CN101684088A - Cyanomethyl pyrrole derivative and preparation method and application thereof - Google Patents
Cyanomethyl pyrrole derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN101684088A CN101684088A CN200810151501A CN200810151501A CN101684088A CN 101684088 A CN101684088 A CN 101684088A CN 200810151501 A CN200810151501 A CN 200810151501A CN 200810151501 A CN200810151501 A CN 200810151501A CN 101684088 A CN101684088 A CN 101684088A
- Authority
- CN
- China
- Prior art keywords
- compound
- methyl
- amino
- cyanogen
- ethanoyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Abstract
The invention relates to the field of diabetes associated medicaments, in particular to an N-cyanomethyl pyrrole derivative with a general formula I, a preparation method, a medical composition containing the same and application thereof in preparing diabetes medicaments, wherein all groups are as defined in the specification.
Description
Technical field
The present invention relates to the relevant pharmaceutical field of diabetes, particularly, the present invention relates to have dipeptidyl peptidase-IV (dipeptidyl peptidase IV to the medicative N-of the containing cyanogen of diabetes methylpyrrole structure, DPP-IV) inhibitor and preparation method thereof, and the pharmaceutical composition that contains them.
Background technology
According to World Health Organization statistics, global diabetic subject is nearly about 1.7 hundred million, and wherein about 90% is the type ii diabetes patient.Antidiabetic medicine in clinical use mainly contains Regular Insulin, N1,N1-Dimethylbiguanide, sulfonylureas at present, reach the recent thiazolidinediones medicine that goes on the market, alpha-glucosidase inhibitor etc., these medicines have good curative effect, but there is safety issue in long-term treatment, as: be easy to generate problems such as liver toxicity, weight increase.
DPP IV (dipeptidyl peptidase IV, DPP-IV) can be effectively and the glucagon-like peptide 1 (GLP-1 that can degrade apace, glucagons-like peptide-1), GLP-1 is one of the most effective stimulant of insulin production and secretion, therefore suppress the effect that DPP-IV can strengthen endogenous GLP-1, thereby improve the level (CN200480017355.6) of Regular Insulin in the blood.Medical science has confirmed that the DPP-IV inhibitor is a kind of novel antidiabetic treatment medicine (Deacon C.F. at present, Holst J.J., Dipeptidyl Peptidase IV Inhibitors:A Promising NewTherapeutic Approach for the Management of Type 2Diabetes.The InternationalJournal of Biochemistry ﹠amp; Cell Biology, 2006,38 (5-6): 831-844).Clinical effectiveness shows that such medicine has good hypoglycemic effect, untoward reaction things such as common weight increase of simultaneously not finding other diabetes medicaments and being produced and hypoglycemia.The present invention has found to reduce very effectively the novel DPP-IV inhibitor of plasma glucose levels, and these compounds are that the medicine that further discovery can be used for the treatment of diabetes, 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 and the pharmacy acceptable salt thereof of general formula I.
Another object of the present invention provides the method that preparation has the compound and the pharmacy acceptable salt thereof of general formula I.
A further object of the present invention provide contain general formula I compound as effective constituent, and the medicinal compositions of one or more pharmaceutically acceptable carriers, vehicle or thinner, and the application aspect the treatment diabetes.
Now content of the present invention is specifically described in conjunction with purpose of the present invention.
The compound that the present invention has general formula I has following structural formula:
Wherein,
R '=H, R
1, F, Cl, Br, I, NO
2, NR
2R
3, COOR
4, CONR
2R
3Or R
4CO, and they two replace or trisubstituted combination, wherein R
1Be C
1-C
8Alkyl, R
2, R
3And R
4Be H or C
1-C
8Alkyl.Preferred following compound of Formula I or its pharmacy acceptable salt,
Wherein,
Perhaps
R '=H, R
1, F, Cl, Br, I, NO
2, NR
2R
3, CONR
2R
3Or R
4CO, and they two replace or trisubstituted combination, wherein R
1Be C
1-C
4Alkyl, R
2, R
3And R
4Be H or C
1-C
4Alkyl.
