CN104356047B - Substituted cyclohexane-carboxylic acid amide derivatives and its medicinal usage - Google Patents
Substituted cyclohexane-carboxylic acid amide derivatives and its medicinal usage Download PDFInfo
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- CN104356047B CN104356047B CN201410635707.XA CN201410635707A CN104356047B CN 104356047 B CN104356047 B CN 104356047B CN 201410635707 A CN201410635707 A CN 201410635707A CN 104356047 B CN104356047 B CN 104356047B
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- compound
- present
- carboxylic acid
- acid amide
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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 related to diabetes.Specifically, the present invention relates to have inhibitors of dipeptidyl IV containing cyclohexane-carboxylic acid amide structure of formula I and preparation method thereof, the pharmaceutical composition containing them and their applications in diabetes medicament is prepared.Wherein, R1May be selected from the alkyl of H and C1 C5;R2May be selected from CN, NO2。
Description
Technical field
The present invention relates to the drug world related to diabetes.Specifically, the present invention relates to there is treatment to make to diabetes
Dipeptidyl peptidase-iv inhibitor containing cyclohexane-carboxylic acid amide structure and preparation method thereof, the drug regimen containing them
Thing and the medicine in terms for the treatment of diabetes.
Background technology
According to statistics, global diabetic about 2.5 hundred million or so in 2007, wherein number big absolutely is II types (i.e. non-pancreas
Island element dependent form) diabetic.At present the antidiabetic medicine in Clinical practice mainly have sulfonylurea, melbine class and
Trypsin class medicine, what is listed in recent years also have medicament of insulin sensitizer and Alpha-glucosidase inhibitor etc..These medicines
With good therapeutic effect, but the serious side effects such as generally existing hypoglycemia, and there is safety issue in long-term treatment, such as
The problems such as hepatotoxicity wind agitation and increased weight.
DPP IV (dipeptidyl peptidase IV, DPP-IV) can effectively and pancreas of rapidly degrading is high
Blood sugar element sample peptide 1 (GLP-1), GLP-1 are one of insulin production and the maximally effective stimulant of secretion, therefore suppress DPP-IV energy
Strengthen the effect of endogenous GLP-1, so as to improve the level of insulin in blood.Medical science has confirmed DPP-IV inhibitor at present
It is a kind of new antidiabetic treatment medicine, there are multiple medicine list marketings at present.Clinical effectiveness shows such medicine
With good hypoglycemic effect, while not finding that common increased weight and hypoglycemia produced by other diabetes medicaments etc. are bad
Reactant.
The invention discloses a class cyclohexane-carboxylic acid amide-type DPP-IV inhibitor, these compounds can be used for preparation and control
Treat the medicine of diabetes.
The content of the invention
It is an object of the present invention to provide a kind of have excellent activity, with compounds of formula I and its pharmaceutically may be used
The salt of acceptance.
It is a further object to provide preparing the method with compounds of formula I and its salt.
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 its application in terms for the treatment of diabetes.
Present invention is specifically described in conjunction with the purpose of the present invention.
The present invention has following structural formula with compounds of formula I:
Wherein,
R1Selected from the alkyl of H and C1-C5;
R2Selected from CN, NO2。
Further, the preferred present invention has compounds of formula I as follows:
Compound of Formula I of the present invention is synthesized by following steps:
Compound II obtains corresponding acyl chlorides with thionyl chloride reaction, then reacts with compound III in the presence of a base
To IV;IV obtains compound V with hydrolysis in the basic conditions;Compound V is reacted in the presence of condensing agent with compound VI and is obtained
Compound I;Above-mentioned condensing agent includes N, N '-dicyclohexyl carbodiimide (DCC), N- ethyl-N '-(3- dimethylamino-propyls)
Carbodiimide hydrochloride (EDC) and carbonyl dimidazoles (CDI) etc., these condensing agents can be used in combination with organic base, and such as three
Ethamine, diisopropyl ethyl amine (DIPEA) and DMAP (DMAP) etc..
Wherein, R1And R2It is defined 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, for example,
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 for being generated.
Compound or its salt shown in formula I has the inhibitory action of DPP-IV, can be used to make as active ingredient
In standby treatment diabetes medicament;Preferably, the diabetes are Non-Insulin Dependent Diabetes Mellitus.The activity of the compounds of this invention
It is by vitro to the inhibitory action of DPP-IV enzymes verifying.
Compound of Formula I of the present invention or its salt have the inhibitory action of DPP-IV, can be used to make as active ingredient
Medicine in terms of standby diabetes.The activity of compound of Formula I of the present invention is verified by internal hypoglycemic model.
