CN104356047A - Substituted cyclohexane carboxylic acid amide derivative and pharmaceutical application thereof - Google Patents
Substituted cyclohexane carboxylic acid amide derivative and pharmaceutical application thereof Download PDFInfo
- Publication number
- CN104356047A CN104356047A CN201410635707.XA CN201410635707A CN104356047A CN 104356047 A CN104356047 A CN 104356047A CN 201410635707 A CN201410635707 A CN 201410635707A CN 104356047 A CN104356047 A CN 104356047A
- Authority
- CN
- China
- Prior art keywords
- carboxylic acid
- compound
- acid amide
- cyclohexane carboxylic
- amide derivative
- Prior art date
- Legal status (The legal status 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 status listed.)
- Granted
Links
- PNZXMIKHJXIPEK-UHFFFAOYSA-N cyclohexanecarboxamide Chemical class NC(=O)C1CCCCC1 PNZXMIKHJXIPEK-UHFFFAOYSA-N 0.000 title abstract description 5
- 239000003814 drug Substances 0.000 claims abstract description 19
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 13
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 229940079593 drug Drugs 0.000 abstract description 12
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 abstract description 4
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 abstract description 4
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 3
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 12
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000002218 hypoglycaemic effect Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 229940125396 insulin Drugs 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 2
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 2
- 208000013016 Hypoglycemia Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 102100040918 Pro-glucagon Human genes 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000003472 antidiabetic agent Substances 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 229940122355 Insulin sensitizer Drugs 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- -1 and the like Chemical class 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000225 effect on diabetes Effects 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002608 insulinlike Effects 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the field of diabetes related medicines. Specifically, the invention relates to a cyclohexane carboxylic acid amide structure-containing dipeptidyl peptidase-IV inhibitor with the general formula I shown in specifications and a preparation method thereof, a pharmaceutical composition containing the dipeptidyl peptidase-IV inhibitor and application of the dipeptidyl peptidase-IV inhibitor in preparation of medicines for treating diabetes, wherein R1 can be selected from H and C1-C5 alkyl; R2 can be selected from CN and NO2.
Description
Technical Field
The present invention relates to the field of diabetes related drugs. In particular to a dipeptidyl peptidase-IV inhibitor containing a cyclohexane carboxylic acid amide structure and having a treatment effect on diabetes, a preparation method thereof, a pharmaceutical composition containing the same and a medicament for treating diabetes.
Background
According to statistics, the number of diabetes patients worldwide in 2007 is about 2.5 hundred million, and the vast majority of them are type II (i.e. non-insulin-dependent) diabetes patients. Currently, the antidiabetic drugs used clinically are mainly sulfonylurea drugs, metformin drugs and insulin-like drugs, and recently, insulin sensitizer drugs, α -glucosidase inhibitors and the like have been marketed. These drugs have good therapeutic effects, but have serious side effects such as hypoglycemia and the like generally, and have safety problems such as hepatotoxicity and weight gain in long-term treatment.
Dipeptidyl peptidase IV (DPP-IV) is capable of effectively and rapidly degrading glucagon-like peptide 1(GLP-1), GLP-1 is one of the most effective stimulators of insulin production and secretion, so that inhibiting DPP-IV enhances the action of endogenous GLP-1, thereby increasing the level of insulin in blood. The DPP-IV inhibitor is proved to be a novel antidiabetic therapeutic agent in the present medicine, and a plurality of drugs are commercially available at present. Clinical results show that the medicine has good hypoglycemic effect, and meanwhile, adverse reactions such as common weight gain, hypoglycemia and the like generated by other diabetes medicines are not found.
The invention discloses cyclohexane carboxylic acid amide DPP-IV inhibitors which can be used for preparing medicines for treating diabetes.
Disclosure of Invention
An object of the present invention is to provide a compound having good activity and having the general formula I and pharmaceutically acceptable salts thereof.
It is another object of the present invention to provide a process for the preparation of compounds having the general formula I and salts thereof.