It is as shown in the table that preferred the present invention has the compound of general formula I:
| Code name | The compound title |
| ??I-1 | (S)-and 2-{{[2-(benzamido group) ethanoyl] amino } methyl }-1-cyanogen methylpyrrole |
| ??I-2 | (S)-and 1-cyanogen methyl-2-{{{2-{[(4-fluorophenyl) methyl] amino } ethanoyl } amino } methyl } pyrroles |
| ??I-3 | (S)-and 1-cyanogen methyl-2-{{{2-{[(1,2-dihydroquinoline-2-ketone-4-yl) methyl] amino } ethanoyl } amino } methyl } pyrroles |
| ??I-4 | (S)-and 2-{{{2-{[(2-chloro-3-aminomethyl phenyl) methyl] amino } ethanoyl } amino } methyl }-1-cyanogen methylpyrrole |
| ??I-5 | (S)-and 2-{{{2-{[(4-bromo-2-formyl radical-3-aminomethyl phenyl) methyl] amino } ethanoyl } amino } methyl }-1-cyanogen methylpyrrole |
| ??I-6 | (S)-and 1-cyanogen methyl-2-{{{2-{[(6-methyl isophthalic acid, 2-dihydroquinoline-2-ketone-4-yl) methyl] amino } ethanoyl } amino } methyl } pyrroles |
| ??I-7 | (S)-and 2-{{[2-(benzamido group) ethanoyl] amino } methyl }-1-cyanogen methylpyrrole trifluoroacetate |
| ??I-8 | (S)-and 1-cyanogen methyl-2-{{{2-{[(1,2-dihydroquinoline-2-ketone-4-yl) methyl] amino } ethanoyl } amino } methyl } pyrroles's acetate |
Compound of Formula I of the present invention is synthetic by following steps:
The glycine PG-Gly-OH II and the compound III of protection are reacted in the presence of condensing agent, obtain compound IV, and wherein, PG-Gly-OH II is the glycine through overprotection, and wherein PG is protecting group (as Boc and Cbz etc.).
Compound IV obtains compound V through behind the deprotection method deprotection corresponding to protecting group PG.
Compound VI and compound V are at mineral alkali, as Na
2CO
3And K
2CO
3, existing down, reaction obtains Compound I.Compound I and sour HA at room temperature act on, and obtain Compound I-s.R's wherein is described as defined above.
Wherein, the compound III in the above-mentioned route is by following route synthetic:
Starting raw material is the L-proline(Pro).The L-proline(Pro) is through LiAlH
4Reduction obtains compound VI I.Compound VI I and bromoacetonitrile are at mineral alkali, as Na
2CO
3And K
2CO
3, existing down, reaction obtains compound VIII.Compound VIII and methylsulfonyl chloride MsCl act in the presence of organic bases such as triethylamine etc. and obtain Compound I X.Compound I X and NaN
3The heating reflection obtains compounds X in non-proton dipole solvent.Compounds X is shortening under normal pressure, obtains compound III.
The pharmacy acceptable salt of formula I compound of the present invention comprises, but be not limited to and various mineral acids, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid etc., or organic acid, for example pharmacy acceptable salt that generated such as formic acid, acetate, citric acid, oxalic acid, fumaric acid, toxilic acid, amino acid.
Formula I compound of the present invention or its pharmacy acceptable salt can be made pharmaceutical composition jointly with one or more pharmaceutically acceptable carriers, vehicle or thinner.This pharmaceutical composition can be made formulations such as solid orally ingestible, liquid oral medicine, injection.Described 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.
Composition 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.
Composition of the present invention can be accepted auxiliary material on described pharmacy or the bromatology.Weighting agent is one or more the composition 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 composition of sucrose, starch, polyvidone, Xylo-Mucine, hypromellose, hydroxypropylcellulose, methylcellulose gum, polyoxyethylene glycol, medicinal alcohol, water; Described disintegrating agent comprises one or more composition of starch, crosslinked polyvidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carmethose, gas-producing disintegrant.
Compound of Formula I of the present invention or its salt have the restraining effect of DPP-IV, can be used as the medicine that effective constituent is used to prepare the diabetes aspect.The activity of compound of Formula I of the present invention is by hypoglycemic modelling verification in the body.
Compound of Formula I of the present invention is effective in quite wide dosage range.For example the dosage of 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 situations comprise: by curer's physical state, route of administration, age, body weight, to the individual reaction of medicine, the severity of symptom etc.
Embodiment
The present invention is further illustrated below in conjunction with embodiment.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.
Instrument and reagent, unless specified otherwise, agents useful for same all is commercially available analytical pure level reagent, infrared spectra is by U.S. ThermoNicolet AVATAR FT370 type Fourier transformation infrared spectrometer (KBr compressing tablet or pure product membrane process are measured).
