CN104529857B - Halo diamantane amide derivatives, Preparation Method And The Use - Google Patents
Halo diamantane amide derivatives, Preparation Method And The Use Download PDFInfo
- Publication number
- CN104529857B CN104529857B CN201510017048.8A CN201510017048A CN104529857B CN 104529857 B CN104529857 B CN 104529857B CN 201510017048 A CN201510017048 A CN 201510017048A CN 104529857 B CN104529857 B CN 104529857B
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- acceptable salt
- present
- pharmacy acceptable
- 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.)
- Expired - Fee Related
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the pharmaceutical field relevant to diabetes.Specifically, the present invention relates to the Halogen with general formula I for dipeptidyl peptidase-iv inhibitor, its preparation method of diamantane amide structure and preparing the application in diabetes medicament.
wherein, R
1be selected from halogenic substituent.
Description
Technical field
The present invention relates to the pharmaceutical field relevant to diabetes.Specifically, the present invention relates to the dipeptidyl peptidase-iv inhibitor and preparation method thereof of the medicative Halogen of diabetes for diamantane amide structure, the pharmaceutical composition containing them and the medicine in treatment diabetes.
Background technology
According to statistics, global diabetic subject nearly about 2.5 hundred million in 2007, wherein large absolutely number is II type (i.e. non-insulin-depending type) diabetic subject.Mainly contain sulfonylurea, N1,N1-Dimethylbiguanide class and trypsin class medicine at the antidiabetic medicine of Clinical practice at present, what go on the market in recent years also has medicament of insulin sensitizer and alpha-glucosidase inhibitor etc.These medicines have good therapeutic action, but the serious side effects such as ubiquity hypoglycemia, and there is safety issue in long-term treatment, as problems such as liver toxicity and body weight increases.
DPP IV (dipeptidylpeptidaseIV, DPP-IV) can effectively and to degrade rapidly glucagon-like peptide 1 (GLP-1), GLP-1 is one of insulin production and the most effective stimulant of secretion, therefore suppress DPP-IV can strengthen the effect of endogenous GLP-1, thus improve the level (CN200480017355.6) of Regular Insulin in blood.Current medical science has confirmed that DPP-IV inhibitor is a kind of novel antidiabetic treatment medicine, has had multiple medicine list marketing at present.Clinical effectiveness shows such medicine and has good hypoglycemic effect, does not find the untoward reaction thing such as the common body weight increase that other diabetes medicaments produce and hypoglycemia simultaneously.
The major structural types of existing DPP-IV inhibitor has: chemically structure type divides and is mainly divided into piperazine and triazole species, 2-cyano-pyrolidin class, thiazolidines, Pyrimdinone, and other types structure medicament.
The invention discloses a class halo diamantane amides DPP-IV inhibitor, these compounds may be used for the medicine preparing treatment diabetes.
Summary of the invention
An object of the present invention is to provide one and there is excellent activity, there is compound and the pharmacy acceptable salt thereof of general formula I.
Another object of the present invention is to provide preparation and has the compound of general formula I and the method for salt thereof.
Another object of the present invention is to provide the application of compound in treatment diabetes containing general formula I.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The compound that the present invention has general formula I has following structural formula:
Wherein, R
1be selected from halogenic substituent.
Be preferably as follows the compound with general formula I:
Further, preferably there is the compound of general formula I as follows:
Compound of Formula I of the present invention is synthesized by following steps:
Compound II per reacts with III under condensing agent exists, and obtains compound IV; Compound IV uses the method for catalytic hydrogenolysis to slough Bn protecting group and obtains V; Compound V reacts with VI under condensing agent exists, and obtains compound VI I; Compound VI I acid treatment is sloughed Boc protecting group and is obtained I.
