CN85101548A - Improve about anticonvulsant - Google Patents
Improve about anticonvulsant Download PDFInfo
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- CN85101548A CN85101548A CN 85101548 CN85101548A CN85101548A CN 85101548 A CN85101548 A CN 85101548A CN 85101548 CN85101548 CN 85101548 CN 85101548 A CN85101548 A CN 85101548A CN 85101548 A CN85101548 A CN 85101548A
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- benzoylamide
- phenethyl
- acid
- amino
- salt
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Abstract
The invention provides some heterocyclic carbamate derivatives preparation method, their medicinal formula, and the purposes of using as anticonvulsant.
Description
In several anticonvulsants that American market is sold, the misery in the time of can only removing serious attack for 50-75% De epilepsy patient.And therapeutic effect also is subjected to serious influence of paying effect frequently.These pairs effect comprises: sedation, movement disorder, psychopathia, suicide depression of sex, gastrointestinal disorder, gum hypertrophy, lymphadenopathy, nuclear macrocyte anemia, liver poisoning, nephropathy, hirsutism are arranged, also have fetal anomaly.Because the therapeutic efficiency of most anticonvulsants that sell in market is very low, these pairs effect, strictness are said, just seem more thorny from slight sedation to dead (dying from aplastic anemia).For example phenhtoin is to use one of anticonvulsant widest in area, has only when its content in human plasma reaches 10mcg/ml, could the Taking Control of Epilepsy outbreak.And the toxic action as the nystagmus when needing only the 20meg/ml of plasma content, can be found out.During 30mcg/ml, obvious movement disorder appears.During 40mcg/ml, lethargy appears.Referring to " treatment pharmacological basis " P.455(Gilman, Goodman.Gilman, sixth version, the New York mcmillan is published joint-stock company, New York (1980)).Consider that the sick scholars of these true ， epilepsy mostly point out, need selectivity better, the anticonvulsant drug that toxicity is less really.
United States Patent (USP) is treated the method proposition claim of epilepsy and other spasm diseases for No. 4379165 to amino-Benzoylamide of taking some N-replacement.The selected chemical compound of this patent is racemic 4-amino-N-(a-methylbenzyl) Benzoylamide, also be called 4-amino-N-(1-phenethyl) Benzoylamide.According to reports, the prevention index (pI) of this chemical compound is 9.48.It prevents exponential definition is TD
50ED in (, being decided to be intoxicating dosage) and the maximum electric shock shock property outbreak experiment to 50% experimenter according to the Rotorod toxicity test
50The ratio of (promptly removing the required effective dose of hind leg extensor rigidity of 50% animal subject).This patent has only disclosed the racemic form of this chemical compound, does not propose any enantiomorph form.The invention provides up-to-date 4-amino-N-(1-phenethyl) (S) of Benzoylamide-and (R)-enantiomorph, or its salt that pharmaceutically uses.It is shocking that the prevention index of each enantiomorph is all much bigger than the prevention index of racemic mixture, and the toxicity of each enantiomorph itself also the toxicity than racemic mixture is little.
Except proposing these chemical compounds, the invention allows for the method that the mammal of needs treatment convulsions disease is treated and prevents.This method comprises to mammal to be treated takes (R)-or (S)-4-amino-N-(1-phenethyl)-effective dose of Benzoylamide or its salt that pharmaceutically uses.
Another aspect of the present invention has provided medical prescription.This prescription comprises: with (R)-or (S)-amino-N-(1-phenethyl) Benzoylamide, or its salt that pharmaceutically uses makes active constituent, is equipped with the carrier or the diluent that pharmaceutically use.
In addition, the invention provides preparation (S)-or (R)-4-amino-N-(1-phenethyl) method of Benzoylamide or the salt that pharmaceutically uses.This method comprises:
(a) reduction (S)-or (R)-4-nitro-N-(1-phenethyl) Benzoylamide; Or
(b) separate (R, S)-4-amino-N-(1-phenethyl) Benzoylamide; With
(c) in case of necessity, salinization product.
The present invention be used for the treatment of and prevent the organic compound of mammal convulsions disease relevant.
As anticonvulsant, though the drug effect that (S)-isomer provided by the invention produces is bigger than the drug effect of (R)-isomer or racemic mixture, (seeing below), but because (R)-the prevention index ratio of isomer is higher, so preferably select (R)-isomer for use.
(promptly spendable in the chemotherapy of the warm blood animal) acid-addition salts that uses on the Chinese medicine of the present invention, known standard method preparation on the adopting process utilizes those acid enough strong, can generate the acid of acid-addition salts with weak base amino.These acid-addition salts comprise from deutero-salt of mineral acid such as hydrochloric acid, nitric acid, phosphoric acid, sulphuric acid, hydrobromic acid, hydroiodic acid or phosphorous acid.And the alkanoic acid, hydroxyl alkane acid and the hydroxyl chain docosandioic acid that replace from aliphatic monobasic and dicarboxylic acids, phenyl, the deutero-salt of organic acid such as aromatic acid, aliphatic series and aromatic sulfonic acid.Pharmaceutically the salt of Shi Yonging can comprise sulfate, metaphosphate, hypophosphites, hydrochloride, hydrobromide, hydriodide, hydrofluoride, oxalates, maleate, benzene sulfonate, toluene fulfonate, closilate, mesylate, propane sulfonic acid salt, naphthalene sulfonate or naphthalene-2-sulfonic acid salt.The salt that the present invention selects is that those are from mineral acid, particularly from the deutero-salt of hydrochloric acid.
Chemical compound among the present invention can prepare from racemic mixture by the standard method such as known isomer separation such as crystallization, generation salt, high pressure liquid chromatography.In addition, also can be by separating the nitro-derivative intermediate, a kind of isomer of hydrogenation according to a conventional method then, the chemical compound in the preparation invention.
Preparing the selected method of chemical compound among the present invention, is to utilize to have enantiomorphous pure Alpha-Methyl Benzoylamide, and its two kinds of isomers all can obtain from commercial channels.That is: with the isomer of suitable Alpha-Methyl Benzoylamide, with the 4-nitrobenzoyl chloride in the atent solvent as oxolane, preferably have under the reagent of the acid of removing such as potassium carbonate participate in, react.Though the reinforced mol ratio of reactant has selected 1.5: 1.0(4-nitrobenzoyl chloride/Alpha-Methyl Benzoylamide), also can adopt other mol ratios.Reaction can be carried out between the reactant reflux temperature about room temperature.Under the counterflow condition of selecting, generally can finish reaction less than 12 hours.
The method for hydrogenation of preparation end-product is equivalent to the situation of the reaction B that introduces in No. 4379165, the United States Patent (USP).Generally, the hydrogenation of nitro intermediate under low pressure, in the atent solvents such as alcohol, carries out under the Pd/C catalyst action.Usually finished reaction in 2-4 hour.
Chemical compound among the present invention is an anticonvulsant, can take by variety of way, comprising: oral, rectal application, through dermatologic, subcutaneous medication, intravenous injection, muscle medication, Nasacort etc.And being made into pharmaceutical composition usually takes.The special feature of these chemical compounds is by oral generation drug effect.The compound method of this class pharmaceutical composition is well-known in medical technology.Comprise at least a reactive compound in the compositions.Therefore, the pharmaceutical composition among the present invention comprises usefulness (R)-or (S)-4-amino-N-(1-phenethyl) Benzoylamide, or its salt that pharmaceutically uses makes active constituent, and formulated together with the carrier or the diluent that pharmaceutically use.
During the pharmaceutical composition of preparation among the present invention, active component mixes with carrier usually, or dilutes with carrier, or wraps in the carrier of forms such as capsule, sachet, paper or other containers.The carrier that uses as diluent is as the excipient of active constituent, and solid, semisolid or the liquid substance of medium.Therefore, compositions can be mixed with tablet, pill, lozenge, sachet agent, cachet,
Agent, suspensoid, Emulsion, solution, syrup, aerosol (solid or in liquid medium), contain ointment, soft and hard gelatine capsule, the sterile solution that suppository, injectable are used and the sterilized powder of packing up to the 10Wt% reactive compound.
Some carrier and diluent that are suitable for comprise: lactose, glucose, sucrose, Pyrusussuriensis (sugar) alcohol, mannitol, starch, Radix Acaciae senegalis, calcium phosphate, alginate, Tragacanth, gelatin, calcium silicates, microcrystalline Cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methyl and propyl group-hydroxy benzoate, Talcum, magnesium stearate and mineral oil.In addition, also can comprise lubricant, wetting agent, emulsifying agent and suspending agent, antiseptic, sweetening agent or flavoring agent in the prescription.Compositions among the present invention, as known in the technology, can prepare make patient's medication after, the active constituent in the medicine can be promptly, play a role constantly or lentamente.
Compositions is preferably by unit dose preparation, in every dose the content of active constituent be about 5～500mg commonly used be 25～300mg." unit dose " refers to unit discrete on the physical significance, is suitable for the dosage that human body or other mammals are once taken.Per unit contains the active substance of scheduled volume, and this is to calculate according to the needs that produce expected effect, mixes necessary pharmaceutical carrier again.
In bigger dosage range, reactive compound all is effective.As: be about 0.5～300mg/kg body weight day dosage scope.The scope of medication of treatment during the adult is preferably in about 1-50mg/kg body weight, once or part vic.But, be understandable that the actual dose of chemical compound is determined by the internist, need to consider various relevant situations, comprise: situation to be treated, to the selection of medicinal compound, to the selection of medicinal mode, age, body weight, each patient's reaction, the order of severity of disease etc.Therefore, in any case can not use and state dosage range and limit the scope of the invention.
Following non-limiting preparation method and example further specify preparation, the compound method of intermediate among the present invention, chemical compound and prescription.
Example 1
A.(S)-and 4-nitro-N-(1-phenethyl) Benzoylamide
The tetrahydrofuran solution that 100ml is contained 4-nitrobenzoyl chloride (23.3g) be added drop-wise to vigorous agitation, by (S)-Alpha-Methyl Benzoylamide (10g), in the solution that wet chemical (solution of 200ml 20%) and 200ml oxolane mix.After spending the night under mixture heated refluxes, cooling, dilute with water is used ethyl acetate extraction.Organic facies is through salt water washing, drying (MgSO
4), and concentrate in a vacuum.
Generate solid and obtain 22.19g 184% yellow product by recrystallize in the benzene, cotton-shaped crystalline melt point 136-137.5 ℃ (α)
25 D=+37.7 ℃ (methanol)
Analyze: C
15H
14N
2O
3
Value of calculation: C, 66.66, H5.22, N10.36
Implementation value: C, 66.86, H5.11, N10.42
R-(4)-and nitro-N-(1-phenethyl) Benzoylamide
The tetrahydrofuran solution that 100ml is contained 4-nitrobenzoyl chloride (23.3g) is added to vigorous agitation, in the solution that is mixed by (R)-Alpha-Methyl Benzoylamide (10g) wet chemical (solution of 200ml 20%) and 200ml oxolane.After spending the night under mixture heated refluxes, cooling, dilute with water uses the ethyl acetate extraction organic facies through salt water washing drying (MgSO
4) and vacuum concentration.Generate the solid recrystallize and get its (78%) yellow product, be cotton-shaped crystallization, fusing point 136-137.5 ℃ (α)
25 D=36.7 ℃ (methanol)
Analyze: C
15H
14N
2O
3
Value of calculation: C, 66.66, H5.22, N10.36
Experiment value: C, 66.62, H5.19, N10.40
B. the reduction of nitro intermediate
(S)-and 4-amino-N-(1-phenethyl) Benzoylamide
By (S)-4-nitro-N-(1-phenethyl) Benzoylamide (5g), the mixture that 5% palladic C catalyst (0.5g) and 200ml ethanol are formed in the Paar hydrogenator, under the 34p.s.i hydrogen pressure, shook 1 hour.Remove catalyst with diatomite filtration then, steam ethanol, obtain a solid matter.With obtaining 4.01g(90% behind benzene/oxolane recrystallization) the white crystal product.Fusing point 185-186.5 ℃, (α)
25 O:+96.2 ° (methanol)
Analyze: C
15H
16N
2O
Value of calculation: C, 74.97; H, 6.71; N, 11.66
Experiment value: C, 74.80; H, 6.98; N, 11.43
(R)-and 4-amino-N-(1-phenethyl) Benzoylamide
By (R)-4-nitro-N-(1-phenethyl) Benzoylamide (5g), 5%Pd/c(0.5g) and the mixture formed of 200ml ethanol in the Paar hydrogenation reactor, in the 34p.s.i hydrogen pressure, shook 1 hour.Remove catalyst with diatomite filtration, steam ethanol, obtain a solid residue, behind the recrystallization, obtain the white crystals product of yield 85%.Fusing point: 185-187 ℃, (α)
25D:-96.3 ° (methanol)
Analyze: C
15H
16N
2O
Value of calculation: C, 74.97; H, 6.71; N, 11.66
Experiment value: C, 74.73; H, 6.82; N, 11.40.
