CN104478860B - Diamantane (obsolete) tetrazole derivant, Preparation Method And The Use - Google Patents
Diamantane (obsolete) tetrazole derivant, Preparation Method And The Use Download PDFInfo
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- CN104478860B CN104478860B CN201510016587.XA CN201510016587A CN104478860B CN 104478860 B CN104478860 B CN 104478860B CN 201510016587 A CN201510016587 A CN 201510016587A CN 104478860 B CN104478860 B CN 104478860B
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- XDHZLCLUZVLCRX-GVHYBUMESA-N C=NC(CCC1)C[C@@H]1C#N Chemical compound C=NC(CCC1)C[C@@H]1C#N XDHZLCLUZVLCRX-GVHYBUMESA-N 0.000 description 1
- DOHIYSMCCCDEPN-BNNQUZSASA-N CC1(CC2CC3C4)C23C4(CNC(C/C=C2\N=NC(C(C)=O)=NC2)=O)C1 Chemical compound CC1(CC2CC3C4)C23C4(CNC(C/C=C2\N=NC(C(C)=O)=NC2)=O)C1 DOHIYSMCCCDEPN-BNNQUZSASA-N 0.000 description 1
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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
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Abstract
The present invention relates to the drug world relevant to diabetes.Specifically, the present invention relates to inhibitors of dipeptidyl IV containing diamantane (obsolete) tetrazole structure with formula I and preparation method thereof, and they application in preparing diabetes medicament.Wherein, R1Alkyl, the cycloalkyl of C3 C5 selected from H, C1 C5.
Description
Technical field
The present invention relates to the drug world relevant to diabetes.Specifically, the present invention relates to diabetes
Medicative dipeptidyl peptidase-iv inhibitor containing diamantane (obsolete) tetrazole structure and preparation method thereof, contain
Their pharmaceutical composition and the medicine in terms for the treatment of diabetes.
Background technology
According to statistics, global diabetics about about 2.5 hundred million in 2007, wherein the biggest number is II type
(i.e. non-insulin-depending type) diabetics.Antidiabetic medicine at Clinical practice mainly has sulfonylureas at present
Class, metformin class and trypsin class medicine, list in recent years also have medicament of insulin sensitizer and α-
Alpha-glucosidase inhibitors etc..These medicines have good therapeutic effect, but generally there is the serious pairs such as hypoglycemia
Effect, and there is safety issue in long-term treatment, such as problems such as liver toxicity and body weight increases.
DPP IV (dipeptidyl peptidase IV, DPP-IV) can effectively and pancreas of degrading rapidly
Glucagon-like peptide 1 (GLP-1), GLP-1 is insulin production and secretes one of maximally effective stimulant, therefore
Suppression DPP-IV can strengthen the effect of endogenous GLP-1, thus improves the level of insulin in blood.Doctor at present
Learning and it turned out DPP-IV inhibitor is a kind of novel antidiabetic treatment medicine, has had multiple medicine
Thing list marketing.Clinical effectiveness shows that such medicine has good hypoglycemic effect, does not finds other glycosurias simultaneously
The untoward reaction thing such as the increase of common body weight and hypoglycemia produced by medicine.
The major structural types of existing DPP-IV inhibitor has: chemically structure type divides and is broadly divided into piperazine
Piperazine triazole type, 2-cyano-pyrolidin class, thiazolidines, Pyrimdinone, and other types structure medicament.
The invention discloses an adamantane-like tetrazole DPP-IV inhibitor, these compounds may be used for
The medicine of preparation treatment diabetes.
Summary of the invention
It is an object of the present invention to provide one and there is excellent activity, have compounds of formula I and
Pharmaceutically acceptable salt.
It is a further object to provide the method that preparation has compounds of formula I and salt thereof.
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, the cycloalkyl of C3-C5 selected from H, C1-C5.
Preferably, R1Alkyl, cyclopropane selected from H, C1-C3.
Further, following compound:
Compound of Formula I of the present invention is synthesized by following steps:
Compound II and bromoacetyl bromide III reacts in the presence of a base and obtains compound IV, the latter and 2H-tetra-
Nitrogen azoles-5-formic acid V reacts in the presence of a base and obtains compound VI, compound VI with in the presence of condensing agent with
VII reacts, 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 contractings
Mixture can be used in combination with organic base, such as triethylamine, diisopropyl ethyl amine (DIPEA) and 4-dimethylamino
Pyridine (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 inorganic with various
Acid, such as, hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid etc., or organic acid, such as formic acid, acetic acid, citric acid,
The pharmaceutically acceptable salt that oxalic acid, fumaric acid, maleic acid, aminoacid etc. are generated.
Compound or its salt shown in formula I has the inhibitory action of DPP-IV, can be as effectively
Composition is used for preparing in treatment diabetes medicament；Preferably, described diabetes are non-insulin-dependent diabetes mellitus.
The activity of the compounds of this invention 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 as effectively
Composition medicine in terms of preparing diabetes.The activity of compound of Formula I of the present invention is to pass through body
Interior blood sugar lowering modelling verification.