The compound of Formula I of the present invention is effective in comparatively wide dosage range.The dosage for example taken daily is about
In the range of 1mg-1000mg/ people, it is divided into and is administered once or for several times.The dosage for actually taking compound of Formula I of the present invention can be by
Doctor is determined according to relevant situation.These situations include:The condition of patient, method of administration, the age, body weight,
Individual reaction to medicine, order of severity of symptom etc..
Specific embodiment
With reference to embodiment, the present invention is further illustrated.It should be noted that following embodiments are only for
Illustrate, and be not intended to limit the present invention.The various change that those skilled in the art's training centre of the invention is made all should
Within the protection domain required by the application claim.
Embodiment 1
14.22g (100mmol) compound II-1 flow back 5 hours in 50mL thionyl chlorides, then divide exactly excessive chlorination
Sulfoxide, the dichloromethane that the residue for obtaining is dissolved in 20mL dryings are standby.By 19.61g (100mmol) compound III-1 and
30.36g (300mmol) triethylamine is dissolved in dichloromethane, and ice-water bath cooling is lower to stir, and above-mentioned preparation is then slowly added dropwise
The solution of acid chloride of II-1, after completion of dropping, continues to be stirred overnight under room temperature.Reactant mixture is poured in 500mL frozen water, is stirred
Mix, extracted with 100mL × 3 dichloromethane, merge extraction phase brine It, anhydrous sodium sulfate drying is then steamed in rotation
Send out, the residue column chromatography purifying for obtaining obtains the sterling of IV-1.ESI-MS, m/z=321 ([M+H]+)。
Take 6.40g (20mmol) compound IV-1 to be dissolved in 50mL methyl alcohol, add 30%NaOH solution 10mL, then flow back
1 hour.Pour in 200mL frozen water after reactant mixture is slightly cold, pH=2 is adjusted with hydrochloric acid, then with 50mL × 3 dichloromethane
Extraction, merges extraction phase brine It, and anhydrous sodium sulfate drying is then evaporated on a rotary evaporator, the remnants for obtaining
Thing column chromatography is purified, and obtains the sterling of V-1.ESI-MS, m/z=307 ([M+H]+)。
3.06g (10mmol) compound V-1,1.08g (10mmol) compound VI and 2.06g (10mmol) DCC is in 10mL
It is stirred overnight under room temperature in dry THF.Suction filtration removes the solid in reactant mixture, and filtrate is evaporated on a rotary evaporator,
Residue column chromatography purifying obtains the sterling of product I-1, ESI-MS, m/z=397 ([M+H]+)。
Embodiment 2-4
With reference to the method for embodiment 1, following compounds can be prepared.
5 compound of embodiment is determined to the inhibitory action of DPP-IV enzymes
The compound of the present invention is determined to DPP-IV enzymes using the Fluorogenic DPP4Assay Kit of BPS companies
Inhibitory activity.
Sample is respectively by gradient dilution concentration successively:5th, 10,30,100 and 200ng/kg, 96 orifice plate of fluorescence reaction,
According to the form below adds sample:
22 DEG C of water-baths, place 10min, Spectra Max M5 type fluorescence detector exciting light 350am, with 450nm fluorescence
Determine absorption value.IC is calculated according to concentration-fluorescence intensity curves50Value, as a result see the table below.
IC of the compound to the suppression of DPP-IV enzymes50Value
As can be seen from the above table, compound of the invention has very strong inhibitory action to DPP-IV enzymes.
Claims (3)
1. there is compounds of formula I or its salt:
Wherein,
R1Selected from the alkyl of H and C1-C5;
R2Selected from CN, NO2。
2. compound of Formula I defined in claim 1 or its salt, are selected from:
3. compound of Formula I defined in any one of claim 1-2 or its salt in terms for the treatment of diabetes medicament is prepared should
With.
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CN201410635707.XA CN104356047B (en) | 2014-11-02 | 2014-11-02 | Substituted cyclohexane-carboxylic acid amide derivatives and its medicinal usage |
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CN104356047B true CN104356047B (en) | 2017-04-05 |
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Family Cites Families (4)
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WO2007029086A2 (en) * | 2005-09-05 | 2007-03-15 | Ranbaxy Laboratories Limited | Derivatives of 3-azabicyclo[3.1.0]hexane as dipeptidyl peptidase-iv inhibitors |
RU2012102094A (en) * | 2009-06-26 | 2013-08-10 | Панацеа Биотек Лтд. | New azabicyclohexanes |
WO2012162507A1 (en) * | 2011-05-24 | 2012-11-29 | Apicore, Llc | Process for preparing saxagliptin and its novel intermediates useful in the synthesis thereof |
CN103896923B (en) * | 2012-12-27 | 2016-03-02 | 北京莱博赛路森药物科技有限公司 | A kind of Hypoglycemics, its preparation method, comprise its medical composition and its use |
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