CN103304502A - 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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- CN103304502A CN103304502A CN2013102214212A CN201310221421A CN103304502A CN 103304502 A CN103304502 A CN 103304502A CN 2013102214212 A CN2013102214212 A CN 2013102214212A CN 201310221421 A CN201310221421 A CN 201310221421A CN 103304502 A CN103304502 A CN 103304502A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 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 11
- 239000003814 drug Substances 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims description 4
- 229910020889 NaBH3 Inorganic materials 0.000 claims description 3
- 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 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 6
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 abstract 2
- 229940126033 PPAR agonist Drugs 0.000 abstract 1
- 239000002253 acid Substances 0.000 abstract 1
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 108010016731 PPAR gamma Proteins 0.000 description 8
- 102000000536 PPAR gamma Human genes 0.000 description 8
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 8
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- 235000012000 cholesterol Nutrition 0.000 description 7
- 239000008103 glucose Substances 0.000 description 7
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 7
- 108010028924 PPAR alpha Proteins 0.000 description 6
- 102000023984 PPAR alpha Human genes 0.000 description 6
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 5
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- 239000008280 blood Substances 0.000 description 5
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- 206010022489 Insulin Resistance Diseases 0.000 description 4
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- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 4
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- 229940125396 insulin Drugs 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000012360 testing method Methods 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
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 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
- 239000000556 agonist Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229940122355 Insulin sensitizer Drugs 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- -1 adamantane tetrazole acetic acid skeleton Chemical group 0.000 description 2
- 210000001789 adipocyte Anatomy 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
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- 230000002526 effect on cardiovascular system Effects 0.000 description 2
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- 238000011160 research Methods 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
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- 150000003626 triacylglycerols Chemical class 0.000 description 2
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- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- 0 *c1cc(CNCC(CC(C2)C3)(CC2C2)CC32O)ccc1C[n]1nnnc1CC(O)=O Chemical compound *c1cc(CNCC(CC(C2)C3)(CC2C2)CC32O)ccc1C[n]1nnnc1CC(O)=O 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- CBEGBDXSEZGMEG-UHFFFAOYSA-N Cc1c(C[n]2nnnc2CC(O)=O)ccc(CNCC(CC(C2)C3)(CC2C2)CC32O)c1 Chemical compound Cc1c(C[n]2nnnc2CC(O)=O)ccc(CNCC(CC(C2)C3)(CC2C2)CC32O)c1 CBEGBDXSEZGMEG-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 108010015776 Glucose oxidase Proteins 0.000 description 1
- 239000004366 Glucose oxidase Substances 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- ZRFSVALGPOPQML-UHFFFAOYSA-N OC1(CC(CCCNCc2ccc(C[n]3nnnc3CC(O)=O)c(C3CC3)c2)C2)CNCC2C1 Chemical compound OC1(CC(CCCNCc2ccc(C[n]3nnnc3CC(O)=O)c(C3CC3)c2)C2)CNCC2C1 ZRFSVALGPOPQML-UHFFFAOYSA-N 0.000 description 1
- 108010015181 PPAR delta Proteins 0.000 description 1
- 108010044210 PPAR-beta Proteins 0.000 description 1
- 229940080774 Peroxisome proliferator-activated receptor gamma agonist Drugs 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
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- 239000003937 drug carrier Substances 0.000 description 1
- 229940125542 dual agonist Drugs 0.000 description 1
- 230000000225 effect on diabetes Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
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- 150000004665 fatty acids Chemical class 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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 field of diabetes related drugs. In particular to peroxisome proliferator-activated receptor (PPAR) agonists containing an adamantane tetrazole acetic acid skeleton and having a treatment effect on diabetes, a preparation method thereof and a pharmaceutical composition containing the same.
Background
Diabetes is a disease in which the ability of a patient to control blood glucose is impaired, and the patient has lost the ability to respond appropriately to the action of insulin to varying degrees. Most of the diabetes mellitus is type II diabetes mellitus (namely non-insulin-dependent diabetes mellitus) which accounts for about 80% -90%, and researches show that the insulin resistance of peripheral tissues (comprising skeletal muscle, liver, adipose tissues and the like) plays an extremely important role in the occurrence and development of the type II diabetes mellitus. A class of drugs that sensitize patients to self-insulin, insulin sensitizers, has been introduced to restore insulin and triglycerides to normal. Peroxisome proliferator-activated receptors (PPARs) become ideal targets in the research of diabetes treatment, are one of nuclear receptor superfamily members, can simultaneously regulate and control the expression of various genes, and participate in physiological processes such as adipocyte differentiation, lipid metabolism regulation, insulin sensitivity increase and the like. There are three types of PPAR families: PPAR α, PPAR β (also called PPAR δ) and PPAR γ. PPAR α is involved in the stimulation of beta-oxidation of fatty acids and in the control of HDL cholesterol levels, playing an important role in liver lipid metabolism, while PPAR γ receptor is involved in the activation of adipocyte differentiation programs, improving insulin resistance and increasing insulin sensitivity (Yanjun, Zhoujin, PPAR α/γ dual motivation and type 2 diabetes mellitus, medical review, 2008, 14 (16): 2492-. PPAR γ is considered as a main molecular target of the glitazone insulin sensitizer, and although glitazone compounds are effective drugs for treating type II diabetes, side effects of such compounds are very significant, such as severe liver toxicity, weight gain and anemia, which are mainly that glitazones are main or full agonists of PPAR γ (N aje, D rocate, S. itu von, CN 101098865A). Therefore, the dual agonist of PPAR alpha and PPAR gamma can reduce or even eliminate the side effect of the PPAR gamma agonist of glitazone, and has the effects of reducing blood fat and inhibiting cardiovascular complications besides normalizing blood sugar and insulin.
The invention discloses adamantane tetrazole acetic acid compounds serving as dual agonists of PPAR alpha and PPAR gamma, and the inhibitors can be used for preparing medicines for treating diabetes, in particular to medicines for treating non-insulin-dependent diabetes mellitus.
Disclosure of Invention
It is an object of the present invention to overcome the disadvantages and drawbacks of the prior art and to provide a compound having the general formula I and pharmaceutically acceptable salts thereof with good activity.
It is another object of the present invention to provide a process for the preparation of compounds having the general formula I and pharmaceutically acceptable salts thereof.
It is a further object of the present invention to provide pharmaceutical compositions containing compounds of formula I and pharmaceutically acceptable salts thereof as active ingredients, together with one or more pharmaceutically acceptable carriers, excipients or diluents, and their use in the treatment of diabetes.
The present disclosure will now be described in detail for the purpose of the invention.
The compounds of the present invention having the general formula I have the following structural formula:
wherein,
r is selected from C1-C5 alkyl and C3-C5 cycloalkyl.
Preferred are compounds of the following general formula I:
r is selected from C1-C3 alkyl and cyclopropyl.
Preferred compounds of the invention having the general formula I are shown below:
more preferred compounds of the invention having the general formula I are as follows:
further, more preferred compounds of the invention having the general formula I are as follows:
the compound of the general formula I is synthesized by the following steps:
compounds A and B in NaBH3CN, to obtain a compound C; bromine for Compound CTreating with a chemical reagent to obtain a compound D, and reacting the compound D with the compound E in the presence of alkali to obtain a compound I.
The compound of the general formula I has the double agonism of PPAR alpha and PPAR gamma, and can be used as an effective component for preparing a therapeutic medicament for diabetes and can reduce weight gain and inhibit cardiovascular complications. The activity of the compounds of formula I according to the invention was verified by in vivo hypoglycemic and hypocholesterolemic cholesterol and triglyceride lowering models.
The compounds of formula I of the present invention are effective over a relatively wide dosage range. For example, the daily dosage may be in the range of about 20mg to about 400mg per person, divided into one or more administrations. The actual dosage of the compounds of formula I to be administered according to the invention can be determined by the physician in the light of the relevant circumstances. These include: the physical state of the subject, the route of administration, the age, body weight, individual response to the drug, severity of the symptoms, and the like.
Detailed Description
The present invention will be further described with reference to the following examples. It should be noted that the following examples are only for illustration and are not intended to limit the present invention. Variations of the teachings of the present invention may be made by those skilled in the art without departing from the scope of the claims of the present application.
Example 1
The starting materials for the reaction are commercially available.
1.81g (10mmol) of Compound A and 1.50g (10mmol) of Compound B-1 are dissolved in 20mL EtOH and reacted at room temperature for 3 hours, followed by addition of 1.89g (30mmol) NaBH3CN, and then stirring was continued overnight. The reaction mixture was poured into 100mL of ice water, stirred, and adjusted for p with concentrated hydrochloric acidExtracting with 50mL × 3 dichloromethane, combining the extract phases, washing with brine, drying over anhydrous sodium sulfate, evaporating the solvent in a rotary evaporator to obtain a residue, and purifying by column chromatography to obtain pure C-1 product, ESI-MS, M/z 334([ M + NH ])4]+).
2.21g (7mmol) of Compound C-1 were dissolved in 10mL of dry toluene, slowly stirred with cooling in an ice-water bath, and 2.71g (10mmol) of PBr were slowly dropped3Dissolving in 2mL of dried dichloromethane, stirring at room temperature for half an hour after dropwise addition, pouring into 100mL of ice water, stirring, extracting with 50mL of × 3 dichloromethane, combining the extract phases, washing with brine once, drying with anhydrous sodium sulfate, evaporating the solvent in a rotary evaporator to obtain a residue, and purifying by column chromatography to obtain pure D-1 product ESI-MS, M/z 378 and 380([ M + H ])]+).
1.89g (5mmol) of Compound D-1 and 0.64g (5mmol) of E-1 are dissolved in 10mL of DMF and stirred, 2.07g (15mmol) of K are added2CO3Stirring was continued at 100 ℃ until the starting material was consumed (12 hours). The reaction mixture was poured into 100mL of ice water, stirred, adjusted to pH 2 with concentrated hydrochloric acid, extracted with 50mL × 3 dichloromethane, the extract phases were combined, washed once with brine, dried over anhydrous sodium sulfate, evaporated in a rotary evaporator to give a residue, which was purified by column chromatography to give I-1 as a pure product, white solid, M-MS, ESI-MS, M/z 424([ M-H ] M-H) (M-H ═ 176 ℃; melting point: ESI-MS)]-)。
Examples 2 to 4
Following the procedure of example 1, the compounds of formula I shown in the following table were prepared.
Example 5
Samples were prepared as 5mg/mL suspensions in 1% sodium carboxymethylcellulose in a volume of 0.4mL/20g body weight corresponding to a 100mg/kg dose.
Healthy ICR mice, each half male and female, weigh 20-24g, and meet the first-class standard. Animals are fasted for 16 hours, the test compound is administrated by gastric lavage for 15 minutes, then 2g/kg glucose saline solution is injected into abdominal cavity, capillaries are taken at regular time of 0.5h, 1h, 1.5h and 2h after molding, blood is taken from venous plexus after mice ball, serum is centrifugally separated, and the glucose content of the serum at each time point is measured by a glucose oxidase method. The blank mice were given neither glucose nor the test compound, and the model mice were given only glucose and no test compound.
As can be seen from the data in the above table, the compounds of the present invention significantly enhanced glucose-induced glucose tolerance in mice.
Example 6
Samples were prepared as 5mg/mL suspensions in 1% sodium carboxymethylcellulose in a 0.4mL/20g body weight dose equivalent to a 100mg/kg dose.
Healthy Wister rats, half male and female, weigh about 300g, and meet the first-class standard. Animals are fed with high-fat feed for 30 days, the contents of cholesterol and triglyceride in serum are measured, the animals are randomly grouped by taking the contents of cholesterol and triglyceride as standards, the compound to be measured is continuously administered by intragastric administration for 7 days after the animals are grouped, the animals are fasted for 12 hours before the last administration, blood is taken from the retrobulbar venous plexus of rats by a capillary tube 1 hour after the administration, the serum is centrifugally separated, and the contents of cholesterol and triglyceride in serum are measured by a kit of cholesterol and triglyceride. The test results are shown below.
Cholesterol content (g/dl)
Triglyceride content (g/dl)
The data in the above two tables demonstrate that the compounds of the present invention are effective in lowering cholesterol and triglycerides.
Claims (7)
1. A compound having the structure of formula I:
wherein R is selected from C1-C5 alkyl and C3-C5 cycloalkyl.
2. A compound having the general formula I as defined in claim 1 wherein R is selected from the group consisting of C1-C3 alkyl, cyclopropyl.
3. A compound of formula I as defined in claim 2, selected from:
4. a compound of formula I as defined in claim 3, selected from:
5. a compound of formula I as defined in claim 3, selected from:
6. a process for the synthesis of a compound of general formula I as defined in claims 1 to 5, comprising the steps of:
compounds A and B in NaBH3CN, to obtain a compound C; and treating the compound C with a brominating reagent to obtain a compound D, and reacting the compound D with the compound E in the presence of alkali to obtain a compound I.
7. Use of a compound of general formula I as defined in any of claims 1 to 5 for the preparation of a medicament for the treatment of diabetes.
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|---|---|---|---|---|
| CN1329593A (en) * | 1998-12-10 | 2002-01-02 | 诺瓦提斯公司 | N-substituted 2-cyanopyrrolidines |
| US6492355B1 (en) * | 1999-04-09 | 2002-12-10 | Astrazeneca Ab | Adamantane derivatives |
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