PH26333A - A process for the preparation of 1-(1-aryl-2-hydroxyethyl)-imidazoles - Google Patents

Description

i» 2%”

Description t= (-Aryl-2-hydroxyethyl)-migagoyes and galtg thereor, Processes for the Preparation thereof, ’ medicaments Containing thege Compoundy, and the uge thereof :

Thig applicatioy; is a divigiona]l application of

Serial No, 36596 filed op March 4, 1918,

The invention relates to substituteq l-(1-Aryl-2. hydroxyethyl)-imidazol es, including their salts,

Processes for the Preparation thereof, medicaments ¢tontalning these Compounds, ang their uge as medi- camentg,

It has already beep Proposed (or, German Patent

Application p 31624, 545, 5) that substituteq aryl- methylagolesg and salts thereof which are produced from the reaction of 1-(arylmethyl)-azo]es with ketones and aldehydes pe used for the treatment : of depressive States ag g consequence of their

Faychopharmacologica) action, in Farticular their antidepressive action.

The invention had the object of providing compounds whicn Produce g therapeutically utiligable anti- depressive action with goog telerance, '

The substances Proposed in German Patent Applica- tion p 5,628,545, 5 have one or two asymmetrical - 3 - | >

GINA

2,2) 3 carbon atoms. It hag Low been found that compounds having at least two asymmetrical carbon atoms produce, in varticular, a good antidepressive action, besides an antimycotic action, simul taneously with good tolerance.

The invention therefore relates to l-(l-aryl-2- hydroxyethyl )-1tmivazoles of the Formula I,

A il on nt

J

CC -C~C =~ IG I

Fs

Y NK HH R o 4 / in which

X aenotes MN, (Cy-C4)-alkyl-phenyl, F, C1,

Br, Iu, CFg, (Cy=¢4)-alkoxy, (C}-C,)- alkylthio, (Cy-C4)-alkoxymethyl, (C3~Cg)- 4 alkenyloxymethgl or -nif, in which R’ are identical or different and denote (Cy-C4)- alzyl or, together witn the nitrogen atom, a pyrrolidine, piperidine or morpholine radical,

Y denotes H, (C1-C4)-alkyl, F, C1, Br or (¢,=C,)-alkoxy, or

X and Y together in the Je4-position denote a : -(Cd,), ~chain, where L = 5 or 4, -UCH,CH,-, =0-Chiu- or -Cllz i=. HaCli-, - 4} - |” ‘BAD ORIGINAL £

Lo

0%"

K yl /

W denotes ii, vig or UGH, & : al Ny 1 denotes 1i, (€,=C,)-alkyl, (Cy=Cy)-alkenyl, (C=C) alkynyl, (CqwC,)-cycloalkyl, (¢,~C,)-cocloalkensl, (C3~Cq)-cycloalkyl- 9 CHy, (C,-C,)-l-cycloalkenyl-Ch,, (C1-Cy)- alkoxy, (C;=C,)-alkoxymethyl, (C5-Cg)-alkenyl- oxymethyl or 2-propyn-l-yloxymethyl, . ( )- (C,=C5)-alkyl or 'y

Co Ra

Qr (CHECH-CH,) in which . 5 . fn ®° denotes CH,» C, Hg, OCH,, F, Cl, Bro or } 30 2 5? 50 ? ’ .

CFas and : n denotes 0, 1) or 2 and, in the case where

R° denotes OF 5 nis 1,

Rr? denotes (C,=U,)-alkyl or (C,-C.)-alkenyl 17%4 375 ak > denotes (Cy-Cy)-alkyl or 1 3 2 5 eh

RT and Kk” or R° and R7, together witn the carbon atom to wuich they are bound, denote -5 = r

BAD ORIGINAL J t a v5”

FU” (C5~Cy)-cycloal«yl, Co-bicycloalkyl, (C4-C,)-cycloalkenyl or C,-bicycloalkenyl which is in each case unsubstituted or substituted by 1-3% Cli and/or OCH, and/or

Cl and in which, in the cycloalkenyl and bicycloalkenyl radicals, the (C=C double bond 1s not in the l-position, or (oxa-C,-

Cg)-cycloalkyl, and

Q denotes H or Cis or Cob in the 4-and/or 5- position, and the physiologically accept- able acid-addition salts thereof and the stereoisomers and optically active enan- timers thereof,

Preferred compounds of the formula I are those in which at least one of the substituents has the following meaning: ‘ x denotega 1, (C1-Cy)-alkyl, phenyl, &, Cl, Br, 1, OH, Cu50CH,, Cy HOC, , 8H,=CHCH,OCH,, (C,-C,)-alkoxy, 3-R(CHy), or 3-CFy,

Y denotes H, CH, Cl or VCH, or }

X and Y together in the 3,4-position denote a ~(CH,) =, -0-C1,=0- or -CHeCli-CH=CH~ chain,

W denotes H, . rt denotes (Cp-U,)-alkyl, (C,¥Cg)-alkenyl, 2-propyn-1l-yl, (C3-Cg)-cycloalkyl, (Cy=Cy)- - 6 - f } J or DAD ORC... AL 9 “ N &

Y ow” alkoxymethyl, (Cx-Cg5)-alkenyloxymethyl or 2-propyn-l-yloxymethyl,

Qr (C3=C5)-alkyl, in which :

Ry

Nt denotes Vil, F or C1 and n denotes 0Oorl, 2 3 ‘om : 5 R™ and R” denote (Cy-C4)-alkyl or 1 3 42 3

R- and R” or #° and R”, together with the carbon atom to which they are bound, denote (C5-Cq)- cycloalkyl, ¢;-bicycloalkyl or Cq-bicyclo- alkenyl whose 0 = C double bond is not in the 1-position, each of which is unsubstituted or substituted by 1 or 2 Chi and/or OCH4, -or (oxa-C,-Cg)-cycloalkyl, and

Q : denotes. i! or CH in the 4- or 5-position. rarticularly preferred compounds of the formula I are those in which at least one of the subatituénts has the following meaning:

X © denotes il, Clg phenyl, ¥, C1, Br, 3- or 4-0CH5 or 3-0F4, « = 1 -

Fr" . ~ BAD ORIGINAL 9

Cl 2, cyt’

Y denotes Ii, Chiz, 3. or 4-Cl or 3- or 4-

OCH, or

X and Y together in the 3,4~jo0sition denote a -CH=CH~ClisCH~ chain,

I] denotes I,

Rl 1 A} NY 1

R denotes (C,=C4)-alkyl, (C3-C4)-alkenyl, 2-propyn-1l-yl, bensyl, (C,-C4)-alkoxymethyl or (C3=vy) alcenyloxymethyl, 2 3 ~ -

K and HR” denote (C=C4)-akxyl or 1 ana #2 or RC and #° together with the : carbon atom to which they are bound, denote (Cy=Cq)-cycicalkyl, 2-norbornyl, nortornen- ’ 2-yl or (oxe-C,=Cy)-~~cycloalkyl, and

Q denotes H or CHy in the 4- or 5-position.

