CA2101783A1 - Amide derivatives and their therapeutic use - 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

~: .

2~1783 ~MIDE DERIVATIVES AND ~HEIR T~ERAPEUTIC_USE

The pr&sen~ invention relates to 3-phenyl-2-alkenamide derivatives, ?hysiologically functionaL derivatives ,hereof, pharmaceu~ical preparations containing them and ths use or such compounos and preparations in therapy, particularly as muscle relaxants, anxiol~tics and anti-convulsants.

The hypnotic and sedative effects of certain 3-phenyl-2-alkena~ide derivatives, usua}ly referred ~o by their ~rivial chemical name cinnamamides, have been disclosed by Lott and Christiansen, J.Am.
Yharm.Assoc., 23,788 (1934) and Van Heyningen et al., ~.Med.Ghem., 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 relaxin~, muscle tone, for exa~ple, 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 induc~ion 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 dri~e or participate in certain occup~tions.

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 ~. , : ,, ,, , , ~, W 0 92/129~9 21017 8 3 2 - PCT/GB92/00108 ~e have no~ surprisingly found that certain 3-phenyl-2-alke~a#ides have potent muscle relaxant activity but with significantiy educed liability to the sedation and incoordination side-effscts cbse~ved with known ~uscle relaxants. These compounds have also been found ~o have anxiolytic and anti-convulsant activity According to the present invention there is provided 3-ph~ny.~ alke~
amide derivatives of general formula (I): -C(El1)=~,1iCONHR

P~

wherein Rl represents Cl 6 alkyl, R2 represents hydrogen or C3 6 cycloalkyl and R represents one or more ring substituents selected from halogen (for examp}ej Cl,Br,I,F) and perhaloCl 4alkyl (for, example trifluoromethyl);
' ~.
with the following provisos that:

(i) when R is me~hyl and R is cyclopropyl ~hen the or one of ~3 is in the 2-position; and (ii) said compound of formula (I) is not 3-(4-chlorophenyl)-2-butena-mide;

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 brsnched chain alkyl group. Such alkyl groups preferably have l to 3 carbon atoms and are more preferably methyl or ethyl, most preferably methyl.

.

W O 92/12959 , PCT/GB92/00108 21 0~783 Preferred compounds of formula (I) include those wherein Rl represents ~ethyl and/or, R 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 for3ula (I) include those wherein R represents methyl and/or, R represents cyclopropyl and/or R is a single ring subs~ituent at the 2-position, preferably bro~o, chloro, iodo or trifluoromethyl; or a base salt or other physiologically functional deriva~ive thereof.

The (E) isomers of compounds of for~ula (I) or a base salt or other ?hysiologically func~ional derivative thereof are preferred.
. ~
Especially preferred co~pounds of formula (I) are:

l. (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-bu~enamide;

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

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

6. (E)-3-(2-bromophenyl)-2-bu~enamide.

The compounds of formula (I) above and their base salts, or oeher physiolo~ically functional derivatives are hereinaftsr referred to as the compounds according eo the invention.

21~17~3 , t will be appreciated that the compounds of formula (I) may exist in various geoisomeric forms and as mixtures thereof in any proportions.
The present invention includes wi~hin its scope the use of such geoisomeric forms or mixtures of geoisomers, including the individual E and Z isomers of the compounds of formula (I) as weil 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 (direc~ly or indirectly) the said compound or an active metabolite or residue thereof.

Examples of base salts according to ~he invention include salts, for example, derived from an appropriate base, such as alkali metal (e.g.
sodium), alkaline earth metal (e.g. magnesium) salts, am~oniu~ and NX4 (wherein X is Cl 4 alkyl).

~or therapeutic use, salts of compounds of formula (I) will be physiologically accepeable, 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 ~re to be considered as being within the scope of the present invention.

Accordin~ 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 abnor~ally raised muscle tone, - convulsive states, and - anxiety.

The compounds are thus of particular value in the relaxation of skeletal muscle in spastic, hypertonic and hyperkinetic conditions.

: . , : -: :,: . ~ . . ... . .

W O 92/12959 PCr/GB92/001D8 ~' ' ,` , , 1, ! ! .
21~ 783 In particular the compounds may be used 'n the treatment and symptomatic relief of conditions such as spinal cord in~ury, parkinsonism, chorea, arthritis, athetosis, status epilepticus and tetanus and especially in the relief of muscle spasm in csnditions such as myositis, spondylitis, cerebral palsy, cerebrovascular disease amd multiple sclerosis.

The compounds may also be used for the treatment of exertion-in~uced skeietal muscle spasm, for exa~ple, lower back pain.

Convulsive states for which the compounds mav be employed include grand mal, petit mal, psychomotor epilepsy and focal seizure. The compounds according to the invention ~ay also be used in the treatment or 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 treat~ent or propnylaxis of conditions associated with abnor~ally raised muscle tone, convulsive states or anxie~y in a host, for example, a mammal including man, and mice which comprises treating said ma~mal with an effeceive non-toxic amount of a compound according to the invention.

b) use of a co~pound according to ehe invention in the manufacture of a medicament for the treae~ent or prophylaxis of conditisns associated with abnormally raised muscle tone, convulsive st~tes or anxiety.

The above compounds according to the invention may be employed in combination with other therapeutic agents for the treat~ent of the W O 92/l2959 PCT/GB92/00108 21~178.i3. ` 1 .
" .
conditions associaced with abnormally raised muscle tone. Examples of such therapeu~ic agents include analgesics, such as, codeine, acetaminophen, phenacetin or ibuprofen.

The present invention further provides pharmaceutioal formulations of the compounds according to the invention, also referred to herein as r active ingredients, which may be administered for therapy by any suitable route including oral, rectal, nasal, topical (including buccal and sublingual), vaginal and paranteral (including subcutaneous, intramuscular, intravenous and in~radermal). It will also be appreciated that the preferred route will vary with the conditions and age of the recipient, the nacure 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 t~e foregoing conditions a suitable dose of a compound of formula (I) or a base salt or other physiologically funccional derivatives thereof (estimated as the parent compound) is in the range of 0.05 to lOOmg 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 O.S to 20mg per kilogram body wei~ht per day a~d optimally 3mg per kilogram body weight per day. The desired dose is preferably presen~ed 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 example, containing 1 to 1500mg, preferably 5 to lOOO~g, and most preferably 10 to 700=g of active- ingredient per unit dosage form.

- - I

W 0 92/12959 PCT~GBg2/0~1~8 21 0~ 78;3 " ~ ii .;

~ile it is possible for the active ingredient to be ad~inistered alone it is preferable to present it as a pharmaceu~ical formulation The for~ulations of the present invsntion co~prises at ~east 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 tincluding 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 ~he art of pharmacy. Such methods include the step of bringing into association che active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the for~ulations are prepared by uniformly and ineimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.

Formulaeions of the presen~ 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, ~he active ingredienC may also be presented as a bolus, èle~tuary or pasce.

A tablet may be made by co~pression or molding, optionally wieh one or more accessory ingredients. Compressed tablets may be prepared by co~pressing in a suicable machine the acti~e ingredien~ in a free-flowing for~ such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluen~, preservati~e, disineegrant (e.g. sodium .

2~ 3 .., `;
starch glycollate, cross-linked povidone, cross-linked sodiu~
carboxymethyl cellulose) surface-active or dispersing agent. .~olded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an iner~ liquid diluent. The cablets 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 va~ying 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.

For~ulations 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 salcs.

Formulations suitable for copical ad~inistration in the mouth include lo~enges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles co~prising the acti~e ingre,dient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes co~prising 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.

Fo~ulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels pastes, foams or spray formulations containing in addition to the aceive ingredienc such carriers as are known in the art to be appropriate, Formulations suitable for parenteral ad~inistration include aqueous and non-aqueous isotonic sterile injections solutions .which may contain anti-oxidants, buffers, bacteriostats and solutes which render ,, . :.-, ~ , :

W O 92/l2959 PCT/GB92/0010~

21~783 ~he formulation isotonic with ehe blood of the intended recipien~; and aqueous and non-aqueous seerile suspensions which may include suspending agents and thickening agencs, as liposomes or other microparticulate systems which are designed to target the compounds to blood componenr.s or one or more organs. The formulations may 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 ths addition of the sterile liquid carrier, for exa~ple water for injections, immediarely prior to usa.
Extemporaneous injection solutions and suspensions may be psepared 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 opcionally buffered, aqueous solution of, for example, 0.1 to 0.2M coDcentration 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, ~6, 3l8 (1986).
.
Preferred unit dosage formulations are those containing a daily dose or unit, daily su'o-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.

It should be underseood that in addition to the ingredients particularly mentioned aDOve the formulations of this invention ~ay include other agents conventional in the art having regard to the tvpe of for~ulation in question, for example, those suitable for oral administration may include such further agents as sweeteners;
thi~keners and flavoring agents.

. .

W O 92112959 PCT/GB92/00~08 ;
- 10 - ~t'`
2101783 ~'1 t~

The compounds of formula (I) may be prepared in any conventional manner and in accordance with the present invention, may, for example, be prepared by any method hereinafter described.

Thus, the present in~ention further includes a process for the preparation of compounds of formula (I) and base salts, and o~her physiologically functional derivatiYes thereof which comprises:- i A) reacting a compound of formula (II) ,~r x (wherein R3 is as hereinbefore defined and X is a sltitable leaving group, for exanple a halogen a~om such as bromine or iodine or a sulphonate such as CF3S(0)20- with a compou~d of formula (III) R CH = CHCOR (III) (wherein R represents NHR2 and R and R2 are as hereinbefore defined);

B) reacting a compound of formula (IV) W O 92/12959 ~ PCT/GB92/001a8 .~' `~, ,-. . . ' ~ ., . , . i 2101783 `

~ ( Rl )=o ;
~ J (IV) ?3 (wherein Rl and R3 are as hereinbefore defined) with a Wlttig reagent of formuia (V) :

YC~2COR (V) (wherein R is as hereinbefore defined and Y is -~(-O)(OR)2 :
wherein R is a Cl 4 alkyl, aryl or aralkyl group, or Y is a triarylphosphine) under Wietig conditions;

C) dehydrating a compound of formula (VII) R3 ~ C(Rl ~ - CH CoR4 (V11) (wherein Rll R3 and R are as hereinbefore defined).

D) reacting a compound of formula (VIII) ~ C(Rl)=~RCOZ (VII1) `

(wherein R and R3 are as hereinbefore defined and Z is asuitable leaving group, for example, a halogen atom, such as bromine or chlorine, azido, amino, or a ROC(0)0- group wherein R
represents Cl 6 alkyl, for example, CH3CH20C(0)0- or an alkanoyloxy group, such as acetyloxy) with a compound of formula (I2) H-R (IX) (wherein R4 is as hereinbefore defined).

and thereafter, or simultaneously therewith, effeccing one or more or the following optional conversions:-(i) converting the compound of formula (I) so formed into a basesalt, or other physiologically f~nctional derivative thereof;

(ii) when a base salt, or other physiologically functional derivarive of a compound of formula (I) is formed, converting the said derivative into a compound of formula (I), or a differen~
derivative thereof.

In process A), a compound of formula (II), is reacted with a compound of formula (III), typically in the presence of a caealyst, such as a transition metal catalyst, for example, a palladiu~ catalys~, in particular, palladium acetate, conveniently in the presence of an or~anic base such as triethylamine (TEA) and in a suitable polar solvent, for example, acetonitrile, dimethylforma~ide (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.

,, . ~: :' ::

2~01783 ` `
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, bv wav of ' ;
i;lustration only to the following texts~

) "Protective Groups in Or~anic Chemistry" ed. J.~.W.McOmie, Plenu~ ' Press (1973), ISBN 0-306-30717-0; , i -:
ii) "Compendium of Or~_ic SYnthetic .~ethods" ed. I.T.Harrison and S.Harrison, Wiley-Interscience, VoL.I (1971) ISBN 0.471-35550-X, Vol.II (1974) ISBN 0-471-35551-8 and Vol.III (ed. L.S.Hegedus and L.~ade) (1977) ISBN 0-471-36752-4; and iii) Rodd's "Chemistry of Carbon Com~ounds" second edition, Elsevier Publishing Company.

Compounds of formula (III) wherein Rl and R are as hereinbefore defined may conveniently be prepared either directly from a compound of formula (III) wherein R is as hereinbefore defined and R
represents hydroxy, for example, by treat~ent with the appropriate amine in the presence of a reagent such as dicyclohexylcarbodiimide (DCC) or by conversion of the latter-compound of formula (III) tQ 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.

Compounds of formula (II}) wherein Rl is as hereinbefore defined and R is hydro~y may be obtained commercially or by methods known to a skilled person.
.
In process B), a compound of formula (IV), is reacted with a ~it_ig reagent of formula (V), generally in the presence of a strong base such as sodil~m hydride or lithium hydride and conveniently in an inert .. .... . . ~ . . . . .

' .: -: ,: : , ` ` ' ':: ': ', ' " , . ',' .~.,.. . ': ' ' ~

W O 92/129~9 PC~/GB~2/00108 - 14 ~
~17$3 ^
solvent, for example, dimethoxyethane (DME). The relative proportions of E and Z isomers in the compound of formula (I) so formed will depend on the naeure of the alkyl, aryl or aralkvl group in the pnosphorus-containing group of the Wittig rea~ent.

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

Compounds of formula (V) where Y and R4 are as hereinbefore defined may be prepared by ~ethods well known in the art, but are typically prepared from compounds of formula (V) wherein R4 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 (V) wherein R is as hereinbefore defined and Y is a leaving group may be prepared from compounds of formula (V) wherein Y is the aforementioned leaving group and R is another suieable leaving group, for example a halogen atom such as chlorine or bromine. Such compounds, for example, ClCOCH2Cl, may be obtained from commercial sources or prepared by methods kno~n to a skilled person or readily available from ~he chemical litérature.

In process C), 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 ~-toluenesulphonic acid.

Compounds of formula (VII) may co~veniently be prepared by reactin~ a co~pound of formula (IV) as defined in process B) with a compound of formula (V) wherein R is as hereinbefore defined and Y is bromine, in the presen~e of zinc (Refor~atski reaction). The compound of formula (VII) ob~ained may be isolated or dehydrated in situ.

Compounds of for~ula (V) wherein R4 is as he~einbefore defined and is bromine may be prepared by methods analogous to those d~scribed above for the preparation of compounds of formula (V) wherein R4 is as W O 9Z/129~ rcT/~ 9~ D
. - 15 -~-; 2~01783 ~ I ~

hereinbefore defined and Y is a suitable leaving group, in this case bromine and compounds of for~Zula (IV) may be obtained coZ~ercially or by methods known to a skilled person. Z

Process D) may be carried out by treating a compound of formula (VIII) with a compound of formula (IX), 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 p~rson.

Compounds OI formula ~VIII) wherein Rl, R3 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(0)0- group wherein R is as hereinbefore defined, by treat~en~
with the appropriate alkylchloroformate in the presence of an organic base such as TEA and in an inert sol~ent such as THF. The compound of for~ula (VIII) obtained may be isolated or a~inated in situ.

Compounds of formula (I) may also be prepared direc~ly from a compou~d of formula (VIII) wherein Rl and R3 are as hereinbefore defined and Z
is hydroxy by treatment with a compound of formula (IX) wherein R is as hereinbefore defined in a suitable solvent.

Compounds of formula (VIII) where Rl and R3 are as hereinbefore defined and Z is hydroxy may conveniently be prepared by ehe hydrolysis of a compound of fo~mula (VIII) wherein Rl and R3 are as hereinbefore defined and Z is a suitable leaving group, such as alkoxy, fDr exa~ple, (E~-methyl-3-(2-brom~phenyl)-2-butenoate wherein Rl is ~thyl, R3 is 2-brono 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 exa~ple, eehanol. Compounds of formula (VIII) wherein Z is alXoxy may be made by the dehydration of a compound of : . .. . , : : ,. . ;: .; .. , ,; , ,,. " . . .

W O 92/l2959 PCT/GB92/00108 2 ~ 3 `
formula (VII) wherein R and R are as hereinbefore defined and R
Z. Such compaunds may be prepared by the Reformatski reaction desc~ibed in process C) above.

The compound of formula (I) may be co~verted into a pharmaceu~ically acceptable base salt in a conventional mannerl for example, by treat~ent with the appropriate base.

~he present invention further includes the following novel intermediates which are of particular value for the preparation of compounds of formula ~I) wherein Rl and R2 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.

Exampie 1 Pre~aration of (E)-3-(2-Bromophen~ cvclopropyl-2~butenamide A) PreDaration of 2-chloro-N-cyclopropvlacetamide ~-A solution of chloroacetyl chloride (33.8g, 0.3~oles) in lOOml of ethyl ether was added dropwise over 30 minutes to cyclopropyl amine (34.2g, 0.6moles, Aldrich) in 400ml of ethyl ether at 0C
with stirring. After and additional 30 minutes at this temperature, the ether was evaporaeed with a stream of nitrogen ........... . . . . ..

:;~ 17 - :
` 2~1783 -while heating on a steam bath. The residue was dissolved in dichloromethane (400ml) and washed successively with lOOml portions of dilute hydrochloric acid tlN), aqueous sodium bicarbona~e (5~), and distilled water. The volatiles were removed by spin evaporation ~ vacuo, and the residue was recrystallized from dichloromethane/hexanes to give 26.4g (66%) of 2-chloro-N-cyclopropylacetamide, m.p. 80-83C.

Anal. Caicd. for C5H8ClNO: C, 44.56; 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 Die~hyl((cvclo~ropvlcarbamoyl~methvl)phos~hona~e 2-Chloro-N-cyclopropylacetamide (20~, 0.15moles) was added in portions with stirring to triethyl phosphite ~28g, 0.17moles, Aldrich) at 110 C. The solution was then heated to 155 C for 30 minutes, cooled to 125C, and the volatiles were removed by distillation under aspir~tor vacuum (15~m Hg) at this temperature The rssidual oil was stirred with pentane (200ml) while cooling in an ice bath to induce crystallization. Fil~ra~
tion ga~e 5.2g (14%) of diethyl((cyclopropy}carba~oyl)methyl)~
phopsphonate as white crystals; m.p. 51-56C. The liquor was concentrated and cooled to giYe 25.3g (71%) of a second crop;
m.p. 50-56C. Recrystallization from dichloromethane/hexanes ; gave the analytical sample, m.p. 55-57C.

Anal. Calcd. for C9H18N04P: C, 45.96; H, 7-71; N, 5.95.
Fo~nd. C, 45.85; H, 7.76; N, 5.90.
:' ;
C~ Pre~aration of (~)-3-(2-Bromophenvl)-N-cvclopropyl-2-butenamide .
To an ice-cold, stirred suspension of NaH (80% dispersion in minsral oil, (0.67g, 28m~oles, Aldrich) in di~ethoxyethane (25ml) was added a solution of diethyl((cyclopropylcarbamoyl)methyl)-phosphonate (5.0g, 21mmoles) in dime~hoxyethane t60ml). After :: .,, , : . , , , , - .,- : - .... ;.. , .,. .. :. , W O g2/12959 PCT/~B92/00108 2~ 017 83 - 18 - ~ 1 :
1.5 hours, a solution of 2'-bromoacetophenone (4.0g, 20mmol~
Aldrich) in dimethoxyethane (60ml) was added, and the mixture was allowed to warm to room temperature overnight. The reaction mixture was poured into lL o ice water and the ~ixture was extracted with dichloromethane. The residue was chromatographed on Silica Gel 60 using dichloromeehane-ethyl acetate (9:1) as eluent. The fractions containing only (E)-3-(2-bromophenyl) ~o cyclopropyl-2-butenamide were co~bined and spin e~aported in ~acuo to give 2.2g of a colorless oil. Trituration with pentane gave 1.85g (33~) of (E)-3-(2-bromophenyl)-N-cyclopropyl-2-butenamide, m.p. 82-84C; NMR (DMSO-d6): 8.04 (d, lH, J ~ 4.02 Hz, NH), 7.64-~.19 (m, 4H, Ar), 5.64 (d, lH, J - 1.36 Hz, -CH), 2.68 (m, lH, NCH), 2.36 (d, 3H, J - 1.17 H7, CH3), 0.68-0.35 (2m's, 4H, CH2CH2); steady-state nOe: irradiation at 2.36, observed 4.9% nOe at 7.25 and 1.3~ nOe at 5.64.

Anal. Calcd. for C13H14BrNO: C, 55.73; H, 5.04; N, 5.00. ;
Found: C, 55.82; H, 5.09; N, 4.95.

Example 2 P eparation or tE~-3-(2-Bromophen~l)-N-c~clo~ropYl-2-butenamide (A) re~3~ ion of tE)-N-Cvclopropyl~-butenamide Thionyl chloride (24mL, 0.33mol) was added dropwise during 15 minutes to a stirred solution of crotonic acid (25.8g, 0.30mol, Aldrich) in benzene (400mL) protected from moisture by a drying ~ube containing Drierite. The resulting clear solution was heated at reflux for 3 hours before a portion of the solvent (lOOmL) was removed by distillation (atmospheric pressure). The re~aining solution was stirred, chilled (ice bath) and treated dropwise with cyclopropyla~ine (20.6g, 0.36mol, Aldrich) ~ollowed by triethylamine (41.8mL, 0.30mol). A white solid precipitated.
~a~er (50mL) was added to the mixture and the resulting layers , .: , . . : ~ , ,: ~ , ; . :

W O 92/12959 PCT~G~92/00~08 21017~3 were separaeed. The aqueous layer was saturated with NaCl and extracted with methylene chloride (5 x lOOmL). The organic layers were combi~ed, dried o~er Na2S04, filtered and concentra-ted to a solid residue, which subsequently was subjected to bulb to bulb distillation (pot temperature 90-110C) at 0.1 torr;
yield, 31.2g (83~), m.p. 63-65 C; NMR (DMSO-d6): ~ 7.91 (br s, lH, NH), 6.48-6.66 (m, lH, -C~CH3), 5.79 (d x d, J ~ 1.6, I - 15.2 Hz; lH, -CHCO), 2.65 (m, lH, NCH), 1.74 (d x d, J ~ 1.7, J - 6.8 Hz, 3H, CH3), 0.39 and 0.60 (2 m's, 4H, CH2CH2).

Anal. Calcd. for C7HllNO.O.1 H20: C, 66.22; H, 8.89; N, 11.03.
Found: C, 66.10; H, 8.90; N, 11.07.

(B) reparation of (E~-3-t2-Bromophenyl)-N-cyclo~ro~yl-2-butenamide A stirred mixture of 1,2-dibromobenzene (Aldrich) (2.36g, lO.Ommol), (E)-N-Cyclopropyl-2-butenamide (1.30g, lO.Ommol), triethylamine (l.Olg, lO.Ommol), tri-o-tolylphosphine (AldriGh) (0.24g, 0.8mmol), palladium acetate (Aldrich) (0.04g, 0.2mmol) and acetonitrile (25mL) was heated in a stoppered flask at 120C
for 18 hours. The mixture was cooled to ambient temperature, ~iltered, 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-b~tenamide were combined and spin evaporated in vacuo to give 1.2g (42.8~) of the product. An analytical sample obtained by recrystalliza-tion from dichloromethane/hexanes was identical to the co~pound prepared in Example 1 by mixed m.p. (82-84C) and NMR.

Anal. Calcd. for C13H14BrNO: C, 55.73; H, 5.04; ~. 5.00;
Br, 28.52.
Found: C, 55.81; H, 5.06; N, 5.01; Br, 28.44.

- 20 ~
210~7~3 ~
, . .
-xample 3 ?re~aration of (E)-3-(2-Bromophenyl)-N-cyclopropyl~2-butenamide A) Pre~aration of tE)-EthYl 3-(2-Bromophenvl~-2-butenoa~e A stirred mixture of 2'-bromoacetophenone (Aldrich) (14.7g, 74mmol), zinc powder (Mallinckrodt) (9.0g), ethyl bromoacetate (Aldrich) (18.5g, lllm~ol), a crystal of iodine, benzene (100mL) and diethyl ether (lOOmL) was heated at reflux under nitrogen for 2 hours. The resulting grey suspension was cooled to a~bient temperature, filtered and the filtrate was concentrated to a vellow foam. The residue was dissolved in acetic anhydride (50mL) with cooling, treated with ~-toluenesulfonic acid (50mg, Aldrich) and heated at 70-80C for 0.5 hours. The solution was cooled to ambient temperature, concentrated in vacuo and chromatographed on a Waters Prep 500 using ethyl acetate-hexa~es (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 (15~) of a clear oil; NMR (DMSO-d6):

7.67-7.23 (m, 4H, Ar), 5.72 (d, lH, J-1.4 Hz, -CH), 4.13 (q, 2H, CH20), 2.37 (d, 3H, J-1.4 Hz, CH3), 1.21 (t, 3H, CH3CH20);
steady-state nOe: irradiation at 2.37 ~, obser~ed 2% nOe at 7.45 ~ and 1% nOe at 5.72 ~. -Anal- Calcd- for C12Hl3BrO2: C, 53.55; H, 4-87; Br, 29.69.
Found: C, 53.61; H, 4.83; ~r, 29.76.
.
B) reparation of tE)-3-(2-Bromo~enyl)-2-butenoic Acid .
A mix~ure of (E)-ethyl 3-(2-bromophenyl~-2-butenoate (2.7g, 10.0m~ol), ethanol (20mL) and lN NaOH (11.0mL) 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 conc HCl :: . , : :: :: : , , .: .: : : : . , .

W O 92/1295~ PCT/GB9~i~0~8 ; .,' ~ _ 7 1 ,

8 3 (1.2mL) and exeracced with diethyl ether. The e~her layer was dried over Na2S04, filtered, concentrated and chromatographed on Silica Gel 60 using eshyl acetate-dichloromethane (1 4). The fractions containing only (E)-3-(2-bro~ophenyl)-2-butenoic acid were combined and concentrated to give white crystals (lo0g~
~1.7~) of ehe product, m.p. 109-111 C; NMR (D~SO-d ): ~ 12.43 (br s, lH, COOH), 7.67-7.22 (m, 4H, Ar), 5.66 (d, lH, J-1.4 Hz, CH), 2.34 (d, 3H, J-1.4 Hz, CH3); steady-state nOe: irradia~ion at 2.34 ~, observed 1% nOe at 7.29 ~ and 1% nOe at 5.6O ~.

Anal. Calcd. for C10HgBrO2: C, 49.82; H, 3-76; Br, 33-14-Found: C, 49.92; H, 3.77; Br, 33.21.
~`
C) ?re~aration of (E~-3-(2-Bromophenyl)-N-cvclopropvl-2-butenamide A solution of (E)-3-(2-bromophenyl)-2-butenoic acid (l.Og, 4.0mmol) and oxalyl chloride (1.7g, 13.8mmol, Aldrich) in benzene (50mL) was refluxed for 2 hours and concentrated to give (~)-3-(2-bromophenyl)-2-butenoylchloride as a pale yellow oil;
IR: 1773, 1611 cm . Cyclopropylamine (0.9g, 16mmol, Aldrach) was added to the acid chloride in benzene (60mL), and the mixture was stirred overnight at room te~perature. The solution was washed sequentially with saturated NaHC03 (50mL), lN HCl (SOmL) and brine (50mL), dried over Na2S04, filtered and concentrated vacuo to a cloudy oil (0.9g). Recrystallization from dichloromethane-hexanes gave white crys~als (0.3g, 30~) of the product identical to the compound prepared in Example 1 by mixed m.p. (82-84C? and NMR.

Anal. Calcd. for C13H14BrN0: C, 55.73; H, 5.04; N, 5.00;
~r, 28.52.
Found: C, 55.77; H, 5.02; N, 5.01; Br, 28.44.

W O 92/12959 PCT/GBg2/00108 21~7~3 "
E~ample 4 Pre~aration of '~-3-(2 Bromophenyl)-N cvclopropvl 2 butena~ide Ethyl chloroformate (Aldrich) (0.13g, 1.24~mol) was added dropwise ~o a stirred solution of (E) 3-(2-bromophenyl)-2-butenoic acid (0.30g, 1.24mmol), triethylamine (0.12g, 1.24mmol) and te~rahydrofuran (5ml,) t 0C After 2h at 0C, the precipitated triethylamine hydrochloride was removed by filtering and a solution o~
cyclopropylamine (71mg, 1.24~ol) in tetrahydrofuran (lmL) was added dropwise to the ice cold filtrate. The mixture was stirred overn:ight a~ ambient temperature, concentrated and chromatographed on Silica Gel using ethyl acetate dichloromethane (1:19) as eluent. ~he fractions containing only (E) 3-(2 Bromophenyl) N cyclopropyl-2 buten amide were combined and spin evaporated n vacuo to give 0.21g (60~) of the product. An analytical sample obtained by recrystallization from dichloromethane/ hexanes was identical to the compounds prepared in Example 1 by mixed m.p. (82 84C) and NMR.

Anal. Calcd. for C13H14BrNO: 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.

Exam~le 5 Preparation of tZ~ 3:~2 Bromophenyl) N-cyclopropyl-2-butenami-de The fractions from Example lC containing only (Z)-3 (2-bromophenyl)-N
cyclopro~yl-2-butenamide were combined and spin evaporated in vacuo to give 1.7g of a white solld. Trituration with pentane gave 1.31g (23~) of (Z)-3-(2-bromophenyl)-N-cyclopropyl-2-butenamide, m.p. 144-146C;
NMR (DMSO-d6): ~ 7.82 (d, lH, NH), 7 55-7.05 (m, 4H, Ar), 5.90 (d, lH, J - 1.47 Hz, -CH), 2.48 ~m, lH, NCH), 1.97 (d, 3H, J ~ 1.47 Hz, CH3) 0.57-0.27 (2m s, 4H, CH2CH2); steady-state nOe: irradiation at 1.97, obser~ed 8.2~ nOe at 7.1 and 17.0~ nOe at 5.90.

, . : : , : . ., . : :

W O 92/12959 PCT/~B92~00108 ~` `` 2 ~

Anal. Calcd. for C13H14BrNO: C, 55.73; H, 5.04; .~, 5.00.
Found: C, 55.73; H, 4.99; N, 4.99.

~D~ :`' PreDaration o~ (E~-N-Crclopropyl-3-(2-(trifluoro~ethyl~henyl)~2 butena~ide This compound was prepared in an analogous manner to that of ~xample 1 with the replacement o 2'-bromoacetophenone in Example lC wi~h 2'-(trifluoromethyl)acetophenone ~Aldrich). The chromatography solutions that contained (E)-N-cyclopropyl-3-(2-(trifluoromethyl))-2-phenyl)-2-butenamide were spin evaporated Ln vacuo The solid was collected and recrystallized from ethanol-wa~er co ~,ive 0.74g (10~) of (E)-N-cyclopropyl-3-(2-(trifluoromeehyl))phenyl)-2-b~tenamide, m.p. -114-116C; NMR (DMSO-d6): ~ 8.06 (d, lH, J - 4.16 Hz, NH), 7.76-7.36 `
(m, 4H, Ar), 5.62 (d, lH, J ~ 1.31 ~z, -CH), 2.70 (m, lH, NCH), 2.40 (d, 3H, J - 1.07 Hz, CH3), 0.66-0.40 (2m's, 4H, CH2CH2); steady-state ~-~
nOe: irradiation at 2.40 ~, observed 4.9~ nOe at 7.4 and 1.4% nOe at 5.628 ~.

Anal. Calcd. for C14H14F3NO: C, 62.45; H, 5.24; N, 5.20.
Found: C, 62.37; H, 5.28; N, 5.19.
:
Exa~le 7 Preparation of (E)-N-Cyclopropyl-3-(2 3-dichloroPhenYl)-2 bucenamide This compound was prepared in an analogous manner to that of Example 1 with the replacement of 2'-bromoace~ophenone in Example lC wieh 2',3'-(dichloro)acetophenone (~aybrid~,e). The chromatography solutions that contained (E)-N-cyclopropyl-3-(2,3-dichlorophenyl)-2-bu~enamide were spin evaporated, and the solid was collected and dried; yield, 6.73g (47~), m.p. 111-113C; N~R (DMSO-d6~: ~ 8.08 (d, lH, J - 4.06 Hz, NH), 7.62-7.21 (m, 3H, Ar), 5.69 ~d, lH, 1 ~

: , :, ; , . . ~ ,., " . . - ,- . . . .

W O 92t~2959 PCT/GB92/00~08 ~ 7 ~ 3 - 24 - ~ ~
. ,.

.22 Hz, -CH), 2.67 (m, lH, NCH), ~.63 (d, 3H, J - 0.97 H-, CH3), 0.66-0.37 (2m's, 4H, CH2CH2).

Anai. Calcd. for C13H13C12NO: C, 57.80: H, 4.85; N, 5.18; Cl, 26.25.
~ound: C, 57.71; H, 4.83; N, 5.13; Cl, 26.34.

Example 8 Preoaration of (E)-3-(2-Chlorophenyl)-N-cyclopropvl-2-bu~enamide This compound was prepared in an analogous manner to that of Example 1 with the replacement of 2'-bromoacetophenone in Example lC wieh 2'-chloroacetophenone (Aldrich). The chromatography solutions that con~ained (E)-3-(2-chlorophenyl)-N-cyclopropyl-2-butenamide were spin evaporated Ln vacuo. The solid was collected and dried; yield, 28.30 (32%), m.p. 92.5-94 C; NMR (DMSO-d6): ~ 8.05 (d, lH, J ~ 3.86 Hz, NH), 7.48-7.22 (m, 4H, Ar), 5.68 (d, lH, J - 1.28 H7, -CH), 2.68 (m, lH, NCH), 2.38 (d, 3H, J - 1.44 Hz, CH3), 0.68-0.37 (2m's, 4H, CH2CH~); steady-state nOe: irradiation at 2.38 ~, observed 4% nOe a~ 7.3 and 1~ nOe at 5.68 ~.

Anal. Calcd. for C13H14ClNO: 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.

E~_m~le 9 Dre~aration of (Z~-3-~2-ChlorophenYl~-N-cyclo~ropyl-2-butena~ide This compound was prepared in an analogous ~anner to that of Example 1 wi~h the replacement of 2'-bromoacetophenone in Example lC with 2'-chloroacetophenone (Aldrich). The chromatography solutions that contained (Z)-3-(2-chlorophenyl)-N-cyclopropyl-2.butenamide were spin evaporated and the solid was collected and dried; yield, 3.52g (4~), .p. 125-132 C; NMR (DMSO-d6) ~ 7.83 (d, lH, NH), 7.38-7.06 (m, 4H, Ar), 5.92 (d, lH, J - 1.45 Hz, -CH), 2.48 ~m, lH, NCH), .
W O 92/12959 PCT/GB92/0010~
.~ 25 - ; :

1.98 (d, 3H, J - 1.41 Hz, CH3)l 0.57-0.24 (2m's, 4H, CH~CH2);
steady-state nOe: irradiation at 1.98 ~, observed 5~ nOe at 7.1 and 14~ nOe at 5.92 ~. ;

Anal. Calcd. for C13H14ClNO: C, 66.24; H, S.99; N, 5-94; Cl, 15-04-Found: C, 66.33; H, 6.04; N, 5.88; Cl, 15.11.
:` :
Ex~m~le 10 PreParation of (E)-N-Cvclopropyl-3-(2-fluorophenyl)-2-butenamide .:
This compound was prepared in an ana}ogous manner to that of Example 1 with the replacament of 2'-bromoacetophenone in Example lC with 2'-fluoroacetophenone (Aldrich). The chromatography solutions were spin evaporated, and the solid was collected and dried; yield, 8.50g -~
(55~), m.p. 59-5.62 C; NMR (DMSO-d6): ~ 8.08 (d, lH, J - 3.82 Hz, NH), 7.37-7.15 (m, 4H, Ar), 5.89 (d, lH, J - 1.21 Hz, -CH), 2.67 (m, lH, NCH), 2.40 (s, 3H, CH3), 0.66-0.37 (2m's, 4H~ CH2C~2);
steady-state nOe: irradiation at 2.49 ~, obser~ed 5.3% nOe at 7.3 and 0.7% nOe at 5.89 ~.

Anal. Calcd. for C13H14FNO: C, 71.21; H, 6-44: ~, 6-39-Found: C, 71.30; H, 6.46; ~, 6.35.

Example 11 Pre~aration of (E)-3-(3-Chlorophenvl) N-cyclobutvl-2-butena~ide To a stirred, ice bath-cooled solution of (E)-3-(3-chlorophenyl)-2-butenoic acid (E. Van ~eyningen et al. J.Med.Chem, 9, 675 (1966) (5.00g, 254~mole) and triethylamine (2.57g, 254~ole) in tetrahydrofuran (120ml) was added eehyl chloroformate (2.76g, 254mmole) in tetrahydrofuran (20ml). After 30 minutes cyclobutylamine (l.lg, 254m~ole, Aldrich) in tetrahydrofuran (30ml) was added slowly.
The reaction mixture ~as stirred at a~bisnt te~perature for 15 hours.

~. , 2~0~783 j~ - ~

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 lN hvdrochloric acid and brine. The ethyl acetate solution was dried (sodlu~ sulfate) and spi~
evaporated n vacuo, The residual yellow solid was purified by flash chromatography on silica gel 60 (40-63 m, E. Merck No. 9385) usin~
ethyl acetate-hexan~ 4) as eluent. The fractions that contaiaed (E)-3-(3-chlorophenyl)-N-cyclobutyl-2-butenamide were combined and evaporated to give 3.93g (61%) of product, m.p. 89-90 C; NMR
(DMSO-d6): 8.2 (br d, lH, NH), 7.54-7.35 (m, 4H, Ar), 6.21 (d, lH, J - 1.3 Hz, -CH), 4.28 (m, lH, NCH), 2.45 (d, 3H, J ~
1-2 Hz, CH3), 2.32-1.55 (m, 6H, (CH2)3); steady-sta~e nOe: irradia~ion at 2.45, observed 18.1~ nOe at 7.5 and -0.2% nOe at 6.21.

Anal. Calcd. for C14H16ClNO: C, 67-33: H, 6-46; N, 5-61-Found: C, 67.34; H, 6.46; N, 5.58.

Example 12 PreDaration of (E)-3-(2-BromophenYl~-N-cvclobl~yl-2-butenamide ~his compound was prepared in an analogous manner to that of Example 3 with the replacement of cyclopropyla~ine in Example 3C with cvclobutylamine (Aldrich). The solid was recrystallized from dichloromethane-hexanes to give off ~hite crystals (l.lg, 64~) of ehe product, m.p. 128-130 C; NMR (DMSO-d6): ~ 8.22 (d, lH, J ~ 7.7 Hz, NH), 7.66-7.20 (m, 4H, Ar), 5.68 (d, lH, J - 1.4 Hz, - CH), 4.25 (m, lH, NCH), 2.36 ~d, 3H, J ~ 1.3 Hz, CH3), 2.20-1.58 (3 ~'s, 6H, (CH2)3); steady-state nOe: irradiation at 2.36 ~, observed 4~ nOe at 7.24 ~ and 1~ nOe at 5.68 ~.

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.

~ , ; : : : ; " , ; ,,,:

W O 92/12959 PCT~GB92/00108 21~ 7~3 ` ; 1 :
_~ample 13 Preparation of tE~-3-t2-Chlorophenvl)-N-cYclopropvl-2-pentenamLde ~his compound was prepared in an analogous manner to that of Example 1 with the replace~ent of 2'-bromoacetophenone in Example lC wi~h 2'-choropr~piophenone (B.L.Jenson, S.E. Burke and S.E.Thomas, Te~rahedron, 34, 1627-1631 (1978)). The chromatography solutions ~ha~
contained (E)-3-t2-Chlorophenyl)-N-cyclopropyl-2-peneen~mide were combined and spin evaporated in ~acuo to give 6.60g (37~) of (E)-3-(2-Chlorophenyl)-N-cyclopropyl-2-pentenamide, m.p. - 148-150C; N~R
(DMSO-d6): ~ 8.06 (d, lH, J - 3.9 Hz, N~), 7.50-7.22 (3 m's, 4H, Ar), 5.64 (s, lH, - CH), 3.01 (q, 2H, J - 7.5 Hz, CH2C-), 2.70 (m, lH, ~CH), 0.86 (t, 3H, J - 7.5 Hz, CH3), 0.68-0.40 (2 m's, 4H, CH2CH2);
steady-state mOe: irradiation at 3.01 ~, observed 19.7~ nOe at 0.86 and 1.1~ nOe at 5.64 ~.

Anal. Calcd. for C14H16Cl,N,0: C, 67.33; H, 6.46; N, 5.61;
- Cl, 1~.19.
Found: C, 67.35; H, 6.48; N, 5.62; Cl, 14.12.

Exam~le 14 Pr~aration of (E)-N-Cyclopropyl-3-~iodophenyl~2-butenamide A) Pre~aration of Diisopropyl~(cycloRropylcarbamoyl~methyl~-phosDhonate 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 tAldrich) and pentane wieh hexane: yield, 385g (48.7%) as a fluffy white solid, m.p.
58-60C; the analytical sample was recrystallized from hexane.

2 ~ O 1 7 8 3 ` ' ,! !, 11 22 4P , .1 ; H, 8.42; N, 5.32 Found: C, 50.08; H, 8.44; N, 5.26.

B) Pre~aration of (E)-N-CvclopropYl-3-(2-iodophen~1)-2-butenamide This compound was prepared in an analogous man~ier eo thaE of Exa~ple 1 with (Aldrich) the replacement of 2'-bromoacetophenone in Example lC with 2'-iodoacetophenone tAldrich) and thie replacement of diethyl((cyclopropylcarbamoyl)methyl~phosphonatP
with diisopropyl((cyclopropylcarbamoyl)methyl)phosphonate. The chromatography solutions that contained (E)-N-cyclopropyl-3-(2-iodophenyl)-2-butena~ide were spin evaporated in vacuo The residue was recrystallized from dichloromethane-hexanes to give 1.7g (51~) of the product as white crystals, m.p. 120-122C; N~R
(DMSO-d6): ~ 8.04 (d, lH, J - 4.0 H7, NH), 7.88-7.00 (m, 4~, Ar), 5.57 (d, lH, J - 1.4 Hz, -CH), 2.68 (m, lH, CH), 2.34 (d, 3H, J - 1.3 Hz, CH3), 0.68-0.35 (2 ~'s, 4H, CH2CH2);
steady-state nOe: irradiation a~ 2.34 C, observed 5~ nOe at 7.04 ~ and 1~ nOe at 5.57 ~.

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.

Pharmiaceutical Formulations In the following formulation Exa~ples, the "Active Ingredient" may be any compound of formula (I) or base salt or other physiologically functiGnal derivative thereof, for example, compounds of Examples 1 to 14.

W O 92/12959 PCr/GB92/00l08 i .,: ,,; . i c, ~ ' ;

27ll~783 _xample 15 . , Tablet Formulati~ns The following formulations A, B and C are prepared by wet granularion o~ the ingredients with a solution of povidone, followed bv addi.ion of magnesium stearate and compression.

Formulat on A
m~/table~ m~/tablet :

(aj Acti~e ingredien,250 250 (b) Lactose 3.P 210 26 (c) Povidone B.P. 15 9 (d) Sodium Starch Glvcollate 20 12 (e) Magnesium Stearate 5 1 .

Formulation B
m~/tablet m~tablet (a) Active ingredien~250 250 (b) Lactose 150 (c) Avicel P~ 101 60 26 (d) Povidone B.P. 15 9 (e) Sodium Starch Glycoilate 20 12 (f) Magnesium Stearate 5 3 ;' W O 92/12959 PCT/GB92/00~08 2~0~783 ~-. . I
-^rmulation C
m~/tablet .ictive ingredienc 100 ~accose 2()0 Starch 5;0 Povidone 5 ~Yagnesium Stearate _ ~ ¦

;
~he following formulations. D and E, are prepared bv direct compression of the admixed ingredients. . The lactose in formulation E
s of the direct compression type (Dairy Crest - "Zeparox").

Formulation D
mg~tablet .

Active ingredient 250 Pregelacinized Starch NF15 150 ~or~ulacion E

m~/tabler .~c-ive ingredienc 250 Tactose 150 .~vicel 100 Formulatlon ~ (Controlled Release Formulation) The formulation is prepared by wet granulation of the ingredientS r (~elow) with a solution of povidone followed by the addition of magnesium stearate and compression.

.` ' . '.' . '. '. . ' . ' ", . ' !.' ' .,1 ~.~, ' .; ' ' ' '; , '` . ........... .,' ~. ' .. '~ ' .. ' ''' ., ., . . ' :
.. - . . . ~ ': ' W O 92/12959 - 31 - PCT/GBg2/00108 ~ ~ 2:l 0~. 7~ 3 mg~table~

(a~ Ac~ive ingredienc ;00 ~o) Hydroxypropylmethylcellulose 112 (Methocel K4~ Premium) ! Lactose B.P. 53 ~d) Povidone B.P. 28 .e) ~agnesium Stearate 7 ,00 _~iample 16 ~aDsule For~ulations .-or~ula~ion A

.~ capsule formulation is prepared bv admixing the ingredients o~^
rormulation D in Example 15 above and filling into a two-part hard elatin capsule. For~ulation B (infra) is prepared in a similar ~anner.

~ormula~ion B
~capsule 12) Active ingredien~ 250 (b) Lactose B.P. 143 'c) Sodium Starch Glvcollate 25 ,.
(d`~ Magnesium Stearate . 420 :

W 0 92/12959 - 32 - PCT/GB92/00~08 21~78~ ~
~ ,, . .`1 ~ `, ~
Eormulation C
~3~:apsule (a) Active ingredien~ 250 ~b) Macrogol 6~00 B.P. 350 Formulation D
~.~/ca~sule Ac~ive ingrediene 250 Leci_hin 100 Arachis Oi1 100 4~0 Capsules of formulation D are prepared bv cispersing ehe active ingredient in the lecithin and arachis oil and filling the dispersion into soft, elastic gelatin capsules.

mulation E (Controlled_Release Capsule) ~he following controlled release capsule formulation is prepared by extruding ingredients a, b and c using an ex~ruder, lollowed by spneronization of the extrudate and drving. The dried pellets are .hen coated with release-con~rolling memDrane (d) and illed in~o a two-piecP, hard gelatin capsule.

mg~ca~suie ~ `

(a) Active ingredient 250 (b) Microcrystalline Cellulose 125 (c) Lactose B.P. 12S
(d) Ethyl Cellulose ~

~ ; , .,; ,, , ~ ; ; :

:

W O 92/12959 PCT/GB92/OO~OB
f: ^ . .
; .! , , 21~17~3 _xample î

~.lectable Formulation Accive ingredient 0.200 g 95~ Ethanol and PEG 400, 1:1 ratio .~.
Sterile water q.s. to 10 mL

The active ingredient is dissolved in 95% Ethanol and PEG 400 (1:1).
~he batch is then made up to volume with the water and filtered .hrough a sterile micropore filter into a sterile 10 mL amber glass ~ .:
~iai (type 1) and sealed with sterile closures and overseals.

_xamPle 18 : -Syru~ , Active ingredient 0.25 g Sorbitol Solution 1.50 g Glycerol ~ oo g Sodium Benzoate o 005 g Fiavor, Peach i7.42.3169 0.0125 mL
Purified Water q.s. to 5.00 mL `' .
The active ingredient is. ~issoived in a uixture or the glycerol and most or the purified wa~er An aqueous solution of the sodium benzoate is then added to the solution, followed bv addition of the sorbitol solution and finally the flavor. The voiume is made up with purified water and mixed well W O 92/]2959 PCT/GB92/00108 ... ,;; ~ .
2 ~ 3 ;
~ mPle 1~ ¦

S~o~sito~

m~.~suPPos i torY

.~c~ive ingredient 250 Hard Fat, B.P. (Witepsol H15 - Dynamit NoBel) 1770 O.,e-fifth of the Witepsol H15 is melted in a steam-jacketed pan a~
-~5C maximum, The active ingredient is sifted through a 200 .~ sie~e and added to ,he molten base ~ith mixing, using a Silverson fitted ~i.h a cu.ting head, until smooth dispersion is achieved. Main~aining the mixture at 45C, the remaining Witepsol Hl5 is added ~o the suspension and stirred to ensure a homogenous mix. The entire suspension is passed through a 250 M stainless steel screen and, with concinuous stirring, is allowed to cool to 40~C. At a temperature of 38C to 40C, 2.02 g of the mixture is filled into suitable, 2 mL
piastic molds. The suppositories are allowed to cool to room .
t2mperature.
.~ .
~ample 20 '' ~essaries mg/pessarv -Ac: ve ingredient 250 Anhydrate Dextrose 380 Po:ato Starch 363 .~agnesiu~ Stearate 7 ~e above ingredients are mixed directly and pessaries prepared by c -ect compression of the resulting mixture.

' , , ', ' .''', '' ,', " ', . . " ' ' " ' . .,, " ', '~ ' ' ~. 'I' ',' , . "' '' . ' W O 92tl2959 PCT/GB92/00~08 "
'`~. 2~0~7~3 ~~am~`~e .~lscie Relaxant Activit~
i .Yuscie relaxant activity of compounds of formula ~I) was de~en~ined using a Straub tail test based on that described by KØ rllis and .r. Carpenter Neuropharmacol, 13, 211 (1974).
~he Straub eail test result is reported as an ED50.in mg/kg. The ED50 s defined as the dose of compound aa~inis.ered, wnich prevents Scraub ail in 50~ of mice. The compound is adminis~ered by oral gavage (pQ) 60 min. pr-or to scoring.

~he side effect potential or^ these compounàs was deeermined using ,he ~ouse rotorod test as described bv G.D. ~ovak and J..~.-Zwolshei, i.Pharmacological. Methods, lO, 1,5 (1983). Rotorod result s .
reported as ED50 in mg/kg. The ED;o is the dose which causes 50~ o.f ~n~ animals to fail to maintain position on a cylinder rocating a~ 11 ~.-.m.
::
.~ntagonism of morphine-induced Straub tail -eflects muscle relaxa~
erf cacy while failure in the rotorod tes~ reflects sedation and ``
ncoordination. Determination of the ratio of rotorod _ailure to antagonism of morphine-induced Straub tail s a means or assessin~
side effect liabilitY of muscle relaxants (G.D. ~ovak, Drug Dev. Res., ^, ~~' (1982).

Compound of Straub Rotorod Rotorod/
_~ampie ~o. Tail Straub Tail p.o. ED50, p,o. ED50, ratio mg/kg. mg/kg.

1 ~5 ~5 ~.8 .. , , . - . ~: .

':'' ' W O 92/12959 ~- ~ PCT/GB92/00108.`i' 21~ 3 ``` ; 36 - ~
! ., .... ~

~xamPie 22 :
~nt-convulsant Act-vir Anticonvulsant activity of compounds of formula (I) was determined ' : using a method described bY ~ehtà et al., J.Med.Ghem., Al, ~ 46O (1981).

,: ... . ~ ' ! . , . . ' The ànticonvulsant activity is reported as an ED o In mg/kg. he ED50 ~or protect.on against maximal electroshock-induced convulsions was the dose which prevented hind limb extension in 50% of the animals.
~he ~ 0 for protection agains~ ,~ecrazol-induced convulsions was the dose wnich prevented? convulsions in so% or ~he animals.

Compound of i.p. ED50, ~g/kg ~rat) Example No. ~ES MET

i 9.6 3.6 .~ES - maximal eiectrosnock ~ET - metrazol Example 23 ~nxiolvtic Activity .
Anxiolytic activity of che compounds according ~o the invention was measured using method of Geller and Seifter, J.Psychopharmacolgia, ~` 1, 482 (1960) as modified by Pollard and Howard, Psychopharmacology, c2, 117 (1979). Clinically efficacious anxiolytics increase punished responding. The anxiolytic activicy of the compound is reported as W O 92/12959 PCT/GBg2/~010$ :
2101 ~8~ ~

the dose necessarv to produce a ,~ increase in punished responding i~
racs .

Compound of Exa~nPle ~o . P . o . ED~ ~g~ .
:s `' ~ .; : . , . : i . ;:. , . , . : , ,

Claims (26)

1. A compound of formula (I):

(I) wherein R1 represents C1-6 alkyl, R2 represents hydrogen or C3-6 cvcloalkyl and R3 represents one or more ring substituents selected from halogen and perhaloC1-4alkyl;

with the following provisos that:

(i) when R1 is methyl and R2 is cyclopropyl then the or one of R3 is in ehe 2-position; and (ii) said compound of formula (I) is not 3-(4-chlorophenvl)-2-butenamide;

or a base salt or other physiologically functional derivative thereof.

2. A compound according to claim 1 wherein R1 represents methyl and/or, R represents cyclopropyl and/or the or one of R3 as defined in formula (I) is in the 2-position; or a base salt or other physiologically functional derivative thereof.

3. A compound according co claims l or 2 wherein R- represents methyl and/or, R2 represents cyclopropyl and/or the or one of R
represents bromo, chloro, iodo or trifluoromethvl and is in the 2-position; or a base salt or other physioiogically functional derivative thereof.
I

4. A compound according to any one of claims 1 to 3 wherein represents methyl and/or, R2 represents cyclopropyl and/or R3 is as hereinbefore defined and is in the 2-position or a base salt or other physiologically functional derivative thereof.

5. (E) isomers of compounds of formula (I) or a base salt or other physiologically functional derivative thereof according to any one of claims 1 to 4.
':

6. A compound according to ciaim 1 which compound is:-1. (E)-N-cyclopropyl-3-(2-(crifluoromethyl)phenyl))-2-buten-amide;

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

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

4. (E)-3-(2-chlorophenyl)-N-cyclopropyl-2-butenamide;

5. (E)-3-(2-bromophenyl)-2-butenamide;

or a base sale or other physiologically functional derivatives thereof.

7. (E)-3-(2-bromophenyl)-N-cyclopropyl-2-butenamide.

8. A base salt or other physiologically functional derivative of a compound according to any one of claims 1 to 7.

9. A compound according to any one of claims 1 to 8 for use in medical therapy.

10. Use of a compound according to any one of claims 1 to 8 in the manufacture of a medicament for the treatment or prophylaxis of the conditions associated with aonormally raised muscle tone.

11. Use or a compound according to any one of claims 1 to 8 in the manufacture of a medicament for the treatment or prophylaxis of convulsive states.

12. Use or a compound according to any one of claims 1 to 8 in the manufacture of a medicament for the treatment of anxiety.

13. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 8, together with a pharmaceutically acceptable carrier therefor.

14. A formulation according to claim 13 adapted for oral administration.

15. A formulation according to claim 14 in the form of a tablet or capsule.

16. A process for the preparation of a compound of formula (I) (I) wherein R1 represents C1-6 alkyl, R2 represents hvdrogen or C3-6 cvcloalkyl and R3 represents one or more ring substituents selected from halogen and perhaloC1-4alkyl;

with tne following provisos that:

(i) when R1 is methyl and R2 is cvclopropvl then the or one of R3 is in the 2- position: and (ii) said compound of formula (I) is not 3-(4-chlorophenyl)-2-butenamide;

or a base salt or other phvsiologically functional derivative thereof, which process comprises:

A) reacting a compound of formula (II) (II) (wherein R3 is as hereinbefore defined and X is a leaving group) with a compound of formula (III) R1CH?CHCOR4 (III) (wherein R represents -NHR2 and R1 and R2 are as hereinbefore defined);

B). reacting a compound of formula (IV) (IV) (wherein R and R' are as hereinbefore defined) wlth Wittig reagent of formula (V) YCH2COR4 (V) (wherein R is as hereinbefore derined and Y is -P(-O)(OR)2 wherein R is a C1-4 alkyl, aryl or aralkyl group, or Y is a triarylphosphine) under Wittig conditions;

C) dehydrating a compound or formuia (VII) (VII) (wherein R1, R3 and R4 are as hereinbefore defined).

D) reaceing a compound of formula (VIII) (VIII) (wherein R1 and R3 are as hereinbefore defined and Z is a leaving group) with a compound of formula (IX) H-R4 (IX) (wherein R4 is as hereinbefore defined).

and thereafter, or simultaneously therewith, effecting one or more of the following optional conversions:-(i) converting the compound of formula (I) so formed into a base salt, or other physiologically functional derivative thereof;

(ii) when a base salt, or ocher physiologically functional derivative of a compound of formula (I) is formed, converting the said derivative into a compound of formula (I), or a different derivative thereof.

17. A process according to claim 16 for the preparation of a compound of formula (I) wherein R1 represents methyl and/or, R2 represents cyclopropyl and/or the or one of R3 as defined in formula (I) is in the 2-position; or a base salt or other physiologically functional derivative thereof.

18. A process according to claims 16 or 17 wherein R1 represents methyl and/or, R2 represents cyclopropyl and/or the or one of R
represents bromo, chloro, iodo or trifluoromethyl and is in the 2-position; or a base salt or other physiologically functional derivative thereof.

19. A process according to any one of claims 16 to i8 wherein represencs methyl and/or, R2 represents cyclopropyl and/or R3 is as hereinbefore defined and is in the 2-position or a base salt or ocher physiologically functional derivative thereof.

20. A process according to claim 16 for the preparation of (E) isomers or compounds of formula (I) or a base salt or other physiologically functional derivative thereof, according to any one of claims 16 to 19.

21. A process according to claim 16 for the preparation of a compound:-1. (E)-N-cyclopropyl-3-(2-(trifluoromethyl)phenyl))-2-buten-amide;

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

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

4. (E)-3-(2-chlorophenyl)-N-cyclopropyl-2-butenamide;

5. (E)-3-(2-bromophenyl)-2-butenamide;
or a base salt or ocher physiologically functional derivative thereof.

22. A process according to claim 16 for the preparation or (E)-3-(2-bromophenyl)-N-cyclopropyl-2-butenamide.

23. A process according to claim 16 wherein the product is isolated as a base salt or other physiologically functional derivative of formula (I) according to anv one of claims 16 to 22.

24. A method for the treatment or prophylaxis of conditions associated with abnormally raised muscle tone in a host, which comprises treating said host with an effective non-toxic amount of a compound according to claims 1 to 8.

25. 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 1 to 8.

26. A method for the treatment or prophylaxis of anxiety in a host, which comprises treating said host with an effective non-toxic amount or a compound according to claims 1 to 8.