Embodiment 1
(S)-and the 2-{{2-[(tertbutyloxycarbonyl) amino] ethanoyl } amino } methyl isophthalic acid-cyanogen methylpyrrole (IV-a) synthetic
The glycine II-a that adds 1.75g (10mmol) Boc protection in the round-bottomed flask of 100mL; with the anhydrous THF dissolving of 20mL, then add 2.06g (10mmol) DCC, stirred 1 hour under the room temperature; then add 1.39g (10mmol) compound III, stir under the gained system room temperature and spend the night.Remove by filter the solid in the reaction mixture, gained filtrate boils off solvent on Rotary Evaporators, obtains a resistates, and column chromatography obtains product I V-a, 2.66g, productive rate 90%, colourless oil liquid.IR(thin?film)，3321，3217，2228，1690，1684cm
-1.
Compound I I-a is one of them of Compound I I with general formula, and this moment, IV-a also was one of them that has in the compound of general formula I V.Blocking group PG is tertbutyloxycarbonyl Boc (t-Butoxycarbonyl) at this moment.
Embodiment 2
(S)-and 2-{[2-(amino) ethanoyl] amino } methyl isophthalic acid-cyanogen methylpyrrole (V) synthetic
Add 2.96g (10mmol) compound IV-a in the reaction flask of 100mL, with 20mL CH
2Cl
2Dissolving adds 1mL trifluoroacetic acid (TFA) under the stirring at room, then continue under the room temperature to stir 2 hours.Reaction system is poured the Na of 100mL 2% into
2CO
3In the solution, stir, with the CH of 50mL * 3
2Cl
2Extraction merges extracted organic phase, with the saturated common salt water washing once, and dry (Na
2SO
4), on Rotary Evaporators, boil off solvent, obtain the pure product of compound V, colourless oil liquid, 1.90g, productive rate 97%.IR (thin film), 3321,3313,2226,1686cm
-1.
Embodiment 3
(S)-and 2-{{[2-(benzamido group) ethanoyl] amino } methyl }-1-cyanogen methylpyrrole (1-1)
Add 1.71g (10mmol) compound VI-1 in the round-bottomed flask of a 100mL, 1.96g (10mmol) compound V and 1.06g (10mmol) solid Na
2CO
3, then add 10mL MeOH and 10mL CH
2Cl
2System at room temperature stirs spends the night.Remove by filter the solid that exists in the reaction system, filtrate boils off solvent on Rotary Evaporators, and the resistates that obtains obtains product I-1, colorless oil, 2.55g, productive rate 89% through column chromatography purification.IR(thin?film)，3030，3332，3251，2229，1687cm
-1.
Compound VI-the 1st has in the compound of general formula VI.
Embodiment 4-7
With the operation of embodiment 3, difference is that the VI in the following table replaces the VI-1 among the embodiment 3, and remaining is operated with embodiment 3, and the Compound I-2 that obtains in the following table arrives I-5.
| The embodiment sequence number | Productive rate/% | ??VI | ??I |
| ??4 | ??90 | The 4-fluoro benzyl bromide | I-2:(S)-and 1-cyanogen methyl-2-{{{2-{[(4-fluorophenyl) methyl] amino } ethanoyl } amino } methyl } pyrroles |
| ??5 | ??89 | (1,2-dihydroquinoline-2-ketone-4-yl) monobromomethane | I-3:(S)-and 1-cyanogen methyl-2-{{{2-{[(1,2-dihydroquinoline-2-ketone-4-yl) methyl] amino } ethanoyl } amino } methyl } pyrroles |
| ??6 | ??87 | 2-chloro-3-methyl-benzyl bromine | I-4:(S)-and 2-{{{2-{[(2-chloro-3-aminomethyl phenyl) methyl] amino } ethanoyl } amino } methyl }-1-cyanogen methylpyrrole |
| ??7 | ??90 | 4-bromo-2-formyl radical-3-aminomethyl phenyl bromotoluene | I-5:(S)-and 2-{{{2-{[(4-bromo-2-formyl radical-3-aminomethyl phenyl) methyl] amino } ethanoyl } amino } methyl }-1-cyanogen methylpyrrole |
| ??8 | ??88 | (6-methyl isophthalic acid, 2- | I-6:(S)-and 1-cyanogen methyl-2-{{{2-{[(6-methyl isophthalic acid, the 2-dihydro |
| Dihydroquinoline-2-ketone-4-yl) monobromomethane | Quinoline-2-one--4-yl) methyl] amino } ethanoyl } amino } methyl } pyrroles |
The characterization data of the Compound I in the last table is as follows:
I-2:(S)-and 1-cyanogen methyl-2-{{{2-{[(4-fluorophenyl) methyl] amino } ethanoyl } amino } methyl } pyrroles, colorless oil, IR (thin film), 3033,3335,3253,2229,1688cm
-1.