The compound of Formula I of the present invention is effective in comparatively wide dosage range.Such as every day takes
Dosage about in the range of 1mg-1000mg/ people, be divided into once or be administered for several times.The actual present invention that takes is led to
The dosage of compound of formula I can be determined according to relevant situation by doctor.These situations include: patient
Condition, route of administration, 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
It is only for explanation, and is not intended to limit the present invention.Those skilled in the art are done according to the teachings of the present invention
The various changes gone out all should be within the protection domain required by the application claim.
Embodiment 1
1.79g (10mmol) compound II-1 and 3.04g (30mmol) triethylamine is dissolved in what 20mL was dried
In dichloromethane, the lower stirring of ice-water bath cooling, the most slowly drip 2.42g (12mmol) compound III and be dissolved in
The solution made in the dichloromethane that 5mL is dried.After dropping, reactant mixture at room temperature continues to stir
Mix 1 hour.Reactant mixture is poured in 200mL frozen water, stirring, extracts with 50mL × 3 dichloromethane
Taking, merge extraction phase brine It, anhydrous sodium sulfate is dried, and is evaporated the most on a rotary evaporator,
The residue column chromatography purification arrived, obtains the sterling of IV-1, white solid, ESI-MS, m/z=299 and 301
([M+H]+)。
1.80g (6mmol) compound IV-1,0.68g (6mmol) compound V, 1.00g (6mmol)
Solid potassium iodide and 4.15g (30mmol) solid carbonic acid potassium are in the DMF that 20mL is dried under 120 DEG C of nitrogen
It is stirred overnight.Being poured into after reactant mixture is the coldest in 200mL frozen water, stirring, with 50mL × 3 dichloro
Methane extracts, and merges extraction phase brine It, and anhydrous sodium sulfate is dried, and steams the most on a rotary evaporator
Dry, the residue column chromatography purification obtained, obtain the sterling of VI-1, white solid, ESI-MS, m/z=
333([M+H]+)。
0.99g (3mmol) compound VI-1,0.29g (mmol) compound VII and 0.62g (3mmol)
DCC is stirred overnight under room temperature in the THF that 6mL is dried.Sucking filtration removes the solid in reactant mixture,
Filtrate is evaporated on a rotary evaporator, and residue column chromatography purification obtains the sterling of product I-1, white solid,
ESI-MS, m/z=411 ([M+H]+)。
Embodiment 2-5
Use method same as in Example 1, following compounds can be prepared.
The inhibitory action of DPP-IV enzyme is measured by embodiment 6 compound
Use the fluorescence DPP4 activity detection kit of BPS Biological Science Co., Ltd, measure the change of the present invention
The compound inhibitory activity to DPP-IV enzyme.
Sample is respectively as follows: 5,10,30,100 and 200ng/kg by gradient dilution concentration successively, glimmering
Photoreaction 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 fluoremetry absorption value.IC is calculated according to concentration-fluorescence intensity curves50Value, result see table:
The compound IC to the suppression of DPP-IV enzyme50Value
As can be seen from the above table, the compound of the present invention has the strongest inhibitory action to DPP-IV enzyme.
Claims (5)
1. there is compounds of formula I or its pharmaceutically acceptable salt:
Wherein, R1Alkyl, the cycloalkyl of C3-C5 selected from H, C1-C5.
2. have defined in claim 1 compounds of formula I or or its pharmaceutically acceptable salt:
Wherein, R1Alkyl, cyclopropane selected from H, C1-C3.
3. compound of Formula I defined in claim 2 or its pharmaceutically acceptable salt, is selected from:
4. compound of Formula I or the method for its pharmaceutically acceptable salt defined in synthesis claim 1-3 any one,
Comprise the following steps:
Compound II and bromoacetyl bromide III reacts in the presence of a base and obtains compound IV, compound IV and 2H-
Tetrazole-5-formic acid V reacts in the presence of a base and obtains compound VI, compound VI in the presence of condensing agent with
VII reacts, and obtains compound I, wherein R1Corresponding by described in any one of claim 1-3.
5. compound of Formula I defined in claim 1-3 any one or its pharmaceutically acceptable salt are controlled in preparation
Treat the application in terms of diabetes medicament.
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| WO2003042190A1 (en) * | 2001-11-12 | 2003-05-22 | Pfizer Products Inc. | N-alkyl-adamantyl derivatives as p2x7-receptor antagonists |
| CN103304504B (en) * | 2013-06-02 | 2015-03-04 | 张远强 | Anti-diabetic compound, as well as preparation method and application thereof |
| CN103304501B (en) * | 2013-06-02 | 2015-03-04 | 张远强 | Anti-diabetic compound, as well as preparation method and application thereof |
| CN103304500B (en) * | 2013-06-02 | 2015-03-04 | 张远强 | Novel anti-diabetic compound, as well as preparation method and application thereof |
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Denomination of invention: Adamantane tetrazole derivative and preparation method and application thereof Effective date of registration: 20170816 Granted publication date: 20160824 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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