Above-mentioned condensing agent comprises N, N'-dicyclohexyl carbodiimide (DCC), N-ethyl-N'-(3-dimethylamino-propyl) carbodiimide hydrochloride (EDC) and carbonyl dimidazoles (CDI) etc., these condensing agents can with organic bases conbined usage, as triethylamine, diisopropyl ethyl amine (DIPEA) and DMAP (DMAP) etc.The condition of above-mentioned catalytic hydrogenolysis comprises and using such as Pd/C and Pd (OH)
2deng catalyzer, hydrogen source comprises hydrogen, HCO
2h, HCO
2nH
4with tetrahydrobenzene etc.Above-mentioned acid comprises hydrochloric acid, sulfuric acid, methylsulfonic acid, trifluoroacetic acid and tosic acid etc.
Wherein, R
1definition as previously mentioned.
The pharmacy acceptable salt of formula I of the present invention comprises, but be not limited to and various mineral acid, such as, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid etc., or organic acid, the pharmacy acceptable salt that such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, toxilic acid, amino acid etc. generate.
Compound or its salt shown in formula (I) has the restraining effect of DPP-IV, can be used as effective constituent for the preparation of in treatment diabetes medicament; Preferably, described diabetes are non insulin dependent diabetes.The activity of the compounds of this invention is verified by the external restraining effect to DPP-IV enzyme.
Compound of Formula I of the present invention or its salt have the restraining effect of DPP-IV, can be used as the medicine of effective constituent for the preparation of diabetes aspect.The activity of compound of Formula I of the present invention is by hypoglycemic modelling verification in body.
Compound of Formula I of the present invention is effective in quite wide dosage range.The dosage that such as every day takes, within the scope of 1mg-1000mg/ people, is divided into once or administration for several times.The actual dosage taking compound of Formula I of the present invention can be decided according to relevant situation by doctor.These situations comprise: the physical state of patient, route of administration, age, body weight, individual reaction to medicine, the severity etc. of symptom.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that, following embodiment be only for illustration of, and not for limiting the present invention.The various changes that those skilled in the art's training centre according to the present invention is made all should within the protection domain required by the application's claim.
Embodiment 1
2.28g (10mmol) Compound II per-1,3.21g (10mmol) compound III, 2.06g (10mmol) N is added in the round-bottomed flask of a 100mL, N'-dicyclohexyl carbodiimide (DCC) and 1.22g (10mmol) DMAP (DMAP), dissolve with the THF of 20mL drying, room temperature for overnight, TLC display reaction completes substantially.Reaction mixture suction filtration removing solid, filtrate is evaporate to dryness on a rotary evaporator, and resistates column chromatography purification, obtains compound IV-1, white solid, ESI-MS, m/z=550 ([M+NH
4]
+).
3.19g (6mmol) compound IV-1 is dissolved in 30mLTHF, adds 0.10g10%Pd/C, and catalytic hydrogenolysis under room temperature is reacted and completed in 12 hours.Reaction mixture suction filtration removing catalyzer, filtrate pours in 200mL water after concentrating on a rotary evaporator, stirs, with 50mL × 3 dichloromethane extraction.Merge extraction phase, with brine It, anhydrous sodium sulfate drying, on a rotary evaporator evaporate to dryness, resistates column chromatography purification, obtain V-1 sterling, white-yellowish solid, ESI-MS, m/z=440 ([M-H]
-).
1.76g (4mmol) compound V-1,0.38g (4mmol) compound VI, 0.82g (4mmol) DCC and 0.49g (10mmol) DMAP (DMAP) stir and spend the night in the THF of 15mL drying.Reaction mixture suction filtration removing solid, filtrate is evaporate to dryness on a rotary evaporator, and resistates column chromatography purification, obtains compound VI I-1, white solid, ESI-MS, m/z=538 ([M+NH
4]
+).
1.04g (2mmol) compound VI I-1 is dissolved in the mixed solvent of 1mL methylene dichloride and 1mL trifluoroacetic acid, room temperature for overnight.Reaction mixture is poured in 100mL frozen water, stirs, with 50mL × 3 dichloromethane extraction.Merge extraction phase, with brine It, anhydrous sodium sulfate drying, on a rotary evaporator evaporate to dryness, resistates column chromatography purification, obtain I-1 sterling, white solid, ESI-MS, m/z=437 ([M+NH
4]
+).
