CA2009009A1 - Pharmaceutical use for cinnamamide derivatives - Google Patents
Pharmaceutical use for cinnamamide derivativesInfo
- Publication number
- CA2009009A1 CA2009009A1 CA002009009A CA2009009A CA2009009A1 CA 2009009 A1 CA2009009 A1 CA 2009009A1 CA 002009009 A CA002009009 A CA 002009009A CA 2009009 A CA2009009 A CA 2009009A CA 2009009 A1 CA2009009 A1 CA 2009009A1
- Authority
- CA
- Canada
- Prior art keywords
- butenamide
- cyclopropyl
- cinnamamide derivative
- cinnamamide
- formula
- 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.)
- Abandoned
Links
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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Neurology (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pain & Pain Management (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurosurgery (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Biomedical Technology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT
A cinnamamide derivative represented by the formula
A cinnamamide derivative represented by the formula
Description
X()0~ 9 1 E~ACKGROUND OF THE INVENTION
~1) Field of the Invention The present invention relates to a new pharmaceutical use for cinnamamide derivatives and more particularly to use of cinnamamide derivatives for centrally relaxing muscle tone.
~1) Field of the Invention The present invention relates to a new pharmaceutical use for cinnamamide derivatives and more particularly to use of cinnamamide derivatives for centrally relaxing muscle tone.
(2) Prior Art The cinnamamide derivatives of the present invention have not been reported except that (E)-N-cyclopropyl-3-(3-chlorophenyl)-2-butenamide has disclosed as showing sedative or taming action in J.
Med. Chem., vol. 9 (No. S), page 675 - 681 (1966). The drugs showing the sedative or taming action lower the abnormally high psychic state of the upper central nervous system or depress the hyperemotion. On the contrary, the muscle relaxant normalizes the disorder of motor nervous system. Therefore, these two pharma-cological actions are different apparently each other.
Accordingly, it has heretofore been realized that the muscle relaxant is different from the sedative agent in the object of the use.
Furthermore, there are known other cinnamamide derivatives having the muscle relaxing activity, of which a typical compound i5 cinflumide that has the most preferred effect (Japanese Patent Publication z~ )9 1 No. 60-56700).
As a result of the earnest researches, the present inventors have found some cinnamamide deriva-tives to have much stronger and prolonged centrally-acting muscle relaxation activity, and have accomplishedthe present invention.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a method for relaxing muscle tone which comprises administering to a patient a pharmaceutically effective amount of a cinnamamide derivative represented by the formula ~ NH
where X is a halogen atom.
In one aspect of the present invention, there is provided use of a cinnamamide derivative of Formula I
for the manufacture of a pharmaceutical composition for relaxing muscle tone.
In further another aspect of the present invention, there is provided a pharmaceutical composition for relaxing muscle tone which comprises a cinnamamide derivative represented by Formula I as 2~0~9 1 active ingredient and a pharmaceutically acceptable carrier~
~ETAILED DESCRIPTION OF THE INVENTION
In Formula I, the halogen atom refers to a s fluorine, chlorine, bromine or iodide atom, and preferably a fluorine or chlorine atom.
The compound of Formula I can be prepared, for example, as follows: a (E)-3-(3-halogenophenyl)-2-butenoic acid well-known is first reacted with an ordinary halogenating agent (e.g., thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride, thionyl bromide or phosphorus tribromide) to give an acid halide of the formula ~ COX' II
wherein X is as defined above, and X' is a halogen atom.
Although the halogenating agent itself in this reaction can be a solvent, the reaction is also achieved in an inert-solvent (e.g., benzene, toluene, tetrahydrofuran, ether, methylene chloride or chloroform) with stirring at room temperature to the reflux temperature of the solvent for 30 minutes to 5 hours. A catalyst is not necessarily used, but acceleration of the reaction can 2~ )9 1 be achieved by the addition of a catalystic amount to an equimolar amount of a catalyst such as pyridine, triethylamine or N,N-dimethylformamide.
The compound of Formula II dissolved in the same inert-solvent as described above is then reacted with cyclopropylamine to give the compound of Formula I.
In order to eliminate the halogenated hydrogen which forms in the reaction, it is preferable to use more than two molar equivalents of cyclopropylamine, or it is preferable to coexist a tert-amine such as pyridine or triethylamine. The reaction is carried out at from -30 to 50C, and finished by 1 to 24 hours.
Alternatively, a (E)-3-(3-halogenophenyl)-2-butenoic acid is reacted with an alkyl halogenocarbonate (e.g., methyl chlorocarbonate, ethyl chlorocarbonate and isobutyl chlorocarbonate) in the presence of a base (e.g., triethylamine, diisopropylethylamine and N-methylmorpholine) in the same inert-solvent as described above at -30 to 30C for 0.2 to 3 hours to give a mixed acid anhydride represented by the formula ~ C02C02R III
wherein X is as defined above and R is an alkyl group having 1 to 7 carbon atoms, which is then in the 2 ~ 9 l reaction solution, without isolation, reacted with cyclopropylamine at the same temperature to give the compound of Formula I.
