AU655000B2 - Substituted (3) phenyl-2-butenamides their pharmaceutical applications and methods of preparation - Google Patents

Description

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OPI DATE 27/08/92 AOJP DATE n1/10/92 APPLN. TD 11710 92 PCT NUMBER PCT/GB92/no108

INTERNAI.

.'REATY (PCT) (51) International Patent Classification 5 (11) International Publication Number: WO 92/12959 C07C 233/11, A61K 31/165 A l (43) Inter ational Publication Date: 6 August 1992 (06.08.92) (21) International Application Number: PCT/GB92/00108 (74) Agent: GARRETT, The Wellcome Foundation Limited, Langley Court, Beckenham, Kent BR3 3BS (GB).

(22) International Filing Date: 17 January 1992 (17.01.92) (81) Designated States: AT (European patent), AU, BB, BE Priority data: (European patent), BG, BR, CA, CH (European patent), 9101244.3 19 January 1991 (19.01.91) GB CS, DE (European patent), DK (European patent), ES (European patent), FI, FR (European patent), GB (European patent), GR (European patent), HU, IT (Euro- (71) Applicant (for all designated States except US): THE WELL- pean patent), JP, KR, LK, LU (European patent), MC COME FOUNDATION LIMITED [GB/GB]; Unicorn (European patent), NL (European patent), NO, RO, House, 160 Euston Road, London NWI 2BP RU, SE (European patent), US.

(72) Inventors; and Inventors/Applicants (for US only) KELLEY, James, Leroy Published [US/US]; 10928 Raven Rock Drive, Raleigh, NC 27614 With international search report.

STYLES, Virgil, Lee [US/US]; 5807 Lake Elton Road, Durham, NC 27713 (US).

(54) Title: AMIDE DERIVATIVES AND THEIR THERAPEUTIC USE (57) 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.

I (i i I P rrmr T T" i WO 92/12959 PCr/GB92/00108 I. AMIDE DERIVATIVES AND THEIR THERAPEUTIC USE The present invention relates to 3-phenyl-2-alkenamide derivatives, physiologically functional derivatives thereof, pharmaceutical preparations containing them and the use of such compounds and preparations in therapy, particularly as muscle relaxants, anxiolvtics and anti-convulsants.

The hypnotic and sedative effects of certain 3-phenyl-2-alkenamide derivatives, usually referred to by their trivial chemical name cinnamamides, have been disclosed by Lott and Christiansen, J.Am.

Pharm.Assoc., 23,788 (1934) and Van Heyningen et al., J.Med.Chem., 9,675 (1966) respectively.

In US patent no. 4,190,674 there is disclosed cinnamamide derivatives which are active in the treatment of convulsion of a mammal and their use in relaxing muscles, for example, treatment of increased skeletal muscle tone.

European patent specification no. 0381508 describes the use of certain cinnamamides for relaxing muscle tone, for example, in the treatment of muscle spasm or spastic paralysis such as cerebral injuries.

The major limiting side effects of many clinically effective muscle relaxants and anticonvulsants are the induction of sedation and incoordination in the recipient, which severely limits the usefulness of these compounds. .Similar side effects have been found with drugs used in the treatment of anxiety, such as, benzodiazepines. Although these effects may be transient, patients on such therapy are often unable to drive or participate in certain occupations.

This side-effect liability of potential muscle relaxant compounds can be determined experimentally from studies on the efficacy and depressant potential of muscle relaxants (Drug Dev. Res., 2,383 (1982)).

i lii .1 B WO 92/12959 PCT/GB92/00108 2 We have now surprisingly found that certain 3-phenyl-2-alkenamides have potent muscle relaxant activity but with significantly reduced liability to the sedation and incoordination side-effects observed with known muscle relaxants. These compounds have also been found to have anxiolytic and anti-convulsant activity.

According to the present invention there is provided 3-pheny!-2-alkenamide derivatives of general formula SC(R1)= CHCONHR 2 R3 1 2 wherein R represents C- alkyl, R represents hydrogen or C36 3 1-6 3-6 cycloalkyl and R represents one or more ring substituents selected from halogen (for example, Cl,Br,I,F) and perhaloC 1 4 alkyl (for, example trifluoromethyl); with the following provisos that: when R is methyl and R 2 is cyclopropyl then the or one of R is in the 2-position; and (ii) said compound of formula is not 3-(4-chlorophenyl)-2-butenamide; or a base salt or other physiologically functional derivative thereof.

As used herein the term "alkyl" as a group or part of a group means a straight or branched chain alkyl group. Such alkyl groups preferably have 1 to 3 carbon atoms and are more preferably methyl or ethyl, most preferably methyl.

-i i I c;-l;.e r i 1' PCT/GB92/00108 WO 92/12959 -3 Preferred compounds of formula include those wherein R represents methyl and/or, R 2 represents cyclopropyl and/or the or one of R is a ring substituent at the 2-position, preferably bromo, chloro or iodo or a perhalomethyl, for example trifluoromethyl; or a base salt or other physiologically functional derivative thereof.

Particularly preferred compounds of formula include those wherein

R

1 represents methyl and/or, R 2 represents cyclopropyl and/or R 3 is a single ring substituent at the 2-position, preferably bromo, chloro, iodo or trifluoromethyl; or a base salt or other physiologically functional derivative thereof.

The isomers of compounds of formula or a base salt or other physiologically functional derivative thereof are preferred.

Especially preferred compounds of formula are: 1. (E)-3-(2-bromophenyl)-N-cyclopropyl-2-butenamide; 2. (E)-N-cyclopropyl-3-(2-(trifluoromethyl)phenyl))-2-butenamide; 3. (E)-N-cyclopropyl-3-(2-iodophenyl)-2-butenamide; 4. (E)-N-cyclopropyl-3-(2,3-dichlorophenyl)-2-butenamide; (E)-3-(2-chlorophenyl)-N-cyclopropyl-2-butenamide; and 4 6. (E)-3-(2-bromophenyl)-2-butenamide.

The compounds of formula above and their base salts, or other physiologically functional derivatives are hereinafter referred to as the compounds according to the invention.

1 I: :o i :I l II-- t-i .1-_I WO 92/12959 PCT/GB92/00108 17 i i i ).n WO 921 /12959 PC/GB92/0108 4 It will be appreciated that the compounds of formula may exist in various geoisomeric forms and as mixtures thereof in any proportions.

The present invention includes within its scope the use of such geoisomeric forms or mixtures of geoisomers, including the individual E and Z isomers of the compounds of formula as well as mixtures of such isomers, in any proportions.

By "other physiologically functional derivatives" is meant any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) the said compound or an active metabolite or residue thereof.

Examples of base salts according to the invention include salts, for example, derived from an appropriate base, such as alkali metal (e.g.

sodium), alkaline earth metal magnesium) salts, ammonium and NX+ (wherein X is C alkyl).

For therapeutic use, salts of compounds of formula will be physiologically acceptable, i.e. they will be salts derived from a physiologically acceptable base. However, salts of bases which are not physiologically acceptable may also find use, for example in the preparation or purification of the compound. All base salts whether or not derived from a physiologically acceptable base are to be considered as being within the scope of the present invention.

According to further aspects of the invention there are provided the compounds according to the invention for use in medical therapy, in particularly for the treatment or prophylaxis of conditions associated with abnormally raised muscle tone, convulsive states, and anxiety.

The compounds are thus of particular value in the relaxation of skeletal musle T-n -spa sic, hypertonic ard hyperkinetic conditions.

"4 i. r; WO 92/12959 PCT/GB92/00108 5 In particular the compounds may be used in the treatment and symptomatic relief of conditions such as spinal cord injury, parkinsonism, chorea, arthritis, athetosis, status epilepticus and tetanus and especially in the relief of muscle spasm in conditions such as myositis, spondylitis, cerebral palsy, cerebrovascular disease amd multiple sclerosis.

The compounds may also be used for the treatment of exertion-induced skeletal muscle spasm, for example, lower back pain.

Convulsive states for which the compounds may be employed include grand mal, petit mal, psychomotor epilepsy and focal seizure. The compounds according to the invention may also be used in the treatment of anxiety including generalised anxiety disorders, obsessive compulsive disorder, panic disorder, phobic anxiety, separation anxiety and post-traumatic stress disorder.