In this connection, the term "(Cy=Cs)=, (Cy=Cy)- or (C,=C,)-alkyl” is in each case taken to mean an unbranched or branched alkyl radical, the term nig. .=-C_J=- -g,)- L=0. Jal " - - (Cc, ¢;) , (c, Cy) or (Cy C,) alkenyl" or (C, Cg) alkynyl is in each case taken to mean an unbranced or branched alkenyl or alkynyl radical respectively, oy I -( - \ Y - — " the term "(Cy Cy) alkoxy or (Cy Cy) alkylthio is taken to wean an unbranched or branched alkoxy or alkylthio radical, thc term i 03=Cy)-cycloalkyl and (Uy-Cg)-cycloatkenil ie in each case taken to * mean a saturated or unsaturated cyclic hydrocarbon - 8 - : {

BAD O...7 7 Pp ha + os v7 § radical having a total of 3~-¢ or 4-8 carbon atoms respectively, where these carbon atoms may be members of the ring or (¢)=C5)-alkyl substituents, and the term Cq-bicycloalkyl or Cq-bicyclical-

D xenyl is taken to mean a saturated or unsaturated vicycllic ring system having 7 ring carbon atoms. '

In the meanings mentioned for nit and ® or 2 and Ro together", the terms (C3=C,)-cycloalkyl and (€,=C,)-cycloalkeny) are taken tO mean a saturated ring system comprising 3-7 carbon atoms or an unsaturated ring system comprising 4-7 carbon atoms, in each case including the carbon atom carrying the rl and R> or Rr? and R> radicals, and the terms C,-bicycloalkyl and C,-bicycloalkenyl are taxén to mean a paturated or unsaturated res- pectively, bicyclic ring system comprising 7 ring carbon atous, in each case including the carbon atom carrying the xt and K> or p? and Ro radicals, the CaC double bond being present in one of the possible positions in the case of unsaturated ring systems.

The term (oxa-C,=Cg)= or (oxa-C3-Cg)=-cycloalkyl is taken to mean a ring systen which has 3 to 6 or 4 to 6 members respectively, including the carbon ‘ atom carrying the gL and > or #® and > radicals, is substituted by al or #° and comprises 2 to 5 or . 3-5 carbon atoms respectively and an oxygen atom as -9 -

Cr

BAD ORIGINAL Pp)

ie 7 a further ring member. Examples of these which may be mentioned are the oxetane, tetrahydrofuran and tetrahydropyran structure.

The compounds of the formula 1 contain at least two asymmetrical carbon atoms, to be precise those to which the lmidazole radical and the hydroxyl group are bound. in addition, a third asymmetrical carbon atom is present if rt, 2° and R> are dif- ferent or at and R> or rR? and R> together form an asymmetrical ring nyatem. Further asymmetrical sa:bon atoms may be present in the iY, rR? and/or

R> radicals. Conseguently, the compounds I are produced in the synthesis at least as a racemate.

Depending on the number of centers of asymmetry | and depending on the degree of stereoselectivity under the conditions used, stereoisomers are pro- duced, in addition, in the form of racemates. For example, in the synthesis ol compounds of the rormula I which contain two centers of asymmetry, two diastereomeric racemates can be formed in identical or different amounts. Such diastereo- meric racemates are frequently produced in dif- terent amounts as a result of stereoselectivity, or only one is formed in the extreue case. The invention therelore also relates to the possible stereoisvmers, in the simplest case the diastereo- isomers, oi ihe compounds I in the torm of thelr . - 10 - [— oo (BAD ORIGINAL 9

. r “)

Ae” racemates or in the form of the optically active enantiomers, and the pharmaceutically aceptable salts thercol.

The!.compbdbunda of the formula I can be prepared, 9 for example, by three.processes. :

It has already been proposed (of. Uerman Fatent

Application Fb 3,624,543.5) that l-arylmethylagoles, atter deprotonation using strong vases, be hydroxy- alkylated at ine methylene group using carbonyl compounds, strongly solvating solvents and/or two equivalents of this type of strong base being used. } Un the other hand, it was known from Org. Ract. 26, p. 120 (L979) that, in the reaction of 1- bengzylimidagole with n-butyllithium in diethyl ether at temperatures between 0°C and -70% and subseyuent addition :f carbonyl compounds, hydro- xyalkylaiion occurs only at the 2-pveltion of the oo imidazole ring. it has turthermore been proposed (of. German Yatent

Application F 5,626,545.5) that 2-aryl-2-(l-agolyl)- l-substituted ethanols be prepared by nucleophilic- ally opening oxiranes of ih: formula Ila . 0 Rr" > ! 1la int .

Lryl K .

Ho Ce - 11 - f ope TA . 0 oreinaL )

Px

W in which aryl, R', KX" and R''' have the meanings mentioned in German latent Application I 3,628,545.5 (there it' = ol R" = Ro and R''' = ry, using a compound of the formula Illa

M i 7 \ > “

Sy IIIa

Q in which M denotes hydrogen or an alkali metal or } an alkaline-earth metal, and J and Z have the mean- ing specified in German Patent Application P 3,628,545,5, + at a temperature tetween ~20°¢ and 150°¢, prefer- ably in a polar colvent, and then further reacting with a trotonic acid.

Ihe compounds of the formule I are 1.0ow prepared analogously to these preparation processes proposed in German Patent Application ¥ 3,628,545.5, in a process in which A) one or up to two equivalents of a strong base are added to a l-benzylimidazole ot tne formula 1V

A

-y 1 : _ [2 Iv . ¢ 5 be / - 12 -~ BAD ORIGIN \

in which Z, Y, w and J have the al.ovementioned mean- ings, in an aprotic, expediently polar solvent at a temperature between #40°¢C, preferably 0°c, and -100°¢, preferably -80°%, and the mixture 1s sub- sequently reacted initially with an aldehyde of the formula V hk rl

C~—Cc — IG Vv 0 3 in which R, R® and RA have the abovementioned meanings, and then with a protonic acid, prefer- ably with water, or

B) an oxirane »f the formula II } x AN Kr : 0 YE —— CH — CH— R II ; Is " 1.2 3 in which X, ¥, Ww, RR", R® and R” have the above- mentioned meanings, is nucleophilically opened through feaction with a compound of the formula III oo - 13% =

Cay, ens BAD ORIGINAL 9 ha ,

_— fade ge Cn ping v7

M

AN

Q

£) -

In which i dencteg hydrogen or an alkali metal op alkaline-eart, fetal, and 4d has the abovementioneq

Meaning, gat a teuperatyre between -20°%, Prefer. ably 0°, and 150°, Preferably 60°¢, Preferably in a polar 80lveny 4,4 4 protonie acid ig then added, or

C) in the cage Of compoundg of the formula 7 which have been Prepared p, process A) op RB), ‘ 8 substitieng y and/or ul and/or i° is con- verted int, ansther Subytituent x and/or pl and/or Hn? by known methods, ang the Compounds of the formula | Obtainegd by Processes A), B)

