CN104356048B - Cyclohexane-carboxylic acid amide derivatives, Preparation Method And The Use - Google Patents
Cyclohexane-carboxylic acid amide derivatives, Preparation Method And The Use Download PDFInfo
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- CN104356048B CN104356048B CN201410635734.7A CN201410635734A CN104356048B CN 104356048 B CN104356048 B CN 104356048B CN 201410635734 A CN201410635734 A CN 201410635734A CN 104356048 B CN104356048 B CN 104356048B
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- 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
Abstract
The present invention relates to the drug world relevant to diabetes.Specifically, the present invention relates to inhibitors of dipeptidyl IV containing cyclohexane-carboxylic acid amide structure with formula I and preparation method thereof, containing their pharmaceutical composition and their application in preparing diabetes medicament.
Description
Technical field
The present invention relates to the drug world relevant to diabetes.Specifically, the present invention relates to have treatment to make to diabetes
The dipeptidyl peptidase-iv inhibitor containing cyclohexane-carboxylic acid amide structure and preparation method thereof, containing their drug regimen
Thing and the medicine in terms for the treatment of diabetes.
Background technology
According to statistics, global diabetic about about 2.5 hundred million in 2007, wherein the biggest number is II type (the most non-pancreas
Island element dependent form) diabetic.At present the antidiabetic medicine at Clinical practice mainly have sulfonylurea, melbine class and
Trypsin class medicine, list in recent years also has medicament of insulin sensitizer and Alpha-glucosidase inhibitor etc..These medicines
There is good result for the treatment of, but generally there is the serious side effects such as hypoglycemia, and long-term treatment exists safety issue, as
The problems such as hepatotoxicity wind agitation and body weight increase.
DPP IV (dipeptidyl peptidase IV, DPP-IV) can effectively and pancreas of degrading rapidly is high
Blood sugar element sample peptide 1 (GLP-1), GLP-1 is insulin production and secretes one of maximally effective stimulant, therefore suppression DPP-IV energy
Strengthen the effect of endogenous GLP-1, thus improve the level of insulin in blood.Medical science it turned out DPP-IV inhibitor at present
It is a kind of novel antidiabetic treatment medicine, has had multiple medicine list marketing.Clinical effectiveness shows such medicine
There is good hypoglycemic effect, do not find that common body weight produced by other diabetes medicaments increases bad with hypoglycemia etc. simultaneously
Reactant.
The invention discloses a class cyclohexane-carboxylic acid amide-type DPP-IV inhibitor, these compounds may be used for preparation and control
Treat the medicine of diabetes.
Summary of the invention
It is an object of the present invention to provide one and there is excellent activity, there is compounds of formula I and pharmaceutically may be used
The salt accepted.
It is a further object to provide the method that preparation has compounds of formula I and salt thereof.
It is also another object of the present invention to provide containing compounds of formula I as active ingredient, and one or more
The Pharmaceutical composition of pharmaceutically acceptable carrier, excipient or diluent, and the application in terms for the treatment of diabetes.
In conjunction with the purpose of the present invention, present invention is specifically described.
The present invention has compounds of formula I and has a following structural formula:
Wherein, R1Alkyl selected from H, C1-C10.
R1It preferably is selected from the alkyl of H and C1-C5.
Further, to have compounds of formula I as follows for the preferred present invention:
Compound of Formula I of the present invention is synthesized by following steps:
Change platform thing II reacts with thionyl chloride and obtains corresponding acyl chlorides, reacts with compound III the most in the presence of a base
To IV;IV obtains compound V with hydrolysis in the basic conditions;Compound V and compound VI reacts in the presence of condensing agent and obtains
Compound I;Above-mentioned condensing agent includes N, N '-dicyclohexyl carbodiimide (DCC), N-ethyl-N '-(3-dimethylamino-propyl)
Carbodiimide hydrochloride (EDC) and carbonyl dimidazoles (CDI) etc., these condensing agents can be used in combination with organic base, such as three
Ethamine, diisopropyl ethyl amine (DIPEA) and DMAP (DMAP) etc..
Wherein, R1Defined as described above.
The pharmaceutically acceptable salt of compound of formula I of the present invention includes, but are not limited to and various inorganic acids, such as,
Hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid etc., or organic acid, such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, amino acid
Deng the pharmaceutically acceptable salt generated.
Compound or its salt shown in formula I has the inhibitory action of DPP-IV, can be used for making as active ingredient
In standby treatment diabetes medicament;Preferably, described diabetes are Non-Insulin Dependent Diabetes Mellitus.The activity of the compounds of this invention
It is to be verified by the external inhibitory action to DPP-IV enzyme.
Compound of Formula I of the present invention or its salt have the inhibitory action of DPP-IV, can be used for making as active ingredient
Medicine in terms of standby diabetes.The activity of compound of Formula I of the present invention is by internal hypoglycemic modelling verification.
