CA1111433A

CA1111433A - Imidazole derivatives and their salts

Info

Publication number: CA1111433A
Application number: CA313,653A
Authority: CA
Inventors: Peter B. Thorogood
Original assignee: Wellcome Foundation Ltd
Current assignee: Wellcome Foundation Ltd
Priority date: 1977-10-19
Filing date: 1978-10-18
Publication date: 1981-10-27
Also published as: IE47749B1; JPS5488268A; IL55858A; IT7851570A0; ATA747378A; JPS6233227B2; AU522055B2; AT370095B; AU4082478A; DE2845406A1; FI783175A; DK464278A; IT1109321B; MC1221A1; ZA785863B; IL55858A0; IE782067L

Abstract

ABSTRACT OF THE INVENTION

Imidazole derivatives and salts thereof, their synthesis, and intermediates, and pharmaceutical formulations The invention relates to 1-arylalkylimidazoles of formula in which A is a straight or branched alkylene group of from 1 to 3 carbon atoms, or a straight or branched alkenylene or alkynylene group of 2 or 3 carbon atoms, n is an integer which is at least 1, and the or each R substituent, which when n is greater than 1 may be the same or different, is a saturated alkyl group of from 1 to 4 carbon atoms or an unsaturated alkyl group of from 2 to 4 carbon atoms, with the proviso that when A is unsaturated, R may also be alkoxy of from 1 to 4 carbon atoms;
(when n is at least 2) alkylenedioxy of from 1 to 4 carbon atoms;
halo; trihalomethyl; hydroxy; carboxyl; a salt of such a carboxyl group; carboalkoxy; carboaryloxy; carboarylalkyloxy;
-NR6R7 or -CCNR6R7, in which R6 and R7 may be the same or different and are hydrogen or alkyl of from 1 to 4 carbon atoms;
or an acid addition salt of such a 1-arylalkylimidazole.
Methods of preparing these 1-arylalkylimidazoles are disclosed.
The 1-arylalkylimidazoles have pharmacological properties of use in medicine, in particular for the treatment or prophylaxis of thrombo-embolic disorders.

Description

:

Imidazole derivatives and salts thereof, their synthesis, and intermediates and harmaceutical formulations.
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The present invention relates to imidazole derivatives and salts thereof, to their cynthesis and intermediates therefor, to pharmaceutical formulations containing such compounds and to ,; ~he use of these compounds in medicine.
Thromboxane A2 (TXA2~, a potent stimulator of blood pla~elet aggreqation, is produced, in pl~telets, from the prostaglandin ~ endoperoxides PGG2 and PGH2. Prostacyclin (PGI2), which has ; 10 potent anti-aggregatory activity, is also produced (in blood vessel walls) from PGG2 and PGH2 and it has been suggested that a balance between the production of TXA2 and PGI2 is the controlling factor in thrombus formation. It would, in ~- consequence, be desirable in the treatment and prophylaxis of thrombo-embolic disorders to be able to selectively inhlbit TXA2 synthetase, thereby favouring the production of the anti-aggre-gatory agnet PGI2.
Imidazole and l-methylimidazole are known to pro~ de some degree of inhibition of the enzymic conversion of the endoperoxides (PGG2 and PGH2) to thromboxane A2 by platelet microsomes (Moncada et al., Prostaglandins, 13/4, 611-618, 1~77). Certain l-n-alkyllmidazoles, especially l-n-dodecylimidazole and its higher ; ~k .
, . .

homologues have been described as being capable of lowering - serum cholesterol levels (U.K. Patent No. 1 364 312; Biochem.
Pharmacol. 24, 1902-1903, 1975).
;~; We have now discovered that TXA2 synthetase may be - inhibited byl-arylalkylimidazoles of formula (I) and acid ad-^; dition salts thereof. The compounds of formula (I) and their salts are hereinafter referred to as the "active compounds".
The compounds of formula (I) are novel and of formula:
~' N \ ~ (R) ~ N - A ~\ ~ (I) in which A is a straight or branched alkylene group of from - 1 to 3 carbon atoms, or a straight or branched alkenylene or ~ alkynylene group of from 2 or 3 carbon atoms, n is an integer ,, which is at least 1, and the or each R substituent, which when n is greater than 1 may be the same or different, is an alkyl group of from 1 to 4 carbon atoms, or an unsaturated aliphatic hydrocarbon group of from 2 to 4 carbon atoms with the provisos that (a) when A is a methylene or ethylidene group, n is ; 20 at least 2 when R is alkyl, (b) when A is a branched propylene, or straight propyl-idene group, n is at least 3 when r is alkyl.
: , ..:

' ' :

`
; (c) when A is unsaturated R may also be selected from alkoxy of from 1 to 4 carbon atoms, when n is at least 2, alkylenedioxy of from 1 to 4 carbon atoms;
halo; trihalomethyl; hydroxy; carboxyl; a salt of : such a carboxyl group; carboalkoxy; carboaryloxy;
~- carboa~ylalkyloxy, -NR6R7 or -CONR6R , in which R
and R7 may be the same or different and are hydro-gen or alkyl of from 1 to 4 carbon atoms, with the further proviso that when n is 1, R is not an :::. 10 alkyl group;
or an acid addition salt of such a l-arylalkylimidazole.
In formula (I) examples of the group A are:-methylene, propylene, and in the orientation of formula (I);
:. -CH2-CH=CH- , (cisor trans or isomeric ; mixture thereof).
A valuable class of compounds of formula (I) are :. those in which the aromatic ring is substituted by at least two alkyl or unsaturated aliphatic hydrocarbon radicals, . .
especially if one substituent is in the 4-position in the : ;:
benzene ring and A is either methylene t_CH2_) or, in the : orientation of formula (I), -CH2-CH=CH- (cis or trans or a . _ /trans mixture-cinnamyl compounds). When A is unsatu-rated, preferred compounds are those in which the aromatic ring contains alkyl, chloro or methoxy substituents.