I-3:(S)-and 1-cyanogen methyl-2-{{{2-{[(1,2-dihydroquinoline-2-ketone-4-yl) methyl] amino } ethanoyl } amino } methyl } pyrroles, colorless oil, IR (thin film), 3031,3329,3251,2228,1684,1663cm
-1.
I-4:(S)-and 2-{{{2-{[(2-chloro-3-aminomethyl phenyl) methyl] amino } ethanoyl } amino } methyl }-1-cyanogen methylpyrrole, colorless oil, IR (thin film), 3035,3322,3253,2229,1682cm
-1.
I-5:(S)-and 2-{{{2-{[(4-bromo-2-formyl radical-3-aminomethyl phenyl) methyl] amino } ethanoyl } amino } methyl }-1-cyanogen methylpyrrole, colorless oil, IR (thin film), 3039,3324,3255,2227,1702,1686cm
-1.
I-6:(S)-and 1-cyanogen methyl-2-{{{2-{[(6-methyl isophthalic acid, 2-dihydroquinoline-2-ketone-4-yl) methyl] amino } ethanoyl } amino } methyl } pyrroles, colorless oil, IR (thin film), 3039,3324,3255,2227,1702,1686,1655cm
-1.
Embodiment 9
(S)-2-methylol pyrroles (VII) synthetic
The exsiccant THF that adds 11.5g (0.1mol) solid L-proline(Pro) and 200mL in the round-bottomed flask of a 500mL, ice bath cooling then adds 7.6g (0.2mol) solid LiAlH down in batches
4, then at room temperature stir and spend the night.Dropwise 5 0mL anhydrous methanol slowly, restir half an hour, suction filtration is removed solid, and filtrate boils off solvent on Rotary Evaporators, obtain an oily matter, is compound VI I, 8.6g, productive rate 85%.IR (thin film), 3451,3325cm
-1.
Embodiment 10
(S)-1-cyanogen methyl-2-methylol pyrroles (VIII) synthetic
Add 10.1g (0.1mol) in the round-bottomed flask of 250mL, 12.0g (0.1mol) and 10.6g (0.1mol) solid Na
2CO
3, then adding the anhydrous MeOH of 100mL, reaction system at room temperature stirs spends the night.Suction filtration is removed the solid in the system, and filtrate boils off solvent and obtains product VII I, colorless oil, 12.0g, 0.86% on Rotary Evaporators.IR(thin?film)，3454，2229cm
-1.
Embodiment 11
(S)-1-cyanogen methyl-2-methylsulfonyl oxygen methylpyrrole (IX) synthetic
14.0g (0.1mol) compound VIII is dissolved in the 50mL ethyl acetate, adds 11.1g (0.1mol) triethylamine, stirs under the room temperature, slowly drips 11.5g (0.1mol) methylsulfonyl chloride, after dropwising, reaction system at room temperature stirs spends the night.Reaction mixture is used the saturated common salt water washing once in separating funnel, dry (Na
2SO
4), on Rotary Evaporators, boiling off solvent, the resistates that obtains is product IX, colourless oil liquid, 20.3g, productive rate 93%.IR(thinfilm)，2228cm
-1.
Embodiment 12
(S)-2-azido-methyl-1-cyanogen methylpyrrole (IX) synthetic
21.8g Compound I X (0.1mol) is dissolved among the 60mL exsiccant DMF, adds 19.5g (0.3mol) solid NaN
3, reaction system is spent the night at 80 ℃ of following stirring reactions.System is poured in the 500mL water, with the CH of 70mL * 3
2Cl
2Extraction merges extracted organic phase, with the saturated common salt water washing once, and dry (Na
2SO
4), on Rotary Evaporators, boil off solvent, obtain compounds X, colourless oil liquid, 13.9g, productive rate 84%.IR (thin film), 2241,2226cm
-1.
