CN101805336B - Compound containing tryptophane and isoxazole skeleton and preparation method and application thereof - Google Patents
Compound containing tryptophane and isoxazole skeleton and preparation method and application thereof Download PDFInfo
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- CN101805336B CN101805336B CN2009100678517A CN200910067851A CN101805336B CN 101805336 B CN101805336 B CN 101805336B CN 2009100678517 A CN2009100678517 A CN 2009100678517A CN 200910067851 A CN200910067851 A CN 200910067851A CN 101805336 B CN101805336 B CN 101805336B
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- dimethylamino
- indol
- propionic acid
- isoxazole
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- 0 *C(*)Cc1c[n]c2c1cccc2 Chemical compound *C(*)Cc1c[n]c2c1cccc2 0.000 description 6
- GBTYCTDFAOKQTE-CYVLTUHYSA-N CCOC(CC/C(/c1c(C)cccc1)=C/c1cc(-c(cc2)ccc2[F]C)n[o]1)=O Chemical compound CCOC(CC/C(/c1c(C)cccc1)=C/c1cc(-c(cc2)ccc2[F]C)n[o]1)=O GBTYCTDFAOKQTE-CYVLTUHYSA-N 0.000 description 1
- RDWIQJGMNXOEON-WYMLVPIESA-N CS(OCCO/N=C(\C=C)/c(cc1)ccc1F)(=O)=O Chemical compound CS(OCCO/N=C(\C=C)/c(cc1)ccc1F)(=O)=O RDWIQJGMNXOEON-WYMLVPIESA-N 0.000 description 1
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Abstract
The invention relates to the medicine filed related to diabetes, in particular to a peroxisome proliferator-activated receptor (PPAR) agonist which has the general formula I shown in the specification, has treatment effect on diabetes and contains tryptophane and an isoxazole skeleton, a preparation method of the PPAR agonist and application of the PPAR agonist in preparing medicines for treating diabetes, wherein, the group definition refers to the specification.
Description
Technical field
The present invention relates to the pharmaceutical field relevant with mellitus.Particularly, the present invention relates to medicative one type of peroxisome proliferator-activated property acceptor (PPAR) agonist, its preparation method and the pharmaceutical composition that contains them that contains tryptophane and isoxzzole skeleton of mellitus.
Background technology
Mellitus are the impaired diseases of patient's controlling blood sugar ability, and the patient has lost the ability of insulin action being made appropriate reaction to some extent.Major part is type ii diabetes (being non insulin dependent diabetes) in the mellitus; Account for 80%-90%; Discover that the insulin resistant of peripheral tissues's (comprising Skelettmuskel, liver and fatty tissue etc.) plays a part very important in the generation of type ii diabetes, development.Introduced at present one type and made the patient recover one type of responsive medicine to self Regular Insulin, i.e. insulin sensitizers is so that Regular Insulin and triglyceride level return to normally.Peroxisome proliferator-activated property acceptor (PPARs) becomes the ideal target in the research treatment of diabetes; It is one of nuclear receptor superfamily member; Can regulate and control several genes simultaneously and express, participate in physiological processs such as adipocyte differentiation, lipid metabolism adjusting and increase insulin sensitivity.PPAR family has three types: PPAR α, PPAR β (also being PPAR δ) and PPAR γ.PPAR α relates to the β-Yang Hua that stimulates lipid acid, also relates to control HDL cholesterol levels, in the liver lipid metabolism, is bringing into play important effect; And PPAR γ acceptor relates to the adipocyte differentiation program and must activate, and can improve insulin resistant and improve insulin sensitivity (Yang Jun, Zou Xiulan; PPAR α/γ double excitations machine and diabetes B; The medical science summary, 2008,14 (16): 2492-2496).PPAR γ is considered to the main molecules target of glitazone insulin sensitizers; Although the glitazone compound is the active drug of treatment type ii diabetes, the spinoff of this compounds is very obvious, for example serious toxin for liver type, weight increase and anaemia; This mainly is that glitazone is main or full agonist (the N A Jie of PPAR γ; Sieve D is thorough, her Feng of S, CN 101098865A).Therefore, the dual agonists of PPAR α and PPAR γ just can alleviate even eliminate the spinoff of glitazone PPAR gamma agonist, except making blood sugar and Regular Insulin normalizing, also has reduce fat and the effect that suppresses cardiovascular complication.
We have found one type of dual agonists that contains tryptophane and isoxzzole skeleton PPAR α and PPAR γ, have good treating diabetes effect and have littler spinoff.These suppressor factor are that the medicine of the medicine that further preparation can be used to treat mellitus, particularly non insulin dependent diabetes lays the foundation.
Summary of the invention
An object of the present invention is to overcome the shortcoming and defect of prior art, a kind of excellent activity that has is provided, have the compound of general formula I.
Another object of the present invention provides the method that preparation has compound and the salt and the ester of general formula I.
A further object of the present invention provide contain general formula I compound as effective constituent, and the medicinal compsns of one or more pharmaceutically acceptable carriers, vehicle or thinner, and the application aspect the treatment mellitus.
Combine the object of the invention that content of the present invention is specifically described at present.
The compound that the present invention has general formula I has following structural formula:
Wherein,
N is selected from 0,1 and 2.
R is selected from H, C
1-C
5Alkyl, X, NO
2, CN, OR
1And NR
2R
3, and their two replacement combinations and three replacement combinations, wherein, X is selected from F, Cl, Br and I, R
1Be selected from C
1-C
5Alkyl, R
2And R
3Independently be selected from H and C
1-C
5Alkyl.
Preferred following compound of Formula I
Wherein,
n＝1。
R is selected from H, C
1-C
3Alkyl, X, NO
2, CN, OR
1And NR
2R
3, and their two replacement combinations, wherein, X is selected from F and Cl, R
1Be selected from C
1-C
3Alkyl, R
2And R
3Independently be selected from H and C
1-C
3Alkyl.
It is as shown in the table that preferred the present invention has the compound of general formula I:
| Compound number | The compound title |
| I-1 | (S)-and 2-dimethylamino-3-{1-[(3-phenyl isoxzzole-5-yl) ethyl] indol-3-yl } propionic acid |
| I-2 | (S)-and 3-{1-{ [3-(2-chloro-phenyl-) isoxzzole-5-yl] ethyl } indol-3-yl }-2-dimethylamino propionic acid |
| I-3 | (S)-and 2-dimethylamino-3-{1-{ [3-(4-fluorophenyl) isoxzzole-5-yl] propyl group } indol-3-yl } propionic acid |
| I-4 | (S)-and 2-dimethylamino-3-{1-{ [3-(4-nitrophenyl) isoxzzole-5-yl] propyl group } indoles-3-yl } propionic acid |
| I-5 | (S)-and 3-{1-{ [3-(3-aminophenyl) isoxzzole-5-yl] propyl group } indol-3-yl }-2-dimethylamino propionic acid |
| I-6 | (S)-and 2-dimethylamino-3-{1-{ [3-(4-dimethylamino phenyl) isoxzzole-5-yl] propyl group } indol-3-yl } propionic acid |
| I-7 | (S)-and 3-{1-{ [3-(3-cyano-phenyl) isoxzzole-5-yl] butyl } indol-3-yl }-2-dimethylamino propionic acid |
| I-8 | (S)-and 2-dimethylamino-3-{1-{ [3-(2-p-methoxy-phenyl) isoxzzole-5-yl] butyl } indoles-3-yl } propionic acid |
| I-9 | (S)-and 3-{1-{ [3-(2-chloro-4-nitrophenyl) isoxzzole-5-yl] propyl group } indol-3-yl }-2-dimethylamino propionic acid |
| I-10 | (S)-and 3-{1-{ [3-(2-cyanic acid-3-dimethylamino-4-p-methoxy-phenyl) isoxzzole-5-yl] propyl group } indol-3-yl }-2-dimethylamino propionic acid |
Compound of Formula I according to the invention is synthetic through following steps:
Compound I I and III reaction obtain compound IV, and compound IV is used formaldehyde treated in formic acid, obtain compound I.Wherein, compound I I according to literature method preparation (Liu Lijun, Yong Jianping, Dai Xiaojun etc., SCI, 2006,27 (9), 1669-1672), R
4Be C
1-C
5Alkyl, the definition of R and n is as previously mentioned.
The pharmacy acceptable salt of formula I compound according to the invention comprises; But be not limited to and various mineral alkalis, for example, yellow soda ash, salt of wormwood, sodium hydrogencarbonate; Or organic bases, the for example pharmacy acceptable salt that generated such as methylamine, ethamine, n n dimetylaniline, diethylamine, triethylamine.The pharmaceutically acceptable ester of formula I compound according to the invention includes but not limited to pharmaceutically acceptable esters such as methyl esters, ethyl ester, n-propyl, isopropyl ester, positive butyl ester, the tert-butyl ester.
Formula I compound according to the invention can be processed pharmaceutical composition jointly with one or more pharmaceutically acceptable carriers, vehicle or thinner.This pharmaceutical composition can be processed formulations such as solid orally ingestible, liquid oral medicine, injection.Said solid and liquid oral medicine comprise: tablet, dispersible tablet, sugar-coat agent, granule, dry powder doses, capsule and solution.Described injection comprises: little pin, infusion solutions, freeze-dried powder etc.
Compsn of the present invention can be accepted auxiliary material and be selected from: weighting agent, disintegrating agent, lubricant, glidant, effervescent, correctives, sanitas, coating material or other vehicle on described pharmacy or the bromatology.
Compsn of the present invention can be accepted auxiliary material on described pharmacy or the bromatology.Weighting agent is one or more the compsn that weighting agent comprises lactose, sucrose, dextrin, starch, pregelatinized Starch, N.F,USP MANNITOL, sorbyl alcohol, secondary calcium phosphate, calcium sulfate, lime carbonate, Microcrystalline Cellulose; Described tackiness agent comprises one or more compsn of sucrose, starch, polyvidone, Xylo-Mucine, hypromellose, TSK-Gel G 2000HXL, methylcellulose gum, polyoxyethylene glycol, medicinal alcohol, water; Described disintegrating agent comprises one or more compsn of starch, crosslinked polyvidone, Sodium Croscarmellose, low-substituted hydroxypropyl cellulose, carmethose, gas-producing disintegrant.