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.., ; Compounds of formula (I~ may also be used as acid addition salts thereof, especially as pharmaceutically acceptable ones.
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Especially preferred compounds include:-- 1-~3,4-dimethylbenzyl)imidazole -- 5 1-(2,4-dichlorocinnamyl)imidazole i.e 1-[3-(2,4-dichlorophenyl) prop-2-enyl~imidazole 3-(2,6-dichlorophenyi)prop-2-enyl~imidazole, and acid addition salts thereof.
Other preferred compounds include:-1-(2,4,6-trimethylbenzyl)imidazole ~;.;
1-[3-53,4,5-trimethoxyphenyl)prop-2-enyl]imidazole 1-[3-(3,4-dimethoxyphenyl)prop-2-eny~ imidazole 3-(2-hydroxyphenyl)prop-2-enyl]imldazole 3-(3-bromophenyl)prop-2-enyl]imidazole 1-~3-(4-chlorophenyl)prop-2-eny~ imidazole 1-~3- 3,4-dimethylphenyl)prop-2-enyl~imidazole 3-(2-methoxyphenyl)prop-2-enyl~imidazoleJand acid addition salts thereof.

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5 ~ A553 In contrast to imidazole and l-methylimidazole, the compounds of formula ~I~ are more potent inhibitors of TXA2 synthetase. ; Many of the compounds (for example in formula (I) R is 3,4-dimethyl and A is -CH2- or in the orientation of formula (I), -CH2CH=CH-) are also more selective in their action in not inhibiting other anti aggregatory prostaglandin--generating enzymes. The compounds of formula (I) also do not p-:oduce the side-e~fe~-~s found with imidazole upon in vivo administration. The compounds of formula (I) are further capable of inhibiting platelet aggregation in vivo and also are :. . .
capable of disaggregating platelet clumps, the compounds 1-(3, ~ 4-dimethylbenzyl)imidazole, 1-~2,4-dichlorocinnamyl)imidazole ; and 1-(2,6-dichlorocinnamyl)lmidazole, and their salt.
especially displaying these properties.
Imidazoles of formula (I) and acid addition salts thereof may be made by any method known in the art for the s~nthesis of compounds of analogous structure. In general these methods `. comp_i.se linking the imidazole ring to the remainder of the molecule; converting a precursor molecule by elimination of a functional group; and formction of the desired compound from a corresponding pyrazole, imidazoline or other unsaturated analogue.
A most convenient method of synthesis involves the reaction :'"
of imidazole (formula (II) or a salt thereof with an arylalkyl-ating agent of formula (III):

: . : . ,.

.-................................... ' .~ :

. A553 :

'~ N~ ~ )n ~ (II) (III) ;~ wherein R, n, and A are as defined in formula (I) and Z is a .~..
leaving group. This reaction is well established in ;he - literature, and the leaving group may be chosen from a variety of substituents but es~ecially halo, preferably chloro or bromo, or from p-toluenesulphonyloxy but other aryl-sulphonyloxy, alkanesulphonyloxy or arylalkylsulphonyloxy radicals may be used. The ~saction is preferably performed in the presence of an acid acceptor, for example an alkali metal alkoxide, such as sodium methoxide or potassium tertiary butoxide, in the presence of an alkanol. The leaving group Z may itself be formed in situ from the corresponding alkanol . .
(Z = 0~) by reaction with a hydrohalogenic acid (e.g. hydro-. ~ .
chloric acid or a Lewis acid, such as aluminium chloride: see -` Japanese ~atent Kokai No. 131577~77) and the resuLting agent of formula (III) reacted directly with imida~ole without prior isolation. Alternatively an alkanol (Z = 0~) or a derivative thereof (e.g. Z =( ) ~ A-o~)may be reacted directly with "' '' '' ::
~:' - ` .

~ . . .
, -~.' imidazole ~ by heating in the presence of a dehydrating agent, such as phosphoric acid, or a phosphate (see Japanese Patent Publication No. 51 105 060~, sulphuric acid or sulphates (see Japanese Patent Publication No. 51 105 061~.
A~ong precursor molecules which may be converted to a compound of formula (I~ or an acid addition salt thereof, are substituted imidazole derivatives of formula (IV) or addition salts thereof N-A
Ql (Q4) wherein A, n and R are as defined in formula (I), and Q , Q , Q
and Q are the same or different, at least one being a radical capable of removal by, for example reduction or oxidation, the - remaining radical or ~ dicals being selected from hydrogen or a radical capable of removal in the same or another manner (e.g.
a carboxyl grou~ -see formula (VI)-removed J,y decarboxylation)) y is 0 o~ an integer with the proviso that y and n together do not - exceed 5. Ql, Q , Q ard Q may be select`ed for example from thio (-SH), alkylthio (-S-alkyl, wherein alkyl has from 1 to 4 carbon atoms) or halo preferably chloro or bromo. The reaction conditions are chosen according to -che nature of the radicals Q , Q , Q and Q . Desulphurisation may be performed by oxid-ative or reductive procedures using for example nitric acid or Raney ', ;

, r -.. . .
nickel; and reductive dehalogenation by the use of zinc and acetic acid or Raney nickel or other reagents known in the art ~ .
or described in the literature.

Another class of examples include carboxyimidazoles or S de~ivatives thereof of formula (VI);

~ ~ ~C~

wherein A, n, and R are as defined in formula ~I), at least one of R , R and R is carboxyl or a derivative thereof (for example an ester such as an alkyl ester, an acid hal;de such as the chloride, or the nitrile) and the other(s) is hydrogen or carboxyl or a derivative as described. The compounds of ~- formu;a (VI) may be converted into the imidazoles o': formula (I) by any suitable decarboxylation conditions which may simply comprise heating the compounds with or wit.~out a catalyst, such as copper.
... .
. 15 The imidazoles of formula (I) may also be made fr^m a compound of formula (VII):

,' N-Al-R3 (VII) wherein ~N is l-imidazoline, l-imidazole or l-pyrazole, A
is straight or branched saturated or unsaturated acyclic ~ .

~ 9 ~ 433 hydrocarbon radical which may include a keto-group, and R
is ~ (R~n wherein R and n are as defined in formula (I) and when A is unsaturated R may also be nitro provided that at least one of N, Al and R3 is other than l-imidazole, a saturated acyclic hydrocarbon group and ~ (R)n as defined in formula (I). Thus an imidazoline (VIII):
' :

~ (R)n (VIII) : N

: (H) wherein one of ----- represents an extra bond, and A, n and R are as defined in formula (I), may be dehydrogenated to the corresponding imidazole in the presence of a catalyst, ` 10 for example by heating to 250C in the presence of palladium, nickel or platinum under pressure, or by heating with a : ` dehydrogenating agent, such as selenium or copper oxide.
Pyrazole compounds (VII) may be treated with ultra-violet ~- irradiation, optionally under an inert atmosphere (e.g.
., argon) in for example 1,2-dimethoxyethane at room or eleva-, ted temperatures (see for example "Ring Transformations of . Heterocycles" edited van der Plas, Academic Press, 1973 at ; page 261). The unsaturated imidazoles of formula (I) (in formula (VII), Al and/or R (within R ) are unsaturated) may . 20 be reduced to corresponding less saturated or completely . - saturated compounds (but not reducing the aromatic nucleus) ,:
with a noble metal catalyst for example platinum or pal-ladium in an alkanol. If R is amino in the final product then its precusor may be a nitrogen-containing group reducible to ."' ~

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amino e.g. nitro. A compound for example of formula ~ N-CH2-~ ~ (IX) where R and n are as for formula (I), may be reduced at the keto group to a -CH2- group for example by a Clemmensen reduction.
Where one or more of the R groups is a saturated or unsaturated .~
alkyl group it may be introducel into the phenyl ring by a Friedel Crafts or similar Lewis-acid catalysed reaction of the -:, ' ty~e.

N-A ~ ~ R)n-x ~ N
,,. (X) N ~ ~ ~ ~Rl D
--;~ (I) -.. . .
: - wherein A, R and n are as defined for formula (I), x lS an integer less than or e~ua; to n and zl is a leaving group, e.g. halo, suitable fcr use in this type of alkylation.
Compounds of formula (I) may also be prepared by cyclising preferably in the presence of an acid acceptor, a compound of formula , ! A553 .

,:

NH-A ~ _ ~ n (XI`

CHX
,'`' wherein A, R and n are as defined for formula (I) and X is a leaving group.
Compounds of formula (I) may also be prepared by reactir.g ~. .
~ a compound of formula :?: RN C~ R~n (XII) 5 wherein A, R and n are as de.ined for formul (I), with a compound .,; .:: .
of formula:

X ~X
\ / (XIII) CH CH
` y3 / \ y4 wherein either of X and Y is a leaving group such as halo or hydroxy and the other is hydrogen, or X3 and Y3 are both halo or together form a keto group or an acetal derivative ~nereof e.g. both X and Y are alkoxy, and X and Y are 2~ define~ -for X and Y , although they may be the same as or different from X3 and Y .
An imine salt of or example formula : : .

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~ -3 .~ N ~ N - C _A2 ~ (R)n ~IIIa) ~; (wherein R and n are as for formula I, X is an anion, q A is a chemical bond or a straight or branching saturated or unsaturated acyclic hydrocarbon radical, which may include a - keto group, A is hydrogen or a saturated ~?
or unsaturated acyclic hydrocarbon radical, which may include a keto group, with the proviso that A and A together contain no more tnan 2 carbon atoms~ may be reduced to the : corresponding compound of formula ~I), by e.g. zinc and a mineral `~ acid e.g., hydrochloric acid.
, . .
The intermedlates for use in the above described reactions may also be made by conventional methods known in the art. Thus the l-pyrazole and l-imidazoline intermediates tformula (VII) may - be prepared by alkylation of pyrazole and imidazoline in an analogous manner to that described above for preparation of the corresponding imidazoles. The intermediates of formula (III) may be made in known manner preferably by halogenation of the - corresponding alcohols ~formula (IIIJ, Z = -o~) where A is unsaturated in such compounds the alcohol is conveniently prepared from paraformaldehyde and a precusor molecule with an unsaturated A group Gontaining two ',':
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carbon atoms ~cf Bull. Che~. Soc. Japan, 46/8, 2512-5, 1973). The substituted imidazole intermediates of formula (IV) may be made in known manner, for example see "Imldazole and lts ; derivatives" Part I, Ed. K. Hofmann, Interscience Publishers Inc. New York, 1973. For example the 2-thioimidazoles of formula ~IV) may be made by cyclisation of an acetal of formula (XIV) \CH-CH .NH.- A
R5 ~ (XIV) with thlocyanate, wherein RS is alkyl, aryl or arylalkyl.
The pharmaceutically acceptable addition sa]ts of the compo~nds of formula (I) may be prepared by any method kncwn in the art. In particular they may be prepared by treating thè parent imidazole with the appropriate acid.
Examples of the addition salts of the compounds of formula (I) include those salts derived from the following acids: oxalic, hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic~lactic, sallcyclic, succinic, toluene-p-sulphonic, tartaric, acetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-

2-sulphonic and benzenesulphonic.
The imidazoles of formula (I) may be used in conjunction ` with a phosphodiesterase inhibitor, which provides a further '. , ' . , .; :~. , .
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synergistic increase in effect, as it acts against platelet aggregation by a different pathway.
Suitable phosphod-esterase inhibitors for use in potentiating the anti-aggregatory effe-ts of the active compounds include as ' i ':
such or as pharmaceutically acceptable salts:-"~, , -`; (a) Xanthine derivatives such as:-:, .
.:
Theophylline(3,7-dihydro-1,3-dimethyl-lH- purine-2,6-dione), and salts thereof.
~ 3-Isobutyl-l-methyl-xanthine;
'; 10 Caffeine(3,7-dihydro-1,3,7-trimethyl-lH-purine-2,6-dione) and salts thereof; and Aminophylline (adduct of Theophylline and 1,2-ethaned-amine (2:1)) (b) Isoquinoline derivatives, for example:-Papaverine 1- r(3,4-dimethoxyphenyl)methyl~-6,7-dimethoxyisoquinoline) and salts thereof; and 6~7-Diethoxy-1-(4,5-diethoxybenzyl)isoquinoline or its salts e.g. its hydrochloride;
(c) Derivatives of pyrimido(5,4-d- pyrimidine, for example:-Dipyridamole(2,2',2"'-(4,8-dipiperidino-pyrimido ~5,4-~ pyrimidin-2,6-diyldinitrilo;-tetraethanol) . and its salts;
. : 2~2',2"'-r~4-(1-pip~ridinyl)pyrimido[5,4-d~ .
; pyrimidin-2,6-diyl~initrilo~tetrakisethanol and its salts; and 2,4,6-tri-4-morpholinylpyrimido[5,4-d~pyrimidine and its salts.
(d) Derivatives of th~eno ~3,2-d~pyrimidine, for example:-N-C4-(4-morpholinyl)thienot3,2-d~pyrimidin-2-yl]-1,2-ethanediamine.

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- 15 - A553 i ;;' .
(e) Derivatives of pyrazolo~3',4':2,3~pyrido ~4,5-~~1,5~ benzodiazepin-6-(3H)-one, for example:-

3-Ethyl-7,12-dihydro-7,12-dimethylpyrazolo-[4',3':5,6~pyrido~4,3-b~- 1,5 benzodiazepin-6~3H)-one;
10--Chloro-3-e~hyl-7,12-dimethyl-7,12-dihydro-pyrazolo[4',3':5,6~pyrido~4,3-b~ C1,5~benzo-diazepin-6-(3H)-one.

(f) Derivatives of 1_- or 2H-pyrazolo[3,4-b]-pyridine, for example:-

4-(Butylamino`-l-ethyl-lH-pyrazolo[3,4-b~-pyridine-5-carboxylic acid ethyl e;ter 4-(Butylamino)-lH-pyrazolo [3,4-b~pyridine-6-carboxylic acid ethyl ester;
4-Chloro-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]-pyridine-5-acetonitrile;

l-Ethyl-4-(iscpropylidenehydrazino)-3-methyl-H-pyrazoloc3~4-b~pyridine-5-carboxylic acid ethyl ester or its salts such as its hy~rochloride hemihydrate; and 2-Methyl-6-phenyl-4-(1-piperidinyl)-2H-pyrazolo-r3,4-b]pyridine or its salts e.g. its hydrochloride.

(g) Derivatives of 5H-furo-~3,4-e~pyrazolo-~3,4-b]
pyridine-5-one, for example:-4-(Butylamino)-l-ethyl-1,7-dihydro-7-~ydroxy-5H-furo-~3,4-e~pyrazolo[3,4-b~pyridine-5-one; and (h) Derivatives of 1(2H)--naphthalenone, for example:-- 2 ~Dimethylamino)methyl3-3,4-dihydro-i-methoxy-1~2H) naphthalenone or its salts e.g. its 1:1 hydrochloride.
;~ The active compounds are particularly useful in the treat-ment and/or prophylaxis of thrombo-embolic disorders in mammals, including man. It is to be understood that the term "thrombo-embolic disorders" includes those disorders whose etiology is associated with platelet aggregation.

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The active compounds are useful wherever it is desi~ed to inhibit platelet aggregation and/or to reduce the adhesive character of platelets, and consequently to treat or prevent the for~ation of thrombi J~n mammals, including man. For example, the compounds are useful in the treatment and prevention of myocardial infarcts, cerebro-vascular thrombosis and ischaemic peripheral vascular disease; to treat and prevent post-operative thrombosis; and to promote patency of vascul~r grafts following surgery.
The active compounds are also useful as an addition to blood, blood products, blood substitutes, and other fluids - which are used in artificial extra-corporeal circulation and ,. ~
. .
`~ perfusion of isolated body portions, e.g., limbs and organs, whether attached to the original body, detached and being preserved or prepared for transplant,,or attached to a new '':: .
body. It may also be used in laboratory animals, e.g. cats, dogs, rabbits, monkeys and rats, for these purposes in order to develop new methods and techniques for organ and limb transplants.
The active compound 5 also exhibit some vasodilatory action on blood vessels and thereforc have a utility as anti-hypertensives for the treatment of high b]ood pressure in mammals, including man.
The amount of active compound required for therapeutic or prophylactic effect will vary with the Ioute of administration, .

1111~33 .
:`' :, and the nature of the condition under treatment. In general a suitable dose for a mammal, including man, of active compound will lie in the range of 0.1 to 300 mg per kg body wsight, particularly from C.5 to 10 mg per kg body weight, for example `~ 5 2 mg per kg. A suitable single oral dose for an adult human :
lies within the range of 50 to 600 mg, for example 1'0 mg given say three times a day.
While it is poss ble for the active compounds to be admin-istered as the raw chemical it is preferable to present them as a pharmaceutical formulation. The formuIations, both for veterinary and .or human medical use, of the present invention comprise an active compound as above defined, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients. The carrier~s) must be 'acceptab7e' , ~ . .
; 15 in the sence of being compati~le with the other ingredients of ,, the formulation and not deleterious to the recipient thereof.
Unit doses of a formulation may contain between 60 mg and 1.5 -:
g ol an active compound.
The formulations include those suitable for oral, rectal, vaginal or parenteral (including subcutaneous, intramlscular and intravenous) administration. Preferred formulations nclude ' tablets, capsules and injectable suspensions or solutions.
' The formulations may conveniently be presented in unit dosage from and may be prepared by any o the methods well known in the art of pharmacy. All methods include the step of ~ ' ., .

.''.'~
bringing into association ;he active compound (in the form of the base or a pharmaceutically acceptable acid addition salt) with the carrier which constitutes one or more accessory : .
ingredients. In general the formulations are prepared by uniform~y and intimately bringing into association the active compound with l quid carriers or finely divided solid carriers or botn, and then, if necessary; shaping the product into the desired formulation.
It will be appreciated from the foregoing that the present invention provides the following features:-(a) Novel l-arylalkylimida~oles of formula (I), and acid addition salt thereof.
(b) Methods of proparing imidazoles of formula (I) and acid addition salts thereof.
(c) Pharmaceutical formulations containing the imidazoles of ,:, formula (I; or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier.
(d) Methc~ of preparing the pharmaceutical formulations containing the imidazoles of formula (I) or a pharmaceutlcally acceptable acid addition salt thereof.
(e) A method for the treatment of prophylaxis of a thrombo-embolic disorder in a mammal or mammalian tissue, including man or human tissue, comprising administering an active compound.

111~433 :: .
; (f) An l-arylalkylimida~ole of formula ~I) or salt thereof as - an active agent for the treatment of a thrombo-embolic disorder in a mammal or mammalian tissue, including man or human tissue.
The following Examples are provided by way of an illus-tration of the present invention and should in no way be con-, strued as constituting a limitation thereof. All temperatures are given in degrees Celsius.

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` ` 1113L9~33 Preparation of 1-(3,4-Dimethylbenzyl)imidazole - l-Chloromethyl-3,4-dimethylbenzene (34.76 g, 0.225 mol) was added to a mixture of imidazole ~13.6 g, 0.2 mol) and sodium - :
bicarbonate (16.8 g, 0.2 mol) in dry methanol ~100 ml).
Following the addition, the reaction mixture was stirred and heated under reflux for 3 h.
After cooling, the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure to afford a yellow oil. The residue was extracted with chloroform (3 x 100 -~ ml), and the combined extracts were washed with saturated brine (100 ml). The chloroform solution was dried over magnesium .;
sulphate, and then concentrated under reduced pressure. The resulting oil ~as purified using a silica gel column and ethyl acetaté~methanol ~9:1) as el-lent. The product fractions were : ':
-~ - pooled, concentrated, and the resulting oil was distilled to afford 1-(3,4-dimethylbenzyl)imidazole b.p. 128-130 /0.3mm Hg.

EXAMPLE 2 - Salts of 1-(3,4-Dimethylbenzyl)imidazole A ydrogen Fumarate A solution of fumaric acid (0.29 g, 0.0025 mol) in hot ethanol (10 ml) was added to a stirred solution of 1-(3,4-di-methylbenzyl)imidazole ~0.46 g, 0.0025 mol) in hot ethanol (10 ml). After boiling for 0.25 h, the solution was evaporated to afford a white solid. Recrystallisation of the solid from - ethyl acetate afforded 1-~3,4-dimethylbenzyl)imidazole hydrogen fumarate 1/6 hydrate as a white solid m~p. 138-140.
B. Hydrogen Succinate A hot solution of succinic acid (0.295 g, 0.0025 mol) in hot ethanol (20 ml) was added to a stirred, hot solution of 1-(3,4-dimethylbenzyl)imidazole ~0.46 g, 0.0025 mol) in hot ethanol (10 ml). After boiling for 0.25 h, the solution was evaporated under re~uced pressure to aford a white solid.
Recrystallisation of the solid from ethyl acetate/petroleum lo ether (b.p. 40-60 ) afforded 1-(3,4-dimethylbenzyl)imidazole hydrogen succinate as white crystals, m.p. 134-135 .
- C. Hydrogen Oxalate A hot solution of oxalic acid ~0.225 g, o.oo25 mol) in dry ethanol (10 ml~ was added to a solution of 1-(3,4-dimethyl-benzyl)imidazole (0.46 g, 0.0025 mol) in hot ethanol (20 ml).
~; After boiling for 0.25 h, the solution was evaporat~d to afford a white solid. Recrystallisation of the solid from ethanol/
petroleum ether (b.p. 40-60 ) afforded 1-(3,4-dimethylbenzyl) imidazole hydrogen oxalate as a white solid, m.p. 92-93 .
,: ' ' ' ' ` 20 EXAMPLE 3 Preparation of 1-[3-(2,4-Dichlorophenyl)prop-2-enyl~imidazole l-Chloro-3-(2,4-dichlorophenyl)prop-2-ene (11.1 g, 0.05 mol) was added dropwise to a stirred solution of imidazole (3,4 g, 0.05 mol) and potassium tert-butoxide ~5:6 g, 0.05 mol) in .-......................... .
.~ . .

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butan-l-ol (100 ml). Following the addition, the reaction mixture was stirred and heated under reflux for 3.5 h.
After cooling, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Hydrochloric acid (150 ml, 2M) was then added to the residue and the aqueou~
~ mixture was washed with ether (1 x 60 ml). The acidic - solution was then basified with sodium hydroxide solution (lOM) :~ .
and the resulting oil was extracted with chloroform. The chloroform extracts were combired and dried over magnesi~m sulphate. Evaporation of the chloroform under reduced pressure afforded a pale yellow oil which was purified using a silica gel column and by elution with ethyl acetate/methanol (9:1).
The product fractions w~re pooled and concentrated to afford ; an oil which wzs distilled, to afford 1-[3-(2,4-dichlorophenyl) prop-2-enyl~imidazole, b.p. 144-148 /0.007 mmHg.
. .
., .
,. ,: . .

Preparation of i-~3-(2,6-Dichlorophenyl) ro~-2-eny~ imidazole l-chloro-3-(2~6-Dichlorophenyl)prop-2-ene (11.1 g, 0.05 mol) was added dropwise to a stirred solution of imidazole (3.4 g, 20 0.05 mol) and potassium tert-butoxide (5.6 g, 0.05 mol) in butan-l-ol (100 ml). Follow-ng the addition, the reaction mixture was stirred and heated under reflux for 3.5 h.
- After cooling, the reaction mixture was filtered, and the fil~rate was concentrated under reduced pressure. Hydrochloric ':,' : ~111433 . . .

., .' acid (150 ml, 2M) was then added to the residue, and the aqueous mixture was washed with ether (1 x 60 ml). The acidic solution was then basified with sodium hydroxide solution (lOM), and the resulting oil was extracted with chloroform. The chloroform extracts were combined and dried over magnesium sulphate.
Evaporation of the chloroform under reduced pressure afforded a pale yellow oil which was purified using a silica gel column and by elution with ethyl acetate/methanol ~9:1). The p:oduct fractions were pooled and concentrated to afford an oil which was distilled, to afford 1-r3-(2,6-dichlorophenyl)-prop-2-enyl~imidazole, b.p. 156-158 /0.02 mmHg.
;. . .

Biological Results , Horse platelets were prepared from whole horse blood by ; 13 differential centrifugation. Apprcximately 10 platelets : were homogenised in 1 ml 100 mM Tris buffer pH 7.4. Various ~ concentrations of active compound were added and the reaction sets incubated for 5 minutes at arnbient ternperature. To each tube was added 20 nM of arachidonic acid containing 10 : ..
disintegrations per minute (DPM) of labelled arachidonic acid ~ and the tubes incubated for 3 minutes at 37 C in a shaking .; . .
water bath. After incubation the radioactive products were - extracted frGm the acidified aqueous phase with ethyl acetate and after concentration resolved by thin layer chromotography on silica gel with chloroform~me~hanol/ace'ic acid/water :.:
.... ' ''.- -.
, ` -`" 11114;33 .

(90:8:1:0.8) as a developing solvent. The amount of thromboxane produced was measured by scraping the radioactive zone corres-- ponding to thromboxane B2 and estimating the radioactivity in a liquid scintillation counter.
The concentration of active compound to reduce the enzyme activity by 50% (ED50) ~as established. The results are shown in Table A.
: . , The selectivity of the active compounds was measured in a similar manner to that described above and the amount of PGE
PGF and PGD produced was determined. The greater the selec-tivity, the more of the anti-aggregating prostaglandins are . produced.
. .
The ED50 and Selectivity results are shown in Table A in which 0 indicates no selectivity; + low selectivity;
> 15 ++ medium selectivity; +++ high selectivity, and ~+++ excep-tionally high selectiv'ty TABLE A
Compound 50 (Reference Compound) ug/ml Selectivity (Imidazole) ~ 500 0 to +
(l-Methylimidazole) ~200 ~+
1-(3,4-dimethylbenzyl)imidazole 6 ++
1- ~-(2,4-dichlorophenyl)prop-2-enyl~imidazole l-C3-(2,6-dichlorophenyl)prop-2-eny~
imidazoie 11~1433 , ' .

Tablet formulation .
1-(3,4-dimethylbenzyl)imidazole (as a salt) 150 mg . Starch 25 mg Polyvinylpyrrolidone 2 mg Magnesium stearate 3 mg ~ . The imidazole salt is ground to a fine powder, blended ;.- with the starch and then the mixture granulated with an . aqueous solution of the polyvinylpyrrolidone. The granules :;. 10 are sieved 1000 lu, dried, sieved again and the magnesium stearate added. The mixture is then compressed into tablets.
In the same manner, tablets of l-r3-(2,4-dichlorophcnyl)-prop-2-enyl~imidazole 2nd 1-[3-(2,6-dichlorophenyl)prop-2-enyl~
:
~.~ imidazole are prepared.

....j EXAMæLR 7 , _ .~
Tablet formulation Tablets (150 mg) of the imidazoles described in the . preceding example 6 are prepared in the same manner from the following ingredients--The Imidazole Compound (as a salt) 150 mg Lactose 100 mg Starch 30 mg . Polyvinylpyrrolidone 2 mg -~ Magnesium stearate 3 mg . . .

., ':.' ' ", ~ .

,''. ~

:;
. In the preparation, the lactose is blended with the --, starch.
,''' , , Tablet foxmulation Tablets (100 mg~ of the imidazoles of Example 6 are prepared in the same manner from the following ingredients:
- The Imidazole Compound tas a salt) 100 mg :. .
Sodium starch glycollate 10 mg : Polyvinylpyrrolidone 2 mg Magnesium stearate 3 mg . .' ' ~ , .

- : EXAMPLE 9 . ~ Tablet formulation Tablets ~150 mg) of the imidazoles of Example 6 are : prepared in the same manner from the following ingr~dients, except that the starch, pregelled starch and imidazole compou~d ; are all blended together prior to granulatior.:-The Imidazole ~ompound (as a salt) 150 mg Starch 25 mg Pregelled starch 5 mg Magnesium stearate 3 mg .

~' . .

.
, . .

.

- Injectable formulation Imidazole compound of formula (I) 15.0 g - Lactic Acid B.P. q.s. to pH 3.0 Water for Injections B.P. to 100.0 ml . .: ., Suspend the compound in 3/4 of the available quantity of water. Add sufficient lactic acid to dissolve the ., .
compound and to reduce the pH to 3Ø Dilute to volume with - Water for Injections.
Sterilise the solution by passage through a membrane filter, pore size 0.22 ,um.
Distribute the solution using aseptic precautions into sterilised ampoules, 1 ml per ampoule. Seal by fusion of the glass.
~-~ 15 Each 1 ml ampoule supplies 150 mg of the imidazole .. :
compound: 1-(3,4-dimethylbenzyl)im dazole hydrogen fumarate.

~ EXAMPLE 11 - Injectable formulation Imidazole compound of formula (I) lS.0 g Citric Acid B.P. q.s. to pH 3.0 ~.
. C~lorocresol 0.1 g ; Water for Injections to 100.0 ml Suspend the compound in ~ the final volume of Water for Diections~ Add sufficient citri~ acid as a 10~ solution in 11~1433 . . .
, . .

. ' : .
Water for Injections to dissolve the compound and reduce the p~ to 3Ø Dilute to volume with Water for Injections.
Sterilise the solution by passage through a membrane ,, filter, pore size 0.22,um.
Distribute the solution with aseptic precautions into .: -sterilised vials, 25 ml per vial. Stopper with sterile rubber closures and seal with an aluminium cap.
Each 1 ml of solution provides 150 mg of the compoundO
1-(3,4-dimethylbenzyl)imidazole hydrogen fumarate.
'' ~

Injectable formulation In the manner descLibed in the preceding two Examples, injectable formulations of 1-[3-(2,4-dichlorophenyl)prop-2-enyl~imidazole and 1-[3-(2,6-dichlorophenyl)prop-2-eny~
imidazole salts were p.epared.

By the method described in Example 1 above the following compounds were prepared:-(a) 1-(2,~l,6-trimethylbenzyl~imidazole ~ 20 (b) 1-l3-(3,4,S-trimethoxyphenyl)prop-2-eny]~imidazole - (c) 1-[3-(3,4-dimethoxyphenyl)prop-2-enyl~imidazole (d~ 1-[3-(2-hydroxyphenyl)prop-2-eny~ imidazo1e .'.'' , :`
, -`-:. A553 ;........................ (e) l-C3-(3-bromophenyl)prop-2-enyl~imidazole (f) 1-~3-(4-chlorophenyl)prop-2-eny].~imidazole . (g) l-[3-(3,4-dimethylphenyl)prop-2-eny~ imidazole (h) 1- t3- (2-methoYyphenyl)prop-2-eny~ imidazole . ' '' :

-''` ' ' ~ .
. , ' ' .

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A method of preparing a l-arylalkylimidazole of the formula (I):

(I) in which A is a straight or branched alkylene group of from 1 to 3 carbon atoms, or a straight or branched alkenylene or alkynylene group of 2 or 3 carbon atoms, n is an integer which is at least 1, and the or each R
substituent, which when n is greater than 1 may be the same or different, is an alkyl group of from 1 to 4 carbon atoms or an alkenyl or alkynyl group of from 2 to 4 carbon atoms, with the proviso that (a) when A is a methylene or ethylidene group, n is at least 2 when each R is alkyl;
(b) when A is a branched propylene or straight pro-pylidene group, n is at least 3 when each R is alkyl;
(c) when A is unsaturated, R may also be selected from alkoxy of from 1 to 4 carbon atoms; when n is at least 2, alkylenedioxy of from 1 to 4 carbon atoms; halo;
trihalomethyl; hydroxy; carboxyl, a salt of such a carboxyl group; carboalkoxy; carboaryloxy; carboaryl-alkyloxy; -NR6N7 N or -CONR6R7, in which R6 and R7 may be the same or different and are hydrogen or alkyl of from 1 to 4 carbon atoms, with the further proviso that when n is 1, R is not an alkyl group; or an acid addition salt thereof comprising (a) reacting imidazole or a salt thereof with an alkylating agent of the formula wherein A, n and R are as defined above, and Z is a leaving group; or (b) converting a substituted imidazole of the formula:

wherein A, n and R are as defined above and Q1, Q2, Q3 and Q4 are the same or different, at least one being a radical capable of removal by reduction or oxidation, the other being a radical having the same or other function removable by reduction or oxidation or is hydrogen, y is 0 or an integer, with the proviso that y and n together do not exceed 5; or (c) decarboxylating a carboxyimidazole derivative of the formula:

wherein A, n and R are as defined above, one of R1, R2 and R4 is carboxyl or a derivative thereof, and the other is hydrogen, carboxyl or a functional derivative thereof, or (d) converting a presursor of the formula:

wherein is 1-imidazoline, 1-imidazole or 1-pyrazole, A1 is a straight or branched saturated or unsaturated acyclic hydrocarbon radical which may include a keto group and R3 is a group of formula wherein R and n are as defined above, or R may include nitro when A is unsaturated provided that at least one of , A1 and R3 is other than 1-imidazole, a saturated acyclic hydrocarbon group and respectively;
(e) alkylating a compound of formula (X):

(X) wherein A, R and n are as defined above, and x is an integer less than or equal to n, with a compound of formula:

wherein R is an alkyl group of from 1 to 4 carbon atoms or an alkenyl or alkynyl group of from 2 to 4 carbon atoms, and Z1 is a leaving group; or (f) cyclising a compound of formula (XI):

(XI) wherein A, R and n are as defined above and X2 is a leaving group;
(g) reacting a compound of formula (XII):

(XII) wherein A, R and n are as defined above with a compound of formula (XIII):

(XIII) wherein either of X3 and Y3 is a leaving group and the other is hydrogen or X3 and Y3 are both halo or together form a keto group or an acetal derivative thereof, and X4 and Y4 are as defined for X3 and Y3, being the same as or different from X3 and Y3; or (h) reducing an imino salt of formula (XIIIa):

(XIIIa) wherein R and n are as for formula (I), X- is an anion, A2 is a chemical bond or a straight or branching, saturated or unsaturated acyclic hydrocarbon radical, which may include a keto group, A3 is hydrogen or a saturated or unsaturated acyclic hydrocarbon radical, which may include a keto group, with the proviso that A2 and A3 together contain no more than 2 carbon atoms, and when desired converting a l-arylalkylimidazole of formula (I) obtained to a corresponding acid addition salt.

2. A method according to claim 1, wherein A is -CH2- or, in the orientation of formula (I), -CH2-CH=CH-,

3. A method according to claim 1, wherein R and n together are 3,4-dimethylsubstituents in the benzene ring.

4. A method according to claim 1, including a step of reacting a compound (I) obtained with a pharmaceutically acceptable acid to produce a corresponding pharmaceutically acceptable acid addition salt.

5. A method according to claim 1(a) for preparing 1-(3,4-dimethylbenzyl)imidazole comprising reacting imidazole with 1-chloromethyl-3,4-dimethylbenzene.

6. A method according to claim 5, including a step of reacting the resulting 1-(3,4-dimethylbenzyl)imidazole with a pharmaceutically acceptable acid to produce a corresponding pharmaceutically acceptable acid addition salt.

7. A method according to claim 1(a), for preparing 1-(2,4-dichlorocinnamyl)imidazole comprising reacting imidazole with 1-chloro-3-(2,4-dichlorophenyl)prop-2-ene.

8. A method according to claim 7, including a step of reacting the resulting 1-(2,4-dichlorocinnamyl)-imidazole with a pharmaceutically acceptable acid to pro-duce a corresponding pharmaceutically acceptable acid addition salt.

9. A method according to claim 1(a), for preparing 1-(2,6-dichlorocinnamyl)imidazole comprising reacting imidazole with 1-chloro-3-(2,4-dichlorophenyl)prop-2-ene.

10. A method according to claim 9, including a step of reacting the resulting 1-(2,6-dichlorocinnamyl)-imidazole with a pharmaceutically acceptable acid to produce a corresponding pharmaceutically acceptable acid addition salt.

11. A 1-arylalkylimidazole compound of formula (I):

(I) in which A is a straight or branched alkylene group of from 1 to 3 carbon atoms, or a straight or branched alkenylene or alkynylene group of 2 or 3 carbon atoms, n is an integer which is at least 1, and the or each R
substituent, which when n is greater than 1 may be the same or different, is an alkyl group of from 1 to 4 carbon atoms or an alkenyl or alkynyl group of from 2 to 4 carbon atoms, with the proviso that (a) when A is a methylene or ethylidene group, n is at least 2 when each R is alkyl, (b) when A is a branched propylene or straight propylidene group, n is at least 3 when each R is alkyl;

(c) when A is unsaturated, R may also be selected from alkoxy of from 1 to 4 carbon atoms; when n is at least 2, alkylenedioxy of from 1 to 4 carbon atoms; halo; tri-halomethyl; hydroxy; carboxyl; a salt of such a carboxyl group; carboalkoxy; carboaryloxy; carboarylalkyloxy;
-NR6R7 -CONR6R7, in which R6 and R7 may be the same or different and are hydrogen or alkyl of from 1 to 4 carbon atoms, with the further proviso that when n is 1, R is not an alkyl group; or an acid addition salt thereof, whenever prepared by the method of claim 1, or by an obvious chemical equivalent.

12. A 1-arylalkylimidazole of formula (I), as defined in claim 1, wherein A is -CH2- or, in the orient-ation of formula (I), -CH2-CH=CH-, whenever prepared by the method of claim 2, or by an obvious chemical equivalent.

13. A 1-arylalkylimidazole of formula (I), as defined in claim 1, wherein R and n together are 3,4-dimethyl substituents in the benzene ring, whenever prepared by the method of claim 3, or by an obvious chemical equivalent.

14. A pharmaceutically acceptable acid addition salt of a 1-arylalkylimidazole of formula (I), as defined in claim 1, whenever prepared by the method of claim 4, or by an obvious chemical equivalent.

15. 1-(3,4-Dimethylbenzyl)imidazole, whenever prepared by the method of claim 5, or by an obvious chemical equivalent.

16. A pharmaceutically acceptable acid addition salt of 1-(3,4-dimethylbenzyl)imidazole, whenever prepared by the method of claim 6, or by an obvious chemical equivalent.

17. 1-(2,4-dichlorocinnamyl)imidazole, whenever prepared by the method of claim 7, or by an obvious chemical equivalent.

18. A pharmaceutically acceptable acid addition salt of 1-(2,4-dichlorocinnamyl)imidazole, whenever prepared by the method of claim 8, or by an obvious chemical equivalent.

19. 1-(2,6-dichlorocinnamyl)imidazole, whenever prepared by the method of claim 9, or by an obvious chemical equivalent.

20. A pharmaceutically acceptable acid addition salt of 1-(2,6-dichlorocinnamyl)imidazole, whenever prepared by the method of claim 10, or by an obvious chemical equivalent.