It is a further object of the present invention to provide pharmaceutical compositions containing a compound of formula I as an active ingredient, together with one or more pharmaceutically acceptable carriers, excipients or diluents, and their use in the treatment of diabetes.
The present disclosure will now be described in detail for the purpose of the invention.
The compounds of the present invention having the general formula I have the following structural formula:
wherein,
R1an alkyl group selected from H and C1-C5;
R2selected from CN, NO2。
Further, preferred compounds of the invention having the general formula I are as follows:
the compound of the general formula I is synthesized by the following steps:
reacting the compound II with thionyl chloride to obtain corresponding acyl chloride, and then reacting with the compound III in the presence of alkali to obtain IV; IV and hydrolyzing under alkaline condition to obtain a compound V; reacting the compound V with a compound VI in the presence of a condensing agent to obtain a compound I; the above-mentioned condensing agents include N, N '-Dicyclohexylcarbodiimide (DCC), N-ethyl-N' - (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), Carbonyldiimidazole (CDI), etc., and these condensing agents may be used in combination with an organic base such as triethylamine, Diisopropylethylamine (DIPEA), 4-Dimethylaminopyridine (DMAP), etc.
Wherein R is1And R2As defined above.
The pharmaceutically acceptable salts of the compounds of formula I of the present invention include, but are not limited to, pharmaceutically acceptable salts formed with various inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or organic acids, such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, amino acids, and the like.
The compound shown in the formula I or the salt thereof has the DPP-IV inhibiting effect and can be used as an active ingredient for preparing a medicament for treating diabetes; preferably, the diabetes is non-insulin dependent diabetes mellitus. The activity of the compounds of the invention is demonstrated by the inhibition of the DPP-IV enzyme in vitro.
The compound of the general formula I or the salt thereof has the DPP-IV inhibiting effect and can be used as an active ingredient for preparing a medicament for treating diabetes. The activity of the compound of the general formula I is verified by an in vivo hypoglycemic model.
The compounds of formula I of the present invention are effective over a relatively wide dosage range. For example, the daily dosage may be in the range of about 1mg to about 1000mg per person, divided into one or more administrations. The actual dosage of the compounds of formula I to be administered according to the invention can be determined by the physician in the light of the relevant circumstances. These include: the physical state of the subject, the route of administration, the age, body weight, individual response to the drug, severity of the symptoms, and the like.
Detailed Description
The present invention will be further described with reference to the following examples. It should be noted that the following examples are only for illustration and are not intended to limit the present invention. Variations of the teachings of the present invention may be made by those skilled in the art without departing from the scope of the claims of the present application.
Example 1
14.22g (100mmol) of Compound II-1 are refluxed in 50mL of thionyl chloride for 5 hours, then excess thionyl chloride is removed in a lump, and the resulting residue is dissolved in 20mL of dry dichloromethane for further use. 19.61g (100mmol) of Compound III-1 and 30.36g (300mmol) of triethylamine are dissolved in dichloromethane and stirred with cooling in an ice-water bath, and then the solution of the acid chloride of II-1 prepared above is slowly added dropwise and, after the addition, stirring is continued overnight at room temperature. The reaction mixture was poured into 500mL of ice water, stirred, extracted with 100mL of 3 dichloromethane, the combined extract phases were washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator, and the resulting residue was purified by column chromatography to give pure IV-1. ESI-MS, m/z 321 ═ and ([M+H]+)。
6.40g (20mmol) of Compound IV-1 was dissolved in 50mL of methanol, 10mL of a 30% NaOH solution was added, and then refluxed for 1 hour. The reaction mixture was poured into 200mL of ice water after a little cooling, the pH was adjusted to 2 with hydrochloric acid, and then extracted with 50mL of × 3 dichloromethane, the combined extract phases were washed with brine, dried over anhydrous sodium sulfate, and then evaporated to dryness on a rotary evaporator, and the resulting residue was purified by column chromatography to give a pure product of V-1. ESI-MS, M/z 307([ M + H)]+)。
3.06g (10mmol) of compound V-1, 1.08g (10mmol) of compound VI and 2.06g (10mmol) of DCC are stirred in 10mL of dry THF at room temperature overnight. Filtering to remove solid in the reaction mixture, evaporating the filtrate to dryness on a rotary evaporator, and purifying the residue by column chromatography to obtain pure product I-1, ESI-MS, M/z ═ 397([ M + H ])]+)。
Examples 2 to 4
The following compounds may be prepared by reference to the procedure of example 1.
EXAMPLE 5 determination of the inhibitory Effect of Compounds on DPP-IV enzyme
The inhibitory activity of the compounds of the present invention on the DPP-IV enzyme was determined using Fluorogenic DPP4Assay Kit from BPS.
Sequentially diluting the samples according to the gradient concentration respectively as follows: 5. 10, 30, 100 and 200ng/kg, fluorescence reaction 96 well plates, samples were added according to the following table:
the sample was placed in a 22 ℃ water bath and left for 10min, and then excited with light 350am by a Spectra Max M5 type fluorescence detector, and absorbance was measured by fluorescence at 450 nm. Calculation of IC from concentration-fluorescence intensity curves50Values, results are given in the table below.
IC for inhibition of DPP-IV enzyme by compounds50Value of
As can be seen from the above table, the compounds of the present invention have strong inhibitory effect on DPP-IV enzyme.
Claims (3)
1. A compound having the general formula I:
wherein,
R1an alkyl group selected from H and C1-C5;
R2selected from CN, NO2。
2. A compound of formula I as defined in claim 1, or a salt thereof, selected from:
。
3. use of a compound of general formula I as defined in claims 1-2 or a salt thereof for the preparation of a medicament for the treatment of diabetes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410635707.XA CN104356047B (en) | 2014-11-02 | 2014-11-02 | Substituted cyclohexane-carboxylic acid amide derivatives and its medicinal usage |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410635707.XA CN104356047B (en) | 2014-11-02 | 2014-11-02 | Substituted cyclohexane-carboxylic acid amide derivatives and its medicinal usage |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104356047A true CN104356047A (en) | 2015-02-18 |
| CN104356047B CN104356047B (en) | 2017-04-05 |
Family
ID=52523384
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410635707.XA Expired - Fee Related CN104356047B (en) | 2014-11-02 | 2014-11-02 | Substituted cyclohexane-carboxylic acid amide derivatives and its medicinal usage |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104356047B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007029086A2 (en) * | 2005-09-05 | 2007-03-15 | Ranbaxy Laboratories Limited | Derivatives of 3-azabicyclo[3.1.0]hexane as dipeptidyl peptidase-iv inhibitors |
| CN102803224A (en) * | 2009-06-26 | 2012-11-28 | 万能药生物有限公司 | Novel azabicyclohexanes |
| WO2012162507A1 (en) * | 2011-05-24 | 2012-11-29 | Apicore, Llc | Process for preparing saxagliptin and its novel intermediates useful in the synthesis thereof |
| CN103896923A (en) * | 2012-12-27 | 2014-07-02 | 北京莱博赛路森药物科技有限公司 | Blood sugar reducing compound, preparation method of blood sugar reducing compound, medicine composition including blood sugar reducing compound and application of medicine composition |
-
2014
- 2014-11-02 CN CN201410635707.XA patent/CN104356047B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007029086A2 (en) * | 2005-09-05 | 2007-03-15 | Ranbaxy Laboratories Limited | Derivatives of 3-azabicyclo[3.1.0]hexane as dipeptidyl peptidase-iv inhibitors |
| CN102803224A (en) * | 2009-06-26 | 2012-11-28 | 万能药生物有限公司 | Novel azabicyclohexanes |
| WO2012162507A1 (en) * | 2011-05-24 | 2012-11-29 | Apicore, Llc | Process for preparing saxagliptin and its novel intermediates useful in the synthesis thereof |
| CN103896923A (en) * | 2012-12-27 | 2014-07-02 | 北京莱博赛路森药物科技有限公司 | Blood sugar reducing compound, preparation method of blood sugar reducing compound, medicine composition including blood sugar reducing compound and application of medicine composition |