Embodiment 13
(S)-2-aminomethyl-1,2-cyanogen methylpyrrole (III) synthetic
16.5g (0.1mol) compounds X is dissolved in the 60mL anhydrous methanol, adds the Pd/C of 1.0g 5%, spends the night according to standard method of hydrotreating hydrogenation.Suction filtration is removed catalyzer, and filtrate boils off solvent on Rotary Evaporators, obtains product III, colorless oil, 11.8g, productive rate 85%.IR(thin?film)，3323，3312，2229cm
-1.
Embodiment 14
(S)-and 2-{{[2-(benzamido group) ethanoyl] amino } methyl }-1-cyanogen methylpyrrole trifluoroacetate (I-7) synthetic
2.86g (10mmol) Compound I-1 be dissolved into 20mL exsiccant ethyl acetate in, then add 1.14g (10mmol) trifluoroacetic acid, stirred under the room temperature 1 hour.Filter and collect crystal, drying obtains product I-7, clear crystal, 3.60g, productive rate 90%.IR(KBr)，3030，2543，2226，1683cm
-1。
Embodiment 15
(S)-and 1-cyanogen methyl-2-{{{2-{[(1,2-dihydroquinoline-2-ketone-4-yl) methyl] amino } ethanoyl } amino } methyl } pyrroles's acetate (I-8) synthetic
With the operation of embodiment 14, difference is that with the I-1 among the I-3 replacement embodiment 14, with the trifluoroacetic acid among the acetic acid replacement embodiment 14, remaining is operated with embodiment 14, obtains Compound I-8.
I-8:(S)-and 1-cyanogen methyl-2-{{{2-{[(1,2-dihydroquinoline-2-ketone-4-yl) methyl] amino } ethanoyl } amino } methyl } pyrroles's acetate, clear crystal, productive rate 91%, IR (KBr), 3031,2551,2228,1683,1664cm
-1
Embodiment 16
Consumption/sheet
Embodiment 5 samples (I-3) 100mg
Microcrystalline Cellulose 80mg
Pregelatinized Starch 70mg
Polyvinylpyrrolidone 6mg
Carboxymethyl starch sodium salt 5mg
Magnesium Stearate 2mg
Talcum powder 2mg
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, thorough mixing, add polyvinylpyrrolidonesolution solution, mix, the system softwood, sieve, the system wet granular is in 50-60 ℃ of drying, with the carboxymethyl starch sodium salt, Magnesium Stearate and talcum powder sieve in advance, join compressing tablet in the above-mentioned particle then.
Embodiment 17
With reference to the operation of embodiment 16, with the I-3 among sample (I-1) the replacement embodiment 16 of embodiment 3, all the other are operated with embodiment 16, obtain compressing tablet.
Embodiment 18
Consumption/grain
Embodiment 6 samples (I-4) 50mg
Microcrystalline Cellulose 30mg
Pregelatinized Starch 20mg
Polyvinylpyrrolidone 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.
Embodiment 19
With reference to the operation of embodiment 18, with the I-4 among sample (I-2) the replacement embodiment 18 of embodiment 4, all the other are operated with embodiment 18, obtain capsule.
Embodiment 20
Consumption/50ml
Embodiment 15 sample 50mg
Citric acid 100mg
NaOH an amount of (transferring pH 4.0-5.0)
Distilled water 50ml
In distilled water, add earlier distilled water and citric acid, stirring and dissolving and after, add sample again, low-grade fever makes dissolving, and adjust pH is 4.0-5.0, add 0.2 gram activated carbon, stirred 20 minutes under the room temperature, filter filtrate, 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 21
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.The diamicron time spent is mixed with 4mg/ml concentration with 1% Xylo-Mucine, and the administration capacity is the 0.4ml/20g body weight, is equivalent to 80mg/kg dosage.Be mixed with 15mg/ml with fresh physiological saline during the tetraoxypyrimidine injection.0.1ml/20g body weight is equivalent to 75mg/kg.
