benzyl)-3-(3- trifluoromethyl-5,6-dihydro-8H-[1 ,2,4]triazolo[4,3-a]pyrazin-7-yl)-propyl]-butyramide
Hydrochloride (Formula 16) is prepared by saltification of the compound of formula 15 (1 .2 gm) using hydrochloric acid. (Yield: 1 .03 gms, 95%)
Example 11 :
Analogously to example 1 , {1 -[3-Oxo-1 -(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6- dihydro-8H-[1 ,2,4]triazolo[4,3-a]pyrazin-7-yl)-propylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester (Formula 17) is prepared by the reaction of compound having formula 4 (1 gm) and 2- tert-Butoxycarbonyl amino-propionic acid (0.464). The residue was purified by silica gel chromatography using CH2CI2 / MeOH (9.8: 0.2) as an eluent. (Yield: 1 .3 gm, 90%)
Figure imgf000009_0001
{ l-[3-Oxo-l-(2,4,5-trifluoro-benzyl)-3-(3- 2-Amino-N-[3-oxo-l-(2,4,5-trifluoro-benzyl)-3-(3- trifluoromethyl-5,6-dihydro-8 i-[l,2,4]triazolo[4,3- trifluoromethyl-5,6-dihydro-8 i-[l,2,4]triazolo[4,3- a]pyrazin-7-yl)-propylcarbamoyl]-ethyl}-carbamic a]pyrazin-7-yl)-propyl]-propionamide
acid iert-butyl ester Hydrochloride
Example 12:
Analogously to example 2, 2-Amino-N-[3-oxo-1 -(2,4,5-trifluoro-benzyl)-3-(3- trifluoromethyl-5,6-dihydro-8H-[1 ,2,4]triazolo[4,3-a]pyrazin-7-yl)-propyl]-propionamide
Hydrochloride (Formula 18) is prepared by saltification of the compound of formula 17 (0.6 gm) using hydrochloric acid. The hydrochloride salt was dissolved in saturated aq. NaHC03 and was extracted with EtoAC (50 ml x 3). The combined EtoAC layers were dried over Na2S04 and were concentrated under vaccum to give the title compound. (Yield: 0.454 gm, 89%)
Example 13:
Analogously to example 1 , {2-(3-Benzyloxy-phenyl)-1 -[3-oxo-1 -(2,4,5-trifluoro- benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[1 ,2,4]triazolo[4,3-a]pyrazin-7-yl)- propylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester (Formula 19) is prepared by the reaction of compound having formula 4 (0.49 gm) and 3-(3-Benzyloxy-phenyl)-2-tert- butoxycarbonylamino-propionic acid (0.44 gm). The residue was purified by silica gel chromatography using CH2CI2 / MeOH (9.25: 0.75) as an eluent. (Yield = 0.62 gm, 68%)
Formula 19
Figure imgf000010_0001
{ 2-(3-Benzyloxy-phenyl)- 1 -[3-oxo- 1 -(2,4,5-trifluoro- 2- Amino-3-(3-benzyloxy -phenyl)-^- [3-oxo-l- benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8/i- (2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6- [ 1 ,2,4] triazolo [4,3-a]pyrazin-7-yl)-propylcarbamoyl] - dihydro-8/i-[l,2,4]triazolo[4,3-a]pyrazin-7-yl)- ethyl }-carbamic acid tert-butyl ester propyl] -propionamide Hydrochloride
Example 14:
Analogously to example 2, 2-Amino-3-(3-benzyloxy-phenyl)-N-[3-oxo-1 -(2,4,5-trifluoro- benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[1 ,2,4]triazolo[4,3-a]pyrazin-7-yl)-propyl]- propionamide Hydrochloride (Formula 20) (0.5 gm) is prepared by saltification of the compound of formula 19 using hydrochloric acid at room temperature. (Yield = 0.43 gm, 93.48%) Example 15:
Analogously to example 1 , {1 -[3-Oxo-1 -(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl- 5,6-dihydro-8H-[1 ,2,4]triazolo[4,3-a]pyrazin-7-yl)-propylcarbamoyl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester (Formula 21 ) is prepared by the reaction of compound having formula 4 (0.5 gm) and 2-tert-Butoxycarbonylamino-3-phenyl-propionic acid (0.325 gm). The residue was purified by silica gel chromatography using CH2CI2 / MeOH (9.5: 0.5) as an eluent. (Yield = 0.49 gm, 61 .25%)
Figure imgf000010_0002
{ l-[3-Oxo-l-(2,4,5-trifluoro-benzyl)-3-(3- 2-Amino-^-[3-oxo-l-(2,4,5-trifluoro-benzyl)-3-(3- trifluoromethyl-5,6-dihydro-8i - trifluoromethyl-5,6-dihydro-8ff-[l,2,4]triazolo[4,3- [1,2,4] triazolo [4, 3 -a]pyrazin-7-yl)- a] pyrazin-7 -y 1) -propyl] - 3 -pheny 1-propionamide propylcarbamoyl] -2-phenyl-ethyl } -carbamic Hydrochloride
acid tert-butyl ester Example 16:
Analogously to example 2, 2-Amino-N-[3-oxo-1 -(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl- 5,6-dihydro-8H-[1 ,2,4]triazolo[4,3-a]pyrazin-7-yl)-propyl]-3-phenyl-propionamide
Hydrochloride (Formula 22) is prepared by saltification of the compound of formula 21 (0.42 gm) using hydrochloric acid at room temperature followed concentrated the filtrate under vaccum. (Yield = 0.37 gm, 97.37%)
Example 17:
Analogously to example 1 , {2-[3-Oxo-1 -(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl- 5,6-dihydro-8H-[1 ,2,4]triazolo[4,3-a]pyrazin-7-yl)-propylcarbamoyl]-ethyl}-carbamic acid tert- butyl ester (Formula 23) is prepared by the reaction of compound having formula 4 (1 gm) and 2-tert-Butoxycarbonylamino-propionic acid (0.464 gm). The residue was purified by silica gel chromatography using CH2CI2 / MeOH (9.5: 0.5) as an eluent. (Yield = 0.91 gm, 65%)
Figure imgf000011_0001
{ [3-Oxo-l-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl- 2-Amino-^V-[3-oxo-l-(2,4,5-trifluoro-benzyl)-3-(3- 5,6-dihydro-8H-[l,2,4]triazolo[4,3-a]pyrazin-7-yl)- trifluoromethyl-5,6-dihydro-8H-[l,2,4]triazolo[4,3- propylcarbamoyl] -methyl }-carbamic acid iert-butyl ester a]pyrazin-7-yl)-propyl]-acetamide Hydrochloride
Example 18:
Analogously to example 2, 3-Amino-N-[3-oxo-1 -(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl- 5,6-dihydro-8H-[1 ,2,4]triazolo[4,3-a]pyrazin-7-yl)-propyl]-propionamide Hydrohloride
(Formula 24) is prepared by saltification of the compound of formula 23 (0.89 gm) using hydrochloric acid at room temperature followed concentrated the filtrate under vaccum.
(Yield: 0.78 gm, 98.73%)
Example 19:
Figure imgf000012_0001
To a stirred solution of 2-tert-Butoxycarbonylamino-3-methyl-butyric acid (Compound of formula 25) [8 gm, 0.037 mole] and tri ethyl amine (5.15 ml, 0.037 mole) in THF (120 ml), ethyl chloro formate (3.52 ml, 0.037 mole) was added drop wise at 0-5 °C. The reaction was stirred at 0 °C for 15 minutes and stirred at room temperature for 1 hour. Then keep the reaction at 0 °C and add mixture of tri ethyl amine (10.3 ml, 0.074 mole) and THF (60 ml).
Finally L-Proline (4.25 gm, 0.037 mole) was added to above mixture at 0 °C. Reaction was stirred at 0 °C for 30 minutes and stirred at room temperature for over night. After being stirred, THF was concentrated under vacuum and residue was acidified with 1 N HCI (till pH ~ 3). The product layer was extracted with ethyl acetate. The organic extracts were dried over Na2S04 and concentrated. The resulted product was subjected to column chromatography using EtoAC / Hexane 5/5 as an eluent to give 1 -(2-tert-Butoxycarbonylamino-3-methyl-butyryl)-pyrrolidine-2- carboxylic acid (Formula 26). (Yield = 3.6 gm, 31 %) Example 20:
To a stirred solution of 1 -(2-tert-Butoxycarbonylamino-3-methyl-butyryl)-pyrrolidine-2- carboxylic acid (Formula 26) (0.39 gm, 1 .23 mmol) in MDC (40 ml), dicyclohexyl di-carbobiimide (0.4 gm, 0.0019 mole) was added at 0 °C, the reaction mixture was stirred for 5 - 10 minutes at 0 °C. Then 3-Amino-1 -(3-trifluoromethyl-5,6,7,8-tetrahydro-[1 ,2,4]triazolo[4,3-a]pyridin-7-yl)-4- (2,4,5-trifluoro-phenyl)-butan-1 -one (0.5 gm, 0.00123 mole) was added to this mixture at 0 °C. Then reaction was stirred at room temperature for 4 hours. Take the TLC for the completion of reaction. Reaction mixture was filtered to remove urea derivative of DCC. Then filtrate was concentrated in vacuum. Take the column chromatography of this compound for purification using CHCI3 / MeOH (9/1 ) as a solvent system to give (2-Methyl-1 -{2-[3-oxo-1 -(2,4,5-trifluoro- benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[1 ,2,4]triazolo[4,3-a]pyrazin-7-yl)-propylcarbamoyl]- pyrrolidine-1 -carbonyl}-propyl)-carbamic acid tert-butyl ester (Compound of formula 27) [0.54 gm, 62% yield]. 1 -(2-ferf-B
butyryl)-p
Figure imgf000013_0001
yrrolidine-2-carboxylic acid
Formula 26
Figure imgf000013_0002
(2-Methyl-l-{2-[3-oxo-l-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6,7,8- tetrahydro- [ 1 ,2,4]triazolo [4,3-a]pyridin-7-yl)-propylcarbamoyl]-pyrrolidine- 1 - carbonyl}-propyl)-carbamic acid tert-butyl ester
Example 21 :
Figure imgf000013_0003
(2-Methyl-1 -{2-[3-oxo-1 -(2,4,5-trifluoro-benzyl)-3-(3- 1 -(2-Amino-3-methyl-butyryl)-pyrrolidine-2- trifluoromethyl-5,6,7,8-tetrahydro-[1 ,2,4]triazolo[4,3- carboxylic acid [3-oxo-1 -(2,4,5-trifluoro-benzyl)-3-(3- a]pyridin-7-yl)-propylcarbamoyl]-pyrrolidine-1 -carbonyl}- trifluoromethyl-5,6,7,8-tetrahydro-[1 ,2,4]triazolo[4,3- propyl)-carbamic acid ferf-butyl ester a]pyridin-7-yl)-propyl]-amide To a stirred solution of (2-Methyl-1 -{2-[3-oxo-1 -(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-
5,6-dihydro-8H-[1 ,2,4]triazolo[4,3-a]pyrazin-7-yl)-propylcarbamoyl]-pyrrolidine-1 -carbonyl}- propyl)-carbamic acid tert-butyl ester (Formula 27) (0.54 gm, 0.00077 mole) in ethyl acetate (5 ml), solution of 3M HCI in ethyl acetate (5ml) was added at room temperature. Then reaction was stirred at room temperature for 1 hour. Take the TLC for the completion of reaction. Then finally, reaction mixture was concentrated in vaccum to give Hydrochloride salt of 1 -(2-Amino-3-methyl-butyryl)-pyrrolidine-2-carboxylic acid [3-oxo-1 -(2,4,5-trifluoro-benzyl)-3-(3- trifluoromethyl-5,6-dihydro-8H-[1 ,2,4]triazolo[4,3-a]pyrazin-7-yl)-propyl]-amide. Thus obtain hydrochloric acid salt of compound is treated with sodium bicarbonate to give corresponding free base compound of formula 28. [0.46gm, 93.88% yield]
Example 22:
Process for the preparation of 3-[2-(2-Amino-3-phenyl-propylamino)-2-(3-hydroxy- adamantan-1 -yl)-acetyl]-3-aza-bicyclo-[3.1 .0]-hexane-2-carbonitrile triflouro acetic acid (Compound of formula 29)
Step A: The tert-Butoxycarbonylamino-(3-hydroxy-adamantan-1 -yl)-acetic acid
(13.56 gm, 0.0418 moles) and 3-Aza-bicyclo[3.1 .0]hexane-2-carboxylic acid amide methane sulfonic acid (9.3 gm, 0.0418 moles) in ACN were stirred and added with stirring to the mixture of HoBT and DIPEA at room temperature. The above stirred solution was added into EDC.HCI at 0 °C followed by the addition of DIPEA and was stirred over 12 Hrs at room temperature. The acetonitrile was evaporated and residue was taken into EtOAC. The EtOAC layer was washed with 1 N HCI and saturated bi-carbonate solution. The saturated mixture was dried over Na2S04 and concentrated in vaccum. The pure compound of formula 27 was obtained by Column chromatography using MeOH:CH2CI2 (0.5:9.5) as a mobile phase. (Yield: 13 gm)
Step B: 13 gm of [2-(2-Carbamoyl-3-aza-bicyclo[3.1 .0]hex-3-yl)-1 -(3-hydroxy- adamantan-1 -yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (0.0300moles) was taken into CH2CI2 (30 ml) and trifluoroacetic acid (15 ml) was added to the solution at room temperature. The reaction mixture was stirred for 3 hours. Di-chloromethane was evaporated to give oily residue which on titration with Et20 to afford as the white solid having formula 27a). (Yield
a
Figure imgf000014_0001
Figure imgf000015_0001
Trifluoro acetic acid salt of 2-Amino- V-[2-(2-cyano-3-aza- bicyclo[3.1.0]hex-3-yl)-l-(3-hydroxy-adamantan-l-yl)-2-oxo- ethyl]-3-phenyl-propionamide
The solution of 2.27 gm (0.00507 moles) of compound 27a and 1 .34 gm (0.00507 moles) of 2-tert-Butoxycarbonylamino-3-phenyl-propionic acid in TFA was added into HoBT (0.93 gm) and DIPEA (1 .72 ml) at room temperature and stirred for 10 minutes. To this stirred solution EDC-HCI (1 .2 gm) and DIPEA (1 .76 ml) were added at 0 °C and the reaction mixture was stirred over 12 hrs at room temperature. THF was evaporated and residue was taken into EtOAC (40 ml). The EtOAC layer was washed with 1 N HCI and aq. NaHC03, dried over Na2S04 and concentrated in vaccum to give crude product. The crude product was purified by silica gel column chromatography using MeOH:CH2CI2 (0.5:9.5) as a mobile phase to give pure {1 -[2-(2-Carbamoyl-3-aza-bicyclo[3.1 .0]hex-3-yl)-1 -(3-hydroxy- adamantan-1 -yl)-2-oxo-ethylcarbamoyl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester (Formula 33). [Yield: 1 .5 gm]
Step C: 1 .5 gm of {1 -[2-(2-Carbamoyl-3-aza-bicyclo[3.1 .0]hex-3-yl)-1 -(3-hydroxy- adamantan-1 -yl)-2-oxo-ethylcarbamoyl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester of formula 33 (0.0031 moles) in THF was added into the mixture of pyridine (1 .26 ml). Triflouro acetic anhydride (10 ml) was added at 0 °C and stirred for 3 hours at room temperature. THF was evaporated and residue was taken into MeOH (30 ml) and 10 ml 10% K2C03 solution was added. The reaction mixture is further stirred at room temperature for 3 hours. MeOH was evaporated and aq. layer was extracted with EtoAC. The combined EtoAC layers were washed with 1 N HCI and bi-carbonate solution, dried over sodium sulphate and concentrated in vacuum to get crude product. The crude product was purified by silica gel column chromatography using MeOH:CH2CI2 (9.8:0.2) as a mobile phase to get pure compound of formula 33a. (Yield: 0.8 gm) 0.8 gm of compound of formula 33a (0.0014 moles) was added to a mixture of CH2CI2 (10 ml) and trifluoro acetic acid (5 ml) at room temperature and stirred for 3 hours. After being stirred CH2CI2 was evaporated and di-ethyl ether was added to remaining residue to afford white solid Trifluoro acetic acid salt of 2- Amino-N-[2-(2-cyano-3-aza-bicyclo[3.1 .0]hex-3-yl)-1 -(3-hydroxy-adamantan-1 -yl)-2-oxo- ethyl]-3-phenyl-propionamide (Formula 34). (Yield: 0.8 gm)
Figure imgf000016_0001
Trifluoro acetic acid salt of l-(2-Amino-3- methyl-butyryl)-pyrrolidine-2-carboxylic acid [2-(2-cyano-3-aza-bicyclo[3.1.0]hex- 3-yl)-l-(5-hydroxy-adamantan-2-yl)-2- oxo-ethyl]-amide ~[ o the stirred solution 1 .7 gm (0.00380 moles) of 3-[2-Amino-2-(5-hydroxy-adamantan-2-yl)- acetyl]-3-aza-bicyclo[3.1 .0]hexane-2-carboxylic acid amide trifluoro acetic acid of formula 35 and 1 .19 gm (0.00380 moles) of 1 -(2-tert-Butoxycarbonylamino-3-methyl-butyryl)-pyrrolidine-2- carboxylic acid (Formula 26) in THF was added into HoBT (0.6 gm) and DIPEA (1 .3 ml) at room temperature and stirred for 10 minutes. To this stirred solution EDC.HCI (0.94 gm) and DIPEA (1 .10 ml) were added at 0 °C and the reaction mixture was stirred over night at room temperature. THF was evaporated and residue was taken into EtOAC. The EtOAC layer was washed with 1 N HCI and aq. NaHC03 solution, dried and concentrated in vaccum to get crude product. The crude product was purified by silica gel column chromatography to get pure (1 -{2-[2-(2-Carbamoyl-3-aza-bicyclo[3.1 .0]hex-3-yl)-1 -(5-hydroxy-adamantan-2-yl)-2- oxo-ethylcarbamoyl]-pyrrolidine-1 -carbonyl}-2-methyl-propyl)-carbamic acid tert-butyl ester (Formula 36). (Yield: 1 .7 gm)
Analogously to example 23 the solution of 1 .7 gm of (2-{2-[2-(2-Carbamoyl-3-aza- bicyclo[3.1 .0]hex-3-yl)-1 -(5-hydroxy-adamantan-2-yl)-2-oxo-ethylcarbamoyl]-pyrrolidin-1 -yl}- 1 -methyl-2-oxo-ethyl)-carbamic acid tert-butyl ester in THF was added into the mixture of pyridine (1 .0 ml) and Triflouro acetic anhydride (0.95 ml). The reaction mixture was stirred at room temperature. THF was evaporated and residue was taken into MeOH and 10 ml 10% K2C03 solution was added. MeOH was evaporated and aq. layer was extracted with EtoAC. The combined EtoAC layers were washed with 1 N HCI and aq. NaHC03, dried over sodium sulphate and concentrated in vacuum to give crude product. The crude product was purified by column chromatography to get pure Trifluoro acetic acid salt of 1 -(2-Amino-3-methyl- butyryl)-pyrrolidine-2-carboxylic acid [2-(2-cyano-3-aza-bicyclo[3.1 .0]hex-3-yl)-1 -(5-hydroxy- adamantan-2-yl)-2-oxo-ethyl]-amide of formula 37. (Yield: 0.7 gm) In view of the present scope of invention, additionally the following novel compounds were also synthesized by the process as exemplified in the specification. The synthesized compound were screened to check their hypoglycemic effect through in vivo screening using Sitagliptin, Saxagliptin and other commercially available compound as control. The structures of some of the compounds prepared as per process described in present invention are as under:
• The amino acid analogue of 2-({6-[(3R)-3-substituted-aminopiperidin-1 -yl]-3-methyl-2,4- dioxo-3,4-dihydropyrimidin-1 (2H)-yl}methyl)-benzonitrile and pharmaceutically acceptable salts is synthesized as per the process exemplified in the specification are given in Table 1 :
Figure imgf000017_0001
Table : 1 Formula 2
Figure imgf000017_0002
Figure imgf000018_0001
An amino acid analogue of 1 -[2-Amino-3,3-bis-(4-fluoro-phenyl)-propionyl]-4-fluoro- pyrrolidine-2-carbonitrile and pharmaceutically acceptable salts is synthesized as per the process exemplified in the specification are given in Table 2.
Figure imgf000018_0002
Formula 3
Figure imgf000019_0001

Figure imgf000020_0001
An amino acid analogue of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro[1 ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1 -(2,4,5-trifluorophenyl)butan-2-amine and pharmaceutically acceptable salts is synthesized as per the process exemplified in the specification are given in Table 3
Table : 3
Figure imgf000020_0002
Sr.
Figure imgf000020_0003
Figure imgf000021_0001
An amino acid analogue of 8-[(3R)-3-aminopiperidin-1 -yl]-7-(but-2-yn-1 -yl)-3-methyl-1 - [(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1 H-purine-2,6-dione and pharmaceutically acceptable salts is synthesized as per the process exemplified in the specification are given in Table 4:
Table : 4
Figure imgf000021_0002
Sr.
Figure imgf000021_0003
Figure imgf000022_0001
An amino acid analogue of (1 S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1 - adamantyl)acetyl]-2-azabicyclo-[3.1 .0]-hexane-3-carbonitrile and pharmaceutically acceptable salts is synthesized as per the process exemplified in the specification are given in Table 5:
Figure imgf000022_0002
Table : 5 Form
Sr.
Figure imgf000022_0003
Figure imgf000023_0001
The novel hypoglycemic compounds according to present invention on reaction with DPP IV enzyme release an entity that inhibits the DPP IV enzyme. The inhibition of DPP IV enzyme by compound of formula 1 is attributed to the particular amino acid analogues synthesized as per present invention. These are evaluated by the in vivo screening of the compounds of present invention.
In vivo study of synthesized compounds:
The efficacy compound CPL-2009-0030 and CPL-2009-0031 were prepared as per present invention. They were evaluated through Oral Glucose Tolerance Test in animals. Each group consist of 10-12 weeks old Wistar female rats. The animals were divided into 4 different groups of 6 animals per group. The group I received vehical (WFI Placebo), Group II received Sitagliptin as positive control, Group III received CPL-2009-0030 and Group IV received CPL-2009-0031 . All animals had over night fasting.
Table: 01 Dose groups, no. of animals and dose of drugs for in vivo study:
Figure imgf000024_0001
The drug was administrated as per table 01 at 0 hour to all the study group animals with 10 mL/kg of dose volume. The compounds were administered orally. The glucose (2 gm / Kg body weight) was administered 3 hrs after the administration of compounds. Blood glucose was measured at the time of administration of compound, glucose and 30 min, 1 hr, 2 hr, 3 hr and 4 hr after the glucose administration. The change in glucose levels over time is shown in figure 1 . All animals showed rise in blood glucose level following administration of glucose. The rise was maximum at 30 min after glucose administration. The rise in glucose is significantly lower when compound of present invention were administered compared to no treatment group. The difference between no treatment group and other three groups is maximum at 30 min and it decreases over time (Figure 01 ). The findings also show that the compound of present invention does not alter the fasting glucose levels from 0 to 3 Hrs. Thus, the compound of present invention reduces hyperglycaemic effect of glucose without inducing hypoglycaemia. In other words, compounds of present invention provide hypoglycaemic effect only to reduce post-prandial hyperglycaemia without inducing fasting hypoglycaemia.
To confirm the finding the experiment was repeated three times and the percentage change in glucose level over time of three experiments is presented in table 02. The repeat experiments also confirm the findings.
Table: 02 In vivo results of novel h o l caemic com ounds
Figure imgf000024_0002
Similarly in identical experiments were performed to evaluate the in vivo screening of compounds as per present invention. The result of in vivo screening for evaluation of hypoglycemic effect of CPL-2009-001 1 , CPL-2009-0012, CPL-2009-0015 and CPL-2009- 0020 are given in figure 2. The result of in vivo screening for evaluation of hypoglycemic effect against Saxagliptin as control compound for CPL-2010-0079, CPL-2010-0085 is given in figure 3 whereas the same compound were screened against sitagliptin control and results are given in Figure 4.
The above results indicate that the newly synthesized compounds are showing hypoglycemic activity as compared to standard. The novel hypoglycemic compounds according to present invention on reaction with DPP IV enzyme release an entity that inhibits the DPP IV enzyme. This is further evaluated by following analytical method.
Analytical Method to analyze the DPP IV compounds of present invention: Reagents and Solvents: The reagents, solvents, standards and equipments to analyze the DPP IV compounds of present invention are as under:
• Trifluoro Acetic acid (AR grade)
• Acetonitrile (HPLC grade)
• Milli Q water
· Sitagliptin Base as working standard DPP IV inhibitor
• Shimadzu LC-2010 equipped with UV detector and Auto Sampler
• Diluent: Acetonitrile
Preparation of Buffer
Transfer accurately measured 1000 ml. Milli Q water in a beaker. Adjust pH 2.00±0.05 with Trifluoro acetic acid. Shake it gently and filter through 0.45μ membrane filter.
Preparation of Mobile phase
Transfer 300 ml. acetonitrile in 1000 ml. volumetric flask and make the volume up to the mark with buffer pH 2.00±0.05
Standard Preparation
Exactly weigh about 20 mg Sitagliptin Base working standard in 10 mL volumetric flask. Add 5.0 mL diluent and sonicate it (if required) to dissolve the solids and make the volume up to the mark with diluent giving a standard solution having concentration 2000 ppm (Stock solution).
Above stock solution was further diluted to get different concentration solution varying from 0.025μΜ to 100 μΜ. Linearity curve of peak area against concentration in μΜ was plotted for different concentration.
Sample Preparation Extracted samples (after removing proteneous matter) were provided from different organs (Liver, Kidney and Pancreas) and serum samples which were directly injected on to HPLC system.
Chromatographic conditions:
The liquid chromatography is equipped with variable wavelength UV detector, Auto sampler and Data processor
• Column : ypersil BDS C8, 4.6mm x 250 mm, 5μ
• Detector wavelength : 54 nm
• Flow Rate 1 .0 mL/min
• Injection volume : 20μΙ_
• Column Temperature : 60° C
Procedure
Inject blank (diluent) and blank extraction samples, inject standard preparation of varying concentration from 0.025μΜ to 100 μΜ and plot a graph of Area under curve against concentration in μΜ. Inject sample preparation and record the chromatogram. Disregard any peak due to blank and calculate concentration of an entity which is released from the extracted samples collected at different time intervals. The retention time of Sitagliptine is about 5.0 to 6.0 minutes.
The following compounds are exemplified with non-limiting scope of the invention for their in vivo screening of the compound presented according to present invention. The results are discussed in relevant example and presented as figure 1 -4.
Figure imgf000026_0001
Figure imgf000027_0001
CPL-2010-0079 CPL-2011-0085 N
The novel hypoglycemic compounds of formula I and its pharmaceutically acceptable salts thereof according to present invention are showing hypoglycemic activity in vivo model comprising the pharmaceutical composition combining a compound of the present invention with a pharmaceutical carrier or diluent.

Claims

We claim,
1 . A novel hypoglycemic compounds of formula 1 ,
A
I
R
Formula 1
Wherein, A is amino acid; B is peptide bond; R-NH- wherein R-NH- is together having group of formula
Figure imgf000028_0001
Formula 6
2. The compounds of formula 1 as claimed in claim 1 wherein the amino acid is selected from amino acid analogues.
3. The compounds of formula 1 as claimed in claim 1 wherein the amino acid is selected from glycine, alanine, valine, histidine, serine, leucine, isoleucine, phenylalanine, methionine, tryptophan, lysine, glutamine, glutamic acid, serine, proline, cysteine, tyrosine, histidine, arginine, asparagines, aspartic acid, threonine or mixtures of amino acid thereof.
4. An amino acid analogue of 2-({6-[(3R)-3-substituted-aminopiperidin-1 -yl]-3-methyl-2,4- dioxo-3,4-dihydropyrimidin-1 (2H)-yl}methyl)-benzonitrile and pharmaceutically acceptable salts thereof.
5. An amino acid analogue of 1 -[2-Amino-3,3-bis-(4-fluoro-phenyl)-propionyl]-4-fluoro- pyrrolidine-2-carbonitrile and pharmaceutically acceptable salts thereof.
6. An amino acid analogue of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1 ,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl]-1 -(2,4,5-trifluorophenyl)butan-2-amine and pharmaceutically acceptable salts thereof.
7. An amino acid analogue of 8-[(3R)-3-aminopiperidin-1 -yl]-7-(but-2-yn-1 -yl)-3-methyl-1 -[(4- methylquinazolin-2-yl)methyl]-3,7-dihydro-1 H-purine-2,6-dione and pharmaceutically acceptable salts thereof.
8. An amino acid analogue of (1 S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1 -adamantyl)acetyl]- 2-azabicyclo-[3.1 .0]-hexane-3-carbonitrile and pharmaceutically acceptable salts thereof.
Date: 31 March 201 1
PCT/IB2011/051407 2010-04-05 2011-04-01 Novel hypoglycemic compounds WO2011125011A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CN201180022812.0A CN102946726B (en) 2010-04-05 2011-04-01 Novel blood sugar lowing compound
CA2795514A CA2795514A1 (en) 2010-04-05 2011-04-01 Novel hypoglycemic compounds
EP11765149.7A EP2555617A4 (en) 2010-04-05 2011-04-01 Novel hypoglycemic compounds
US13/639,596 US9029567B2 (en) 2010-04-05 2011-04-01 Hypoglycemic compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1130MU2010 2010-04-05
IN1130/MUM/2010 2010-04-05

Publications (1)

Publication Number Publication Date
WO2011125011A1 true WO2011125011A1 (en) 2011-10-13

Family

ID=44762070

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2011/051407 WO2011125011A1 (en) 2010-04-05 2011-04-01 Novel hypoglycemic compounds

Country Status (5)

Country Link
US (1) US9029567B2 (en)
EP (2) EP2769978A1 (en)
CN (1) CN102946726B (en)
CA (1) CA2795514A1 (en)
WO (1) WO2011125011A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103848816A (en) * 2012-12-03 2014-06-11 成都地奥制药集团有限公司 Reductive amination preparation method for dipeptidyl peptidase inhibitor, and intermediate and preparation method thereof
CN103848817A (en) * 2012-12-03 2014-06-11 成都地奥制药集团有限公司 Iodination preparation method for dipeptidyl peptidase inhibitor, chlorination and iodination intermediates of dipeptidyl peptidase inhibitor and preparation methods for intermediates
WO2014108830A1 (en) 2013-01-10 2014-07-17 Wockhardt Limited A process for preparing pharmaceutically acceptable salt of saxagliptin

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106543141A (en) * 2015-09-21 2017-03-29 成都苑东生物制药股份有限公司 Uracil derivative
EP3389664A4 (en) * 2015-12-14 2020-01-08 Raze Therapeutics Inc. Caffeine inhibitors of mthfd2 and uses thereof
CN115246816B (en) * 2022-01-12 2024-03-26 聊城大学 Double-target alogliptin derivative
CN115304604B (en) * 2022-01-12 2024-03-26 聊城大学 Double-target sitagliptin derivative

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090137457A1 (en) * 2007-10-02 2009-05-28 Concert Pharmaceuticals, Inc. Pyrimidinedione derivatives

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19828113A1 (en) * 1998-06-24 2000-01-05 Probiodrug Ges Fuer Arzneim Prodrugs of Dipeptidyl Peptidase IV Inhibitors
US6395767B2 (en) * 2000-03-10 2002-05-28 Bristol-Myers Squibb Company Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method
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
CN101925603B (en) * 2007-12-13 2013-12-04 沃泰克斯药物股份有限公司 Modulators of cystic fibrosis transmembrane conductance regulator
AU2009290531B2 (en) * 2008-09-12 2014-08-21 Cadila Pharmaceuticals Ltd. Novel dipeptidyl peptidase (DP-IV) compounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090137457A1 (en) * 2007-10-02 2009-05-28 Concert Pharmaceuticals, Inc. Pyrimidinedione derivatives

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GUPTA ET AL.: "Emerging Drug Candidates of Dipeptidyl Peptidase IV (DPP IV) Inhibitor Class for the Treatment of Type 2 Diabetes", CURRENT DRUG TARGETS, vol. 10, 2009, pages 71 - 87, XP009122106 *
TSAI ET AL.: "Rational design and synthesis of potent and long-lasting glutamic acid-based dipeptidyl peptidase IV inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 19, no. 7, 2009, pages 1908 - 1912, XP025974887 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103848816A (en) * 2012-12-03 2014-06-11 成都地奥制药集团有限公司 Reductive amination preparation method for dipeptidyl peptidase inhibitor, and intermediate and preparation method thereof
CN103848817A (en) * 2012-12-03 2014-06-11 成都地奥制药集团有限公司 Iodination preparation method for dipeptidyl peptidase inhibitor, chlorination and iodination intermediates of dipeptidyl peptidase inhibitor and preparation methods for intermediates
CN103848816B (en) * 2012-12-03 2016-06-15 成都地奥制药集团有限公司 The reduction amination method for making of depeptidyl peptidase inhibitors, intermediate and method for making
CN103848817B (en) * 2012-12-03 2016-07-06 成都地奥制药集团有限公司 The iodo method for making of depeptidyl peptidase inhibitors, chloro, iodo intermediate and method for making
WO2014108830A1 (en) 2013-01-10 2014-07-17 Wockhardt Limited A process for preparing pharmaceutically acceptable salt of saxagliptin

Also Published As

Publication number Publication date
CN102946726B (en) 2015-08-19
CN102946726A (en) 2013-02-27
US9029567B2 (en) 2015-05-12
EP2555617A1 (en) 2013-02-13
EP2769978A1 (en) 2014-08-27
EP2555617A4 (en) 2013-08-14
US20130150578A1 (en) 2013-06-13
CA2795514A1 (en) 2011-10-13

Similar Documents

Publication Publication Date Title
US9029567B2 (en) Hypoglycemic compounds
US8178575B2 (en) Derivatives of azabicyclo octane, the method of making them and the uses thereof as inhibitors of dipeptidyl peptidase IV
AU2008241692B2 (en) DPP-IV inhibitor including beta-amino group, preparation method thereof and pharmaceutical composition containing the same for preventing and treating a diabetes or an obesity
US8173643B2 (en) N-substituted thiomorpholine derivatives as the inhibitors of dipeptidyl peptidase IV and the pharmaceutical uses thereof
JP5968455B2 (en) Thieno [3,2-d] pyrimidin-4-one compound, method for producing the same, pharmaceutical composition and use
EA007434B1 (en) Glutaminyl based dpiv inhibitors
CN102159578B (en) Salts of tetrahydroimidazo [1,5-a] pyrazine derivatives, preparation methods and pharmaceutical use thereof
JP2022533914A (en) Catecholamine carbamate prodrugs for use in treating Parkinson's disease
TWI395582B (en) Dicyclic azaalkane derivatives,preparing method and use thereof
US8729014B2 (en) Specific HCV NS3 protease inhibitors
US20200148681A1 (en) Crystalline spirocyclic compound, a dosage form containing, a method for using in treatment of disease, and a method for recrystallizing
US8765953B2 (en) Compounds and methods for the treatment of pain and other diseases
JP2016026142A (en) Neurotrophin mimetics and use thereof
KR20240000510A (en) Sortilin activity modulator
EA024688B1 (en) Process for the preparation of sitagliptin and its pharmaceutically acceptable salts
US20140045771A1 (en) Novel dipeptidyl peptidase iv (dp-iv) compounds
US20240083846A1 (en) Smac mimetics for treatment of cancer, process for preparation and pharmaceutical composition thereof
WO2018102256A1 (en) Pyrrolidinone compounds
US20130137852A1 (en) Novel compounds as dpp-iv inhibitors and process for preparation thereof
EP4034525A1 (en) Astaxanthin esters and methods of use thereof
JP2024505609A (en) Compounds for the treatment of partial progeria
JP2021513564A (en) Glucagon receptor antagonist

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 201180022812.0

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11765149

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2795514

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 12012501974

Country of ref document: PH

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2011765149

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 13639596

Country of ref document: US