Embodiment 2-4
Use the method identical with embodiment 1, can following compounds be prepared.
Embodiment 5 compound measures the restraining effect of DPP-IV enzyme
Use the fluorescence DPP4 activity detection kit of BPS Biological Science Co., Ltd, measure the inhibit activities of compound of the present invention to DPP-IV enzyme.
Be respectively by gradient dilution concentration successively by sample: 5,10,30,100 and 200ng/kg, fluorescent reaction 96 orifice plate, according to the form below adds sample:
22 DEG C of water-baths, place 10min, SpectraMaxM5 type fluorimetric detector exciting light 350nm, with 450nm fluorometric assay absorption value.IC is calculated according to concentration-fluorescence intensity curves
50value, the results are shown in following table.
Compound is to the IC of the suppression of DPP-IV enzyme
50value
As can be seen from the above table, compound of the present invention has very strong restraining effect to DPP-IV enzyme.
Claims (5)
1. there is compound or its pharmacy acceptable salt of general formula I:
Wherein, R
1be selected from halogenic substituent.
2. the compound of Formula I that defines of claim 1 or its pharmacy acceptable salt, is selected from:
3. the compound of Formula I that defines of claim 2 or its pharmacy acceptable salt, is selected from:
4. synthesize the method for compound of Formula I that any one of claim 1-3 defines or its pharmacy acceptable salt:
Compound II per reacts with III under condensing agent exists, and obtain compound IV, wherein, condensing agent is N, N'-dicyclohexyl carbodiimide; Compound IV uses the method for catalytic hydrogenolysis to slough Bn protecting group and obtains V, and wherein, the catalyzer of catalytic hydrogenolysis is Pd/C, and hydrogen source is hydrogen; Compound V reacts with VI under condensing agent exists, and obtain compound VI I, wherein, condensing agent is N, N'-dicyclohexyl carbodiimide; The process of compound VI I trifluoroacetic acid is sloughed Boc protecting group and is obtained I; Wherein, R
1definition as shown in any one of claim 1-3.
5. the compound of Formula I that defines of any one of claim 1-3 or the application of its pharmacy acceptable salt in preparation treatment diabetes medicament.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510017048.8A CN104529857B (en) | 2015-01-13 | 2015-01-13 | Halo diamantane amide derivatives, Preparation Method And The Use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510017048.8A CN104529857B (en) | 2015-01-13 | 2015-01-13 | Halo diamantane amide derivatives, Preparation Method And The Use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104529857A CN104529857A (en) | 2015-04-22 |
| CN104529857B true CN104529857B (en) | 2016-03-30 |
Family
ID=52845538
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510017048.8A Expired - Fee Related CN104529857B (en) | 2015-01-13 | 2015-01-13 | Halo diamantane amide derivatives, Preparation Method And The Use |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104529857B (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CO5150173A1 (en) * | 1998-12-10 | 2002-04-29 | Novartis Ag | COMPOUNDS N- (REPLACED GLYCLE) -2-DIPEPTIDYL-IV PEPTIDASE INHIBITING CYANOPIRROLIDINS (DPP-IV) WHICH ARE EFFECTIVE IN THE TREATMENT OF CONDITIONS MEDIATED BY DPP-IV INHIBITION |
| EP1572196B1 (en) * | 2002-12-10 | 2008-08-13 | Novartis AG | Combination of a dpp-iv inhibitor and a ppar-alpha compound |
| CN101870671B (en) * | 2010-06-11 | 2012-06-27 | 漆又毛 | Adamantly pyrrolidine derivative, and preparation and application thereof |
-
2015
- 2015-01-13 CN CN201510017048.8A patent/CN104529857B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN104529857A (en) | 2015-04-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104529857B (en) | Halo diamantane amide derivatives, Preparation Method And The Use | |
| CN104447479B (en) | Containing diamantane and amide derivatives, Preparation Method And The Use | |
| CN104478778B (en) | Diamantane amide derivatives, Preparation Method And The Use | |
| CN104529855B (en) | Derivative, the Preparation Method And The Use of a kind of hydroxyl diamantane and amide structure | |
| 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 | |
| CN104530010B (en) | A kind of hydroxyadamantane tetrazotized zole compound, Preparation Method And The Use | |
| CN104530012B (en) | Amantadine tetrazole derivative, Preparation Method And The Use | |
| CN104447704A (en) | Nitrile grouping adamantine tetrazole compound and preparing method and application thereof | |
| CN104529858A (en) | Derivative with halogeneated and amides and preparation method and application thereof | |
| CN104478860A (en) | Adamantane tetrazole derivative and preparation method and application thereof | |
| CN104530009A (en) | Amantadine tetrazolium derivative, and preparing method and application thereof | |
| CN104478859A (en) | Hydroxyl adamantane tetrazole compound, and preparation method and application thereof | |
| CN104496968A (en) | Compound with halogen-substituted adamantane tetrazole structure and preparation method and application thereof | |
| CN104496876A (en) | Hydroxyl diamantane amide derivative, preparation method and use thereof | |
| CN104529856A (en) | Nitro adamantine amide derivative and preparing method and application thereof | |
| CN104478861A (en) | Nitro adamantane-tetrazole compound, preparing method of nitro adamantane-tetrazole compound and application of nitro adamantane-tetrazole compound | |
| CN104478777A (en) | Derivative with nitro adamantine structure and amide structure and preparation method and application thereof | |
| CN104530011B (en) | A kind of itrile group diamantane tetrazotized zole compound, Preparation Method And The Use | |
| CN104447703A (en) | Nitro adamantine tetrazole compound and preparation method and application thereof | |
| KR102783030B1 (en) | Pharmaceutical composition for treating or preventing middle east respiratory syndrome | |
| CN104356046B (en) | Cyclohexane-carboxylic acid amide derivatives that cycloalkyl replaces and application thereof | |
| CN104356047B (en) | Substituted cyclohexane-carboxylic acid amide derivatives and its medicinal usage | |
| CN104447501B (en) | Alkyl-substituted benzamidocyclohexanecarboxylic acid derivatives and applications thereof | |
| CN104356048B (en) | Cyclohexane-carboxylic acid amide derivatives, Preparation Method And The Use |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Halogen-substituted adamantane amide derivant, and preparing method and application thereof Effective date of registration: 20170816 Granted publication date: 20160330 Pledgee: Guangdong Nanhai Rural Commercial Bank branch branch of Limited by Share Ltd. Pledgor: FOSHAN SAIWEISI PHARMACEUTICAL TECHNOLOGY Co.,Ltd. Registration number: 2017990000756 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20190604 Granted publication date: 20160330 Pledgee: Guangdong Nanhai Rural Commercial Bank branch branch of Limited by Share Ltd. Pledgor: FOSHAN SAIWEISI PHARMACEUTICAL TECHNOLOGY Co.,Ltd. Registration number: 2017990000756 |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20190910 Address after: 064200 Huaming Jiayuan Commercial and Residential Building H7, West of Huaming South Road, Zunhua City, Tangshan City, Hebei Province Patentee after: Tangshan Chuangke Jinfu Technology Co.,Ltd. Address before: Chancheng district has 528000 Taiwan public in Guangdong province Foshan City No. 32 first floor 1636, shop No. 1637 Patentee before: FOSHAN SAIWEISI PHARMACEUTICAL TECHNOLOGY Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20210112 Address after: 221000 building 68, health food science park, Fazhan Avenue, suyangshan Town, Pizhou City, Xuzhou City, Jiangsu Province Patentee after: JIANGSU TIANSUYUAN FOOD Co.,Ltd. Address before: 064200 commercial building H7, Huaming Jiayuan commercial and residential building, west of Huaming South Road, Zunhua City, Tangshan City, Hebei Province Patentee before: Tangshan Chuangke Jinfu Technology Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160330 Termination date: 20220113 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |