US2678296A - Nu-benzyl-betachloropropionamide anticonvulsant article of manufacture - Google Patents
Nu-benzyl-betachloropropionamide anticonvulsant article of manufacture Download PDFInfo
- Publication number
- US2678296A US2678296A US300348A US30034852A US2678296A US 2678296 A US2678296 A US 2678296A US 300348 A US300348 A US 300348A US 30034852 A US30034852 A US 30034852A US 2678296 A US2678296 A US 2678296A
- Authority
- US
- United States
- Prior art keywords
- benzyl
- manufacture
- article
- anticonvulsant
- betachloropropionamide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 9
- 239000001961 anticonvulsive agent Substances 0.000 title description 6
- 230000001773 anti-convulsant effect Effects 0.000 title description 4
- 229960003965 antiepileptics Drugs 0.000 title description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- JPYQFYIEOUVJDU-UHFFFAOYSA-N beclamide Chemical compound ClCCC(=O)NCC1=CC=CC=C1 JPYQFYIEOUVJDU-UHFFFAOYSA-N 0.000 description 11
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000002775 capsule Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000000203 mixture Substances 0.000 description 4
- 229940125681 anticonvulsant agent Drugs 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 206010003591 Ataxia Diseases 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- 206010010947 Coordination abnormal Diseases 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 208000002173 dizziness Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 208000016290 incoordination Diseases 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000008014 pharmaceutical binder Substances 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- 201000010000 Agranulocytosis Diseases 0.000 description 1
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
- 239000001692 EU approved anti-caking agent Substances 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000034308 Grand mal convulsion Diseases 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010024264 Lethargy Diseases 0.000 description 1
- 241000238367 Mya arenaria Species 0.000 description 1
- 206010029216 Nervousness Diseases 0.000 description 1
- VQASKUSHBVDKGU-UHFFFAOYSA-N Paramethadione Chemical compound CCC1(C)OC(=O)N(C)C1=O VQASKUSHBVDKGU-UHFFFAOYSA-N 0.000 description 1
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 206010047571 Visual impairment Diseases 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000009429 distress Effects 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 108010025899 gelatin film Proteins 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229960003274 paramethadione Drugs 0.000 description 1
- 229960002695 phenobarbital Drugs 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- 229960002036 phenytoin Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229960004453 trimethadione Drugs 0.000 description 1
- IRYJRGCIQBGHIV-UHFFFAOYSA-N trimethadione Chemical compound CN1C(=O)OC(C)(C)C1=O IRYJRGCIQBGHIV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
Definitions
- Phenobarbital leads to dizziness, lethargy and incoordination in the patient.
- Trimethadione often causes dizziness, nervousness and visual disturbances.
- Paramethadione exhibits similar effects.
- Diphenylhydantoin often results in incoordination, gastric distress and other undesirable reactions in the patient.
- Certain anti-convulsants also have other toxic effects which lead to agranulocytosis and apiastic anemia. There is a need, therefore, for new anticonvulsant agents which are less toxic and have fewer side effects upon the patient.
- N-benzylbeta-chloropropionamide is a highly effective anti-convulsant agent. It is relatively more effective against epileptic seizures of the grand mal type than other types. It has remarkably low toxicity and does note tend to produce physiological disturbances such as those mentioned above and can be administered orally in dosage units of the size, type and kind to be described herein.
- N-benzyl-beta-chloropropionamide is a White crystalline solid which has a melting point of 94 C. and the following structural formula:
- N- benzyl-beta-chloropropionamide as an eifective anti-convulsant of low toxicity. Clinical investigations have confirmed the laboratory results and the compound has been proven to be eiiective and reliable in treatment of both idiopathic and symptomatic epilepsy, note Hawkes, C. D.: N- Benzyl-beta-chloropropionamide (Hibicon), A. M, A. Archives of Neurology and Psychiatry 6'7; 815-820, June 1952.
- the drug is only very slightly soluble in water, between about 0.005% and 0.01% by weight, it is readily absorbed by the body after oral administration.
- the efiective clinical dose for adults ranges from 0.5 to 1.5 grams taken 1 to 3 times daily. In children, the dosage ranges correspondingly lower according to the age and weight of the child.
- a preferred form of administration is a quantity of the drug Within the range of about 0.2 to 1.5 grams enclosed in a gelatin capsule. Capsules are preferred over other dosage unit forms because, while the compound is only slightly soluble in water, it has an unpleasant taste which is difiicult to mask by flavoring agents or other devices which are used in tablet manufacture.
- the capsule may be of either the hard shell or soft shell type and is generally of gelatin, although any water soluble capsulating material that will disintegrate after oral administration is suitable.
- Lubricants such as magnesium stearate and anti-caking agents to keep the drug in a readily dispersible form may be incorporated in the dosage unit.
- tablets When tablets are prepared, they may be made in various sizes containing from about 0.2 to 1.5 grams or more of the drug. These are generally compounded with binding agents, lubricants and other substances which are commonly used in tablet manufacture such as magnesium stearate, stearic acid, talc, corn starch, lactose or the like. If desired, these tablets may be coated with sugar or shellac preparations in accordance with the common practices in the tablet manufacturing art.
- N-benzyl-beta-chloropropionamide 500 parts by weight of N-benzyl-beta-chloropropionamide, parts of corn starch and 35 parts of gum acacia were mixed, moistened, granulated and dried. To this granulation was then added 1.74 parts by weight of magnesium stearate and the composition was pressed into scored tablets containing one-half gram each of N-benzyl-beta-chloropropionamide. These tablets may be administered orally to the patient at intervals of 4 to 8 hours, or whenever needed, in amounts depending upon the age and weight of the patient and the nature of the attack.
- the above described tablets are covered with a soft gelatin film on a capsulating machine to obtain capsules in which the effective ingredients are protected and the unpleasant taste of uncoated tablets is avoided.
- a less preferred form of the invention is one of the above described tablets coated with sugar or other water-soluble coatings known to the art.
- An article of manufacture comprising a K quantity of from about 0.2 to 1.5 grams of N- benzyl-betach1oropropionamide and a pharmaceutical carrier in dosage unit form.
- An article of manufacture comprising a quantity ranging from :-about 052 grams to 1.5 grams of N-benzyl-beta-chloropropionamide in a pharmaceutical capsule.
- An article of manufacture comprising "a quantity ranging from about flzmtosl tggwmseof N-benzyl-beta-ch1oropropionamide in a ggelatin capsule.
- composition of matter comprising a quantity of from about 0.2 to l'fi grams ofiN-benzylbeta-chloropropionamide andan effectivetamount of a non-toxic pharmaceutical binding agent pressed together in a dosage unit form.
- composition or matter comprising a quantity of from about 0.2 to 1.5 grams of N-benzylbeta-chloropropionamide and an eifective amount of a non-toxic pharmaceutica1 binding agent 5 :presse'd together in a. tablet.
- composition of matter comprising a quantity of from about 0.2 to 1.5 grams of N-benzylbeta-chloropropionamide and an effective amount 10f 2a rnomtoxic pharmaceutical binding agent :presseditogetheraand coated to form tablets effective inccontrdll-ing epileptic seizures.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Description
Patented May 11, 1954 N BENZYL BETACHLOROPROPIONAMIDE ANTICONVULSANT ARTICLE OF MANU- FACTURE Raymond W. Cunningham, Ben King Harned, and Mary 0. Clark, Pearl River, N. Y., assignors to American Cyanamid Company, New York, N. Y., a corporation of Maine No Drawing. Application July 22, 1952, Serial No. 300,348
6 Claims.
sions of various types but, unfortunately, most of these possess undesirable side reactions. Phenobarbital, for example, leads to dizziness, lethargy and incoordination in the patient. Trimethadione often causes dizziness, nervousness and visual disturbances. Paramethadione exhibits similar effects. Diphenylhydantoin often results in incoordination, gastric distress and other undesirable reactions in the patient. Certain anti-convulsants also have other toxic effects which lead to agranulocytosis and apiastic anemia. There is a need, therefore, for new anticonvulsant agents which are less toxic and have fewer side effects upon the patient.
We have found that the compound N-benzylbeta-chloropropionamide is a highly effective anti-convulsant agent. It is relatively more effective against epileptic seizures of the grand mal type than other types. It has remarkably low toxicity and does note tend to produce physiological disturbances such as those mentioned above and can be administered orally in dosage units of the size, type and kind to be described herein.
The compound N-benzyl-beta-chloropropionamide is a White crystalline solid which has a melting point of 94 C. and the following structural formula:
The compound and a process of preparing it is described in U. S. Patent No. 2,569,288, issued September 25, 1951, to Cassell and Kushner.
Extensive laboratory tests have established N- benzyl-beta-chloropropionamide as an eifective anti-convulsant of low toxicity. Clinical investigations have confirmed the laboratory results and the compound has been proven to be eiiective and reliable in treatment of both idiopathic and symptomatic epilepsy, note Hawkes, C. D.: N- Benzyl-beta-chloropropionamide (Hibicon), A. M, A. Archives of Neurology and Psychiatry 6'7; 815-820, June 1952.
Although the drug is only very slightly soluble in water, between about 0.005% and 0.01% by weight, it is readily absorbed by the body after oral administration. The efiective clinical dose for adults ranges from 0.5 to 1.5 grams taken 1 to 3 times daily. In children, the dosage ranges correspondingly lower according to the age and weight of the child. A preferred form of administration is a quantity of the drug Within the range of about 0.2 to 1.5 grams enclosed in a gelatin capsule. Capsules are preferred over other dosage unit forms because, while the compound is only slightly soluble in water, it has an unpleasant taste which is difiicult to mask by flavoring agents or other devices which are used in tablet manufacture. The capsule may be of either the hard shell or soft shell type and is generally of gelatin, although any water soluble capsulating material that will disintegrate after oral administration is suitable. Lubricants such as magnesium stearate and anti-caking agents to keep the drug in a readily dispersible form may be incorporated in the dosage unit.
When tablets are prepared, they may be made in various sizes containing from about 0.2 to 1.5 grams or more of the drug. These are generally compounded with binding agents, lubricants and other substances which are commonly used in tablet manufacture such as magnesium stearate, stearic acid, talc, corn starch, lactose or the like. If desired, these tablets may be coated with sugar or shellac preparations in accordance with the common practices in the tablet manufacturing art.
In illustration of the above, 500 parts by weight of N-benzyl-beta-chloropropionamide, parts of corn starch and 35 parts of gum acacia were mixed, moistened, granulated and dried. To this granulation was then added 1.74 parts by weight of magnesium stearate and the composition was pressed into scored tablets containing one-half gram each of N-benzyl-beta-chloropropionamide. These tablets may be administered orally to the patient at intervals of 4 to 8 hours, or whenever needed, in amounts depending upon the age and weight of the patient and the nature of the attack.
More preferably, the above described tablets are covered with a soft gelatin film on a capsulating machine to obtain capsules in which the effective ingredients are protected and the unpleasant taste of uncoated tablets is avoided.
A less preferred form of the invention is one of the above described tablets coated with sugar or other water-soluble coatings known to the art.
We claim:
1. An article of manufacture comprising a K quantity of from about 0.2 to 1.5 grams of N- benzyl-betach1oropropionamide and a pharmaceutical carrier in dosage unit form.
2. An article of manufacture comprising a quantity ranging from :-about 052 grams to 1.5 grams of N-benzyl-beta-chloropropionamide in a pharmaceutical capsule.
3. An article of manufacture comprising "a quantity ranging from about flzmtosl tggwmseof N-benzyl-beta-ch1oropropionamide in a ggelatin capsule.
4. A composition of matter comprising a quantity of from about 0.2 to l'fi grams ofiN-benzylbeta-chloropropionamide andan effectivetamount of a non-toxic pharmaceutical binding agent pressed together in a dosage unit form.
4 5. A composition or matter comprising a quantity of from about 0.2 to 1.5 grams of N-benzylbeta-chloropropionamide and an eifective amount of a non-toxic pharmaceutica1 binding agent 5 :presse'd together in a. tablet.
6. A composition of matter comprising a quantity of from about 0.2 to 1.5 grams of N-benzylbeta-chloropropionamide and an effective amount 10f 2a rnomtoxic pharmaceutical binding agent :presseditogetheraand coated to form tablets effective inccontrdll-ing epileptic seizures.
"Rferencesflited in the file of this patent ii-lowandizModem Drug Encyclopedia, fifth ed., *DnugFEaibLiIncorpu page 1203, New York, 1952.
Claims (1)
1. AN ARTICLE OF MANUFACTURE COMPRISING A QUANTITY OF FROM ABOUT 0.2 TO 1.5 GRAMS OF NBENZYL-BETA-CHLOROPROPIONAMIDE AND A PHARMACEUTICAL CARRIER IN DOSAGE UNIT FORM.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US300348A US2678296A (en) | 1952-07-22 | 1952-07-22 | Nu-benzyl-betachloropropionamide anticonvulsant article of manufacture |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US300348A US2678296A (en) | 1952-07-22 | 1952-07-22 | Nu-benzyl-betachloropropionamide anticonvulsant article of manufacture |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US2678296A true US2678296A (en) | 1954-05-11 |
Family
ID=23158728
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US300348A Expired - Lifetime US2678296A (en) | 1952-07-22 | 1952-07-22 | Nu-benzyl-betachloropropionamide anticonvulsant article of manufacture |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US2678296A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2897229A (en) * | 1954-02-09 | 1959-07-28 | Kali Chemie Ag | Phenyl acetonitrile compounds and a process of making same |
-
1952
- 1952-07-22 US US300348A patent/US2678296A/en not_active Expired - Lifetime
Non-Patent Citations (1)
| Title |
|---|
| None * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2897229A (en) * | 1954-02-09 | 1959-07-28 | Kali Chemie Ag | Phenyl acetonitrile compounds and a process of making same |
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