L> and/or ) are Couverted, [gy appropriate, into their PhyeLlologicaly acceptalle acid- additioy salts Using inorganic Or organic acids, ang g “empound obtafpneq by 4), B) or Cc) ig resolved, ir Appropriate, into jtg sterep- isomers and/or its 9rticall, active engne tiomersg, “uitavle ror tpe lormatjon 4; acid-addition salts . vre all acids which 10ypy Fhysiclogically accept- able Salty, Lhey. include inorganic acids ang mono-, - 14 - BAD ORIGINAL 9 be

* bi- and trifunctional organic acids, such as, for example, hydrochloric, hydrobromie or hydro- lodie, sulfuric, Phosphoric, nitric, benzene ) sulfonic, toluenesulfonic, sulfamic, methylsul- furie, acetic, Propionic, oleic, palmitic,

Stearic, malonic, maleic, Bucecinic, #lutaric, malic, tartaric, citric, fumaric, lactic, &ly~- colic, Pyruvic, benzoic, toluic, &€lutamic, furan- carboxylic, salicylic or mandelic acidq, Preferred salts are thoge with Physiologically acceptable inorganic aclaa, strong to medlium-strong acidic derivatives of such acids or with Buccini. acid,

L(#£)-tartaric acid D(=-)~tartarjc acid, malice ucld, ftumaric acid (8)-(#)- or (#)=(=)-mandelic acid,

Suitable strong bases in process A) are, above - all, alkall metal hydrides, such as, for example, sodium hydride, or alkaline-earth metal and alkali metal alkyls, such as, for e¢xample, n-butyllithium tert.-butyllithium, methyllithium, pheny111thium,

Or methylmaznesium chloride or tromide, or metal- lated amines, such as, for example, 1ithiun ai- isopropylamide, potassium amide or sodium amide; lithium alkyls, such as n-butyllithium or lithium diisopropylamide, are preferably used.

The use of two equivalents 01 strong bases ig appropriate in the majority of the substituents occurring according to the invention in the 1- - 15 =~

BAD ORIGINAL Pp) fo ART nh? vengylimidagoles 10 bb uscd as starting materials, and also in such c¢oapounds of tne tormula 1V which are unsubstituted in the bengyl radical. 1-Benzyl- imidazoles which are substituted in the phpnyl radical by distinct acceptor substituents, such as, for example, CFa, or which are substitueed in the ortho- and/or para-position by F, Cl and/or Br represent an exception to these. In these and in 1-(%~chloropbenyimethyl )--imidazoles, the use of one equivalent of & strong base, preferably butyl-

Lithium, is wuiiicient to obtaln adgquately good yields of compounus of the formulae I. “he reaction can be carri€a out in the solvents which are customary lor organometalllc reactions, 1° such ns, for example, dimethyliormamide, dimethyl sulfoxide, Jimethoxyethane, diethyl ether or, preferatly, tetrahydrofuran, Mixtures of dif- ferent aprotic solvents can also be uged, includ- ing mixtures of polar and nonjclar solvents. In Bh #0 addition, additives such as, MLN, RR ~tetramethyl~ ethylene-diamine or sexame th, lphosptioric triamide can be used as solvents, ihe reaction according to the invention with the girong base and tue uidehyaz of the formula V can 29 | be carried vut at temperatures butween #40°¢ and -100%c, but preferabiy tahcs (luce in the range . between 0°¢ and -+6%C. Ine reaction can also be - 16 - oo BAD ORIGINAL 9

Co ae v7 26333 carried out at a temperature above #40%c, The compounds of the formula I are 1solated in the fashion which ia vonventional and i«nown in organo- metallic reactions. fhe compounus ot the formula

I are generally purified for recrystallization from an organic solvent, such as, for example, hexane, cyclohexane, @thanol, ethyl acetate, di- isopropyl cther or acetonitrile, or a mixture of solvent, or by column chromatography on silica gel.

I'he l-bengyliniuazoles of the formula IV which are unsubstituted or substituted according to the ine vention and used as starting material are obtained i by known methods througn eldylation of imidazole or imidazoles which are substituted in tha 3- and/or 4-position using benzyl halides or using 2-chloro- | : or bromomethylnaphthalene, ’ So . I'he majority of the benzyl halides and chloro- or bromomethylnaphthalenes required as starting matericls are known or can be prepared ty known methods, for example by reaction of appropriate hydroxymethyl compounds with thionyl chloride or by bromination of appropriate methyl compounds using NBS (N- vromosuccinimide). some of the aldehydes oft the formula V are xnown or edd be prepared by known methods. sor example, . aldehydes naving a tertiary tormyl group can be synthesized by substitution of aldehyde of the formula

VI. - | BN oo- LT BAD ORIGINAL 9 oo nh) ok )

H nl b — . — Rr? (V1)

Job where ie and i nave the abovementioned meanings, in the o-posiiion uy suitable alkylating, alkenyl- ating or aliyuyleling reagents ot the ilormula omit

S in wnicn al has Lae ii.vowentioned meanings and bh denotes Cl, wr, | or one of the leavius groups which are conventionally used Lor such purposes, such as, lor example, methanesultonyloxy, benzene- or toluene- sulfonyloxy., 3uch rcuctions may advantageously be carried out under the conditions of a phase~transier reaction by ailowing the reactants to act on one &nother in a eultatle soivent, such as, for example, ether, dioxa.:c, tetranydroturan, methylene chloride, tertsbutanol, an alighatic, cycloaliphatic or aro- matic n,drocarbon, such a: hexane, cyclohexane, bengene, toluene or xylene, anisole ovr chioro- benzene, with vigorous stirring in the presence of a phase-trausfer catalyst and either a powdered alkali metal nyarcxide, such as, tor example, sodium hydroxide or potassium nydroxide, or a con- centrated ajueous solution thereof, preterably in a tenperature ran e€ rruom 200 to 120%.

Suitable phasc-transier catalysts are, lor ex- : ample, trialkylbevz,laamonium or tetraalkyl- ammonium halides, hydroxides or hydrogen sulfates - 18 -

BAD ORIGINAL 9

: preteravly having 1 to 12 carbon atoms in the alkyl radical, or crown ethers, such as, for example, 12-crown-4, lY-crown-5%; l&-crown-6-or dibengo-18- crown-6.

Y Un the other hand, aldehydes of the formula V can also be syntherized, lor example, by mono- or dialkylatiny or -al«enylating aluehydes of the : structure VI1 : il

N 1

C -—- CH, — 2 VII

A

: 0 in the g-position in a fashion which is in principle similar to that described above.

Another way of preparing aldehydes of the formula V comprises oxidising appropriate alcohole using me thods which are known irom the literature, for example : 15 using pyridinium chlorochromate (PCC). This method is used, inter alias, tor the preparation of oxa- ’ : cycloalkane aldehydes, for example, from correspond- ing hydroxymethyl compounds.

In process B), compounds of the formula III in 20. which ¥ denotes Li, Na or ¥, in particular Na, and : J denotes hydrogen or Lily are preferably used, The

J) compounds of the formula 111 are known Jr can be prepared by KIOWH methods.

