CN103304501B - Anti-diabetic compound, as well as preparation method and application thereof - Google Patents
Anti-diabetic compound, as well as preparation method and application thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 230000003178 anti-diabetic effect Effects 0.000 title description 2
- 239000003472 antidiabetic agent Substances 0.000 title description 2
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 5
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
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- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
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- 235000012000 cholesterol Nutrition 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 229940125396 insulin Drugs 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- NKOHRVBBQISBSB-UHFFFAOYSA-N 5-[(4-hydroxyphenyl)methyl]-1,3-thiazolidine-2,4-dione Chemical compound C1=CC(O)=CC=C1CC1C(=O)NC(=O)S1 NKOHRVBBQISBSB-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
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- JUNAPQMUUHSYOV-UHFFFAOYSA-N 2-(2h-tetrazol-5-yl)acetic acid Chemical class OC(=O)CC=1N=NNN=1 JUNAPQMUUHSYOV-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 206010022489 Insulin Resistance Diseases 0.000 description 2
- 229940122355 Insulin sensitizer Drugs 0.000 description 2
- 210000001789 adipocyte Anatomy 0.000 description 2
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- 210000003462 vein Anatomy 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- 0 CBrCc(ccc(CNCC1(CC(C2)C3)CC3(*)CC2C1)c1)c1F Chemical compound CBrCc(ccc(CNCC1(CC(C2)C3)CC3(*)CC2C1)c1)c1F 0.000 description 1
- 108010015776 Glucose oxidase Proteins 0.000 description 1
- 239000004366 Glucose oxidase Substances 0.000 description 1
- RYKCTCWOWSGKPH-UHFFFAOYSA-N NCC(CC(C1)C2)(CC1C1)CC21O Chemical compound NCC(CC(C1)C2)(CC1C1)CC21O RYKCTCWOWSGKPH-UHFFFAOYSA-N 0.000 description 1
- SIBJBAXLIQBENV-UHFFFAOYSA-N OCc1ccc(C=O)cc1F Chemical compound OCc1ccc(C=O)cc1F SIBJBAXLIQBENV-UHFFFAOYSA-N 0.000 description 1
- 108010015181 PPAR delta Proteins 0.000 description 1
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- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 1
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- 229940080774 Peroxisome proliferator-activated receptor gamma agonist Drugs 0.000 description 1
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- 208000005727 Retropneumoperitoneum Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
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Abstract
The invention relates to the field of medicines which are related to diabetes. Specifically, the invention relates to a compound containing an adamantane tetranitrazoleacetic acid structure, which is as shown in a general formula I, has a treatment effect against the diabetes and is used as a peroxisome proliferator-activated receptor (PPAR) agonist, as well as a preparation method and an application in the aspect of treating the diabetes, wherein the groups are as defined in the specification.
Description
Technical field
The present invention relates to the pharmaceutical field relevant to diabetes.Specifically, the present invention relates to peroxisome proliferator-activated property acceptor (PPAR) agonist of the medicative class of diabetes containing diamantane tetrazoleacetic acid skeleton, its preparation method and the pharmaceutical composition containing them.
Background technology
Diabetes are diseases of Patients' rights blood sugar capability deteriorates, and patient loses ability insulin action being made to appropriate reaction to some extent.In diabetes, major part is type ii diabetes (i.e. non insulin dependent diabetes), account for 80%-90%, research finds, the insulin resistant of peripheral tissues's (comprising skeletal muscle, liver and fatty tissue etc.) plays a part very important in the generation, development of type ii diabetes.Having introduced a class at present makes patient recover responsive class medicine, i.e. an insulin sensitizers to own insulin, returns to normally to make Regular Insulin and triglyceride level.In the treatment of research diabetes, peroxisome proliferator-activated property acceptor (PPARs) becomes desirable target, it is one of nuclear receptor superfamily member, several genes can be regulated and controled express simultaneously, take part in Adipocyte Differentiation, lipid metabolism adjustment and increase the physiological processs such as insulin sensitivity.There is three types in PPAR family: PPAR α, PPAR β (being also PPAR δ) and PPAR γ.PPAR α relates to the β-oxidation stimulating lipid acid, also relate to control HDL cholesterol levels, play an important role in Liver lipids metabolism, and PPAR γ acceptor relates to Adipocyte Differentiation program and must activate, insulin resistant can be improved and improve insulin sensitivity (Yang Jun, Zou Xiulan, PPAR α/γ double excitations machine and diabetes B, Medical review, 2008,14 (16): 2492-2496).PPAR γ is considered to the main molecules target of glitazone insulin sensitizers, although glitazone compound is the active drug for the treatment of type ii diabetes, but the side effect of this compounds clearly, such as serious toxin for liver type, body weight increase and anaemia, this mainly glitazone be the main of PPAR γ or full agonist (N A Jie, sieve D is thorough, her Feng of S, CN101098865A).Therefore, the dual agonists of PPAR α and PPAR γ just can alleviate the side effect even eliminating glitazone PPAR gamma agonist, except making blood sugar and Regular Insulin normalizing, also has the effect reducing blood fat and suppress cardiovascular complication.
The invention discloses the dual agonists of an adamantane-like tetrazoleacetic acid compounds as PPAR α and PPAR γ, these inhibitor may be used for the medicine of the medicine, particularly non insulin dependent diabetes preparing treatment diabetes.
Summary of the invention
An object of the present invention is the shortcoming and defect overcoming prior art, provide one to have 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 pharmacy acceptable salt thereof.
Another object of the present invention be to provide compound containing general formula I and pharmaceutically acceptable salt as effective constituent, and the medicinal compositions of one or more pharmaceutically acceptable carrier, vehicle or thinners, and the application in treatment diabetes.
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 is selected from F, Cl, Br, I, CN.
Preferred following compound of Formula I:
The compound that preferred the present invention has general formula I is as follows:
Compound of Formula I of the present invention is synthesized by following steps:
Compd A and B are at NaBH
3there is lower reaction in CN, obtains Compound C; The process of Compound C bromide reagent obtains Compound D, and D and E is obtained by reacting Compound I in the presence of a base; Wherein, R is selected from F, Cl, Br, I, CN.
Compound of Formula I of the present invention has the double excitations effect of PPAR α and PPAR γ, can be used as effective constituent for the preparation of the medicine of diabetes aspect can lose weight and increase and suppress cardiovascular complication disease.The activity of compound of Formula I of the present invention is by hypoglycemic in body and fall blood cholesterol levels and triglyceride level model is verified.
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 20mg-400mg/ 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
Reaction initial feed is from commercially available.
1.81g (10mmol) compd A and 1.54g (10mmol) compd B-1 are dissolved in 20mL EtOH, react after 3 hours and add 1.89g (30mmol) NaBH again under room temperature
3cN, then continues stirring and spends the night.In reaction mixture impouring 100mL frozen water, stir, regulate pH=6 with concentrated hydrochloric acid, with the dichloromethane extraction of 50mL × 3, merge extraction phase, once, anhydrous sodium sulfate drying, boils off solvent at Rotary Evaporators and obtains a resistates in salt water washing, then column chromatography purification, obtain the sterling of C-1, ESI-MS, m/z=337 ([M+NH
4]
+).
2.23g (7mmol) Compound C-1 is dissolved in the toluene of 10mL drying, slowly stirs, slowly drip 2.71g (10mmol) PBr under ice-water bath cooling
3the solution that the methylene dichloride being dissolved in 2mL drying is made, dropwising rear reaction mixture at room temperature stirs after half an hour in impouring 100mL frozen water, stirs, with the dichloromethane extraction of 50mL × 3, merge extraction phase, once, anhydrous sodium sulfate drying, boils off solvent at Rotary Evaporators and obtains a resistates in salt water washing, then column chromatography purification, obtain the sterling of D-1, ESI-MS, m/z=381 and 383 ([M+H]
+).
1.91g (5mmol) Compound D-1 and 0.64g (5mmol) E-1 are dissolved in 10mL DMF, stir, add 2.07g (15mmol) K
2cO
3, continue at 100 DEG C to stir until raw material consumption complete (12 hours).In reaction mixture impouring 100mL frozen water, stir, regulate pH=2 with concentrated hydrochloric acid, with the dichloromethane extraction of 50mL × 3, merge extraction phase, once, anhydrous sodium sulfate drying, boils off solvent at Rotary Evaporators and obtains a resistates in salt water washing, then column chromatography purification, obtain the sterling of I-1, ESI-MS, m/z=428 ([M-H]
-).
Embodiment 2-4
According to the method for embodiment 1, prepare the compound that the general formula shown in following table is I.
Embodiment 5
Sample is mixed with the suspension of 5mg/mL concentration with 1% Xylo-Mucine, and administration volume is 0.4mL/20g body weight, is equivalent to 100mg/kg dosage.
Healthy ICR mouse, male and female half and half, body weight 20-24g, meets primary standard.Animal fasting 16 hours, gavage gives the dextrose in saline solution of testing compound 15 minutes pneumoretroperitoneum injection 2g/kg, after modeling, 0.5h, 1h, 1.5h and 2h timing is taken kapillary and is got blood from mouse ball rear vein beard, centrifugation serum, with each time point serum glucose level of determination of glucose oxidase.Blank mouse neither gives glucose and does not also give testing compound, and model mice only gives glucose and do not give testing compound.
Data as can be seen from upper form, the compounds of this invention significantly can strengthen the mouse blood sugar dosis tolerata that glucose causes.
Embodiment 6
Sample is mixed with the suspension of 5mg/mL concentration with 1% Xylo-Mucine, and administration capacity is 0.4mL/20g body weight, is equivalent to 100mg/kg dosage.
Healthy Wister rat, male and female half and half, about body weight 300g, meets primary standard.Animal feeds 30 days with high lipid food, measure cholesterol in serum and content of triglyceride, with cholesterol and content of triglyceride for standard random packet, after animal grouping, gavage gives testing compound 7 days continuously, fasting 12 hours before last administration, after medicine, 1h kapillary gets blood from rat ball rear vein beard, centrifugation serum, measures serum cholesterol and content of triglyceride with cholesterol and Triglyceride Reagent box.Test result is as shown in the table.
Cholesterol level (g/dl)
Content of triglyceride (g/dl)
The data declaration of above-mentioned two tables, compound of the present invention can effectively reduce cholesterol and triglyceride level.
Claims (6)
1. there is the compound of general formula I:
Wherein, R is selected from F, Cl, Br, I, CN.
2. the compound of Formula I that defines of claim 1, is selected from:
3. the compound of Formula I that defines of claim 2, is selected from:
4. synthesize the method for the compound of Formula I that claim 1-3 defines, comprise the following steps:
Compd A and B are at NaBH
3there is lower reaction in CN, obtains Compound C; The process of Compound C bromide reagent obtains Compound D, and D and E is obtained by reacting Compound I in the presence of a base; Wherein, R is selected from F, Cl, Br, I, CN.
5. synthesize the method for the compound of Formula I that claim 3 defines, comprise the following steps:
6. the purposes of arbitrary the defined compound of Formula I of claim 1-3 in preparation treatment diabetes medicament.
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| CN201310221416.1A CN103304501B (en) | 2013-06-02 | 2013-06-02 | Anti-diabetic compound, as well as preparation method and application thereof |
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| CN103304501B true CN103304501B (en) | 2015-03-04 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104447704B (en) * | 2015-01-13 | 2016-07-27 | 佛山市赛维斯医药科技有限公司 | A kind of itrile group diamantane (obsolete) tetrazotized zole compound, Preparation Method And The Use |
| CN104478861B (en) * | 2015-01-13 | 2016-07-27 | 佛山市赛维斯医药科技有限公司 | A kind of nitro diamantane (obsolete) tetrazotized zole compound, Preparation Method And The Use |
| CN104478860B (en) * | 2015-01-13 | 2016-08-24 | 佛山市赛维斯医药科技有限公司 | Diamantane (obsolete) tetrazole derivant, Preparation Method And The Use |
| CN104478859B (en) * | 2015-01-13 | 2016-07-27 | 佛山市赛维斯医药科技有限公司 | A kind of hydroxyadamantane tetrazotized zole compound, Preparation Method And The Use |
| CN104447703B (en) * | 2015-01-13 | 2016-07-27 | 佛山市赛维斯医药科技有限公司 | A kind of nitro diamantane (obsolete) tetrazotized zole compound, Preparation Method And The Use |
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