The compound of Formula I of the present invention is effective in comparatively wide dosage range.The dosage that such as every day takes is about
In the range of 1mg-1000mg/ people, it is divided into once or is administered for several times.The actual dosage taking compound of Formula I of the present invention can be by
Doctor determines according to relevant situation.These situations include: the condition of patient, method of administration, the age, body weight,
Individual reaction to medicine, the order of severity etc. of symptom.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that following embodiment is only for
Illustrate, and be not intended to limit the present invention.Those skilled in the art all should according to the various changes that the teachings of the present invention is made
Within the protection domain required by the application claim.
Embodiment 1
14.22g (100mmol) compound II-1 refluxes 5 hours in 50mL thionyl chloride, then divides exactly the chlorination of excess
Sulfoxide, it is standby that the residue obtained is dissolved in the dichloromethane that 20mL is dried.By 15.12g (100mmol) compound III-1 and
30.36g (300mmol) triethylamine is dissolved in dichloromethane, the lower stirring of ice-water bath cooling, the most slowly drips above-mentioned preparation
The solution of acid chloride of II-1, after dropping, continues to be stirred overnight under room temperature.Reactant mixture is poured in 500mL frozen water, stirs
Mixing, extract with 100mL × 3 dichloromethane, merge extraction phase brine It, anhydrous sodium sulfate is dried, and is then rotating steaming
Sending out and be evaporated on instrument, the residue column chromatography obtained purifies, and obtains the sterling of IV-1.ESI-MS, m/z=276 ([M+H]+)。
Take 5.51g (20mmol) compound IV-1 to be dissolved in 50mL methyl alcohol, add 30%NaOH solution 10mL, then reflux
1 hour.Pour into after reactant mixture is the coldest in 200mL frozen water, regulate pH=2 with hydrochloric acid, then with 50mL × 3 dichloromethane
Extraction, merges extraction phase brine It, and anhydrous sodium sulfate is dried, and is evaporated the most on a rotary evaporator, the remnants obtained
Thing column chromatography purifies, and obtains the sterling of V-1.ESI-MS, m/z=262 ([M+H]+)。
2.61g (10mmol) compound V-1,1.08g (10mmol) compound VI and 2.06g (10mmol) DCC is at 10mL
The THF being dried is stirred overnight under room temperature.Suction filtration removes the solid in reactant mixture, and filtrate is evaporated on a rotary evaporator,
Residue column chromatography purifies the sterling obtaining product I-1, ESI-MS, m/z=352 ([M+H]+)。
Embodiment 2-4
With reference to the method for embodiment 1, following compounds can be prepared.
The inhibitory action of DPP-IV enzyme is measured by embodiment 5 compound
The Fluorogenic DPP4Assay Kit using BPS company measures the compound of the present invention to DPP-IV enzyme
Inhibitory activity.
Sample is respectively as follows: 5,10,30,100 and 200ng/kg by gradient dilution concentration successively, fluorescence reaction 96 orifice plate,
According to the form below addition sample:
22 DEG C of water-baths, place 10min, Spectra Max M5 type fluorescence detector exciting light 350nm, with 450nm fluorescence
Measure absorption value.Calculating IC50 value according to concentration-fluorescence intensity curves, result see table.
The compound IC to the suppression of DPP-IV enzyme50Value
As can be seen from the above table, the platform thing of changing of the present invention has the strongest inhibitory action to DPP-IV enzyme.
Claims (5)
1. there is compounds of formula I or its salt:
Wherein, R1Alkyl selected from H, C1-C10.
2. there is defined in claim 1 compounds of formula I or its salt:
Wherein, R1Alkyl selected from H, C1-C5.
3. compound of Formula I defined in claim 2 or its salt, is selected from:
4. compound of Formula I or the method for its salt defined in synthesis any one of claim 1-3, comprises the following steps:
Compound II reacts with thionyl chloride and obtains corresponding acyl chlorides, reacts with compound III the most in the presence of a base and obtains IV;
IV obtains compound V with hydrolysis in the basic conditions;Compound V and compound VI reacts in the presence of condensing agent and obtains compound
I。
5. compound of Formula I defined in any one of claim 1-3 or its salt answering in terms of preparation treatment diabetes medicament
With.
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CN104356048B true CN104356048B (en) | 2016-08-24 |
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Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7741082B2 (en) * | 2004-04-14 | 2010-06-22 | Bristol-Myers Squibb Company | Process for preparing dipeptidyl peptidase IV inhibitors and intermediates therefor |
ZA200708179B (en) * | 2005-04-22 | 2009-12-30 | Alantos Pharmaceuticals Holding Inc | Dipeptidyl peptidase-IV inhibitors |
WO2007029086A2 (en) * | 2005-09-05 | 2007-03-15 | Ranbaxy Laboratories Limited | Derivatives of 3-azabicyclo[3.1.0]hexane as dipeptidyl peptidase-iv inhibitors |
TWI412367B (en) * | 2006-12-28 | 2013-10-21 | Medarex Llc | Chemical linkers and cleavable substrates and conjugates thereof |
WO2012162507A1 (en) * | 2011-05-24 | 2012-11-29 | Apicore, Llc | Process for preparing saxagliptin and its novel intermediates useful in the synthesis thereof |
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