GB1568401A - Biologically active amides - Google Patents
Biologically active amides Download PDFInfo
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- GB1568401A GB1568401A GB4168/76A GB416876A GB1568401A GB 1568401 A GB1568401 A GB 1568401A GB 4168/76 A GB4168/76 A GB 4168/76A GB 416876 A GB416876 A GB 416876A GB 1568401 A GB1568401 A GB 1568401A
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- cyclopropylcinnamamide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/11—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/09—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an acyclic unsaturated carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
- C07C59/48—Unsaturated compounds containing hydroxy or O-metal groups containing six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
- C07C69/618—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety having unsaturation outside the six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Abstract
The compounds of the formula I are prepared by reacting a compound of the formula III R.NH.W, in which W denotes hydrogen or a group which can be eliminated, with an acid of the formula II <IMAGE> . Instead of the free acid, an active derivative of this acid can be used. The substituents in the formulae have the meanings given in Claim 1. The compounds of the formula I possess useful pharmacological properties. <IMAGE>
Description
(54) BIOLOGICALLY ACTIVE AMIDES
(71) We, THE WELLCOME FOUNDATION LIMITED, of 183-193 Euston
Road, London N.W.I. a company incorporated in England do hereby declare the invention which was communicated from BURROUGHS WELLCOME CO., of 3030 Cornwallis Road, Research Triangle Park, North Carolina 27709, being incorporated in the State of North Carolina, United States of America, for which we pray that a Patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention is concerned with chemicals which have valuable pharmacological properties. In particular, the invention concerns cinnamamides, their synthesis, pharmaceutical preparations containing them, and their use in medicine.
It has been found that the cinnamamides of formula (I), as defined below, have anti-convulsant activity in mammals as is shown by their effects upon mice when administered to them in established pharmacological tests. These tests are:
1. Maximal Electroshock Test (MES) in mice, a method described by
Woodbury and Davenport, Arch int Pharmacodyn, Ther. 92, P. 97-107 (1952).
2. Metrazol Seizure Test (MET) in mice, a method described by Swinyard,
Brown and Goodman, J. Pharmacol, Exp. Therap. 106, 319-330 (1952).
In formula (I):
X is fluoro, chloro, bromo, iodo or trifluoromethyl; and
R is branched alkyl having 4 to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, cycloalkylalkyl wherein the cycloalkyl moiety has from 3 to 8 carbon atoms and the alkyl moiety has 1 to 3 carbon atoms, and when X is fluoro or trifluoromethyl then R may also be hydrogen or alkyl having 1 to 3 carbon atoms.
The compounds of formula (I) having the trans configuration are preferred.
A subclass of compounds within formula (I) are those compounds wherein X is fluoro or trifluoromethyl and R is hydrogen or alkyl having 1 to 3 carbon atoms.
A further subclass of compounds within formula (I) are these wherein X is fluoro, chloro, bromo, iodo or trifluoromethyl and R is branched alkyl having 4 to 8 carbon atoms. Suitable branched alkyl groups include iso butyl, sec butyl, t butyl and those of the higher homologues pentyl, hexyl, heptyl and octyl.
A still further subclass of compounds of formula (I) are those compounds wherein X is fluoro, chloro, bromo, iodo or trifluoromethyl and R is cycloalkyl having 3 to 8 carbon atoms, and these wherein the cycloalkyl moiety has 3 to 6 carbon atoms; in particular may be mentioned those compounds wherein R is cyclopropyl.
Also included in formula (I) is the subclass of compounds wherein R is cycloalkylalkyl.
Among the compounds within formula (I) may specifically be mentioned: 3-fluorocinnamamide;
3-fluoro-N-ethylcinnamamide; 3-fluoro-N4so-propylcinnamamide; 3-fluoro-N-cyclopropylcinnamamide;
3-fluoro-N-cyclopentylcinnamamide; 3-fluoro-N-cyclohexylcinnamamide; 3-fluoro-N-cycloheptylcinnamamide;
3-fluoro-N-cyclooctylcinnamamide;
3-fluoro-N-cyclobutylcinnamamide; 3-chloro-N4so-butylcinnamamide; 3-chloro-N-cyclopropylcinnamamide;
3-chloro-N-cyclopentylcinnamamide; 3-chloro-N-cyclohexylcinnamamide; 3-chloro-N-cycloheptylcinnamamide; 3-chloro-N-cyclooctylcinnamamide;
3-chloro-N-cyclobutylcinnamamide;
3-bromo-N-iso-butylcinnamamide; 3-bromo-N-cyclopropylcinnamamide; 3-bromo-N-t-butylcinnamamide;;
3-bromo-N-cyclobutylcinnamamide;
3-bromo-N-cyclopentylcinnamamide; - 3-bromo-N-cyclohexylcinnamamide;
3-bromo-N-cycloheptylcinnamamide;
3-bromo-N-cyclooctylcinnamamide;
3-bromo-N-cyclohexylmethylcinnamamide; 3-iodo-N-iso-butyldnnamamide;
3-iodo-N-t-butylcinnamamide ;
3-iodo-N-cyclopropylcinnamamide;
3-iodo-N-cyclopentylcinnamamide ;
34rifluoromethylcinnamamide; 3-trifluoromethyl-N-methylcinnamamide; 34rifluoromethyl-N-ethylcinnamamide; 3-trifluoromethyl-N-n-propylcinnamamide; 3-trifluoromethyl-N4so-propylcinnamamide;
3-trifluoromethyl-N4so-butylcinnamamide; 3-trifluoromethyl-N-cyclopropylcinnamamide; 34rifluoromethyl-N-cyclobutylcinnamamide;
3-trifluoromethyl-N-cyclopentylcinnamamide;
34rifluoromethyl-N-cyclohexylcinnamamide;; 3-trifluoromethyl-N-cycloheptylcinnamamide;
3-trifluoromethyl-N-cyclooctylcinnamamide; and
3-trifluoromethyl-N-cyclohexylmethylcinnamamide.
The compounds of formula (I) may be made by any method known for the synthesis of cinnamamides of analogous structure. For example they may be prepared by the acylation of an amine RNH2 (wherein R is the same as in the formula (I) by the corresponding acid of formula (II): m-X-PhCH=CHCO2H (wherein X has the meaning given for formula (I) or a reactive derivative thereof such as a thioester or an ester (e.g. an alkyl ester or thioester where the alkyl has e.g. 1 to 4 carbon atoms), an amide, an acid halide (e.g. an acid chloride) or an acid anhydride. A wide variety of reaction conditions may be employed depending upon the nature of the acylating agent, but in general the reactants may be refluxed together, preferably in an inert liquid medium such as ether, benzene, toluene or cyclohexane.
A most convenient method of synthesis is to react the acid chloride with the appropriate amine. Preferably one equivalent of the halide should be used with two or more equivalents of the amine, but the molar excess of the amine may be replaced by another base such as triethylamine, pyridine, dimethylaniline, or potassium or sodium carbonate. A wide variety of polar or non-polar liquid media may be used including water, alkanols such as methanol or ethanol, ether, dioxane, benzene, toluene, xylene, petroleum ether, cyclohexane, tetrahydrofuran, chloroform and carbon tetrachloride. A wide range of temperature conditions may be employed, for example from -10"C to the reflux temperature of the reaction mixture.
The compounds of formula (I) may be further prepared directly from the corresponding alcohol or aldehyde of formulae (III) and (IV) at a temperature below 10 C.
wherein X has the meaning in formula (I), by reaction with the appropriate amine RNH2 in the presence of nickel peroxide and an inert liquid medium such as ether, benzene, tetrahydrofuran, or a petroleum hydrocarbon.
The compounds of formula (I) may also be made by the reaction of an amide of formula (V): R . NH . W wherein W is a leaving group, for example -CO. . H (a formamide), -CO. alkyl wherein the alkyl has e.g. 1 to 4 carbon atoms (an amide), CONH2 (urea), -CONHR wherein R has the same meaning as formula (I) (substituted urea, -COO. alkyl (urethane having '4 carbon atoms in the alkyl group), with an acid of formula (II) or a reactive derivative thereof, for example the acid anhydride or halide. When the anhydride is used, a catalytic amount of sulphuric acid is preferably included. The reactants are convenient'y heated together in a liquid medium.
In a further method of making a compound of formula (I), water, a hydrogen halide or molecular halogen is eliminated from a compound of formula (VI):
wherein A and B are the same and each is halo or one of A and B is halo or hydroxy and the other is hydrogen, and X and R have the meaning given in formula (I) above. For example, the elimination of water from the - or hydroxy compounds of formula (VI) may be effected by reaction with a dehydrating agent such as a base (e.g. aqueous sodium hydroxide) or concentrated sulphuric or polyphosphoric acid.
The monohalo intermediates may be treated with a base (e.g. potassium hydroxide or dimethylaniline) or merely heated to release the hydrogen halide. The dihalo intermediates may be reduced, for example with zinc and ethanol or converted to the diiodo compounds by treatment with potassium iodide with subsequent release of molecular iodine.
The intermediate acids of formula (II) may be made by classical organic synthetic methods such as the Perkin synthesis, the Reformatsky reaction and the
Knoevenagel condensation.
The compounds of formula (I) may be used for the treatment or prophylaxis of convulsions of mammals such as mice, dogs and cats, and more importantly of man.
In particular they may be used in the treatment of grand mal, petit mal, psychomotor epilepsy and focal seizures. The compound 3-trifluoromethyl-N-cyclopropylcinnamamide is particularly valuable for its anticonvulsant properties.
The compounds of formula (I), in particular the compound 3-fluoro-N-cyclopropylcinnamamide, may also be used to decrease skeletal muscle tone. For example they may be used to induce relaxation of skeletal muscle in the treatment or prophylaxis of spastic, hypertonic and hyperkinetic conditions associated with disorders due to increased skeletal muscle tone. In particular the compounds may be used in the treatment and symptomatic relief of conditions such as parkinsonism, chorea, arthritis, athetosis, status epilepticus and tetanus and especially in the relief of muscle spasm in conditions such as myositis, spondylitis, cerebral palsy and multiple sclerosis.
For the treatment or prophylaxis of convulsions, or for decreasing muscular tone, the compounds of formula (I) may be used at a dose of from 2 to 200 mg/kg of bodyweight per day. The optimum dose of course will vary with the nature of the compound, the condition of the patient and the route of administration, but the preferred dose is in the range of from 20 to 60 mg/kg, most conveniently from 30 to 50 mg(kg body weight, per day. Administration of the desired daily dose is preferably in three divided doses. For example, convenient forms of administration include tablets each containing from 100 to 500 mg of a compound of formula (I).
For use in medicine the compounds of formula (I) may be administered as a pure chemical but are preferably presented with an acceptable carrier therefor as a pharmaceutical composition. The carrier must of course be 'acceptable' in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient of the composition. The carrier may be a solid or a liquid or a mixture of solid and liquid substances, and is preferably formulated with a compound of formula (I) as a unit-dose composition, for example a tablet, capsule or cachet for oral administration or a suppository for rectal administration.
Other pharmaceutically active substances may also be present in compositions of the present invention and the composition may be formulated by any of the wellknown techniques of pharmacy consisting basically of admixture of its components. Unit-dose compositions, for oral, rectal or parenteral administration (vid. ins), conveniently contain a compound of formula (I) in an amount in the range 100 to 500 mg.
For oral administration, fine powders or granules of the compounds may contain diluents and dispersing and surface active agents, and may be presented in a draught in water or in a syrup; in capsules or cachets in the dry state or in an aqueous or non-aqueous suspension, when a suspending agent may also be included; in tablets, preferably made from granules of the active ingredient with a diluent, by compression with binders and lubricants; or in a suspension in an orally ingestible liquid carrier, such as water or a syrup or an oil or in a water/oil emulsion, when flavouring, preserving, suspending, thickening and emulsifying agents may also be included. The granules or the tablets may be coated, and the tablets may be scored.
For parenteral administration (by intramuscular or intraperitoneal injection), the compounds may be presented in unit dose or multi-dose containers in aqueous or non-aqueous injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the compounds isotonic with the blood; or in aqueous or non-aqueous suspensions when suspending agents and thickening agents may also be included; extemporaneous injection solutions and suspensions may be made from sterile powders, granules or tablets which may contain diluents, dispersing and surface active agents, binders and lubricants.
It will be understood from the foregoing description that what we will claim in accordance with this invention comprises any novel feature described herein, principally but not exclusively as follows:- (a) Novel compounds of formula (I) hereinabove defined.
(b) Novel compounds of formula (I) hereinabove defined having the trans configuration.
(c) The synthesis of a novel compound of formula (I) by any known method and in particular the methods specifically described above and including the reaction of an acid m-X-PhCH=CHCO2H or a reactive derivative thereof with a compound of the formula R . NH . W wherein W is a leaving group and R and X have the meaning in formula (I).
(d) A pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier therefor.
(e) A method for the treatment or prophylaxis of convulsions of a mammal excluding man comprising the administration to the mammal of an anti-convulsant effective, non-toxic amount of a compound of formula (I).
(f) A method of decreasing skeletal muscle tone in a mammal excluding man which comprises administration to said mammal of a non-toxic effective tone decreasing amount of a compound of formula (I).
It should be understood that excluded from the scope of the pharmaceutical compositions provided by the present invention are non-sterile mixtures which are mere solutions or suspensions of the known compound of formula (I) as hereinabove defined in solvents and liquids known in the literature for use in the synthesis and/or isolation of the compound by the methods described therein.
Included within the scope of the present invention are such solutions and suspensions of the known compound which are pharmaceutically acceptable to the intended recipient thereof and which contain in addition at least one other pharmaceutically acceptable substance.
The following Examples illustrate the present invention but should not be construed as in any way constituting a limitation thereof. All temperatures are in degrees Celsius.
EXAMPLE 1
Trans 3-Bromo-N-cyclopropylcinnamamide
A mixture of trans 3-bromocinnamic acid (m.p. 177179 ; 11.4 g), thionyl chloride (11.9 g) and dry benzene (150 ml) was heated at reflux for 2 hrs. Solvent and excess thionyl chloride were removed by distillation under reduced pressure leaving trans 3-bromocinnamoyl chloride (12.2 g), b.p. 100--100.5"/0.2 mm Hg.
A solution of trans 3-bromocinnamoyl chloride (12.2 g) in dry toluene (150 ml) was added dropwise (rapidly) with rapid stirring to a solution of cyclopropylamine (6.3 g) in dry toluene (150 ml). The reaction mixture was stirred at room temperature for 2 hrs., then at 3W35 for an additional hour; and the solvent and excess amine were removed under reduced pressure. The residue was triturated with water to remove cyclopropylamine hydrochloride. The product was filtered, washed with dilute hydrochloric acid and then with water. It was then recrystallized from ethanol:water (1:10) to give white crystalline trans 3-bromo-Ncyclopropylcinnamamide m.p. 110--1110. Elemental analysis, NMR and IR data were all consistent with the assigned structure.TLC gave one spot run on silica gel with 5:1 and with 3:1 hexane:ethanol.
EXAMPLE 2
Trans 3-Fluoro-N-cyclopropylcinnamamide
A mixture of 3-fluorobenzaldehyde (40 g), malonic acid (47 g), and an ethanolic solution (150 ml) containing pyridine (10 g) and piperidine (5 g) was heated at reflux with stirring for 8 hrs. The reaction mixture was chilled and water (300 ml) was added, giving crystalline trans 3-fluorocinnamic acid which was removed by filtration, washed with water and dried. The trans 3-fluorocinnamic acid, m.p. 162163 , was obtained in 840/, yield.
A mixture of trans 3-fluorocinnamic acid (32.3 g), thionyl chloride (48 g) and dry benzene (300 ml) was heated at reflux for 2 hrs. Solvent and excess thionyl chloride were removed by distillation under reduced pressure leaving trans 3fluorocinnamoyl chloride as an oil.
A solution of trans 3-fluorocinnamoyl chloride (3.3 g) in dry toluene (100 ml) was added with stirring to a solution of cyclopropylamine (2.5 g) in dry ether (100 ml) at ambient temperature. The reaction mixture was heated at 3034 for 2 hrs., and the solvent and excess amine were removed under reduced pressure. The residue was triturated with water, filtered and recrystallized from ethanol:water (1:10) to give trans 3-fluoro-N-cyciopropylcinnamamide, m.p. 9091 . Elemental analysis, NMR and IR confirmed the structure. TLC gave one spot run on silica gel with 5:1 and with 3:1 hexane:ethanol.
EXAMPLE 3
Trans 3-Trifluoromethyl-N-Cyclopropylcinnamamide
Using a method analogous to that described in Examples 2 and 3, 3-trifluoromethylcinnamoyl chloride was reacted with cyclopropylamine to give trans 3-trifluoromethyl-N-cyclopropylcinnamamide, m.p. 730.
EXAMPLE 4
Trans 3-Bromo-N-iso-butylcinnamamide
Using a method analogous to that described in Examples 2 and 3, 3 bromocinnamoyl chloride was reacted with isobutylamine to give trans 3-bromo-N-isobutylcinnamamide, m.p. 104105 .
EXAMPLE 5
Trans 3-Fluoro-N-cinnamamide
A mixture of 3-fluorobenzaldehyde (40 g), malonic acid (47 g), and an ethanolic solution (150 ml) containing pyridine (10 g) and piperidine (5 g) was heated at reflux with stirring for 8 hrs. The reaction mixture was chilled and water (300 ml) was added, giving crystalline trans 3-fluorocinnamic acid which was removed by filtration, washed with water and dried. The trans 3-fluorocinnamic acid, m.p. 162163 , was obtained.
A mixture of trans 3-fluorocinnamic acid (32.3 g), thionyl chloride (48 g) and dry benzene (300 ml) was heated at reflux for 2 hrs. Solvent and excess thionyl chloride were removed by distillation under reduced pressure leaving trans 3fluorocinnamoyl chloride as an oil.
Dry ammonia was passed slowly into a solution of trans 3-fluorocinnamoyl chloride (5.7 g) in dry toluene (50 ml) with rapid stirring until ammonium chloride was no longer formed. The reaction mixture was stirred at ambient temperature for an additional 30 minutes. The solvent and excess ammonia were then removed under reduced pressure and the residual product triturated with water.
Recrystallization from ethanol:water (1:10) gave trans 3-fluorocinnamamide, m.p.
121--122". Elemental analysis, NMR and IR data were consistent with the assigned structure. TLC gave one spot run on silica gel using 5:1 and using 3:1 hexane:ethanol.
EXAMPLE 6
A suppository was formulated from the following ingredients: trans 3-trifluoromethyl-N-cyclopropylcinnamamide 300 mg cocoa butter 2000 mg
EXAMPLE 7
A soft gelatin capsule was filled with the following ingredients: trans 3-trifluoromethyl-N-cyclopropylcinnamamide 30U mg
lactose 75 mg
starch, corn 20 mg
fused silica 2 mg
magnesium stearate 3 mg
EXAMPLE 8
A syrup suspension was prepared from the following ingredients: trans 3-trifluoromethyl-N-cyclopropylcinnamamide 300 mg
sodium carboxymethylcellulose 20 mg
microcrystalline cellulose 100 mg
glycerin 500 mg
Polysorbate 80 10 ml
flavouring agent q.s.
preserving agent 0.lV0 sucrose syrup q.s. to 5 ml
EXAMPLE 9
A compressed tablet was prepared from the following:
trans 3-trifluoromethyl-N-cyclopropylcinnamamide 300 mg
starch, corn 50 mg
microcrystalline cellulose 50 mg
stearic acid 4 mg
magnesium stearate 1 mg
fused silica 1 mg
EXAMPLE 10
A soft gelatin capsule was filled with the following ingredients: trans 3-fluoro-N-cyclopropylcinnamamide 30d mg
lactose 75 mg
starch, corn 20 mg
fused silica 2 mg
magnesium stearate 3 mg
EXAMPLE 11
A syrup suspension was prepared from the following ingredients: trans 3-bromo-N-cyclopropylcinnamamide 300 mg
sodium carboxymethylcellulose 20 mg
microcrystalline cellulose 100 mg
glycerin 500 mg
Polysorbate 80 10 ml
flavoring agent q.s.
preserving agent 0.1%
sucrose syrup q.s. to 5 ml
EXAMPLE 12
A syrup suspension was prepared from the following ingredients: trans 3-fluoro-N-cyclopropylcinnamamide 300 mg
sodiuin carboxymethylcellulose 20 mg
microcrystalline cellulose 100 mg
glycerin 500 mg
Polysorbate 80 10 ml
flavoring agent q.s.
preserving agent 0.1 ,4.
sucrose syrup q.s. to 5 ml
EXAMPLE 13
A compressed tablet was prepared from the following: trans 3-bromo-N-cyclopropylcinnamamide 300 mg
starch, corn 50 mg
microcrystalline cellulose 50 mg
stearic acid 4 mg
magnesium stearate 1 mg
fused silica 1 mg
EXAMPLE 14
A compressed tablet was prepared from the following ingredients: trans 3-fluoro-N-cyclopropylcinnamamide 300 mg
starch, corn 50 mg
microcrystalline cellulose 50 mg
stearic acid 4 mg
magnesium stearate 1 mg
fused silica 1 mg
EXAMPLE 15
Anticonvulsant activity
In the MES pharmacological test referred to hereinbefore, the sta( compounds had the given ED50 when administered i.p. to mice.
Compound ED50 (mg1l:g) trans 3-fluoro-N-cyclopropylcinnamamide 60 trans 3-bromo-N-cyclopropylcinnamamide 77 trans 3-trifluoromethyl-N-cyclopropylcinnamamide 56 trans 3-bromo-N-isobutylcinnamamide 46 trans 3-fluorocinnamamide 58
EXAMPLE 16
Muscle relaxant activity
The effect of 3-fluoro-N-cyclopropylcinnamamide as a centrally acting muscle relaxant was determined using a method based on that described in Berger, F.M. & BR<
Bradley, W. (Br. J. Pharmac. Chemother., (1946), 1, 265-272) and Crankshaw,
D. P. & Raper, C. (Br. J. Pharmac. (1970), 38, 148-156). At an oral dose of from 100-150 mglkg the compound suppressed polysynaptic reflex contractions in the cat without affecting the monosynaptic knee-jerk reflex.
EXAMPLE 17
Anticonvulsant activity
When trans 3-trifluoromethyl-N-cyclopropylcinnamamide was administered to rats according to the MES test it was found to have an ED50 of 20+6 mg/kg and 18+3 mg/kg when administered orally and intraperitoneally respectively.
EXAMPLE 18
A solution of trans 3-trifluoromethylcinnamoyl chloride (8.5 g) in anhydrous toluene (150 ml) was added to a solution of cyclopropylamine (5 g) in anhydrous toluene (100 ml). The reaction mixture was allowed to stand at room temperature for several hours. The solvent and excess amine were removed under reduced pressure. The residue thoroughly triturated with water and recrystallised from ethanoVwater (1/15) to give trans 3-trifluoromethyl-N-cyclopropylcinnamamide m.p. 980 C. Elemental analysis as well as NMR and IR spectra confirmed the structure.
EXAMPLES 19-55 Following the procedure of Example 1, the following trans cinnamamide derivatives were prepared (in all cases the NMR, IR and elemental analyses confirmed the structures), which derivatives are compounds of formula (I) having the indicated values for X and R::
Example X R m.p. OC 19 F cyclopentyl 138-139 20 F cyclohexyl 150
21 F cycloheptyl 152
22 F cyclooctyl 149-150 23 Cl cyclopentyl 107-108 24 Cl cyclohexyl 153-154 25 Cl cycloheptyl 119-120 26 Cl cyclooctyl 91-92 27 Br cyclopentyl 109-110
28 Br cyclohexyl 158
29 Br cycloheptyl 101-102 30 Br cyclohexylmethyl 120--121 31 I cyclopentyl 126-127 32 CF3 cyclopentyl 9092 33 CF3 cyclohexyl 125
34 CF3 cycloheptyl 98-100 35 CF3 cyclooctyl 80
36 CF3 cyclohexylmethyl 96.5-97.5 37 F C2H5 97
38 F iso-propyl 95-96 39 F cyclobutyl 105
40 Cl iso-butyl 111.5-112.5 41 Cl cyclopropyl 112-113 42 Cl cyclobutyl 99
43 Br tert-butyl 154
44 Br cyclobutyl 114-115 45 Br cyclooctyl 101
46 I iso-butyl 109-110
47 I tert-butyl 152-153 48 I cyclopropyl 123
49 CF3 H 102
50 CF3 CH3 125
51 CF3 C3H5 90
52 CF3 n-propyl 82-83 53 CF3 iso-butyl 116
54 CF3 isobutyl 93
55 CF3 cyclobutyl 132
WHAT WE CLAIM IS:1.A pharmaccutical composition comprising a compound of formula (I):
wherein X is fluoro, chloro, bromo, iodo or trifluoromethyl and R is branched alkyl having 4 to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, cycloalkylalkyl wherein the cycloalkyl moiety has 3 to 8 carbon atoms and the alkyl moiety has 1 to 3 carbon atoms and when X is fluoro or trifluoromethyl R may also be hydrogen or alkyl having 1 to 3 carbon atoms, in association with a pharmaceutically acceptable carrier.
2. The composition of claim 1 wherein in formula (I) when X is chloro then R is not branched alkyl having 4 carbon atoms.
3. The composition of claim 1 or 2 wherein in formula (I) R is cycloalkyl having 3 to 6 carbon atoms.
4. The composition of any preceding claim wherein in formula (I) R is cyclopropyl.
5. The composition of any preceeding claim wherein in formula (I) X is fluoro or trifluoromethyl.
6. The composition of any preceeding claim wherein the compound of formula (I) is 3-fluoro-N-cyclopropylcinnamamide.
7. The composition of any of claims 1 to 5 wherein the compound of formula (I) is 3-trifluoromethyl-N-cyclopropylcinnamamide.
8. The composition of any preceeding claim wherein the compound of formula (I) has the trans configuration.
9. The composition of any preceeding claim wherein the carrier is a solid.
10. A composition according to any of claims 1 to 8 wherein the carrier is a liquid.
11. A sterile, injectable composition according to claim 10.
12. A composition according to any of claims 1 to 10 suitable for administration by the oral or rectal route.
13. A composition according to any of claims 1 to 12 in unit-dose form.
14. A composition according to claim 13 which is an orally ingestible tablet.
15. A unit-dose composition according to either of claims 13 and 14 which contains a compound of formula (I) in an amount in the range 100 to 500 mg.
16. A composition according to any of claims 1 to 8 which comprises a suspension of a compound of formula (I) in an orally ingestible liquid carrier.
17. A composition according to any preceding claim substantially as hereinbefore described with particular reference to the Examples.
18. A method for the preparation of a composition according to any of claims 1 to 17 which comprises admixture of the components thereof followed, where appropriate, by disposition of the bulk composition into unit doses thereof.
19. The compound of formula (I) as defined in any of claims 2 to 8.
20. 3-Fluoro-N-cyclopropylcinnamamide.
21. 3-Trifluoromethyl-N-cyclopropylcinnamamide.
22. 3-Bromo-N-cyclopropylcinnamamide.
23. 3-Bromo-N-isobutylcinnamamide.
24. 3-Fluorocinnamamide.
25. The trans isomer of a compound claimed in any of claims 19 to 24.
26. trans 3-Fluoro-N-cyclopropylcinnamamide.
27. trans 3-Trifluoromethyl-N-cyclopropylcinnamamide.
28. A method for the preparation of a compound according to any of claims 19 to 27 which comprises reaction of an amine R . NH3 with an acid of formula (II); m-X-Ph . CH:CH . CO3H or a reactive derivative thereof, wherein R and X have the meanings defined in formula (I).
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (51)
- **WARNING** start of CLMS field may overlap end of DESC **.53 CF3 iso-butyl 11654 CF3 isobutyl 9355 CF3 cyclobutyl 132 WHAT WE CLAIM IS:1. A pharmaccutical composition comprising a compound of formula (I):wherein X is fluoro, chloro, bromo, iodo or trifluoromethyl and R is branched alkyl having 4 to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, cycloalkylalkyl wherein the cycloalkyl moiety has 3 to 8 carbon atoms and the alkyl moiety has 1 to 3 carbon atoms and when X is fluoro or trifluoromethyl R may also be hydrogen or alkyl having 1 to 3 carbon atoms, in association with a pharmaceutically acceptable carrier.
- 2. The composition of claim 1 wherein in formula (I) when X is chloro then R is not branched alkyl having 4 carbon atoms.
- 3. The composition of claim 1 or 2 wherein in formula (I) R is cycloalkyl having 3 to 6 carbon atoms.
- 4. The composition of any preceding claim wherein in formula (I) R is cyclopropyl.
- 5. The composition of any preceeding claim wherein in formula (I) X is fluoro or trifluoromethyl.
- 6. The composition of any preceeding claim wherein the compound of formula (I) is 3-fluoro-N-cyclopropylcinnamamide.
- 7. The composition of any of claims 1 to 5 wherein the compound of formula (I) is 3-trifluoromethyl-N-cyclopropylcinnamamide.
- 8. The composition of any preceeding claim wherein the compound of formula (I) has the trans configuration.
- 9. The composition of any preceeding claim wherein the carrier is a solid.
- 10. A composition according to any of claims 1 to 8 wherein the carrier is a liquid.
- 11. A sterile, injectable composition according to claim 10.
- 12. A composition according to any of claims 1 to 10 suitable for administration by the oral or rectal route.
- 13. A composition according to any of claims 1 to 12 in unit-dose form.
- 14. A composition according to claim 13 which is an orally ingestible tablet.
- 15. A unit-dose composition according to either of claims 13 and 14 which contains a compound of formula (I) in an amount in the range 100 to 500 mg.
- 16. A composition according to any of claims 1 to 8 which comprises a suspension of a compound of formula (I) in an orally ingestible liquid carrier.
- 17. A composition according to any preceding claim substantially as hereinbefore described with particular reference to the Examples.
- 18. A method for the preparation of a composition according to any of claims 1 to 17 which comprises admixture of the components thereof followed, where appropriate, by disposition of the bulk composition into unit doses thereof.
- 19. The compound of formula (I) as defined in any of claims 2 to 8.
- 20. 3-Fluoro-N-cyclopropylcinnamamide.
- 21. 3-Trifluoromethyl-N-cyclopropylcinnamamide.
- 22. 3-Bromo-N-cyclopropylcinnamamide.
- 23. 3-Bromo-N-isobutylcinnamamide.
- 24. 3-Fluorocinnamamide.
- 25. The trans isomer of a compound claimed in any of claims 19 to 24.
- 26. trans 3-Fluoro-N-cyclopropylcinnamamide.
- 27. trans 3-Trifluoromethyl-N-cyclopropylcinnamamide.
- 28. A method for the preparation of a compound according to any of claims 19 to 27 which comprises reaction of an amine R . NH3 with an acid of formula (II); m-X-Ph . CH:CH . CO3H or a reactive derivative thereof, wherein R and X have the meanings defined in formula (I).
- 29. A method according to claim 28 wherein the reactive derivative of the acidof formula (II) is selected from an amide, an acid halide, the acid anhydride, and an alkyl ester or alkyl thioester where in each case the alkyl has 1 to 4 carbon atoms.
- 30. A method according to claim 29 wherein the acid halide is the acid chloride.
- 31. A method according to any of claims 28 to 30 for th: preparation of trans 3-fluoro-N-cyclopropylcinnamamide which comprises reaction of trans 3-fluorocinnamoyl chloride with cycloproylamine.
- 32. A method according to any of claims 28 to 30 for the preparation of trans 3-trifluoromethyl-N-cyclopropylcinnamamide which comprises reaction of trans 3-trifluoromethylcinnamoyl chloride with cyclopropylamine.
- 33. A method for the preparation of a compound according to any of claims 19 to 27 which comprises reaction of an amine R . NH2 with an alcohol or aldehyde of formula (III) or (IV) respectively,wherein R and X have the meanings defined in formula (I), in the presence of nickel peroxide and an inert liquid medium at a temperature below 10"C.
- 34. A method for the preparation of a compound according to any of claims 19 to 27 which comprises reaction of a compound of formula (V): R . NH . W with an acid of formula (II): m-X-Ph . CH: CM . COSH or a reactive derivative thereof, wherein R and X have the meanings defined in formula (I) and W is a leaving group.
- 35. A method according to claim 34 wherein the leaving group W is selected from -CO. H, -CONH21 -CONHR wherein R has same meaning as in formula (I), --CO . Alk, --COOAlk wherein each Alk represents alkyl having from one to four carbon atoms.
- 36. A method according to either of claims 34 and 35 wherein the reactive derivative of the acid of formula (II) is selected from the acid anhydride and an acid halide.
- 37. A method according to claim 36 wherein the acid halide is the acid chloride.
- 38. A method for the preparation of a compound according to any of claims 19 to 27 which comprises elimination of the elements of water, a hydrogen halide or molecular halogen, as appropriate, from a compound of formula (VI):wherein A and B are the same and each is halo or one of A and B is halo or hydroxy and the other is hydrogen, and R and X have the meanings defined in formula (I).
- 39. A method according to claim 38 wherein one of A and B is hydroxy and the other is hydrogen and the compound of formula (VI) is reacted with a dehydrating agent.
- 40. A method according to claim 38 wherein one of A and B is halo and the other is hydrogen and the compound of formula (VI) is treated with a base or is heated.
- 41. A method according to claim 38 wherein A and B are the same and each is halo and the compound of formula (VI) is treated with a suitable reducing agent.
- 42. A method of preparing a compound of formula (I) as defined in any of claims 19 to 27 substantially as hereinbefore described with particular reference to the Examples.
- 43. A compound of formula (I) as defined in any one of claims 19 to 27 when prepared by a method claimed in any one of claims 28 to 42.
- 44. A method for the treatment or prophylaxis of convulsions of a mammal excluding man comprising administration to said mammal of a non-toxic, effective anti-convulsant amount of a compound of formula (I) as defined in any one of claims I to 8 and 19 to 27.
- 45. The method as claimed in claim 44 wherein the convulsions are associated with grand mal, petit mal, psychomotor epilepsy or focal seizures.
- 46. The method as claimed in claim 44 or 45, wherein the compound is trans 3-trifluoromethyl-N-cyclopropylcinnamamid
- 47. A method of decreasing tone in skeletal muscles of a mammal excluding man which comprises administration to said mammal of a non-toxic effective tone decreasing amount of a compound of formula (I) as defined in any one of claims I to 8 and 19 to 27.
- 48. The method of claim 47 for the treatment of parkinsonism, chorea, arthritis, athetosis, status epilepticus, tetanus, myositis, spondylitis, cerebral palsy or multiple sclerosis.
- 49. The method as claimed in claim 47 or 48 wherein the compound of formula (I) is trans 3 -fluoro-N-cyclopropylcinnamamide.
- 50. The method according to any one of claims 44 to 49 wherein the compound is administered by the oral route.
- 51. The method according to any of claims 44 to 50 wherein the compound is administered at a dose of from 2 to 200 mg/kg mammal bodyweight per day.
Priority Applications (33)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB4168/76A GB1568401A (en) | 1976-02-03 | 1976-02-03 | Biologically active amides |
GR52690A GR66474B (en) | 1976-02-03 | 1977-02-02 | |
DD7700197200A DD130349A5 (en) | 1976-02-03 | 1977-02-02 | PROCESS FOR THE PRODUCTION OF CINEMA ACID AMIDES |
PL1977195740A PL119716B1 (en) | 1976-02-03 | 1977-02-02 | Process for preparing novel amides of cinnamic acid |
PL1977214782A PL119314B1 (en) | 1976-02-03 | 1977-02-02 | Process for preparing novel amides of cinammic acid |
ES455587A ES455587A1 (en) | 1976-02-03 | 1977-02-02 | A method of preparation of cinamamides. (Machine-translation by Google Translate, not legally binding) |
CS77695A CS245756B2 (en) | 1976-02-03 | 1977-02-02 | Production method of n-alkylsubstituted amides of cinnamic acid |
AR266409A AR218865A1 (en) | 1976-02-03 | 1977-02-02 | METHOD FOR PREPARING NEW CINAMAMIDE DERIVATIVES |
DE2704365A DE2704365C2 (en) | 1976-02-03 | 1977-02-02 | Cinnamides, processes for their production and pharmaceutical preparations which contain these compounds |
CS777652A CS245758B2 (en) | 1976-02-03 | 1977-02-02 | Production method of n-alkylsubstituted amides of cinnamic acid |
DK43177A DK43177A (en) | 1976-02-03 | 1977-02-02 | PROCEDURE FOR THE PREPARATION OF BIOLOGICALLY ACIVE AMIDES |
NZ18324177A NZ183241A (en) | 1976-02-03 | 1977-02-02 | Anti-convulsant compostions 3-(halo-or trifluoromethyl)-n-substituted cinnamaides and certain of these derivatives |
SE7701107A SE436870B (en) | 1976-02-03 | 1977-02-02 | SET TO MAKE NEW N-SUBSTITUTED Cinnamic Acid Amides |
HU77WE549A HU175435B (en) | 1976-02-03 | 1977-02-02 | Process for preparing biologically active substituted cinnamic acid amides |
FR7702865A FR2340303A1 (en) | 1976-02-03 | 1977-02-02 | CINNAMIC ACID AMIDS AND MEDICINAL PRODUCTS CONTAINING THESE SUBSTANCES |
CH125377A CH634551A5 (en) | 1976-02-03 | 1977-02-02 | Process for preparing cinnamides |
NL7701088A NL7701088A (en) | 1976-02-03 | 1977-02-02 | PROCESS FOR PREPARING CINNAMIC ACID AMIDES AND CINICLIC ACID AMIDES CONTAINING PHARMACEUTICAL PREPARATIONS AND THEIR USE IN MEDICINE. |
IE212/77A IE44862B1 (en) | 1976-02-03 | 1977-02-02 | Biologically active amides |
JP52010599A JPS6056700B2 (en) | 1976-02-03 | 1977-02-02 | Pharmaceutical compositions comprising new compounds, and methods for producing and using the same |
AT0065277A AT363926B (en) | 1976-02-03 | 1977-02-02 | METHOD FOR PRODUCING NEW Cinnamic Acid Amides |
IL51373A IL51373A (en) | 1976-02-03 | 1977-02-02 | Pharmaceutical compositions containing halocinnamides,certain such compounds and their preparation |
CA270,904A CA1109076A (en) | 1976-02-03 | 1977-02-02 | Biologically active amides |
BE174605A BE851020A (en) | 1976-02-03 | 1977-02-02 | AMIDES WITH BIOLOGICAL ACTIVITY |
ZA00770580A ZA77580B (en) | 1976-02-03 | 1977-02-02 | Biologically active amides |
FI770365A FI69625C (en) | 1976-02-03 | 1977-02-02 | FRAMEWORK FOR CUTTING OF THERAPEUTIC THERAPEUTIC CABLE |
US05/916,275 US4190674A (en) | 1976-02-03 | 1978-06-16 | 3-Fluoro-N-cyclopropylcinnamide |
AT121580A AT371801B (en) | 1976-02-03 | 1980-03-05 | METHOD FOR PRODUCING NEW Cinnamic Acid Amides |
CH504182A CH635820A5 (en) | 1976-02-03 | 1982-08-24 | Process for preparing cinnamides |
CH504282A CH636849A5 (en) | 1976-02-03 | 1982-08-25 | Process for the preparation of cinnamamides |
SE8300432A SE8300432D0 (en) | 1976-02-03 | 1983-01-28 | REACTIVE CINNIC ACID DERIVATIVES FOR THE PREPARATION OF BIOLOGICALLY ACTIVE AMIDES |
KE331183A KE3311A (en) | 1976-02-03 | 1983-07-25 | Biologically active amides |
SG43883A SG43883G (en) | 1976-02-03 | 1983-07-26 | Biologically active amides |
HK69983A HK69983A (en) | 1976-02-03 | 1983-12-15 | Biologically active amides |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB4168/76A GB1568401A (en) | 1976-02-03 | 1976-02-03 | Biologically active amides |
GB417076 | 1976-02-03 | ||
GB416976 | 1976-02-03 | ||
US71213576A | 1976-08-06 | 1976-08-06 | |
US71231876A | 1976-08-06 | 1976-08-06 | |
US71213476A | 1976-08-06 | 1976-08-06 |
Publications (1)
Publication Number | Publication Date |
---|---|
GB1568401A true GB1568401A (en) | 1980-05-29 |
Family
ID=27546490
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB4168/76A Expired GB1568401A (en) | 1976-02-03 | 1976-02-03 | Biologically active amides |
Country Status (20)
Country | Link |
---|---|
JP (1) | JPS6056700B2 (en) |
AR (1) | AR218865A1 (en) |
AT (1) | AT363926B (en) |
BE (1) | BE851020A (en) |
CA (1) | CA1109076A (en) |
CH (1) | CH634551A5 (en) |
CS (2) | CS245758B2 (en) |
DD (1) | DD130349A5 (en) |
DE (1) | DE2704365C2 (en) |
DK (1) | DK43177A (en) |
FI (1) | FI69625C (en) |
FR (1) | FR2340303A1 (en) |
GB (1) | GB1568401A (en) |
GR (1) | GR66474B (en) |
HU (1) | HU175435B (en) |
IE (1) | IE44862B1 (en) |
IL (1) | IL51373A (en) |
NL (1) | NL7701088A (en) |
PL (2) | PL119716B1 (en) |
SE (2) | SE436870B (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0714871B2 (en) * | 1989-02-02 | 1995-02-22 | 大正製薬株式会社 | Muscle relaxant |
DE19931116A1 (en) * | 1999-07-06 | 2001-01-11 | Bayer Ag | Process for the production of phenethylamines and new chemical compounds |
CN104513172B (en) * | 2013-09-30 | 2018-02-02 | 天士力医药集团股份有限公司 | Acid amides alkaloid, preparation method and its medicinal usage containing trifluoromethyl |
CN104432097B (en) * | 2014-12-16 | 2016-08-17 | 广州渔夫堡医药科技有限公司 | A kind of natural enriching substance of alleviating physical fatigue |
-
1976
- 1976-02-03 GB GB4168/76A patent/GB1568401A/en not_active Expired
-
1977
- 1977-02-02 NL NL7701088A patent/NL7701088A/en not_active Application Discontinuation
- 1977-02-02 JP JP52010599A patent/JPS6056700B2/en not_active Expired
- 1977-02-02 DK DK43177A patent/DK43177A/en not_active Application Discontinuation
- 1977-02-02 IE IE212/77A patent/IE44862B1/en unknown
- 1977-02-02 PL PL1977195740A patent/PL119716B1/en not_active IP Right Cessation
- 1977-02-02 FR FR7702865A patent/FR2340303A1/en active Granted
- 1977-02-02 DD DD7700197200A patent/DD130349A5/en not_active IP Right Cessation
- 1977-02-02 AT AT0065277A patent/AT363926B/en not_active IP Right Cessation
- 1977-02-02 IL IL51373A patent/IL51373A/en unknown
- 1977-02-02 CS CS777652A patent/CS245758B2/en unknown
- 1977-02-02 HU HU77WE549A patent/HU175435B/en not_active IP Right Cessation
- 1977-02-02 CA CA270,904A patent/CA1109076A/en not_active Expired
- 1977-02-02 GR GR52690A patent/GR66474B/el unknown
- 1977-02-02 FI FI770365A patent/FI69625C/en not_active IP Right Cessation
- 1977-02-02 DE DE2704365A patent/DE2704365C2/en not_active Expired
- 1977-02-02 CH CH125377A patent/CH634551A5/en not_active IP Right Cessation
- 1977-02-02 PL PL1977214782A patent/PL119314B1/en unknown
- 1977-02-02 AR AR266409A patent/AR218865A1/en active
- 1977-02-02 SE SE7701107A patent/SE436870B/en not_active IP Right Cessation
- 1977-02-02 CS CS77695A patent/CS245756B2/en unknown
- 1977-02-02 BE BE174605A patent/BE851020A/en not_active IP Right Cessation
-
1983
- 1983-01-28 SE SE8300432A patent/SE8300432D0/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
IL51373A (en) | 1981-12-31 |
JPS52116437A (en) | 1977-09-29 |
DE2704365A1 (en) | 1977-08-04 |
SE8300432L (en) | 1983-01-28 |
FI69625C (en) | 1986-03-10 |
AT363926B (en) | 1981-09-10 |
PL195740A1 (en) | 1979-05-07 |
FI770365A (en) | 1977-08-04 |
DD130349A5 (en) | 1978-03-22 |
NL7701088A (en) | 1977-08-05 |
SE7701107L (en) | 1977-08-04 |
SE8300432D0 (en) | 1983-01-28 |
PL119314B1 (en) | 1981-12-31 |
IE44862B1 (en) | 1982-04-21 |
FR2340303B1 (en) | 1979-04-13 |
FI69625B (en) | 1985-11-29 |
IL51373A0 (en) | 1977-04-29 |
CS245758B2 (en) | 1986-10-16 |
DE2704365C2 (en) | 1986-03-20 |
IE44862L (en) | 1977-08-03 |
GR66474B (en) | 1981-03-23 |
PL119716B1 (en) | 1982-01-30 |
CA1109076A (en) | 1981-09-15 |
HU175435B (en) | 1980-07-28 |
SE436870B (en) | 1985-01-28 |
AR218865A1 (en) | 1980-07-15 |
JPS6056700B2 (en) | 1985-12-11 |
CH634551A5 (en) | 1983-02-15 |
ATA65277A (en) | 1981-02-15 |
CS245756B2 (en) | 1986-10-16 |
DK43177A (en) | 1977-08-04 |
FR2340303A1 (en) | 1977-09-02 |
BE851020A (en) | 1977-08-02 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PS | Patent sealed [section 19, patents act 1949] | ||
704A | Declaration that licence is not available as of right for an excepted use (par. 4a/1977) | ||
PCNP | Patent ceased through non-payment of renewal fee |