CA1123841A - Process for the production of novel imidazole compounds - Google Patents

Abstract

Abstract of the Disclosure A process for the production of the imidazole compounds of the general formula (I):

Description

13.~ 3~

lhis invelltioll rclates to a process for thc l)roduction of no~cl imidazole compounds. ~lorc particularly, this invention rclates to a process for the production of imidazole compounds o-f the general formula (I):

N N -alkylene-Y (I) \J
wherein Y is a carboxyl group, a hydroxymethyl group~ an N-di or -mono alkyl substitllted or unsubstituted carbamoyl group, a cyano group or an N-di or -mono alkyl substit-ited or un-suhstituted amillometllyl group, and the alkylene is ~ saturated or unsaturatccl alkylene chain having 3 to 20 carbon atoms, as wcll as pharmaceutically acceptable salts thereof;
which possess a strong inhibitory effect on thromboxane synthetase and are thus useful as therapeutically active agents for inflammation, hypertension~ throlllbus, cerebral apoplexy and 1~ asthma caused by thromhoxctne A2.
Up to no~, of the compoun(ts having imldazole skeleton, it ])as been reported that imidazole and l-methylimidazolc possess an inhibitory action for thromboxane synthetase ~Prostaglandins, Vol. 13, No. 4, 611-~ 1977) However, since __ their inhibitory action for throm~oxane synthetase is weak, these compounds are hardly applicable as practically effective medicines. Therefore, research for some compounds possessing a much stronger and nmore specific inhibitory effect on ' ~

~ Z 3 ~

thlolllboxanc synthetase has been long sougllt after in this field.
On the other hand, N-~6-methoxycarbonylhexyl)illlidazolc has ~]ready been syntllesi~ed by P. Matthias e~ al and publicly knol~n (~lonatsch Chem., Voi. 108, No. 5, 10S9-, 1977). Althougl . . _ .
that compound t~nds to have a stronger inhibitory effect on throml~oxane syntlletase l~hen compared with imidazole or l-methyl-imidazole, the inhibitory effect is not completely satisfactory as a practical medication.
The compounds of this invention possess a strong and spccific inllibitory action for thromboxane synthetase, and are useful as therapeutically active agents for inflalnmation, hypertension, tlllom~us, ccrebral apoplexy and asthma.
~ccordingly, a principal object of this inventioll is to provide novel imidazole compounds which exhibit a strong and specific inhibitory effect on thromboxane synthetase, and which are therapeutically useful, and to provide a process ~or the production of these imida201e compounds.
The term "alkyl" as usecl herein means a straight or Iranched chain alkyl group having 1 to 4 carhon atoms.
The term "alkoxy" as used herein means an alkoxy group having 1 to 4 carbon atoms The term "acyloxy" as used herein means an acyloxy group derived from an aliphatic carboxylic acid having 2 to 5 carbon atoms.

l~.Z3~

I'lle imidazole compo~ ds of the general formula (I) of ~his invelltioll e~llihit an inhibitory action for thromboxane synthetclse from rabbit plate].et microsomes. That is, the imidazole compounds of this invention inhibit conversion of PROSTAGL.i~NnlN ll2 into TIIRO~IBO~ANE B2 via TIIRO~IBO~NE A2 W]liC}I
is an unstable intermediate, and ~hich is kno~n to induce irreversible platelet aggregation and to contract smooth muscle alld partic~llarly a blood vessel muscle. (N _ure, Vol.
261, No. 6, 17-, 1976). 'I'hese results demonstrate tll~t the ln imidazole compounds of this invelltion inhibit the biosynthesis of throlmboxalle A2, ancl are th~ls useful for treatmellt of diseases caused by tllromboxane A2, such as inflammation, hypertension, thrombus, cerebral apople~y and asthma.
The inhibitory action of the imidazole compounds of this -nvention can be confirmed by determination of the thromboxane B2 producetl by thromboxane synthetase from prostaglanclin ~l2 vi.a tllromboxane 42 Furtllermore, the inhil)itory action of the imidazole compol~nds of this invention can be confirmed by determillation of the inhibitory effect on platelet aggregation caused by arachidoJIic acid (arachidonic acid is converted to prostaglandin H2 by cyclooxygenase, and ~rostaglandin H2 is converted to thromboxane B2 via thromboxane A2 l~hich is known to induce platelet aggregation as de.scribed above). Further still, the inhibitory action of the imidazole com~ounds of this invention can be confirmed by ~.Z 3 ~ ~ ~

dctcrmination of the inllibi.tory effect on sudden dcatlls caused by arachidonic acid.
The imidazole compounds of this invcntion are characterized by the presellce of alkylene chain as ~n N-substituent of the imidazole skeleton, wh;ch consi.sts of 3 to20 carbon atoms and which has a functional group at the ~-position of the alkylene chain, selected from the group consisting of a carboxy gro-lp, a hy(lroxylncthyl group, an N-dl or -mono alkyl s~lbstituted or unsubstituted carbamoyl groul~, a cyano group ancl an N-di or -mono alkyl substituted or uns~lbstituted aminomethyl group.
In the present invention, the alkylene chaill can be a saturated or unsaturated straigllt alkylene chain having 3 to 20 carbon atoms.
In the imidazole compounds of this invention, the ccclrbon number of alkylene chain and the species of the func.tional groups at the ~-position of alkylene chain play an importallt role in providing the inhibitory effect. That is, in general, the potency of the inhibitory action for thromboxane synthetase becomes higher as the carbon number of alkylene chaill increases.
Suitable alkylenes are pentamethylene, heptamethylene, octa-methylene, nonamethylene, decametllylene and undecamethylene chains and these unsubstituted alkylene chains.
On the other hand, a carboxyl group, a hydroxyn~etllyl gTOUp, an N-di or -mono alkyl substitured or unsubstitutecl ~ 3 ~ ~ ~

c~rl-amoy~ gro~lp, a cyano ~roup and an N-di or -mono alkyl substitutcd or unsubstituted ami]lomcthyl group can bc employed in this invention as thc function~l group at tlle ~-position of alkylene chain. Of the function~l ~roups at the ~-position of s al~ylen~ chain, a carboxyl group, a hydroxymethyl group, an N-di or -mono alkyl substituted or unsubstituted carbamoyl group and a cyano group are preferred. In t]lis inventioll, a carboxyl group is the more preferable ~unctional group at the ~-position of the alkylene chain.
However, lower alkyl ester compounds of the above general formu]a ~I), i.e., N-(~-lo~er al~oxycarbonylalkyl)imidazoles or compounds carrying a methyl group as a functional gro~lp at the ~-position of the alkylene chain, i.e., N-alkylimidazoles, possess a significantly weaker inhibitory effect in comparison to the corresponding carboxylic acid compounds of the general formula (I) of this invention.
Preferred examples of the imidazole compounds of this invention include coml)o~ ds wherein the alkylene chaill has 5 to 11 carbon atoms and Y is a carboxyl group in the general formula tI). That is, N-(5-carboxypentyl)imidazole, N-~6-carboxyhexyl)imidazole, N-~7-carboxyheptyl)imidazole, N-~8-carboxyoctyl)imidazole, N ~9-carboxynonyl)imidazolel N-(10 carboxydecyl)imidazole, N-(ll-carboxyundecyl)imidazole and N-~7-carboxy-2-heptynyl)imidazole are preferred. More preferred examples of the imidazole compounds of ~his invention 3 ~

include the compounds wherein the a]kylenc C]la.ill has 6 to 9 carbon atoms and Y is a carboxyl group in the imidazole compounds of the general formula (I) That is, N-(6-carhoxy-hexyl)imidazole, N-~7-carbo~yheptyl)iloida2OIe, N-(8-carho~y-octyl)imidazole, N-(7-carboxy-2-heptynyl)imidazole and N-(9-carboxynonyl)imidazole are more preferred.
The imidazole compounds of thc general formula ~]) of this invention can be prepared by the following procedures.
Of the imidazole compou1lds of the general formu.la (I), for example, the compounds of the general form-lla ~Ia):

N N-alkylene-Yl (Ia) wherein Yl is a carboxyl group, a hydroxymetllyl group, an N-di or -mono alkyl substituted or unsubstituted c.arbamoyl groul~ or a cyano group, and the alkylene is a saturated or unsaturated straight alkylene cllain having 3 to 20 carboll atoms, can be prepared by reacting imidazole of the formula ~II):

N ~ ~1 (II) with a compound of the general formula ~III):

X-alkylene-lY (III) wherein X is an acid residual gTOUp, lY iS a carboxyl group, ~ 3 8 ~

an al~o~ycarl)ollyl ~roup, a C)-allO group, an acy]cxyll1et]ly]. group Ol an N-cli or -mono al~yl subst.ituted or unsubstitutc~l car~arllo)~l group, and the alk~lene has the same meaning as given abovc;
and thell opti.ollally }-ydrolyzing thc resulting product and/or red-lcillg tlle unsaturated al~ylene chain of the resul~ing product, On the otller l~alld, of thc imidazole compounds of the general for~ la ~I), thc compoul~ds of the general formula (Il):

~ ' .
N N-alkylene-Y2 (Ib) wherein Yz is an N-di or -mono alkyl substituted or ullsubsti~ut-ed amino]netllyl group and the all;ylene has the san~e meaning as defined above, can be prepared by reacting imida7.ol~ of the formllla (II):

N N~-l ~II) with a compound of the general formula (III'):

X-al~ylene-Wl (III') wherein Wl is a cyano group, or an N-di or -mono-alkyl substituted or unsubstituted carbamoyl group, and X and the alkylene have the same meaning as given above, to produce a com~ound of the gencral formula ~Ic!o 1~3.;~:3~

N N-alkylene-Wl (Ic) wherein IYl and ~he alkylene have the same meaning as given above, then hydrogenating the resulting compound and, optionally, reactillg the resulting compound with an alkyl halide to introduce the desircd N-alkyl group.
Tlle N-alkylation described above in the reaction of imidazole of the ormula (II) Wit]l a compound of the ger;eral formula (III) or (III') can be carried out according to well kno~n methods. That is, imidazole is dissolved in an inert organic solvent, e.g., benzene, tetrahydrofuran, dioxane, toluene, xylene, acetonitrile, N,N-dimethylformamide, ethanol, butanol, etc. Then a basic substance such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hyclroxide, aouium alkoxides, sodium h~dri~e, diisopropylethylamine, pyridine, tricthylamine, etc., in an e~uimolar amount to imidazole, is added to the solution, and the mixture is heated to about 20 to about 150C, preferably about 60 to 100C, for about 10 minutes to about 2 hours, preferably about 30 minutes to 1 hour Subsequently, the compound of the general formula tIII) or ~III') in a proportion of about 1 to 0.9 mol per mol of imidazole is added to the reaction mixture, the reaction mixture is heated to about 50 to about 150C, preferably about 60 to 120C, for about 10 minutes to 5 hours, preferably about

2 hours to 3 hours, and then the reaction product is

3~

concc~ ated uJlder reducecl l)ressure, the residue is recrystallizcd or distilled to obtain the desired product If dcsired, the resulting produc-t is hydrolyzed in an aqueolls solution of an acid or an alkali to obtain the objcct product.
In this process, instead of using the basic substance, thc reaction may be carried out by using imidazole i31 an excess amount, e.g., more than twice the molar amount of the compoulld of the general formula (IIJ) or (III') above. Tlle reaction can also be carried out in the absence o-E all inert orgallic solvent.
Furthermore, the above reaction can be carried out by reacting the compound of the general formula (III) or (III') with a silver salt of the imidazole instead of the imidazole.
The silver salt may be formed by reacting imidazole Wit}l ~
silver salt such as silver nitrate, etc The reaction can also be carried out in the presence oE a crown ether or a phase transfer cat~lyst such as tctrabutyl ammoniunl bromide, etc.
The above-mentioned hydrogenation o the compou3lcl oE
the general formula (Ic) can also be carried out according to well known methods, That is J the compound of the general formula (Ic) may be dissolved in an inert organic solvent, e.g., diethyl ether, tetrahydrofuran, benzene, toluene, xylene, etc., and an adequate amount of hydrogenating agent sucll as lithium aluminium hydride, e~c., is added to the solution, the mixture is stirred at room temperature or hea~ed to about - 10 - . .

~ ~ 3~

30 to abo-lt 100C, prefcrably a~ollt 50 to 100~, for about 3 -to ln hours, preferably about 5 to 8 hours Tl1en, the reaction mixture is treated in the usual manner. If desired, the rcsulting product is treated witl1 an alkyl halide in an iner~ organic solvent, e.g., henzene, dioxane, tetrahydrofuran, dieth~l etl]er, etc., and the object product can be obtained by rccrystalli~ation or distillation.
In this proccss, ~he compound ~herein Wl is a cyano group in the general formula ~Ic) can also be converted to the object product by catalytic hydrogenation in the prese11ce of a catalyst such as palladium-charcoal, platinum dioxide, etc , under hydrogen gas-atmosphere.
In the process of this invention, the imidazole usecl as starting material is well known and can easily be prepared according to methods disclosed in the literature. The compounds of the general ormula ~III) and (III') are also known compounds and can also easily be ~repared according to methods disclosed in tl1e literature. In the compounds of the general formula ~III) and (III')~ halogen atoms and acid residual groups formed from organic sulfonic acids, i.e., an arylsulfonyloxy and alkylsulfonyloxy group, can be employed for the process of this invention as an acid residual group.
In this in~ention, examples of the compounds of the general formula (III) or ~III') include straight chain saturated alkylenes having 3 to Z0 carbon atoms, which ha~e a ~ 3 ~L~

fullct;onal ~rou~ selected -from a carboxyl grollp, all alkoxy-carbollyl group, an acyloxymetllyl group, an N-di or -mono alkyl substitutccl or unsuhstituted carbamoyl group and a cyano gro~lp at the l-position o~ alkylene, and wllicll have an acid rcsidual group at the ~-position Oll the opposite end of the alkylclle chain. Preferred examples of ~.hese compounds include 6-l>romo-hexanoic acid, 7-bromoheptflnoic acid, 8-bromooctanoi.c acicl, ~-bromonollanoic acid, 10-bromodecanoic acid, ll-bromo-lllde~calloic acid, 12-bromododecanoic acid and alkyl esters of these acids, 10 6-bromohexanellitrile, 7-bromo]leptanenitrile, 8-bromooctalle-nitrile, 9-bromononanenitri~.e, 10-bromodecanenitrile, ll-bromo-undecanenitrile, 12-bromododecanenitrile, 6-hromohexaneamide, 7- bromoheptaneamide, S-bromooctaneamide, 9-bromononaneamide~
10-bromodecaneamide, ll-bromoundecaneamide, 12-bromododecane-amide and N-di or -mono alkyl substituted amides o~ these amides, l-acetoxy-6-bromohexane, 1-acetoxy-7-bromolleptanc, l-acetoxy-8-brolllooctane, 1-acctoxy-9-bromononane, l-acetoxy-10-bromodecane, l-acetoxy-ll-bromoundecane, 1-acetoxy-12-bromo-dodecane, 7-bromo-6-heptanoic acid, 7-bromo-2-heptynoic acid, 7-bromo-2-heptenoic acid, 7-bromo-6-heptynoic acid and lo~er alkyl esters of these acids, etc.
Of imidazole compounds of the general formula (I), the compounds of the general formula:

N N-alkylene-COO~I ~I.d) ~.Z3~

wllerein tlle alkylene has tl~e sallle meanillg as given above, can be prepared b)~ hyclrolyzing the compoun~ of the ~eneral formula (Ic) In this case, the hyclrolysis can be carried out by heating ~o about 8noc to about 100C for l to 30 hours, pre-ferably 3 to ln hours, in an agueous solu~ion of an acid, e g., hy~rochloric acid, sulfuric acid, acetic acid, a mixture thereof, or a base, e.g , sodium hydroxide, etc.
The compou2ld of tlle gelleral formula ~Id) above can also be prepared by reacting the compound of the general formula:

N\_ ~N-~C~l2)m -CIIO ~IV~

wherein ml is an integer of 1 to 18; with a compound o the general formula;

Ph3 - P - C~12 - ~ C112 ) m - COORl (V) wherein Ph is a phenyl group, Rl is a hydrogen atom or an alkyl group, Z is a halogen atom, m2 is an integer of zero to 18, with the proviso that ml plus m2 equals an integer not more than 20, or a compound of ~he general formula:

~R20)2-P-Cl-l2COOR3 ~VI) O

wherein R2 and R3, whicll ma~ be the same or different, each is ~3.Z3~

an alkyl grollp; then, optionally, hydrolyzing and/or re(lllcillg the resulting compou]ld to form a compound of thc gencral formula:

~ I I
N N-(Cll2)1o -C~ C~ Cll2)m2 ~ld') ~-herein R? and r~8 are hy(lrogcn atoms or, when takeTl together, they rorm another chemical bond, and ml and m2 have the samc meàning as given above Tlle abo~c Witting reaction hetwee the compounds of the formula ~IV) and the compound oC the formula ~V) or ~V') can be carried out, for example, by a process whcrein a compoulld of the general formllla ~IV) ls reacted in an inert organic solvent SUC]l as cliethyl ether, tetrahydrofuran, dioxane, ben7ene, ~oluene, xylenc, hexane, dimethylsulfoxide, methylene chloriclc, ch]oroform, methanol and ethanol with a compound of the gelleral formula (~) or (V') ]5 at about 0 to about 100C, preferably at room tcmperatllre to 80C. The reduction of the rcsulting product can bc carrie~
out hy using a catalyst such as platinum dioxide~ palladium-charcoal, etc., under hydrogen gas-atmosphere The compounds of the general formllla (~') and ~Y') are kno~n or unkno~n, and can be prepared according to methods disclosed in the l;terature. The compounds of a general formula (IV~ can be prepared by hydrogenating a compound of the general formula:

- 1~ -.23~1 .~ C
~ ~ ( l2)~ OOR (VI) hereill ml has the same n~aning as ~ivcn abovc, R4 is an alkyl group, in all inert ogranic solvent, e.g., diethyl cther, te~rahydrorurall~ dio~arle, Ienzene, etc., using isobutyl a~uJni hydride. In this case, the compounds of the general formula (VI) used ~s starting materials, can be easily prcpared accord-ing to the ahove N-alkylation of the compound of tl~e ~eneral formula (II) with the compound of the general formula (III) Further77l0re, the compo-lnds of the genera~ formula (Id) ca7l bc prepared by reacting the compound of the general formula C7l2-CH-(CH2)m -CooR5 (VII) ~herein m3 is an integer of 1 to 18 and R5 is an alkyl ~roup, with imidazole of the formula ~II) at room temperature for about 5 to 30 hours, preferably 10 to 20 hours, in the lS presence o~ alumina in an amount of 3 to 30 times, preferably 3 to 10 times as much as the amount of imidazole of the formula (II), to produce the compound of the general formula:

~" 5 N N-cH2-cl~-(c~l2)m -COOR (VIII) 0~1 , wherein R5 and m3 have the same mean:i7lg as given ahove, then .23 . 16 -ha]ogenati~1~ thc res11]ti11g compou1ld Wit}l a halogcnati1lg agcnt sucl1 as thid1lyl chloride, h~rogenating the halogcnated roduct Wit]l a cat~lyst such as Raney nickel, and then hydrolyz-ing the res1llting compound to obtain the desired product.
In this case, the compounds of the general formula (VII) can be prepared by oxidizing a compou11d of the general Eormula;

C112=CH-(C}12)n~ -COOR ~IX) wherein R5 and m3 have the same maning as given above, with a ~ero~idc such as m-c11loroper~enzoic acid, etc " for about l ln hour to ahout lO hours, preferred 3 to 8 hours, ln an inert organic sol~ent, e.g., methy]enc chloride, at room temperature The compounds of the general formula (IX) are known and can be prepared to methods disclosed in the literature.
Of imidazole compounds of the general form la fI) of lS this invention, the compounds of the general formula:

N N-alkyle1le-C~120~1 (Ie) wherein alkylene has the same meaning as given above, can be preparcd by hydrogenating the compound of the general formula;

N N-alkylene-COOR6 (VI') \J

~.2 ~ ~ 4 1 whcreill R6 is an alkyl gro~lp, with a reducing agerlt such as lithillm alumin-lm hy~lride and the like in an inert organic solvent, c.g., diethyl ether, dioxane, tetrahydrofuran, toluellc, xylene, etc., at about room temperature to about 100C, prefcrably at room temperature to 80C, for about 1 hour to about 10 hOllrS, prcferably 3 to 8 hours Of imidazole compounds of the general formula (I) of this invention, the compounds of the gcneral formula:

N N-alkylenc-CN (If) \=J
wherein the alk~lene has the same meaning as giVCIl above, Call be prepared by heating a compound of the general formula:

N N-B-Cll2O~I ~Ie') \=/
wherein B is a saturated or unsaturated straight alkylene chain having 2 to 19 carbon atoms, Wit}l a halogenatillg agcnt lS such as thionyl chloride in the presence or absencc of an inert organic solvent, e.g., benzene, chloroform, dioxane~
tetrahydrofuran, toluene, xylene, etc. 9 to about 40 to about 100C, preferably 50 to 80C, then reacting the halogenated product with a cyanating agent such as sodium cyanide9 etc.S
for about 3 to 20 hours, preferably 5 to 10 hours, while heating to about 50 to 100C, preferably 80 to 100C, in an ~.z31~

- 1~

inert solvent, e.g , d-imetllv]-Forma111ic1e~acetonc, an alcohol, etc Furthermore, of imidazole compou1lds of the gencral formula ~I) of the presel;t i21velltioll, the con1pol1nds of the general formula:

N N-al~ylene-CON (Ig) ~J \Rl wherein the alkylene has thc same meaning as given above, ancl R9 and Rl0, which may be the same or different, cach is a hydrogen atom or an alkyl group, can be prepared by reacting the compound of the general formula tId) above, or ~ reactive functional derivative tllereof in the presence or absence of a condensing agent such as phosphorous oxychloride, witl1 a cv...pound of the general for1r.ul~:

N11 R9 (VII) \R10 wherein R9 and Rl0 have the same meaning as given above, in the presence or absence of an inert organic solvent, e.g., benzene~ toluene, xylene, chloroform, methylene chloride, dioxane, tetrahydrofuran, dimethylformamide, water or a mixture thereof, in the presence or absence of a basic substance, e.g., triethylamine, pyridille, sodium carbonate, 3~ ~

potassi~ carbonate, at room temperature or while heating at reflux for about 1 to 6 l~ours, pre-ferably 3 to 5 hours. I]l this case, reactive Eunctional derivatives o r the compound of the general form-lla (Id) include ~cid halides mixed acid S anhydrides, acid anhydrides, esters and reaction products of such compounds and carbodiimides. Tllese reactive functional derivatives can easily be derived from the compound of the gener~l formula (Id) according to a usual techni~ue kno~n in this art. For example, the acid chloTide can be obtained by refluxing for several hours the compound (Id) with thionyl chloride in the absence of ~lny solvent or in dry benzene.
The mixed acid anhydride can be obtained by reacting Wit}l a chloroformic ester.. The compound of the general formula (Ig) can be prepared by hydrolyzing ~he compound of the general formula (I~) in an aqueous solution of an acidJe.g., hydro-chloric acid, sulfuric acid, acetic acid, etc., a Lewis acid, titanium tetrach1Oride, etc , or a base, e g., sodiulll hydro~ide, potassium hydroxide, for about 3 to about 2U hours, preEerably S to 10 hours, while heating about 40 to about 50C, and then, optionally, N-al~ylating the resulting product with an alkyl~halide.
Of imidazole compounds of the general formula (I) of this invention, the compound (Ib) above can also be preyared by halogenating the compound (Ie) above with a halogenatillg agent such as thionyl chloricae in the presence or a~sellce of -~-3.23~

an incr~ organic sol~ent ~hile heating to akout 50 to ~0~
for se~cral hours, preferahly 2 to 4 hours, and then reacting thc haloge~ tec1 com1~ound ~.~ith thc com1ound of the gencral ~ormula ~VII) in an incrt or~a11ic solvent, e.g , an alcohol, xylenc, tolucne, d;oxane, tetrahydrofuran and the likc for several hours, pl-eferably 3 to 6 ho~lrs ~ 13e compounds of the general formula ~I) of this invcntio3l havin~ a free carboxyl group or a free amino group can be converted according to us~lal met11ods to phar1naceutically acceptable salts thcreof. For example, the free-form compou1ld oE the ge1lcral for1llula ~I) is dissolvccl in solvent, e.g , an alcoho~ ater, etc., an ade~uate amowlt o hydrochloric acid or sodium hydro~ide is added to the solution, the mixture is stirred at room temperature or IYarmed for adequate period of time, the solvent is then distilled away, and the residue is recrystallized to obtain the salt o compound of the general formula tI). ~s examples of such pharmaceutically acceptable acid actdition salts, in ad~lition to the hydroclllorlc acid salt~ there are the hydrobromic acid salt, the sulfuric acid salt, the nitric acid salt, the phosphoric acid salt, the sulfonic acid salt, the henzoic acid salt, the succinic acid salt, the tartaric acid salt, the citric acid salt, etc On the other hand, as examples of such pharmaceutically accept-able base addition salts, in addition to the sodium salt, there are the potassium salt, the calcium salt, the ma~nesium 3~1 salt, etc.
In the c~se of the salts of the compounds of the general formula ~I), the salt form of thc compounds can be convelted according to usual methods to the free form Or the compound thercof. ~or example, the salt orm of tl~e compound of the general formula (I) is dissolved ;n l~ater, then an adequate amount of hyclrochloric acid or sodium hydro~ide is added to solution, and the mixture is stirrcd at room temrera-ture for an ade~uate period of time, water is removed, and the residue is distillecl under recluced press~lre or recrystalli~ed frorn an adequate solvent to obtain the dcsired comrouncl Acid or base addition salts of the compounds of this invention have as high an inhibitory effect on thro]nboxane synthetase as the corresponding compounds having a free amino lS group or an acid group.
The imidazole compounds of this invention possess a strong inhibitory effect on thromboxane synthetase, and arc useful as therapeutically active agents ~or inflammatioll, hypertension, thrombus, cerebral apople~y and asthma.
The imidazole compounds of the general formula (I) and the pharmaceutically acceptable salts thereo of the present invention can be administered to mammals including humans by oral, intravenous, intramuscular or intrarectal administration, and for administration they can be form-11ated int,o pharma-ceutical compositions together with conventional pharlnacelltic-ally acceptable carriers.

~.238'~

Tlle compoun~s can be administered in various forlns according to the purposed therapy Typical dossge forms wllich can be used are tablets, pills, powders, ]iquid preparatiolls, suspensions, emulsions, granules, capsules, suppositories and injectable preparatiolls In molding the pharmaceutical composition into a tablet form, a wide variety of conventional carriers known in this art can be used. Examples of suitable carriers are excilients, such as glucose, lactose, starch, cacao butter, harclened vegetable oils, kaolin and talc, binders, such as gum arabic powder, tragacanth powder, and ethanol, and disintegrants, 5UC}I
as laminaria and agar. The tab1ets, if desired, can be coated and made into sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, or tablets coated with two or more layers.
When the pharmaceutical composition is :Formulated into an injectable preparation, the resultillg solution and suspen-sion are preferably sterilized, and are isotonic Wit}l respect to the blood In formulating the pharmaceutical composition into the form oE a solution or suspension, all diluents customarily used in the art can be used Examples of suitable diluents are water, ethyl alcohol, pTopylene glycol, ethoxylate isostearyl alcohol, polyoxyethylene sorbitol, ancl sorbitan esters Sodium chloride, glucose or glycerol may be incorporated into a therapeutic agent in an amount sufficient IL~.Z3~

to prcpare an isotonic solution. The therapeutic agel-lt may further contain ordinary dissolving aids, ~uffers, pain-alleviaiillg agcnts, and preservatives, and optionally, coloring age]lts, perfumes, flavors, sweeteners, and other drugs.
The closage of the compound of this invention is about 1 mg to 1,000 mg/body oral, or about 0,1 mg to 100 mg/body injected per day in multiple doses depellding UpOII the disease wllich is being treated.
~0 This invention is furt]ler illustrated in more detail by way of the followillg Reference Examples and Examples wherein the melting point or the boiling point of the pro~tuct obtailled are uncorrected. Unless otherwise indicated, all parts, percents, ratios and the like are by weight, ~3.'~3~

RE~FERENCE EX~MPLE I
Method A: 1-(7-Methoxycarbonylheptyl)imidazole To a suspension of 4.6`g of sodium hydride (9.2 ~ of 50 ~ sodium hydride was washed with petroleum e-ther to remove the mineral oil) in 400 ml oE dry N,N-dimethylformamide was added 13 g of imidazole at room temperature, and then the mixture was heated to 90C.
A solution of 43 g of methyl 8-bromooctanoate in 50 ml of dry N,N-dimethylformamide was added to the mixture at 90C
over a period of 1 hr., and then the reaction mixture was heated at 90C for 1 hour.
After concentration under reduced pressure, S00 ml of ether was added to the residual oil and washed with water and dried over magnesium sulfate.
The solvent was evaporated and the residual oil was distilled under vacuum (165-170C/1 mmHg) to give 32 g of 1-(7-methoxycarbonylheptyl)imidazole as a pale yellow oil;
IR-absorption spectrum (neat) vCH: 3100 cm vCO: 1730 cm 1 NMR spectrum (CDC13) 2.0 (m,lOH), 2.29(t,2H), 3.64(s,3H), 3.92(t,2H), 6.87(t,lH), 6.98(br-s,lH), and 7.40(br-s,lH).
Elemental analysis as C12H20O2N2 C (%) H (~) N (%) Calcd. 64.25 8.99 12.49 Found 64.12 9.02 14.37 Method B: 1-(8-Methoxycarbonyloctyl)imidazole To a suspension of 0. 21 g of 60 % sodium hydride (dispersed in mineral oil) in 20 ml of dry N,N-dimethyl-formamide was added 0.4 g of imidazole at room temperature, and then the mixture was heated to 90C.
A solution of 1.7 g of methyl 9-tosyloxynonanoate in S ml of dry N,N-dimethylformamide was added to the mixture 3~

at 90C over a period of 20 min., and the reaction mixture was stirred at 90C for 30 min.
After removal of N,N-dimethylformamide under reduced pressure, 100 ml of ether w~s added to the residue and the ether solution was washed with water and dried over magnesium sulfate.
The solvent was evaporated and the residual oil was chromatographed on silica gel using chloroform-methanol (25:1) to give 1.0 g (88 %) of 1-(8-methoxycarbonyloctyl) imidazole as a colorless oil;
IR-absorption spectrum (neat) vCH: 3100 cm vCO: 1730 cm NMR spectrum (cncl3) l.l-l.9(m,12H), 2.31(t,2H), 3.65(s,3H), 3.93(t,2H), 6.89(t,lH), 7.02(br-s,lH), and 7.45(br-s,lH).
Elemental analysis as C13H22O2N2 C (~) H (%) N (%) Calcd. 65.51 9.31 11.76 Found 65.38 9.20 11.84 Method C: 1-(6-Ethoxycarbonylhexyl)imidazole A solution of 2.87 g ~2 equivalents) o~ imidazole and 5.0 g (1 equivalent) of ethyl 7-bromoheptanoate in 10 ml of N,N-dimethylformamide was heated at 150C for 6.5 hr.
After cooling, 50 ml of chloroform was added to the reaction mixture and the chloroform solution was washed with water and dried over magnesium sulfate.
The solvent was evaporated under reduced pressure and the residual oil was distilled under vacuum (142-145C/l mm~g) to give 3.2 g (68 %) o~ 1-(6-ethoxycarbonylhexyl) imidazole as a colorless oil;
IR-absorption spectrum (neat) VCH: 3100 cm vCO: 1735 cm 1 ~r ~ Z 3 . NMn ~pec-t~lm (~1~`13) 1.?-1.9(m,~i~), 1 23(t,311~, 2.2~(t,2H), ~.92(t,2 ~ .ll(q,2H), 6.85(t91E~), 7.00(t,111), and 7.~0(~
Elernental analyqis as C12ll 0~22 C (%) H (%) N (~) Calcd. 64.25 8.99 12.~9 Found 64.02 9.24 12.49 Method D: 1-(6-~thoxycarbonylhexyl)imidazole A mixture of 1.44 g (2 equivalents) of imidazole and 2,5 g (1 equivalent) o~ ethyl 7-bromoheptanoate was heated at 150~C for 6 hr.
After cooling~ 50 ml of chloroform waq added to the reaction mixture and the solution was washed with wat~r and dried over ma~ne~ium sulfate.
~ he 301vent was evaporated and the residual oil wa~
distilled under vacuum to give 1.35 g (56 %) of 1-(6-ethoxycarbonylhexyl)imidazole as the ~ame product in method C.

Method ~ (7-Methoxycarbonylheptyl)imidazole A solution of 0.8~,g of im.idazole, 3.0 g of methyl 8-bromooctanoatQ, and 0.15 g of tetra-n-butylammonium bxomide (phase transfer catalyst) in 30 ml of benzene and 30 ml of 50 % sodium hydroxide aqueous was ~igorously stlrred at room temperature for 6 hr.
The organic pha~e was then separated and wa~hed with water and dricd over magnesium s~llfate.
The sol~ent was evaporated and the residual oil was chromatographed on silica gel u~ing dichloromethane to give 1.~ g o~ 1-(7-methoxycarbonylheptyl)imidazole a~ the ~ame product in method A.

~L ~, ;Z 3 ~3 L~ 1 (,!

Method_F: l~(10-i~ethox~ycarbonyldccyl)imidazole A solutlon of 11~3 g of m-c}lloroperbenzolc acid in 150 ml of dichloromethane was added to a solutlon of lO.Og of methyl 10-undecylenat~ in 100 ml of dichlorome-thane at O C over a period of 30 min., and the solutlon wa~ then stlrred at room temperature for 6 hr.
The reaction mixture was washed with ~aturated sodium thiosulfate (until the iodo-starch paper was no longer colored), 5 ~ sodium bicarbonate, and water.
After drying over magnes1um sulfate and evaporation under reduced pressure, the reqidual oil was distilled under vacuum (116-118C/2 mmHg) to give 8.26 g (77 %) of methyl 10~ epoxyundecylate as a colorless oil~
IR-absorption ~pectrum (neat) ~ CO 1735-1 NMR spectrum (CDC13) l.l-l.9(m,14H), 2.2-3.0(m,5H) 9 and 3.6?(s,3H).
~ o a suspension of 17.5 g of aluminum oxide (W-200N) ~n 300 ml of dry ether was added 5.1 g of imidazole at room temperature ~nd stirred for 40 min. ~he epoxide, 5.35 g, wa~ then added to the suspension and the mlxture was stirred at room temperature for 1 hr. The reaction mixture was diluted with 200 ml of meth~lol and filtered, ~nd the aluminum oxide was wa~hed with 200 ml of methanol.
~ he filtrate and washings were combined and evaporated under reduced pressure.
~ he residue was chromatographed on silica gel using chloroform-methanol t50:1) to give 4.2 ~ (60 %) of 1-(2-hydroxy-10-methoxycarbonyldecyl)imidazole as colorless plates; M.P. 60-62~C;
IR-absorption spectrum (KBr) OH: 3220 cm 1 CH: 3120 cm~
~ CO: 1730 cm~l NMR spectrum (CDC13) ~ 1.1-l.9(m,14H)l 2.29(t,2H), 3.62(s,3H), 3.65-4.1~m,3H)~

4,47(s,lH), 6~87(m,2H), and 7.33(br-s,lH).
~ wo ml of thionyl chloride was added to a sol~ltion of 1.0 g of 1-(2-hydroxy-10-methoxycarbonyldecyl)imidazole in .. . . . . . . . ..

30 ml of dry chloroform at 0 C and stirred at room temperature for 30 min., in addition, the reaction mixture was refluxed for 30 min.
After concentration under reduced pressure, the residue was dissolved in 50 ml of benzene and washed with

5 % sodium bicarbonate and water, and dried over magnesium sulfate.
The solvent was evaporated and the residual oil was chromatographed on silica gel using chloroform-methanol (50:1) to give 880 mg (85 %~ of 1-(2-chloro-10-methoxy-carbonyldecyl)imidazole as a colorless oil;
IR-absorption spectrum (neat) ~CH: 3100 cm vCO: 1730 cm 1 NMR spectrum (CDC13) 1.1-1.85(m,14H), 2.30(t,2H), 3.64(s,3H), 3.9-4.25(m,3H),

6.95(t,lH), 7.04(br-s,lH), and 7.50(br-s,lH).
A solution of 660 mg of the chloride in 50 ml of methanol was hydrogenated using 2 g (wet weight) of Raney-nic~el(W-2) in the presence of 1 ml of triethylamine under atmospheric pressure for a day.
The catalyst was removed by filtration and the filtrate was evaporated under reduced pressure.
The residue was chromatographed on silica gel using chloroform to give 400 mg of l-(10-methoxycarbonyldecyl) imida-zole as coloxless needles; M.P. 39.5-40C (ether-n-hexane) IR-absorption spectrum (neat) ~CH: 3100 cm vCO: 1735 cm NMR spectrum (CDC13) 1.15-1.85(m,16H), 2.30(t,2H), 3.65(s,3H), 3.91(t,2Hj r 6.85(t,lH), 7.00(br-s,l~l), and 7.41(br-s,lH).
Elemental Analysis as ClSH2602N2 C (%) H (%) N (%~
Calcd. 67.63 9.84 10.52 Found 67.89 9.85 10.47 3~

Method G: 1-(6-Ethoxycarbonylhexyl)imidazole A suspension of 1.4~ q of silver salt of imidazole, which was prepared Erom imidazole and silver nitrate in a sodium hydroxide solution, and 2.0 g of ethyl 7-bromo-heptanoate in 50 ml of N,N-dimethylEormamide was heated at 100C ~or 7 hr.
After removal o~ the solvent, 30 ml of dichloromethane and 30 ml of water was added to the residue and the organic phase was separated.
The dichloromethane solution was dried over magnesium sulfate and the residual oil was distilled under vacuum to give 0.76 g (40 ~) of 1-(6-ethoxycarbonylhe~yl)imidazole as the same product in method C.

Me~hod H: (E)-1-(7-Ethoxycarbonyl-6-heptenyl)imidazole To a solution of 2.5 g of 1-(5-ethoxycarbonylpentyl) imidazole, which was prepared by the method A, in 120 ml of dry toluene was added a solution of 8.8 ml of 25 % (W/V) di-isobutyl aluminum hydride in toluene at -70C under nitrogen atmosphere and the solution was stirred at the same temperature for 30 min.
One ml of methanol was then added to the solution at -70C, and the solution was warmed to 0C and 1 ml of water was added.
After stirrin~ at 30C for 1 hr, the mixture was filtered and the filtrate was dried over magnesium sulfate.
The solvent was evaporated under reduced pressure and the residue was chromatographed on silica ~el usin~ chloroform-methanol (25:1) to ~ive 1.15 g of 1-t5-formylpentyl)imidazole as a colorless oil;
IR-absorption spectrum (neat) vCH: 3120 cm vCO: 1730 cm 1 NMR spectrum (CDC13) 1.0-2.05(m,6H), 2.40(t,2H), 3.86(t,2H), 6.77(m,1H), 6.90(m,lH), 7.30~m,lH), and 9.~5(t,lH).
Mass spectrum m/e 165(M-1), 138, 111, 82(base peak), 81, 69, 55, and 54 ~3.'~3~
To a stirred suspension of 120 mg of 63.5 % sodium hydride in 20 ml of dry tetrahydrofuran was added 780 ~g of diethyl ethoxycarbonylmethylphosphonate at room temperature under nitro~en atmosphere and then the mixture was stirred for 15 min.
A solution of 480 mg of 1-(5-Eormylpentyl)imidazole in 5 ml of dry tetrahydroEuran was added to the mix-ture a-t room temperatur~ and the mix.ure was stirred for 1 hr.
The mixture was then treated with saturated ammonium chloride and concentrated under reduced pressure.
The residue was dissolved in 50 ml of ethyl acetate and washed with saturated sodium bicarbonate and saturated sodium chloride, and dried over magnesium sulfate.
After evaporation under reduced pressure, the residue was chromatographed on silica gel using chloroform-methanol (100:3) to give 540 mg of (E)-1-(7-ethoxycarbonyl-6-heptenyl?
imidazole as a colorless oil;
IR-absorption spectrum (neat) vCO : 1720 cm vC=C: 1655 cm 1 NMR spectrum (CDC13) 1.2-2.4(m,8H),1.25(t,3H),3.84(t,2H),4.16(q,2H),5.71(dt,1H), 6.74(m,lH),6.78(dt,lH),6.91(m,lH),and 7.33(s,lH).
Mass spectrum m/e 236(M ), 191, 123, 110, 109, 82(base peak), 81, 69 and 55 Method I: 1-(7-Ethoxycarbonylheptyl)imidazole A solution of 400 mg of (E)-1-(7-ethoxycarbonyl-6-heptenyl)imidazole, which was prepared by the method H, in 50ml of ethanol was hydro~enated over 50 m~ oE platin~lm dioxide under atmospheric pressure to qive 1-(7-ethoxycarbonylheptyl) imidazole in a quantitative yield as a colorless oil;
IR-absorption spectrum (neat) ~CH: 3100 cm 1 vcO: 1730 cm NMR spectrum (CDC13) 1.2-1.95(m,10H), 1.22(t,3H), 2.27(t,2H), 3.90(t,2H~, 4.10(q,2H), 6.82(t,1H), 6.98(t,1H), and 7.39(s,1H).

Elemental analysis as C13~l2202N2 C (~) H (%) N (%) Calcd. 65.51 9.~1 - 11.76 Found 65,77 9.58 11.88 Method J: 1-(7-Methoxycarbonyl-2-heptynyl)imida201e To a 3uspension of 280 mg of 63.5 % ~sodiu~,hydride (disper~ed in mineral oil) in 20 ml of dry N,N-dimethyl-formamide was added 501 mg of imidazole at room temperature under nltrogen atmosphere, and then the mixture was heated to llOnC. A solution of 1.55 g of methyl 8-bromo-6-octynoate in 1 ml of dry N,N-dimethyl~ormamide was added to the mixture at llO~C over a period of 30 min., furthermore, the reaction mixture was heated at 100 C for 1 hr.
After evaporation of N,N-dimethylformamide under reducecl pressure, 50 ml of ether was added to the residual oil and the ether solùtion was washed ~/ith water and dried over magnesium 3ulfate.
~ he solvent was evaporated under reduced pressure and residual oil was chromatographed on silica gel using chloroform ~o give 475 mg of 1-(7-methoxycarbonyl-2-heptynyl)imida~ole as a colorless oil.
IR-absorption spectrum (neat) CH :3130 cm 1 C0C:2250 cm~l ~ C-0:1740 cm 1 NMR spectrum (CDC13) 1.4-1.95(m,4H), 2.1-2.5(m,4H), 3.68(s,3H), 4.7~t,2H),

7.03(m,lH), 7.07(m,1H), and 7.59(m,lH).
Mas~ spectrum m~e 220(M+), 219,189, 161, 133, 119~ 79, 77~ and 69(base peak) Metllod Y~ thoY.~c aI bonyl-2-i~eI~ tenyl )imidclzole A solution of 220 m~ of 1-('7-m~thoxyc~r~onyl-2-heptynyl) lmidazole~which was prep~ ed by the method J~in 6 ml of methanol wa~ ~lydrogenated u~i.ng 16 mg of 5 ~ palladiur~-on-barivln sulfate and 15 m~ o~ quirloli.ne at room tem~erature under atmospheric pressure, until one equivalent of hydrogen having been taken up, the catalyst was removed by filtration and the filtrate was concentrated under re-duced pressure.
The residual oil was chromatographed on silica gel using chloroform to give 192 mg of (Z)-1-(7-methoxycarbonyl 2-hept~nyl)imidazole as a ~olorless oil.
IR-absorption spectrum (neat) CH: 3125 cm 1 ~ CQ: 1740 cm 1 N~1R spectrum (C~13) 1.2-l.9(m,4H), 2.0-2.5(m,4H), 3.68(s,3H), 4.57(d,2H), 5.4-5.9(m,211), 6.91(m,1~), 7.05~m,1H), and 7.48(m,1H)~
Mas~ s~ectrum m/e 222(M )9 191, 154, 81, 80, and 69(base peak) ~ he following compounds were prepared in similar manners:

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EXP~lPL~ 1 Method A: 1-(6-~lydroxyhexyl)imidazole To a suspension of 4.8 g of 50 ~ sodium hydride ~dispersed in mineral oil) in 150 ml of dry N,N-dimethyl-formamide was added slowly 6.8 ~ o~ imidazole a-t room temperature.
The mixture was then heated to 100C and 22.5 g of 1-acetoxy-6-bromohexane was added to the mixture at 100C over a period of 30 min., and the reaction mixture was further heated at 100C for 30 min.
10 After evaporation of N,N-dimethylformamide under reduced pressure, the residual oil was stirred with 40 ml of 10 %
sodium hydroxide at 70 C for 30 min.
Tne solution was concentrated under reduced pressure and the residue was dissolved in dichloromethane. The insoluble solid was filtered off and dried over magnesium sulfate.
After removal of dichloromethane, the residual oil was distilled under vacuum (169-170C/0.5 mm~lg) to give 12.0 g of l-(6-hydroxyhexyl)imidazole as a colorless oil;
IR-absorption spectrum (neat) 20 VOH: 3240 cm vCH: 3100 cm NMR spectrum ~CDC13~
1.2-1.95(m,8H), 3.60(t,2H), 3.84(s,lH), 3.92(t,2H), 6.85(t,1H), 6.97(br-s,lH), and 7.40(s,1H).
Elemental analysis as CgH16ON2 C (~) H (~) N (%) Calcd. 64.25 9.59 16.65 Found 64.32 9.39 16.42 Method B: 1-(7-Hydroxyheptyl)imidazole To a suspension of 3.4 g of lithium aluminum hydride in 100 ml of dry tetrahydrofuran was added slowly 14.0 g of 1-(6-ethoxycarbonylhexyl)imidazole, which was prepared by the method C in reference example 1, at room temperature, and then the mixture was refluxed for 2 hr.

~ ~ 3 ~ ~

After cooling, the mixture was treated with 10 % sodium hydroxide and filtered.
The filtrate was dried over magnesium sulEate and evaporated.
The residual oil was distilled under vacuum (159-162C/lmmHg) to give 7.0 g (86 %) of 1-t7-hydroxyheptyl) imidazole as a colorless oil;
IR-absorption spectrum (neat) vOH: 3250 cm NMR spectrum (CDC13) 1.15-l.90(m,lOH), 3.17(br-s,lH), 3.62(t,2H), 3.91(t,2H), 6.85(br-s,lH), 6.98(br-s,lH), and 7.40(s,lH).
Elemental analysis as CloH180N2 C (%) H (%) N (%) Calcd. 65.89 9.96 15.37 Found 65.97 10.24 15.32 The following compounds were prepared in similar manners:

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EXAMP~E 2:
ethod A: 1-(4-Cyanobutyl)imidazole A mixture of 10.4 ~ of imidazole, 18.0 g. of 5-chloro-valeronitrile, and 25.4 g of anhydrous potassium carbona-te in 200 ml of xylene was refluxed for 4 hr.
After cooling, the reaction mixture was fil-tered and evaporated under reduced pressure.
The residual oil was distilled under vacuum (172-173C/2mmHg) to give 11.6 g of 1-(4-cyanobutyl)imidazole as a colorless oil;
IR-absorption spectrum (neat) vCH: 3100 cm vCN: 2~40 cm NMR spectrum (CDC13) 1.5-2.2(m,4H), 2.38(t,2H), 4.02(t,2H), 6.91(t,1H), 7.04(br-s,lH), and 7.46(s,lH).
Elemental analysis as C8HllN3 C (~) H (~) N (~) Calcd. 64.40 7.~3 28.17 Found 64.27 7.65 28.04 Method B: 1-(6-Cyanohexyl)imidazole To a solution of 9.4 g of 1-(6-hydroxyhexyl)imidazole, which was prepared by the method A in example 1, in 150 ml of dry benzene was added 18 g of thionyl chloride at room temperature over a period of 20 min.
The mixture was then refluxed for 2 hr. and evaporated under reduced pressure, the residual oil was neutralized with saturated sodium carbonate and extracted with chloroform.
The chloroform solution was dried over magnesiurn sul-fate and evaporated under reduced pressure to give 9.5 g of 1-(6-chlorohexyl)imidazole as a pale brown oil;
IR-absorption spectrurn (neat) vCH: 3100 cm .23~

NMR spectrum (CDC13) 1.2~2.0(m,8H), 3.50(t,2H), 3~92(t,2H), 6.87(br-s,lll), 7.02(br-s,lH), and 7.43(br-s,lH).
Then a solution of 9.5 g oE the chloride in 10 ml of dimethyl sulfoxide was added to a s-tirred solution of 3.3 g of sodium cyanide in 50 ml of climethyl sulfoxide a-t 40C over a period of 20 min., and the reac-tion mixture was heated at 100C for 5 hr.
After the solvent was distilled away under vacuum, the residue was diluted with 50 ml of water, extracted wi-th dichloromethane, and dried over magnesium sulfate.
The extract was evaporated and the residual oil was filtered through a short column of silica gel using dichloro-methane, following the eluate was distilled under vacuum (176-177C/0.5mmHg) to give 8.0 g of 1-(6-cyanohexyl)imidazole as a colorless oil;
IR-absorption spectrum (neat) vCH: 3100 cm vCN: 2240 cm NMR spectrum (CDC13) 1.1-2.0(m,8H), 2.33(t,2H), 3.94(t,2H), 6.85(t,1H), 7.00tt,1H), and 7.40(s,1H).
Elemental analysis as CloH15N3 C (%) H (%) N (%) Calcd. 64.25 9.59 16.65 Found 64.32 9.39 16.42 The following compounds were prepared in si~ilar manners:

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EXAMPLE 3:
Method A: 1-(7-Carboxyheptyl)imidazole hydrochloride A solution of 10.0 g of 1-(7-methoxycarbonylheptyl) imidazole, which was prepared by the method A in reference example 1, was stirred with 2.3 g of sodium hydroxide in 30 ml of water at room temperature for 1 hr. ~ter concentra-tion under reduced pressure, an excess of diluted hydrochloric acid was added to the residue and the acidic solution was concentrated under reduced pressure to remove hydrochloric acid completely.
The residual solid was dissolved in ethanol and insoluble salts were filtered off.
The filtrate was evaporated and the residual crystals were recrystallized from ethanol to give 8.7 g of 1-(7-carboxy-heptyl)imidazole hydrochloride as colorless leaflets; M.P. 153-IR-absorption spectrum (KBr) vCH: 3130 cm vCO: 1710 cm 1 NMR spectrum (DMSO-d6) 1.1-2.0(m,10H), 2.19(t,2H), 4.20(t,2H), 7.63(t,1H), 7.77(t,lH), 9.24(br-s,lH), and 10-12(br-2H).
Elemental analysis as CllH19O2N2Cl C (%) H (%) N (%) Calcd. 53.54 7.76 11.35 Found 53.38 7.96 11.41 Method B: l-(9-Carboxynonyl)imidazole hydrobromide A solution of 2.0 g of 1-(9-ethoxycarbonylnonyl) imidazole, which was prepared by the method A in reference example 1, in 15 ml of 47 ~ hydrobromic acid was refluxed for 2 hr.
The reaction mixture was concentrated under reduced pressure to remove hydrobromic acid completely.
The residual solid was recrystallized from ethanol-ether to give 1.8 g of l-(9-carboxynonyl)imidazole hydrobromide as - ~ ~.Z3~a~

colorless leaflets; M.P. 147-150C;
IR-absorption spectrum (KBr) vCH: 3140 cm vCO: 1715 cm 1 NMR~spectrum (DMSO-d6) 1.1-2.0(m,14H), 2.20(t,2H), 4.2~(t,2H), 7.73(t,1H), 7. 85(t, lH), and 9.38(br-s,lH).
Elemental analysis as C13EI23O2N2Br C (%) H (%) N (%) Calcd. 48.91 7. 26 8.78 Found 48.73 7.41 8.70 Method C: 1-(4-Carboxybutyl)imidazole hydrochloride A mixture of 1.0 g of 1-(4-cyanobutyl)imidazole, which was prepared by the method A in example 2, and 20 ml of 20 %
sodium hydroxide was refluxed for 5.5 hr. After cooling, the solution was acidified with concentrated hydrochloric acid and then evaporated under reduced pressure to remove hydro-chloric acid completely.
The residual solid was dissolved in ethanol and insoluble salts were filtered off.
The filtrate was evaporated under reduced pressure and residual crystals were recrystallized from ethanol-ether to give 0.8 g of 1-(4-carboxybutyl)imidazole hydrochloride as colorless leaflets; ~.P. 117-118C
IR-absorption spectrum (KBr) vCo: 1710 cm 1 NMR spectrum (d6-DMSO) 1.3-2.0(m,4H), 2.28(t,2H), 4.24(t,2H), 7.65(t,1H), 7.79(t,lH), 9.23(s,lH), 10-12(br,2H).
Elemental analysis as C8H13N2O2Cl C (~) H (%) N (%) Calcd. 44.10 5.82 14.70 Found 43.96 5.37 14.52 ,. , 3~

Method D: 1-(7-Car~oxyheptyl~imidazole hy~rochloride A solution of 11.4 g of 1-(7-cyanoheptyl)imidazole, which was prepared by the method B in example 2, in 55 ml of concentrated hydrochloric acid was heated at 100C for 1 hr.
After removal of hydrochloric acid under reduced pressure, the residual solid was dissolved in ethanol and insoluble salts were filtered off.
The filtrate was evaporated under reduced pressure and the residual crystals were recrystallized from ethanol to give

8.5 g of 1-(7-carboxyheptyl)imidazole hydrochloride as the same product in method A.

Method E: 1-(6-Carboxyhexyl)imidazole hydrochloride A mixture of 0.7 ~ imidazole, 2.1 ~ of 7-bromoheptanoic acid, and 3.4 g of anhydrous potassium carbonate in 50 ml of n-butanol was refluxed for 8 hr.
The solvent was then evaporated under reduced pressure and diluted sodium hydroxide solution was added to the residue to make alkaline. The alkaline solution was washed with ether and then an excess of 6N hydrochloric acid was added.
The solution was concentrated under reduced pressure and the residual solid was dissolved ill ethanol and insoluble salts were filtered off.
The filtrate was evaporated and the residual solid was recrystallized from ethanol-ether to ~ive 1.1 ~ of 1-(6-carboxyhexyl)imidazole hydrochloride as colorless leaflets;
M.P. 135-136.5 C;
IR-absorption spectrum tKBr) ~CO: 1710 cm 1 NMR spectrum (DMSO-d6) ~ 1.1-2.0(m,8H), 2.20(t,2H), 4.20(t,2H), 7.63(t,1H~, 7.75(t,1H), 9.21(br-s,lH), and 10-12(br,2~I).
Elemental analysis as CloH17N2O2C1 C (%) H (%) N (%) Calcd. 51.61 7.36 12.04 Found 51.42 7.45 12.02 ~3.~

Method F: l-(9-Carboxynonyl)imidazole hydrochloride To a suspension of 1.48 g of 63 % sodium hydride (dispersed in mineral oil) in 80 ml of dry N,N-dimethyl-formamide was added 3.01 g of imidazole at room temperature, and then the mixture was heated to 90C.
A solution ol lO.O g of l-tosyloxy-10-undecene in 10 ml of dry N,N-dimethylformamide was added to the mixture at 90C
over a period of 1 hr., and then the reaction mixture was heated at 90C for 1 hr.
After evaporation of N,N-dimethylformamide under reduced pressure, 100 ml of ether was added to the residual oil and the ether solution was washed with water and dried over anhydrous magnesium sulfate.
The solvent was evaporated under educed pressure and the residual oil was chromatographed on silica gel using dichloromethane-ethanol (20:1) to give 5.6 g of 1-(10-undecenyl)imidazole as a colorless oil.
IR-absorption spectrum (neat) vC=C: 1630 cm NMR spectrlIm (CDC13) 1.10-2.20(m,16H), 3.86(t,2H), 4.75-5.05(m,2H), 5.50-6.00 (m,lH), 6.80(m,lH), 6.96(m,lH), 7.36(br-s,lH).
Elemental analysis as C14H24N2 C (%) H (~) N (%) Calcd. 76.31 10.98 12.71 Found 76.21 11.05 12.96 To a solution of 1.94 ~ oE potassium permanganate and 0.2 g of dicyclohexyl-18-crown-6 in 50 ml of benzene was added 1.0 g of l-(10-undecenyl)imidazole and the mixture was stirred at room temperature for 6 hr.
The resulting precipitates were separated from the solution by filtration and suspended in aqueous potassium hydroxide. The insoluble solid was filtered off and the filtrate was washed with ether. The aqueous layer was acidified with ~3~3~

concentrated hydrochloric acid and then evaporated under reduced pressure to remove hydrochloric acid completely.
The residual solid was dissolved in ethanol and insoluble salts were filtered off. The filtrate was evaporated and the residual crystals were recrystallized from ethanol-e-ther to give 0.84 g of l-(9-carboxynonyl)imidazole hydrochlor:ide as colorless leaflets; M.P. 162-165 C;
IR-absorption spectrum (KBr) vCO: 1710 cm 1 NMR spectrum ~DMSO-d6) 1.1-2.0(m,14H), 2.20(t,2H), 4.22(t,2H), 7.65(t,1H), 7.80(t,1H), 9.29(br-s,lH), and 10-12(br,2H).

~ethod G: (E)-1-(7-Carboxy-6-heptenyl)imidazole hydrochloride Two grams of (E)-1-(7-ethoxycarbonyl-6-heptenyl)imida-zole, which was prepared by the method H in reference example 1, was stirred with 0.68 g of sodium hydroxide in 10 ml of water at room temperature for 1 hr. An excess of diluted hydro-chloric acid was added to the reaction mixture and the acidic solution was evaporated under reduced pressure to remove hydrochloric acid completely.
The residual solid was dissolved in ethanol and insol-uble salts were filtered off. The filtrate was evaporated under reduced pressure and the residual crystals were recrystallized from ethanol-ether to give 1.02 g of (E)-1-(7-carboxy-6-heptenyl)imidazole hydrochloride. M.P. 144-146C;
IR-absorption spectrum (KBr) vC=C: 1650 cm ~C=0: 1700 cm NMR spectrum (DMSO-d6) ~ 1.0-2.4(m,8H), 4.26(t,2H), 5.92(dt,1H), 6.85(dt,1H), 7.72(m,lH), 7.86(m,lH), and 9.28(m,lH).
Mass spectrum m/e 208(M ), 110, 109, 96, 95, 82(base pea~), 81, 69, 68, and 55 ~-3'~3~
Method H: 1-(7-Carboxyheptyl)imidazole hydrochloride A solution of 1.0 g o (E)-1-(7-carboxy-6-heptenyl) imidazole hydrochloride, which was prepared by the method G, in 30 ml of ethanol was hydrogenated over 0.2 g palladium-on-carbon at room temperature under a-tmospheric pressure.
The catalyst was filtered ofE and the filtrate was evaporated under reduced pressure and the residual crystals were recrystallized from ethanol-ether to qive 0.7 g of 1-(7-carboxyheptyl)imidazole hydrochloride as the same product in method A.

The following compounds can be prepared in similar manners:

- ~6 -3~
. ~ . . . _ X--- ~ ^ X ~ ~ _x X ~ ~ U) 'U ----'~ rd 1~ _ ~ ~ X
o ~
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_ .~ 3 N . CO ~J --O
~ n_--a ~ n n . ~ ~ --r~ ~ h ~ `
X a~ ~ a~ ~ r~I~ ` `-- ` ~ --,a 'r h I ~
~o ~ ~ --o ~1 ` `--_ _ ~ _ --_ ~ ~ ~ h u~ _~D -- `-- --m R ~
r-l ~ r~ ~I r-t ~ r o ~ ~ r-l~J r-/l ~ r-t N
~ r-J ~~ O I ` ~
A~ J,J ~ ~ ~~;J ~ ~ ~ ~ r~ _ ~ ~ ~ 3 E r~J
r:. ~ O _ O _ ~ [~ _ ~ ~ ~ ~ 1~ ~3 ~ ~ ~ r~ 1`
f - N ~ ~ ~ r~
. . ~ _ ~ r~ r~
t~ ~D h r~ ~ ~1 ~ r~
~ ~ R ~ ~ R ~ ~ R r-t ` hN r-l r-l~ r~ D
------ E~ ^ ^-- h 5~ 5~ ~ ~ ~ ~ --~ ~ ~j ~--~ u~ u~h u~ m ~: --~`J r-l r-l If) r-l r~ r-l r~~ ~ O ~ I I ~ ~~ ~ r--l N r~J ~7 ~ ~ I o ~ I ~ O NO h ~ ~ ~ ~
t~ ~1 O . ~ O ~ O ,~ Q ~ ~ ~ ; e r~ ---~ ~--1 ~ ~ r--I r-l ~ r-l r~ 1 tC ~Ct~l ~ 5 N ~ ~ ~ ~0 :~ ~ I U) I ~ t II In O I --1 r-l I r-l ~3 I t~) ~) r-l ~D ~5 O ~ ~ r~ ar-l ~r rc~o Lll r~ r~ r~ C0 r~
n h u~
~ 1~ ~ r-l 1~ 0 r-l ~Il] r-l 1~ ~ r~ r-l ~ _ r-l 1~ r~l 11) (d r1 1~ 00 0 00 0 C) O O ~ ~D
I O ~) ~ 1 r~ I O r-l~r--l 1` 1` r-l t~ ~~ 1` 1` 1~ 1~ 1~
r m~ rt r-l ~ r-l r-l r-l r-l r-l r~l r-l m x ~ o o ~:: o o o o o o o :r _ ~ O U C~ ~ U O U
O
a~ o u~ U u~
O u~ ~ O u~ ~ O u~ ~ O ul ~ O u~ ~ O
a~. ~ 7r~Dr-l~~l i~r-lr-l ~r~ 1 ~) 0 0 r~~ r~l ~ ~ r-l ~ ~ r-l ~1 ~ r~ Hr-l ~ ~ ~1 ~ Ul , , O 'a , O ~ , O ~ , O ~, O ~ , cO
(~ r-l a)CO r~l ~ ~ r-l (1) ~ O r~ ~ O r~ U~ O r-l l_ o r-l~D O r~
fa r~ r-l 0r--I 0 r-l t) r--l t)r--l CO C~
;~ rci _ Z ~ ~
5 ~ ~

~' _ ..... _ _ I
~a o X
r~: t~l N ~ t~l O O Z O O O O O O O
C~ ~ U C~
X _ . I
a) ~r r ~ 5, ~

r-l ~ O r~ ; U C.) Id r-l ~ Lf) ~I r-l r~
~ _ _ _ ~111 ~ X
æ~ ~ ~ ~ N
¦ r-l ~ 5 ~ 5 ~ ~ ~ X 1 ~Z~ ~ _ ~ X

~ ~ 3~h~
EXAMPLE 4:
Method A: 1-(7-Carboxyheptyl)ilniaazol~
A solution of 20.0 ml of O.lN sodillm hydroxide (~`~1,000;
2.0 mmole) was added to 493.5 mg (2.0 mmole) of 1-(7-carboxy-heptyl)imidazole hydl~ochloride, which ~a~ prepared by the mcthod A in example ~.
~ he solution was then concentrated under reduced pressure, and the residual solid was dlssolved in ethanol and ln~o]uble salts were filtered off. The filtrate wa~ evaporated and the residual crystals were rec~ystalllzed froTn ethanol-ether to ~ive 340 mg of 1-(7-carboxyheptyl)imidazole a~
colorless crystals; M.P. 91-94C;
IR-absorption spectrum (KBr) CH: 313~ cm 1 ~C0: 1700 crn~1 NMR spectrum (C~13) 1.0-2.0(m,10H), 2.30(t,2H)9 3.92(t,2~I), 6.85(s,1H), 7.03(s,1H), 7.62(s,1H), and ll.~O(br~s,lH).
Elemental analysis as Cll}I1802N2 C (~) H (~) N (%) Calcd. 62.83 8.63 13.32 -Found 62.55 8.83 13.10 .
Method B: 1-(6 Carboxyhexyl)imidazole A solution of 750 mg of 1-(6-benzyloxycarbonylhexyl) imidazole, ~hich was Prepared by the method A in reference example 1, in 100 ml of ethanol was hydrogenated over 50 m~
of 10 ~ palladillm-on-carbon at room temperature under atmospheric press~re to give 37~ mg o~ 1-(6-carboxyhexyl) imidazole as colorless prisms; M.P. 132-133 C (frorn ethanolether);
IR-absorption spect~m (XBr) CH :3140 cm~
~C=0:1705 cm~l NM~ spectl~m (D~iS0-d6) 1.1-1.8(m,8H), 2.17~t,2H), 3~92~t~2H), 6.84(s,1H)~

.231~1 '- 7.10(s,1ll), 7.58~ ), alld 9-lO(br,lll).
Elem~ntal analysig a9 Cl0~162N2 C (%) H (%)N (%) Calcd. 61.20 8.22 . 14.28 Found 61,06 8.07 14.36 Method C. 1-(4-Carboxybutyl)imidazole A water,solution of 1.0 g of 1-(4-carboxybutyl) imidazole hydrochloride, which was prepared by the method C
ln eY.ample 3, was passed through an amberlite IRA 401 packed column, and the eluate wa~ concentrated under reduced ~ressure, ~ he residual solid was recrystallized from ethanol to give 0.4 g of 1-(4-carboxybutyl)imida~ole as colorless needles;
M.P. 165-166.5~C;
IR-absorption spectrum(KRr) ~`C=0: 1705 cm~l NMR spectrum (~MS0-d63 1.3-l.9(m,4H), 2.24(t,2H), 3.96(t,2H),6.86(s,1H), 7.10(s,1H), 7.60(s,1H~, and 8.15(br,1H~.
Elemental anal~sis as C8H1202N2 C (%) H (%) N (%) Calcd. 57.13 7.19 16.66 ~ ound 56.93 7.42. 16.36 The following compounds can be prepared in a similar manners:

~ 3 ~384~ 1 _ ._ __ __ ___ ~

5' ~ ~ h h h ~
_ .~ tq ~ ,9 U) tQ ~_ ~_ _~
f~ 0 0 0 . . ~D ~D ~D C'~
C' ~D
..~ ~, ~ ~ .~~
~ --~ ~Lt, ~t ~ ~t, ' ~ ~ ~ tU ~ ~ ~
~_ ;J ,_ u~^ O F
a:) Lt~ C~ ' Cr~C ~ ~
oo . ~ ~ ~ ~~ ,~
~ -- ~ ~ h ^ F~ ~,_~
~_ ~ ~t 1 X ~ ~ ~t ~ ~t ~ ~
~ U~~ l_t t~ 01_~ 01_~ ~ U~
(~I i ~ .~ ~ ~ ~co ~ ~
h ^ u~ ~ t~ ~11~ ~ IS~ ~ h ,D ~ ~_ ~ _ _~ . ~_ . _~ ,~
~_ o O ~ ~ ~ CO C' ~ ~_ t~ O ~D 1~11~ ~1 ~1 ~ C' ~0' ~ ~ ~iC' ~ ~ ~ ~ O
~1 ~O ~ ~ ~ ~ ~ . _~ ~ ~ ~
_~ ~ ,_ ~ '1~ ~ ~ ~: ~ ',:}
_~ ~ ~ 5: ~ ~ ~ ~ CC~ ~
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~ ~ ~C ~ ~ tq O`_ ,~~_ ~ ~_ ,~ ~ I ~_ I _~ I
V2~ o~o~ ^ o _ CO ~ ~ ~ O ~1 :~ ~ U~ .,~ .,~ ,D
. ~ ~ , ~1 _~ ~ _~ ~1 _~ t~
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ei a~ I o~ o~ ~ ~ o~
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_~ t~ OO O O O C~ O O O U~
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P:: h ~ r~l C~ r~l C~ ~I C~ r-l C~ r-l C~
t ~ m,~ rt t~ r I t~ r-l t~ r-i t~ r-l t~ r-l ~: .... .... .. ~ .. ~ ~ .~ ~
~_ ~ O ~ r ~) ~ O ~ O ._ o ~
:~i ~ ~ ~ ~ r~ ~ ~ ~ ~ 5~ . ~ ~_ \\5~,,1 _ C~

~ ~ c~ u~ c~ Iq t~ t,q t~ c~ t,q t~
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J r-l ~ O~r-l ~ r~ ~t r~ ~rl ~D r-l 5~ ~ r-l tr~ o t~ O I tU O 1~1 O r-l O.l 0 ~f~ O
~1 v r~ r-l v ~t v r-l v . ~
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a~
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~ ._ , ~23~

EXAMPLE 5:
Method A: 1-[8-(N-Methylcarbamoyl)octyl]imidazole To a suspension of 0.18 g o~ 63 % sodium hydride (dispersed in mineral oil~ in 30 ml of dry N,N-dimethylformamide was added 0.21 g of imidazole at room tempera-ture and then the mixture was heated to 80C.
A solution of 0.77 g of 8-(N-methylcarbamoyl~octyl-bromide in 2 ml of dry N,N-dimethylformamide was added slowly at 80C, and then the reaction mixture was stirred at 80 C
for 1 hr.
After removal of N,N-dimethylformamide under reduced pressure, 50 ml of dichloromethane was added to the residue and washed with water, and dried over anhydrous magnesium sul~ate.
The solvent was evaporated and the residuP was chromatographed on silica gel using dichloromethane-ethanol (20:1).
The eluate was recrystallized from chloroform-ether-n-hexane to ~ive 0.12 g o~ 8-(N-methylcarbamoyl)octyl]
imidazole as colorless crystals; M.P. 64-66 C;
IR-absorption spectrum (XBr) vNH :3325 cm vCH :3100 cm vC=0:1640 cm 1 NMR spectrum (CDC13) l.l-l.9(m,16H), 2.08(t,2H), 2.67(d,3H), 3.83(t,2H), 6.25-6.70(br,lH), 6.81(br-s,lH), 6.92(br-s,lH), and 7.35(br-s,lH).
Elemental analysis as C13H23ON3 C (%) H (%) N l~) Calcd. 65.78 9.77 17.71 Found 65.52 9.51 17.41 Method B: 1-(7-Carbamoylheptyl)imidazole A solution of 6.5 g of 1-(7-carboxyheptyl)imidazole hydrochloride, which was prepared by the method A in example 3, in 30 ml of thionyl chloride was refluxed for 1 hr.
After concentration under reduced pressure, 30 ml of dry N,N-dimethylformamide was added to the residue.
The N,~-dimethylformamide solution was added -to 30 ml of 25 % ammonia wa-ter at 0 ~5 C over a period of 1 hr., and then ~he mixture was warmed to room tempera-ture and s-tirred for 1 hr. After concentration under reduced pressure, 10 ml of saturated sodium carbonate was added to the residue, and the mixture was extracted with dichloromethane and dried over anhydrous magnesium sulfate.
The solvent was evaporated and the residual crystals were recrystalli~ed from dichloro~ethane-ether to give 3.5 g of 1-(7-carbamoylheptyl)imidazole as colorless leaflets;
M.P. 112-113 C;
IR-absorption spectrum (KBr) vN~: 3380 cm vCH: 3150 cm vCO: 1665 cm 1 NMR spectrum (DMSO-d6) ~ 1.1-1.85(m,10~), 2.04(t,2H), 3.93(t,2H), 6.62(br,1H), 6.83(t,lH), 7.08(t,lH), 7.15(br,lH), and 7.55(br-s,lH).
Elemental analysis as CllHlgON3 C (%? H (%) N (%) Calcd. 63.12 ~.15 20.08 Found 63.31 9.04 19.97 Method C: 1-(3-Carbamoylpropyl)imidazole To a stirred solution of 1.35 g of 1-(3-cyanopropyl) imidazole, which was prepared by the method A in example 2, in 15 ml of acetic acid was added dropwise a 7.6 g of titanium tetrachloride at room temperature, followed by the addition of 1.44 g,of water, and then stirred at room temperature for 5 hr.
Then the reaction mixture was poured into cold water and made alkaline with 6N sodium hydroxide, and the resulting , .: . .

~,Z~

precipitates were filtered o~f. The Eil-trate was concentrated under reduced pressure and the residual solid was extracted with dichloromethane.
The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated, and the residual crystals were recrystallized ~rom ethanol-benzene to give 0.9 g of 1-(3-carbamoylpropyl)imidazole as colorless prisms;
M.P. 102-103C;
IR-absorption spectrum (KBr) vNH: 3320 cm vCH: 3150 cm 1 vCO: 1690 cm 1 NMR spectrum (DMSO-d6) 1.8-2.2(m,4H), 3.95(t,2H), 6.84(t,lH), 6.75(br,lH), 7.09(t,1H), 7.28(br,1H), and 7.55(br-s,lH)~
Elemental analysis as C7HllN3O

C (~) H (~) N (~) Calcd. 54.88 7.24 27.43 Found 54.68 7.02 27.53 The following compounds were prepared in similar manners:

~-3.'~3 __ _ N r-l ~ ~
~ ~ O m ~ ~ .
o~ co ~c co u) _ ~ ~t Ul ~D R
~ S
N ~1 .4 ~ ~_ ~
J,J ~J Q N 1`
--R ~r N `
N _ . N ~ ) :o _ ~D ~ ~ m C~ ~ ~ ~ `~1 a ~ 1 ~ --N I
f~ ,, QCr. or~o Z; ~ D ~D ~ ~ r~

~; ~ ~D ~ I~ O U~
\ / ~t ~ D _~t o ~ m mN ~ O ~ ~ rt N H Z 1~ C ~ -- ?
m o~
z ~ ~ o <\z3 m 1 ~ 3 ~:~

~ _.
m ~c .

` - -- 54 --.

EX~MPL~ 6;
tho(l .~ (7-Amirlo~le})tyl)imi(l~ ,ole _ ._ __ A solu~ioll of 10.0 g of 1-(6-cyarlohexyl)imidazole, which was prepared by the m~thod B in example 2, in 40 ml of concentrated hydrochloric acld and 100 ml of ethanul was hydr~enated o~-er 1.5 g of platinium dioxide at room ternperature under 4 atms.
After concentration under reduced pres3ure, 20 ml of 10 % ~odium hydroxide was added to the re~idual oil and the alkaline ~olution was extracted with dichloromethane and dried over anhydrous magnesium sulfate.
The sol~ent was evaporated and the residual oil was distilled under vacuum (136-137~C/0.5mmH~) to give 8.0 g (78 %) of 1-(7-aminoheptyl)imidazole as a colorless oil;
IR-absorption spectrum (neat) ~NH2:3350 cm 1 NMR spectrum (~DC13) 1,18(s,2H), 1.2-l.9(m,lOH), 2.66(t,2H), 3.91(t,2H), 6,85(t,1~), 6.99(br~ ), and 7.40(s,1H).
Elemental analysis as CloHlgN3 C (%) H (~) N (%) Calcd. 66.25 10.57 23.18 ~una 66.34 10.81 23025 Method A-2: 1-(4-Aminobutyl)imidazole In a similar manner a~ the method A-l, catalytic hydro~enation of 16.0 g of 1-(3-cyanopropyl)imidazole, which was prepared by the method A in example 2, gave 12 0 g of l-(4-aminobutyl)imidazole a~ a colorless oil;
B.P. 108-109 C/0.5mmHg;
IR-absorption sPectrunl (neat) ~NH2; 3370 and 3290 cm 1 NMR spectrum (CDC13) 1.15(br-s,2H)~ 1.2-2~0(m94H), 2.70ttg2~), 3,93(t~2H), 6,84(t,1H), 6~98(br-s,l~,), and 7.39(s,1H).

~ J

Eleme~tal analy~is a~ C7H13N~

C (~) H (%)` N (~) Calcd. 60.40 9.41 30.19 Found 60~59 9.67 29.92 Method B: 1~[7-(N,N-Diethylamino)heptyl~imidazol0 To a suspension of 0.~ g of lithium aluminum hydride in 100 ml of dry tetrahydrofuran was added 9Iowly 2~0 g of 1- L6-(M,N-diethylcarbamoyl)hexyl~imidazole, which was prepared by the same procedure as described in example 5, in 10 ml of dry tetrahydrofuran at room temperature, and then the reaction mixture was re~luxed for 5 hr.
After cooling, the reaction mixture was treated with 10 ~ sodium hydroxide and filtered.
~ he filtrate was dried over magnesium sulfate and evaporated under reduced presYure.
The re~idual oil was chromatographed on silica gel usin~
dichloromethane-ethanol (5:1)-to give 0~26 g of 1-~7-(N,N-diethylamino)heptyl)imidazole as a colorless oil.
IR-absorption spectrum (neat~
''CH: 3100 cm 1 NMR spectrum (CDC13) ~0,95(t,6H), l.l-l.9(m,lOH), 2.36(t~2H), 2.48(g,4H), 3.88(t,2H), 6.83(t,lH), 6.99(br-s~lH), and 7.39(br-s,lH).
Elemental analysis as C14H27N3 C ~%) H (%) N (~) Calcd. 70,83 11.47 17070 Found 70062 11.31 17.89 REFEI~E~IC~ E~IPIE 2 Acute Toxicity The median lethal dose (I.D50) of N-(7-carboxyl~cptyl)-imiclazolc and l~-(6-methoxycarbonylhexyl)imidazole (known compound) l~ere determined in dd-stain male mice ~7 weeks old) by intravenous administration. The LD50 values were calculated according to the Behrens-Xarber method. The results of ~he test are shown below.
N-~7-carboxylleptyl)imidazole 560 mg/kg N-(6-methoxycarbonylhexyl)imidazole 140 mg/kg (known compound) FOR~IULATION F.X~IPI~ 1 10 g of N-~7-carboxyhe~tyl)imidazole were admixed with 30 g of lactose, 15 g of Indian corn starch, 30 g of hydroxymethylcellulose, 2 g of calcium carboxymethylcellulose ~I~U i ~ of calcium stearate. The mixture was knea'ed and shape(l into 1,000 tablets.
FORMULI~rlON EX~ I.F. 2 ___ _ _ The tablcts obtained in Form-llation Example ] were placed in a rotary coating tank and a 10~ ethanolic solution of 1 g of polyvinylacetal diethylalllinoacetate and 0.3 g of macrogol 6000 was added to the tablets and thc mixture was stirred and dried.

-.231~

T:OR~IUl..l\'l`T ~ 11' L1~ 3 5 g of N-(7-carl)ox~rheptyl.)ilnidazole and 10 g o chloroblltallol werc dissolvcd in distilled water for injectio to make the total amount 1,000 mQ. 1 mQ of the solutior- was po~lrcd into an ampoule to make 1~000 ampoules. The air was pulged with nitrogcn, and the ampoules were heated at 121C
for lS minutes to sterilize the solution to obtain an inject-allle preparation.
IYlIi]e t~le invention has been dcscribed in detail and Wit]l reference to specific embodiments thereo~, it will he apl)arcllt to one skilled in the art that various changes and modifications can be made therein without departing from thc spirit and scope thereof.

Claims (10)

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

1. A process for the production of imidazole compounds of the general formula:

wherein alkylene is a straight saturated alkylene chain having 3 to 20 carbon atoms and a straight unsaturated alkylene chain having 3 to 20 carbon atoms, and pharma-ceutically acceptable salts thereof, which comprises (a) reacting imidazole of the formula:

with a compound of the general formula:

X-alkylene-COOH

wherein X is an acid residual group, alkylene is a straight saturated alkylene chain having 3 to 20 carbon atoms and a straight unsaturated alkylene chain having 3 to 20 carbon atoms;
(b) reacting imidazole of the formula:

with a compound of the general formula:

X-alkylene-W2 wherein X is an acid residual group, W2 is an alkoxy-carbonyl group having 1 to 4 carbon atoms in the alkoxy moiety thereof, a cyano group, and carbamoyl group, and alkylene is a straight saturated alkylene chain having 1 to 4 carbon atoms and a straight unsaturated alkylene chain having 1 to 4 carbon atoms and then, hydrolyzing the resulting product;
(c) reacting a compound of the general formula:

wherein m1 is an integer of 1 to 18, with a compound of the general formula:

wherein Z is a halogen atom, m2 is an integer of 0 to 17 and Ph is a phenyl group, with the proviso that m1 plus m2 equals an integer not more than 20;

(d) reacting a compound of the general formula:

wherein m1 is an integer of 1 to 18, with a compound of the general formula:

wherein R3 is a lower alkyl group, Z is a halogen atom, m2 is an integer of 0 to 17, and Ph is a phenyl group, with the proviso that m1 plus m2 equals an integer not more than 20 and, then hydrolyzing the resulting product;
(e) reacting a compound of the general formula:

wherein m1 is an integer of 1 to 18, with a compound of the general formula:

wherein R2 and R3, which may be the same or different, each is a lower alkyl group and, then hydrolyzing the resulting product;

(f) reacting imidazole of the general formula:

with a compound of the general formula:

wherein R4 is an alkyl group, m3 is an integer of 1 to 18, and halogenating the resulting compound, and then hydrogenating the halogenated product, and hydrolyzing the resulting product;
(g) hydrolyzing a compound of the general formula:

wherein W2 is an alkoxycarbonyl group having 1 to 4 carbon atoms in the alkoxy moiety thereof, a cyano group and a carbamoyl group, and alkylene is a straight saturated alkylene chain having 3 to 20 carbon atoms and a straight unsaturated alkylene chain having 3 to 20 carbon atoms;
(h) hydrogenating the product having an unsaturated alkylene obtained in each step of (a) to (g) above to produce the corresponding compound having a saturated alkylene, and when pharmaceutically acceptable salt is required, reacting the resulting compound with a salt forming agent.

2. Imidazole compounds of the general formula:

wherein alkylene is a straight saturated alkylene chain having 3 to 20 carbon atoms and a straight unsaturated alkylene chain having 3 to 20 carbon atoms, and pharma-ceutically acceptable salts thereof, whenever produced by the process according to Claim 1 and an obvious chemical equivalent thereof.

3. The process according to Claim 1, which comprises reacting imidazole of the formula:

with a compound of the general formula:

X1-alkylene-COOH

wherein X1 is a halogen atoms, and alkylene has the same meaning as given above.

4. The process according to Claim 1, which comprises reacting imidazole of the formula:

with a compound of the general formula:

X1-alkylene-W2 wherein X1 is a halogen atom, and alkylene and W2 have the same meaning as given above, and then hydrolyzing the resulting compound.

5. The process according to Claim 1, which comprises reacting imidazole of the formula:

with a compound of the general formula:

X2-alkylene-COOH

wherein X2 is an acid residual group formed form an organic sulfonic acid, and alkylene has the same meaning as given above.

6. The process according to Claim 1, which comprises reacting imidazole of the formula:

with a compound of the genenral formula:

X2 -alkylene-W2 wherein X2, alkylene and W2 have the same meaning as given above, and then hydrolyzing the resulting product.

7. The process according to Claim 1, which comprises reacting imidazole of the formula:

with a compound of the general formula:

X-alkylene-W3 wherein W3 is an alkoxycarbonyl group having 1 to 4 carbon atoms in the alkoxy moiety thereof, and alkylene has the same meaning as given above, and then hydrolyz-int the resluting product.

8. The process according to Claim 1, which comprises hydrolyzing a compound of the general formula:

wherein alkylene and W2 have the same meaning as given above, in the presence of an acid.

9. The process according to Claim 1, which comprises hydrolyzing a compound of the general formula:

wherein alkylene and W2 have the same meaning as given above, in the presence of a base.

10. The process according to Claim 1, which comprises reacting imidazoid of the formula:

with a compound of the general formula:

wherein m3 is an integer of 1 to 18, R4 is a lower alkyl group, then halogenating the resulting compound with a halogenating agent such as thionyl chloride, and hydrogenating the halogenated product with a catalyst such as Raney Nickel, then hydrolyzing the resulting compound.