HUT65231A - Process for preparing butenamide derivatives and pharmaceutical compositions containing them as active ingredient - Google Patents

Abstract

The present invention relates to certain 3-phenyl-2-alkenamide derivatives, base salts and other physiologically functional derivatives thereof, pharmaceutical preparations containing them and the use of such compounds and preparations thereof in therapy, particularly as muscle relaxants, anxiolytics and anti-convulsants. Processes for the preparation of these 3-phenyl-2-alkenamides are also disclosed.

Description

FIELD OF THE INVENTION This invention relates to 3-phenyl-2-alkenamide derivatives, their physiologically acceptable reactive derivatives, to pharmaceutical compositions containing them, and to the use of the compounds and compositions in medicine, in particular as muscle relaxants, anxiolytics and anticonvulsants.

The hypnotic and sedative action of certain 3-phenyl-2-alkenamide derivatives, trivially known as cinnamamides, is known to Lot and Christiansen, J. Am. Pharm. Assoc. , 23, 788 (1934) and Van Heyningen et al., J. Med. Chem. 9, 675 (1966).

U.S. Pat. No. 4,190,674 discloses cinnamic acid derivatives useful in the treatment of convulsions in mammals, for muscle relaxation, for example in the treatment of increased skeletal muscle tone.

European Patent 0381508 mentions the use of certain cinnamic acid amides for relaxation of muscle tone, for example in the treatment of muscle spasms or spastic paralysis such as brain injury.

Many clinically effective muscle relaxants and antispasmodics, with adverse side effects of sedation and patient coordination, severely limit the utility of known compounds. Similar side effects have been found with medicines used to treat anxiety, such as benzodiazepines. Although their effects may be temporary, patients receiving such therapy are often unable to drive or engage in certain activities.

The side effects of potential muscle relaxant compounds can be determined experimentally by examining the efficacy of muscle relaxants and their potential as depressant [Drug Dev. Res., 2, 383 (1982)].

Surprisingly, it has been found that certain 3-phenyl-2-alkene amides have a potential muscle relaxant effect, but at the same time are substantially the side effect observed for sedation and lack of coordination with other known muscle relaxants. The compounds also have anti-anxiety and anticonvulsant effects.

According to the present invention there is provided 3-phenyl-2-alkenamide derivatives of the formula (I) or their basic salts or other physiologically reactive derivatives wherein R ¹ is C 1-6 alkyl,

R ² is hydrogen or C 3 -C 6 cycloalkyl,

R ³ is one or more ring substituents, preferably halogen, especially chloro, bromo, iodo or fluoro, or perhalo (C 1-4 alkyl) such as trifluoromethyl, with the proviso that

i) when R ¹ is methyl and R ² is cyclopropyl, one of R ³ or R ³ groups at the 2-position, and ii) the compound of formula (I) is not 3- (4-chlorophenyl) -2-butenamide .

The alkyl group may be straight or branched, preferably containing 1 to 3 carbon atoms, more preferably methyl or ethyl, or especially methyl.

Preferred compounds of formula (I) are those wherein R ¹ is methyl and / or R ² is cyclopropyl and / or one of R ³ or more R ³ substituents is a ring substituent at the 2-position, preferably bromo, chloro, , iodine or perhalomethyl, such as trifluoromethyl, or a basic salt or other physiologically acceptable reactive derivative thereof.

Particularly preferred compounds of formula I are those wherein R ¹ is methyl and / or R ² is cyclopropyl and / or R ^{3 is a} single ring substituent at the 2-position, preferably bromo, chloro, iodo or trifluoromethyl; or a basic salt or other physiologically acceptable reactive derivative thereof.

The basic salts or other physiologically acceptable reactive derivatives of the compounds of formula (I) are preferred, the (E) -isomers. Particularly preferred compounds of formula I are:

(E) -3- (2-Bromo-phenyl) -N-cyclopropyl-2-butenamide;

. (E) -N-cyclopropyl-3- (2-trifluoromethyl) phenyl)) - 2-butenamide;

. (E) -N-cyclopropyl-3- (2-iodophenyl) -2-butenamide;

(E) -N-cyclopropyl-3- (2,3-dichlorophenyl) -2-butenamide;

5. (E) -3- (2-Chloro-phenyl) -N-cyclopropyl-2-butenamide; and

6. (E) -3- (2-Bromophenyl) -2-butenamide.

The compounds of formula (I) and their basic salts or other physiologically acceptable reactive derivatives thereof are hereinafter referred to as the compounds of the invention.

• · ·

J-5 The compounds of formula I may exist in various geometric isomeric forms and mixtures thereof in any ratio. The invention encompasses geometric isomeric forms or mixtures thereof, including the (E) and (Z) isomers of the compounds of formula (I) and mixtures thereof in any ratio.

The term physiologically reactive derivatives refers to any other compound which, directly or indirectly, upon administration of the compound produces either the same or an effective meta-titanium residue or residue thereof.

The compounds of the invention include base salts such as an appropriate base such as alkali metal (e.g. sodium), alkaline earth metal (e.g. magnesium) salts resulting from the ammonium and NX4 ⁴ · salts, wherein X 1 - represents 4 carbon atoms.

For therapeutic purposes, physiologically acceptable salts of the compounds of formula (I), i.e. salts derived from a physiologically acceptable base, are preferred. Salts of physiologically unacceptable bases may also be used, for example, in the preparation or purification of the compound. Whether or not they are physiologically acceptable basic salts, these salts are within the scope of the invention.

The compounds of the invention may be used in medicine for the treatment or prevention of the following conditions:

- conditions associated with abnormally increased muscle tone;

cramping conditions and

- anxiety states.

• · ·

The compounds of the present invention are particularly valuable for the relaxation of skeletal muscle in convulsive, hypertonic and hyperkinetic states.

The compounds are particularly useful in the symptomatic alleviation and treatment of conditions such as spinal cord injury, Parkinson's disease, chorea, arthritis, atethosis, status epilepticus, tetanus, and particularly in the treatment of conditions such as myositis, cerebral inflammation, cerebral edema, diseases and multiple sclerosis.

The compounds may also be used to treat stroke-induced muscle spasms such as lower back pain.

The compounds may also be used in seizures such as grand epilepsy, petit epilepsy, psychomotor epilepsy and focal seizure. The compounds of the invention can be used to treat anxiety, including general anxiety disorder, obsessive-compulsive disorder, panic disorder, phobic anxiety, separation anxiety, and post-traumatic stress disorder.

The compounds may also be used as a pre-surgical muscle relaxant and anti-anxiety agent.

The invention thus encompasses:

a) for the treatment and prevention of abnormally increased muscle tone in cramps and anxiety states in mammals, including man, and mice, and the method comprises the mammal being effective non-toxic. Treated with an amount of a compound of the invention.

b) The compound of the invention is used in the manufacture of a medicament for the prevention of abnormally elevated muscle tone, convulsions and anxiety states.

The compounds of the present invention may also be combined with other drugs useful for the treatment of abnormally increased muscle tone, such as codeine, acetaminophen, phenacetin or ibuprofen.

The pharmaceutical compositions of the present invention contain the active ingredient which may be administered by any route, for example, orally, rectally, nasally, topically, including the buccal and sublingual route, and vaginally and parenterally, including subcutaneous, intramuscular, intravenous and intradermal administration. The preferred route of administration will vary with the age and condition of the patient, depending on the nature of the disorder and the drug selected.

For example, the amount of active ingredient required to treat increased muscle tone, cramps, and anxiety will, of course, depend on a number of factors, including the severity of the disease, the patient, and the amount is determined by the physician.

Generally, a suitable dose of the compound of formula (I) or its basic salt or other suitable compound for the above conditions is appropriate.

Of its 8 physiologically acceptable derivatives, 0.05 to 100 mg / kg body weight / day, preferably 0.1 to 50 mg / kg body weight / day, more preferably 0.5 to 20 mg / kg body weight / day, and optimally 3 mg / kg of starting material. kg of body weight per day. Preferably, the desired dose is administered in divided doses of 2, 3, 4, 5, 6 or more at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for example, 1 to 1500 mg, preferably 5 to 1000 mg, more preferably 10 to 700 mg of active ingredient per unit dosage form.

The active ingredient may be administered alone, but it is preferable that it be formulated. The compositions contain at least one active ingredient and one or more suitable carriers and optionally other pharmaceutically acceptable active ingredients. The carrier must be appropriate in the sense that it is compatible with the other components and not deleterious to the patient.

The compositions are suitable for oral, rectal, nasal, topical (including buccal and sublingual) and vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. The compositions are preferably formulated in a unit dosage form known per se. The preparation involves mixing the active ingredient with the carrier which may be one or more accessory ingredients. In general, the formulations are prepared in a homogeneous state by intimately mixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, pouring the product into a mold.

♦ · «··· • * 4 · · ·

The compositions of the invention may be used for oral administration in the form of capsules, pills, tablets containing a predetermined amount of the active ingredient, or in the form of powders or granules, solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water liquid emulsion. in oil type liquid emulsion. The active ingredient may also be in the form of a pill, electuary or paste.

The tablet may be prepared by compression or melting, optionally with one or more accessory ingredients. Compressed tablets are prepared by incorporating, in a suitable machine, the active ingredient in free-flowing form such as powder or granules, optionally with a binder such as povidone, gelatin, hydroxypropylmethylcellulose or a lubricant, inert diluent, preservative, disintegrant. such as sodium starch glycolate, crosslinked povidone, crosslinked sodium carboxymethylcellulose, and a surfactant or dispersant, and then pressed.

The melted tablets are prepared in a suitable machine by melting the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or divided to provide the active ingredient in slow or regular disintegration using, for example, hydroxypropylmethylcellulose in varying amounts, to obtain the desired disintegration profit. The tablets may be coated with an enteric coating, and the active ingredient may be coated with the enteric coating rather than the enteric coating.

- It is released in 10 stomachs.

Formulations suitable for oral administration may also contain a buffering agent which is intended to neutralize the acidity of the stomach. These buffers are selected from various organic or inorganic materials, for example, weak acids or bases, mixed with their conjugated salts.

Formulations for topical administration in the mouth may include lozenges containing the active ingredient in flavored form, usually in sucrose, tragacanth or gum arabic, and in the form of lozenges containing the active ingredient in inert ingredients such as gelatin and glycerol, or in sucrose and gum arabic. containing the active ingredient in a suitable liquid carrier.

Formulations for rectal administration may be in the form of suppositories containing a suitable base such as cocoa butter or salicylate.

Formulations for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art.

Formulations for parenteral administration contain an aqueous or anhydrous isotonic sterile solution for injection that may contain antioxidants, buffers, bacteriostats and solvents which render the product isotonic with the blood of the patient, and may include aqueous and anhydrous sterile suspensions.

Gums, such as liposomes, or other microparticulate systems, wherein the compositions are administered to blood components or one or more organs. The formulations may be presented in unit dose or multi-dose sealed containers, such as ampoules and vials, and may be stored freeze-dried, i.e. lyophilized, and require the addition of a sterile liquid vehicle such as water for injections immediately prior to use. External injection solutions and suspensions are prepared from sterile powders, granules and tablets as described above.

Formulations for transdermal administration may take the form of discrete patches which remain in intimate contact with the epidermis or epidermis of the patient for prolonged periods. Preferably, these spots contain from 0.1 to 0.2 moles of active compound per compound, optionally in buffered aqueous solution. Alternatively, the active ingredient may be delivered from the spot by iontophoresis according to Pharmaceutical Research 3/6, 318 (1986).

Preferred unit dosage formulations are those containing a daily dose or unit, a daily sub-dose, or a suitable fraction thereof.

In addition to the above-mentioned components, the compositions may contain other known components, for example, for oral administration, the compositions may contain additional components such as sweeteners, thickeners, and flavorings.

The compounds of formula (I) may be prepared in known manner. For example, the invention relates to the preparation of basic salts of the compounds of formula I and other physiologically acceptable reactive derivatives by:

A) reacting a compound of formula II wherein R ³ is as defined above and X is a leaving group such as a halogen such as bromine or iodine, or a sulfonate such as CF 3 S (O) 2 S, with a compound of formula III, wherein R ⁴ is -NHR ² and R ¹ and R ² are as defined above, or

B) reacting a compound of formula IV wherein R ¹ and R ³ are as defined above, with a Wittig reagent of formula V wherein R ⁴ is as defined above and Y is -P (= O) (OR) 2, wherein R is C 1 -C 4 alkyl, aryl or aralkyl, or Y is a trialkylphosphine group under Wittig conditions; or ^c ) a compound of formula (VII) - wherein R ¹ , R ³ and R ⁴ is as defined above - dehydrated; or ^D ) a compound of Formula VIII wherein R ¹ and R ³ are as defined above and Z is a leaving group such as halogen such as bromine or chlorine, azo, amido or ROC (0). An O group wherein R is a C 1 -C 6 alkyl group such as CH 3 CH 2 OC (Ο) 0- or an alkanoyloxy group such as acetyloxy, with a compound of formula IX wherein R ⁴ is as defined above and then either one or more of the following steps, or one of them, (i) converting the compound of formula (I) thus obtained into a basic salt or other physiologically acceptable reactive derivative thereof, (ii) if the resulting compound is a basic salt of another compound of formula (I) or another physiologically acceptable reactive derivative thereof, converting the derivative into a compound or derivative of formula (I).

In process A, a compound of formula II is reacted with a compound of formula III, usually in the presence of a catalyst such as a transition metal catalyst such as palladium catalyst, in particular palladium acetate, in an organic base such as triethylamine and in a suitable polar solvent such as acetonitrile. , dimethylformamide, methanol, preferably at high temperature. The reaction is carried out in the presence of a phosphorus reagent such as tri-o-toluylphosphine or triarylphosphine.

The compounds of formula (II) may be commercially available or may be prepared by known procedures analogous to the synthesis of analogous compounds, using the following literature:

i) Protective Groups in Organic Chemistry, J.F.W. McOmie,

Plenum Press (1973); ISN 0-306-30717-0;

ii) Compendium of Organic Synthetic Methods, ed .: I.T. Harrison and S. Harrison, Wiley-Interscience,

Volume I (1971) ISBN 0.471-35550-X, Volume II. volume (1974)

ISN 0-471-35551-8 and III. volume (editor: L.S.

Hegedűs and L. Wade) (1977) ISBN 0-471-36752-4; and (iii) Rodd's Chemistry of Carbon Compounds, 2nd edition,

Elsevier Publishing Company.

R ¹ and R ⁴ is The compounds of formula as defined above (III) are readily prepared, or immediately above defined RI site and a compound of formula R ⁴ is a hydroxyl containing (III), for example by treatment with the appropriate amine, dicyclohexyl carbodiimide ( DCC) or the latter compound can be converted into an activated derivative such as an acid halide such as an acid chloride or an anhydride. In the case of acid chloride, it is reacted with thionyl chloride and then with the appropriate amine in the presence of an organic base such as TEA or in excess of the amine.

Compounds of formula (III) wherein R ¹ is as defined above and R ⁴ is hydroxy may be commercially available or may be prepared by known methods.

In Process B, a compound of Formula IV is reacted with a Wittig reagent of Formula V, usually in the presence of a strong base such as sodium hydride or lithium hydride, and in a known solvent such as dimethoxyethane. The proportion of E and Z isomers in the compound of formula (I) depends on the nature of the alkyl, aryl or aralkyl group in the phosphorus group of the Wittigreagent.

Compounds of formula (IV) are commercially available or can be prepared by known methods.

The compounds of formula (V) wherein Y and R ^{4 are as} defined above may be prepared in a known manner, but are usually prepared from compounds of formula (V) wherein R ⁴ is as defined above and Y is a leaving group, e.g. bromine, by treatment with a suitable phosphorylating agent such as trialkyl phosphite or triarylphosphine. Compounds of formula (V) wherein R ⁴ is as defined above and Y is a leaving group may be prepared from compounds of formula (V) wherein Y is the aforementioned leaving group and R ⁴ is another leaving group such as halogen, such as chlorine or bromine. Such compounds, such as ClCO2CH2Cl, may be obtained commercially or may be prepared in a known manner.

In process C, dehydration of the compound of formula VII can be carried out with a suitable dehydrating agent such as acetic anhydride, usually in the presence of an acid such as para-toluenesulfonic acid.

Compounds of formula (VII) may be prepared by reacting a compound of formula (IV) with a compound of formula (V) wherein R ⁴ is as defined above, Y is bromine, and the reaction is carried out in the presence of zinc (Reformatski reaction). Alternatively, the compound of formula (VII) may be isolated or dehydrated in situ.

Compounds of formula (V) wherein R ⁴ is as defined above and Y is a bromine atom may be prepared by analogy to compounds of formula (V) wherein R ⁴ is as defined above and Y is a leaving group, in this case bromine, and ( Compounds of formula IV are commercially available or can be prepared in a known manner.

Process D) is carried out such that it is a general compound VIII

Compound 16 is treated with Compound IX in an inert solvent such as tetrahydrofuran or benzene.

Compounds of formula (IX) may be commercially available or may be prepared by known methods.

Compounds of formula (VIII) wherein R ¹ , R ³ and Z are as defined above may be prepared from compounds of formula (VIII) wherein R ¹ and R ³ are as defined above and Z is hydroxy, for example Z is halogen. containing a halogenating agent such as oxalyl chloride in an inert solvent such as benzene; in an inert solvent such as tetrahydrofuran. The compound of formula (VIII) may be isolated or aminated in situ.

Compounds of formula (I) may also be prepared directly from compounds of formula (VIII) wherein R ¹ and R ³ are as defined above and Z is hydroxy when treated with a compound of formula (IX) wherein R ⁴ is as defined above and the reaction is carried out in a solvent.

Compounds of formula VIII wherein R ¹ and R ³ are as defined above and Z is hydroxy can be readily prepared by hydrolyzing compounds of formula VIII wherein R ¹ and R ³ are as defined above and Z is leaving, for example alkoxy. such as (E) -methyl-3- (2-bromophenyl) -2-butenoate, wherein R ¹ is methyl, R ³ is 2-bromo, and Z is the same.

4 4 · · · ·

The invention may be prepared in the presence of a methoxy group, in the presence of a base such as sodium hydroxide, or in the presence of an acid such as hydrochloric acid and a polar solvent such as ethanol. Compounds of formula VIII wherein Z is alkoxy can be prepared by dehydrating a compound of formula VII wherein R ¹ and R ³ are as defined above and R ⁴ = Z. These compounds are prepared by the Reformatski reaction (see C). method).

The compound of formula (I) may be converted into a pharmaceutically acceptable basic salt by conventional means, for example by treatment with a suitable base.

The present invention also encompasses the following novel intermediates. They are particularly valuable in the preparation of compounds of formula I wherein R ¹ and R ² are as defined above and R ³ is

2-Br:

1. (E) -3- (2-Bromophenyl) -2-butenoic acid.

2. (E) -ethyl 3- (2-bromophenyl) -2-butenoate.

3. (E) -methyl-3- (2-bromophenyl) -2-butenoate.

4. (E) -3- (2-Bromophenyl) -2-butenoyl chloride.

The following examples further illustrate the invention.

Example 1 Preparation of (E) -3- (2-Bromophenyl) -N-cyclopropyl-2-butenamide

A) Preparation of 2-chloro-N-cyclopropylacetamide

A solution of 33.8 g (0.3 mol) of chloroacetyl chloride in 100 ml of ethyl ether was added dropwise over 30 minutes to 34.2 g of Aldrich cyclopropylamine in 400 ml of ethyl ether. •: ···:.:

• * · · ♦ · · · · ♦ · · «• · · · · ·

- solution of 18 at 0 ° C with stirring. After 30 minutes at this temperature, the ether was evaporated under a stream of nitrogen while heating on a steam bath. The residue was dissolved in 400 ml of dichloromethane and washed successively with 100 ml of 1N dilute hydrochloric acid, 5% aqueous sodium bicarbonate and distilled water. The volatiles were removed by spin evaporation in vacuo and the residue was recrystallized from dichloromethane / hexanes to give 26.4 g (66%) of 2-chloro-N-cyclopropylacetamide, m.p. 80-83 ° C.

Analysis calculated for C ₅ H ₈ ClNO: C, 44.96; H, 6.04; N, 10.48; Cl, 26.54; Found: C, 45.04; H, 6.06; N, 10.45; Cl, 26.52.

B. Preparation of Diethyl (Cyclopropylcarbamoylmethyl) phosphonate 2 g of 0.15 mol of 2-chloro-N-cyclopropylacetamide were added in portions to Aldrich's triethyl phosphite, 28 g, 0.17 mol. C temperature. The solution was then heated to 155 ° C for 30 minutes, cooled to 125 ° C, and the volatiles were removed by distillation under vacuum at 15 mm Hg, at which temperature the residual oil was stirred with 200 ml of pentane in an ice bath and crystallization was initiated. Filtration gave 5.2 g (14%) of diethyl (cyclopropylcarbamoyl) methyl phosphonate as a white crystal. Melting point: 51-56 ° C. The mother liquor was evaporated and cooled to give an additional second crop (25.3 g, 71%). Melting point: 50-56 ° C. Recrystallization from dichloromethane / hexanes gave the analytical sample, m.p. 55-57 ° C.

• 4 · · · ··· * ··· · ···

Analysis calculated for C 9 H ₁₈ NO ₄ P: C, 45.96; H, 7.71; N, 5.95. Found: C, 45.85; H, 7.76; N, 5.90.

C) Preparation of (E) -3- (2-Bromophenyl) -N-cyclopropyl-2-butenamide

To a stirred suspension of 0.67 g of Aldrich's sodium hydride in 80% mineral oil (80 mmol) in 25 ml of dimethoxyethane was added 5 g of 21 mmol of diethyl ((cyclopropylcarbamoyl) methyl) phosphonate in 60 ml of ethyl acetate. After 1.5 hours, a solution of Aldrich's 2H-bromoacetophenone (4 g, 20 mmol) in dimethoxyethane (60 mL) was added and the mixture allowed to warm to room temperature overnight. The mixture was poured into 1 liter of ice-cold water and extracted with dichloromethane. The residue was chromatographed on silica gel 60 using dichloromethane: ethyl acetate 9: 1 as eluent. The fractions containing only (E) -3- (2-bromophenyl) -N-cyclopropyl-2-butenamide were combined, evaporated in vacuo to give 2.2 g of a colorless oil. Trituration with pentane gave 1.85 g (33%) of (E) -3- (2-bromophenyl) -N-cyclopropyl-2-butenamide, m.p. 82-84 ° C.

1 H-NMR (DMSO-d ₆ ): 8.40 (d, 1H, J = 4.02 Hz, NH), 7.64-7.19 (m, 4H, Ar), 5.64 (d, 1H , J = 1.36 Hz, = CH), 2.68 (m, 1H, NCH), 2.36 (d, 3H, J = 1.17 Hz, CH ₃ ), 0.68-0.35 ( 2m's, 4H, CH ₂ CH ₂ ); steady state nOe: radiation at 2.36, 4.9% nOe; 7.25 and 1.3 nOe at 5.64.

• · ·

- 20 Elemental analysis calculated for C ^ HH ^BrNO:

Calculated: C, 55.73; H, 5.04; N, 5.00. Found: C, 55.82; H, 5.09; N, 4.95.

Example 2 Preparation of (E) -3- (2-Bromophenyl) -N-cyclopropyl-2-butenamide (A) Preparation of (E) -N-cyclopropyl-2-butenamide in 0.33 moles of thionyl chloride is added dropwise over 15 minutes to a stirred solution of Aldrich's crotonic acid (25.8 g, 0.30 mol) in benzene (400 ml), protected from moisture by a drying tube containing Drierite. The resulting clear solution was heated under reflux for 3 hours before 100 ml of solvent was removed by distillation at atmospheric pressure. The resulting solution was stirred in an ice bath and treated dropwise with Aldrich's cyclopropylamine (20.6 g, 0.36 mol) followed by triethylamine (41.8 ml, 0.30 mol). A white solid precipitates. Water (50 mL) was added and the remaining layers were separated. The aqueous phase is extracted with 5 x 100 ml of methylene chloride saturated with sodium chloride, the organic phases are combined, dried over sodium sulfate, filtered, evaporated to give a solid residue which is then distilled from a round-bottomed flask (internal temperature 90-110 ° C). C) at a pressure of 0.1 torr. 31.2 g (83%) of product are obtained, m.p. 63-65 ° C. 1 H-NMR (DMSO-d 6): δ 7.91 (bs, 1H, NH), 6.48-6.66 (m, 1H, = CHCH ₃ ), 5.79 (dxd, J = 1.6 , J = 15.2 Hz; 1H, = CHCO), 2.65 (m, 1H, NCH), 1.74 (d X d, J = 1.7, J = 6.8 Hz, 3H, CH ₃ ), 0.39 and 0.60 (2m, 4H, CH ₂ CH ₂ ).

· · · ·······················································•

Analysis: Calculated for C7 NO.O _XX, 1 H ₂ 0: Calc:% C = 66.22, H% = 8.89, N% = 11.03; Found: C, 66.10; H, 8.90; N, 11.07.

(B) (E) -3- (2-Bromophenyl) -N-cyclopropyl-2-butenamide

2.36 g (10.0 mmol) of Aldrich 1,2-dibromobenzene, 1.30 g (10 mmol) of (E) -N-cyclopropyl-2-butenamide, 1.01 g, 10 mmol of triethylamine, A stirred mixture of 0.24 g (0.8 mmol) of Aldrich's tri-o-tolylphosphine, 0.04 g, 0.2 mmol of Aldrich's palladium acetate and 25 mL of acetonitrile was sealed in a flask at 120 ° C for 18 hours. heated. The mixture was cooled to room temperature, filtered, evaporated and chromatographed on silica gel 60. The eluent was a 1: 4 to 1: 1 gradient of ethyl acetate and hexanes. Fractions containing only (E) -3- (2-bromophenyl) -N-cyclopropyl-2-butenamide were combined, spin evaporated in vacuo to give 1.2 g (42.8%) of product. Recrystallization from dichloromethane / hexanes gave an analytical sample identical to the product of Example 1. M.p. 82-84 ° C. The compounds were identical by NMR.

Analysis using the formula C _X 3 H _{X 4} BrNO:

Found: C, 55.73; H, 5.04; N, 5.00; Br, 28.52; Found: C, 55.81; H, 5.06; N, 5.01; Br, 28.44.

Example 3 Preparation of (E) -3- (2-Bromophenyl) -N-cyclopropyl-2-butenamide

A) Preparation of (E) -Ethyl-3- (2-bromophenyl) -2-butenoate

14.7 g (74 mmol) of Aldrich's 2'-bromoacetophenone, 9 g of Mallinckrodt zinc powder, 18.5 g, 111 mmol of Aldrich's ethyl bromoacetate, iodine crystal and 100 mL of benzene and 100 mL of di22 ethyl The stirred mixture of ether was stirred at reflux under nitrogen for 2 hours. The resulting gray slurry was cooled to room temperature, filtered, and the filtrate evaporated to give a yellow foam. The residue was dissolved in 50 ml of acetic anhydride while cooling and treated with 50 mg of Aldrich's para-toluenesulfonic acid and heated at 70-80 ° C for half an hour. The solution was cooled to room temperature, evaporated in vacuo and chromatographed on a Waters Prep 500. Elution was carried out with a 1: 133 mixture of ethyl acetate and hexane. Fractions containing only (E) -ethyl 3- (2-bromophenyl) -2-butenoate were combined and spin evaporated in vacuo. 3 g (15%) of a clear oil are obtained.

NMR _(DMSO-d6): δ 7.67-7.23 (m, 4H, Ar), 5.72 (d, 1H, J = 1.4 Hz, CH), 4.13 (q, 2H , CH ₂ O), 2.37 (d, 3H, J = 1.4 Hz, CH ₃ ),

1.21 (t, 3H, CH ₃ CH ₂ O); steady state nOe: irradiation at 2.37 δ, 2% nOe at 7.45 µ, and 1% nOe at 5.72.

Analysis calculated for C ₂ H ₃₃ BrO ₂ O:

Calculated: C, 53.55; H, 4.87; Br, 29.69; Found: C, 53.61; H, 4.83; Br, 29.76.

B) (E) -3- (2-Bromophenyl) -2-butenoic acid

A mixture of (E) -ethyl 3- (2-bromophenyl) -2-butenoate (2.7 g, 10 mmol) in ethanol (20 mL) and 1N sodium hydroxide (11 mL) was stirred overnight at room temperature. The solution was concentrated in vacuo, diluted with water (30 mL) and extracted with diethyl ether. The aqueous phase was acidified by addition of 1.2 ml of concentrated hydrochloric acid and extracted with diethyl ether. The ethereal layer was dried over sodium sulfate, filtered, evaporated, and silica gel at 60 ° C.

-23kromatografáljuk. A mixture of ethyl acetate and dichloromethane (1: 4) was used. The fractions containing only (E) -3- (2-bromophenyl) -2-butenoic acid were combined and evaporated to give 1 g (41.7%) of white crystals. Melting point: 109-111 ° C.

NMR _(DMSO-d6): δ 12.43 (bs, 1H, COOH), 7.67 to 7.22 (m, 4H, Ar), 5.66 (d, 1H, J = 1.4 Hz (= CH), 2.34 (d, 3H, J = 1.4 Hz, CH 3); steady state nOe: irradiation at 2.34 δ; 1% nOe at 7.29 <5 and 1% nOe at 5.66 <5.

Elemental analysis: Calculated for CHBH; CBrO2: C, 49.82; H, 3.76; Br, 33.14; Found: C, 49.92; H, 3.77; Br, 33.21.

C) Preparation of (E) -3- (2-Bromophenyl) -N-cyclopropyl-2-butenamide

1.0 g (4 mmol) of (E) -3- (2-bromophenyl) -2-butenoic acid and 1.7 g,

A solution of Aldrich's oxalyl chloride (13.8 mmol) in benzene (50 mL) was refluxed for 2 hours and evaporated to give (E) -3- (2-bromophenyl) -2-butenoyl chloride as a pale yellow oil. IR: 1773, 1611 cm -1. Aldrich cyclopropylamine (0.9 g, 16 mmol) was added to the acid chloride, which was dissolved in benzene (60 mL), and the mixture was stirred overnight at room temperature. The solution was washed with saturated sodium bicarbonate (50 mL), 1N hydrochloric acid (50 mL), brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give 0.9 g of a foggy oil. Recrystallization from dichloromethane / hexanes gave 0.3 g (30%) of the product of Example 1, m.p. 82-84 ° C and NMR.

Analysis calculated for C ₁₃ H ₁₄ BrNO: C, 55.73; H, 5.04; N, 5.00; Br, 28.52; Found: C, 55.77; H, 5.02; N, 5.01; Br, 28.44.

Example 4 Preparation of (E) -3- (2-Bromophenyl) -N-cyclopropyl-2-butenamide

Aldrich chloroformate ethyl ester (0.13 g, 1.24 mmol) was added dropwise to (E) -3- (2-bromophenyl) -2-butenoic acid (0.30 g, 1.24 mmol, 0.12 g). To a stirred solution of triethylamine (1.24 mmol) and tetrahydroflirane (5 mL) at 0 ° C. After 2 hours, the precipitated triethylamine hydrochloride was removed by filtration at 0 ° C, and a solution of cyclopropylamine (71 mg, 1.24 mmol) in tetrahydrofuran (71 mg, 1.24 mmol) was added dropwise to the ice-cold filtrate. The mixture was stirred overnight at room temperature, evaporated, chromatographed on silica gel 60, eluting with ethyl acetate / dichloromethane 1:19. Fractions containing only (E) -3- (2-bromophenyl) -N-cyclopropyl-2-butenamide were combined and spin evaporated in vacuo. 0.21 g, 60% of product are obtained. Recrystallization from a mixture of dichloromethane and hexane gave an analytical sample of m.p.

Same as Example 1, m.p. and NMR. M.p. 82-84 ° C.

Analysis: Calculated for C ?? H ?? BrNO: C, 55.73; H, 5.04; N, 5.00; Br, 28.52; Found: C, 55.71; H, 5.04; N, 5.01; Br, 28.60.

Example 5 (Z) -3- (2-Bromophenyl) -N-cyclopropyl-2-butenamide

IC. The fractions containing only (Z) -3- (2-bromophenyl) -N-cyclopropyl-2-butenamide of Example 1c were combined, the spin was evaporated in vacuo to give 1.7 g of a white solid. Trituration with pentane gave 1.31 g (23%) of (Z) -3- (2-bromophenyl) -N-cyclopropyl-2-butenamide, m.p. 144-146 ° C.

NMR (DMSO-d6): δ 7.82 (d, 1H, NH), 7.55-7.05 (m, 4H, Ar), 5.90 (d, 1H, J = 1.47 Hz, = CH), 2.48 (m, 1H, NCH), 1.97 (d, 3H, J = 1.47 Hz, CH ₃ ), 0.57-0.27 (2m's, 4H, CH ₂ CH ₂ ). ]; steady state nOe: irradiation at 1.97, 8.2% nOe at 7.1 and 17.0% nOe at 5.90.

Elemental analysis based on the formula Ο ₁₃ Η ₁₄ ΒγΝΟ:

Calculated: C, 55.73; H, 5.04; N, 5.00. Found: C, 55.73; H, 4.99; N, 4.99.

Example 6 Preparation of (E) -N-Cyclopropyl-3- (2- (trifluoromethyl) phenyl) -2-butenamide

This compound was prepared by analogy to Example 1 with IC. Example 2'-Bromoacetophenone is replaced by 2 '- (trifluoromethyl) acetophenone (Aldrich). The solution containing (E) -N-cyclopropyl-3- (2- (trifluoromethyl) -2-phenyl) -2-butenamide is chromatographed and the spin is evaporated in vacuo. The solid was collected, recrystallized from a mixture of ethanol and water to give 0.74 g (10%) of (E) -N-cyclopropyl-3- (2- (trifluoromethyl) phenyl) -2-butenamide. Melting point 116 ° C.

NMR (DMSO-d6): δ 8.06 (d, 1H, J = 4.16 Hz, NH), 7.76-7.36 (m, 4H, Ar), 5.62 (d, 1H, J = 1.31 Hz, = CH), 2.70 (m, 1H, NCH), »* ·

2.40 (d, 3H, J = 1.07 Hz, CH ₃ ), 0.66-0.40 (2m's, 4H, CH ₂ CH ₂ ); steady state nOe: irradiation at 2.40 <5, 4.9% nOe at 7.4, and 1.4% nOe at 5.628.

Elemental analysis calculated for C14H14F3NO:

Calculated: C, 62.45; H, 5.24; N, 5.20; Found: C, 62.37; H, 5.28; N, 5.19.

Example 7 (E) -N-Cyclopropyl-3- (2,3-dichlorophenyl) -2-butenamide

This compound was prepared by analogy to Example 1, except that IC. Example 2 uses 2 ', 3' - (dichloro) acetophenone (Maybridge) in place of the 2'-bromoacetophenone of Example 1A. The chromatographic solutions containing (E) -N-cyclopropyl-3- (2,3-dichlorophenyl) -2-butenamide were spin evaporated and the solid collected and dried. Yield: 6.73 g (47%). Melting point: 111-113 ° C.

NMR _(DMS0-d6): 5 8.08 (d, 1H, J = 4.06 Hz, NH), 7.62 to 7.21 (m, 3H, Ar), 5.69 (d, 1H, J = 1.22 Hz, = CH), 2.67 (m, 1H, NCH), 2.63 (d, 3H, J = 0.97 Hz, CH3), 0.66-0.37 (2m's, 4H, CH ₂ CH ₂ ). Analysis using the formula C ₁₃ H ₁₃ C _{1 2} NO:

Calculated: C, 57.80; H, 4.85; N, 5.18; Cl, 26.25; Found: C, 57.71; H, 4.83; N, 5.13; Cl, 26.34.

Example 8 Preparation of (E) -3- (2-Chloro-phenyl) -N-cyclopropyl-2-butenamide

This compound was prepared by analogy to Example 1, but using 2'-chloroacetophenone from Aldrich instead of the 2'-bromoacetophenone of Example IC). Chromatographic solutions containing (E) -3- (2-chlorophenyl) -N-cyclopropyl-2-butenamide * * ·· * · * ♦ ·

- 27 raspberries, spin evaporate in vacuo. The solid was collected and dried, yielding 28.30 g (32%). M.p. 92-194 ° C.

NMR _(DMSO-d6): 6 8.05 (d, 1H, J = 3.86 Hz, NH), 7.48-7.22 (m, 4H, Ar), 5.68 (d, 1H, J = 1.28 Hz, = CH), 2.68 (m, 1H, NCH), 2.38 (d, 3H, J = 1.44 Hz, CH ₃ ), 0.68-0.37 (2m's) , 4H, CH ₂ CH ₂ ); steady state nOe: irradiation at 2.38 <S, 4% nOe at 7.3 and 1% nOe at 5.68 h.

Analysis using the formula C13H14CINO:

Found: C, 66.24; H, 5.99; N, 5.94; Cl, 15.04; Found: C, 66.34; H, 6.03; N, 5.90; Cl, 15.10.

Example 9 Preparation of (Z) -3- (2-Chlorophenyl) -N-cyclopropyl-2-butenamide

This compound was prepared according to Example 1, but

IC. Aldrich's 2'-chloroacetophenone is used in place of the 2'-bromoacetophenone of Example 1c. The chromatographic solutions containing (Z) -3- (2-chlorophenyl) -N-cyclopropyl-2-butenamide were spin evaporated and the resulting solid was collected and dried. Yield: 3.52 g (4%). Melting point: 125-132 ° C.

NMR _(DMSO-d6) <5 7.83 (d, 1H, NH), 7.38-7.06 (m, 4H, Ar), 5.92 (d, 1H, J = 1.45 Hz (= CH), 2.48 (m, 1H, NCH), 1.98 (d, 3H, J =

1.41 Hz, CH ₃ ), 0.57-0.24 (2m's, 4H, CH ₂ CH ₂ ); steady state nOe: irradiation at 1.98 at 6, 5% at nOe at 7.1, and 14% at nOe at 5.92 <5.

Analysis using the formula C13H14CINO:

Found: C, 66.24; H, 5.99; N, 5.94; Cl, 15.04; Found: C, 66.33; H, 6.04; N, 5.88; Cl, 15.11.

* · ·

Example 10 Preparation of (E) -N-Cyclopropyl-3- (2-fluorophenyl) -2-butenamide

The compound was prepared according to Example 1 but with IC. Aldrich's 2'-fluoroacetophenone is used in place of the 2'-bromoacetophenone of Example 1A. The chromatographic solutions were spin evaporated and the solid separated and dried. Yield: 8.50 g (55%). Melting point: 59.5-62 ° C.

NMR (DMSO-d6): δ 8.08 (d, 1H, J = 3.82 Hz, NH), 7.37-7.15 (m, 4H, Ar), 5.89 (d, 1H, J = 1.21 Hz, = CH), 2.67 (m, 1H, NCH), 2.40 (s, 3H, CH ₃ ), 0.66-0.37 (2m's, 4H, CH ₂ CH ₂ ). ; steady state nOe: irradiation at 2.49 h, 5.3% nOe at 7.3 and 0.7% nOe and 5.89 at 5.

Elemental analysis calculated for C13H14FNO:

Calculated: C, 71.21; H, 6.44; N, 6.39.

Found: C, 71.30; H, 6.46; N, 6.35.

Example 11 Preparation of (E) -3- (3-Chloro-phenyl) -N-cyclobutyl-2-butenamide

5.00 g (254 mmol) of (E) -3- (3-chlorophenyl) -2-butenoic acid [E. Van Heyningen et al., J. Med. Chem. 9, 675 (1966)] and ice-cold solution of triethylamine (2.57 g, 254 mmol) in tetrahydrofuran (120 mL) were added ethyl chloroformate (254 mmol). 20 ml of tetrahydrofuran. After 30 minutes, Aldrich cyclobutylamine (1.1 g, 254 mmol) was slowly added in tetrahydrofuran (30 mL). After stirring at room temperature for 15 hours, the mixture was concentrated in vacuo to a residue and the residue was taken up in ethyl acetate and 5% aqueous sodium

-hydrogen carbonate. The ethyl acetate layer was washed with 1N hydrochloric acid and brine. The ethyl acetate solution was dried over sodium sulfate and spin evaporated in vacuo. The residual yellow solid was purified by flash chromatography on silica gel 60 (40-63m, E. Merek No. 9385) using ethyl acetate / hexane (1: 4) as eluent. Fractions containing (E) -3- (3-chlorophenyl) -N-cyclobutyl-2-butenamide were combined and evaporated to give 3.93 g (61%). Melting point: 89-90 ° C.

NMR (DMSO-d6): δ 8.2 (bd, 1H, NH), 7.54-7.35 (m, 4H, Ar),

6.21 (d, 1H, J = 1.3 Hz, = CH), 4.28 (m, 1H, NCH), 2.45 (d, 3H, J = 1.2 Hz, CH ₃ ), 2 , 32-1.55 (m, 5H, (CH ₂ ) 3).

Steady state nOe: irradiation at 2.45, 18.1% nOe at 7.5 and -0.2% nOe at 6.21.

Elemental analysis calculated for C14H15CINO:

Calculated: C, 67.33; H, 6.46; N, 5.61. Found: C, 67.34; H, 6.46; N, 5.58.

Example 12 Preparation of (E) -3- (2-Bromophenyl) -N-cyclobutyl-2-butenamide

This compound was prepared according to Example 3, but the compound of Example 3c. Instead of the cyclopropylamide of Example 1b, Aldrich's cyclobutylamine is used. The solid was recrystallized from dichloromethane / hexanes to give 1.1 g (64%) of whitish crystals. 128-130 ° C.

NMR (DMSO-d6): δ 8.22 (d, 1H, J = 7.7 Hz, NH), 7.66-7.20 (m, 4H, Ar), 5.68 (d, 1H, J = 1.4 Hz, = CH), 4.25 (m, 1H, NCH), 2.36 (d, 3H, J = 1.3 Hz, CH ₃ ), 2.20-1.58 (3m's, 6H, (CH ₂ ) 3); constant • ·

- nOe 30: irradiation at 2.36 <5, 4% nOe at 7.24 δ, and 1% nOe at 5.68 δ.

Analysis for C ₁₄ H ₁₆ BrNO:

Found: C, 57.16; H, 5.48; N, 4.76; Br, 27.16; Found: C, 57.08; H, 5.50; N, 4.72; Br, 27.08.

Example 13 Preparation of (E) -3- (2-Chlorophenyl) -N-cyclopropyl-2-pentenamide

This compound was prepared by analogy to Example 1, but IC. 2'-Bromoacetophenone 2'-chloropropiophenone [B.L. Jenson, S.E. Bürke and S.E. Thomas, Tetrahedron, 34, 1627-1631 (1978)]. The chromatographic solutions containing (E) -3- (2-chlorophenyl) -N-cyclopropyl-2-pentenamide were combined and spin evaporated in vacuo.

6.60 g (37%) of (E) -3- (2-chlorophenyl) -N-cyclopropyl-2-pentenamide are obtained. Mp 148-150 ° C.

NMR (DMSO-d6): δ 8.06 (d, 1H, J = 3.9 Hz, NH), 7.50-7.22 (3 m's, 4H, Ar), 5.64 (s, 1H, = CH), 01 (q, 2H, J = 7.5 Hz, _CH2 C =), 2.70 (m, 1H, NCH), 0.86 (t, 3H, J = 7.5 Hz, CH ₃ ), 0.680.40 (2 m's, 4H, CH ₂ CH ₂ ); steady state nOe: irradiation 3.01

6 at 19.7 5 nOe at 0.86 µ and 1.1% nOe at 5.64 <S.

Analysis using the formula C ₁₄ Hf ₅ ClNO:

Found: C, 67.33; H, 6.46; N, 5.61; Cl, 14.19; Found: C, 67.35; H, 6.48; N, 5.62; Cl, 14.12.

Example 14 Preparation of (E) -N-Cyclopropyl-3- (2-iodophenyl) -2-butenamide

A. Preparation of diisopropyl (cyclopropylcarbamoyl) methylphosphonate

This compound was prepared in a molar ratio of 3.0 mol. Prepared by the method of Example 3 using triisopropyl phosphite (Aldrich) instead of triethyl phosphite and using hexane instead of pentane. 385 g (48.7%) of a fluffy white solid melting at 58-60 ° C are obtained. The analytics

sample from hexane recrystallized. Elemental Analysis a ^{c 11h} per 22 ^NO4P formula: Calculated: C% H, 8.42; N, 5.32; Found: C% H, 8.44; N, 5.26.

B) Preparation of (E) -N-Cyclopropyl-3- (2-iodophenyl) -2-butenamide

This compound was prepared according to Example 1, but using 2'-iodoacetophenone from Aldrich instead of 2'-bromoacetophenone and diisopropyl ((cyclopropyl) instead of diethyl (cyclopropylcarbamoyl) methylphosphonate carbamoylmethyl) phosphonate is used. The chromatographic solutions containing (E) -N-cyclopropyl-3- (2-iodophenyl) -2-butenamide were spin evaporated in vacuo. The residue was recrystallized from dichloromethane / hexane

1.7 g (51%) of white crystals are obtained, m.p. 120-122 ° C.

NMR _(DMSO-d6) <5 8.04 (d, 1H, J = 4.0 Hz, NH), 7.88 to 7.00 (m,

4H, Ar), 5.57 (d, 1H, J = 1.4 Hz, = CH), 2.68 (m, 1H, CH), 2.34 (d, 3H, J = 1.3 Hz, CH ₃ ), 0.68-0.35 (2m's, 4H, CH ₂ CH ₂ ),:

- 32 steady state nOe: irradiation at 2.34 h, 5% nOe at 7.04 δ and 1% nOe at 5.57 δ.

Analysis by CX3H14INO:

Found: C, 47.73; H, 4.31; N, 4.28; Cl, 38.79; Found: C, 47.63; H, 4.33; N, 4.26; Cl, 38.86.

Medicinal chewing preparations

In the following formulation examples, the active ingredient may be any of the compounds of Formula I, or a basic salt thereof, or other physiologically acceptable reactive derivative thereof, e.g. Examples 1 to 5.

Example 15

Tablet preparation

The following formulations A, B, and C are prepared by wet granulating the components with a povidone solution, then adding magnesium stearate and pressing.

The preparation

mg / tablet mg / tablet (a) Active substance 250 250 (b) Lactose B.P. 210 26 (c) Povidon B.P. 15 9 (d) Sodium starch glycolate 20 12 (e) Magnesium stearate 5 3

500

300:

Preparation B. mg / tablet mg / tablet (a) Active substance 250 250 (b) Lactose 150 - (c) Avidel PH 101 60 26 (d) Povidon B.P. 15 9 (e) Sodium starch glycolate 20 12 (f) Magnesium stearate 5 3 500 300 Preparation C mg / tablet agent 100 Lactose 200 Starch 50 povidone 5 Magnesium stearate 4 359

agent

Pre-gelled preparation NF15

The following formulations D and E are prepared by direct compression of the blended components. Lactose in formulation E is a direct compression type (Dairy Crest - Zeparox).

Preparation D mg / tablet

250

150

400

This preparation mg / tablet agent 250 Lactose 150 Avicel 100 500

Preparation F (controlled release preparation)

The formulation is prepared by wet granulating the following components and Povidon solution by adding magnesium stearate and pressing.

mg / tablet (a) Active ingredient500 (b) Hydroxypropyl methylcellulose112 (Methocel K4M Premium) (c) Lactose B.P.53 (d) Povidone B.P.28 (e) Magnesium stearate 7

700

Example 16

Capsule preparation

The preparation

Capsule composition A is prepared by mixing the components of composition D of Example 15 and filling it into a two-piece hard gelatin capsule, similarly to composition B (infra).

• · ·

Preparation B

mg / capsule (a) Active substance 250 (b) Lactose B.P. 143 (c) Sodium starch glycolate 25 (d) Magnesium stearate 2

420

C Preparation

mg / capsule (a) Active substance 250 (b) Macrogol 4000 B.P. 350 600 D Preparation mg / capsule agent 250 Lecithin 100 peanut Oil 100 450

Capsules of Formulation D are prepared by dispersing the active ingredient in lecithin and peanut oil and filling the dispersion into soft elastic gelatin capsules.

This preparation (controlled release capsule)

The following controlled degradation capsule is prepared by extruding components a), b) and c) with an extruder, and then forming the extrudate into spheres and drying. The dried pellets are then coated with a degradation control membrane (d) and filled into two-piece hard gelatin capsules.

mg / capsule (a) Active substance 250 (b) Microcrystalline cellulose 125 (c) Lactose B.P. 125 (d) Ethyl cellulose 13 513 Example 17 Injectable preparation agent 0.200 g 95% ethanol and PEG 400, 1: 1 ratio Sterile water To 10 ml

The active ingredient is dissolved in a 1: 1 mixture of 95% ethanol and PEG 400. The mixture is then filled with water to the desired volume, filtered, through a sterile microporous filter, into a sterile 10 ml yellow Type I glass vial and sealed with a sterile seal.

Example 18

Syrup is the active ingredient

Sorbitol dissolved

Glycerol

Sodium benzoate

Seasoning, peaches

17.42.3169

0.25 g

1.50 g

2.00 g

0.005 g

Cleaned water

0.0125 ml to 5 ml as desired

The active ingredient is dissolved in a mixture of glycerol and most of the purified water. An aqueous solution of sodium benzoate is added to the solution, followed by the addition of sorbitol solution and finally the flavoring agent. The volume is filled with purified water and mixed well.

Example 19

Cone mg / Cone

Active ingredient 250 Hard Fat, B.P. (Witepsol H15

- Dynamit Nobel) 1770

2020

1/5 of Witepsol H15 is melted in a steam-cured pan at a maximum temperature of 45 ° C. The active ingredient was sieved through a 200 M sieve, added to the dissolved base with stirring, and Silverson removed with a cutting head was used until a smooth dispersion was obtained. The mixture is kept at 45 ° C, the remaining Witepsol H15 is added to the suspension and stirred to ensure a homogeneous mixture. The whole suspension was passed through a 250 M stainless steel sieve and allowed to cool to 40 ° C with continuous stirring. At 38-40 [deg.] C., 2.02 g of the mixture is poured into appropriate 2 ml plastic molds. Allow the suppositories to cool to room temperature.

Example 20 pessary mg / pessary agent 250 Anhydrous dextrose 380 Potato starch 363 Magnesium zearate 7 1000 The above components and the resulting mixture

by directly pressing the pessaries.

Example 21

Muscle relaxant effect

The muscle relaxant activity of the compounds of formula (I) was determined by the Straub tail test, K.O. Ellis and J.F. Based on the method of Carpenter [Neuropharmacol. 13, 211 (1974)].

Straub tail test result is expressed in mg / kg in ED5Q. ED5Q is the dose of compound administered which inhibits Straub's tail in 50% of the mice. The compound was administered 60 minutes prior to evaluation by oral gavage (p.o.).

The side effects of the compounds were determined using the mouse rotorod assay by GD Novak and JM Zwolshei, J. Pharmacological. Methods, 10, 175 (1983). Rotor result is expressed in ^ED 50 ^_ben mg / kg. ED5Q is the dose that causes 50% of animals to be unable to maintain their position on a rotating roller at 11 rpm.

Morphine-induced Straub tail antagonism shows muscle relaxant activity, while rotorod test showed

- 39 failures indicate a calming and uncoordinated effect. Determining the ratio of rotorod failure to morphine-induced Straub tail antagonism is a measure of the side effect of muscle relaxants [G.D. Novak, Drug. Dev. Res., 2, 383 (1982)].

The compound Straub Rotorod Rotorod / number of tail Straub tail

po ED50 p.o. ED5Q ratio mg / kg mg / kg

25 45 1.8

Example 22

Anticonvulsant effect

The anticonvulsant activity of the compounds of formula (I) was determined by the method of Mehta et al., J. Med. Chem. 24, 465 (1981)].

The antispasmodic effect is expressed in E550 mg / kg. The ED5Q value for maximal electroshock-induced seizure protection is the dose that inhibited elongation of the hind limb in 50% of the animals. The protection against Metrazol-induced convulsions by ED5 ₀ értékeaz dose which prevented convulsions in 50% of the animals.

...., ..., ..

··· ··· · ♦ · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ···

Number of compound

ip ED ₅₀ mg / kg (rat)

First

MES

MET

9.6

3.6

MES - maximum electroshock

MET - Metrazole

Example 23

Anti-anxiety effect

The anti-anxiety effect of the compounds of the invention

It was measured according to the method of Geller and Seifter [J. Psychopharmacology, 1, 482 (1960)], modified by Pollard and Howard (1979, Psychopharmacology, 62, 117). Clinically effective anxiolytics increase the punished response. The compound's anti-anxiety effect is expressed at the dose that elicits a 50% increase in the rat response in the rat.

Claims (26)

A compound of formula (I) wherein R ¹ is C 1-6 alkyl, R ² is hydrogen or C 3 -C 6 cycloalkyl, R ³ is one or more ring substituents, preferably halogen, especially chloro, bromo, iodo or fluoro, or perhalo (C 1-4 alkyl), with the proviso that i) when R ¹ is methyl and R ² is cyclopropyl, one of R ³ or R ³ is in the 2-position and ii) the compound of formula I is not 3- (4-chlorophenyl) -2-butenamide or a physiologically acceptable reactive derivative thereof. Compound according to Claim 1, characterized in that R 1 is methyl and / or R ² is cyclopropyl and / or R ³ or one of R ^{3 is in} the ^{2-position in} the formula (I) or its basic salt or other a physiologically acceptable reactive derivative thereof. A compound according to claim 1 or 2, wherein R ¹ is methyl and / or R ² is cyclopropyl and / or R ³ or one of R ³ is bromo, chloro or iodo or trifluoro. -methyl group and is in the 2-position or its basic salt or other physiologically - 42 reactive derivative. 4. A compound according to any one of claims 1 to ³ , wherein R ³ is methyl and / or R ² is cyclopropyl and / or R ³ is as defined above and in the 2-position or a basic salt or other physiologically acceptable reactive derivative thereof. 5. (E) -isomers or basic salts or other physiologically acceptable derivatives of the compounds of formula (I). Compounds according to claim 1: 1. (E) -N-Cyclopropyl-3- (2-trifluoromethyl) phenyl) -2-butenamide; 2. (E) -N-cyclopropyl-3- (2-iodophenyl) -2-butenamide; 3. (E) -N-Cyclopropyl-3- (2,3-dichloro-phenyl) -2-butenamide; (E) -3- (2-chlorophenyl) -N-cyclopropyl-2-butenamide; and 5. (E) -3- (2-Bromophenyl) -2-butenamide, or its basic salts or other physiologically acceptable reactive derivatives thereof. 7. (E) -3- (2-Bromophenyl) -N-cyclopropyl-2-butenamide. 8. The basic salt or other physiologically acceptable reactive derivative of the compound of any one of claims 1 to 3. 9. Use of a compound according to any one of claims 1 to 5 in medicine. 10. Use of a compound according to any one of claims 1 to 5 for the manufacture of a medicament for the treatment or prevention of conditions associated with abnormally increased muscle tone. 11. The use of a compound according to any one of claims 1 to 4 for use in the manufacture of a medicament for the prevention or treatment of convulsions. 12. Use of a compound according to any one of claims 1 to 6 for the preparation of a medicament for the treatment of anxiety. 13. A pharmaceutical composition according to any one of claims 1-8. A compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier. The composition of claim 13 for oral administration. The composition of claim 14 in the form of a tablet or capsule. 16. A process for the preparation of a compound of formula I wherein R 1 is C 1-6 alkyl, R ² is hydrogen or C 3 -C 6 cycloalkyl, R ³ is one or more ring substituents, preferably halogen, especially chloro, bromo, iodo or fluoro, or perhalo (C 1-4 alkyl), with the proviso that i) when R ¹ is methyl and R ² is cyclopropyl, one of R ³ or R ³ is in the 2-position and ii) the compound of formula I is not 3- (4-chlorophenyl) -2-butenamide various - for the preparation of basic salts or physiologically acceptable reactive derivatives thereof, characterized in that A) reacting a compound of formula II wherein R ³ is a compound of formula III and X is a leaving group, and X is a leaving group, with a compound of formula III. wherein R ⁴ is -NHR ² and R ¹ and R ² are as defined above, or B) reacting a compound of formula IV wherein R ¹ and R ³ are as defined above, with a Wittig reagent of formula V wherein R ⁴ is as defined above and Y is -P (= O) (OR) 2, wherein R is C 1-4 alkyl, aryl or aralkyl, or Y is triarylphosphine, under Wittig conditions, or C) dehydrogenating a compound of formula VII wherein R ¹ , R ³ and R ⁴ are as defined above, or ^D ) reacting a compound of formula VIII wherein R ¹ and R ³ are as defined above and Z is a leaving group. , Reacting a compound of formula (IX) wherein R ⁴ is as defined above, and then or simultaneously carry out one or more of the following transformations: (i) converting a compound of formula (I) into a basic salt or other physiologically acceptable reactive derivative; To a compound of formula (I) or a derivative thereof. A process according to claim 16 for the preparation of a compound of formula (I) wherein R ¹ is methyl and / or R ² is cyclopropyl and / or R ³ or one of R ^{3 is in} the 2-position, or a basic salt or a physiologically acceptable reactive derivative thereof, wherein the appropriate starting materials are reacted. A process according to claim 16 or 17 for the preparation of a compound of formula (I) or a basic salt or a physiologically acceptable reactive derivative thereof wherein R ¹ is methyl and / or R ² is cyclopropyl and / or R ³ or R ^One of bromine, chlorine, iodine or trifluoromethyl, wherein the appropriate starting materials are reacted. 19. Process for the preparation of a compound of formula (I) or a basic salt or a physiologically acceptable reactive derivative thereof according to any one of claims 1 to 3, wherein R ¹ is methyl and / or R ² is cyclopropyl and / or R ³ is as defined above and in the 2-position. , characterized in that the appropriate starting materials are reacted. A process according to claim 16 for the preparation of the (E) -isomer or its basic salt or other physiologically acceptable reactive derivative of the (E) -isomer of formula (I), comprising reacting the appropriate starting materials. The method of claim 16 (E) -N-cyclopropyl-3- (2-trifluoromethyl) phenyl) -2-butenamide; 2. (E) -N-cyclopropyl-3- (2-iodophenyl) -2-butenamide; 3. (E) -N-Cyclopropyl-3- (2,3-dichloro-phenyl) -2-butenamide; (E) -3- (2-chlorophenyl) -N-cyclopropyl-2-butenamide; and 5. (E) -3- (2-Bromo-phenyl) -2-butenamide · · · · · · · · · · · · · · · · · · · · · · Or a basic salt or a physiologically acceptable reactive derivative thereof by reacting the appropriate starting materials. 22. A process according to claim 16 for the preparation of (E) -3- (2-bromophenyl) -N-cyclopropyl-2-butenamide, which comprises reacting the appropriate starting materials. 23. The process of claim 16, wherein the product is isolated as a basic salt or a physiologically acceptable reactive derivative thereof. 24. A method of treating or preventing conditions associated with abnormally elevated muscle tone, wherein the host is in a non-toxic amount of 1-8. A compound according to any one of claims 1 to 6. 25. A method of treating or preventing seizures in a host comprising administering to the host an effective amount of a non-toxic 1-8. A compound according to any one of claims 1 to 6. 26. A method of treating and / or preventing host anxiety, comprising administering to the host an effective amount of a non-toxic 1-8. A compound according to any one of claims 1 to 6.