US2992163A - Use of 4-chloro-1, 2-pyrazole for controlling epileptic seizures - Google Patents
Use of 4-chloro-1, 2-pyrazole for controlling epileptic seizures Download PDFInfo
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- US2992163A US2992163A US545573A US54557355A US2992163A US 2992163 A US2992163 A US 2992163A US 545573 A US545573 A US 545573A US 54557355 A US54557355 A US 54557355A US 2992163 A US2992163 A US 2992163A
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- pyrazole
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/16—Halogen atoms or nitro radicals
Definitions
- R represents hydrogen, an aliphatic hydrocarbon radical having from 1 to carbon atoms, a phenyl substituted lower alkyl radical, a cycloaliphatic radical having from 3 to 6 carbon atoms, or a phenyl radical, and R is hydrogen, chlorine, bromine or an alkyl group having from 1 to 3 carbon atoms.
- anticonvulsant compounds included within the above formula are 1,2-pyrazole, 4- chloro-l,2-pyrazole, 3-methyl-4-bromo-1,2-pyrazole, 3- phenyl-l,2-pyrazole, 4-propyl-3-cyclopentyl-1,2-pyrazole, 3-n-propyl-4-ethyl-1,2-pyrazole, 3-methyl-1,2-pyrazole, 3- n-propyl-LZ-pyrazole, 3-nonyl-l,2-pyrazole, and 3-cyclohexyl-1,2-pyrazole.
- the compounds of this invention most conveniently are administered orally.
- the compounds are provided in suitable oral dosage form such as tablets, filled capsules, and the like.
- suitable oral dosage form such as tablets, filled capsules, and the like.
- the compounds are stable and are quite compatible with the commonly used excipients employed in the preparation of tablets and capsules.
- a suitable compressed tablet consists of 0.5 g. of one of the compounds within the above formula (e.g., 4-chloro-l,2-pyrazole), 0.125 g. of starch as a filler, and 0:001 g. of magnesium stearate as a binder and lubricant.
- a suitable filled gelatin capsule is prepared by mixing the compound to be employed with the required amount of lactose or starch as a filler to provide a free-flowing powder having the bulk required to fill completely an empty capsule of the selected size.
- the anticonvulsant compounds within the above formula can also be administered parenterally in the form of aqueous suspensions or aqueous propylene glycol solutions.
- parenteral administration is in general a less desirable method of administration because of the inconvenience attending a hypodermic injection.
- the l-acyl derivatives e.g., l-acetyl derivatives
- acyl derivatives are equally effective therapeutically since they are readily hydrolyzed in the alimentary canal to yield the u-nacylated base.
- the anticonvuls'ant compounds set forth in the above formula are administered in amounts of about 50 mg. to about 2 g. daily.
- the optimal dose varies with each patient, and accordingly must be determined for each patient by trial and error.
- the smaller daily dose amounts within the above range can be given in a single dose, but preferably the larger amounts are given in several divided doses, most conveniently at meal times.
- the process of this invention is applicable not only as a sole means of controlling epileptic seizures, but is also applicable in conjunction with the administration of other medicaments employed as anticonvulsants. As is well known, it is a common practice in the treatment of patients subject to epileptic seizures to administer a plurality of medicaments, each directed to the control of the seizures.
- the water layer containing the sodium salt of nonan-3- on-l-al was separated and was added to a water solution containing 1 mole of hydrazine hydrate and 1 mole of acetic acid.
- Sufiicient ethyl alcohol was added to make the solution homogeneous, and the mixture was allowed to stand for a'few hours, thus forming 3-n-hexyl-1,2-pyrazole.
- the solution was then concentrated to about onethird its volume and was saturated with sodium carbonate.
- the resulting solution was extracted with ether several times, the ether extracts were combined, and were dried over magnesium sulfate. The magnesium sulfate was then separated by filtration, and the ether was evaporated from the filtrate.
- 3-benzyl-1 ,Z-pyrazole 3-benzyl-1,2-pyrazole was prepared according to the preceding example except that phenyl acetone was used in place of n-hexyl methyl ketone.
- 3-benzy1-1,2-pyrazole prepared in this way boiled at about l65-l70 C. at a pressure of 7 mm. of Hg.
- the hydrochloride of 3-benzyl- 1,2-pyrazole was prepared by treatingan alcoholic solution of the base with an equivalent of hydrogen chloride gas and filtering off the precipitated salt, a sample of which melted at about 125-l26 C. after recrystallization.
- 3-isobatenyl-1,Z-pyrazole 3-isobutenyl-1,2-pyrazole was prepared by the method described above except that mesityl oxide was used in place of n-hexyl methyl ketone, and sodium hydride was used in place of sodium sand. 3-isobutenyl-1,2-pyrazole thus prepared boiled at about 125-130 C. at a pressure of 7 mm. of Hg.
- 3-cycl0propyl-1,2-pyraz0le 3-cyclopropyl-1,2-pyrazole was prepared by the method described above except that cyclopropyl methyl ketone was used in place of n-hexyl methyl ketone.
- 3-cyclopropyl-l,2-pyrazole prepared in this way boiled at about 1l2-l 14 C. at a pressure of 8 mm. of Hg.
- 3-(l-cyclohexenyl)-1,2-pyraz0le 3-( l-cyclohexenyl)-1,2-pyrazole was prepared by the method described above except that l-cyclohexenyl methyl ketone was used in place of n-hexyl methyl ketone and sodium hydride was used in place of sodium sand.
- 3-'(l-cyclohexenyl)-1,2-pyrazole synthesized in this way was isolated as such,and then was converted to the corresponding'ihydrochloride by treatment of an ethanol solution of t-he pyrazole with-hydrogen chloride in ethanol.
- 3-(3-batenyl)-l,2-pyrazole 3-(3-butenyl)-1,2-pyrazole was prepared by themethod described above except that S-butenyl methyl ketone was used in place of n-hexyl methyl ketone and sodium hydride was used in place of sodium sand.
- 3-(3-butenyl)- 1,2-pyrazole prepared in this way boiled at about 125- 130 C. at a pressure of 8 mm. of Hg.
- the ether extract was dried, was filtered to remove the drying agent, and the ether was then removed by evaporation in vacuo.
- the residue which comprised 4-bromo-1,2-pyrazole, was crystallized from methyl cyclohexane to yield crystals melting at about 94-96 C.
- 4-chl0ro-3-methyl-1,Z-pyrazole hydrochloride 4-chloro-3-methyl-1,2-pyrazole was prepared by the method of the preceding example except that 3-methyl-1,2- pyrazole was used in place of 1,2-pyrazole and chlorine gas was bubbled into the solution in place of adding bromine dropwise. 4-chloro-3-methyl-1,2-pyrazole thus prepared was isolated and purified as the corresponding hydrochloride. 4-chloro-3-methyl-1,2-pyrazole hydrochloride melted at about 178 C. with decomposition.
- a process for controlling epileptic seizures which comprises administering to a human being subject to epileptic seizures a daily dosage of about 50 mg. to about 2 g. of 4-chloro-1,2-pyrazole.
- a solid pharmaceutical dosage form for oral-ad- 5 ministration containing from 50 to 500 mg. of 4-ch1oro- FOREIGN PATENTS 1,2-pyrazo1e and a pharmaceutical excipient. 641,015 Great Britain Aug. 2, 1950 References Cited in the file of this patent 170882 Austna 1952 UNITED STATES PATENTS 5 OTHER REFERENCES 1,879,210 Hahl Sept. 27, 1932 Beilstein, vol. 23, p. 43, 1936. 2,623,048 Long Dec. 23, 1952 Millichap: Neurology, vol. 6, 1956, pp. 484-490. 2,636,039 Druey Apr, 21, 1953 Daly: St-afi Meetings of the Mayo Clinic, pp.
Description
United States Patent 2,992,163 USE OF 4-CHLOR0-1,2-PYRAZOLE FOR CON- TROLLING EPILEPTIC SEIZURES Nelson R. Easton, Indianapolis, Ind., assignor to Eli Lilly and Company, Indianapolis, Ind., a corporation of Indiana No Dr awing. Filed Nov. 7, 1955, Ser. No. 545,573 2 Claims. (Cl. 167-65) This invention relates to a method of controlling epileptic seizures in man. More particularly, it relates to a method of treating epilepsy by the administration of certain compounds having anticonvulsant activity.
I have discovered that a control of convulsive seizures in humans afliicted with epilepsy can be secured by the administration of a compound represented by the following formula:
. Him-i1 in which R represents hydrogen, an aliphatic hydrocarbon radical having from 1 to carbon atoms, a phenyl substituted lower alkyl radical, a cycloaliphatic radical having from 3 to 6 carbon atoms, or a phenyl radical, and R is hydrogen, chlorine, bromine or an alkyl group having from 1 to 3 carbon atoms.
Illustrative examples of anticonvulsant compounds included within the above formula are 1,2-pyrazole, 4- chloro-l,2-pyrazole, 3-methyl-4-bromo-1,2-pyrazole, 3- phenyl-l,2-pyrazole, 4-propyl-3-cyclopentyl-1,2-pyrazole, 3-n-propyl-4-ethyl-1,2-pyrazole, 3-methyl-1,2-pyrazole, 3- n-propyl-LZ-pyrazole, 3-nonyl-l,2-pyrazole, and 3-cyclohexyl-1,2-pyrazole.
Some of the compounds within the scope of the above formula have already been described in the chemical literature, and suitable methods for their preparation are known. Those compounds within the above formula whose preparations and properties have not as yet been described 'are readily prepared by customary procedures, such as those described on page 773 etc., of Organic Chemistry, vol 4, H. Gilman (John Wiley and Sons, Inc., 1953).
For the control of epileptic seizures, the compounds of this invention most conveniently are administered orally. For such administration the compounds are provided in suitable oral dosage form such as tablets, filled capsules, and the like. The compounds are stable and are quite compatible with the commonly used excipients employed in the preparation of tablets and capsules.
Illustratively, a suitable compressed tablet consists of 0.5 g. of one of the compounds within the above formula (e.g., 4-chloro-l,2-pyrazole), 0.125 g. of starch as a filler, and 0:001 g. of magnesium stearate as a binder and lubricant. A suitable filled gelatin capsule is prepared by mixing the compound to be employed with the required amount of lactose or starch as a filler to provide a free-flowing powder having the bulk required to fill completely an empty capsule of the selected size.
The anticonvulsant compounds within the above formula can also be administered parenterally in the form of aqueous suspensions or aqueous propylene glycol solutions. However, parenteral administration is in general a less desirable method of administration because of the inconvenience attending a hypodermic injection.
As will readily be understood, simple derivatives of the compounds set forth in the above formula can be employed for the purpose of this invention, and are fully effective equivalents for such purpose. For example, the acid addition salts of the compounds can be employed,
their increased solubility being an advantage in the provision of aqueous solution of the medicaments for parenteral administration. In place of the free bases of the above formula, the l-acyl derivatives (e.g., l-acetyl derivatives) can be employed for oral administration. Such acyl derivatives are equally effective therapeutically since they are readily hydrolyzed in the alimentary canal to yield the u-nacylated base.
For the therapeutic treatment of adults in accordance with this invention, the anticonvuls'ant compounds set forth in the above formula are administered in amounts of about 50 mg. to about 2 g. daily. The optimal dose varies with each patient, and accordingly must be determined for each patient by trial and error. The smaller daily dose amounts within the above range can be given in a single dose, but preferably the larger amounts are given in several divided doses, most conveniently at meal times. i
The process of this invention is applicable not only as a sole means of controlling epileptic seizures, but is also applicable in conjunction with the administration of other medicaments employed as anticonvulsants. As is well known, it is a common practice in the treatment of patients subject to epileptic seizures to administer a plurality of medicaments, each directed to the control of the seizures.
The following case reports illustrate the process of this invention as applied to epileptic patients. In each of the following cases, a plurality of convulsion-controlling medicaments was employed.
Case 1.Patient B. K., a woman 28 years of age, had been under treatment for a focal convulsive disorder occurring only as she was going into or coming out of sleep. Since the major problem of the patient was a fear of sleeping because of convulsive seizures, it was customary to provide phenobarbital and diphenyl hydancoin in suificient amounts to produce a heavy sedation. 4-chloro-l,2-pyrazole was administered in tablet form in increasing daily amounts until the total daily dosage given per day reached 500 mg. This amount, given in four divided doses, relieved her seizures to such an extent that the patient no longer feared going to sleep.
Case 2.-Patient C. G., a forty-four year old woman, had been subject to grand mal epileptic seizures-for forty-two years. A total daily dosage of a combination of 300 mg. diphenyl hydantoin, 400 mg. of phenobarbital, and 600 mg. of trimethadione had failed to control her seizures. The addition to the above medication of 250 mg. daily of 4-chloro-l,2-pyrazole markedly reduced the number and severity of her seizures. Whereas she had averaged '8 to 9 hard convulsive seizures during a twoweek period, the addition to her medication of the above amount of 4-chloro-l,2-pyrazole reduced the attacks during an equivalent period to only two light seizures.
Case 3.Patient M. G., a woman in her middle thirties, had multiple areas of brain damage. She was subject to a wide variety of focal seizures and a great number of seizures of the grand mal type. The number of seizures was so great that the patient was afraid to attempt to walk for fear of injuring herself. In addition to diphenyl hydantoin and 5-ethyl-5-phenylhexahydropyrimidine-4,6- dione, which had been employed in an attempt to control her seizures, she was given 4-chloro-1,2-pyrazole at increasing dose levels until the total daily dose consisted of 1 g. At this dose level she experienced only light seizures which were greatly reduced in frequency. She also showed less mental confusion after seizures. The patient experienced a considerable drowsiness on the combined therapy, but the drowsiness was relieved without any efiect as regards increase in the number or severity of convulsive seizures by the discontinuance of medication with 5-ethyl-5-phenylhexahydropyrimidine-4,6-dione a 3 The following experimental procedures disclose methods of preparing illustrative novel compounds useful for controlling convulsive seizures in accordance with this invention.
Preparation of 3-n-hexyl-1,2-pyrazole 1 mole of sodium sand was covered with 750 ml. of diethyl ether. 6 cc. of anhydrous ethanol were added, thus forming sodium ethoxide. A mixture containing 1 mole of n-hexyl methyl ketone and 1.1 moles of ethylformate was added thereto, whereupon a gelatinous precipitate comprising the sodium salt of nonan-3-on-1-al was formed. Ether was added until the viscosity of the mixture was decreased and efficient stirring again became possible. When the reaction was complete, as was signified by the disappearance of the sodium, water was added. The water layer containing the sodium salt of nonan-3- on-l-al was separated and was added to a water solution containing 1 mole of hydrazine hydrate and 1 mole of acetic acid. Sufiicient ethyl alcohol was added to make the solution homogeneous, and the mixture was allowed to stand for a'few hours, thus forming 3-n-hexyl-1,2-pyrazole. The solution was then concentrated to about onethird its volume and was saturated with sodium carbonate. The resulting solution was extracted with ether several times, the ether extracts were combined, and were dried over magnesium sulfate. The magnesium sulfate was then separated by filtration, and the ether was evaporated from the filtrate. The resulting residue, comprising 3-nhexyl-l,2-pyrazole, was purified by distillation at reduced pressure. 3-n-hexyl-1,2-pyrazole boiled at about 143- 145 C. at a pressure of mm. Hg.
Preparation of 3-benzyl-1 ,Z-pyrazole 3-benzyl-1,2-pyrazole was prepared according to the preceding example except that phenyl acetone was used in place of n-hexyl methyl ketone. 3-benzy1-1,2-pyrazole prepared in this way boiled at about l65-l70 C. at a pressure of 7 mm. of Hg. The hydrochloride of 3-benzyl- 1,2-pyrazole was prepared by treatingan alcoholic solution of the base with an equivalent of hydrogen chloride gas and filtering off the precipitated salt, a sample of which melted at about 125-l26 C. after recrystallization.
Preparation of 3-isobatenyl-1,Z-pyrazole 3-isobutenyl-1,2-pyrazole was prepared by the method described above except that mesityl oxide was used in place of n-hexyl methyl ketone, and sodium hydride was used in place of sodium sand. 3-isobutenyl-1,2-pyrazole thus prepared boiled at about 125-130 C. at a pressure of 7 mm. of Hg.
Preparation of 3-cycl0propyl-1,2-pyraz0le 3-cyclopropyl-1,2-pyrazole was prepared by the method described above except that cyclopropyl methyl ketone was used in place of n-hexyl methyl ketone. 3-cyclopropyl-l,2-pyrazole prepared in this way boiled at about 1l2-l 14 C. at a pressure of 8 mm. of Hg.
Preparation of 3-13-phenylethyl-J ,Z-pyrazole 3-B-phenylethyl-1,2-pyrazole was prepared by the method described above except that methyl fl-phenylethyl ketone was used in place of n-hexyl methyl ketone. 3-5- phenylethyl-1,2-pyrazole prepared in this way boiled at about 184-186 C. at a pressure of 7 mm. of Hg.
Preparation of 3-(l-cyclohexenyl)-1,2-pyraz0le 3-( l-cyclohexenyl)-1,2-pyrazole was prepared by the method described above except that l-cyclohexenyl methyl ketone was used in place of n-hexyl methyl ketone and sodium hydride was used in place of sodium sand. 3-'(l-cyclohexenyl)-1,2-pyrazole synthesized in this way was isolated as such,and then was converted to the corresponding'ihydrochloride by treatment of an ethanol solution of t-he pyrazole with-hydrogen chloride in ethanol.
4 3-( l-cyclohexenyl)-1,2-pyrazole hydrochloride thus prepared was isolated by evaporation of the supernatant ethanol and the residue was crystallized from a mixture of isopropanol and ethyl acetate. Crystalline 3-( l-cyclo hexenyl)-1,2-pyrazole hydrochloride melted at about l78-l80 C.
Preparation of 3-(3-batenyl)-l,2-pyrazole 3-(3-butenyl)-1,2-pyrazole was prepared by themethod described above except that S-butenyl methyl ketone was used in place of n-hexyl methyl ketone and sodium hydride was used in place of sodium sand. 3-(3-butenyl)- 1,2-pyrazole prepared in this way boiled at about 125- 130 C. at a pressure of 8 mm. of Hg.
Preparation of 3-n-butylpyrazole 9.7 g. of 3-(3-butenyl)-1,2-pyrazole were dissolved in ml. of methanol. About 0.5 g. of Adams platinum oxide catalyst was added to this solution and the resulting residue was placed in a hydrogenation apparatus and shaken under about 50 lbs. pressure of hydrogen. After the theoretical quantity of hydrogen had been absorbed, the solution was removed from the hydrogenation ap paratus and was freed from the platinum catalyst by filtration. The filtrate containing 3-n-butyl-l,2-pyrazole was evaporated under reduced pressure and the 3-n-butyl- 1,2-pyrazole which remained as a residue was distilled. It boiled at about -122 C. at a pressure of about 7 mm. of Hg. The distillate was dissolved in ether and alcoholic hydrogen chloride added. A small precipitate resulted which was removed by filtration and discarded. The filtrate was concentrated and the resulting residue containing 3-n-butyl-l,2-pyrazole hydrochloride was dissolved in water. The water solution was neutralized by the addition of aqueous sodium hydroxide solution, causing the free base of 3-n-butyl-1,2-pyrazole to separate. The free base was extracted into ether, and the ether extract was dried with anhydrous magnesuim sulfate. The mixture was filtered to remove the drying agent, and the ether solution containing 3-n-butyl-1,2-pyrazole was distilled. 3-n-butyl-1,2-pyrazole boiled at about 236- 238 C. at atmospheric pressure.
Preparation of 4-br0m0-1 ,Z-pyrazole 0.1 mole of pyrazole was dissolved in 250 ml. of glacial acetic acid and 0.1 mole of bromine was added dropwise to this solution, thus forming 4-bromo-1,2-pyrazole hydrobromide. After the addition had been completed, the acetic acid solvent was removed in vacuo, and 50 ml. of a saturated sodium bicarbonate solution was added to the resulting residue to convert 4-'bromo-1,2-pyrazole hydrobromide to 4-bromo-1,2-pyrazole. This compound was insoluble in the bicarbonate solution and was extracted into ether. The ether extract was dried, was filtered to remove the drying agent, and the ether was then removed by evaporation in vacuo. The residue which comprised 4-bromo-1,2-pyrazole, was crystallized from methyl cyclohexane to yield crystals melting at about 94-96 C.
Preparation of 4-chl0ro-3-methyl-1,Z-pyrazole hydrochloride 4-chloro-3-methyl-1,2-pyrazole was prepared by the method of the preceding example except that 3-methyl-1,2- pyrazole was used in place of 1,2-pyrazole and chlorine gas was bubbled into the solution in place of adding bromine dropwise. 4-chloro-3-methyl-1,2-pyrazole thus prepared was isolated and purified as the corresponding hydrochloride. 4-chloro-3-methyl-1,2-pyrazole hydrochloride melted at about 178 C. with decomposition.
I claim:
1. A process for controlling epileptic seizures which comprises administering to a human being subject to epileptic seizures a daily dosage of about 50 mg. to about 2 g. of 4-chloro-1,2-pyrazole.
2. A solid pharmaceutical dosage form for oral-ad- 5 ministration containing from 50 to 500 mg. of 4-ch1oro- FOREIGN PATENTS 1,2-pyrazo1e and a pharmaceutical excipient. 641,015 Great Britain Aug. 2, 1950 References Cited in the file of this patent 170882 Austna 1952 UNITED STATES PATENTS 5 OTHER REFERENCES 1,879,210 Hahl Sept. 27, 1932 Beilstein, vol. 23, p. 43, 1936. 2,623,048 Long Dec. 23, 1952 Millichap: Neurology, vol. 6, 1956, pp. 484-490. 2,636,039 Druey Apr, 21, 1953 Daly: St-afi Meetings of the Mayo Clinic, pp. 257-258, 2,655,507 Jones Oct. 13, 1953 10 y 1957- 2,655,508 Jones Oct. 13, 1953 UNITED STATES PATENT OFFICE CERTIFICATE 0F CORRECTION Patent No, 2 992 l63 July ll, 1961 Nelson R Easton It is hereby certified that error appears in the above numbered pat- "eouiring correction and that the said Letters Patent. should read as JLau "corrected below.
Column 1 lines 18 to 22 the formula should appear as shown below instead of as in the patent:
Signed and sealed this 21st day of November 1961.,
(SEAL) Attest:
ERNEST W. SWIDER DAVID L. LADD Commissioner of Patents.
Attesting Officer USCOM M-DC
Claims (1)
1. A PROCESS FOR CONTROLLING EPILEPTIC SEIZURES WHICH COMPRISES ADMINISTERING TO A HUMAN BEING SUBJECT TO EPILEPTIC SEIZURES A DAILY DOSAGE OF ABOUT 50 MG. TO ABOUT 2 G. OF 4-CHLORO-1,2-PYRAZOLE.
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3121095A (en) * | 1960-07-23 | 1964-02-11 | Thomae Gmbh Dr K | alpha-enolacylates of beta-acyl-gamma-phenyl-alpha-tetronic acids |
US3161565A (en) * | 1960-07-29 | 1964-12-15 | Aec Chim Organ Biolog | Lysine orotate |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1879210A (en) * | 1932-09-27 | Pyrazole derivatives | ||
GB641015A (en) * | 1946-12-21 | 1950-08-02 | Gen Aniline & Film Corp | Production of pyrazoles |
AT170882B (en) * | 1950-02-13 | 1952-04-10 | Ciba Geigy | Process for the preparation of new 3-amino-5-halopyrazoles |
US2623048A (en) * | 1948-04-05 | 1952-12-23 | Parke Davis & Co | 4-thiazolidone derivatives and process for preparing the same |
US2636039A (en) * | 1953-04-21 | X-distjbstituted j-amino-s-halogen- | ||
US2655508A (en) * | 1950-11-10 | 1953-10-13 | Lilly Co Eli | Pyrazole compound |
US2655507A (en) * | 1950-11-10 | 1953-10-13 | Lilly Co Eli | Pyrazole compounds |
-
1955
- 1955-11-07 US US545573A patent/US2992163A/en not_active Expired - Lifetime
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1879210A (en) * | 1932-09-27 | Pyrazole derivatives | ||
US2636039A (en) * | 1953-04-21 | X-distjbstituted j-amino-s-halogen- | ||
GB641015A (en) * | 1946-12-21 | 1950-08-02 | Gen Aniline & Film Corp | Production of pyrazoles |
US2623048A (en) * | 1948-04-05 | 1952-12-23 | Parke Davis & Co | 4-thiazolidone derivatives and process for preparing the same |
AT170882B (en) * | 1950-02-13 | 1952-04-10 | Ciba Geigy | Process for the preparation of new 3-amino-5-halopyrazoles |
US2655508A (en) * | 1950-11-10 | 1953-10-13 | Lilly Co Eli | Pyrazole compound |
US2655507A (en) * | 1950-11-10 | 1953-10-13 | Lilly Co Eli | Pyrazole compounds |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3121095A (en) * | 1960-07-23 | 1964-02-11 | Thomae Gmbh Dr K | alpha-enolacylates of beta-acyl-gamma-phenyl-alpha-tetronic acids |
US3161565A (en) * | 1960-07-29 | 1964-12-15 | Aec Chim Organ Biolog | Lysine orotate |
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