With similar approach preparation (R.S)-4-amino-N-(1-phenethyl) Benzoylamide, yield 88%, the white crystal that obtains, fusing point 154-155.5 ℃.
Analyze: C
15H
16N
2O
Value of calculation: C, 74.97; H, 6.71; N, 11.66
Experiment value: C, 74.94; H, 6.91; N, 11.42.
In following each Formulation Example, with the medicinal compound among the present invention, or its pharmaceutical salts is made the reactive compound in the prescription.
Example 2
Prepare firmly obviously capsule with following composition.
Consumption (mg/ capsule)
Reactive compound 250
Dry starch 200
Magnesium stearate 10
Above-mentioned composition is inserted hard gelatine capsule by the amount of 460mg after mixing.
Example 3
With following composition preparation tablet.
Consumption (mg/ sheet)
Reactive compound 250
Microcrystalline Cellulose 400
Silicon dioxide, smoke 10
Stearic acid 5
After above-mentioned composition mixes, be pressed into the tablet of each heavy 665mg.
Example 4
With following composition preparation aerosol solution.
Wt%
Active constituent 0.25
Ethanol 29.75
Promoter 22 70.00
(chloro difluoromethane)
Reactive compound with after ethanol mixes, is added in a part of promoter 22, is cooled to-30 ℃, transfer in the filling device.By institute's expense it is added in the rustless steel container again, with remaining promoter dilution.Then valve member is installed on the container.
Example 5
The tablet formulation that respectively contains the 60mg active constituent is as follows.
Active constituent 60mg
Starch 45mg
Microcrystalline Cellulose 35mg
Polyvinylpyrrolidone
(10% aqueous solution) 4mg
Carboxymethyl starch sodium 4.5mg
Magnesium stearate 0.5mg
Talcum 1mg
Amount to 150mg
Active constituent, starch and cellulose by the U.S.'s 45 mesh sieves, are fully mixed.After polyethylene alkane ketone solution and the above-mentioned powder mixes, by the U.S.'s 14 mesh sieves, the pellet that obtains is dry under 50-60 ℃, again by the U.S.'s 18 mesh sieves.Carboxymethyl starch sodium, magnesium stearate and Talcum by the U.S.'s 60 mesh sieves in advance is added in the pellet, after the mixing, tabletting on tablet machine.Every heavy 150mg.
Example 6
The capsule that respectively contains the 80mg medicament is formulated as follows.
Active constituent 80mg
Starch 59mg
Microcrystalline Cellulose 59mg
Magnesium stearate 2mg
Total amount 200mg
After active constituent, cellulose, starch and magnesium stearate mixing,, insert hard gelatine capsule by the amount of 200mg by the U.S.'s 45 mesh sieves.
Example 7
The suppository that respectively contains the 225mg active constituent is formulated as follows.
Active constituent 225mg
Saturated stearic acid
Glyceride to 2,000mg
Active constituent is suspended in minimum it by behind the U.S.'s 60 mesh sieves, mixture in the saturated tristerin that the essential heat of melting melts earlier.Pour in the thromboembolism mould of nominal 2g capacity, make its cooling.
Example 8
The suspension preparation that every 5ml dosage contains the 50mg medicine is as follows.
Active constituent 50mg
Sodium carboxymethyl cellulose 50mg
Syrup 1.25ml
Benzoic acid solution 0.10ml
Flavoring q, v,
Pigment q, v,
5ml purifies waste water
Medicine with sodium carboxymethyl cellulose, syrup, is mixed into even paste by behind the U.S.'s 45 mesh sieves.Stir down, add with a small amount of water-reducible benzoic acid solution, the mixed liquor of flavoring and pigment.Add enough water, meet the requirements of capacity.
Chemical compound among the present invention is the curative effect height, the anticonvulsant of long half time.Be applicable to and treat and/or prevent mammiferous convulsions disease.Particularly, these chemical compounds can resist the extensor rigidity spasm that maximum electric shock shock is brought out effectively.Therefore, can be used for treating (Rimple partial) (motion of focus), and the post-traumatic epilepsy outbreak disease of human general tetanic property clonic spasm disease (" epilepsy grand mal "), the part property epilepsy of cortex, (complex partial) (interim cerebral lobe epilepsy) of comprehensive part, single part.In the determination experiment of the spasm that inhibition electric shock shock is brought out, can demonstrate this activity.
In mensuration (ES) experiment of the spasm that inhibition electric shock shock is brought out, test compound is dissolved in the water, (for the chemical compound that can not as salt, emanate out, add 5% capacity hydrochloric acid, short its dissolving), by research dosage, use gavage, take (18-24g) for the male Mus of albinism of three standard C ox kinds.After the medication 60 minutes, by Corneal electrode, allow mice stand 0.1see, the electric shock of 50MA.After the electric shock, check and evaluate the spasm of clonic, flexor tetanus or the extensor rigidity of appearance immediately, or death condition.Determine the EP50 value of each chemical compound simultaneously, that is: electric shock suppresses the extensor rigidity spasm required dosage in half animal immediately.As blank, 18MA just is enough to produce the extensor rigidity spasm on one's body about half control animal usually.During 50MA, all control animals (only taking excipient) are almost all dead.Experimental result is comprehensively in the table I.
The potential toxicity of chemical compound has also been done appraisal.Measure as when passing through genotoxic potential as shown in neurological deficit, movement disorder or the sedation, used " horizontal screen " (H, S) (" horigontal screen ").This experiment successfully is used for measuring the motor function of damaged in the mice body.Experimental technique and " pharmacology, biochemistry and behavior " 6.351(1977) (Coughenour, the method unanimity of being said in etal.).Measure the ED50 value of each chemical compound, that is: cause half animal can not arrive dosage above the screen.By above-mentioned same method, take chemical compound to mice, the shock that shocks by electricity is measured, and 60 minutes, remakes " horizontal screen " and measures.Experimental result is summarised in the table I.
From top two cover experiments, can calculate prevention index (P, I.), i.e. the ratio of the ED50 that measures of " horizontal screen " ED50 of measuring and electric shock shock.Therefore, P, I, numerical value are big, and the therapeutic domain broad is described, and safety margin is big, and when treatment epilepsy and other spasm diseases, the motility of medication is bigger.
The data of concluding from the table I can obviously be found out, the toxicity of two kinds of individual enantiomers, and as passing through H, S, ED50 are determined like that, and all the toxicity than racemic mixture is little.Compare with racemic mixture, the P of two kinds of chemical compounds, I value all make us having improved uncannily a lot.
The table I
4-amino-N-(1-phenethyl) the active and pair effect of Benzoylamide isomer anticonvulsant
*
Isomer electric shock shock ED
50Horizontal screen ED
50The prevention index
mg/kg ms/kg HSED
50/ESED
50
（R.S） 12.5 105 8.4
(racemic mixture)
（S） 10.0 141 14.1
（R） 17.8 480 27.0
* referring to methodological book
Claims (3)
1, preparation (R)-4-amino-N-(1-phenethyl) Benzoylamide, (S)-4-amino-N-(1-phenethyl) Benzoylamide, or the method for its salt that pharmaceutically uses, comprising:
A) reduction corresponding (S)-or (R)-4-nitro-N-(1-phenethyl) Benzoylamide; Or
B) separate (R, S)-4-amino-N-(1-phenethyl) Benzoylamide; With
C) in case of necessity, salinization product.
2, according to the method for claim 1, prepare (R)-4-amino-N-(1-phenethyl) Benzoylamide, or its pharmaceutical salts.
3, according to the method for claim 1, prepare (S)-4-amino-N-(1-phenethyl) Benzoylamide, or its pharmaceutical salts.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 85101548 CN85101548A (en) | 1984-04-10 | 1985-04-01 | Improve about anticonvulsant |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/598,569 US4629740A (en) | 1984-04-10 | 1984-04-10 | Anticonvulsant agents |
| CN 85101548 CN85101548A (en) | 1984-04-10 | 1985-04-01 | Improve about anticonvulsant |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN85101548A true CN85101548A (en) | 1987-01-24 |
Family
ID=25741443
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 85101548 Pending CN85101548A (en) | 1984-04-10 | 1985-04-01 | Improve about anticonvulsant |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN85101548A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7052599B2 (en) | 1998-12-25 | 2006-05-30 | Fujitsu Limited | Method and apparatus for reuse of abrasive fluid used in the manufacture of semiconductors |
-
1985
- 1985-04-01 CN CN 85101548 patent/CN85101548A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7052599B2 (en) | 1998-12-25 | 2006-05-30 | Fujitsu Limited | Method and apparatus for reuse of abrasive fluid used in the manufacture of semiconductors |
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