Compound of Formula I according to the invention has the double excitations effect of PPAR α and PPAR γ, can be used as effective constituent and is used to prepare the medicine of mellitus aspect and can loses weight increase and inhibition cardiovascular complication disease.The activity of compound of Formula I according to the invention through in the body hypoglycemic with blood cholesterol levels falls and the triglyceride level model is verified.
Compound of Formula I of the present invention is effective in quite wide dosage range.The dosage of for example taking every day is divided into once or administration for several times in 1mg-1000mg/ people's scope.The actual dosage of taking compound of Formula I of the present invention can be decided according to relevant situation by the doctor.These situation comprise: by curer's physical state, route of administration, age, body weight, to the individual reaction of medicine, the severity of symptom etc.
Embodiment
Below in conjunction with embodiment the present invention is further described.Need to prove that following embodiment is used for explanation, and is not to be used to limit the present invention.The various variations that those skilled in the art's training centre according to the present invention is made all should be within the desired protection domain of the application's claim.
Embodiment 1
(S)-and 2-t-butoxycarbonyl amino-3-{1-[(3-phenyl isoxzzole-5-yl) ethyl] indol-3-yl } methyl propionate (IV-1)
Add 2.67g (10mmol) compound I I-1 in the round-bottomed flask of 250mL, 3.18g (10mmol) compound III-1,2.76g (20mmol) solid K
2CO
3And 1.66g (10mmol) solid K I, add the dry DMF of 40mL at last, gained mixture vigorous stirring 3 hours in the time of 100 ℃.Behind the reaction mixture cool to room temperature, be poured in the water, stir,, merge extracted organic phase with the dichloromethane extraction of 50mL * 3, with the saturated common salt water washing once, anhydrous Na
2SO
4Drying boils off solvent and obtains an oily resistates on the Rotary Evaporators, obtain the pure article of compound IV-1 through column chromatography purification.White solid, 4.01g, productive rate 82%.IR(KBr)，v?3239，1740，1691cm
-1。
Compound I I-1, III-1 and IV-1 are respectively one that has in the compound of general formula I I, III and IV.
Embodiment 2
(S)-and 2-t-butoxycarbonyl amino-3-{1-{ [3-(2-chloro-phenyl-) isoxzzole-5-yl] ethyl } indol-3-yl } ethyl propionate (IV-2)
Add 3.02g (10mmol) compound I I-2 in the round-bottomed flask of 250mL, 3.32g (10mmol) compound III-2,2.76g (20mmol) solid K
2CO
3And 1.66g (10mmol) solid K I, add the dry DMF of 40mL at last, gained mixture vigorous stirring 3 hours in the time of 100 ℃.Behind the reaction mixture cool to room temperature, be poured in the water, stir,, merge extracted organic phase with the dichloromethane extraction of 50mL * 3, with the saturated common salt water washing once, anhydrous Na
2SO
4Drying boils off solvent and obtains an oily resistates on the Rotary Evaporators, obtain the pure article of compound IV-2 through column chromatography purification.White solid, 4.57g, productive rate 85%.IR(KBr)，v?3237，1739，1691cm
-1。
Compound I I-2, III-2 and IV-2 are respectively one that has in the compound of general formula I I, III and IV.
Embodiment 3
(S)-and 2-t-butoxycarbonyl amino-3-{1-{ [3-(4-fluorophenyl) isoxzzole-5-yl] propyl group } indol-3-yl } ethyl propionate (IV-3)
Add 2.99g (10mmol) compound I I-3 in the round-bottomed flask of 250mL, 3.32g (10mmol) compound III-2,2.76g (20mmol) solid K
2CO
3And 1.66g (10mmol) solid K I, add the dry DMF of 40mL at last, gained mixture vigorous stirring 3 hours in the time of 100 ℃.Behind the reaction mixture cool to room temperature, be poured in the water, stir,, merge extracted organic phase with the dichloromethane extraction of 50mL * 3, with the saturated common salt water washing once, anhydrous Na
2SO
4Drying boils off solvent and obtains an oily resistates on the Rotary Evaporators, obtain the pure article of compound IV-3 through column chromatography purification.White solid, 4.66g, productive rate 87%.IR(KBr)，v?3240，1740，1692cm
-1。
Compound I I-3 and IV-3 are respectively one that has in the compound of general formula I I and IV.
Embodiment 4
(S)-and 2-t-butoxycarbonyl amino-3-{1-{ [3-(4-nitrophenyl) isoxzzole-5-yl] propyl group } indol-3-yl } methyl propionate (IV-4)
Add 3.26g (10mmol) compound I I-4 in the round-bottomed flask of 250mL, 3.18g (10mmol) compound III-1,2.76g (20mmol) solid K
2CO
3And 1.66g (10mmol) solid K I, add the dry DMF of 40mL at last, gained mixture vigorous stirring 3 hours in the time of 100 ℃.Behind the reaction mixture cool to room temperature, be poured in the water, stir,, merge extracted organic phase with the dichloromethane extraction of 50mL * 3, with the saturated common salt water washing once, anhydrous Na
2SO
4Drying boils off solvent and obtains an oily resistates on the Rotary Evaporators, obtain the pure article of compound IV-4 through column chromatography purification.White solid, 4.61g, productive rate 84%.IR(KBr)，v?3242，1741，1693，1524，1321cm
-1。
Compound I I-4 and IV-4 are respectively one that has in the compound of general formula I I and IV.