The compounds of Formula I exhibit remarkable muscle relaxant and rigidity mitigation activity. On the other hand, their sedative activity is weak at the dose effective to relax muscle tone. Accordingly, these compounds are useful as the therapeutic agents of the disorder of motor nervous system such as dolorous muscle spasm te.g., low-back pain and back pain, and herniated disc of the spine) or spastic paralysis such as the cerebral injuries. For these purposes, the compound of Formula I is mixed with suitable pharma-ceutically acceptable carriers for solid or liquid form to give the pharmaceutical preparation for oral or parenteral administration. Examples of the pharma-ceutical preparation are solid forms such as tablets, pills, capsules and granules, liquid forms such as injectional solutions, syrups and emulsions, and external forms such as ointments and suppositories, all of which can be prepared according to conventional pharmaceutical practices. The carriers in the above-mentioned preparations can include ordinary additives such as auxiliaries, stabilizers, wetting agents and emulsifiers. For example, there can be used solublizers (e.g., injectional distilled water, physiological saline solution and Ringer's solution) and preservers (e.g., methyl p-oxybenzoate and propyl p-oxybenzoate) for 2~ Q~
l injectional solutions; and used sorbitol syrup, methyl-cellulose, glucose, sucrose syrup, hydroxyethylcellu-lose, food oil, glycerin, ethanol, water, emulsifers (e.g., gum arabic and lecithin) and detergents (e.g., ~rween or Span) for syrups and emulsions. For the solid forms, there can be used excipients (e.g., lactose, corn starch and mannitol), lubricants (calcium phosphate, magnesium stearate and tulc), binders (e.g., sodium carboxymethylcellulose and hydroxypropylcellulose), disintegraters (e.g., crystal cellulose, calcium carboxymethylcellulose) and fluid accelerators (e.g., light silicic anhydride).
The dosage of the compound of Formula I
depends on the age of the patient, the kind and conditions of the disease, but usually it is from 5 to 1000 mg in single or several divided doses per adult per day.
Then, the experiments are illustrated below in order to show the effects of the compounds of Formula I.
Experiment 1 [Inhibition test of the mesocephalous decerebrate rididity]
The rigidity animals were prepared according to the method of Ono et al [Gen. Pharm., vol. 18, page 57-59 (1987)].
Four male Wistar rats weighing 250 to 350 g were used for each group. The animals were anesthetized with ethyl ether and fixed on a brain stereotaxic 2~ 9 1 apparatus to break the midbrain bilaterally (APO, V-3, L
* 1.5). The advanced rigidity occurred in the hind limb with awaking from the ethyl ether anesthesia. The test drugs [A; (E)-N-cyclopropyl-3-(3-chlorophenyl)-2-butenamide, B; (E)-N-cyclopropyl-3-(3-fluorophenyl)-2-butenamide and C; cinflumide] dissolved in propylene glycol were each administered intravenously in the amount of 5 mg/kg or 10 mg/kg (0.1 ml per 100 g of rat), and these test drugs suspended in 0.4% aqueous carboxymethylcellulose solution were each administered intraduodenally in the amount of 50 mg/kg (0.1 ml per 100 g of rat) to determine the inhibition time of the rigidity.
Results are shown in Table 1.
Table 1 Dose Dose Drug (mg/kg i-v-) (mg/kg i-d-) C 6 12 36 *
*; The values show the length of time (minutes) during which the inhibition action occurs.
Experiment 2[Inhibition of Anemic Decerebrate rigidity]
The rigidity animals were prepared according to the method of Fukuda et al [Japan J. Pharmacol., vol.
24, page 810-813 (1974)].
2~ )9 1 Four male Wistar rats weighing 250 to 350 g were used for each group.
The animals were anesthetized with ethyl ether and carotid artery was ligated bilaterally. A round hole was digged in the suboccipital skeleton and the basal artery was coagulated using a bipolar electro-coagulator. The advanced rigidity occurred on the fore limb with awaking from the ethyl ether anesthesia. The drugs [A; (E)-N-cyclopropyl-3-(3-chlorophenyl)-2-butenamide, B; (E)-N-cyclopropyl-3-(3-fluorophenyl)-2-butenamide, and C; cinflumide] dissolved in polyethylene glycol ~00 were each administered intravenously in the amount of 5 mg/kg or 10 mg/kg (0.1 ml per 100 g of rat) to determine the inhibition time of the rigidity.
Results are shown in Table 2.
Table 2 Dose Drug (mg/kg i.v.) S '1-0 A 9 13 *
C _ 8 *; The values show the length of time (minutes) during which the inhibition occurs.
1 Experiment 3 [Straub tail reaction]
Test was carried out according to the method of Ellis et al [Neuropharmacology, vol. 13, page 211 to 214 ~1974)].
Six male ICR mice weighing 20 - 30 g were used as the animals for each group. The drugs [A; (E)-N-cyclopropyl-3-(3-chlorophenyl)-2-butenamide, and C;
cinflumide] suspended in 0.4% aqueous carboxymethyl-cellulose solution were each administered orally to the animals in the amounts of 50, 70.7, 100 and 140 mg/kg (0.1 ml per 10 g of mouse). After 15 minutes, 15 mg/kg of morphine hydrochloride were administered subcutaneously. After 30 minutes, the tail-raising reaction was determined. The muscle relaxation activity was judged as positive in case where the drug produces the value of less than 45 degrees of the tail-raising's angle, and the inhibition rate was culculated.
Results are shown in Table 3.
Table 3 Dose Drug (mg/kg i.v.) . . .
5070.7 100 140 A 4040 100 100 *
*; The values show the inhibition rate (%).
2~ )9 1 Experiment 4 [Spontaneous motor activity test]
Six male ICR mice weighing 20 - 30 g were used as the test animals for each group. The test drugs [A:
(E)-N-cyclopropyl-3-(3-chlorophenyl)-2-butenamide and B:
(E)-N-cyclopropyl-3-(3-fluorophenyl)-2-butenamide]
suspended in 0.4% aqueous carboxymethylcellulose solution were each administered orally to mice in the amounts of 50, 70.7 and 100 mg/kg (0.1 ml per 10 g of mouse). The control group were administered with 0.4%
aqueous carboxymethylcellulose solution only. After 15 minutes, mice were placed in ANIMEX apparatus (manufactured by Muromachi Kikai K.K.) to determine the spontaneous moter activity for 30 minutes.
Results after 30 minutes of the administration are shown in Table 4.
From the results the group treated with the test drugs was found not to have substantial inhibition activity when compared with the control group.
Table 4 .. __ . .
Dose Spontaneous moter activity Drug (mg/kg p.o.)(Counts/30 minutes) 1736.0 + 366.6 A 70.7 1570.2 + 326.9 Control2116.0 + 256.6 _ 70.72264.2 + 506.0 B 100 1667.8 + 152.4 Control2128.7 + 228.0 2~ )9 1 Experiment 5 [Acute toxicity test~
Ten male ICR mice weighing 25 to 34 g were used. (E)-N-cyclopropyl-3-(3-chlorophenyl)-2-butenamide suspended in 0.4% aqueous carboxymethylcellulose S solution was each administered orally to mice in the amount of 0.1 ml per 10 g of mice. The survivals were observed for 7 days after administration, but no death occurred in case of the dose of 1 g/kg. The LD50 values were more than 1 g/kg p.o.
The present invention is illustrated by the following examples in more detail, and Compounds 1 and 2 in Examples 1 to 5 mean (E)-N-cyclopropyl-3-(3-chlorophenyl)-2-butenamide and (E)-N-cyclopropyl-3-(3-fluorophenyl)-2-butenamide, respectively.
Example 1 (Tablets) Compound 1 600 g Crystal cellulose 120 g Corn starch 125 g Hydroxypropylcellulose45 g Magnesium stearate 10 g Total 900 g The above components were mixed according to an ordinary manner and tableted to give 9 mm diameter tablets weighing 300 mg.
2~ )9 1 Example 2 (Cupseles~
Compound 2 600 g Crystal cellulose 150 g Corn starch 140 g Magnesium stearate 10 g Total 900 g The above components were mixed according to an ordinary manner, and each 300 mg of the mixture was filled into a No. 1 cupsule.
Example 3 (Granules) Compound 1 200 g Mannitol 300 g Corn starch 450 g Magnesium stearate 10 g Hydroxypropylcellulose50 g Total 1010 g Granules were prepared from the above components by a wet granulation method.
Example 4 (Powders) Compound 1 200 9 Lactose 800 g Total 1000 g ~ 9 1 The above components were mixed uniformly according to an ordinary manner to give powders, each 1000 mg of which were filled into a pack.
Example 5 Fifty g of Compound 2 was dissolved in 1000 ml of distilled water for injection and filled into 2 ml ampules.
Example 6 To a solution of 18.0 g of (E)-3-(3-fluoro-phen~l)-2-butenoic acid in 200 ml of benzene was added 14.S ml of thionyl chloride, and the mixture was stirred at reflux under heating. The benzene and the excess amount of thionyl chloride were evaporated under reduced pressure, and the residue was concentrated to give 19 g of the crude acid cloride. To a solution of the crude chloride in 200 ml of toluene was added dropwise a solu-tion of 15.2 ml of cyclopropylamine in 50 ml of toluene under ice-cooling with stirring, and the mixture was stirred at room temperature for 6 hours. The reaction solution was washed, in turn, with water, a saturated a~ueous bicarbonate solution, dilute hydrochloride and water, and dried over magnesium sulfate. The toluene was evaporated under reduced pressure, and the residue was recrystallized from n-hexane - acetone to give 12.9 g of (E)-N-cyclopropyl-3-(3-fluorophenyl)-2-butenamide as colorless needles.
m.p. 119.0 - 120.5C.
Z~ Q~
1 Example 7 To a solution of 18.0 9 of (E)-3-(3-fluorophenyl)-2-butenoic acid in 200 ml of toluene was added 13.9 ml of triethylamine under cooling and a nitrogen atmosphere with stirring, followed by the addition of 13.0 ml of isobutyl chlorocarbonate, and then the solution was stirred at room temperature for 30 minutesO To the reaction solution cooled on ice was added dropwise 7.6 ml of cyclopropylamine with stirring, and the mixture was stirred at room temperature for 2 hours. Then, following a procedure similar to that of Example 6 to give 14.0 g of (E)-N-cyclopropyl-3-(3-fluorophenyl)-2-butenamide.
m.p. 119.0 - 120.5C.
Following a procedure similar to that of Example 7, there was obtained (E)-N-cyclopropyl-3-(3-bromophenyl)-2-butenamide.
m.p. 129.0 - 131.5C.
Med. Chem., vol. 9 (No. S), page 675 - 681 (1966). The drugs showing the sedative or taming action lower the abnormally high psychic state of the upper central nervous system or depress the hyperemotion. On the contrary, the muscle relaxant normalizes the disorder of motor nervous system. Therefore, these two pharma-cological actions are different apparently each other.
Accordingly, it has heretofore been realized that the muscle relaxant is different from the sedative agent in the object of the use.
Furthermore, there are known other cinnamamide derivatives having the muscle relaxing activity, of which a typical compound i5 cinflumide that has the most preferred effect (Japanese Patent Publication z~ )9 1 No. 60-56700).
As a result of the earnest researches, the present inventors have found some cinnamamide deriva-tives to have much stronger and prolonged centrally-acting muscle relaxation activity, and have accomplishedthe present invention.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a method for relaxing muscle tone which comprises administering to a patient a pharmaceutically effective amount of a cinnamamide derivative represented by the formula ~ NH
where X is a halogen atom.
In one aspect of the present invention, there is provided use of a cinnamamide derivative of Formula I
for the manufacture of a pharmaceutical composition for relaxing muscle tone.
In further another aspect of the present invention, there is provided a pharmaceutical composition for relaxing muscle tone which comprises a cinnamamide derivative represented by Formula I as 2~0~9 1 active ingredient and a pharmaceutically acceptable carrier~
~ETAILED DESCRIPTION OF THE INVENTION
In Formula I, the halogen atom refers to a s fluorine, chlorine, bromine or iodide atom, and preferably a fluorine or chlorine atom.
The compound of Formula I can be prepared, for example, as follows: a (E)-3-(3-halogenophenyl)-2-butenoic acid well-known is first reacted with an ordinary halogenating agent (e.g., thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride, thionyl bromide or phosphorus tribromide) to give an acid halide of the formula ~ COX' II
wherein X is as defined above, and X' is a halogen atom.
Although the halogenating agent itself in this reaction can be a solvent, the reaction is also achieved in an inert-solvent (e.g., benzene, toluene, tetrahydrofuran, ether, methylene chloride or chloroform) with stirring at room temperature to the reflux temperature of the solvent for 30 minutes to 5 hours. A catalyst is not necessarily used, but acceleration of the reaction can 2~ )9 1 be achieved by the addition of a catalystic amount to an equimolar amount of a catalyst such as pyridine, triethylamine or N,N-dimethylformamide.
The compound of Formula II dissolved in the same inert-solvent as described above is then reacted with cyclopropylamine to give the compound of Formula I.
In order to eliminate the halogenated hydrogen which forms in the reaction, it is preferable to use more than two molar equivalents of cyclopropylamine, or it is preferable to coexist a tert-amine such as pyridine or triethylamine. The reaction is carried out at from -30 to 50C, and finished by 1 to 24 hours.
Alternatively, a (E)-3-(3-halogenophenyl)-2-butenoic acid is reacted with an alkyl halogenocarbonate (e.g., methyl chlorocarbonate, ethyl chlorocarbonate and isobutyl chlorocarbonate) in the presence of a base (e.g., triethylamine, diisopropylethylamine and N-methylmorpholine) in the same inert-solvent as described above at -30 to 30C for 0.2 to 3 hours to give a mixed acid anhydride represented by the formula ~ C02C02R III
wherein X is as defined above and R is an alkyl group having 1 to 7 carbon atoms, which is then in the 2 ~ 9 l reaction solution, without isolation, reacted with cyclopropylamine at the same temperature to give the compound of Formula I.
The compounds of Formula I exhibit remarkable muscle relaxant and rigidity mitigation activity. On the other hand, their sedative activity is weak at the dose effective to relax muscle tone. Accordingly, these compounds are useful as the therapeutic agents of the disorder of motor nervous system such as dolorous muscle spasm te.g., low-back pain and back pain, and herniated disc of the spine) or spastic paralysis such as the cerebral injuries. For these purposes, the compound of Formula I is mixed with suitable pharma-ceutically acceptable carriers for solid or liquid form to give the pharmaceutical preparation for oral or parenteral administration. Examples of the pharma-ceutical preparation are solid forms such as tablets, pills, capsules and granules, liquid forms such as injectional solutions, syrups and emulsions, and external forms such as ointments and suppositories, all of which can be prepared according to conventional pharmaceutical practices. The carriers in the above-mentioned preparations can include ordinary additives such as auxiliaries, stabilizers, wetting agents and emulsifiers. For example, there can be used solublizers (e.g., injectional distilled water, physiological saline solution and Ringer's solution) and preservers (e.g., methyl p-oxybenzoate and propyl p-oxybenzoate) for 2~ Q~
l injectional solutions; and used sorbitol syrup, methyl-cellulose, glucose, sucrose syrup, hydroxyethylcellu-lose, food oil, glycerin, ethanol, water, emulsifers (e.g., gum arabic and lecithin) and detergents (e.g., ~rween or Span) for syrups and emulsions. For the solid forms, there can be used excipients (e.g., lactose, corn starch and mannitol), lubricants (calcium phosphate, magnesium stearate and tulc), binders (e.g., sodium carboxymethylcellulose and hydroxypropylcellulose), disintegraters (e.g., crystal cellulose, calcium carboxymethylcellulose) and fluid accelerators (e.g., light silicic anhydride).
The dosage of the compound of Formula I
depends on the age of the patient, the kind and conditions of the disease, but usually it is from 5 to 1000 mg in single or several divided doses per adult per day.
Then, the experiments are illustrated below in order to show the effects of the compounds of Formula I.
Experiment 1 [Inhibition test of the mesocephalous decerebrate rididity]
The rigidity animals were prepared according to the method of Ono et al [Gen. Pharm., vol. 18, page 57-59 (1987)].
Four male Wistar rats weighing 250 to 350 g were used for each group. The animals were anesthetized with ethyl ether and fixed on a brain stereotaxic 2~ 9 1 apparatus to break the midbrain bilaterally (APO, V-3, L
* 1.5). The advanced rigidity occurred in the hind limb with awaking from the ethyl ether anesthesia. The test drugs [A; (E)-N-cyclopropyl-3-(3-chlorophenyl)-2-butenamide, B; (E)-N-cyclopropyl-3-(3-fluorophenyl)-2-butenamide and C; cinflumide] dissolved in propylene glycol were each administered intravenously in the amount of 5 mg/kg or 10 mg/kg (0.1 ml per 100 g of rat), and these test drugs suspended in 0.4% aqueous carboxymethylcellulose solution were each administered intraduodenally in the amount of 50 mg/kg (0.1 ml per 100 g of rat) to determine the inhibition time of the rigidity.
Results are shown in Table 1.
Table 1 Dose Dose Drug (mg/kg i-v-) (mg/kg i-d-) C 6 12 36 *
*; The values show the length of time (minutes) during which the inhibition action occurs.
Experiment 2[Inhibition of Anemic Decerebrate rigidity]
The rigidity animals were prepared according to the method of Fukuda et al [Japan J. Pharmacol., vol.
24, page 810-813 (1974)].
2~ )9 1 Four male Wistar rats weighing 250 to 350 g were used for each group.
The animals were anesthetized with ethyl ether and carotid artery was ligated bilaterally. A round hole was digged in the suboccipital skeleton and the basal artery was coagulated using a bipolar electro-coagulator. The advanced rigidity occurred on the fore limb with awaking from the ethyl ether anesthesia. The drugs [A; (E)-N-cyclopropyl-3-(3-chlorophenyl)-2-butenamide, B; (E)-N-cyclopropyl-3-(3-fluorophenyl)-2-butenamide, and C; cinflumide] dissolved in polyethylene glycol ~00 were each administered intravenously in the amount of 5 mg/kg or 10 mg/kg (0.1 ml per 100 g of rat) to determine the inhibition time of the rigidity.
Results are shown in Table 2.
Table 2 Dose Drug (mg/kg i.v.) S '1-0 A 9 13 *
C _ 8 *; The values show the length of time (minutes) during which the inhibition occurs.
1 Experiment 3 [Straub tail reaction]
Test was carried out according to the method of Ellis et al [Neuropharmacology, vol. 13, page 211 to 214 ~1974)].
Six male ICR mice weighing 20 - 30 g were used as the animals for each group. The drugs [A; (E)-N-cyclopropyl-3-(3-chlorophenyl)-2-butenamide, and C;
cinflumide] suspended in 0.4% aqueous carboxymethyl-cellulose solution were each administered orally to the animals in the amounts of 50, 70.7, 100 and 140 mg/kg (0.1 ml per 10 g of mouse). After 15 minutes, 15 mg/kg of morphine hydrochloride were administered subcutaneously. After 30 minutes, the tail-raising reaction was determined. The muscle relaxation activity was judged as positive in case where the drug produces the value of less than 45 degrees of the tail-raising's angle, and the inhibition rate was culculated.
Results are shown in Table 3.
Table 3 Dose Drug (mg/kg i.v.) . . .
5070.7 100 140 A 4040 100 100 *
*; The values show the inhibition rate (%).
2~ )9 1 Experiment 4 [Spontaneous motor activity test]
Six male ICR mice weighing 20 - 30 g were used as the test animals for each group. The test drugs [A:
(E)-N-cyclopropyl-3-(3-chlorophenyl)-2-butenamide and B:
(E)-N-cyclopropyl-3-(3-fluorophenyl)-2-butenamide]
suspended in 0.4% aqueous carboxymethylcellulose solution were each administered orally to mice in the amounts of 50, 70.7 and 100 mg/kg (0.1 ml per 10 g of mouse). The control group were administered with 0.4%
aqueous carboxymethylcellulose solution only. After 15 minutes, mice were placed in ANIMEX apparatus (manufactured by Muromachi Kikai K.K.) to determine the spontaneous moter activity for 30 minutes.
Results after 30 minutes of the administration are shown in Table 4.
From the results the group treated with the test drugs was found not to have substantial inhibition activity when compared with the control group.
Table 4 .. __ . .
Dose Spontaneous moter activity Drug (mg/kg p.o.)(Counts/30 minutes) 1736.0 + 366.6 A 70.7 1570.2 + 326.9 Control2116.0 + 256.6 _ 70.72264.2 + 506.0 B 100 1667.8 + 152.4 Control2128.7 + 228.0 2~ )9 1 Experiment 5 [Acute toxicity test~
Ten male ICR mice weighing 25 to 34 g were used. (E)-N-cyclopropyl-3-(3-chlorophenyl)-2-butenamide suspended in 0.4% aqueous carboxymethylcellulose S solution was each administered orally to mice in the amount of 0.1 ml per 10 g of mice. The survivals were observed for 7 days after administration, but no death occurred in case of the dose of 1 g/kg. The LD50 values were more than 1 g/kg p.o.
The present invention is illustrated by the following examples in more detail, and Compounds 1 and 2 in Examples 1 to 5 mean (E)-N-cyclopropyl-3-(3-chlorophenyl)-2-butenamide and (E)-N-cyclopropyl-3-(3-fluorophenyl)-2-butenamide, respectively.
Example 1 (Tablets) Compound 1 600 g Crystal cellulose 120 g Corn starch 125 g Hydroxypropylcellulose45 g Magnesium stearate 10 g Total 900 g The above components were mixed according to an ordinary manner and tableted to give 9 mm diameter tablets weighing 300 mg.
2~ )9 1 Example 2 (Cupseles~
Compound 2 600 g Crystal cellulose 150 g Corn starch 140 g Magnesium stearate 10 g Total 900 g The above components were mixed according to an ordinary manner, and each 300 mg of the mixture was filled into a No. 1 cupsule.
Example 3 (Granules) Compound 1 200 g Mannitol 300 g Corn starch 450 g Magnesium stearate 10 g Hydroxypropylcellulose50 g Total 1010 g Granules were prepared from the above components by a wet granulation method.
Example 4 (Powders) Compound 1 200 9 Lactose 800 g Total 1000 g ~ 9 1 The above components were mixed uniformly according to an ordinary manner to give powders, each 1000 mg of which were filled into a pack.
Example 5 Fifty g of Compound 2 was dissolved in 1000 ml of distilled water for injection and filled into 2 ml ampules.
Example 6 To a solution of 18.0 g of (E)-3-(3-fluoro-phen~l)-2-butenoic acid in 200 ml of benzene was added 14.S ml of thionyl chloride, and the mixture was stirred at reflux under heating. The benzene and the excess amount of thionyl chloride were evaporated under reduced pressure, and the residue was concentrated to give 19 g of the crude acid cloride. To a solution of the crude chloride in 200 ml of toluene was added dropwise a solu-tion of 15.2 ml of cyclopropylamine in 50 ml of toluene under ice-cooling with stirring, and the mixture was stirred at room temperature for 6 hours. The reaction solution was washed, in turn, with water, a saturated a~ueous bicarbonate solution, dilute hydrochloride and water, and dried over magnesium sulfate. The toluene was evaporated under reduced pressure, and the residue was recrystallized from n-hexane - acetone to give 12.9 g of (E)-N-cyclopropyl-3-(3-fluorophenyl)-2-butenamide as colorless needles.
m.p. 119.0 - 120.5C.
Z~ Q~
1 Example 7 To a solution of 18.0 9 of (E)-3-(3-fluorophenyl)-2-butenoic acid in 200 ml of toluene was added 13.9 ml of triethylamine under cooling and a nitrogen atmosphere with stirring, followed by the addition of 13.0 ml of isobutyl chlorocarbonate, and then the solution was stirred at room temperature for 30 minutesO To the reaction solution cooled on ice was added dropwise 7.6 ml of cyclopropylamine with stirring, and the mixture was stirred at room temperature for 2 hours. Then, following a procedure similar to that of Example 6 to give 14.0 g of (E)-N-cyclopropyl-3-(3-fluorophenyl)-2-butenamide.
m.p. 119.0 - 120.5C.
Following a procedure similar to that of Example 7, there was obtained (E)-N-cyclopropyl-3-(3-bromophenyl)-2-butenamide.
m.p. 129.0 - 131.5C.
Claims (12)
1. A method for relaxing muscle tone which comprises administering to a patient a pharmaceutically effective amount of a cinnamamide derivative represented by the formula wherein X is a halogen atom.
2. A method according to claim 1, wherein the cinnamamide derivative is (E)-N-cyclopropyl-3-(3-chlorophenyl)-2-butenamide.
3. A method according to claim 1, wherein the cinnamamide derivative is (E)-N-cyclopropyl-3-(3-fluorophenyl)-2-butenamide.
4. A method according to claim 1, wherein a dosage of the cinnamamide derivative is from 5 to 1000 mg per adult per day.
5. A method according to claim 1, wherein the cinnamamide derivative is administered in the form of tablet, pill, capsule, granule, injectional solution, syrup, emulsion, ointment or suppository.
6. A pharmaceutical composition for relaxing muscle tone which comprises as an active ingredient a cinnamamide derivative represented by the formula wherein X is a halogen atom, and pharmaceutically acceptable carriers.
7. A pharmaceutical composition according to claim 6, wherein the cinnamamide derivative is (E)-N-cyclopropyl-3-(3-chlorophenyl)-2-butenamide.
8. A pharmaceutical composition according to claim 6, wherein the cinnamamide derivative is (E)-N-cyclopropyl-3-(3-fluorophenyl)-2-butenamide.
9. A pharmaceutical composition according to claim 6, wherein the composition is tablet, pill, capsule, granule, injectional solution, syrup, emulsion, ointment or suppository.
10. Use of a cinnamamide derivative represented by the formula wherein X is a halogen atom, for the manufacture of a pharmaceutical composition for relaxing muscle tone.
11. Use according to claim 10, wherein the cinnamamide derivative is (E)-N-cyclopropyl-3-(3-chlorophenyl)-2-butenamide.
12. Use according to claim 10, wherein the cinnamamide derivative is (E)-N-cyclopropyl-3-(3-fluorophenyl)-2-butenamide.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2415989 | 1989-02-02 | ||
| JP01-024159 | 1989-02-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2009009A1 true CA2009009A1 (en) | 1990-08-02 |
Family
ID=12130557
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002009009A Abandoned CA2009009A1 (en) | 1989-02-02 | 1990-01-31 | Pharmaceutical use for cinnamamide derivatives |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US5116877A (en) |
| EP (1) | EP0381508B1 (en) |
| JP (1) | JPH0714871B2 (en) |
| AT (1) | ATE91077T1 (en) |
| CA (1) | CA2009009A1 (en) |
| DE (1) | DE69002062T2 (en) |
| DK (1) | DK0381508T3 (en) |
| ES (1) | ES2058780T3 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007046721A2 (en) | 2005-10-20 | 2007-04-26 | Instytut Chemii Bioorganicznej Pan | A method of manufacturing 3-(4-hydroxyphenyl)propanoic acid amide, its application in the manufacture of anti-aging compositions and an anti-aging composition |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9101244D0 (en) * | 1991-01-19 | 1991-02-27 | Wellcome Found | Amide derivatives and their therapeutic use |
| FR2739216B1 (en) * | 1995-09-22 | 1997-10-24 | Commissariat Energie Atomique | METHOD OF TREATING METALLIC ALUMINUM-BASED FUELS AND / OR NUCLEAR TARGETS WITH TETRAMETHYLAMMONIUM HYDROXIDE SOLUTIONS |
| US7329767B2 (en) * | 2003-10-03 | 2008-02-12 | International Flavors & Fragrances Inc. | Conjugated dienamides, methods of production thereof, compositions containing same and uses thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1131727A (en) * | 1966-05-10 | 1968-10-23 | Smith Kline French Lab | Antidepressant n,n-dimethylcinnamamide compositions |
| FR2040181A1 (en) * | 1969-04-02 | 1971-01-22 | Lipha | |
| US4309444A (en) * | 1976-02-03 | 1982-01-05 | Burroughs Wellcome Co. | Biologically active amides |
| GB1568401A (en) * | 1976-02-03 | 1980-05-29 | Wellcome Found | Biologically active amides |
| US4190647A (en) * | 1979-01-26 | 1980-02-26 | Sloan-Kettering Institute For Cancer Research | Polypeptides and methods |
-
1990
- 1990-01-29 JP JP2018716A patent/JPH0714871B2/en not_active Expired - Lifetime
- 1990-01-29 US US07/471,596 patent/US5116877A/en not_active Expired - Fee Related
- 1990-01-31 CA CA002009009A patent/CA2009009A1/en not_active Abandoned
- 1990-02-01 EP EP90301082A patent/EP0381508B1/en not_active Expired - Lifetime
- 1990-02-01 AT AT90301082T patent/ATE91077T1/en active
- 1990-02-01 DE DE90301082T patent/DE69002062T2/en not_active Expired - Fee Related
- 1990-02-01 ES ES90301082T patent/ES2058780T3/en not_active Expired - Lifetime
- 1990-02-01 DK DK90301082.5T patent/DK0381508T3/en active
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007046721A2 (en) | 2005-10-20 | 2007-04-26 | Instytut Chemii Bioorganicznej Pan | A method of manufacturing 3-(4-hydroxyphenyl)propanoic acid amide, its application in the manufacture of anti-aging compositions and an anti-aging composition |
Also Published As
| Publication number | Publication date |
|---|---|
| DE69002062D1 (en) | 1993-08-05 |
| ES2058780T3 (en) | 1994-11-01 |
| JPH02288823A (en) | 1990-11-28 |
| DK0381508T3 (en) | 1993-08-02 |
| EP0381508A3 (en) | 1990-09-19 |
| US5116877A (en) | 1992-05-26 |
| EP0381508B1 (en) | 1993-06-30 |
| EP0381508A2 (en) | 1990-08-08 |
| DE69002062T2 (en) | 1993-10-21 |
| ATE91077T1 (en) | 1993-07-15 |
| JPH0714871B2 (en) | 1995-02-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR20140099492A (en) | Tricyclic compounds, compositions comprising them and uses thereof | |
| EP0248824B1 (en) | Use of cis-n-(2 aminocycloaliphatic) benzene acetamide and benzamide for the manufacture of anticonvulsants | |
| EP0381508B1 (en) | Use of cinnamamide for relaxing muscle tone | |
| EP0273744B1 (en) | Centrally-acting muscle relaxants | |
| JPS62181246A (en) | Novel oxidated alkyl derivatives of glutamic acids and aspartic acids having antagonistic activity against bioactive polypeptides and manufacture | |
| US4127671A (en) | P-acetamidophenyl diethylaminoacetate | |
| JPS63203691A (en) | Piperazinecarboxylic acid, its production method and pharmaceutical compositions containing it | |
| KR900003301B1 (en) | Method for preparing 2-piperazinyl-4-phenyl quinazoline derivatives and their salts | |
| JP3032053B2 (en) | Uridine derivatives and pharmaceuticals containing the same | |
| EP0853478B1 (en) | New n-acylated 4-hydroxyphenylamine derivatives with analgesic properties and pharmaceutical compositions containing them | |
| US3445517A (en) | Aryl acetamidines | |
| WO2011081445A2 (en) | Treatment use of ethylamino benzoic acid derivatives | |
| EP0045473B1 (en) | A pharmaceutical composition containing a benzofuran-carboxamide derivative as the active ingredient | |
| JPS6056142B2 (en) | New derivatives of thiazoline and their pharmaceutical applications | |
| JPH02292213A (en) | Carcinostatic agent | |
| SU1447283A3 (en) | Method of producing condensed derivatives of as-triazine | |
| JP2543955B2 (en) | Central muscle relaxant containing piperazine derivative | |
| EP0454459A2 (en) | Sulfonylalkanoic acid amide derivatives | |
| JPS59231057A (en) | Carboxylic acid amide compound and its derivative | |
| JP2582402B2 (en) | Isoxazolin-3-one derivatives and uses thereof | |
| JPH0453870B2 (en) | ||
| JP2802778B2 (en) | Homopiperazine derivatives and cerebral protective agents containing the same | |
| JPH051003A (en) | Cinnamic acid amide derivative | |
| JPH04352763A (en) | Sulfonylalkanoic acid amide derivative | |
| JPS63198622A (en) | Neutral muscle relaxant containing indole derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |