CN108640893A - A kind of dipeptidyl peptidase-IV inhibitors compound and its preparation method and application - Google Patents
A kind of dipeptidyl peptidase-IV inhibitors compound and its preparation method and application Download PDFInfo
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- CN108640893A CN108640893A CN201810361183.8A CN201810361183A CN108640893A CN 108640893 A CN108640893 A CN 108640893A CN 201810361183 A CN201810361183 A CN 201810361183A CN 108640893 A CN108640893 A CN 108640893A
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- dipeptidyl peptidase
- alkyl
- hydrogen
- inhibitors compound
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/14—Nitrogen atoms not forming part of a nitro radical
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
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Abstract
The present invention provides a kind of dipeptidy peptidase in inhibitors compound, and structure is as shown in formula I：Its pharmaceutically acceptable salt, solvate or crystal, wherein R is selected from hydrogen, halogen, amino, C1‑C6Alkyl, C1‑C4Alkoxy, C1‑C4Alkylamino, nitro, cyano, C1‑C4Alkyl amido, trifluoromethyl, trifluoromethoxy, C1‑C4Alkoxy carbonyl group, C1‑C4Alkanoyl；N=0 2；X is O, S or NH；R3、R4And R5It is each independently selected from hydrogen, C1‑C4Alkyl,R6、R7And R8It is each independently selected from hydrogen, C1‑C4Alkyl, compound provided by the invention have extraordinary blood sugar decreasing effect.
Description
Technical field
The invention belongs to field of medicaments, and in particular to a kind of dipeptidyl peptidase-IV inhibitors compound and preparation method thereof
And purposes.
Background technology
Diabetes are a kind of chronic metabolic diseases as caused by interacting h and E factor, it is due to pancreas
Caused by island β cell functions exception, hypoinsulinism, pancreas islet are resisted and/or liver glucose generates the reason of increasing.It can
It is divided into insulin-dependent diabetes mellitus (Type I diabetes) and non-insulin-dependent disease (type II diabetes).Type II diabetes
Mainly since hypoinsulinism or defect of insulin secretion are with or without disease caused by insulin resistance, account for
The 90-95% of diabetes sum.
Type II diabetes has become the global public health problem of getting worse.Therefore seek safe, long-acting and targeting
Islet beta cell function decay this basic cause of disease newtype drug be the following diabetes study Main way.GLP-1 is a kind of
The polypeptide secreted by mammal intestine L cells belongs to intestines drop insulin, can promote the secretion of insulin under hyperglycemia state.
But its effect weakens significantly in patients with NIDDM body.GLP-1 half-life period is only 1-2min in vivo, and research is found can
With by the activity for inhibiting dipeptidyl peptidase-IV (DPP-IV), the half-life period of GLP-1, increases the concentration of GLP-1 in extension body.
Ao Gelieting, i.e. Omarigliptin (MK-3102) are a kind of potent and long-acting antidiabetics for oral use,
It is a kind of dipeptidyl peptidase-IV (DPP-IV) inhibitor, is researched and developed by MSD Corp. of the U.S., is used for the treatment of type II diabetes.
Ao Gelieting Clinical practices do not change weight, do not cause the hypoglycemia drug efforts be made so that patients with NIDDM can will be used
Medicine frequency is reduced to weekly.It is horizontal (GLP-1 and GIP) that the drug promotes duodenin by inhibiting DPP-IV, from
And glucagon suppression discharges so that insulin secretion increases, and slows down gastric emptying, reduces blood glucose level.
The DPP-IV such as Ao Gelieting inhibitor is widely concerned in the treatment of diabetes, therefore is developed various efficient
DPP-IV inhibitor becomes the important research topic of pharmaceuticals industry.
Invention content
The present inventor is a series of by being obtained to dipeptidyl peptidase-IV inhibitors Ao Gelieting progress structural modifications
Structure novel and the compound with extraordinary hypoglycemic effect.
Specific technical solution of the present invention is as follows：
The present invention provides a kind of dipeptidyl peptidase-IV inhibitors compound, and structure is as shown in formula I：
Or its pharmaceutically acceptable salt, solvate or crystal, wherein
R is selected from hydrogen, halogen, amino, C1-C6Alkyl, C1-C4Alkoxy, C1-C4Alkylamino, nitro, cyano, C1-C4Alkane acyl
Amino, trifluoromethyl, trifluoromethoxy, C1-C4Alkoxy carbonyl group, C1-C4Alkanoyl；
N=0-2；
X is O, S or NH；
R3、R4And R5It is each independently selected from hydrogen, C1-C4Alkyl,
R6、R7And R8It is each independently selected from hydrogen, C1-C4Alkyl.
Preferably, R is selected from halogen, amino, C1-C4Alkyl, C1-C4Alkoxy or trifluoromethyl.
Preferably, n=2.
Preferably, X is oxygen.
Preferably, R3For hydrogen orR6For H, R7And R8For CH3。
Preferably, R4For hydrogen, R5ForR6For H, R7And R8For CH3。
The preferred following compounds of dipeptidyl peptidase-IV inhibitors compound of the present invention：
Another aspect of the present invention provides a kind of preparation method of dipeptidyl peptidase-IV inhibitors compound, the preparation method
Include the following steps：
Wherein, R3' beR7' and R8' it is each independently selected from BOC or C1-C4Alkyl, R3ForR7
And R8At least one is hydrogen；
R4And R5It is each independently selected from BOC or C1-C4Alkyl.
Wherein intermediate 1 is prepared via a method which to obtain：
Term is explained
Term used herein " halogen " includes but not limited to fluorine, chlorine, bromine etc..
Term used herein " C1-C6Alkyl " refers to linear chain or branched chain saturated hydrocarbyl, C1-C6The non-limiting implementation of alkyl
Example includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, sec-butyl, tertiary butyl, amyl, hexyl etc..
Term used herein " C1-C4Alkoxy " refers to the group with " W-O- " structure, and wherein W is C1-C4Alkyl,
C1-C4The non-limiting embodiment of alkoxy includes methoxyl group, ethyoxyl, propoxyl group, isopropoxy and tert-butoxy etc..
Term used herein " C1-C4Alkoxy carbonyl group " refers to " group of W-O-C (O) structures, wherein W are C1-
C4Alkyl, the C1-C4The non-limiting embodiment of alkoxy carbonyl group includes methoxycarbonyl group, carbethoxyl group, propylene carbonyl oxygen, tertiary fourth oxygen
Carbonyl etc..
Term used herein " C1-C4Alkyl amido " refers to the group with " W-C (O) NH- " structure, and wherein W is C1-
C4Alkyl, C1-C4Its non-limiting embodiment of alkyl amido includes formamido group, acetylamino etc..
Term used herein " C1-C4Alkylamino " refers to the group with " W-NH- " structure, and wherein W is C1-C4Alkyl,
C1-C4The non-limiting embodiment of alkylamino includes methylamino, ethylamino, N, N- dimethylaminos etc..
Term used herein " C1-C4Alkanoyl " refers to the group with " W-CO- " structure, and wherein W is C1-C4Alkyl,
C1-C4The non-limiting embodiment of alkanoyl includes formoxyl, acetyl group etc..
Dipeptidyl peptidase-IV inhibitors compound of the present invention can be administered by following approach：Parenteral, office
Portion, intravenous, oral, subcutaneous, intra-arterial, intradermal, in percutaneous, rectum, encephalic, peritonaeum, intranasal, intramuscular route or as suction
Enter agent.
Another aspect of the present invention provides a kind of dipeptidyl peptidase-IV inhibitors compound or its pharmaceutically acceptable salt, molten
Agent compound, crystal and pharmaceutically acceptable carrier or excipient.
Dipeptidyl peptidase-IV inhibitors compound shown in formula I can be administered in the form of a pharmaceutical preparation, the drug
Composition includes dipeptidyl peptidase-IV inhibitors compound and pharmaceutically acceptable carrier or auxiliary material.
The dipeptidyl peptidase-IV inhibitors compound of the present invention can be made into suitable dosage form according to administration route.
When oral medication, the compounds of this invention, which can be made into, arbitrarily takes orally acceptable dosage form, including but not limited to
Tablet, capsule.Wherein, the carrier that tablet uses generally comprises lactose and cornstarch, and it is such as stearic that lubricant in addition can also be added
Sour magnesium.The diluent that capsule preparations use generally comprises lactose and dried corn starch.
Dipeptidyl peptidase-IV inhibitors compound of the present invention can the medication in the form of aseptic injection preparation, including sterile note
Jetting or aseptic injectable solution can also be lyophilized form.Wherein, workable carrier and solvent include water, Ringer's solution
And isotonic sodium chlorrde solution.
Another aspect of the present invention provides a kind of dipeptidyl peptidase-IV inhibitors compound answering in preparing hypoglycemic drug
With.
The beneficial effects of the present invention are：It is very good that dipeptidyl peptidase-IV inhibitors compound provided by the invention has
Hypoglycemic activity.
Specific implementation mode
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.It is not specified in embodiment specific
Condition person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer is
It can be with conventional products that are commercially available.
The general formula of each compounds process for production thereof of the present invention is as follows：
Wherein, R3' beR7' and R8' it is each independently selected from BOC or C1-C4Alkyl, R3ForR7
And R8At least one is hydrogen；
R4And R5It is each independently selected from BOC or C1-C4Alkyl.
Intermediate 1 is prepared by conventional method first.
Intermediate 1 (1mmol) and intermediate 2 or intermediate 3 (1.15mmol) are dissolved in 200mL tetrahydrofurans and DMSO
In mixed liquor, the volume ratio of tetrahydrofuran and DMSO are 3.5:2；Normal-temperature reaction under nitrogen protection, the reaction was complete for TLC monitorings, removes
Solvent is removed, reactant is obtained, reactant is dissolved in 200mL dichloromethane, trifluoroacetic acid (60mL) is added dropwise, it is dense after stirring 2h
Using the dichloromethane solution neutralization reaction of 15% tetrahydrofuran and 2.5% ammonium hydroxide solvent is removed under reduced pressure, in 65i in contracting reaction solution
BiotageTMThe dichloromethane that 2.5% tetrahydrofuran and 0.125% ammonium hydroxide are used on column, purifies to obtain target chemical combination
Object, products therefrom is 100:20:It is recrystallized in the mixed liquor of 1 dichloromethane, tetrahydrofuran and ammonium hydroxide, obtains target chemical combination
Object, yield 10-30%.
Test example：The compounds of this invention tests DPP-IV enzyme inhibition activity
Appropriate DPP-IV enzyme (SIGMA), the diluted sample box HEPES buffer solution of 3 times of concentration gradients are added in reaction system
(25mM HEPES, 140mM NaCl, 1%BSA, 80mM MgCl2), while setting up blank control group and (being free of DPP-IV enzyme and sample
Product box), negative control (physiological saline) and positive control (MK-3102) react at room temperature 15min, and substrate SIGMA, room temperature is added
Black out reacts 30min, detects fluorescence, excitation wavelength 355nm, launch wavelength 460nm.
Inhibiting rate is calculated according to fluorescence measurement value, inhibiting rate=[1- (sample-blank)/(feminine gender-blank)] * 100% is answered
IC is calculated with Xlfit softwares50, test result is shown in Table 1.
1 each compound of table is to DPP-IV external activity test result
As can be seen from the table, dipeptidyl peptidase-IV inhibitors compound provided by the invention has extraordinary drop blood
Sugared effect.
Claims (10)
1. a kind of dipeptidyl peptidase-IV inhibitors compound, structure is as shown in formula I：
Or its pharmaceutically acceptable salt, solvate or crystal, wherein
R is selected from hydrogen, halogen, amino, C1-C6Alkyl, C1-C4Alkoxy, C1-C4Alkylamino, nitro, cyano, C1-C4Alkyl amido,
Trifluoromethyl, trifluoromethoxy, C1-C4Alkoxy carbonyl group, C1-C4Alkanoyl；
N=0-2；
X is O, S or NH；
R3、R4And R5It is each independently selected from hydrogen, C1-C4Alkyl,
R6、R7And R8It is each independently selected from hydrogen, C1-C4Alkyl.
2. dipeptidyl peptidase-IV inhibitors compound as described in claim 1, wherein
R is selected from halogen, amino, C1-C4Alkyl, C1-C4Alkoxy or trifluoromethyl.
3. dipeptidyl peptidase-IV inhibitors compound as claimed in claim 2, wherein n=2.
4. dipeptidyl peptidase-IV inhibitors compound as described in claim 1, wherein X is oxygen.
5. dipeptidyl peptidase-IV inhibitors compound as described in claim 1, wherein R3For hydrogen orR6For H, R7
And R8For CH3。
6. dipeptidyl peptidase-IV inhibitors compound as described in claim 1, wherein R4For hydrogen, R5ForR6For
H, R7And R8For CH3。
7. dipeptidyl peptidase-IV inhibitors compound as described in claim 1 is selected from following compound：
8. a kind of preparation method of dipeptidyl peptidase-IV inhibitors compound, the preparation method include the following steps：
Wherein, R3' beR7' and R8' it is each independently selected from BOC or C1-C4Alkyl, R3ForR7And R8Extremely
It is few that there are one be hydrogen；
R4And R5It is each independently selected from BOC or C1-C4Alkyl.
9. pharmaceutical composition, including claim 1-7 any one of them dipeptidyl peptidase-IV inhibitors compounds and pharmacy
Acceptable carrier or excipient.
10. a kind of application of dipeptidyl peptidase-IV inhibitors compound in preparing hypoglycemic drug.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810361183.8A CN108640893B (en) | 2018-04-20 | 2018-04-20 | Dipeptidyl peptidase-IV inhibitor compound and preparation method and application thereof |
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| CN201810361183.8A CN108640893B (en) | 2018-04-20 | 2018-04-20 | Dipeptidyl peptidase-IV inhibitor compound and preparation method and application thereof |
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| CN108640893B CN108640893B (en) | 2023-02-21 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101991572A (en) * | 2009-08-21 | 2011-03-30 | 华东理工大学 | Novel dipeptidyl peptidase IV inhibitor |
| US20140228303A1 (en) * | 2011-06-13 | 2014-08-14 | Panacea Biotec Ltd | Novel sglt inhibitors |
| US20140378540A1 (en) * | 2011-09-13 | 2014-12-25 | Rajesh Jain | Novel sglt inhibitors |
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2018
- 2018-04-20 CN CN201810361183.8A patent/CN108640893B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101991572A (en) * | 2009-08-21 | 2011-03-30 | 华东理工大学 | Novel dipeptidyl peptidase IV inhibitor |
| US20140228303A1 (en) * | 2011-06-13 | 2014-08-14 | Panacea Biotec Ltd | Novel sglt inhibitors |
| US20140378540A1 (en) * | 2011-09-13 | 2014-12-25 | Rajesh Jain | Novel sglt inhibitors |
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| CN108640893B (en) | 2023-02-21 |
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