CN104447500B - Halogen-substituted benzamidocyclohexanecarboxylic acid derivatives and applications thereof - Google Patents
Halogen-substituted benzamidocyclohexanecarboxylic acid derivatives and applications thereof Download PDFInfo
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- CN104447500B CN104447500B CN201410635649.0A CN201410635649A CN104447500B CN 104447500 B CN104447500 B CN 104447500B CN 201410635649 A CN201410635649 A CN 201410635649A CN 104447500 B CN104447500 B CN 104447500B
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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 invention relates to the field of diabetes mellitus related drugs and particularly relates to dipeptidyl peptidase-IV inhibitors with benzamidocyclohexanecarboxylic acid structures as shown in the general formula I, preparation methods of the dipeptidyl peptidase-IV inhibitors, pharmaceutical compositions containing the dipeptidyl peptidase-IV inhibitors and applications of the dipeptidyl peptidase-IV inhibitors to preparation of drugs for treating diabetes mellitus, wherein R1 can be selected from H and C1-C5 alkyls, and R2 can be selected from halogens.
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, containing their drug regimen
Thing and the medicine in terms for the treatment of diabetes.
Background technology
According to statistics, global diabetic about 2.5 hundred million about in 2007, wherein number is ii type (i.e. non-pancreas greatly absolutely
Island element dependent form) diabetic.At present the antidiabetic medicine in 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 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 body weight increase.
Dipeptidyl peptidase 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 is insulin production and secretes one of maximally effective stimulant, therefore suppresses dpp-iv energy
Strengthen the effect of endogenous glp-1, thus improving the level of insulin in blood.Medical science has confirmed dpp-iv inhibitor at present
It is a kind of new antidiabetic treatment medicine, had multiple medicine list marketings at present.Clinical effectiveness shows such medicine
There is good hypoglycemic effect, do not find that produced by other diabetes medicaments, common body weight increase and hypoglycemia etc. are bad simultaneously
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.
Content of the invention
It is an object of the present invention to provide one kind has excellent activity, there is the compound of formula i and its pharmaceutically may be used
The salt accepting.
It is a further object to provide preparation has the compound of formula i and its method for salt.
It is also another object of the present invention to provide the compound containing formula i is 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.
In conjunction with the purpose of the present invention, present invention is specifically described.
The compound that the present invention has formula i has a following structural formula:
Wherein,
r1Alkyl selected from h and c1-c5；
r2Selected from halogen.
Further, formula i compound or its salt:
r1Alkyl selected from h and c1-c3；
r2Selected from f, cl, br, i.
Formula i compound or its salt, further preferably following compound:
Formula i compound of the present invention is synthesized by following steps:
Compound ii is reacted with thionyl chloride and obtains corresponding acyl chlorides, 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 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, and such as three
Ethamine, diisopropyl ethyl amine (dipea) and DMAP (dmap) etc..
Wherein, r1And r2Defined as described above.
The pharmaceutically acceptable salt of formula i compound 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 being 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.
Formula i compound or its salt of the present invention has the inhibitory action of dpp-iv, can be used for making as active ingredient
The medicine of standby diabetes aspect.The activity of formula i compound of the present invention is to be verified by internal hypoglycemic model.
The formula i compound 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 being administered once or for several times.The actual dosage taking formula i compound 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, 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.Those skilled in the art all should according to the various change that the teachings of the present invention is made
Within protection domain required by the application claim.
Embodiment 1
14.22g (100mmol) compound ii-1 flows back 5 hours in 50ml thionyl chloride, then divides exactly excessive chlorination
Sulfoxide, it is standby that the residue obtaining is dissolved in the dry dichloromethane of 20ml.By 18.56g (100mmol) compound iii-1 and
30.36g (300mmol) triethylamine is dissolved in dichloromethane, and ice-water bath cooling is lower to stir, and then slowly drips above-mentioned preparation
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, stirs
Mix, with the extraction of 100ml × 3 dichloromethane, merge extraction phase brine It, anhydrous sodium sulfate drying, then steam in rotation
Send out and be evaporated on instrument, the residue column chromatography obtaining purifies, and obtains the sterling of iv-1.Esi-ms, m/z=310 ([m+h]+).
Take 6.18g (20mmol) compound iv-1 to be dissolved in 50ml methyl alcohol, add 30%naoh solution 10ml, then flow back
1 hour.Pour into after reactant mixture is slightly cold in 200ml frozen water, adjust ph=2 with hydrochloric acid, then use 50ml × 3 dichloromethane
Extraction, merges extraction phase brine It, anhydrous sodium sulfate drying, is then evaporated on a rotary evaporator, the remnants obtaining
Thing column chromatography purifies, and obtains the sterling of v-1.Esi-ms, m/z=296 ([m+h]+).
2.95g (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 the thf being dried.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=386 ([m+h]+).
Embodiment 2-9
With reference to the method for embodiment 1, following compounds can be prepared.
Embodiment 10 compound measures to the inhibitory action of dpp-iv enzyme
Measure the compound of the present invention using the fluorogenic dpp4assay kit of bps company 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.Calculate ic according to concentration-fluorescence intensity curves50Value, result see table.
The ic of the suppression to dpp-iv enzyme for the compound50Value
As can be seen from the above table, the compound of the present invention has very strong inhibitory action to dpp-iv enzyme.
Claims (4)
1. there is the compound or its salt of formula i:
Wherein,
r1Alkyl selected from h and c1-c5；
r2Selected from halogen.
2. formula i compound or its salt defined in claim 1,
Wherein,
r1Alkyl selected from h and c1-c3；
r2Selected from f, cl, br, i.
3. formula i compound or its salt defined in claim 2, is selected from:
4. the answering in terms of preparation treatment diabetes medicament of formula i compound or its salt defined in any one of claim 1-3
With.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410635649.0A CN104447500B (en) | 2014-11-02 | 2014-11-02 | Halogen-substituted benzamidocyclohexanecarboxylic acid derivatives and applications thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410635649.0A CN104447500B (en) | 2014-11-02 | 2014-11-02 | Halogen-substituted benzamidocyclohexanecarboxylic acid derivatives and applications thereof |
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| Publication Number | Publication Date |
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| CN104447500A CN104447500A (en) | 2015-03-25 |
| CN104447500B true CN104447500B (en) | 2017-01-18 |
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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 CN201410635649.0A patent/CN104447500B/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 (1)
| Title |
|---|
| 二酰基甘油酰基转移酶I抑制剂的研究进展;囯欣等;《中国药物化学杂志》;20140430;第24卷(第2期);第157-164页 * |
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Granted publication date: 20170118 Termination date: 20171102 |