US2762805A - 3-ethyl-3-phenyl-2, 6-piperazinedione and derivatives thereof - Google Patents
3-ethyl-3-phenyl-2, 6-piperazinedione and derivatives thereof Download PDFInfo
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- US2762805A US2762805A US461280A US46128054A US2762805A US 2762805 A US2762805 A US 2762805A US 461280 A US461280 A US 461280A US 46128054 A US46128054 A US 46128054A US 2762805 A US2762805 A US 2762805A
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- piperazinedione
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
Definitions
- This invention relates to a series of 'new organic com- More particularly this invention relates to 3- 'tives thereof, and methods for their manufacture.
- the compounds of the present invention may be represented by the following general formula:
- R1 is :a member selected from the group consisting of hydrogen, lower alkyl, carboalkyloxy,
- R2 is a member selected from the group consisting of lower alkyloxy, carboaralkyloxy and acyl radicals, and R2 is a member selected from the group consisting of lower alkyl and lower alkyl radicals.
- lower alkyl and lower carboalkyloxy are used herein to include all alkyl and carboalkyloxy radicals containing from 1 to 6 carbon atoms such as for example'methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, carbomethoxy, carboethoxy, carbopropoxy, carbobutoxy, carbopentoxy and carbohexoxy.
- a suitable carboaralkyloxy substituent substitutable in the R1 position is the carbobenzyloxy.
- suitable acyl radical substitutable in the R1 position may be given acetyl, propionyl, butyryl and the like.
- the compounds of this invention are useful in the pharmacuetical field. We have found that they are particularly advantageous as anticonvulsants, being efi'ective in varying degrees against seizures of both the grand mal and petit .mal types.
- the compounds of our invention can be prepared from previously known organic compounds by a novel series of chemical transformations which we have discovered. In these syntheses there are involved a number of new intermediate organic compounds and it is intended that these be included within the scope of our invention.
- glycine ethyl ester is ice condensed with propiophenone and hydrogen cyanide in ethanol to form alpha carbethoxymethylamino alphaphenylbutyronitrile in accordance with the following equation:
- This product may then behydrolyzed with a mineral acid, for example, hydrochloric acid, to the correspondin carboxyamide:
- the carboxyl group of the resulting alpha-(carboxyrnethylamino) alpha-'phenylbutyronitrile hydrochloride may then be esterified by treatment with a lower alkyl alcohol, such as methyl alcohol, to form the corresponding alpha (carbomethoxymethylamino) alpha- (phenylbutyramide) hydrochloride. Condensation of this product in the presence of sodium methoxide gives the desired 3-ethyl-3-phenyl-2,6-piperazinedione.
- Cyclization of alpha '(carbome'thoxymethylaminwalpha-phenylbutyramide hydrochloride may be suitably eifected in the presence of alkali metal alcoholates for example, sodium methoxide, sodium ethoxide, sodium isopropoxide; alkali metal amides, for instance, sodamide or the alkali metals, for instance, metallic sodium or lithium.
- alkali metal alcoholates for example, sodium methoxide, sodium ethoxide, sodium isopropoxide
- alkali metal amides for instance, sodamide or the alkali metals, for instance, metallic sodium or lithium.
- the 3 ethyl 3 phenyl 2,6 piperazinedione formed as a result of the cyclization is in itself an effec tive anticonvulsant agent.
- Other groups may be conveniently substituted into either the N or N or to both the N and N positions to obtain a variety of equally efficacious anticonvulsants.
- one may conveniently prepare the N carboalkoxy substituted piperazinediones in accordance with conventional procedures.
- the piperazinedione is dissolved in a suitable inert organic solvent such as acetone, benzene, chloroform, or dimethylformamide and the corresponding acid chloride is added thereto to obtain substitution of the desired radical.
- the introduction of an alkyl group into the N position may be suitably effected by processes known in the art for the N-alkylation of amines.
- processes known in the art for the N-alkylation of amines For example, to introduce the methyl group into the 4 position one maydissolve 3 ethyl 3 phenyl 2, 6- piperazinedione in acetic acid, treat the resulting solution with formaldehyde, and then with ethanol and platinum oxide catalyst in an atmosphere of hydrogen.
- r 1 3 troduction of other alkyl groups may be advantageously effected by corresponding treatment.
- various methods known to those skilled in the art may be employed for introducing various substituents into the N and N positions.
- Example 1 200 grams of glycine ethyl ester hydrochloride was suspended in 80 ml. of hot anhydrous ethanol,-and 81 grams of 95% sodium methoxide in ethanol was added. The mixture was stirred and filtered, and the filtrate was added to a solution of l92grams of propiophenone in 350 ml. of liquid hydrogen cyanide at C. This mixture was stirred at room temperature for 4 days.
- reaction mixture was concentrated under reduced pressure to a solid residue which was triturated with ether and filtered.
- the filtrate was saturated with dry hydrogen chloride at room temperature, and the oil which separated solidified on standing.
- the solid was filtered and dried to yield alpha-(carbethoxymethylamino)alpha-phenyl- .butyronitrile hydrochloride, melting at 114 C. to 116 .C. (decomp.).
- This crude product was evaporatively sublimed under reduced pressure giving a purified product melting at 121 C. to 123 C.
- Example 11 30 grams of alpha-(carboxymethylamino)-alpha-phenylbutyramide hydrochloride, the product of Example II, was dissolved in 1500 ml. of dry 3% hydrogen chloride in methanol. The mixture was stored at room temperature for 1 day and then concentrated under reduced pres sure to a dry solid to yield alpha-(carbomethoxymethylamino)-alpha-phenylbutyramide hydrochloride melting at 218 C. to 221 C. (decomp.).
- Example IV A'solution of 10.8 grams of sodium methoxide in 100 ml. of methanol was added to a solution of 27 grams (0.095 mole) of alpha-carbomethoxymethylamino-alphaphenylbutyramide hydrochloride in 900 ml. of dry methanol. The solution was kept at room temperature for '45 minutes and then concentrated under reduced pressure to a dry solid. 95 ml. of cold 1 N aqueous hydrochloric acid was added to the residue, and the oil which separated was extracted with chloroform.
- the chloroform extract was dried with anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to a dry solid to yield 3-ethyl-3-phenyl- 2,6-piperazinedione, melting at 114 C. to 115 C.
- a sample recrystallized from isopropyl alcohol melted at 114C. to 115 C.
- Example V grams of 3-ethyl3-phenyl-2,6-piperazinedione, the product of Example IV, was dissolved in ml. of acetone, and 100 ml. of 90% carbobenzyloxy chloride was added. The mixture was kept at room temperature, and "the solid which-separated was filtered and dried. The
- Example VI 10 grams of 3-ethyl-3phenyl-2,6-piperazinedione was dissolved in 20 ml. of acetic acid, and 7.6 grams of 37% formaldehyde and 10 ml. of ethanol were added. Onehalf gram of platinum oxide catalyst was suspended in the mixture while 1 liter of hydrogen was added. The mixture was then filtered, and the filtrate was concentrated under reduced pressure to an oily residue. The oil was taken up in isopropyl alcohol and 5.3 N ethanolic hydrogen chloride was added to pH 1, causing a solid to separate. The solid was filtered and 'dried in air to yield 3-ethyl-4-methyl-3-phenyl-2,6-piperazinedione hydrochloride melting at 201 C. to 204 C. (decomp).
- Example VII 3 grams of 3-ethyl-3-phenyl-2,6-piperazinedione was dissolved in 15 ml. of beta-ethoxyethanol, and 0.87 gram of sodium methoxide was added. The mixture was warmed to C. and a solution of 2.6 grams of methyl iodide in 10 ml. of beta-ethoxyethanol was added dropwise with stirring. After the addition was complete, the reaction mixture was kept at 60 C. for an additional 10 minutes. The mixture was then poured into ice-water, causing a solid to precipitate. The crude product was filtered and dried to yield 3-ethyl-1-methyl-3-phenyl-2,6- piperazinedione melting at 104 C. to 106 C. A sample recrystallized from isopropyl alcohol, melted at 106 C. to 109 C.
- Example- VIII 3 grams of 3-ethyl-3-phenyl 2,6-piperazinedione was dissolved in 20 ml. of dry acetone, and 1.2 grams of phenoxyacetylchloride was added. The mixture was refluxed for 3 minutes and then cooled. The precipitate, 1.6 grams of 3-ethyl-3-phenyl-2,6-piperazinedione hydrochloride, was filtered. The filtrate was concentrated under reduced .pressure to an oily residue which was crystallized from isopropyl alcohol to yield 3-ethyl-4-phenoxyacetyl-3- phenyl-2,6-piperazinedione melting at 117 C. to 119 C.
- R1 is a member selected from the group consisting of hydrogen, lower alkyl, carbobenzyloxy and phenoxyacetyl radicals
- R2 is a member selected from the group consisting of hydrogen and lower alkyl radicals; the acid addition, and alkali metal salts thereof.
Description
pounds. ethyl 3 phenyl-2,6- piperazinedione, N and N deriva- 3 ETHYL-3-PHENYL-2,G-PIPERAZINEDIONE AND DERIVATIVES THEREOF Sidney R. Safir, River Edge,.N. J., and Joseph J. Hlavka, Cambridge, Mass., assiguors to American Cyanamid "Company, New York, N. Y., a corporation of Maine No Drawing. Application October 8,1954, Serial No. 461,280
12 Claims. (Cl. 260-208) This invention relates to a series of 'new organic com- More particularly this invention relates to 3- 'tives thereof, and methods for their manufacture.
The compounds of the present invention may be represented by the following general formula:
CH -O wherein R1 is :a member selected from the group consisting of hydrogen, lower alkyl, carboalkyloxy,
c'arboaralkyloxy and acyl radicals, and R2 is a member selected from the group consisting of lower alkyloxy, carboaralkyloxy and acyl radicals, and R2 is a member selected from the group consisting of lower alkyl and lower alkyl radicals. The terms lower alkyl and lower carboalkyloxy are used herein to include all alkyl and carboalkyloxy radicals containing from 1 to 6 carbon atoms such as for example'methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, carbomethoxy, carboethoxy, carbopropoxy, carbobutoxy, carbopentoxy and carbohexoxy. A suitable carboaralkyloxy substituent substitutable in the R1 position is the carbobenzyloxy. As examples of suitable acyl radical substitutable in the R1 position may be given acetyl, propionyl, butyryl and the like. Inasmuch as the parent compound 3-ethyl-3-phenyl-2,6-piperazinedione and the N alkyl substituted derivatives thereof 'form addition salts with mineral acids, and the N unsubstituted derivatives form metallic salts with alkali metal bases, it is intended that these salts also be included within the scope of the present invention.
The compounds of this invention are useful in the pharmacuetical field. We have found that they are particularly advantageous as anticonvulsants, being efi'ective in varying degrees against seizures of both the grand mal and petit .mal types.
The compounds of our invention can be prepared from previously known organic compounds by a novel series of chemical transformations which we have discovered. In these syntheses there are involved a number of new intermediate organic compounds and it is intended that these be included within the scope of our invention.
In accordance with our process, glycine ethyl ester is ice condensed with propiophenone and hydrogen cyanide in ethanol to form alpha carbethoxymethylamino alphaphenylbutyronitrile in accordance with the following equation:
This product may then behydrolyzed with a mineral acid, for example, hydrochloric acid, to the correspondin carboxyamide:
The carboxyl group of the resulting alpha-(carboxyrnethylamino) alpha-'phenylbutyronitrile hydrochloride may then be esterified by treatment with a lower alkyl alcohol, such as methyl alcohol, to form the corresponding alpha (carbomethoxymethylamino) alpha- (phenylbutyramide) hydrochloride. Condensation of this product in the presence of sodium methoxide gives the desired 3-ethyl-3-phenyl-2,6-piperazinedione.
Cyclization of alpha '(carbome'thoxymethylaminwalpha-phenylbutyramide hydrochloride may be suitably eifected in the presence of alkali metal alcoholates for example, sodium methoxide, sodium ethoxide, sodium isopropoxide; alkali metal amides, for instance, sodamide or the alkali metals, for instance, metallic sodium or lithium. We prefer to use sodium methoxide for this purpose. 7
The 3 ethyl 3 phenyl 2,6 piperazinedione formed as a result of the cyclization is in itself an effec tive anticonvulsant agent. Other groups, however, may be conveniently substituted into either the N or N or to both the N and N positions to obtain a variety of equally efficacious anticonvulsants. For example, one may conveniently prepare the N carboalkoxy substituted piperazinediones in accordance with conventional procedures. The piperazinedione is dissolved in a suitable inert organic solvent such as acetone, benzene, chloroform, or dimethylformamide and the corresponding acid chloride is added thereto to obtain substitution of the desired radical. Alternatively, the introduction of an alkyl group into the N position may be suitably effected by processes known in the art for the N-alkylation of amines. For example, to introduce the methyl group into the 4 position one maydissolve 3 ethyl 3 phenyl 2, 6- piperazinedione in acetic acid, treat the resulting solution with formaldehyde, and then with ethanol and platinum oxide catalyst in an atmosphere of hydrogen. In-
r 1 3 troduction of other alkyl groups may be advantageously effected by corresponding treatment. In a like manner, various methods known to those skilled in the art may be employed for introducing various substituents into the N and N positions.
The following examples will serve to describe more particularly the invention contemplated by this disclosure although it is not intended that such examples be construed as limitations upon the scope thereof. All parts are by weight unless otherwise indicated.
- Example 1 200 grams of glycine ethyl ester hydrochloride was suspended in 80 ml. of hot anhydrous ethanol,-and 81 grams of 95% sodium methoxide in ethanol was added. The mixture was stirred and filtered, and the filtrate was added to a solution of l92grams of propiophenone in 350 ml. of liquid hydrogen cyanide at C. This mixture was stirred at room temperature for 4 days.
The reaction mixture was concentrated under reduced pressure to a solid residue which was triturated with ether and filtered. The filtrate was saturated with dry hydrogen chloride at room temperature, and the oil which separated solidified on standing. The solid was filtered and dried to yield alpha-(carbethoxymethylamino)alpha-phenyl- .butyronitrile hydrochloride, melting at 114 C. to 116 .C. (decomp.). This crude product was evaporatively sublimed under reduced pressure giving a purified product melting at 121 C. to 123 C.
Example 11 30 grams of alpha-(carboxymethylamino)-alpha-phenylbutyramide hydrochloride, the product of Example II, was dissolved in 1500 ml. of dry 3% hydrogen chloride in methanol. The mixture was stored at room temperature for 1 day and then concentrated under reduced pres sure to a dry solid to yield alpha-(carbomethoxymethylamino)-alpha-phenylbutyramide hydrochloride melting at 218 C. to 221 C. (decomp.).
Example IV A'solution of 10.8 grams of sodium methoxide in 100 ml. of methanol was added to a solution of 27 grams (0.095 mole) of alpha-carbomethoxymethylamino-alphaphenylbutyramide hydrochloride in 900 ml. of dry methanol. The solution was kept at room temperature for '45 minutes and then concentrated under reduced pressure to a dry solid. 95 ml. of cold 1 N aqueous hydrochloric acid was added to the residue, and the oil which separated was extracted with chloroform. The chloroform extract was dried with anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to a dry solid to yield 3-ethyl-3-phenyl- 2,6-piperazinedione, melting at 114 C. to 115 C. A sample recrystallized from isopropyl alcohol melted at 114C. to 115 C.
Example V grams of 3-ethyl3-phenyl-2,6-piperazinedione, the product of Example IV, was dissolved in ml. of acetone, and 100 ml. of 90% carbobenzyloxy chloride was added. The mixture was kept at room temperature, and "the solid which-separated was filtered and dried. The
latter material is 7 grams of 3-ethyl-3-phenyl-2,6-piperazinedione hydrochloride. The filtrate was concentrated under reduced pressure to an oily residue which was crystallized from water-ethanol solution to yield 4-carbobenzyloxy-3-ethyl- 3 -phenyl-2,6-piperazinedione, melting at86" C. to 89 C.
Example VI 10 grams of 3-ethyl-3phenyl-2,6-piperazinedione was dissolved in 20 ml. of acetic acid, and 7.6 grams of 37% formaldehyde and 10 ml. of ethanol were added. Onehalf gram of platinum oxide catalyst was suspended in the mixture while 1 liter of hydrogen was added. The mixture was then filtered, and the filtrate was concentrated under reduced pressure to an oily residue. The oil was taken up in isopropyl alcohol and 5.3 N ethanolic hydrogen chloride was added to pH 1, causing a solid to separate. The solid was filtered and 'dried in air to yield 3-ethyl-4-methyl-3-phenyl-2,6-piperazinedione hydrochloride melting at 201 C. to 204 C. (decomp).
Example VII 3 grams of 3-ethyl-3-phenyl-2,6-piperazinedione was dissolved in 15 ml. of beta-ethoxyethanol, and 0.87 gram of sodium methoxide was added. The mixture was warmed to C. and a solution of 2.6 grams of methyl iodide in 10 ml. of beta-ethoxyethanol was added dropwise with stirring. After the addition was complete, the reaction mixture was kept at 60 C. for an additional 10 minutes. The mixture was then poured into ice-water, causing a solid to precipitate. The crude product was filtered and dried to yield 3-ethyl-1-methyl-3-phenyl-2,6- piperazinedione melting at 104 C. to 106 C. A sample recrystallized from isopropyl alcohol, melted at 106 C. to 109 C.
Example- VIII 3 grams of 3-ethyl-3-phenyl 2,6-piperazinedione was dissolved in 20 ml. of dry acetone, and 1.2 grams of phenoxyacetylchloride was added. The mixture was refluxed for 3 minutes and then cooled. The precipitate, 1.6 grams of 3-ethyl-3-phenyl-2,6-piperazinedione hydrochloride, was filtered. The filtrate was concentrated under reduced .pressure to an oily residue which was crystallized from isopropyl alcohol to yield 3-ethyl-4-phenoxyacetyl-3- phenyl-2,6-piperazinedione melting at 117 C. to 119 C.
We claim: 1. Compounds having the general formula:
0 CHz- Il -N wherein R1 is a member selected from the group consisting of hydrogen, lower alkyl, carbobenzyloxy and phenoxyacetyl radicals, and R2 is a member selected from the group consisting of hydrogen and lower alkyl radicals; the acid addition, and alkali metal salts thereof.
2. The 4-lower alkyl-3ethyl-3-phenyl-2,6piperazinediones.
3. The l-lower alkyl-3-ethyl-3-phenyl-2,6-piperazinediones.
4. The new compound 3-ethy1-3-pheny1-2,6-piperazinedione.
5. The new compound 4-carbobenzyloxy-3-ethyl-3- phenyl-2,6-piperazinedione.
6. The new compound 3-ethyl-4-methy1-3-phenyl-2,6- piperazinedione.
7. The new compound 3-ethyl-1-methyl-3-phenyl-2,6- piperazinedione.
'8. The new compound 3 ethyl 4 phenoxyacetyl-laphenyl-2,6-piperazinedione. I r
9. A method for preparing compounds having the formula:
treating said compound with a mineral acid to obtain:
OHQOOOH Hl I HsCz-{F-C ONE:
6 contacting said compound with a lower alkyl alcohol under esterifying conditions to obtain:
cyclizing said compound in the presence of an alkali metal alkoxide to obtain 3-ethy1-3-phenyl-2,6-piperazinedione and then treating said compound with a member selected from the group consisting of lower alkyl and phenoxyacetyl chlorides whereby the hydrogen atoms in the N and N positions of 3-ethyl-3-phenyl-2,6-piperazinedione are selectively replaced with a member selected from the group consisting of lower alkyl and phenoxyacetyl radicals.
10. A method as set forth in claim 9 wherein the mineral acid is hydrochloric acid.
11. A method as set forth in claim 9 wherein the lower alkyl alcohol is methyl alcohol.
12. A method as set forth in claim 9 wherein the alkali metal alkoxide is sodium methoxide.
References Cited in the file of this patent Ciamician et al., Ber. Deut. Chem. 39, 3942-59 (1906).
Jonkees et al.: Rec. Trav. Chem. 27, 287-326 (1908).
Franchimont et al.: Rec. Trav. Chem. 36, -109 (1916).
Dubski et al.: Ber. Deut. Chem. 66, 1497-98 (1933).
Stewart et al.: J. Org. Chem. 13, 134-143 (1948).
Claims (2)
1. COMPOUNDS HAVING THE GENERAL FORMULA:
9. A METHOD OF PREPARING COMPOUNDS HAVING THE FORMULA:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US461280A US2762805A (en) | 1954-10-08 | 1954-10-08 | 3-ethyl-3-phenyl-2, 6-piperazinedione and derivatives thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US461280A US2762805A (en) | 1954-10-08 | 1954-10-08 | 3-ethyl-3-phenyl-2, 6-piperazinedione and derivatives thereof |
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| Publication Number | Publication Date |
|---|---|
| US2762805A true US2762805A (en) | 1956-09-11 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US461280A Expired - Lifetime US2762805A (en) | 1954-10-08 | 1954-10-08 | 3-ethyl-3-phenyl-2, 6-piperazinedione and derivatives thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1138056B (en) * | 1958-09-10 | 1962-10-18 | Nl Combinatie Voor Chemische I | Process for the preparation of 4- [ª ‰ - (3 ', 4'-Dimethoxyphenyl) -aethyl] -2, 6-diketopiperazine |
| US3252240A (en) * | 1963-08-20 | 1966-05-24 | American Cyanamid Co | 3-substituted piperazinediones and method of preparing same |
| US3275677A (en) * | 1963-08-20 | 1966-09-27 | American Cyanamid Co | Alpha-cyanomethylaminonitrile and alpha-carboxamidomethylaminonitrile compounds |
| US3318876A (en) * | 1962-12-11 | 1967-05-09 | Lepetit Spa | Substituted piperazines and process for preparing same |
-
1954
- 1954-10-08 US US461280A patent/US2762805A/en not_active Expired - Lifetime
Non-Patent Citations (1)
| Title |
|---|
| None * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1138056B (en) * | 1958-09-10 | 1962-10-18 | Nl Combinatie Voor Chemische I | Process for the preparation of 4- [ª ‰ - (3 ', 4'-Dimethoxyphenyl) -aethyl] -2, 6-diketopiperazine |
| US3318876A (en) * | 1962-12-11 | 1967-05-09 | Lepetit Spa | Substituted piperazines and process for preparing same |
| US3252240A (en) * | 1963-08-20 | 1966-05-24 | American Cyanamid Co | 3-substituted piperazinediones and method of preparing same |
| US3275677A (en) * | 1963-08-20 | 1966-09-27 | American Cyanamid Co | Alpha-cyanomethylaminonitrile and alpha-carboxamidomethylaminonitrile compounds |
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