Non-Patent Citations (2)
| Title |
|---|
| MASAKI SETOGUCHI 等: "A novel, potent, and orally active VLA-4 antagonist with good aqueous solubility: trans-4-[1-[[2-(5-Fluoro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl]acetyl]-(5S)-[methoxy(methyl)amino]methyl-(2S)-pyrrolidinyl-pyrrolidinylmethoxy]cyclohexanecarboxylic", 《BIOORGANIC & MEDICINAL CHEMISTRY》, vol. 21, no. 1, 10 November 2012 (2012-11-10), XP 028961406, DOI: doi:10.1016/j.bmc.2012.11.003 * |
| 囯欣 等: "二酰基甘油酰基转移酶1抑制剂的研究进展", 《中国药物化学杂志》, vol. 24, no. 2, 28 February 2014 (2014-02-28) * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104356047B (en) | 2017-04-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2404909A1 (en) | Amide thiazole derivative, preparation method and uses thereof | |
| CN103387601B (en) | Anti-dengue virus (DENV) heterocyclic peptide compounds and preparing methods and uses thereof | |
| JP5661177B2 (en) | Hexahydropyrrolo [3,4-b] pyrrole derivative, production method and use thereof | |
| CN104356047B (en) | Substituted cyclohexane-carboxylic acid amide derivatives and its medicinal usage | |
| CN104356046B (en) | Cyclohexane-carboxylic acid amide derivatives that cycloalkyl replaces and application thereof | |
| CN104447500B (en) | Halogen-substituted benzamidocyclohexanecarboxylic acid derivatives and applications thereof | |
| CN104447501B (en) | Alkyl-substituted benzamidocyclohexanecarboxylic acid derivatives and applications thereof | |
| CN104530009B (en) | Amantadine tetrazole derivant, Preparation Method And The Use | |
| CN104478861B (en) | A kind of nitro diamantane (obsolete) tetrazotized zole compound, Preparation Method And The Use | |
| CN104478859B (en) | A kind of hydroxyadamantane tetrazotized zole compound, Preparation Method And The Use | |
| CN104478860B (en) | Diamantane (obsolete) tetrazole derivant, Preparation Method And The Use | |
| CN104447704B (en) | A kind of itrile group diamantane (obsolete) tetrazotized zole compound, Preparation Method And The Use | |
| CN104530010B (en) | A kind of hydroxyadamantane tetrazotized zole compound, Preparation Method And The Use | |
| CN104530012B (en) | Amantadine tetrazole derivative, Preparation Method And The Use | |
| CN103421083A (en) | Anti-dengue virus heterocycle peptide compounds having 1,2,3-triazole structure, preparation method and use thereof | |
| CN104447703B (en) | A kind of nitro diamantane (obsolete) tetrazotized zole compound, Preparation Method And The Use | |
| CN104529857B (en) | Halo diamantane amide derivatives, Preparation Method And The Use | |
| CN104530011A (en) | Nitrile adamantane and tetrazole compound and preparing method and application thereof | |
| CN104356048B (en) | Cyclohexane-carboxylic acid amide derivatives, Preparation Method And The Use | |
| CN104478777B (en) | A kind of containing nitro diamantane (obsolete) with the derivant of amide structure, Preparation Method And The Use | |
| CN104529855B (en) | Derivative, the Preparation Method And The Use of a kind of hydroxyl diamantane and amide structure | |
| CN104447479B (en) | Containing diamantane and amide derivatives, Preparation Method And The Use | |
| CN104478778B (en) | Diamantane amide derivatives, Preparation Method And The Use | |
| CN104447478B (en) | Derivative, the Preparation Method And The Use of a kind of nitrile group-containing diamantane and amide structure | |
| CN104496877B (en) | A kind of itrile group diamantane amide derivatives, Preparation Method And The Use |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20170405 Termination date: 20171102 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |