CN104530011B - A kind of itrile group diamantane tetrazotized zole compound, Preparation Method And The Use - Google Patents
A kind of itrile group diamantane tetrazotized zole compound, Preparation Method And The Use Download PDFInfo
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- CN104530011B CN104530011B CN201510016687.2A CN201510016687A CN104530011B CN 104530011 B CN104530011 B CN 104530011B CN 201510016687 A CN201510016687 A CN 201510016687A CN 104530011 B CN104530011 B CN 104530011B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The present invention relates to the pharmaceutical field relevant to diabetes. Specifically, the present invention relates to the dipeptidyl peptidase-iv inhibitor of a kind of nitrile group-containing diamantane and tetrazole structure and its preparation method, and prepare the application in diabetes medicament.
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 of a kind of itrile group diamantane tetrazole structure that diabetes are had therapeutic action and its preparation method, containing their pharmaceutical composition and the medicine in treatment diabetes.
Background technology
According to statistics, global diabetic subject nearly about 2.5 hundred million in 2007, wherein big absolutely number is II type (i.e. non-insulin-depending type) diabetic subject. The current antidiabetic medicine at Clinical practice mainly contains sulfonylurea, N1,N1-Dimethylbiguanide class and trypsin class medicine, and what list in recent years also has medicament of insulin sensitizer and alpha-glucosidase inhibitor etc. These medicines have good therapeutic action, but generally there is the serious side effects such as hypoglycemia, and long-term treatment exists safety issue, such as problems such as liver toxicity and body weight increases.
DPP IV (dipeptidylpeptidaseIV, DPP-IV) can effectively and glucagon peptide 1 (GLP-1) of degrading fast, GLP-1 is one of insulin production and the most effective stimulant of secretion, therefore suppress DPP-IV can strengthen the effect of endogenous property GLP-1, thus improve the level 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 type structure medicines.
The present invention discloses the DPP-IV inhibitor of a kind of itrile group diamantane tetrazole structure, and these compounds may be used for preparing the medicine for the treatment of diabetes.
Summary of the invention
It is an object of the present invention to provide one and there is excellent activity, there is compound and the pharmacy acceptable salt thereof of formula I structure.
It is a further object to provide preparation and there is the compound of formula I structure and the method for salt thereof.
Now content of the present invention is specifically described by object in conjunction with the present invention.
The compound that the present invention has formula I structure has following structural formula:
Formula I of the present invention is synthesized by following step:
Compound I I and bromoacetyl bromide III is obtained by reacting compound IV in the presence of a base, and the latter and 2H-tetrazole-5-formic acid V are obtained by reacting compound VI in the presence of a base, and compound VI is reacted with VII with under condensing agent existence, obtains Compound 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, such as triethylamine, diisopropyl ethyl amine (DIPEA) and DMAP (DMAP) etc.
The pharmacy acceptable salt of formula I of the present invention comprises, but it is 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 of the present invention 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.
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 formula I of the present invention is by falling sugar modelling verification in body.
The 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 formula I of the present invention can be determined 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. Those skilled in the art all should within the protection domain required by the application's claim according to the various changes that the teachings of the present invention is made.
The preparation of embodiment 1 Compound I
1.90g (10mmol) Compound I I and 3.04g (30mmol) triethylamine is dissolved in the methylene dichloride of 20mL drying, ice-water bath cooling is lower stirs, and then slowly drips and adds 2.42g (12mmol) compound III and be dissolved in the methylene dichloride of 5mL drying the solution made. After dropwising, reaction mixture at room temperature continues to stir 1 hour. Reaction mixture is poured in 200mL frozen water, stir, with 50mL �� 3 dichloromethane extraction, merge extraction phase brine It, anhydrous sodium sulfate drying, then steam dry on a rotary evaporator, the resistates column chromatography purification obtained, obtains the sterling of IV, white solid, ESI-MS, m/z=310 and 312 ([M+H]+)��
1.86g (6mmol) compound IV 0.68g (6mmol) compound V, 1.00g (6mmol) solid potassiumiodide and 4.15g (30mmol) solid carbonic acid potassium stir under 120 DEG C of nitrogen in the DMF of 20mL drying and spend the night. It is poured in 200mL frozen water after reaction mixture is slightly cold, stir, with 50mL �� 3 dichloromethane extraction, merge extraction phase brine It, anhydrous sodium sulfate drying, then steam dry on a rotary evaporator, the resistates column chromatography purification obtained, obtains the sterling of VI, white solid, ESI-MS, m/z=344 ([M+H]+)��
1.03g (3mmol) compound VI, 0.29g (mmol) compound VI I and 0.62g (3mmol) DCC room temperature for overnight in the THF of 6mL drying. Taking out the solid filtering in reaction mixture, filtrate is steamed dry on a rotary evaporator, and resistates column chromatography purification obtains the sterling of product I, white solid, ESI-MS, m/z=422 ([M+H]+)��
The preparation of embodiment 2 reference compound D
For absolutely proving the useful effect of the compounds of this invention, applicant describes in experimentation the following formula: compound D (unexposed) found, as drug effect reference compound.
Its preparation method is as follows:
1.65g (10mmol) Compound I I-1 and 3.04g (30mmol) triethylamine is dissolved in the methylene dichloride of 20mL drying, ice-water bath cooling is lower stirs, and then slowly drips and adds 2.42g (12mmol) compound III and be dissolved in the methylene dichloride of 5mL drying the solution made. After dropwising, reaction mixture at room temperature continues to stir 1 hour. Reaction mixture is poured in 200mL frozen water, stirs, and with 50mL �� 3 dichloromethane extraction, merges extraction phase brine It, anhydrous sodium sulfate drying, then steams dry on a rotary evaporator, and the resistates column chromatography purification obtained, obtains the sterling of IV-1. ESI-MS, m/z=286 and 288 ([M+H]+)��
1.72g (6mmol) compound IV-1,0.68g (6mmol) compound V, 1.00g (6mmol) solid potassiumiodide and 4.15g (30mmol) solid carbonic acid potassium stir under 120 DEG C of nitrogen in the DMF of 20mL drying and spend the night. It is poured in 200mL frozen water after reaction mixture is slightly cold, stirs, with 50mL �� 3 dichloromethane extraction, merge extraction phase brine It, anhydrous sodium sulfate drying, then steam dry on a rotary evaporator, the resistates column chromatography purification obtained, obtains the sterling of VI-1. ESI-MS, m/z=320 ([M+H]+)��
0.96g (3mmol) compound VI-1,0.29g (mmol) compound VI I and 0.62g (3mmol) DCC room temperature for overnight in the THF of 6mL drying. Taking out the solid filtering in reaction mixture, filtrate is steamed dry on a rotary evaporator, and resistates column chromatography purification obtains the sterling of product D, ESI-MS, m/z=398 ([M+H]+)��
The restraining effect of DPP-IV enzyme is measured by embodiment 3 compound
Using the fluorescence DPP4 Activity determination test kit of BPS Biological Science Co., Ltd, the compound measuring the present invention is to the inhibit activities of DPP-IV enzyme.
Being respectively by gradient dilution concentration successively by sample: 5,10,30,100 and 200ng/kg, fluorescent reaction 96 orifice plate, adds sample by following table:
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 curves50Value, the results are shown in following table:
Compound is to the IC of the suppression of DPP-IV enzyme50Value
As can be seen from the above table, DPP-IV enzyme is had very strong restraining effect by the compound of the present invention.
Claims (3)
1. formula I or its pharmacy acceptable salt:
��
2. synthesize the method for compound or its pharmacy acceptable salt described in claim 1, comprise the following steps:
Compound I I and bromoacetyl bromide III is obtained by reacting compound IV in the presence of a base, and compound IV and 2H-tetrazole-5-formic acid V are obtained by reacting compound VI in the presence of a base, and compound VI is reacted with VII under condensing agent exists, and obtains Compound I.
3. compound described in claim 1 or its pharmacy acceptable salt treat the application in diabetes medicament in preparation.
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| CN201510016687.2A CN104530011B (en) | 2015-01-13 | 2015-01-13 | A kind of itrile group diamantane tetrazotized zole compound, Preparation Method And The Use |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006012441A1 (en) * | 2004-07-23 | 2006-02-02 | Susan Marie Royalty | Peptidase inhibitors |
| CN1921856A (en) * | 2004-02-20 | 2007-02-28 | 诺瓦提斯公司 | Dpp-iv inhibitors for treating neurodegeneration and cognitive disorders |
| CN101318922A (en) * | 2007-06-08 | 2008-12-10 | 上海阳帆医药科技有限公司 | Novel dipeptidyl peptidase restrainer, synthesizing process and uses thereof |
| CN101448785A (en) * | 2006-04-03 | 2009-06-03 | 矩阵实验室有限公司 | Novel dipeptidyl peptidase IV inhibitors and processes for their preparation and pharmaceutical compositions containing them |
| EP2318007B1 (en) * | 2008-08-15 | 2013-01-23 | N30 Pharmaceuticals, Inc. | Novel pyrrole inhibitors of s-nitrosoglutathione reductase as therapeutic agents |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1921856A (en) * | 2004-02-20 | 2007-02-28 | 诺瓦提斯公司 | Dpp-iv inhibitors for treating neurodegeneration and cognitive disorders |
| WO2006012441A1 (en) * | 2004-07-23 | 2006-02-02 | Susan Marie Royalty | Peptidase inhibitors |
| CN101448785A (en) * | 2006-04-03 | 2009-06-03 | 矩阵实验室有限公司 | Novel dipeptidyl peptidase IV inhibitors and processes for their preparation and pharmaceutical compositions containing them |
| CN101318922A (en) * | 2007-06-08 | 2008-12-10 | 上海阳帆医药科技有限公司 | Novel dipeptidyl peptidase restrainer, synthesizing process and uses thereof |
| EP2318007B1 (en) * | 2008-08-15 | 2013-01-23 | N30 Pharmaceuticals, Inc. | Novel pyrrole inhibitors of s-nitrosoglutathione reductase as therapeutic agents |
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Denomination of invention: Nitrile grouping adamantine tetrazole compound and preparing method and application thereof Effective date of registration: 20170816 Granted publication date: 20160601 Pledgee: Guangdong Nanhai Rural Commercial Bank branch branch of Limited by Share Ltd Pledgor: FOSHAN SAIWEISI PHARMACEUTICAL TECHNOLOGY CO., LTD. Registration number: 2017990000756 |
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Effective date of registration: 20191014 Address after: 244000 Fengxin Group 7, Charencun, Tongling Development Zone, Tongling City, Anhui Province Patentee after: Tongling Mdt InfoTech 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. |