Embodiment 5
(S)-and 3-{1-{ [3-(3-aminophenyl) isoxzzole-5-yl] propyl group } indol-3-yl }-2-t-butoxycarbonyl amino methyl propionate (IV-5)
Add 2.96g (10mmol) compound I I-5 in the round-bottomed flask of 250mL, 3.18g (10mmol) compound III-1,2.76g (20mmol) solid K
2CO
3And 1.66g (10mmol) solid K I, add the dry DMF of 40mL at last, gained mixture vigorous stirring 3 hours in the time of 100 ℃.Behind the reaction mixture cool to room temperature, be poured in the water, stir,, merge extracted organic phase with the dichloromethane extraction of 50mL * 3, with the saturated common salt water washing once, anhydrous Na
2SO
4Drying boils off solvent and obtains an oily resistates on the Rotary Evaporators, obtain the pure article of compound IV-5 through column chromatography purification.White solid, 4.15g, productive rate 80%.IR(KBr)，v?3242，3223，3192，1740，1691cm
-1。
Compound I I-5 and IV-5 are respectively one that has in the compound of general formula I I and IV.
Embodiment 6
(S)-and 2-t-butoxycarbonyl amino-3-{1-{ [3-(4 dimethylamino phenyl) isoxzzole-5-yl] propyl group } indol-3-yl } methyl propionate (IV-6)
Add 3.24g (10mmol) compound I I-6 in the round-bottomed flask of 250mL, 3.18g (10mmol) compound III-1,2.76g (20mmol) solid K
2CO
3And 1.66g (10mmol) solid K I, add the dry DMF of 40mL at last, gained mixture vigorous stirring 3 hours in the time of 100 ℃.Behind the reaction mixture cool to room temperature, be poured in the water, stir,, merge extracted organic phase with the dichloromethane extraction of 50mL * 3, with the saturated common salt water washing once, anhydrous Na
2SO
4Drying boils off solvent and obtains an oily resistates on the Rotary Evaporators, obtain the pure article of compound IV-6 through column chromatography purification.White solid, 4.37g, productive rate 80%.IR(KBr)，v?3223，1743，1695cm
-1。
Compound I I-6 and IV-6 are respectively one that has in the compound of general formula I I and IV.
Embodiment 7
(S)-and 2-t-butoxycarbonyl amino-3-{1-{ [3-(3-cyano-phenyl) isoxzzole-5-yl] butyl } indol-3-yl } methyl propionate (IV-7)
Add 3.20g (10mmol) compound I I-7 in the round-bottomed flask of 250mL, 3.18g (10mmol) compound III-1,2.76g (20mmol) solid K
2CO
3And 1.66g (10mmol) solid K I, add the dry DMF of 40mL at last, gained mixture vigorous stirring 3 hours in the time of 100 ℃.Behind the reaction mixture cool to room temperature, be poured in the water, stir,, merge extracted organic phase with the dichloromethane extraction of 50mL * 3, with the saturated common salt water washing once, anhydrous Na
2SO
4Drying boils off solvent and obtains an oily resistates on the Rotary Evaporators, obtain the pure article of compound IV-7 through column chromatography purification.White solid, 4.61g, productive rate 85%.IR(KBr)，v?3234，2223，1745，1692cm
-1。
Compound I I-7 and IV-7 are respectively one that has in the compound of general formula I I and IV.
Embodiment 8
(S)-and 2-t-butoxycarbonyl amino-3-{1-{ [3-(2-p-methoxy-phenyl) isoxzzole-5-yl] butyl } indol-3-yl } ethyl propionate (IV-8)
Add 3.25g (10mmol) compound I I-8 in the round-bottomed flask of 250mL, 3.32g (10mmol) compound III-2,2.76g (20mmol) solid K
2CO
3And 1.66g (10mmol) solid K I, add the dry DMF of 40mL at last, gained mixture vigorous stirring 3 hours in the time of 100 ℃.Behind the reaction mixture cool to room temperature, be poured in the water, stir,, merge extracted organic phase with the dichloromethane extraction of 50mL * 3, with the saturated common salt water washing once, anhydrous Na
2SO
4Drying boils off solvent and obtains an oily resistates on the Rotary Evaporators, obtain the pure article of compound IV-8 through column chromatography purification.White solid, 5.05g, productive rate 90%.IR(KBr)，v?3245，1742，1691cm
-1。
Compound I I-8 and IV-8 are respectively one that has in the compound of general formula I I and IV.
Embodiment 9
(S)-and 2-t-butoxycarbonyl amino-3-{1-{ [3-(2-chloro-4-nitrophenyl) isoxzzole-5-yl] propyl group } indol-3-yl } ethyl propionate (IV-9)
Add 3.61g (10mmol) compound I I-9 in the round-bottomed flask of 250mL, 3.32g (10mmol) compound III-2,2.76g (20mmol) solid K
2CO
3And 1.66g (10mmol) solid K I, add the dry DMF of 40mL at last, gained mixture vigorous stirring 3 hours in the time of 100 ℃.Behind the reaction mixture cool to room temperature, be poured in the water, stir,, merge extracted organic phase with the dichloromethane extraction of 50mL * 3, with the saturated common salt water washing once, anhydrous Na
2SO
4Drying boils off solvent and obtains an oily resistates on the Rotary Evaporators, obtain the pure article of compound IV-9 through column chromatography purification.White solid, 5.43g, productive rate 91%.IR(KBr)，v?3242，1744，1523，1695，1326cm
-1。
Compound I I-9 and IV-9 are respectively one that has in the compound of general formula I I and IV.
Embodiment 10
(S)-and 2-t-butoxycarbonyl amino-3-{1-{ [3-(2-cyanic acid-3-dimethylamino-4-p-methoxy-phenyl) isoxzzole-5-yl] propyl group } indol-3-yl } ethyl propionate (IV-10)
Add 3.79g (10mmol) compound I I-10 in the round-bottomed flask of 250mL, 3.32g (10mmol) compound III-2,2.76g (20mmol) solid K
2CO
3And 1.66g (10mmol) solid K I, add the dry DMF of 40mL at last, gained mixture vigorous stirring 3 hours in the time of 100 ℃.Behind the reaction mixture cool to room temperature, be poured in the water, stir,, merge extracted organic phase with the dichloromethane extraction of 50mL * 3, with the saturated common salt water washing once, anhydrous Na
2SO
4Drying boils off solvent and obtains an oily resistates on the Rotary Evaporators, obtain the pure article of compound IV-10 through column chromatography purification.White solid, 5.85g, productive rate 95%.IR(KBR)，v?3241，2224，1742，1697cm
-1。
Compound I I-10 and IV-10 are respectively one that has in the compound of general formula I I and IV.
Embodiment 11
(S)-and 2-dimethylamino-3-{1-[(3-phenyl isoxzzole-5-yl) ethyl] indol-3-yl } propionic acid (I-1)
Add 2.45g (5mmol) compound IV-1 in the round-bottomed flask of 100mL, then add 36% formalin 1mL and 90% formic acid 5mL, the gained mixture refluxes 30 minutes postcooling to room temperature.Reaction mixture is poured in the 100mL water, stirs, and with the dichloromethane extraction of 50mL * 3, merges extracted organic phase, with the saturated common salt water washing once, and anhydrous Na
2SO
4Drying steams solvent on Rotary Evaporators, the resistates that obtains obtains the pure article of compound I-1 through column chromatography purification, white solid, 1.63g, productive rate 81%.IR(KBr)，v?2500-3200，1739cm
-1。
Embodiment 12
(S)-and 3-{1-{ [3-(2-chloro-phenyl-) isoxzzole-5-yl] ethyl } indol-3-yl }-2-dimethylamino propionic acid (I-2)
Add 2.69g (5mmol) compound IV-2 in the round-bottomed flask of 100mL, then add 36% formalin 1mL and 90% formic acid 5mL, the gained mixture refluxes 30 minutes postcooling to room temperature.Reaction mixture is poured in the 100mL water, stirs, and with the dichloromethane extraction of 50mL * 3, merges extracted organic phase, with the saturated common salt water washing once, and anhydrous Na
2SO
4Drying steams solvent on Rotary Evaporators, the resistates that obtains obtains the pure article of compound I-2 through column chromatography purification, white solid, 1.95g, productive rate 89%.IR(KBr)，v?2503-3205，1740cm
-1。
Embodiment 13
(S)-and 3-{1-{ [3-(4-fluorophenyl) isoxzzole-5-yl] propyl group } indol-3-yl }-2-dimethylamino propionic acid (I-3)
Add 2.68g (5mmol) compound IV-3 in the round-bottomed flask of 100mL, then add 36% formalin 1mL and 90% formic acid 5mL, the gained mixture refluxes 30 minutes postcooling to room temperature.Reaction mixture is poured in the 100mL water, stirs, and with the dichloromethane extraction of 50mL * 3, merges extracted organic phase, with the saturated common salt water washing once, and anhydrous Na
2SO
4Drying steams solvent on Rotary Evaporators, the resistates that obtains obtains the pure article of compound I-3 through column chromatography purification, white solid, 1.79g, productive rate 82%.IR(KBr)，v?2504-3200，1740cm
-1。
Embodiment 14
(S)-and 3-{1-{ [3-(4-nitrophenyl) isoxzzole-5-yl] propyl group } indol-3-yl }-2-dimethylamino propionic acid (I-4)
Add 2.74g (5mmol) compound IV-4 in the round-bottomed flask of 100mL, then add 36% formalin 1mL and 90% formic acid 5mL, the gained mixture refluxes 30 minutes postcooling to room temperature.Reaction mixture is poured in the 100mL water, stirs, and with the dichloromethane extraction of 50mL * 3, merges extracted organic phase, with the saturated common salt water washing once, and anhydrous Na
2SO
4Drying steams solvent on Rotary Evaporators, the resistates that obtains obtains the pure article of compound I-4 through column chromatography purification, white solid, 1.92g, productive rate 83%.IR(KBr)，v?2501-3204，1741，1523，1325cm
-1。
Embodiment 15
(S)-and 3-{1-{ [3-(3-aminophenyl) isoxzzole-5-yl] propyl group } indol-3-yl }-2-dimethylamino propionic acid (I-5)
Add 2.59g (5mmol) compound IV-5 in the round-bottomed flask of 100mL, then add 36% formalin 1mL and 90% formic acid 5mL, the gained mixture refluxes 30 minutes postcooling to room temperature.Reaction mixture is poured in the 100mL water, stirs, and with the dichloromethane extraction of 50mL * 3, merges extracted organic phase, with the saturated common salt water washing once, and anhydrous Na
2SO
4Drying steams solvent on Rotary Evaporators, the resistates that obtains obtains the pure article of compound I-5 through column chromatography purification, white solid, 1.71g, productive rate 79%.IR(KBr)，v?2500-3206，1740cm
-1。
Embodiment 16
(S)-and 3-{1-{ [3-(4-dimethylamino phenyl) isoxzzole-5-yl] propyl group } indol-3-yl }-2-dimethylamino propionic acid (I-6)
Add 2.73g (5mmol) compound IV-6 in the round-bottomed flask of 100mL, then add 36% formalin 1mL and 90% formic acid 5mL, the gained mixture refluxes 30 minutes postcooling to room temperature.Reaction mixture is poured in the 100mL water, stirs, and with the dichloromethane extraction of 50mL * 3, merges extracted organic phase, with the saturated common salt water washing once, and anhydrous Na
2SO
4Drying steams solvent on Rotary Evaporators, the resistates that obtains obtains the pure article of compound I-6 through column chromatography purification, white solid, 1.89g, productive rate 82%.IR(KBr)，v?2507-3201，1739cm
-1。
Embodiment 17
(S)-and 3-{1-{ [3-(3-cyano-phenyl) isoxzzole-5-yl] butyl } indol-3-yl }-2-dimethylamino propionic acid (I-7)
Add 2.71g (5mmol) compound IV-7 in the round-bottomed flask of 100mL, then add 36% formalin 1mL and 90% formic acid 5mL, the gained mixture refluxes 30 minutes postcooling to room temperature.Reaction mixture is poured in the 100mL water, stirs, and with the dichloromethane extraction of 50mL * 3, merges extracted organic phase, with the saturated common salt water washing once, and anhydrous Na
2SO
4Drying steams solvent on Rotary Evaporators, the resistates that obtains obtains the pure article of compound I-7 through column chromatography purification, white solid, 1.96g, productive rate 86%.IR(KBr)，v?2507-3201，2224，1738cm
-1。
Embodiment 18
(S)-and 3-{1-{ [3-(2-p-methoxy-phenyl) isoxzzole-5-yl] butyl } indol-3-yl }-2-dimethylamino propionic acid (I-8)
Add 2.81g (5mmol) compound IV-8 in the round-bottomed flask of 100mL, then add 36% formalin 1mL and 90% formic acid 5mL, the gained mixture refluxes 30 minutes postcooling to room temperature.Reaction mixture is poured in the 100mL water, stirs, and with the dichloromethane extraction of 50mL * 3, merges extracted organic phase, with the saturated common salt water washing once, and anhydrous Na
2SO
4Drying steams solvent on Rotary Evaporators, the resistates that obtains obtains the pure article of compound I-8 through column chromatography purification, white solid, 1.98g, productive rate 86%.IR(KBr)，v?2506-3203，1738cm
-1。
Embodiment 19
(S)-and 3-{1-{ [3-(2-chloro-4-nitrophenyl) isoxzzole-5-yl] propyl group } indol-3-yl }-2-dimethylamino propionic acid (I-9)
Add 2.99g (5mmol) compound IV-9 in the round-bottomed flask of 100mL, then add 36% formalin 1mL and 90% formic acid 5mL, the gained mixture refluxes 30 minutes postcooling to room temperature.Reaction mixture is poured in the 100mL water, stirs, and with the dichloromethane extraction of 50mL * 3, merges extracted organic phase, with the saturated common salt water washing once, and anhydrous Na
2SO
4Drying steams solvent on Rotary Evaporators, the resistates that obtains obtains the pure article of compound I-9 through column chromatography purification, white solid, 2.16g, productive rate 87%.IR(KBr)，v?2506-3203，1738，1524，1323cm
-1。
Embodiment 20
(S)-and 3-{1-{ [3-(2-chloro-4-nitrophenyl) isoxzzole-5-yl] propyl group } indol-3-yl }-2-dimethylamino propionic acid (I-10)
Add 3.08g (5mmol) compound IV-10 in the round-bottomed flask of 100mL, then add 36% formalin 1mL and 90% formic acid 5mL, the gained mixture refluxes 30 minutes postcooling to room temperature.Reaction mixture is poured in the 100mL water, stirs, and with the dichloromethane extraction of 50mL * 3, merges extracted organic phase, with the saturated common salt water washing once, and anhydrous Na
2SO
4Drying steams solvent on Rotary Evaporators, the resistates that obtains obtains the pure article of compound I-10 through column chromatography purification, white solid, 2.19g, productive rate 85%.IR(KBr)，v?2503-3204，2223，1739cm
-1。
Embodiment 21
Consumption/sheet
Embodiment 11 samples (I-1) 100mg
Microcrystalline Cellulose 80mg
Pregelatinized Starch 70mg
Vinylpyrrolidone polymer 6mg
CMS sodium salt 5mg
Magnesium Stearate 2mg
Talcum powder 2mg
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, and thorough mixing adds polyvinylpyrrolidonesolution solution; Mix, the system softwood sieves; The system wet granular is in 50-60 ℃ of drying, with the CMS sodium salt; Magnesium Stearate and talcum powder sieve in advance, join compressing tablet in the above-mentioned particle then.
Embodiment 22
Consumption/grain
Embodiment 13 samples (I-3) 50mg
Microcrystalline Cellulose 30mg
Pregelatinized Starch 20mg
Vinylpyrrolidone polymer 3mg
Magnesium Stearate 2mg
Talcum powder 1mg
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, and thorough mixing adds polyvinylpyrrolidonesolution solution, mixes; The system softwood sieves, and the system wet granular is in 50-60 ℃ of drying; Magnesium Stearate and talcum powder are sieved in advance, join then in the above-mentioned particle, encapsulated, promptly get.
Embodiment 23
Consumption/50mL
Embodiment 15 samples (I-5) 50mg
Hydrocerol A 100mg
NaOH an amount of (transferring pH 4.0-5.0)
Zero(ppm) water 50mL
In zero(ppm) water, add earlier zero(ppm) water and Hydrocerol A, stirring and dissolving and after, add sample again; Low-grade fever makes dissolving, and adjust pH is 4.0-5.0, adds 0.2 gram activated carbon, stirs 20 minutes under the room temperature; Filter, filtrating, strength of solution is decided in middle detection; By 5 milliliters of packing of every peace bottle, high-temperature sterilization 30 minutes promptly gets injection liquid.
Embodiment 24
Embodiment 17 samples (I-7) 3.0g
Prist 1.0g
Sodium hydroxide 0.2g
Citric Acid QS
N.F,USP MANNITOL 26.0g
Lactose 23.0g
Water for injection 100mL
Preparation technology: get water for injection 80mL, add main ingredient, N.F,USP MANNITOL, lactose, Prist stir make dissolving after, the Citric Acid that adds 1mol/L is regulated PH to 7.0-9.0, mends and adds water to 100mL.Add the 0.5g gac, stirred 20 minutes down, take off charcoal, adopt the filtering with microporous membrane degerming at 30 ℃; Filtrating is carried out packing by every 1mL, and pre-freeze is after 2 hours, freezing drying under reduced pressure down 12 hours, to sample temperature after room temperature; Drying is 5 hours again, makes the white loose block, seals promptly to get.
Embodiment 25
100 bags of granules
Embodiment 19 samples (I-9) 30.0g
Lactose 55.0g
N.F,USP MANNITOL 14.0g
The sweet 0.05g of A Siba
Essence 0.05g
2% hypromellose (pure water preparation) QS
Preparation technology: main ingredient and auxiliary material are crossed 100 mesh sieves respectively, and thorough mixing takes by weighing recipe quantity auxiliary material and main ingredient thorough mixing then.Add tackiness agent system softwood again, 14 mesh sieves are granulated, 55 ℃ of dryings, and the whole grain of 12 mesh sieves is measured heavily packing of bag.
Instance 26
Sample is mixed with the suspension of 5mg/mL concentration with 1% Xylo-Mucine, and the administration capacity is the 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; The dextrose in saline solution of 15 minutes abdominal injection 2g/kg behind the medicine; 0.5h, 1h, 1.5h, 2h, 2.5h, 3h and 4h regularly take kapillary and get blood from mouse ball rear vein beard after modeling; Two hours injectable dextrose monohydrates again behind the injectable dextrose monohydrate for the first time, spinning serum is with each time point serum glucose level of determination of glucose oxidase.Result's form that vides infra, data can be found out from form, each administration all can significantly reduce the mouse blood sugar dosis tolerata that glucose causes.
Instance 27
Sample is mixed with the suspension of 5mg/mL concentration with 1% Xylo-Mucine, and the administration capacity is the 0.4mL/20g body weight, is equivalent to 100mg/kg dosage.
Healthy Wister rat, male and female half and half about body weight 300g, meet primary standard.Animal was fed 30 days with high lipid food; Measuring cholesterol in serum and content of triglyceride, is the standard random packet with SUV and content of triglyceride, oral successive administration 3 days (positive drug is a single-dose) after animal divides into groups; Fasting is 16 hours before the last administration; 1h gets blood with kapillary from rat ball rear vein beard behind the medicine, and spinning serum is with SUV and triglyceride level kit measurement serum cholesterol and content of triglyceride.
Cholesterol level (g/dl)
Content of triglyceride (g/dl)
Claims (8)
1. the compound that has the general formula I structure
Wherein,
N is selected from 0,1 and 2;
R is selected from H, C
1-C
5Alkyl, X, NO
2, CN, OR
1And NR
2R
3, and they
Two replace combination and three replaces combination, and wherein, X is selected from F, Cl, Br and I, R
1Be selected from C
1-C
5Alkyl, R
2And R
3Independently be selected from H and C
1-C
5Alkyl.
2. the defined compound of claim 1 with general formula I
Wherein,
n＝1；
R is selected from H, C
1-C
3Alkyl, X, NO
2, CN, OR
1And NR
2R
3, and their two replacement combinations, wherein, X is selected from F and Cl, R
1Be selected from C
1-C
3Alkyl, R
2And R
3Independently be selected from H and C
1-C
3Alkyl.
3. the defined compound with general formula I of claim 1 is selected from:
(S)-and 2-dimethylamino-3-{1-[(3-phenyl-isoxazole azoles-5-yl) ethyl] indol-3-yl } propionic acid
(S)-3-{1-{ [3-(2-chloro-phenyl-) isoxazole-5-base] ethyl } indol-3-yl }-2-dimethylamino propionic acid
(S)-and 2-dimethylamino-3-{1-{ [3-(4-fluorophenyl) isoxazole-5-base] propyl group } indol-3-yl } propionic acid
(S)-and 2-dimethylamino-3-{1-{ [3-(4-nitrophenyl) isoxazole-5-base] propyl group } indol-3-yl } propionic acid
(S)-3-{1-{ [3-(3-aminophenyl) isoxazole-5-base] propyl group } indol-3-yl }-2-dimethylamino propionic acid
(S)-and 2-dimethylamino-3-{1-{ [3-(4-dimethylamino phenyl) isoxazole-5-base] propyl group } indol-3-yl } propionic acid
(S)-3-{1-{ [3-(3-cyano-phenyl) isoxazole-5-base] butyl } indol-3-yl }-2-dimethylamino propionic acid
(S)-and 2-dimethylamino-3-{1-{ [3-(2-p-methoxy-phenyl) isoxazole-5-base] butyl } indol-3-yl } propionic acid
(S)-3-{1-{ [3-(2-chloro-4-nitrophenyl) isoxazole-5-base] propyl group } indol-3-yl }-2-dimethylamino propionic acid
(S)-3-{1-{ [3-(2-cyanic acid-3-dimethylamino-4-p-methoxy-phenyl) isoxazole-5-base] propyl group } indol-3-yl }-2-dimethylamino propionic acid.
4. synthesize the method for the defined compound of Formula I of claim 1, may further comprise the steps:
Compound I I and III reaction obtain compound IV, and compound IV is used formaldehyde treated in formic acid, obtain compound I, wherein, and R
4Be C
1-C
5Alkyl, the definition of R and n is according to claim 1.
5. the application of the defined compound of Formula I of claim 1 aspect preparation treatment diabetes medicament.
6. pharmaceutical composition contains compound of Formula I and the appropriate carriers of one of claim 1-3.
7. the described pharmaceutical composition of claim 6, wherein, described compsn is solid orally ingestible, liquid oral medicine or injection.
8. the pharmaceutical composition described in the claim 7, wherein said solid orally ingestible comprises tablet, capsule, granule; Said liquid oral medicine comprises oral solution; Said injection preparation comprises injection liquid drugs injection, injection freeze-dried powder, infusion solutions, primary infusion.
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|---|---|---|---|
| CN2009100678517A CN101805336B (en) | 2009-02-13 | 2009-02-13 | Compound containing tryptophane and isoxazole skeleton and preparation method and application thereof |
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|---|---|---|---|
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|---|---|
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| CN101805336B true CN101805336B (en) | 2012-05-30 |
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|---|---|---|---|
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1702068A (en) * | 2004-05-24 | 2005-11-30 | 中国人民解放军军事医学科学院毒物药物研究所 | Alkanoyl substituted tyrosine derivatives as hPPAR alpha and hPPAR gamma agonist |
-
2009
- 2009-02-13 CN CN2009100678517A patent/CN101805336B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1702068A (en) * | 2004-05-24 | 2005-11-30 | 中国人民解放军军事医学科学院毒物药物研究所 | Alkanoyl substituted tyrosine derivatives as hPPAR alpha and hPPAR gamma agonist |
Non-Patent Citations (3)
| Title |
|---|
| Kevin G. Liu et al..Synthesis and Biological Activity of L-Tyrosine-based PPARγ Agonists with Reduced Molecular Weight.《 Bioorganic & Medicinal Chemistry Letters》.2001,第11卷第3111-3113页. |
| Kevin G. Liu et al..Synthesis and Biological Activity of L-Tyrosine-based PPARγ Agonists with Reduced Molecular Weight.《 Bioorganic & * |
| Medicinal Chemistry Letters》.2001,第11卷第3111-3113页. * |
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