US3098791A - Anti-epileptic tertiary alicyclic urea derivative - Google Patents
Anti-epileptic tertiary alicyclic urea derivative Download PDFInfo
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- US3098791A US3098791A US145483A US14548361A US3098791A US 3098791 A US3098791 A US 3098791A US 145483 A US145483 A US 145483A US 14548361 A US14548361 A US 14548361A US 3098791 A US3098791 A US 3098791A
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- epileptic
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- urea
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- 239000001961 anticonvulsive agent Substances 0.000 title description 10
- -1 alicyclic urea derivative Chemical group 0.000 title description 8
- 230000003556 anti-epileptic effect Effects 0.000 title description 7
- 206010010904 Convulsion Diseases 0.000 claims description 20
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 17
- 239000004202 carbamide Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 230000001037 epileptic effect Effects 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 description 16
- 239000003814 drug Substances 0.000 description 16
- 229940079593 drug Drugs 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 238000011282 treatment Methods 0.000 description 14
- 206010015037 epilepsy Diseases 0.000 description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 208000034308 Grand mal convulsion Diseases 0.000 description 8
- 206010034759 Petit mal epilepsy Diseases 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 8
- 238000002560 therapeutic procedure Methods 0.000 description 8
- 239000002552 dosage form Substances 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- ZVELGQJLEWIYHZ-UHFFFAOYSA-N (1-ethylcyclopentyl)urea Chemical compound NC(=O)NC1(CC)CCCC1 ZVELGQJLEWIYHZ-UHFFFAOYSA-N 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 206010041349 Somnolence Diseases 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 230000001773 anti-convulsant effect Effects 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
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- 230000000694 effects Effects 0.000 description 3
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- 239000001923 methylcellulose Substances 0.000 description 3
- 235000010981 methylcellulose Nutrition 0.000 description 3
- CMUOJBJRZUHRMU-UHFFFAOYSA-N nitrourea Chemical compound NC(=O)N[N+]([O-])=O CMUOJBJRZUHRMU-UHFFFAOYSA-N 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- SOPWCEFXKLAPKS-UHFFFAOYSA-N (1-methylcyclopentyl)urea Chemical compound NC(=O)NC1(C)CCCC1 SOPWCEFXKLAPKS-UHFFFAOYSA-N 0.000 description 2
- 206010003591 Ataxia Diseases 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 206010012735 Diarrhoea Diseases 0.000 description 2
- 208000010201 Exanthema Diseases 0.000 description 2
- 206010028813 Nausea Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 208000006633 Tonic-Clonic Epilepsy Diseases 0.000 description 2
- 206010047700 Vomiting Diseases 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 208000022531 anorexia Diseases 0.000 description 2
- 229940125681 anticonvulsant agent Drugs 0.000 description 2
- 229960003965 antiepileptics Drugs 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
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- 229920002678 cellulose Polymers 0.000 description 2
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- 239000008120 corn starch Substances 0.000 description 2
- 206010061428 decreased appetite Diseases 0.000 description 2
- 201000002933 epilepsy with generalized tonic-clonic seizures Diseases 0.000 description 2
- 201000005884 exanthem Diseases 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 230000008693 nausea Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 206010037844 rash Diseases 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
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- 239000005720 sucrose Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 230000008673 vomiting Effects 0.000 description 2
- BDAOVJXWRKUWIE-UHFFFAOYSA-N (1-methylcyclohexyl)urea Chemical compound NC(=O)NC1(C)CCCCC1 BDAOVJXWRKUWIE-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- UBLAMKHIFZBBSS-UHFFFAOYSA-N 3-Methylbutyl pentanoate Chemical compound CCCCC(=O)OCCC(C)C UBLAMKHIFZBBSS-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 208000019838 Blood disease Diseases 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 241000206575 Chondrus crispus Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920002907 Guar gum Polymers 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
- 241000195947 Lycopodium Species 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 208000026911 Tuberous sclerosis complex Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 230000009471 action Effects 0.000 description 1
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- 239000008272 agar Substances 0.000 description 1
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- 230000001476 alcoholic effect Effects 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- 235000012216 bentonite Nutrition 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- 231100001015 blood dyscrasias Toxicity 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 229940023913 cation exchange resins Drugs 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 201000005108 complex partial epilepsy Diseases 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- 208000018706 hematopoietic system disease Diseases 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 201000008383 nephritis Diseases 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
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000009491 slugging Methods 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 201000008914 temporal lobe epilepsy Diseases 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 208000009999 tuberous sclerosis Diseases 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 238000002562 urinalysis Methods 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Definitions
- This invention relates to the use of certain cycloalkyl urea compounds for the treatment of epilepsy and to compositions including such compounds which are useful for this purpose. More particularly, this invention relates to methods for preventing disabling reactions such as epileptic seizures in patients afiiicted with epilepsy.
- Drowsiness is a side effect which is frequently encountered by patients undergoing various types of anti-epileptic therapy.
- Other side effects encountered moreor less frequently include anorexia, nausea, vomiting, diarrhea, ataxia and various kinds of rashes. Then, to,'various withdrawal symptoms.
- Another object of this invention is to provide formulations of chemo-therapeutic agents which are effective in the prevention or control of various forms of epileptic seizures.
- Another object of this invention is to provide pharmaceutical compositions useful in the treatment of epileptic patients, particularly epileptic patients who have proved refractory to other drugs.
- Another object of this invention is to provide such pharmaceutical compositions in convenient dosage forms.
- the compounds in question may be prepared. by various synthetic procedures exemplified by one or more of the reactions shown in the following equations:
- EXAMPLE 4 The cycloalkylurea compounds of Examples 1, 2 and 3, were each administered in the form of tablets containing 0.2 gram of active ingredients per tablet at regular intervals of time to human patients who were epileptics of various types and who had been refractory to the common anti-convulsants in various combinations and in large doses. Each patient was diagnosed by an electroenceph alographic study and the clinical response of the patient evaluated by the change in seizure frequency. In mixed cases, such as those including both petit mal and grand mal seizures, the clinical response was evaluated by the change in seizure frequency of the dominating type of epilepsy.
- EXAMPLE 5 Nine patients were treated using the compound of Example 2 in accordance with the procedure set forth in Example 4 above. The daily dosage, the duration and the effects of treatment are summarized in Table 2 below.
- disintegrants there may be used, in addition to the corn starch in the above formulation, potato starch, methyl cellulose, agar, bentonite, purified cellulose, natural sponge, various cation exchange resins, alginic acid, guar gum, or citris pulp.
- Lubricants may be of various types, including, in addition to the magnesium stearate used in the above described formulation, talc, starch, lycopodium, calcium stearate, boric add, sugar, sodium chloride, paraffin, stearic acid, cocoa butter, and soaps.
- Diluents commonly used include starches and various sugars.
- Each of the materials mentioned above may be used in combina- TABLE 3 Degree of seizure control Patient (Percent) Duration Daily No. Age Type of epllepsy (months) dosage Worse 0 50 75 90 100 5 1.0 6 0.4 23--" 27 4 0. (3 24" 4% 0.4 25-- 33 6% 0.8 26 4% 0. 5 27 34 Pmotor 1 0. 2 21 Gmal (tuberous sclerosis) 1 6 0.8
- the compounds of this invention may be formulated in any of the conventional dosage forms commonly used in the treatment of epilepsy.
- a preferred form which may be used is tablets containing the active ingredient together with various other materials which facilitate the compounding of the drug, enhance its stability, or affect the convenience of treatment with the drug.
- the tablets may contain various pharmaceutical adjuvants including disintegrants, diluents, binders and lubricants.
- l-( l-methylcyclohexyl)urea is the active ingredient
- corn starch is a disintegrant and diluent
- lactose and sucrose are diluents
- methyl cellulose is a binder
- magnesium stearate is a lubricant.
- binders may include glucose, gum acacia, gelatin, sucrose, starch, carboxymethyl tion with various other materials depending upon the type of tablet which it is desired to form.
- the tablets may be prepared by any of the conventional tableting techniques including slugging and wet granulation methods.
- the compounds which constitute the active ingredient of the anti epileptic compo- 5 sitions of this invention may be formulated as pills, capsules, suppositories, liquid suspensions or parenterals, as well as alcoholic solutions. If desired, the compounds may be formulated in delayed action compositions by the use of enteric coatings and the like.
- the precise formulations utilized tor purposes of this invention are not critical depending only upon common usage and considerations of convenience, stability, and ease in handling.
- the unit dosage form for anti-epileptic therapy can most conveniently be supplied in forms wherein the unit dosage, that is, the amount of active ingredient present, falls within the range of from 0.1 gram to 0.5 gram. It is desirable to administer the unit dosage form to the patient at regular intervals during the course of treatment, such that the patient receives daily at least about 0.4 gram of the active ingredient.
- this invention relates to a process for preventing epileptic seizures, particulanly in patients who are ordinarily refractory to other anti-epileptic therapy, which consists in administering to the patients at least about 0.4
- an anti-epileptic drug which is one of a series of tertiary alicyclic urea derivatives having the formula CH2 R C 2 NHCONHa wherein n is 2 or 3 and R is lower alkyl.
- These drugs may be formulated in any convenient unit dosage form for ease of administration.
- a method for preventing epileptic seizures in epileptic patients which comprises administering to epileptic patients at least about 0.4 gram daily of a member selected from the group consisting of 1-( l'-methylcyclohexy:l)urea, 1-( l'-methylcyclopentyl)urea and 1-( l-ethylcyclopentyl)- urea.
- a method for preventing epileptic seizures in epileptic patients which comprises administering to epileptic patients a daily dosage of at least 0.4 gram of a cycloalkyl urea selected from the group consisting of 1-(l'- methylcyclohexyburea, 1-(1'-m'ethylcyclopenyl)urea and 1-(1-ethylcyclopentyl)urea, said cycloalkyl urea being incorporated in a unit dosage form comprising said cycloalkyl urea and a pharmaceutical adjuvant therefor.
- a cycloalkyl urea selected from the group consisting of 1-(l'- methylcyclohexyburea, 1-(1'-m'ethylcyclopenyl)urea and 1-(1-ethylcyclopentyl)urea
- a pharmaceutical formulaion for use in preventing epileptic seizures in epileptic patients which comprises a member selected from the group consisting of 1-(1-methylcyclo-hexyDurea, 1-(l' methylcyclopentyDurea and 1- (1'-ethylcyclopentyl)urea in unit dosage form.
- a formulation for use in preventing epileptic seizures in epileptic patients which comprises a member selected from the group consisting of 1-(1'-methylcyclohexyl)- urea, 1-(1-methylcyclopentyl)urea and 1-(1'-ethylcyclopentyDurea and a pharmaceutical :adjuvant therefor.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Unite States Patent 3,098,791 Patented July 23, 1963 This invention relates to the use of certain cycloalkyl urea compounds for the treatment of epilepsy and to compositions including such compounds which are useful for this purpose. More particularly, this invention relates to methods for preventing disabling reactions such as epileptic seizures in patients afiiicted with epilepsy.
A number of drugs have been used more or less satisfactorily in the treatment and control of various types epilepsy. Many of the pharmaceutical compositions heretofore utilized in epilepsy therapy have proved to be effective therapeutic agents in one or more of the common forms of epilepsy. Even with the most satisfactory of these compositions, however, the use has been effective only in the prevention of epileptic seizures in certain for-ms of epilepsy. Thus, no known drug has been effective in the treatment of all forms of epilepsy. In the case of certain patients, in fact, it has been found that these patients are non-responsive or refractory to all known drugs for the treatment of epilepsy. Even where a drug has been found effective for treatment of the condition, in many instances the benefit to the patient has been found to be overshadowed by a high incidence of side efiects. Drowsiness, in particular, is a side effect which is frequently encountered by patients undergoing various types of anti-epileptic therapy. Other side effects encountered moreor less frequently include anorexia, nausea, vomiting, diarrhea, ataxia and various kinds of rashes. Then, to,'various withdrawal symptoms.
have been evidenced in cases where the drug being used in anti-epileptic therapy has been. changed and another drug substituted therefor. In many instances it has been necessary to utilize relatively high dosages of. the drugs used, which is undesirable from the standpoint of con venience of treatment. In some cases, drug metabolism has raised serious problems.
It is accordingly an objective of the instant invention to provide a means of prevention of epileptic seizures which has few of the disadvantages inherent in previous methods of therapy.
Another object of this invention is to provide formulations of chemo-therapeutic agents which are effective in the prevention or control of various forms of epileptic seizures.
Another object of this invention is to provide pharmaceutical compositions useful in the treatment of epileptic patients, particularly epileptic patients who have proved refractory to other drugs.
Yet, another object of this invention is to provide such pharmaceutical compositions in convenient dosage forms.
Other objects and advantages of this invention will become apparent in the course of the following disclosure and description.
It has now been tound that a series of tertiary alicyclic urea derivatives having the formula- CH2 R where n is 2 or 3 and R is lower alkyl, particularly methyl.
and ethyl, have outstanding anti-epileptic activity.
The compounds in question may be prepared. by various synthetic procedures exemplified by one or more of the reactions shown in the following equations:
(1) CH2 R Thus, it may 'beseenthat compounds of the class depicted above may be readily prepared using either the amine or the alkanol corresponding to the desired urea derivative. The reaction conditions used in conducting the various reactions, which may be used for the preparation of these compounds, are not in any way critical.
The preparative methods as well as the intended methods for use of these compounds will be exemplified in the following examples which, however, are intended merely for purposes of illustration and are not to be construed as in any way limiting the scope of this in- Mention. i
EXAMPLE 1 Preparation of ]-(1 -Methylcycl0 hexyl) Urea To 28.3 grams (0.25 mole) of 1-Inethylcyclohexyl amine in 200 ml. of ethyl alcohol was added 28.9 grams (0.275 mole) of nitrourea over a period of 30 minutes. The temperature was maintained at 4050 C. during the addition. The reaction mixture was gradually heated to reflux and approximately m1. of alcohol removed by distillation. Dilution of the residue with water precipitated a semi-solid mass which was filtered and dried under vacuum over calcium chloride. Crystallization from water gave 13 grams of crystalline product which melted at 99-l01 C.
Analysis.-Calcd. for C H N O: N, 17.92%. Found: N, 17.50%.
EXAMPLE 2 Preparation of 1-(1'-Methylcyclopentyl) Urea A quantity of 28.6 grams (10% excess) of nitrourea was added in portions to a solution of 24.5 grams of l-methylcyclopentylamine in 200 ml. of 95% ethyl alcohol initially heated to 45 C. As no detectable reaction occurred, the temperature was raised to' 55 C. 10 whereupon gas evolution indicated that the reaction was proceeding. The temperature was maintained at 55 C. during the remainder of the addition and was then gradually raised and the alcohol removed by distillation at reduced pressure. Benzene was then added and distillation continued until traces of water were removed. Filtration gave 29 grams of crystalline product and cooling of the benzene solution gave an additional 2.5 grams of crystalline material. The two crystalline fractions were combined, recrystallized from aqueous ethyl alcohol and gave 23.6 grams of product which melted at 175.5- 177.5 C.
Analysis.-Calcd. for C H N O: N, 19.70%. Found:
EXAMPLE 3 Preparation of 1-(1'-Ethylcyclopentyl) Urea A quantity of 46 grams of l-ethylcyclopentylamine was dissolved in 300 m1. of 95% ethyl alcohol and 48 grams of nitrourea was added in one portion. The reaction mixture was heated rapidly until there was vigorous gas evolution. When the vigorous reaction was completed, the solution was refluxed for minutes. The
mal seizures a day and only a grand mal seizure once in three to six months, the response of the petit mal seizures was evaluated. However, if the grand mal seizures were the more incapacitating, the response of the grand mal was evaluated. Each patient received -a CBC (complete blood count), urinalysis and urinary ur-obilinogen determination before the drug was started and at monthly intervlals. The drug was added to whatever anti-convulsant the patient had been taking. No patient reported any abnormality indicating a blood dyscrasia, nephritis or hepatitis. Clinical response was evaluated in patients who had taken the cycloalkyl urea drugs for as long as seven months or as short a period as one month. Adverse reactions were generaly not encountered. Where it was possible to reduce the dosage of other anti-convulsants, it was evident that the patients had become more alert. No patient reported anorexia, nausea, vomiting, diarrhea, ataxia or rash. Only one patient reported drowsiness.
Eleven patients were given the compound of Example 1 in the form of tablets consisting of the following ingredients:
The particular dosages, the duration of treatment and the results of the therapy are summarized in Table 1 below.
TABLE 1 Degree of seizure control Patient (percent) Duration Daily No. Age Type of epilsepsy (months) dtzsaige Reaction g. Worse 0 50 75 90 100 40 Pmotor 1 40 Pmal and Gmal Drowsy. 12 Gmal 35 Pmotor 4O Gmal 30 Pmal and GmaL. 56 Pmotor 28 Pmal and Gmal 1s Pmal and 6515111..
34 Pmomr andfimall 15 Pmal var. and Gma 1 Pmotor, Psychomotor Pmal, Petit mal; Gmal, Grand mal Pmal van, Petit mal variant.
alcohol was removed under reduced pressure and the solid residue was extracted with 50 ml. of boiling benzene and crystallized from absolute alcohol as white EXAMPLE 4 The cycloalkylurea compounds of Examples 1, 2 and 3, were each administered in the form of tablets containing 0.2 gram of active ingredients per tablet at regular intervals of time to human patients who were epileptics of various types and who had been refractory to the common anti-convulsants in various combinations and in large doses. Each patient was diagnosed by an electroenceph alographic study and the clinical response of the patient evaluated by the change in seizure frequency. In mixed cases, such as those including both petit mal and grand mal seizures, the clinical response was evaluated by the change in seizure frequency of the dominating type of epilepsy. In other words, if a patient had many petit From the tabulated results, it may be seen that of the eleven refractory patients treated with the compound of Example 1, five showed a 75% reduction in seizure frequency in cases of grand mal, petit mal, psychomotor, and petit mal variant epilepsy. All five of these patients had grand mal epilepsy, but in addition two were complicated with petit mal, one with psyohomotor and another with petit mal variant patterns. Referring again to the tabulation of therapeutic results, it may be seen that three additional patients showed 50% improvement in seizure control. In. two other patients there was no improvement and in one who was treated for only one month, the patient complained of drowsiness and reported more seizures than previously experienced. It may be seen that the dosages in the cases that responded favorably to the drug varied from 0.4 gram to 1.3 grams daily.
EXAMPLE 5 Nine patients were treated using the compound of Example 2 in accordance with the procedure set forth in Example 4 above. The daily dosage, the duration and the effects of treatment are summarized in Table 2 below.
From the foregoing tabulated data, it may be seen that of the nine patients treated with the compound of Ex- EXAMPLE 6 The compound of Example 3 was administered to eight patients over periods varying from 1 month to 6 /2 months in accordance with the procedure of Example 4. The results of these treatments are tabulated in Table 3 below.
cellulose, methyl cellulose, sodium alginate, extract of Irish moss, polyvinyl pyrrolidone, water and alcohol (denatured). As disintegrants there may be used, in addition to the corn starch in the above formulation, potato starch, methyl cellulose, agar, bentonite, purified cellulose, natural sponge, various cation exchange resins, alginic acid, guar gum, or citris pulp. Lubricants may be of various types, including, in addition to the magnesium stearate used in the above described formulation, talc, starch, lycopodium, calcium stearate, boric add, sugar, sodium chloride, paraffin, stearic acid, cocoa butter, and soaps. Diluents commonly used include starches and various sugars. Each of the materials mentioned above may be used in combina- TABLE 3 Degree of seizure control Patient (Percent) Duration Daily No. Age Type of epllepsy (months) dosage Worse 0 50 75 90 100 5 1.0 6 0.4 23--" 27 4 0. (3 24" 4% 0.4 25-- 33 6% 0.8 26 4% 0. 5 27 34 Pmotor 1 0. 2 21 Gmal (tuberous sclerosis) 1 6 0.8
From a study of the data tabulated above, it may be seen that one patient was 75% improved upon treatment using 0.8 gram of the compound of Example 3 over a 5 /2 month period. Three other patients were improved using dosages ranging from 0.45 gram to 1.0 gram per day. Three other patients were unimproved and one patient suffering from both grand mal and psychomotor epilepsy showed a greater incidence of seizures following therapy. In the case of the compound of Example 3, the eiiective daily dosage was found to be in the range of from 0.45 gram to 1.0 gram.
The compounds of this invention may be formulated in any of the conventional dosage forms commonly used in the treatment of epilepsy. A preferred form which may be used is tablets containing the active ingredient together with various other materials which facilitate the compounding of the drug, enhance its stability, or affect the convenience of treatment with the drug. For example, the tablets may contain various pharmaceutical adjuvants including disintegrants, diluents, binders and lubricants.
In the formulation detailed in Example 4, for instance, l-( l-methylcyclohexyl)urea is the active ingredient, corn starch is a disintegrant and diluent, lactose and sucrose are diluents, methyl cellulose is a binder and magnesium stearate is a lubricant.
Various other adjuvants known to those killed in the art may be used for each of the purposes outlined above. For example, commonly used binders may include glucose, gum acacia, gelatin, sucrose, starch, carboxymethyl tion with various other materials depending upon the type of tablet which it is desired to form.
0 The tablets may be prepared by any of the conventional tableting techniques including slugging and wet granulation methods.
Instead of using tablets the compounds which constitute the active ingredient of the anti epileptic compo- 5 sitions of this invention may be formulated as pills, capsules, suppositories, liquid suspensions or parenterals, as well as alcoholic solutions. If desired, the compounds may be formulated in delayed action compositions by the use of enteric coatings and the like.
The precise formulations utilized tor purposes of this invention are not critical depending only upon common usage and considerations of convenience, stability, and ease in handling. The unit dosage form for anti-epileptic therapy can most conveniently be supplied in forms wherein the unit dosage, that is, the amount of active ingredient present, falls within the range of from 0.1 gram to 0.5 gram. It is desirable to administer the unit dosage form to the patient at regular intervals during the course of treatment, such that the patient receives daily at least about 0.4 gram of the active ingredient.
In summary, this invention relates to a process for preventing epileptic seizures, particulanly in patients who are ordinarily refractory to other anti-epileptic therapy, which consists in administering to the patients at least about 0.4
gram daily of an anti-epileptic drug which is one of a series of tertiary alicyclic urea derivatives having the formula CH2 R C 2 NHCONHa wherein n is 2 or 3 and R is lower alkyl. These drugs may be formulated in any convenient unit dosage form for ease of administration.
What is claimed is:
1. A method for preventing epileptic seizures in epileptic patients which comprises administering to epileptic patients at least about 0.4 gram daily of a member selected from the group consisting of 1-( l'-methylcyclohexy:l)urea, 1-( l'-methylcyclopentyl)urea and 1-( l-ethylcyclopentyl)- urea.
2. A method for preventing epileptic seizures in epileptic patients which comprises administering to epileptic patients a daily dosage of at least 0.4 gram of a cycloalkyl urea selected from the group consisting of 1-(l'- methylcyclohexyburea, 1-(1'-m'ethylcyclopenyl)urea and 1-(1-ethylcyclopentyl)urea, said cycloalkyl urea being incorporated in a unit dosage form comprising said cycloalkyl urea and a pharmaceutical adjuvant therefor.
3. A pharmaceutical formulaion for use in preventing epileptic seizures in epileptic patients which comprises a member selected from the group consisting of 1-(1-methylcyclo-hexyDurea, 1-(l' methylcyclopentyDurea and 1- (1'-ethylcyclopentyl)urea in unit dosage form.
4. A formulation for use in preventing epileptic seizures in epileptic patients which comprises a member selected from the group consisting of 1-(1'-methylcyclohexyl)- urea, 1-(1-methylcyclopentyl)urea and 1-(1'-ethylcyclopentyDurea and a pharmaceutical :adjuvant therefor.
No references cited.
Claims (1)
1. A METHOD FOR PREVENTING EPILEPTIC SEIZURES IN EPILEPTIC PATIENTS WHICH COMPRISES ADMINISTERING TO EPILEPTIC PATIENTS AT LEAST ABOUT 0.4 GRAM DAILY OF A MEMBER SELECTED FROM THE GROUP CONSISTING OF 1-(1''-METHYLCYCLOAHEXY) UREA, 1-(1''-METHYLCYCLOPENTYL) UREA AND 1-(1''-ETHYCYELOPENTYL)UREA.
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US145483A US3098791A (en) | 1961-10-16 | 1961-10-16 | Anti-epileptic tertiary alicyclic urea derivative |
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US145483A US3098791A (en) | 1961-10-16 | 1961-10-16 | Anti-epileptic tertiary alicyclic urea derivative |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3221011A (en) * | 1962-12-17 | 1965-11-30 | Sandoz Ltd | Dibenzazepine derivatives |
US4161479A (en) * | 1978-07-10 | 1979-07-17 | Morton-Norwich Products, Inc. | 5-(4-Chlorophenyl)furfurylurea |
-
1961
- 1961-10-16 US US145483A patent/US3098791A/en not_active Expired - Lifetime
Non-Patent Citations (1)
Title |
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None * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3221011A (en) * | 1962-12-17 | 1965-11-30 | Sandoz Ltd | Dibenzazepine derivatives |
US4161479A (en) * | 1978-07-10 | 1979-07-17 | Morton-Norwich Products, Inc. | 5-(4-Chlorophenyl)furfurylurea |
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