CN101255136B - 5-cyclopropane toroid hydantoin derivatives as well as preparation method and uses thereof - Google Patents
5-cyclopropane toroid hydantoin derivatives as well as preparation method and uses thereof Download PDFInfo
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- CN101255136B CN101255136B CN2008100470266A CN200810047026A CN101255136B CN 101255136 B CN101255136 B CN 101255136B CN 2008100470266 A CN2008100470266 A CN 2008100470266A CN 200810047026 A CN200810047026 A CN 200810047026A CN 101255136 B CN101255136 B CN 101255136B
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Abstract
The present invention relates to 5-cyclopropane spirocyclic hydantoin derivates with a structural formula, wherein R1 in the formula represents hydrogen, alkyl group, benz or substituted benz. The preparation method comprises: reacting 1-carboxyl-2, 2-dimethyl carbethoxycyclopropane with ethyl chloroformate, generating 1-acid azide-2, 2- dimethyl carbethoxycyclopropane under the action of NaN3; generatingcorresponding isocyanate by curtius rearing 1-acid azide-2, 2- dimethyl carbethoxycyclopropane, wherein the isocyanate is reacted with primary amine, secondary amine or ammonia water to obtain N-substituted ureido cyclopropane which closes loop to generate 5-cyclopropane spirocyclic hydantoin derivates. The preparation method of the invention is simple, the yield is high, and 5-cyclopropane spirocyclic hydantoin derivates can be easy to prepare. The compounds of the present invention have good anticonvulsant activity.
Description
Technical field
The present invention relates to intermediate the N '-replacement urea groups cyclopropane of 5-cyclopropane toroid hydantoin derivatives and its production and application and 5-cyclopropane toroid hydantoin derivatives.
Background technology
Glycolylurea (hydantoin) claim glycolylurea again, ureido-hydantoin amine, and chemical name 2, the 4-imidazole diketone is a kind of unitary five member ring heterocyclic compound of urea that contains.Glycolylurea has attracted people's extensive concern always since 1861 are found.Some hydantoin derivatives has unique pharmacologically active, is widely used aspect medical.Wherein, a kind of representative be phenytoin Sodium, chemical name 5-ethyl-5-phenyl glycolylurea, it is the common medicine of treatment epilepsy.But clinical discovery is taken phenytoin Sodium for a long time can cause gingival hyperplasia, and side effect is big.
Summary of the invention
Problem to be solved by this invention provides 5-cyclopropane toroid hydantoin derivatives and its production and application, and described preparation method is not only simple, productive rate is higher, and the 5-cyclopropane toroid hydantoin derivatives that makes can be used for treating anticonvulsion outbreak.
Technical scheme provided by the invention is: the 5-cyclopropane toroid hydantoin derivatives, and its structural formula is:
R in the formula
1Phenyl for hydrogen, alkyl, phenyl or replacement.
Above-mentioned R
1Be hydrogen, methyl, sec.-propyl, butyl, 1-methylol propyl group, benzyl, phenyl, 4-aminomethyl phenyl, 4-p-methoxy-phenyl, 4-fluorophenyl, 3,5-dichlorophenyl or 4-nitrophenyl.
N '-replacement urea groups cyclopropane, its structural formula is:
R in the formula
1, R
2Be selected from the phenyl of hydrogen, alkyl, phenyl or replacement respectively.
Above-mentioned R
1, R
2Be selected from hydrogen, methyl, sec.-propyl, butyl, 1-methylol propyl group, benzyl, phenyl, 4-aminomethyl phenyl, 4-p-methoxy-phenyl, 4-fluorophenyl, 3 respectively, 5-dichlorophenyl, 4-methoxycarbonyl phenyl or 4-nitrophenyl, promptly N '-replacement urea groups cyclopropane is:
2,2-dimethyl-1-urea groups cyclopropane carboxylic acid acetoacetic ester, 2,2-dimethyl-1-(3-methyl urea groups) cyclopropane carboxylic acid acetoacetic ester, 2,2-dimethyl-1-(3-sec.-propyl urea groups) cyclopropane carboxylic acid acetoacetic ester, 2,2-dimethyl-1-(3-butyl urea groups) cyclopropane carboxylic acid acetoacetic ester, 2,2-dimethyl-1-[3-(1-methylol propyl group) urea groups] the cyclopropane carboxylic acid acetoacetic ester, 2,2-dimethyl-1-(3-benzyl urea groups) cyclopropane carboxylic acid acetoacetic ester, 2,2-dimethyl-1-(3-phenyl urea groups) cyclopropane carboxylic acid acetoacetic ester, 2,2-dimethyl-1-[3-(4-aminomethyl phenyl) urea groups] the cyclopropane carboxylic acid acetoacetic ester, 2,2-dimethyl-1-[3-(4-p-methoxy-phenyl) urea groups] the cyclopropane carboxylic acid acetoacetic ester, 2,2-dimethyl-1-[3-(4-fluorophenyl) urea groups) cyclopropane carboxylic acid acetoacetic ester, 2,2-dimethyl-1-[3-(3 ', 5 '-dichlorophenyl) urea groups] the cyclopropane carboxylic acid acetoacetic ester, 2,2-dimethyl-1-[3-(4-methoxycarbonyl phenyl) urea groups) cyclopropane carboxylic acid acetoacetic ester, 2,2-dimethyl-1-[3-(4-nitrophenyl) urea groups] the cyclopropane carboxylic acid acetoacetic ester, 2,2-dimethyl-1-(3-methyl-3-phenyl urea groups) cyclopropane carboxylic acid acetoacetic ester or 2,2-dimethyl-1-(3,3-di-isopropyl urea groups) cyclopropane carboxylic acid acetoacetic ester etc.
The present invention also provides the preparation method of above-mentioned 5-cyclopropane toroid hydantoin derivatives, with 1-carboxyl-2,2-dimethyl cyclopropane carboxylic acid ethyl ester and Vinyl chloroformate (ClCOOEt) 0 ℃～-20 ℃ the reaction 20～30 minutes after, at sodiumazide (NaN
3) following 1-acid azide-2, the 2-dimethyl cyclopropane carboxylic acid ethyl ester of generating of effect; 1-acid azide-2; 2-dimethyl cyclopropane carboxylic acid ethyl ester is reset the isocyanic ester that generates correspondence through Curtius under 35-110 ℃; isocyanic ester and primary amine, secondary amine or ammoniacal liquor reaction obtain the described N ' of claim 3-replacement urea groups cyclopropane, and N '-replacement urea groups cyclopropane closes ring and generates claim 1 or 2 described 5-cyclopropane toroid hydantoin derivatives under alkaline condition then.
Above-mentioned 1-carboxyl-2, the consumption mol ratio of 2-dimethyl cyclopropane carboxylic acid ethyl ester and Vinyl chloroformate is 1: 1～3.
Above-mentioned NaN
3Consumption be 1-carboxyl-2,1～4 times of 2-dimethyl cyclopropane carboxylic acid ethyl ester molar weight.
The application of above-mentioned 5-cyclopropane toroid hydantoin derivatives in preparation treatment convulsive attack medicine.
Reaction formula is as follows:
(work as R
2During=H)
The present invention has that the preparation method is simple, productive rate is higher, and can easily prepare the 5-cyclopropane toroid hydantoin derivatives.
The trial model that the present invention adopts maximum electrofit (MES test) and Yetrazol to bring out two kinds of classics of convulsions (scPTZ test) carries out mouse anti convulsions activity research to the synthetic new compound, the result shows that 5-cyclopropane toroid hydantoin derivatives 4 all shows the provide protection to MES, compound 4b wherein, 4d and 4e comparison have better anti-convulsant activity according to the medicine phenytoin Sodium, and the anti-convulsant activity of compound 4g and 4j and phenytoin Sodium is suitable; Compound 4b, 4d, 4e, 4g compares with the standard drug Sodium Valproate the provide protection of scPTZ, reduced activity, and compound 4j compares with the standard drug Sodium Valproate, quite active.
Embodiment
Below in conjunction with specific embodiment technical scheme of the present invention and application are described further:
Embodiment 1:1-isocyanic ester-2,2-dimethyl cyclopropane carboxylic acid ethyl ester (compound 2) synthetic
With 1-carboxyl-2,2-dimethyl cyclopropane carboxylic acid ethyl ester 1 (10mmol) is dissolved in the anhydrous tetrahydro furan (30mL), cryosel bathe be cooled to 0 ℃～below-20 ℃, add Vinyl chloroformate and triethylamine or N-Methyl pyrrolidone (NMM) then successively, produce white precipitate immediately.Under this temperature, mixture continues to stir after 20 minutes, will be dissolved with NaN
3The 5mL aqueous solution add in the reaction solution, continue to stir 1 hour.After reaction finishes, add less water dissolving insolubles, use ethyl acetate extraction, (2 * 10mL) wash saturated aqueous common salt, anhydrous Na
2SO
4Dried overnight.Filter, the pressure reducing and steaming solvent obtains light yellow liquid (note: contain the compound explosive of nitrine, can not be with its evaporate to dryness).To silicagel column, is leacheate with petrol ether/ethyl acetate with this thick transferred product, collects R
f=0.7 place's component, the pressure reducing and steaming solvent gets colourless liquid.It is dissolved in the toluene (30mL), the installation spherical condensation tube, oil sealing stirs heating down, produces until no gas, and the pressure reducing and steaming solvent gets colourless thick shape liquefaction compound 2.This compound is used for next step reaction immediately without being further purified.
Embodiment 2:2,2-dimethyl-1-urea groups cyclopropane carboxylic acid acetoacetic ester (compound 3a) synthetic
Under the room temperature, the colourless thick shape liquid (compound 2) that embodiment 1 is obtained all is dissolved in the tetrahydrofuran (THF) (30mL), the ammoniacal liquor (about 8mmol) of 28%-30% is dissolved in a small amount of tetrahydrofuran (THF), join then in the tetrahydrofuran solution of above-claimed cpd 2, reacted 15 minutes, the pressure reducing and steaming solvent, column chromatography gets compound 3a immediately.Product is a white solid; Productive rate: 52%; Fusing point: 127-129 ℃; IR (KBr): 3355 (N-H), 1704 (C=O), 1658 (C=O), 1534,1365,1318cm
-1 1H NMR (300MHz, CDCl
3): δ 0.98 (d, 1H, J=4.6Hz, Cpr-H), 1.20 (s, 3H ,-CH
3), 1.27 (t, 3H, J=7.2Hz ,-CH
3), 1.29 (s, 3H ,-CH
3), 1.72 (d, 1H, J=4.6Hz, Cpr-H), 4.19 (q, 2H, J=7.2Hz, CH
2), 4.97-5.01 (m, 2H, NH), 5.62 (br s, 1H, NH); MS (m/z): 223[M+Na]; Anal.Calcd.forC
9H
16N
2O
3: C, 53.98; H, 8.05; N, 13.99; Found:C, 54.05; H, 7.83; N, 14.18%.
Embodiment 3:2,2-dimethyl-1-[3-(4-methoxycarbonyl phenyl) urea groups) cyclopropane carboxylic acid acetoacetic ester (compound 31) is synthetic
Under the room temperature, the colourless thick shape liquid (compound 2) that embodiment 2 is obtained all is dissolved in the tetrahydrofuran (THF) (30mL), to be dissolved in the tetrahydrofuran (THF) methoxycarbonyl aniline (8mmol), join then in the THF solution of above-claimed cpd 2, reacted 30 minutes, the pressure reducing and steaming solvent, column chromatography gets compound 31 immediately.White solid; Productive rate: 45%; Fusing point: 159-161 ℃; IR (KBr): 3391 (N-H), 1712 (C=O), 1687 (C=O), 1608,1589,1525,1438,1384cm
-1 1H NMR (300MHz, DMSO-d
6): δ 1.04 (d, 1H, J=5.1Hz, Cpr-H), 1.23 (s, 3H ,-CH
3), 1.27 (s, 3H ,-CH
3), 1.26 (s, 3H ,-CH
3), 1.83 (d, 1H, J=5.1Hz, Cpr-H), 3.86 (s, 3H, CH
3), 4.18-4.25 (m, 2H, CH
2), 7.36 (d, 2H, Ar-H), 7.85 (d, 2H, Ar-H);
13C NMR (150MHz, DMSO-d
6): δ 14.94,20.27, and 22.67,27.28,29.11,42.86,52.43,61.13,117.46,122.61,131.09,145.46,155.78,166.64,172.11; MS (m/z): 357[M+Na]; Anal.Calcd.for C
17H
22N
2O
5: C, 61.07; H, 6.63; N, 8.38; Found:C, 59.86; H, 6.83; N, 8.21%.
Embodiment 4:2,2-dimethyl-1-(3-methyl-3-phenyl urea groups) cyclopropane carboxylic acid acetoacetic ester (compound 3n) synthetic
Under the room temperature, the colourless thick shape liquid (compound 2) that embodiment 2 is obtained all is dissolved in the methylene dichloride (30mL), adds n-formyl sarcolysine base aniline (8mmol), reacted 30 minutes, and the pressure reducing and steaming solvent, column chromatography gets compound 3n immediately.White solid; Productive rate: 50%; Fusing point: 80-82 ℃; IR (KBr): 3335 (N-H), 1721 (C=O), 1654 (C=O), 1596,1490,1448,1381cm
-1 1H NMR (300MHz, CDCl
3): δ 0.98 (d, 1H, J=5.4Hz, Cpr-H), 1.05 (s, 3H ,-CH
3), 1.15 (s, 3H ,-CH
3), 1.27 (t, 3H, J=7.2Hz ,-CH
3), 1.74 (d, 1H, J=5.4Hz, Cpr-H), 3.27 (s, 3H, CH
3), 4.16 (q, 2H, J=7.2Hz, CH
2), 4.95 (s, 1H, NH), 7.29-7.46 (m, 5H, Ar-H);
13C NMR (150MHz, CDCl
3): δ 14.50,19.91, and 22.15,27.49,28.89,37.36,43.61,61.23,127.48,127.63,130.21,143.50,157.70,172.37; MS (m/z): 313[M+Na]; Anal.Calcd for C
16H
22N
2O
3: C, 66.18; H, 7.64; N, 9.65.Found:C, 66.14; H, 7.68; N, 9.60%.
Synthesizing of embodiment 5:5-cyclopropane toroid hydantoin derivatives (compound 4)
The top synthetic urea 3 (1mmol) that obtains is dissolved in the dehydrated alcohol (10mL), adds metal Na then, room temperature reaction, TLC monitoring, after reaction finishes, pressure reducing and steaming ethanol, resistates adds less water, ethyl acetate extraction (3 * 20mL), collected organic layer, saturated common salt washing, anhydrous Na
2SO
4Dried overnight.Filter, the pressure reducing and steaming solvent, silica gel column chromatography separates, and gets compound 4.
1,1-dimethyl-4,6-phenodiazine spiral shell [2.4] heptane-5,7-diketone (4a): white solid; Productive rate: 94%; Fusing point: 196-198 ℃; IR (KBr): 3441 (N-H), 1767 (C=O), 1722 (C=O), 1412,1381cm
-1 1H NMR (300MHz, CDCl
3): δ 1.02 (s, 1H, Cpr-H), 1.03 (s, 1H, Cpr-H), 1.18 (s, 3H ,-CH
3), 1.24 (s, 3H ,-CH
3), 8.15 (s, 1H, NH), 10.65 (s, 1H, NH);
13C NMR (150MHz, CDCl
3): δ 18.83,22.28, and 26.12,26.36,49.32,157.66,175.44; MS (m/z): 177[M+Na]; Anal.Calcd.for C
7H
10N
2O
2: C, 54.45; H, 6.54; N, 18.17; Found:C, 54.18; H, 6.66; N, 17.94%.
1,1-dimethyl-6-sec.-propyl-4,6-phenodiazine spiral shell [2.4] heptane-5,7-diketone (4c): white needle-like crystals; Productive rate: 92%; Fusing point: 122-124 ℃; IR (KBr): 3427 (N-H), 1768 (C=O), 1708 (C=O), 1421,1385cm
-1 1H NMR (300MHz, CDCl
3): δ 1.29 (d, 1H, J=5.1Hz, Cpr-H), 1.28 (s, 6H, 2-CH
3), 1.36 (d, 6H, 2-CH
3), 1.42 (d, 1H, J=5.1Hz, Cpr-H), 4.30-4.39 (m, 1H, CH), 7.54 (br s, 1H, NH);
13C NMR (150MHz, CDCl
3): δ 18.41,19.96, and 22.53,26.79,27.74,43.72,48.13,158.64,173.52; MS (m/z): 219[M+Na]; Anal.Calcd.for C
10H
16N
2O
2: C, 61.20; H, 8.22; N, 14.27; Found:C, 61.08; H, 8.11; N, 14.14%.
1,1-dimethyl-6-(1-methylol propyl group)-4,6-phenodiazine spiral shell [2.4] heptane-5,7-diketone (4e): white solid; Productive rate: 93%; Fusing point: 94-95 ℃; IR (KBr): 3519 (N-H), 1760 (C=O), 1692 (C=O), 1426,1385cm
-1 1H NMR (300MHz, CDCl
3): δ 0.90 (m, 3H ,-CH
3), 1.18 (d, 1H, J=5.1Hz, Cpr-H), 1.26 (s, 3H ,-CH
3), 1.34 (s, 3H ,-CH
3), 1.47 (d, 1H, J=5.1Hz, Cpr-H), 1.83-1.96 (m, 2H ,-CH
2), 3.73-3.91 (m, 3H ,-CH
2,-CH), 4.07 (br s, 1H, OH), 7.60 (br s, 1H, NH);
13C NMR (150MHz, CDCl
3): δ 10.92,18.39, and 21.69,22.50,27.55,28.19,48.59,56.03,63.29,159.31,174.36; MS (m/z): 249[M+Na]; Anal.Calcd.for C
11H
18N
2O
3: C, 58.39; H, 8.02; N, 12.38; Found:C, 58.06; H, 8.26; N, 12.09%.
1,1-dimethyl-6-benzyl-4,6-phenodiazine spiral shell [2.4] heptane-5,7-diketone (4f): white solid; Productive rate: 95%; Fusing point: 142-144 ℃; IR (KBr): 3218 (N-H), 1755 (C=O), 1712 (C=O), 1497,1445,1407cm
-1 1H NMR (300MHz, CDCl
3): δ 1.12 (d, 1H, J=5.1Hz, Cpr-H), 1.21 (s, 3H ,-CH
3), 1.27 (s, 3H ,-CH
3), 1.28 (d, 1H, J=5.1Hz, Cpr-H), 4.57 (s, 2H ,-CH
2), 7.25-7.37 (m, 5H, Ar-H), 8.57 (s, 1H, NH);
13C NMR (150MHz, CDCl
3): δ 18.53,22.52, and 26.99,27.92,42.50,48.71,127.98,128.82,136.57,158.14,173.23; MS (m/z): 267[M+Na]; Anal.Calcd.for C
14H
16N
2O
2: C, 68.83; H, 6.60; N, 11.47; Found:C, 68.96; H, 6.32; N, 11.64%.
1,1-dimethyl-6-(4-p-methoxy-phenyl)-4,6-phenodiazine spiral shell [2.4] heptane-5,7-diketone (4i): white needle-like crystals; Productive rate: 94%; Fusing point: 143-145 ℃; IR (KBr): 3446 (N-H), 1759 (C=O), 1717 (C=O), 1516,1420,1321cm
-1 1HNMR (300MHz, CDCl
3): δ 1.20 (d, 1H, J=5.1Hz, Cpr-H), 1.29 (s, 3H ,-CH
3), 1.40 (s, 3H ,-CH
3), 1.55 (d, 1H, J=5.1Hz, Cpr-H), 3.82 (s, 3H ,-OCH
3), 7.00 (d, 2H, J=8.4Hz, Ar-H), 7.05 (br s, 1H, NH), 7.32 (d, 2H, J=8.4Hz, Ar-H);
13C NMR (150MHz, CDCl
3): δ 18.54,22.57, and 27.51,28.06,48.51,55.72,114.56,124.82,127.87,157.64,159.36,172.67; MS (m/z): 283[M+Na]; Anal.Calcd.for C
14H
16N
2O
3: C, 64.60; H, 6.20; N, 10.76; Found:C, 64.79; H, 6.05; N, 10.43%.
1,1-dimethyl-6-(4-nitrophenyl)-4,6-phenodiazine spiral shell [2.4] heptane-5,7-diketone (4m): light yellow needle-like crystal; Productive rate: 92%; Fusing point: 162-164 ℃; IR (KBr): 3217 (N-H), 1771 (C=O), 1716 (C=O), 1522,1408,1346,1123cm
-1 1H NMR (300MHz, DMSO-d
6): δ 1.21 (d, 1H, J=5.4Hz, Cpr-H), 1.25 (s, 3H ,-CH
3), 1.30 (s, 3H ,-CH
3), 1.37 (d, 1H, J=5.4Hz, Cpr-H), 7.76 (d, 2H, J=9.3Hz, Ar-H), 8.32 (d, 2H, J=9.3Hz, Ar-H), 8.97 (br s, 1H, NH);
13C NMR (150MHz, DMSO-d
6): δ 18.95,22.20, and 27.43,27.70,48.39,124.66,127.38,138.95,146.33,155.10,172.30; MS (m/z): 298[M+Na]; Anal.Calcd.forC
13H
13N
3O
4: C, 56.72; H, 4.76; N, 15.27; Found:C, 56.64; H, 4.65; N, 15.09%.
Following table is the embodiment of the invention
Above embodiment can prepare urea 3 with reference to the described method of embodiment 2-4.
Shown in the foregoing description, primary amine and secondary amine all can obtain corresponding urea 3 with isocyanic ester 2 effects fast.Hale the arylamine of electronics base (as: nitro, methoxycarbonyl) for band, carry out fast, preferably add the p-methyl benzenesulfonic acid catalyzed reaction of catalytic amount in order to make reaction.
The urea 3 that above embodiment prepares forms toroid hydantoin 4 with reference to embodiment 5 at alkaline condition ShiShimonoseki ring.But urea 31 can not close ring under this condition, but the hydrolysis of methoxycarbonyl has taken place.
Pharmacology in the body
Can comprise that maximal electroshock convulsive attack test (MES) and Yetrazol bring out anti-convulsant activity in the body of convulsive attack experiment (scPTZ test) test The compounds of this invention after mouse is oral with the anticonvulsion mouse test model of two kinds of classics.
Maximal electroshock convulsive attack test (MES): by how applying electric current with instrument apparatus with YSD-4G type pharmacology Physiological Experiment (electric current is 25mA, voltage 100V, stimulation time 0.25s. single stimulates), in being the male mouse of kunming of 18-22g, body weight brings out maximal electroshock seizure.The mouse random packet, 10 every group, oral (30mg/kg, 15mg/kg 7.5mg/kg), behind the 1h, fixedly scribble the ear-drum electrode of physiological saline lightly on two ears of mouse, decontrol mouse then and make its free movement to the The compounds of this invention various dose.Apply electric current and the animal observation is reached 30 seconds time, to observe the generation of THE reaction.The hind leg stretching, extension is surpassed health plane 90 degree be defined as tonic seizures.Mode result with amount.
Pentetrazole brings out convulsive attack test (scPTZ): the mouse random packet, every group 10, the oral The compounds of this invention various dose (80mg/kg that gives, 40mg/kg, 20mg/kg), behind the 1h, subcutaneous injection causes frightened agent Yetrazol (70mg/kg), observe 30min, keep at least more than the 5s or the hind leg tonic convulsion is the final observation index of experiment can prevent that mouse paroxysmal from twitching.
The compounds of this invention 4 is as anticonvulsive drug
Measure The compounds of this invention 4 blocking-up maximal electroshock convulsive attack (MES) abilities according to above method, The compounds of this invention 4 all shows the provide protection to MES, and the convulsions inhibiting rate is 50-90% (seeing Table).Compound 4b wherein, 4d, 4e, 4g and 4j anticonvulsant action are the strongest.Compound 4b, 4d and 4e comparison have better anti-convulsant activity according to the medicine phenytoin Sodium, as: when dosage is 30mg/kg, compound 4b, the convulsions inhibiting rate of 4d and 4e is 90%, and the convulsions inhibiting rate of phenytoin Sodium is 80%; The anti-convulsant activity of compound 4g and 4j and phenytoin Sodium is suitable, and inhibiting rate is 80%.Further measure The compounds of this invention 4b, 4d, 4e then; the ability that 4g and 4j blocking-up pentetrazole bring out convulsive attack (scPTZ) is found compound 4b, 4d; 4e, 4g compares with the standard drug Sodium Valproate, and the provide protection of scPTZ is weakened; and compound 4j compares with the standard drug Sodium Valproate, and is suitable to the provide protection of scPTZ, at dosage 80mg/kg; 40mg/kg; the convulsions inhibiting rate is respectively 80%, 50% during 20mg/kg, and 30%.
Table: to the anticonvulsion assessment behind the mouse oral administration
Claims (6)
1.5-cyclopropane toroid hydantoin derivatives, its structural formula is:
R in the formula
1Be hydrogen, methyl, sec.-propyl, butyl, 1-methylol propyl group, benzyl, phenyl, 4-aminomethyl phenyl, 4-p-methoxy-phenyl, 4-fluorophenyl, 3,5-dichlorophenyl or 4-nitrophenyl.
2.N '-replace the urea groups cyclopropane, its structural formula is:
R in the formula
1Be selected from hydrogen, methyl, sec.-propyl, butyl, 1-methylol propyl group, benzyl, phenyl, 4-aminomethyl phenyl, 4-p-methoxy-phenyl, 4-fluorophenyl, 3,5-dichlorophenyl or 4-nitrophenyl; R
2Be hydrogen.
3. the preparation method of the described 5-cyclopropane toroid hydantoin derivatives of claim 1 is characterized in that: with 1-carboxyl-2,2-dimethyl cyclopropane carboxylic acid ethyl ester and Vinyl chloroformate are 0 ℃～-20 ℃ reactions after 20～30 minutes, at NaN
3Effect generates 1-acid azide-2,2-dimethyl cyclopropane carboxylic acid ethyl ester down; 1-acid azide-2; 2-dimethyl cyclopropane carboxylic acid ethyl ester is reset the isocyanic ester that generates correspondence through Curtius under 35-110 ℃; isocyanic ester and primary amine or ammoniacal liquor reaction obtain the described N ' of claim 2-replacement urea groups cyclopropane, and N '-replacement urea groups cyclopropane closes ring and generates the described 5-cyclopropane toroid hydantoin derivatives of claim 1 under alkaline condition then.
4. preparation method according to claim 3 is characterized in that: 1-carboxyl-2, the consumption mol ratio of 2-dimethyl cyclopropane carboxylic acid ethyl ester and Vinyl chloroformate is 1: 1～3.
5. according to claim 3 or 4 described preparation methods, it is characterized in that: NaN
3Consumption be 1-carboxyl-2,1～4 times of 2-dimethyl cyclopropane carboxylic acid ethyl ester molar weight.
6. the application of the described 5-cyclopropane toroid hydantoin derivatives of claim 1 in preparation treatment convulsive attack medicine.
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| US4105774A (en) * | 1975-07-28 | 1978-08-08 | The United States Of America As Represented By The Secretary Of State | Hydantoin compounds and methods of use thereof |
| WO1992008702A1 (en) * | 1990-11-16 | 1992-05-29 | Jouveinal S.A. | Chiral hydantoin resolution |
| CN1192736A (en) * | 1995-08-10 | 1998-09-09 | 德雷斯顿药品工厂有限公司 | Novel imidazoline-2,4-diones with an ortho-substituted ar(alk)yl radical in position 1, having an anti-convulsive effect, and prodn. therefor |
| WO1999048873A1 (en) * | 1998-03-25 | 1999-09-30 | Bristol-Myers Squibb Company | Imidazolone anorectic agents: i. acyclic derivatives |
| CN1337938A (en) * | 1999-01-07 | 2002-02-27 | 安万特作物科学公司 | Novel method for preparing chiral amino acids |
| WO2004010950A2 (en) * | 2002-07-31 | 2004-02-05 | Euro-Celtique S.A. | Aryl substituted hydantoin compounds and their use as sodium channel blockers |
-
2008
- 2008-03-11 CN CN2008100470266A patent/CN101255136B/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4105774A (en) * | 1975-07-28 | 1978-08-08 | The United States Of America As Represented By The Secretary Of State | Hydantoin compounds and methods of use thereof |
| WO1992008702A1 (en) * | 1990-11-16 | 1992-05-29 | Jouveinal S.A. | Chiral hydantoin resolution |
| CN1192736A (en) * | 1995-08-10 | 1998-09-09 | 德雷斯顿药品工厂有限公司 | Novel imidazoline-2,4-diones with an ortho-substituted ar(alk)yl radical in position 1, having an anti-convulsive effect, and prodn. therefor |
| WO1999048873A1 (en) * | 1998-03-25 | 1999-09-30 | Bristol-Myers Squibb Company | Imidazolone anorectic agents: i. acyclic derivatives |
| CN1337938A (en) * | 1999-01-07 | 2002-02-27 | 安万特作物科学公司 | Novel method for preparing chiral amino acids |
| WO2004010950A2 (en) * | 2002-07-31 | 2004-02-05 | Euro-Celtique S.A. | Aryl substituted hydantoin compounds and their use as sodium channel blockers |
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| CN101255136A (en) | 2008-09-03 |
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