A further use of such compounds is as presurgical muscle relaxants and anti-anxiety agents.

In a further aspect of the present invention there is included: a) a method for the treatment or prophylaxis of conditions associated with abnormally raised muscle tone, convulsive states or anxiety in a host, for example, a mammal including man, and mice which comprises treating said mammal with an effective non-toxic amount of a compound according to the invention.

b) use of a compound according to the invention in the manufacture of a medicament for the treatment or prophylaxis of conditions associated with abnormally raised muscle tone, convulsive states or anxiety.

The above compounds according to the invention may be employed in combination with other therapeutic agents for the treatment of the -e -e trl WO 92/12959 PCT/GB92/00108 -6conditions associated with abnormally raised muscle tone. Examples of such therapeutic agents include analgesics, such as, codeine, acetaminophen, phenacetin or ibuprofen.

The present invention further provides pharmaceutical formulations of the compounds according to the invention, also referred to herein as active ingredients, which may be administered for therapy by any suitable routec including oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intradermal). It will also be appreciated that the preferred route will vary with the conditions and age of the recipient, the nature of the disorder and the chosen active ingredient.

The amount required of the individual active ingredient for the treatment of, for example, increased muscle tone, convulsive states and anxiety of course depends upon a number of factors including the severity of the condition to be treated and the identity of the recipient and will ultimately be at the discretion of the attendant physician.

In general, for the foregoing conditions a suitable dose of a compound of formula or a base salt or other physiologically functional derivatives thereof (estimated as the parent compound) is in the range of 0.05 to 100mg per kilogram body weight of the recipient per day, preferably in the range of 0.1 to 50mg per kilogram body weight per day, most preferably in the range 0.5 to 20mg per kilogram body weight per day and optimally 3mg per kilogram body weight per day. The desired dose is preferably presented as two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for j example, containing 1 to 1500mg, preferably 5 to 1000mg, and most J'* preferably 10 to 7 0 0mg of active ingredient per unit dosage form.

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ija WO 92/12959 PCT/GB92/00108 7 While it is possible for the active ingredient to be administered alone it is preferable to present it as a pharmaceutical formulation.

The formulations of the present invention comprises at least one active ingredient, as defined above, together with one or more acceptable carriers thereof and optionally other therapeutic agents.

Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

Formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a freeflowing form such as a powder or granules, optionally mixed with a binder povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant sodium

L.

WO 92/12959 PCT/GB92/00108 -8 starch glycollate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets i may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.

Formulations suitable for oral use as described above may also include buffering agents designed to neutralize stomach acidity. Such buffers may be chosen from a variety of organic or inorganic agents such as weak acids or bases admixed with their conjugated salts.

Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.

Formulations suitable 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 to be appropriate.

Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injections solutions which may contain anti-oxidants, buffers, ac.teriostats and solutes which render

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;i i-- X i WO 92/12959 PCrGB92/00108 9 the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents, as liposomes or other microparticulate systems which are designed to target the compounds to blood comp..rants or one or more organs. The formulations way be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.

Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

Formulations suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain the active compound as an optionally buffered, aqueous solution of, for example, 0.1 to 0.2M concentration with respect to the said compound. As one particular possibility, the active compound may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 1/6, 318 (1986).

Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.

It should be understood that in addition to the ingredients particularly mentioned aoove the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and flavoring agents.

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Wb I WO 92/12959 PCT/GB92/00108 10 The compounds of formula may be prepared in manner and in accordance with the present invention, be prepared by any method hereinafter described.

Thus, the present invention further includes a preparation of compounds of formula and base physiologically functional derivatives thereof which any conventional may, for example, process for the salts, and other comprises:- A) reacting a compound of formula (II)

(II)

(wherein R" is as hereinbefore defined and X is a suitable leaving group, for example a halogen atom such as bromine or iodine or a sulphonate such as CF 3 S(0) 2 0- with a compound of formula (III) 1 4 R CNHr=ICOR I) (III)

U

4 2 1 2 (wherein R represents -NHR and R and R are as hereinbefore defined); B) reacting a compound of formula (IV) P1 5431-DQ WO 92/12959 PCT/GB92/00108 II

(IV)

-3 (wherein R 1and R 3are as hereinbefore defined) with a Wittig reagent of formula (V) YCHICOR 4VM (wherein R 4 is as hereinbefore defined and Y is P- (R2 wherein R is a C alkyl, aryl or aralkyl group, or Y is a 1-4 triaryiphosphine) under Wittig conditions; C) dehydrating a compound of formula (VII) CRI)--CH COR 4VI

(VI

1 3 4 (wherein R, R and R are as hereinbefore defined).

D) reacting a compound of formula (VIII) C(R )CHCOZ(VIII with the following provisos that: /2 0 1 .oI V: 1- a.

r; i__l r--r WO 92/12959 PCT/GB92/00108 12 (wherein R~ and R 3 are as hereinbefore defined and Z is a suitable leaving group, for example, a halogen atom, such as bromine or chlorine, azido, amino, or a ROC(O)0- group wherein R represents C1-6 alkyl, for example, CH3CH2OC(O)0- or an alkanoyloxy group, such as acetyloxy) with a compound of formula

(IX)

H-R (IX) (wherein R is as hereinbefore defined).

4t and thereafter, or simultaneously therewith, effecting one or more of the following optional conversions:converting the compound of formula so formed into a base salt, or other physiologically functional derivative thereof; (ii) when a base salt, or other physiologically functional derivative of a compound of formula is formed, converting the said derivative into a compound of formula or a different derivative thereof.

In process a compound of formula is reacted with a compound of formula (III), typically in the presence of a catalyst, such as a transition metal catalyst, for example, a palladium catalyst, in particular, palladium acetate, conveniently in the presence of an organic base such as triethylamine (TEA) and in a suitable polar solvent, for example, acetonitrile, dimethylformamide (DMF) or methanol, preferably at an elevated temperature. The reaction may be carried out in the presence of a phosphorus reagent such as tri-o-toluyl phosphine or another triarylphosphine.

II WO 92/12959 1PCT/GB92/00108 13 Compounds of formula (II) may be obtained commercially or, may be prepared by methods known in the art for the synthesis of compounds of analogous structure and in this regard reference is made, by way of illustration only to the following texts:i) "Protective Groups in Organic Chemistry" ed. J.F.W.McOmie, Plenum Press (1973), ISBN 0-306-30717-0; ii) "Compendium of Organic Synthetic Methods" ed. I.T.Harrison and S.Harrison, Wiley-Interscience, Vol.I (1971) ISBN 0.471-35550-X, Vol.11 (1974) ISBN 0-471-35551-8 and Vol.111 (ed. L.S.Hegedus and L.Wade) (1977) ISBN 0-471-36752-4; and iii) Rodd's "Chemistry of Carbon Compounds" second edition, Elsevier Publishing Company.

1 4 Compounds of formula (III) wherein R and R are as hereinbefore defined may conveniently be prepared either directly from a compound 1 4 of formula (III) wherein R is as hereinbefore defined and R represents hydroxy, for example, by treatment with the appropriate amine in the presence of a reagent such as dicyclohexylcarbodiimide (DCC) or by conversion of the latter compound of formula (III) to an activated derivative, such as an acid halide, for example, the acid chloride, or an acid anhydride. In the case of the acid chloride, by reaction with thionyl chloride, followed by reaction with the appropriate amine in the presence of an organic base such as TEA or an excess of the amine itself.

1 Compounds of formula (III) wherein R is as hereinbefore defined and 4 4 R is hydroxy may be obtained commercially or by methods known to a skilled person.

In process a compound of formula is reacted with a Wittig reagent of formula generally in the presence of a strong base such as sodium hydride or lithium hydride and conveniently in an inert i t~b~- WO 92/12959 PC/GB92/00108 14 solvent, for example, dimethoxyethane (DME). The relative proportions of E and Z isomers in the compound of formula so formed will depend on the nature of the alkyl, aryl or aralkyl group in the phosphorus-containing group of the Wittig reagent.

Compounds of formula (IV) may be obtained commercially or prepared by methods well known to a skilled person.

Compounds of formula where Y and R are as hereinbefore defined may be prepared by methods well known in the art, but are typically prepared from compounds of formula wherein R is as hereinbefore defined and Y is a suitable leaving group, for example, a halogen atom, such as chlorine or bromine, by treatment with a suitable phosphorylating agent such as a trialkylphosphite or a triarylphosphine. Compounds of formula wherein R is as hereinbefore defined and Y is a leaving group may be prepared from compounds of formula wherein Y is the aforementioned leaving group 4 and R is another suitable leaving group, for example a halogen atom such as chlorine or bromine. Such compounds, for example, C1COCH2C1, may be obtained from commercial sources or prepared by methods known to a skilled person or readily available from the chemical literature.

In process dehydration of a compound of formula (VII), may be effected with a suitable dehydrating agent, such as acetic anhydride, typically in the presence of an acid such as p-toluenesulphonic acid.

Compounds of formula (VII) may conveniently be prepared by reacting a compound of formula (IV) as defined in process B) with a compound of formula wherein R is as hereinbefore defined and Y is bromine, in the presence of zinc (Reformatski reaction). The compound of formula (VII) obtained may be isolated or dehydrated in situ.

Compounds of formula wherein R is as hereinbefore defined and Y is bromine may be prepared by methods analogous to those described above for the preparation of compounds of formula wherein R is as above for the preparation of compounds of formula wherein R is as ft -C i S -WO 92/12959 PC'/GB92/ 0 0 1 08 15 hereinbefore defined and Y is a suitable leaving group, in this case bromine and compounds of formula (IV) may be obtained commercially or by methods known to a skilled person.

Process D) may be carried out by treating a compound of formula (VIII) with a compound of formula typically in an inert solvent such as THF or benzene.

Compounds of formula (IX) may be obtained commercially or made by methods well known to a skilled person.

1 3 Compounds of formula (VIII) wherein R R and Z are as hereinbefore defined may be prepared from compounds of formula (VIII) wherein R and R are as hereinbefore defined and Z is hydroxy, for example where Z is to be halogen, by treatment with a halogenating agent such as oxalyl chloride in an inert solvent such as benzene or, where Z is to be a ROC(O)0- group wherein R is as hereinbefore defined, by treatment with the appropriate alkylchloroformate in the presence of an organic base such as TEA and in an inert solvent such as THF. The compound of formula (VIII) obtained may be isolated or aminated in situ.

ij Compounds of formula may of formula (VIII) wherein R1 is hydroxy by treatment with as hereinbefore defined in a also be prepared directly from a compound and R 3 are as hereinbefore defined and Z a compound of formula (IX) wherein R is suitable solvent.

1 3 Compounds of formula (VIII) where R and R are as hereinbefore defined and Z is hydroxy may conveniently be prepared by the 1 3 hydrolysis of a compoune of formula (VIII) wherein R and R are as hereinbefore defined and Z is a suitable leaving group, such as alkoxy, for example, (E)-methyl-3-(2-bromophenyl)-2-butenoate wherein R1 is methyl, R 3 is 2-bromo and Z is methoxy, in the presence of a base such as sodium hydroxide or an acid such as hydrochloric acid and in a polar solvent, for example, ethanol. Compounds of formula (VIII) wherein Z is alkoxy may be made by the dehydration of a compound of i i WO 92/12959 PCT/GB92/00108 16 ii formula (VII) wherein R and R are as hereinbefore defined and R Z. Such compounds may be prepared by the Reformatski reaction described in process C) above.

The compound of formula may be converted into a pharmaceutically acceptable base salt in a conventional manner, for example, by treatment with the appropriate base.

The present invention further includes the following novel intermediates which are of particular value for the preparation of compounds of formula wherein R and R are as hereinbefore defined and R' is 2-bromo:- 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-butenoylchloride.

The following examples illustrate the present invention but should not be construed as limitations thereof.

Example 1 Preparation of (E)-3-(2-Bromophenvl)-N-cyclopropvl-2-butenamide A) Preparation of 2-chloro-N-cvclopropvlacetamide A solution of chloroacetyl chloride (33.8g, 0.3moles) in 100ml of ethyl ether was added dropwise over 30 minutes to cyclopropyl amine (3 4 .2g, 0.6moles, Aldrich) in 400ml of ethyl ether at OoC with stirring. After and additional 30 minutes at this temperature, the ether was evaporated with a stream of nitrogen i i- I, fl .3 IW; a

I

-a- WO 92/12959 PCT/GB92/00108 17 while heating on a steam bath. The residue was dissolved in dichloromethane (400ml) and washed successively with 100ml portions of dilute hydrochloric acid 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 26.4g (66%) of 2-chloro-N-cyclopropylacetamide, m.p. 80-83 0

C.

Anal. Caicd. for CH HC1NO: 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.

Preparation of Diethyl((cyclopropylcarbamoyl)methyl)phosphonate 2-Chloro-N-cyclopropylacetamide (20g, 0.15moles) was added in portions with stirring to triethyl phosphite (28g, 0.17moles, Aldrich) at 1100C. The solution was then heated to 1550C for minutes, cooled to 125 0 C, and the volatiles were removed by distillation under aspirator vacuum (15mm Hg) at this temperature. The residual oil was stirred with pentane (200ml) while cooling in an ice bath to induce crystallization. Filtration gave 5.2g of diethyl((cyclopropylcarbamoyl)methyl)phopsphonate as white crystals; m.p. 51-56 C. The liquor was concentrated and cooled to give 25.3g of a second crop; m.p. 50-56 0 C. Recrystallization from dichloromethane/hexanes gave the analytical sample, m.p. 55-570C.

Anal. Calcd. for C gH NO P: C, 45.96; H, 7.71; N, 5.95.

Found. C, 45.85; H, 7.76; N, 5.90.

Preparation of (E)-3-(2-Bromophenyl)-N-cvclopropyl-2-butenamide To an ice-cold, stirred suspension of NaH (80% dispersion in mineral oil, (0.67g, 28mmoles, Aldrich) in dimethoxyethane was added a solution of diethyl((cyclopropylcarbamoyl)methyl)phosphonate (5.0g, 21mmoles) in dimethoxyethane (60ml). After 4.

1- WO 92/12959 PCT/GB92/00108 -18 hours, a solution of 2'-bromoacetophenone 4 .0g, Aldrich) in dimethoxyethane (60ml) was added, and the mixture was allowed to warm to room temperature overnight. The reaction mixture was poured into 1L of ice water and the mixture was extracted with dichloromethane. The residue was chromatographed on Silica Gel 60 using dichloromethane-ethyl acetate as eluent. The fractions containing only (E)-3-(2-bromophenyl)-Ncyclopropyl-2-butenamide were combined and spin evaported in vacuo to give 2.2g of a colorless oil. Trituration with pentane gave 1.85g of (E)-3-(2-bromophenyl)-N-cyclopropyl- 2-butenamide, m.p. 82-84 0 C; NMR (DMSO-d 6 8.04 IH, J 4.02 Hz, NH), 7.64-7.19 4H, Ar), 5.64 1H, J 1.36 Hz, -CH), 2.68 1H, NCH), 2.36 3H, J 1.17 Hz, CH 3 0.68-0.35 (2m's, 4H, CH 2

CH

2 steady-state nOe: irradiation at 2.36, observed 4.9% nOe at 7.25 and 1.3% nOe at 5.64.

Anal. Calcd. for C 3H14BrNO: 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-Bromophenvl)-N-cyclopropvl-2-butenamide Preparation of (E)-N-Cvclopropyl-2-butenamide Thionyl chloride (24mL, 0.33mol) was added dropwise during minutes to a stirred solution of crotonic acid (25.8g, 0.30mol, Aldrich) in benzene (400mL) protected from moisture by a drying tube containing Drierite. The resulting clear solution was heated at reflux for 3 hours before a portion of the solvent (100mL) was removed by distillation (atmospheric pressure). The remaining solution was stirred, chilled (ice bath) and treated dropwise with cyclopropylamine (20.6g, 0.36mol, Aldrich) followed by triethylamine (41.8mL, 0.30mol). A white solid precipitated.

Water (50mL) was added to the mixture and the resulting layers .F r i*I i Lcl 1' i 1 L PCT/GB92/00108 WO 92/12959 19 were separated. The aqueous layer was saturated with NaCI and extracted with methylene chloride (5 x 100mL). The organic layers were combined, dried over Na2SO, filtered and concentrated to a solid residue, which subsequently was subjected to bulb to bulb distillation (pot temperature 90-110°C) at 0.1 torr; yield, 31.2g m.p. 63-650C; NMR (DMSO-d 6 6 7.91 (br s, 1H, NH), 6.48-6.66 1H, -CHCH 3 5.79 (d x d, J 1.6, J 15.2 Hz; 1H, -CHCO), 2.65 1H, NCH), 1.74 (d x d, J 1.7, J 6.8 Hz, 3H, CH 3 0.39 and 0.60 (2 m's, 4H, CH 2

CH

2 Anal. Calcd. for C7H11NO.0.1 H20: C, 66.22; H, 8.89; N, 11.03.

Found: C, 66.10; H, 8.90; N, 11.07.

Preparation of (E)-3-(2-Bromophenvl)-N-cyclopropvl-2-butenamide A stirred mixture of 1,2-dibromobenzene (Aldrich) (2.36g, 10.0mmol), (E)-N-Cyclopropyl-2-butenamide (1.30g, 10.0mmol), triethylamine (l.01g, 10.0mmol), tri-o-tolylphosphine (Aldrich) (0.24g, 0.8mmol), palladium acetate (Aldrich) (0.04g, 0.2mmol) and acetonitrile (25mL) was heated in a stoppered flask at 120 0

C

for 18 hours. The mixture was cooled to ambient temperature, filtered, concentrated and chromatographed on Silica Gel 60 using ethyl acetate-hexanes (1:4 to 1:1 gradient) as eluent. Fractions containing only (E)-3-(2-bromophenyl)-N-cyclopropyl-2-butenamide were combined and spin evaporated in vacuo to give 1.2g (42.8%) of the product. An analytical sample obtained by recrystallization from dichloromethane/hexanes was identical to the compound prepared in Example 1 by mixed m.p. (82-84 0 C) and NMR.

V

Anal. Calcd. for C 3H14BrNO: 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.

LI c j Y yC_ WO 92/12959 PCT/GB92/00108 20 Example 3 Preparation of (E)-3-(2-Bromophenyl)-N-cvclopropvl-2-butenamide A) Preparation of (E)-Ethyl 3-(2-Bromophenvl)-2-butenoate A stirred mixture of 2'-bromoacetophenone (Aldrich) (14.7g, 74mmol), zinc powder (Mallinckrodt) ethyl bromoacetate (Aldrich) (18.5g, lllmmol), a crystal of iodine, benzene (100mL) and diethyl ether (100mL) was heated at reflux under nitrogen for 2 hours. The resulting grey suspension was cooled to ambient temperature, filtered and the filtrate was concentrated to a yellow foam. The residue was dissolved in acetic anhydride with cooling, treated with p-toluenesulfonic acid Aldrich) and heated at 70-800C for 0.5 hours. The solution was cooled to ambient temperature, concentrated in vacuo and chromatographed on a Waters Prep 500 using ethyl acetate-hexanes (1:133) as eluent. Fractions containing only (E)-ethyl 3-(2-bromophenyl)-2-butenoate were combined and spin evaporated in vacuo to give 3.0g of a clear oil; NMR (DMSO-d 6 6 7.67-7.23 4H, Ar), 5.72 1H, J-1.4 Hz, 4.13 2H, 2.37 3H, J-1.4 Hz, CH 3 1.21 3H, CH3CH20); steady-state nOe: irradiation at 2.37 6, observed 2% nOe at 7.45 and 1% nOe at 5.72 6.

Anal. Calcd. for C 2H13BrO2: C, 53.55; H, 4.87; Br, 29.69.

Found: C, 53.61; H, 4.83; Br, 29.76.

B) Preparation of (E)-3-(2-Bromophenvl)-2-butenoic Acid -mixture of (E)-ethyl 3-(2-bromophenyl)-2-butenoate (2.7g, ethanol (20mL) and 1N NaOH (ll.OmL) was stirred overnight at ambient temperature. The solution was concentrated in vacuo, diluted with water (30mL) and extracted with diethyl ether. The aqueous layer was acidified by adding cone HC1 z WO 92/12959 PCr/GB92/00108 22.

(1.21nL) and extracted with diethyl ether. The ether layer was dried over Na 2so 4 filtered, concentrated and chromatographed on Silica Gel 60 using ethyl acetate-dichloromethane The fractions containing only CE) -3-(2-bromophenyl)-2-butenoic acid were combined and concentrated to give white crystals 41.7%) of the product, m.p. 109-111 0 C; NMR (DMS0-d 5 12.43 (br s, IH, COOH), 7.67-7.22 (in, 4H, Ar), 5.66 lH, J-1.4 Hz, 2.34 3H, J-1.4 Hz, CH 3 steady-state nOe: irradiation at 2.34 8, observed 1% n~e. at 7.29 6 and 1% n~e. at 5.66 S.

Anal. Calcd. for C 10 H 9 Br 2 C, 49.82; H, 3.76; Br, 33.14.

Found: C, 49.92; H, 3.77; Br, 33.21.

C) Preparation of (E',-3(2Bromohenvl)-N-cvclopropv1-2-butenamid A solution of (E)-3-(2-bromophenyl)-2-butenoic acid (l.Og, 4.Ommiol) and oxalyl chloride (1.7g, 13.8mmol, Aldrich) in benzene was refluxed for 2 hours and concentrated to give (E)-3-(2-bromophenyl)-2-butenoylchloride as a pale yellow oil; IR: 1773, 1611 cm 1. Cyclopropylanine (0.9g, l6minol, Aldrich) was added to the acid chloride in benzene (60mL), and the mixture was stirred overnight at room temperature. The solution was washed sequentially with saturated NaHCO 3 (5OmL.), 1N HCl and brine (5OmL), dried over Na 2so 4 filtered and concentrated in vacuo to a cloudy oil Recrystallization fProm dichloromethane-hexanes gave white crystals (0.3g, 30%) of the product identical to the compound prepared in Example 1 by mixed m.p. (82-84 C and NM'R.

ftAnal. Calcd. for C 13H 14BrNO: 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.

AF.

WO 92/12959 PC&/GB92/O1O8 -22- Example 4 Preparation of (2-Bromophenyl)-N-cycloprovvl-2-butenamide Ethyl chioroformate (Aldrich) (0.13g, l.24mmol) was added dropwise to a stirred solution of (E)-3-(2-bromophenyl)-2-butenoic acid (0.30g, l.24mmol), triethylamine (0.12g, l.24mxnol) and tetrahydrofuran at 0 0C. After 2h at 0 0 C, the precipitated triethylamine hydrochloride was removed by filtering and a solution of cyclopropylamiaie (71mg, l.24mmol) in tetrahydrofuran (lmL) was added dropwise to the ice-cold filtrate. The mixture was stirred overnight at ambient temperature, concentrated and chromatographed on Silica Gel using ethyl acetate -dichloromethane (1:19) as eluent. The fractions containing only (2-Bromophenyl)-N-cyclopropyl-2-butenainide were combined and spin evaporated in vacuo to give 0.21g of the product. An analytical sample obtained by recrys tall ization from dichloromethane/ hexanies was identical to the compounds prepared in Example 1 by mixed m.p. (82-84 C) and NMR.

Anal. Cac.frCH BrN0: C, 55.73; H, 5.04; N, 5.00; Br, 28.52.

Cald. or 1 3 14 Found: C, 55.71; H, 5.04; N, 5.01; Br, 28.60.

Example Preparation of (2-Bromonhenyl) -N-cyclonrovvl-2-butenamide The fractions from Example 1C containing only (Z)-3-(2-bromophenyl)-Ncyclopropyl-2-butenamide were combined and spin evaporated in vacuo to give 1.7g of a white solid. Trituration with pentane gave 1.31g (23%) of (2-bromophenayl)-N-cyclopropyl-2-butenamide, m.p. 144-146 C NMR (DMSQ-d 6 6 7.82 1H, NH), 7.55-7.05 (in, 4H, Ar), 5.90 (d, 1H, J 1.47 Hz, 2.48 (in, 1H, NCH), 1.97 3H, J 1.47 Hz, CH 3 0.57-0.27 (2m's, 4H, CH 2 CH 2 steady-state n~e: irradiation at 1.97, obser-ved 8.2% n~e at 7.1 and 17.0% noe at 5.90.

I WO 92/12959 3-PCT/GB92/00108

V

I

Anal. Calcd. for C 13

H

14 BrNO: C, 55.73; H, 5.04; N, 5.00.

Found: C, 55.73; H, 4.99; N, 4.99.

Exarnvle 6 Preparation of -N-Cvcloproyl-3-(2- (trifluoromethvl))vhenvl) -2butenaxnide This compound was prepared in an analogous manner to that of Example 1 with the replacement of 2'-bromoacetophenone in Example 1C with 2' -(trif'.Luorouiethyl) acetophenone (Aldrich). The chromatography solutions that con~tained (E)-N-cyclopropyl-3- (2-(trifluoromethyl) phenyl)-2-butenamide were spin evaporated in vacuc. The solid was collected and recrystallized from ethanol-water to give 0.

74 g of (E-)-N-cyclopropyl-3-(2-(trifluoromethyl))phenyl)-2-butenamide, m.p.

114-116 0C NNR (DMSO-d 6 6 8.06 lH, J 4.16 Hz, NHl), 7.76-7.36 (in, 4H, Ar), 5.62 1H, JL 1.31 Hz, -CGH), 2.70 (mn, 1H, NCH), 2.40 3H, J 1.07 Hz, CH 3 0.66-0.40 (2m's, 4H, CH 2 CH 2 steady-state n~e: irradiation at 2.40 6, observed 4.9% noe at 7.4 and 1.4% nOe at 5.628 6.

Anal. Calcd. for C 14H 14F 3NO: C, 62.45; H, 5.24; N, 5.20.

Found: C, 62.37; H, 5.28; N, 5.19.

Exainle 7 Preparation of (E)-N-Cyclovropyl-3-(2.3-dichlorophenyl)-2-butenamide This compound was prepared in an analogous manner to that of Example 1 with the replacement of 2'-broraoacetophenone in Example 1C with 3' -(dichloro)acetophenone (Maybridge). The chromatography solutions that contained -N-cyclopropyl-3-(2,3-dichlorophenyl) -2butenamide were spin evaporated, and the solid was collected and dried; yield, 6.73g m.p. 111-1131 0 C; NMR (DMSO-d 6 8 8.08 1H, J 4.06 Hz, NH), 7.62-7.21 (in, 3H, Ar), 5.69 1H, JL

I

Ii 3L~i WO 92/12959 PCT/GB92/OO1 08 -24 -22 Hz, 2.67 (in, lH, NCH), 2.63 3H, J 0.97 Hz, CH 3 0.66-0.37 (2m's, 4H, CH CH').

2 2 Anal. Calcd. for C 13H 13Cl 2NO: 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)J-3-(2-Chloroyhenyl) -N-cycloyropyl-2-butenamide This compound was prepared in an analogous manner to that of Example 1 with the replacement of 2' -bromoace~ophenone in Example 1C with 2' -chloroacetophenone (Aldrich) The chromatography solutions that contained (2-chiorophenyl) -N-cyclopropyl-2-butenamide were spin evaporated in vacuo. The solid was collected and dried; yield, 28.30g m.p. 92.5-94OC NKR (DI'ISO-d 6 6 8.05 lH, J 3.86 Hz, NH), 7.48-7.22 (in, 4H, Ar), 5.68 1H, J 1.28 Hz, 2.68 (in, 1H, NCH), 2.38 3H, J 1.44 Hz, CH 3 0.68-0.37 (2in's, 4H, CH 2 steady-state n~e: irradiation at 2.38 6, observed 4% n~e at 7.3 and 1% n~e at 5.68 6.

Anal. Calcd. for C 1 I- H 14ClNO: 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 (2-Chlorophenyl) -N-cvclopropyl-2-butenamide This compound was prepared in an analogous manner to that of Example 1 with the replacement of 2'-bronoacetophenane in Example 1C with 2'-chloroacetophenone (Aldrich). The chromatography solutions that contained (2-chlcrophenyl) .N-cyclopropyl-2-butenamide were spin evaporated and the solid was collected and dried; yield, 3.52g m.p. 125-132 0 C; NMR (DMSO-d 6 6 7.83 1H, NH), 7.38-7.06 (mn, 4H, Ar), 5.92 1H, J 1.45 Hz, 2.48 (mn, 1H, NCH) Ii ~7j~1I WO 92/12959 PCT/GB92/00108 11 ft til

I

ii ~L1 25 1.98 3H, J 1.41 Hz, Cl-I 3 0.57-0.24 (2m's, 4H, CH.,CH 2 steady-state nOe: irradiation at 1.98 6, observed 5% n~e at 7.1 and 14% nOe at 5.92 S.

Anal. Calcd. for C 13H 14CiNO: 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.

Exampl1e Preparation of (E)-N-Cyclopropyl-3-(2-fluoropheyl)-2-butenamide This compound was prepared in an analogous manner to that of Example 1 with the replacement of 2'-bromoacetophenone in Example 1C with 2'-fluoroacetophenone (Aldrich). The chromatography solutions were spin evaporated, and the solid was collected and dried; yield, 8.50g m.p. 59-5.62 C; NlM. (DMSQ-d 6 6 8.08 1H, J 3.82 Hz, NH), 7.37-7.15 (in, 4H, Ar), 5.89 1H, J 1.21 Hz, 2.67 (in, 1H, NCH), 2.40 3H, CHR 3 0.66-0.37 (2m's, 4H, CHR 2 CH 2 steady-state nOe: irradiation at 2.49 6, observed 5.3% noe at 7.3 and 0.7% nOe at 5.89 6.

Anal. Calcd. for C 13H 14FNO C, 71.21; H, 6.44; N, 6.39.

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

Example 11 Preparation of 3 -(3-Chlorophenyl)-N-cyclobutvl-2-butenamide, To a stirred, ice bath-cooled solution of (E)-3-(3-chlorophenyl)-2butenoic acid Van Heyningen et al. J.NMed.Chem, 9, 675 (1966) (5.00g, 254mmole) and triethylamine (2.57g, 254mmole) in tetrahydrofuran (120m1) was added ethyl chloroformate (2.76g, 254mmole) in tetrahydrofuran (20m1). After 30 minutes cyclobutylamine (1.1g, 254mmole, Aldrich) in tetrahydrofuran (30m1) was added slowly.

The reaction mixture was stirred at ambient temperature for 15 hours.

-26 The reaction mixture was spin evaporated in vacuo, and the residue was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate.

The ethyl acetate layer was washed with IN hydrochloric acid and brine. The ethyl acetate solution was dried (sodium sulfate) and spin evaporated in vacuo. The residual yellow solid was purified by flash chromatography on silica gel 60 (40-63 m, E. Merck No. 9385) using ethyl acetate-hexane as eluent. The fractions that contained (E)-3-(3-chlorophenyl)-N-cyclobutyl-2-butenamide were combined and evaporated to give 3.93g of product, m.p. 89-900C; NMR (DMSO-d 6 8.2 (br d, 1H, NH), 7.54-7.35 4H, Ar), 6.21 1H, j 1.3 Hz, 4.28 1H, NCH), 2.45 3H, J 1.2 Hz, CH3), 2.32-1.55 6H, (CH 2 3 steady-state nOe: irradiation at 2.45, observed 18.1% nOe at 7.5 and nOe at 6.21.

Anal. Calcd. for C14H16 CNO: 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-Bromophenvl)-N-cvclobutvl-2-butenamide This compound was prepared in an analogous manner to that of Example 3 with the replacement of cyclopropylamine in Example 3C with cyclobutylamine (Aldrich). The solid was recrystallized from dichloromethane-hexanes to give off white crystals (l.lg, 64%) of the product, m.p. 128-130 0 C; NMR (DMSO-d 6 6 8.22 1H, J 7.7 Hz, NH), 7.66-7.20 4H, Ar), 5.68 1H, J 1.4 Hz, CH), 4.25 1H, NCH), 2.36 3H, J 1.3 Hz, CH 3 2.20-1.58 (3 m's, 6H,

(CH

2 3 steady-state nOe: irradiation at 2.36 6, observed 4% nOe at 7.24 6 and 1% nOe at 5.68 6.

Anal. Calcd. for C14H16BrNO: 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.

r WO 92/12959 PCT/GB92/001 08 -27 Example 13 Preparation of (E)-3-(2-Chlorophenvl)-N-c' Joprooyl-2-pentenamide This compound was prepared in an analogous manner to that of Example I with the replacement of 2'-bromoacetophenone in Example 1C with 2'-choropropiophenone (B.L.Jenson, S.E. Burke and S.E.Thomas, Tetrahedron, 34, 1627-1631 (1978)). The chromatography solutions that contained (E)-3-(2-Chlorophenyl) -N-cyclopropyl-2-pentenanide were combined and spin evaporated in vacuo to give 6.60g of (2-Chlorophenyl) -N-cyclopropyl-2-pentenamide, m.p. 148-150 0 C; NNR (DMSO-d 6 8.06 IH, J 3.9 Hz, NH), 7.50-7.22 (3 m's, 4H, Ar), 5.64 1H, CH), 3.01 2H, J 7.5 Hz, CH 2 2.70 (in, 1H, NCH), 0.86 3H, J 7.5 Hz, CH 0.68-0.40 (2 m's, 4H, CH 2 CH 2 steady-state mOe: irradiation at 3.01 8, observed 19.7% noe at 0.86 8 and 1.1% n~e at 5.64 8.

Ana. Clcd fo C14 H16 C,N,0: 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 -N-Cvclopropyl-3- (2-iodophenyl)2-butenamide A) Preparation of DiisOpropyl((cyclopropvlcarbamoyl)methyl) phosvhonate This compound was prepared (3.0 molar scale) in a manner analogous to that of Example lB with the replacement of triethyl Phosphite with triisopropylphosphite (Aldrich) and pentane with hexane: yield, 385g as a fluffy white solid, m.p. A 58-60 0C; the analytical sample was recrystallized from hexane.

WO 92/12959 Ana Fou ai; u .xrx._u rjr i li' i L -1~ PCF/GB92/00108 28 1. Calcd. for C11H22NO P: C, 50.18; H, 8.42; N, 5.32 nd: C, 50.08; H, 8.44; N, 5.26.

B) Preparation of (E)-N-Cvclopropyl-3-(2-iodophenyl)-2-butenamide This compound was prepared in an analogous manner to that of Example 1 with (Aldrich) the replacement of 2'-bromoacetophenone in Example 1C with 2'-iodoacetophenone (Aldrich) and the replacement of diethyl((cyclopropylcarbamoyl)methyl)phosphonate with diisopropyl((cyclopropylcarbamoyl)methyl)phosphonate. The chromatography solutions that contained (E)-N-cyclopropyl-3-(2iodophenyl)-2-butenamide were spin evaporated in vacuo. The residue was recrystallized from dichloromethane-hexanes to give 1.7g of the product as white crystals, m.p. 120-122 0 C; NMR (DMSO-d 6 6 8.04 1H, J 4.0 Hz, NH), 7.88-7.00 4H, Ar), 5.57 1H, J 1.4 Hz, 2.68 1H, CH), 2.34 3H, J 1.3 Hz, CH3), 0.68-0.35 (2 m's, 4H, CH 2

CH

2 steady-state nOe: irradiation at 2.34 6, observed 5% nOe at 7.04 6 and 1% nOe at 5.57 6.

Anal. Calcd. for C13H14INO: C, 47.73; H, 4.31; N, 4.28; I, 38.79.

Found: C, 47.63; H, 4.33; N, 4.26; I, 38.86.

Pharmaceutical Formulations

A

WI'

In the following formulation Examples, the "Active Ingredient" may be any compound of formula or base salt or other physiologically functional derivative thereof, for example, compounds of Examples 1 to 14.

I i i ~1 LI .L IL-l

I

1 I *^sc- ,,cl P- it

I

i WO 92/12959 PCU/GB92/00108 29 Example Tablet Formulations The following formulations A, B and C are prepared by wet granulation of the ingredients with a solution of povidone, followed by addition of magnesium stearate and compression.

Formulation A mg/tablet Active ingredient Lactose B.P.

Povidone B.P.

Sodium Starch Glycollate Magnesium Stearate 250 210 15 20 5 500 mg/tablet 250 26 9 12 3 300 i i Formulation B mg/tablet Active ingredient Lactose Avicel PH 101 Povidone B.P.

Sodium Starch Glycollate Magnesium Stearate mg/tablet 250 26 9 12 300 ii i_ ii ii

II~

lii:~ d::r arpli e i _IJ I ~n nl

I~

WO 92/12959 PC/GB92/00108 30 Formulation C mg/tablet Active ingredient 100 Lactose 200 Starch Povidone Magnesium Stearate 4 359 The following formulations, D and E, are prepared by direct compression of the admixed ingredients. The lactose in formulation E is of the direct compression type (Dairy Crest "Zeparox").

Formulation D mg/tablet Active ingredient Pregelatinized Starch Formulation E mg/tablet 11 Active ingredient Lactose Avicel 250 150 100 500 Formulation F (Controlled Release Formulation) The formulation is prepared by wet granulation of the ingredients (below) with a solution of povidone followed by the addition of magnesium stearate and compression.

I

WO 92/12959 PCr/GB92/ 09108 31 z/tablet Active ingredient Hydroxypropylmethylcellulose (Methocel K4M Premium) 1c) Lactose B.P.

A)Povidone B.P.

Magnesium Stearate 500 112 53 28s 7 700 Example 16 4 Capsule-Formulations r7ormulation A A capsule formulation is prepared by admixing the ingredients of Formulation D in Example 15 above and filling into a two-part hard gelatin capsule. Formulation B (infra) is prepared in a similar manner.

:7ormulation B mg/capsule Active ingredient Lactose B.P.

Sodium Starch Glycollate Magnesium Stearate WO 92/12959 32 2 PCT/GB92/00108 Fornulation C mg/capsule Active ingredient Macrogol 4000 B.P.

250 350 600 Formulation D mg/capsule Active ingredient Lecithin Arachis Oil 250 100 100 450 Capsules of formulation D are prepared by dispersing the active ingredient in the lecithin and arachis oil and filling the dispersion into soft, elastic gelatin capsules.

Formulation E (Controlled Release Capsule) The following controlled release capsule formulation is prepared by extruding ingredients a, b and c using an extruder, followed by spheronization of the extrudate and drying. The dried pellets are then coated with release-controlling membrane and filled into a two-piece, hard gelatin capsule.

I~

I

1d *rC:t1 mg/capsuie Active ingredient Microcrystalline Cellulose Lactose B.P.

Ethyl Cellulose C. .ii i I tC i i i i *i WO 92/12959 PCT/GB92/00108 1 3 Example 17 Iniectable Formulation Active ingredient Ethanol and PEG 400, 1:1 ratio Sterile water 0.200 g q.s. to 10 mL The active ingredient is dissolved in 95% Ethanol and PEG 400 The batch is then made up to volume with the water and filtered through a sterile micropore filter into a sterile 10 mL amber glass vial (type 1) and sealed with sterile closures and overseals.

Example 18 Sv.rup

I

I

i: Active ingredient Sorbitol Solution Glycerol Sodium Benzoate Flavor, Peach 17.42.3169 Purified Water 0.25 g 1.50 g 2.00 g 0.005 g 0.0125 mL q.s. to 5.00 mL The active ingredient is dissolved in a mixture of the glycerol and most of the purified water. An aqueous solution of the sodium benzoate is then added to the solution, followed by addition of the sorbitol solution and finally the flavor. The volume is made up with purified water and mixed well.

i e i- -I I ii h.

c; :r .i i ~I r WO 92/12959 P(3r/GB92/00108 34

I

S=Rpositorv mg/suppositorv Active ingredient Hard Fat, B.P. (Witepsol H15 Dynamit NoBel) 250 1770 2020 One-fifth of the Witepsol H15 is melted in a steam-jacketed pan at maximum. The active ingredient is. sifted through a 200 M sieve and added to the molten base with mixing, using a Silverson fitted with a cutting head, until smooth dispersion is achieved. Maintaining the mixture at 45"C, the remaining Witepsol H15 is added to the suspension and stirred to ensure a homogenous mix. The entire suspension is passed through a 250 M stainless steel screen and, with continuous stirring, is allowed to cool to 40'C. At a temperature of 38°C to 40°C, 2.02 g of the mixture is filled into suitable, 2 mL plastic molds. The suppositories are allowed to cool to room temperature.

Example Pessaries mg/pessarv Active ingredient Anhydrate Dextrose Potato Starch Magnesium Stearate 250 380 363 7 1000 The above ingredients are mixed directly and pessaries prepared by direct compression of the resulting mixture.

c 1ii' 7 i r~ I I r~lr_ PCT/GB92/00108 WO 92/12959 35 Example 21 Muscle Relaxant Activity Muscle relaxant activity of compounds of formula was determined using a Straub tail test based on that described by K.O. Ellis and J.F. Carpenter Neuropharmacol, 13, 211 (1974).

The Straub tail test result is reported as an ED, in mg/kg. The ED0 50 is defined as the dose of compound administered, which prevents Straub zail in 50% of mice. The compound is administered by oral gavage (po) min. prior to scoring.

The side effect potential of these compounds was determined using the mouse rotorod test as described by G.D. Novak and J.M.-Zwolshei, J.Pharmacological. Methods, 10, 175 (1983). Rotorod result is reported as ED, in mg/kg. The EDo is the dose which causes 50% of the animals to fail to maintain position on a cylinder rotating at 11 .m.

Antagonism of morphine-induced Straub tail reflects muscle relaxant efficacy while failure in the rotorod test reflects sedation and incoordination. Determination of the ratio of rotorod failure to antagonism of morphine-induced Straub tail is a means of assessing side effect liability of muscle relaxants Novak, Drug Dev. Res., 383 (1982).

4 Compound of Example No.

Straub Tail p.o. ED50, mg/kg.

Rotorod p.o.

ED

50 mg/kg.

Rotorod/ Straub Tail ratio 1.8 L~ F

~-T

i r i li WO 92/12959 PCT/GB92/00108 36 Example 22 Anticonvulsant Activity- Anticonvulsant activity of compounds of formula was determined using a method described by Mehta et ai., J.Med.Chem., 465 (1981).

The anticonvulsant activity is reported as an ED50 in mg/kg. The ror protection against maximal electroshock-induced convulsions was the dose which prevented hind limb extension in 50% of the animals.

The ED for protection against Metrazol-induced convulsions was the dose which prevented? convulsions in 50% of the animals.

p ft

I.

U'

Cj Compound of Example No.

i.p.

ED

50

MES

mg/kg (rat)

MET

MES maximal electroshock MET metrazol Example 23 Anxiolvtic Activity Anxiolytic activity of the compounds according to the invention was measured using method of Geller and Seifter, J.Psychopharmacolgia, 1, 482 (1960) as modified by Pollard and Howard, Psychopharmacology, 117 (1979). Clinically efficacious anxiolytics increase punished responding. The anxiolytic activity of the compound is reported as

.II

zJi WO 92/12959 PCr/G B92/001 08 3' 37 the dose necessary to produce a 50% increase in punished responding in rats.

Compound of Example No.

P.o. EDo 11z/kz

Claims (21)

1. 2-posici on; or a base saic or other phys ioiogically functcional derivative thereof. 4j. A compound according to any one of claims t. to 3 whereinR1 represents methyl and/or, R- represents cyclopropyl and/or R is as hereinoefore defined and is in the 2-oosition; or a base salt or ocher physiologically functional derivative thereof. S. isomers of compounds of formula or a base salz or other physiologically functional derivative thereof according to any one of claims I to L 4
2. 6. A compound according to claim I. which compound 'is:- 1. (E-)-.-cvclopropyl-3-(2-(c:ri4fluoromethvl,)phenyl))-2-but-en- amide; 2. (E)-N-cvclopropyl-3-(2-iodophenvl)-'2-bucenamide; 1. (E)-N-cv clonropyl-3-(2,3-dichlorophenvl)-2-butenamide; 4. %'7)-3-(2-chloroohenvl) -N-cvclotropyl-'--bur-enamide, )-3-(2-bromophenvl)-2-bucenamide; or a base salt or other physiologically functional derivatives thereof.
3. 7. -3-(2-bromophenyl)-N4-cyclopropyl-2-butenamide. S8. A base salt or other physiologically functional derivative-of a comrpound according to any one rf claims. 1 to 7. -Now 1 PCT/GB92/00108 WO 92/12959 40
4. 9. Use of a compound according to any one of claims 1 co 8 in the manufacture of a medicament for the creatment or prophylaxis of che conditions ast6diated with abnormally raised muscle tone. Use of a compound according to any one of claims 1 to 8 in the manufacture of a medicament for the treatment or prophvlaxis of convulsive states.
5. 11. Use of a compound according to any one of claims 1 to 8 in the manufacture of a medicament for the treatment of anxietv.
6. 12. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 8, together with a pharmaceucically acceptable carrier therefor.
7. 13. A formulation according to claim 12 administration. adapted for oral
8. 14. A formulation according to claim 13 in the form of a tablec capsule. A process for the preparation of a compound of formula (I) SI r *1 A CC C(R) zCjCRCqHR- 1 2 wherein.. R- represents. C 6 alkyl, R represents hydrogen or C 3 cycloalkyl and R' represents one or more ring substituencs selected from halogen and perhaloC1-4alkyi; 1-4 with the following provisos that: C r Y I F~ I I' t ~.ca il+: 1 WO 92/12959 PCT/GB92/00108 41 when R' is methyl and R- is cyclopropyl then the or one of R" is in the 2- position; and (ii) said compound of formula is not 3-(4-chlorophenyl)-2- butenamide; or a base salt or other physiologically functional derivative thereof, which process comprises: A) reacting a compound of formula (II) x (II) (wherein R is as hereinbefore defined and X is a leaving group) with a compound of formula (III) RCH CHCOR 4 (III) 4 0 (wherein R represents -NHR- and R~ and R~ are as hereinbefore defined); -P B) reacting a compound of formula (IV) C- i ;i I .i ;t i- i 1 _1:i I WO 92/12959 PCT/GB92/00108 42 Z. ==O (IV) (wherein R~ and R' are as hereinbefore defined) with a Wittig reagent of formula (V) YCHICOR 4 (wherein R is as hereinbefore defined and Y is -P(-0)(OR)g wherein R is a alkyl, aryl or aralkyl group, or Y is a triarylphosphine) under Wittig conditions; C) dehydrating a compound of formula (VII) CI( OH (VII) (wherein R R and R- are as hereinbefore defined). D) reacting a compound of formula (7III) C(R HCOZ (VIII) Ek, I i 1 "t,~i WO 92/12959 PCT/GB92/00108 43 (wherein R and R are as hereinbefore defined and Z is a leaving group) with a compound of formula (IX) (IX) (wherein R is as hereinbefore defined). and thereafter, or simultaneously cherewith, effecting or more of the following optional conversions:- one converting the compound of formula so formed into a base salt, or other physiologically functional derivative thereof; (ii) when a base salt, or other physiologically functional derivative of a compound of formula is formed, converting the said derivative into a compound of formula or a different derivative thereof.
9. 16. A process according to claim 15 Eor the preparation of a compound of formula wherein R1 represents mechyl and/or, R 2 represents 3 cyclopropyl and/or the or one of R as defined in formula is in the 2-position; or a base salt or other physiologically functional derivative thereof.
10. 17. A process according to claims 15 or 16 wherein RP represents 2) 3 methyl and/or, R' represents cyclopropyl and/or the or one of R represents bromo, chloro, iodo or trifluoromechyl and is in the 2-position; or a base sale or other physiologically functional derivative thereof. o 0 ot fti C IC C cc $4 811 i i $i IL_ i ',i iti i;i I 1:_I i i WO 92/12959 AA- PCT/GB92/00108
11. 18. A process according to any one of claims 15 to 17 wherein R represents methyl and/or, R 2 represents cyclopropyl and/or R is as hereinbefore defined and is in the 2-position; or a base salt or other physiologically functional derivative thereof.
12. 19. A process according to claim 15 for the preparation of (E) isomers of compounds of formula or a base salt or other physiologically functional derivative thereof, according to any one of claims 15co 18. A process according to claim 15 for the preparation of a compound:- 1. (E)-N-cyclopropyl-3-(2-(trifluoromechyi)phenyl))-2-bucen- amide; 2. (E)-N-cyclopropyl-3-(2-iodophenyl)-2-butenamide; 3. (E)-N-cyclopropyl-3-(2,3-dichlorophenyl)-2-butenamide; a. (E)-3-(2-chlorophenyl)-N-cyclopropyl-2-butenamide; I' A I It *r, tied o 14 C 5. (E)-3-(2-bromohenvl)-2-bucenamide; or a base salt or other physiologically functional derivative thereof.
13. 21. A process according to claim 16 for the preparation of bromophenyl)-N-cyclopropyl-2-butenamide.
14. 22. A process according to claim 15 wherein the product is isolated as a base salt or other physiologically functional derivative of formula according to any one of claims 16 to 22. t 4 WO 92/12959 PCT/GB92/00108 45
15. 23. A method for the treament or prophylaxis of conditions associated with abnormally raised muscle cone in a host, which comprises creating said host with an effective non-coxic amount of a compound according to claims 1 to 8.
16. 24. A method for the treatment or prophylaxis of convulsive states in a host, which comprises treating said host with an effective non-toxic amount of a compound according to claims i to 8. A method for the treatment or prophylaxis of anxiety in a host, which comprises treating said host with an effective non-toxic amount of a compound according to claims 1 to 8. tt w A f 1 I Oh- I t i i~tii I 46
17. 26. Use of a compound of formula or a base salt or other physiologically functional derivative thereof in a method of treatment or prophylaxis of conditions associated with abnormally raised muscle tone, convulsive states or anxiety in a host which method comprises treating said host with an effective non-toxic amount of a compound of formula or a base salt or other physiologically functional derivative thereof as defined in claims 1 to 8.
18. 27. A compound of formula or a base salt or other physiologically functional derivative thereof substantially as herein described with reference to any one of examples 1 to 14.
19. 28. A process of preparing a compound of formula or a base salt or other physiologically functional derivative thereof substantially as herein described with reference to any one of examples 1 to 14.
20. 29. A pharmaceutical formulation comprising a compound of formula or a base salt or other physiologically functional derivative thereof substantially as herein described with reference to any one of examples 15 to A method of treatment or prophylaxis of conditions 25 associated with abnormally raised muscle tone, convulsive states or anxiety in a host which comprises treating said host with an effective non- toxic amount of a compound of formula (I) substantially as herein described. cct# I A c, Dated THE WE 4VDSM.Aq By the: GRIFFI Ts5431 DQ/245.4 §16431 DQ/24.5.94 this 24th day of May 1994 LLCOME FOUNDATION LIMITED ir Patent Attorneys TH HACK CO O i I~ ::ir 4 -Q;I INTERNATIONAL SEARCH REPORT International Application No PCT/GB 92/00108 I. CLASSIFICATION OF SUBJECT MATTER (if several classification symbols apply, indicate all) o According to International Patent Classification (IPC) or to both National Classification and IPC C 07 C 233/11 A 61 K 31/165 1l. FIELDS SEARCHED Minimum Documentation Searched 7 Classific:aion System Classification Symbols C 07 C 233/00 A 61 K 31/00 Documentation Searched other than Minimum Documentation to the Extent that such Documents are Included in the Fields Searched6 III. DOCUMENTS CONSIDERED TO BE RELEVANT 9 Category o Citation of Document, 1l with indication, where appropriate, of the relevant passages Relevant to Claim No. 13 A US,A,4190674 GRIVSKY) 26 1-26 February 1980, see claims (cited in the application) A EP,A,0381508 (TAISHO PHARMACEUTICAL 1-26 CO.) 8 August 1990, see claims (cited in the application) A Journal of Medicinal Chemistry, vol. 9, no. 5, 1-26 September 1966, (Washington, US), E. VAN HEYNINGEN: "N-monoal kyl-beta-al kylcinnamamides as sedatives", pages 675-681, see page 675; examples 16,18-20; table II (cited in the application) A FR,A,2132547 (ETABLISSEMENTS 1-26 CLIN-BYLA) 8 April 1972, see claims; table I 0 Special categories of cited documents :o later document published after the international filing date or pilorit, date and not in conflict with the application but document defining the general state of the art which is not cited to understand the principle or theor underlying the considered to be of particular relevance invention 'E earlier document but published on or after the international XI document of particular relevance: the claimed invention filing date cannot be considered novel or cannot be consitered to document which may throw doubts on priority claimis) or involve an inventive step which is cited to establish the publication date of another document of particular relevance: the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu- other means ments, such combination being obvious to a person skilled document published prior to the international filing date but in the art. later than the priority date claimed document member of the same patent family IV. CERTIFICATION Date of the Actual Completion of the International Search Date of Mailing of this International Search Report 03-04-1992 .1 05. 92 International Searching Authority Sigusalt Uf Authorized Officer EUROPEAN PATENT OFFICE Form PCTI1SA/210 lsoecod heetl (Janatry 19L51 .vine Damar FRANK t -i Y I i i i b-, D i: i l. I- Internationa. ppllcation No. PCTI GB92100108 FURTHER INFORMATION CONTINUED FROM THE SECOND SHEET I r V. X OBSERVATION WHERE CERTAIN CLAIMS WERE FOUND UNSEARCHABLE I This International search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons: 1. E Claim numbers PL. SEE REMARK!! because they relate to subject matter not required to be searched by this Authonty, namely ALTHOUGH CLAIMS 24-26 ARE DIRECTED TO A METHOD OF TREATMENT OF (DIAGNOSTIC METHOD PRACTISED ON) THE HUMAN/ANIMAL BODY THE SEARCH HAS BEEN CARRIED OUT AND BASED ON THE ALLEGED EFFECTS OF THE COMPOUND/COMPOSITION. 2. O Claim numbers because they relate to parts of the International application that do not comply with the prescnbed requirements to such an extent that no meaningful International search can be camed out. specifically. 3. Claim numbers the second and third sentences of PCT Rule 6.4(a). because they are dependent claims and are not drafted in accordance with \r jl.C- Vl.D OBSERVATIONS WHERE UNITY OF INVENTION IS LACKING 2 This International Searching Authorityfound multiple Inventions in this International application as follows: 1. I As all required additional search fees were timely paid by the applicant, this International search report covers all searchable claims of the International application 2. O As only some of the required additional search fees wre timely paid by the applicant, this international search report covers only those claims of the International application for which fees were paid, specifically claims: 3. No required additional search fees were timely paid by the applicant. Consequently, this international search reprt is restricted to the inventon firs; mentioned in the claims; it is covere by claim numbers: 4. O As all searchable claims could be searched without effort justifyin an additional fee, the international Searching Authonty did not invite payment of any additional fee. Remark on Protest W The additional search fees were accompanied by applicants protest. No protest accompanied the payment of additional search fees. I Form PCT/ISA/210 (supplemental sheet P9412B 05/91 r j I; r.- L-: ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. GB 9200108 SA 55568 This annex lists the patent family members relating to the patent documents cited in the above-mentioned international sfarch report. The members are as contained in the European Patent Office EDP file on 28/04/92 The European Patent Office is in no way liable for these particulars which are merely given for the purpose of information. Patent document Publication Patent family Publication cited in search report date member(s) date US-A- 4190674 26-02-80 GB-A- AT-B- AT-B- AU-A- BE-A- CA-A- CH-A- CH-A- CH-A- DE-A,C FR-A,B JP-C- JP-A- JP-B- NL-A- SE-B- SE-A- SE-A- AU-B- 1568401 363926 371801 2183777 851020 1109076 634551 635820 636849 2704365 2340303 1330798 52116437 60056700 7701088 436870 7701107 8300432 513540 29-05-80 10-09-81 10-08-83 10-08-78 02-08-77 15-09-81 15-02-83 29-04-83
21. 30-06-83 04-08-77 02-09-77 14-08-86 29-09-77 11-12-85 05-08-77 28-01-85 04-08-77 28-01-83 11-12-80 EP-A- 0381508 08-08-90 CA-A- 2009009 02-08-90 JP-A- 2288823 28-11-90 FR-A- 2132547 24-11-72 None a -Fo e at ts ax se O l J l of te E n Pt w For more details about this annex :see Official Journal of the European Patent Office, No. 12/82 y :i