Healthy ICR mouse, male and female half and half, body weight 20～24g meets primary standard.The animal fasting is the tail vein injection tetraoxypyrimidine after 16 hours.Fasting 6 hours is got blood with kapillary from mouse ball rear vein beard after 48 hours, and centrifugation serum is used the determination of glucose oxidase serum glucose level.Select blood glucose value to be higher than the mouse of 300mg/dl, be divided into 4 groups according to the blood-sugar content that records again, be respectively model, the positive (diamicron 80mg/kg) and administration group.Administration 3 days, fasting in 24 hours was got blood in 1 hour after the last administration, measure blood-sugar content.The results are shown in Table
Tetraoxypyrimidine is caused the influence of hyperglycemia model mouse's blood sugar content
Annotate: * * compares p＜0.01 with model group
Claims (8)
1. the compound or its pharmacy acceptable salt that have general formula I:
Wherein,
R '=H, R
1, F, Cl, Br, I, NO
2, NR
2R
3, COOR
4, CONR
2R
3Or R
4CO, and they two replace or trisubstituted combination, wherein R
1Be C
1-C
8Alkyl, R
2, R
3And R
4Be H or C
1-C
8Alkyl.
2. the defined compound of Formula I of claim 1 or its pharmacy acceptable salt are wherein preferred,
R '=H, R
1, F, Cl, Br, I, NO
2, NR
2R
3, CONR
2R
3Or R
4CO, and they two replace or trisubstituted combination, wherein R
1Be C
1-C
4Alkyl, R
2, R
3And R
4Be H or C
1-C
4Alkyl.
3. the defined compound of Formula I of claim 1 or its pharmacy acceptable salt are selected from:
(S)-and 2-{{[2-(benzamido group) ethanoyl] amino } methyl }-1-cyanogen methylpyrrole
(S)-and 1-cyanogen methyl-2-{{{2-{[(4-fluorophenyl) methyl] amino } ethanoyl } amino } methyl } pyrroles
(S)-and 1-cyanogen methyl-2-{{{2-{[(1,2-dihydroquinoline-2-ketone-4-yl) methyl] amino } ethanoyl } amino } methyl } pyrroles
(S)-and 2-{{{2-{[(2-chloro-3-aminomethyl phenyl) methyl] amino } ethanoyl } amino } methyl }-1-cyanogen methylpyrrole
(S)-and 2-{{{2-{[(4-bromo-2-formyl radical-3-aminomethyl phenyl) methyl] amino } ethanoyl } amino } methyl }-1-cyanogen methylpyrrole
(S)-and 1-cyanogen methyl-2-{{{2-{[(6-methyl isophthalic acid, 2-dihydroquinoline-2-ketone-4-yl) methyl] amino } ethanoyl } amino } methyl } pyrroles
(S)-and 2-{{[2-(benzamido group) ethanoyl] amino } methyl }-1-cyanogen methylpyrrole trifluoroacetate
(5)-and 1-cyanogen methyl-2-{{{2-{[(1,2-dihydroquinoline-2-ketone-4-yl) methyl] amino } ethanoyl } amino } methyl } pyrroles's acetate
4. synthesize the method for the compound of Formula I of one of claim 1-3, may further comprise the steps:
The glycine PG-Gly-OH and the compound III of Compound I I protection are reacted in the presence of condensing agent, obtain compound IV, and wherein, Compound I I PG-Gly-OH is the glycine through overprotection, and wherein PG is protecting group (as Boc and Cbz etc.).
Compound IV obtains compound V through behind the deprotection method deprotection corresponding to protecting group PG.
Compound VI and compound V are at mineral alkali, as Na
2CO
3And K
2CO
3, existing down, reaction obtains Compound I.Compound I and sour HA at room temperature act on, and obtain Compound I-s.R's wherein is described as defined above.
5, method as claimed in claim 4, wherein III is by following route synthetic:
Starting raw material is the L-proline(Pro); The L-proline(Pro) is through LiAlH
4Reduction obtains compound VI I; Compound VI I and bromoacetonitrile are at mineral alkali, as Na
2CO
3And K
2CO
3, existing down, reaction obtains compound VIII.Compound VIII and methylsulfonyl chloride MsCl act in the presence of organic bases such as triethylamine etc. and obtain Compound I X.Compound I X and NaN
3The heating reflection obtains compounds X in non-proton dipole solvent.Compounds X is shortening under normal pressure, obtains compound III.
6. the defined compound of Formula I of claim 1-5 or its pharmacy acceptable salt application aspect the preparation diabetes medicament.
7. pharmaceutical composition contains compound of Formula I or its pharmacy acceptable salt of one of claim 1-6 and appropriate carriers or vehicle.
8. the described pharmaceutical composition of claim 7, wherein, described composition is solid orally ingestible, liquid oral medicine or injection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008101515014A CN101684088B (en) | 2008-09-22 | 2008-09-22 | Cyanomethyl pyrrole derivative and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008101515014A CN101684088B (en) | 2008-09-22 | 2008-09-22 | Cyanomethyl pyrrole derivative and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101684088A true CN101684088A (en) | 2010-03-31 |
| CN101684088B CN101684088B (en) | 2011-05-11 |
Family
ID=42047504
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008101515014A Expired - Fee Related CN101684088B (en) | 2008-09-22 | 2008-09-22 | Cyanomethyl pyrrole derivative and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101684088B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108752255A (en) * | 2018-07-19 | 2018-11-06 | 重庆医科大学 | A kind of preparation method of pabishta and its key intermediate |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2822826B1 (en) * | 2001-03-28 | 2003-05-09 | Servier Lab | NOVEL ALPHA-AMINO ACID SULPHONYL DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME |
| EP1604662A1 (en) * | 2004-06-08 | 2005-12-14 | Santhera Pharmaceuticals (Deutschland) Aktiengesellschaft | 1-[(3R)-Amino-4-(2-fluoro-phenyl)-butyl]-pyrrolidine-(2R)-carboxylic acid benzyl amine derivatives and related compounds as dipeptidyl peptidase IV (DPP-IV) inhibitors for the treatment of type 2 diabetes mellitus |
| ATE553077T1 (en) * | 2004-07-23 | 2012-04-15 | Nuada Llc | PEPTIDATE INHIBITORS |
-
2008
- 2008-09-22 CN CN2008101515014A patent/CN101684088B/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108752255A (en) * | 2018-07-19 | 2018-11-06 | 重庆医科大学 | A kind of preparation method of pabishta and its key intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101684088B (en) | 2011-05-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101445492B (en) | Amide thiazole derivant, preparation method and use thereof | |
| EP2568971B1 (en) | Canagliflozin containing tablets | |
| CN1918119B (en) | Bicycloester derivative | |
| CN101445527B (en) | Five-membered heteroaromatics tolylene glucoside and preparation method and use thereof | |
| CN106458857A (en) | Crystalline free acid, hemicalcium salt and alfa-phenylethylamine salt of ahu-377 as well as preparation method therefor and application thereof | |
| CN101508712A (en) | Glucoside containing tetrazole structure, preparation method and application | |
| JP4854158B2 (en) | Formulations containing benzamide derivatives as active ingredients | |
| CN103058972A (en) | Phenyl C-glucoside derivatives containing cyclohexane structure as well as preparation method and application thereof | |
| CN103896923A (en) | Blood sugar reducing compound, preparation method of blood sugar reducing compound, medicine composition including blood sugar reducing compound and application of medicine composition | |
| CN101550112B (en) | 4,5-disubstituted thiazole derivative, preparation method and use thereof | |
| CN101684088B (en) | Cyanomethyl pyrrole derivative and preparation method and application thereof | |
| CN101684103B (en) | Compound with 1,2,4-triazole structure and preparation method and application thereof | |
| CN101445528A (en) | Sulpho-glucosan derivative and preparation method and application thereof | |
| CN104672210A (en) | Preparation method of alogliptin and alogliptin benzoate | |
| CN114671839B (en) | Dapagliflozin solid form compound and preparation method and application thereof | |
| CN104302648A (en) | Crystalline form of succinate salt | |
| CN113929698A (en) | Diaryl heptane dimer, pharmaceutical composition thereof, preparation method and application thereof | |
| CN101463055B (en) | O-indican compounds, preparation and use thereof | |
| CN113831336A (en) | Praziquantel and ferulic acid eutectic compound, preparation method, composition and application thereof | |
| CN102675378A (en) | C-glucoside derivative containing cyclopropane structure and method and application of C- glucoside derivative | |
| CN102241644B (en) | Alpha-azyl-3-aryl propionamido thiazole derivative, preparation method and purpose thereof | |
| CN104513188A (en) | Cyano pyrrolidine derivative and preparation method and application thereof | |
| CN105384730A (en) | Empagliflozin crystal forms, preparation methods and uses thereof, and pharmaceutical composition | |
| CN101508713A (en) | Glucoside containing 1,2,3-triazole structure, preparation method and application | |
| CN110092799B (en) | Cyclic compound, preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110511 Termination date: 20160922 |