Oxiranes of tne formula 11 are obtained by methods which are kn.wn from Llane literature. fhe olefin . .. “precursors are likewise prepared by known methods. - 19 - | fm —

BAD origina: AN xr }

Ine oléfius are oxidizeu to the epoxide by methudis which ave xnown iron the literature using an or;anic per-acid, such as, for example, peracetic acid or m-chloroperbenzoic acid. : - ln process C), a substituent X and/or a substituent wd and/or a substituent w2 in compounds of the

Isrimula 1 which rave been prepared by processes

A) andsor I') is coaveitea into another substituent

X and/or anotuer suogtituent wt and/or another sub- stituent R® Ly »nown methods, for exampie, a benzyloxy radical in tne phenyl group is converted into 3 hydroxyl group and toluene oy catalytic hydrogenolyslis b, process (), or a radical pd and/or a radical WE which in each 15 . case denote (L,-t)- or (L4-C,)=alicenyl is con- verted into a (Cy=Cy)- or (C4-Cy)-alkyl radical respectively by catalytic nydrogenation.

Sulitavle catalysts lor this are in the first case, for example, various typus of iinely divided pal- : 20 ladivm on actlvated charcoal or on calcium carbonate or on barium sulfate, and in the second case, the nyarogeualion of an alkenyl radical, various types of 1inely divided palladium, such as mentioned above lor the Lirst case, or finely 29 divided platinum on zctivated charcoal or on aluminum oxide or platin.u oxide. : - 20 =- ] BAD ORIGINAL 9 a7 of ihe reaction times are several minutes to a few hours, depending on the process variant and de- pending on the temperature range. . “he compounds of the iormula 1 according to the juvention contain two or more centers of asymmetry.

Consegjuently, stereoisomeric mixtures are generally obtained in Lhe g,nvnesis, The iundividuusl sterso- isomers can ove prod ed here in ditferent amounts as a result of ciffer.nt stereoselectivity. In t he case of high stercoselectivity, for example, mainly or virtually exclusively only one dias- tereomer may be produced, as a racemnate, in the ’ cage of diastereoners. uviastereomeric racemates ’ ¢ and diastereoscrs in which, lor example, a center

LE of asyumetry ig present in a uvnitsry (in- or $=) conilgurativi, oJ coupounds ol the tormula I can be resolved in a conventional iasnion, Lor X= ample by seleclive, tlractional crystallization or : column chromatography.

The diastercomeric racemates can tnamselves be resolved into their optical antipodes (enanti :mers) : in a conventional fashion. ‘he racemates and diastereomeric racenales can be resolved vy ne thods which are known in principle, ior example by fractional crystallization of di- : © astereomeric salts using optivalay active carboxylic * - 21 = pT

Rr BAR APIA A

3 v7 a ecids or svuslonic acids 91 uniform contiguration or

Ly chromatography on chirsl separating media (sup- ports). suitable optically active, chiral acids are, {or example: (L(#)- or bL(-)-tartaric acid,

D(#£)= or L{-)-malic acid, h-(-)- or (8)=-(#)~manelic acid, I(f)-lactic acid, (#)=-campror-10-sulfonic acid or (f£)-.=-viomocanpnor-c-cultonic acid. Di- : astereomeric eg&lts of sucn ciiral acids with compounds ot the dvomula Lo oare Iractio.ally recrjs- tullized Irom ewitazcle solvents or mixtures ot solvents until a constant rotation is achieved,

Porous tt the action vl +n eyuivalent amount or an excess of base, Lhe vpuredally pure diastereomeric galls can be couverteu into the pure ecnantiogers 1a orl he compounds lL and isolaiea such,

If alden,des oi inc iormula V are uscd In the formu nf optically (mre cnintiorers in the synthesis of conpounds I t brocess 4), it may occasionally be possible, 11 the crystaliization tendency is suf- ficient, to resolve tne diasilerconers formed into tne optical antipodes without 3 chiral auxiliary, for example a chirai aclu, in a known tashion by fractional crystallization and/or vy neans of cnromatographic metiods. jt is posaiile to carvy out the chromatographic resolution of diastercomers or racecated oun chiral ) , supports by means of conveitional column chronra- en s. - 22 ~ : BAD ORIGINAL G — -

va

Y

. FW graphy, but .o1¢ efrective recgolution is generally achieved using acdium-pressure or high-performance : liquid chromatography. oo The cowpounds of the formula I and the acid-addit- "lon salls tnereof are valuable medicaments. They are distinguished Ly a strong psychotropic action, in particular an auntiuepressive action, and can therelore be useu lor treating depressive, states. .

They are active within a broad dose range, Lhe level of the unee administered depends on the type oi treatment dusired, on the manner of admin- istration, and ou ine condition, pg; ecies and size ’ a4 the mamnal treated. In the case of oral dosa:e, gatistactory results are achieved using doses 1H irom 0.1 mez, preferably tres 0.4 mg, up to 100 mg, yreferatl; vp to 20 mg, of a compound of the formula i per kg v1 body weight.

The compounds of the formula (1) ana the acid- addition salls Lnereof represent valuable psycho- : pharmaceuticals. They nave a very good action in speciiic biochemical and pharmacological test wogely tor untidepreasiveas,

The compounds according to the invention antagonize tetrabenazine-induced ptosis in mice and rats with an orall, administered eDg, of 0.5-60 mg/kg. The - 25 =

Car Fr

BAD ORIgijvAL PD)

appropriszte cooint oi os homogenate of Lhe recpective subgtance in a ceaus enriax,methyl eo Jlulogse is fed to six ale aninvads Lsing a stomach tube one hour before treatuent with tetra-benazine (40 MEF RE y intraperitonen'iyj. Tetr tenozine-induced ptosia is antar>ridsed Ly Lhis pretreatment.

Che compounds | and he acid-addition salts thereof potentiat. the toxicity 90 yohimbine in mice. At 0.% to 100 ug, /. per os, Lype 1 antidepressives cause au increase in the death rate of an other- wise nonfaial dose of yohi.tine hydrochloride {20 m/e administered subcutnneousl;). = sn emsentlal tinding is that the compounds 1 and ire galls thereof do not cause stereotypy in

Ln rats und alce aller cosages in a therapeutically ) relevant rauge., . ) “he antidejressive action and utility, for the treat- ment of depres.ive states wes Lurthermore demons- trated by, mesa of Lhe Inhiciti.on ol reabsorption 29 ni noradrenalin- in o.se brain synawptosoma prepa- rations.

Tre compounds aha the acid-acuition salts thereof are parlicularly vialuabic through a structure differing Iron tne autidepressives known hitherts. their action ts ¢ url oi superior to known com- . mercial products and they have a lower toxicity. - 28 - >)

BAD ORIGINAL &j

CC 7 w

In addition, ac erupounds of the formula I have © an antimycotic action. Juey have a very good a } action in viiro against suin fungi, such as, for example, Trichophyton mnentagrophytes, Microsporum = canis end cpldermojhy ton 1loccosum; against mold lungi, such as, tor example, Aspergillus niger, ’ : or against yeasts, such as, tor example, Candida elbicans, U., troplealis, lorulopsis glabrata and

Irichosporon cutaneun, and, iu addition, against protozoa, such as irichomonas vaginalis. or

Tr, fetus, and alco against Gram-positive and

Jram-negative baucleria,

Phere is likuwise a very good effect azainst various pathopens of skin mycosis (for example 13 itrichophy ton wentagrophytes) in guinea pigs, in pitrticular atier loud administration, ihe present invention includes pharmaceutical preparations which, peusldes aontoxic, inert, phurimaceutically sultavle excipients, contain one or more active ingredients according to the invention or comprise one or .ore active ingred- ients according to Lhe invention, and processes for the pruparation of tuese preparations.

Nontoxic, inert, jharmace.tically suitable excipients are Laren Lo mean solid, semisolid or

Liquid diluents, lilters ond formulation auxillar- : ies of s8li types. - 25 -

AT { .

An BAD ORIGINAL 9

Lee

Ne

I'mgeitble suitable 1orms of administration of the compounds according to the fnvention are, for : exanple, tablets, costed tablets, capsules, pills, ajuecus solutions, suspensions and emulsions, if : appropriate steiile injectacla solutions, non- i ajueour emulsicng, euspensions and solutions, ointwents, creams, pastes, lotions, sprays etc. che therapeutically active compounds should expediently ve precent in the abovementioned 1 pharsacevtical preparations in a concentration of avout ©,01, prercranbl, .10, to +4.0, preferably 5.0, per cent py weight of tre to-.al -ilxture.

Vie adm.nistroation concentraltionyg ior solutions, (els, creas or olowmenls and aerpsols in the

Ah Lor 01 sprays are penerail, votween U,1 = 20, preieraviy; U.b = », per cent by weight. or local administration ss cntinmycotics, suspens- lions, soluti wa, rels, creams, Yintments or suppositories can ve uscd, tor example. “he abovementioned pharmaceutical preparations can also contain further pharmaceutical active ingredients 1n addition ty the active ingredients according to the invention. rhe atovement.onecd phavrmaceuwtical preparations are prepared in a cvuventlional lashion vy known preg methods, 101 examnpic oy oaixing the active - 26 =~

BAD ORIGINAL 9)

Co | | 3% 7

Fb ingredient or ungrevients with the excipient or vxcliplents, +he present invention also includes the use of the active lngredients according to the invention

Z and pharmaceutical proparations wnich contain one ar more active ingredients according to the invent- ion in human and, in the case oi antimycotically active :cesipounds, in human and veterinary medi- cine for prz2vention, laprovement and/or cure of the above.enticnezd digorders. in Lhe case uf antimycotically acting compounds according to tne invention, it has proven advantege- bus, Loth in human and in veterinary medicine, to administer the active ingredient or ingredlents io according to the invention in total amounts of } avout 0.05% to 200, preferably 0.1 to 100, in particular 0,5 to 30, mg/kg of body welght per 24 hours, if appropriate in the form of several individual doses, in order to achieve the desired results. The total amount is uduinistered in 1 to 8, ,rererably in 1 to 3, individual doses. ihe mctive ingredients or the pharmaceutical pre- yarations can be aduainistered locally, parenter- ily, intraperiteneall, and/or rectally. ! .he conpound: oi the resent invention, and the : calts thereoi, which can be used as antidepressives

Co | - 2 -

BAD ORIGINAL Pp)

Yl - can be used for the preparation of pharmaceutical ’ preparations which contain an effective amount of the active substance together. with exciplents and which are suitable for enteral and parenteral administration. lablets or gelatin capsules which contain the aci.ve ingredient torether with diluents, for example Lactose, demtrose, succrose, rannit 1, soreitol, cellulose andysor glycine, } and luvri.antys, such ag siliceous earth, talc, siearic acid sr saits thereol, such as magnesium

Bltearate ur cutclun siearate, andsor polyethylene

Slycoly are ,releratliy used. JLtablets also contain piaders, such as Lagiteslaa aluminum silicate, starch, gz. iaiin Lra,acuaath, methylcellulose, erdium carvox,actnylcecellulose and/or polyvinyl- } pyrrolidoue nd, il necessary, colorants, flavor- ings and swevloners. Injectan.e solutions are preteratly isotonic ajuevus solutions or suspensions ‘ which can be sterilized and can contain auxiliaries, 20) guch 2g pregcrvatlives, statilizurs, wetling agents and/or emulsiiicre, solutilizers, salls lor regu- lation 21 oswotic pressure and/or wuller substances.

The phersaccutical oreparaliong according to the invention, whicn way contaic, if aesired, pharia- cologiceily uselul cibslances, are prepared, lor example, by means of conventional mixing/granulat- ing and coating processes and contain 0.15 to about 94, preteratly about li to about 50%, of ’ the active ingredient.

Te BAD ORIGINAL J

_—_——m _—_-——-— oo CURA st se op, 2b 0 26333

Oral administer yyy Ls carried Sut in pharmaceut jou ally Convention g) Preparations, lor “Xample jn in the roy of tablets, ccated tablets 5p Capsules, which ‘ontain, op example, 5, breferatly 30, to : t00 ne, breferat], Lo 200 “es Of the active ingre- dient per dail, dose .iixed with a tustonary exgj- ~ blent and/or ~Oustivuent, jt Leing Possible roy

Individual doges 9L OH to 200 2 to be adminigtere,, preferably once ty three tigeg daily,

LO Owever, ft iy be Necessary to difter from the dosage tentionca, wag in particular to do 89 as w lunction ,j the species and cody welight of (he 2hicet to be breaded, the nature sng severity ot

Lhe disorder, the types of breparation ang admin~-

Lo istration of Vie tied icament and the periog of i Lime or intervyj within wnich administration takes place, Thug, |g fay in yome ‘u8e8 te gufficient vo nanage with jeg, Lhan une boveirentioneq aaount

O01 active ingeediene, Whereas in gthep cages jit ig 0 necessary yo exceed Lhe ALOVumentioney amount or

Hetive ingredient, The optinwm dosage nd Lype of administration 'L Lhe activ. ingredients neces-~

Bary in eacn cage CAN casily bo determined by those siilled in the art on the Laiis of their expert zh Knovledge, ' . rhe compound: of the Formula jg according to the invention are ajiso lungicidally Active, ihe r } BAD ORIGINAL 9

SE ~ 29 - .

Po range ol oti a oF the wavpounds claived covers a large auwier ot Gi vrent phytapathorenie funei, such as, [21 «:u3le, Piricularia orysae, Fel~ licularia sasn«li, various types 2t rust, (ercoe- pora specles qong Lroe mildew fungi in Iruit, vegetable, cerv aud Lrnsmental plant growing. the 1oliowing, exaples illustrate the breparation ol the coupounds. [he -eactions described in the examples were carried ut _nder a nitrogen atmoa-~ : 4 phere. -xamnple 1 1-(1-Allyl-l-cyclohexyl)=-2=-(3~chlorophenyl)= e=(l-imidnzolsl)=-ethanol 13.6 ml (20.1 wmiol; 91 a l.4c wolar solution oi iy n-butyliithium in nexzne were added dropwise .to ag colution 24 3.0b%g (JUmmol) ot l-{3~chlorolenszyl )- i

Luidazole au 40 wl of alsoiuvte tetrahydrofuran (LiF) at =70%, The wixture was stirred lor a lurther 50 minutes at -i0%, and a solution of 3,60 g ot 5, purity («0 wmol) l-allyl-l-tormylcyclohexano in 30° ml ol absolute tetrahydrofuran (THF) was then added dropwise at -70%: over about 20 minutes. the reaction mixture was subseguently stirred for a further 1% in Les at atout -70°%: aud allowed eh Lo warm Lo roon tesperature over about 2 hours, “ - 20 - BAD ORIGINAL 9)

oo 517 200 ml o1 waler were © - added at about 5-16° with cuoling, “he ixture was stirred for a fur- ther45 uinutes al about 5-15%¢, the phases were separated, and the ayueous phase was extracted - repeatedly wiih ether. ine (omblned organic <olutions were wisiied with about 20 ml of water, dried, f[iltercd and ¢vaporated in vacuo. The extract residue (€.8 g) was dissolved in acetonit- rile, after wnich crystalline 1-(l-allyl-l-cyclo- 19 hexyl)=-2-(3-chlorophenyl)-2-(l-imidazolyl )-ethanol (2.6 g) precipitated. The product (2.6 g) was recrystallized [rom 20 al of acetonitrile. After this, 2.3 g or pure product (melting point 119°C) were produced. After concentration of the uotier

L5 liyuors, a furcher J.0 g ol product were obtained which, after recrystallizatlion from acetonitrile, gave a further 0.42 g of pure product {melting point 119°C). lhe yield of pure 1-(l-allyl-l- cyclohexy )=2-(3-chlorophenyl)-2-(1-imidazolyl)- ethanol woe 2.72 ¢ (@ 39.4% of theoryl).

Coot 5C1N,0 (344.68) : Jalculated: C 63.65 H 7.31 C1 10.28 N 2.12 #% ound : ¢ 69.7 HH 7.3 Cl 10.5 N 2.3 % . | - 31 = 4

OL, | BAD ORIGINAL 9 ! , \

ixampl e 2 l-(5=-vhiorophenyl)=3, 5~dimethyl-1-(1-imidazolyl)- v-hexen-2-o0l 10.2 wl (¢2.1 wold) of a 1.5% molar solution of n-

J | butyllithium in hex ne were adoaed dropwise to a solution ol 4.~2 p (22 mmol) of 1-(3-chlorobenzyl)- imidazole fu 50 ml of =2bsoluie THF at -70°%C. ihe mixture was stirred tor n further 30 minutes at -10°%¢, and a solution of 3.75 g of 75#% purity

HA (25 mmol) {containing lb» of toluene) 2,2-dimethyl- f4~pentenaldenyde in 38 ml of absolute TF was then added dropwise at about -70°C ver about 1% minutes. vie reaction mixture was sutsejuently stirred for a further ib winutes at avout -70°C and allowed to 1" war.: Lo room lemperature over about 2 nours, 350 nl ol water were added at 1-10°C with couiing, -the mixture wae stirred tor a turther 30 minutes at 10-20", Lhe phases were separated, and the ajueous phage was extreeted repeatedly with ether. The

IN concined organic solutions were further worked up ay descrived in cxaaple 1, ihe exiract residue (7.2 2) wag cnrowalograghed, eluting with vi ul, shexane L:2 and 1:1 nixtures, vil, Cl, and

SH, CL ui ut sixtures witn a+ increasing C,H Vi 29 content to a maxamun ol 27 by voiume) on a silica sel 5 wil, C1, : nexéene L:2 column (@2.8 em, . height 453 cn). - 32 - | S—

RAD ORIGINAL P)

ak

Co : i yfter elution of ,60 g preliuvinary tractions, 5.0 g oi product, a owaicn tho eonpound desired was greatly concentrated, were eluted. Irom this proportion, %.10 ¢ (8:00.74 yield) of pure l-(3-chlo- “ rophenyl)=3y3-dimethyl-1=(l-inidazolyl)=-5~-hexen- 2-0l of melting point 35%, were obtained by crys- tallization from diisopropyl ether. 3 glin) ¥177,0 (304.3%) calculated: o< bG.0¢ «4 6.94 C1 11.63 N J.1)

Found: Cc 67.4 ff 7.1 vl 12.0 N 9.2 7%

LXample 3

L=(3=-Chlorophenyl ;=3, 3-dimethyl-1-(4(%,-methyl- i-imidazvulyl)=-o-hexen-2-0l 16.2 ml of 1.4%, molar n-iutyllithium/hexane solution 195 and a solution of 3.79% g of Tul purity 2,2-dimethyl- 4--pentenaldehyde in Zio oml of absolute THE were successively added dropwise, as described in .xample 2, iu a solution ob 5.17 & (25 mmol) of 1- (3-chlorobeazyl)-4(5)-nethylinidazole (6:4 mixture) in 50 ml of absolute [if at =70°C. Ihe further procedure was likewise carried out as described in Ex. aple 2. «he extract reagidue (0.0 g) was chromatographed by elution with CH,Cl, and CHyCL,/ uv, Hgln mixtures with an locreasing C,uigl content 25 . (to a maximum ol 2p jy volume) on a silica gel . - 33 = st Ter ria [——

BAD ORIGINAL 9 pF" oo sloi,el colon if 00 em, hed ht 36m). After lution of nn. 0” prelinipary froctions, 0.75 of impure predrol wes eluted, from which 0,12 + of 1-(3-chloroplien,1)=-3, >~dimeth;1-1-(4(5)-methyl-

I=imidnuolyl)-S~hexen-"-0l (as a 4- and S-meth,1- inidarzolyl mivture) were nbtained in crystalline . corm from dilsopropyl either, 4.80 g of greatly . concentrated product were then eluted, from whieh 3.45 £ 01 uryastanloine product were obtained from

PO diisopropyl etihev. Tp total, 3.57 g (& 44.8) yield) of pure l-(5-culorophenyl)-3,3-dimethyl-1- (4(%)-methyl-l=inidazolyl)-Y-hexen-2-0l (as un 4- and HS=methy,l mixture) ol welting point 32°¢ were © obtaineu.

LafiysClT,0 0 (318.06) ‘aleculated: 0 67.00 i 7.27 vl 11.12 NLT) 0% : round: Co bt. l 1 7.4 cl 11.3 NoOob.S ’ xample 4 1=(2-ALlyl=5-norvorucna=-2-yl)=-2-(3-chlorophenyl}=-2-

A 0 (l-imidazilyl)-cthanol 13.8 ml (20 mmol) of a 1.45 wolar solution of n- : butyllithium in vexcne were added dropwise to 3 solution of 3.05% g (20 mwol) of 1-(3-chlorobenzyl)- © {nidazole in 40 wl >of aLuolute Tif at -70°C. after stirrin. tor 30 wlnutes at -70%¢, a solution : - 34 =

Ce | BAD ORIGINAL J a of 4.3) ¢ ot ij. jutity, (70 mmol) 2-allyl=5-norbornen=- ¢-aldebyde tn 0 5il ni absolute THY was added drop- wise at aloul 70° aver about 12 minutes. lhe lurther procedure was culieguently carried out ; oy describou in xonple 2. the residue (9.0 7) remaining Jvowr Lire srgaale component after removing the solvent by distillation was dissolved in diiso- jruopyl ether/hexane 2:1, whereupon crystalline pro- auct precipitated. After isvlatlon using 20 ml or .

LG acetonitrile, this was boiled briefly, filtered of{ under suction after cooling the mixture, and washed with acetonitrile. 2.70 g (2 38% yield) -f pure 1=-(2-allyl-%-norbornen=-2-yl)-2-(3-chloro- phenyl)-2-(1-imjidazolyl)-ethanol were obtained in is) iorm of a mixture, coiprising 2 diastereomers, of velting polnt 134-135°C. po i 360

Cop fyzCLi 20 (354.07)

Calculated: C€ Tl.C¢ il L.H3 <1 9.93 d 7.89 op»

Yound: c 11.2 de ¢l 10.5% N T.9 =n

S10 Lxample 5

L-(4=viphenyl)-3, 3-dimcthyl-1-(1-imidazolyl)- 1-phenyl-2-butanol 5.86 g (25 mmol) of 1-(4-dipnenylmethyl)-imidazole in 50 ml of absolute 1HE were metallized ‘at -70% oo 2% as described in kxasple 2 using 16.2 wl of 1.55 yh” oA 0lsr n-bub Pr ithica hoexiice So) ulion, A g8o0lution af 1.51 oof IY mit Pyr-dimethyl-3~-phenylpro- pionaldehyde (27 wwnl) in 35 ml of absolute [NF was then added dropwise at 10, the mixture was : : atirred ot Fo Tor 20 minutes and allowed to warm to oo bLoopoeretuve over 2.5% hours, 250 nl of ater were aaded dropwise at about 0°, and the adlxture wos stirred for 1 hour with ice cooling.

During this, a crystalline substance precipitated

Le aut; this was Jiltered otf under suction, washed with water and a2tbher and tnen dissolved in 100 nl LL af CHL, CL, /CH 1:1. ifter riltering, this solution was evaporated in vacuo, and the crystal- fine residue was boiled tor 10 minutes with 3% nl ih of acetonitrile. #lL.r cooling to 5-050, the solid was 1ilevercd oti under suction and washed with acetonitrile. 2.70 g 2 27.3. yield) of pure 1-(4-aiphenyl)=3, 3~ditiethyl~i-(l-imidazolyl)-4- phenyl-2-tuionvl ol weltin, poling 220% were obtained.

C0 J peplig lin (336.54) calculated: © 8i.7¢ HH q.12 oN 7.07 % .ound: Cel. 0 tt 7.1 fil 6.3 - 36 -

BAD ORIGINAL 9

L

.

Example 6 1-(3-Bromophenyl)-3,3-dimethyl-1-(1-imidazolyl)- 5-hexen-2-01

A solution of lithium dilsopropylamide was pre- pared in 40 ml oI absolute tetrahydrofuran (THF) at -30°C starting from 2.06 g (20.4 mmol) of diiso- propylamine and 13.4 ml of 1.5 molar n-butyllithium/ hexane solution (20 mmol). A solution of 4.75 8 (20 mmol) of 1-( 5-bromobenzyl)-imidazole in 25 ml of absolute THF was added dropwise to this solu- tion at -70°¢C to -78%c, the mixture was stirred : at about -70°¢C for a further 30 minutes a solution of 3.22 g of 70% purity (20 mmol) 2,2-dimethyl- 4-pentenaldehyde in 30 ml of absolute THF was subsequently added dropwise at about -70°¢C, and the mixture was stirred at about -70%¢ for a further 20 minutes and allowed to warm to room temperature over about 2.5 nours. 300 ml of water were subsequently added dropwise at 0°c-5°¢c, and the mixture was stirred for 1 hour with ice codl- ing. After separating the phases, the agueous solution was extracted repeatedly with ether.

The combined organic solutions were further worked up as described in Example 1. The extract residue (7:3 g) was chromatographed by elution with CH, Cl, and CH,Cl,/C,Hs0H mixtures with an . increase in C, 40H content (to a maximum of 2% by

A? volume) on a silica gel 3/CH,CL, column (@ 2.8 cm, height 48 cm). After elution of 2.0 g& preliminary fractions, 8.2 g of product were eluted in which the compound desired was greatly concentrated.

Yrom these 5.2 g, 3.05 g (a 43.6% yield) of pure 1-(3-bromopheny1)-3, 5-dimethyl-1-(1~-imidazolyl )- 5-hexen-2-0l of melting point 126°¢ were obtained by crystallization from diisopropyl ether/hexane 2:1,

Cy Hy, Bro, 0 (343.29)

Calculated: C 58.46 H 6.06 Br 22.88 NA 65.02 »

Found: C 58,4 H 6.1 Br 23.8 N 8,0 % fhe following compounds of the formula I were obtained analogously to rxauwples 1 to 6: - 3H -

. Yr

Table 1:

Ex. X Y wy wd HG rR? m.p. [7%7 - . 7 3-C1 id H H CHy=Ca CH, CH CH, 102

Cig 8 3-C1 4-Cl1 11 H CHy-CHz CH, -(Cliy) = 143 9° 3-C1 H H H CHyC=CH, C C,H CoH, = (011)

CHy 3-C1 H H 4d CH, CHy CH, 151 11 3-C1 HOH HH Cii,y= wCl CHg CHy 191 12 3-C1 H H H CH, - (CHy) g= 168 13 4=Ce lis H H HK Cily-CH=CH, CHy CH, 120 14 4=CgHg H dH H Hate Clg CHy : 140

CHy 3-F H H H CH,~CH=CH, CH Cliy 99 16 3-C1 H H H CH,=CHzCH Chg Cy 2117 17 3-Cl H H H CHyOCH,CHy CHy CHy 93

Lxample 1g :

U1 Hog : hp vl q 1-(6,6~Dimethy] bicyclo/3,1 +1/hept-2-y1 )-2-(3- : chlorophenyl)-2-(1-inidazolyl)-ethanol

As described ip kxample, 2,7,70 g (40 mmol) of 3- (3-chlorobensyi -inidazole in 30 ml of absolute

THF were metallized at -70%C using 27 ml of 1.48 molar n-butyllithium/hexane solution, 4 solution of 6.10 g (40 fmol) oi 2-tormyl-t,6-dimethylbicyclo- £3,1,17 heptane (my rtanal) in 60 ml of absolute

IHF was then added dropwise at -70%, and the mix- ture was stirred at -70°% lor 20 minutes and allowed to warm to rocm temperature over 2.5 hours,

The further procedure was carried out analogously to that described in txample 2. The residue (13.60 g) remaining after evaporating the combined organic solution (extracts) was chromatographed by elution with CH,CL, and CHyCl,/ C,H 0H mixtures with an increasing Cohig Ui content (to ga maximum + of 3 by volume) on a silica gel S/cu,cl, column . - 40 - =

BAD ORIGINAL 9

(¢ 2.1 em, height 62.5 cm). After elution of 4.7 g preliminary fractions and 2.4 g of product con- 'taminated by by-products, 6.4 g& of product were eluted in which the compound desired was present virtually pure in tte form of stereoisomers. 1.52 g of a stereoisomer of 1-(6,6-dimethyl-bicyclo- [3,1,17hept-2-y1)-2~(3-chlorophenyl)-2-(1-imid- azolyl)-ethanol of uelting point 149-150°C which was pure according to ILC and the ly NMR spec- trum were obtained from this fraction by crystal-~ ligation from diisopropyl ether,

The yield was 4.85 g (= 35.44 of theory) of stereoisomeric mixture and 1.52 g (2 11% of theory) of a pure, crystalline stereolsomer.

Copllagtli,v (344.88)

Chhculated: C 69.65 H 7.31 Cl 10.28 N 8.12 %

Found : C 69.6 H 7.2 Cl 10.6 RN 8.3 % (stereoiso- meric mixture)

Found : c 70.0 H 7.0 . N 8.0 » : (pure di- astereomer) - 41 - : Sa BAD ORIGINAL 2

+ 397

CY kxampie 1¢ 27 PARC EY A-1- (1- 10850151 )-L-phony1-5-hesen poy 40 al ofr 1.5 aolay H-butyllithivm/hexane 8olution were added dropwise to a solution of 4.75 g (30 mmol) of 1-bens, linidazole and 3,49 g (30 mmol ), of Noll 50 B= te urane thyde shy dened ang ne (THEDA) ‘ : in 60 mi of ebsolute 11K at -70°%. ‘he mixture was stirred ay -10% to ~78% lor a further 30 minutes, a solution of 3.74 g or yo; purity (30 mmol) 212-almethyl-4-pentenaldchyde in 36 ml of } absolute THI was then added drepwise at about -70% over 25 Linutes, ang the nixture wag stirred at about -70°; for a further 20 winutes and allowed to warii to room tewperature over about 2 hours, 350 ml of water were then added at o° -8%, the mix- ture was stirred jor a further 30 minutes while cooling in an ice bain, and the bPhases were sub-

Bejquently separated and the aqueous solution wag extracted repeatedly with ether. The combined organic solutions were further worked up as des- cribed in kxample J, The extract residue (8.4 g) was chromatographed, eluting with CH,CL, and LiCl, / :

CotigUl mixtures with an increasing C,H, 0H content (to a maximum of 2% by volume) on a silica gel 29 3/CH,ClL,, column ( 2.8 cm, height 48 cm). ‘After j elution of 4.8 & preliminary tractions, 3.5% g€ of product were eluted in which the compound desired ~- 42 - ee aap ORIGINAL A

Co Cy?” 26333 was contained. This product (3,5 g) was again chromatographed in the same fashion was described above on a sllica gel 3/CH,C1, column (@ 2.0 cm, : height 6C cm), during which Lhe composition of the fractions eluted was checked by thin-layer chromatography (TLC). After elution of 0.35 g preliminary fractions, 4 fractions were eluted (with CH,CL,/C,H;CH 93.6 : 0.4 - 99.5 0.5) which contained the ®wompound desired in virtually pure torm. These fracticns were combined and evaporated in a nigh vacuwn at a bath temper- ature of 65°C untll the weight remained constant, 0.62 g (a 7.6% yield) of 3,3-dimethyl-1-(1~ imidazolyl)-l-phenyl-5-hexen-2-0l was thus obtalned as a viscous, colorless oll; the ly NMR spectrum confirmed the structure of this compound.

C, yHppl,0 (270.38)

Calculated: C 75.52 H ®.20 HN 10,36 % }

Found : C 74.9 4 8,3 N 10.1 %

The compound was present in turther chromatography fractions, besides various amounts of by-products, so shat the amount formed is well above the proportion specifled above and isolated in virtually pure form. : - 43 - : .

BAD opi, . : | Ola a)

Lxampke 20 2 PARe Ly d=1- (1-4n14050171 )-1(3-me thoxy phony ). 5-hexen-2-0) 7.52 g (40 umol) oi 1=(3-methoxybenzyl)-imidagole pg) and 4,65 g (40 wmol) of IMEDA {n 0 ml of absolute

IHF were netallized using 53,5 py] of 1.5 molar n- butyllithium/hexane solution according to the pro- cedure described in Example 19, and the broduct was reacted with 5,00 £ 01 Y0;¢ bhurity (2 40 mmol) : 2+2-diuethyl-4-pentenaldehyqe. ¥ork-up was effected analogously to that in wXxample 18, "The extract residue (12.2 8) was chromatogra shed a8 describegd in Example 19 on a sllica gel S/€HyC1, column (¢ 3.5 cm, height 40 cm), ang the combined fractions which containegd the compound desired (amount 6.3 eg) were subsequently chromatographed a second time on a eilica gel S/cH,Cl, column (@ 2.4 cm, height 8 : cm). A group of fraciilons (2,5 8) from the second chromatography Crystaliized from a hexane/diigo- propyl ether 3:1 solution, Atter isolation of the substance, 0.77 g (3 6.3, yield) of pure 3,3-dimethyl- 1-{1-1midazolyl)-1-(5-nethoxy phenyl )-5-hexen-z-ol. of melting point 83° were obtained,

Crutp4¥,0, (300.41) co ‘Calculeted: © 71.97 H v.05 HN y,33 %

Found : C bo.y H 4,0 N 5,6 wu (DAD CridiinaL 9 a EE EE Ren, - TO Nd SN ; 7

Example 2) 2 Ae AL (3 lo ropheny1 )-1- (4 (5) me thy. 1. imidazolyl)-s-nexen-2-q;

A solution of 4.7¢ g (25 mmol) of 1-(3-fluore- a) beneyl)-4(5)-methyl imidazole (3:2 mixture) and 2.91 g (25 mmol) of [MEL in 50 ml of absolute IHF was lithiateg as described jp Example 19 using 33,4 ml of 1.5 molar n-butyllithium/hexane solution,

A solution of 2.11 g of yoy burity (25 mmol) 212-dimethyl-4-pentensldenyde in 25 ml of absolute.

THF was then addeg dropwise at -70%, and the mix- ture wag stirred gt about -70% fer a further 20 ‘ minutes ang allowed to warm to room texperature aver about 2.5 hours, York-up wag Sulseqyuently effected as described 1p Example 19, The extract residue (7.6 g) was chromatographed, as described | . in Lxample 13, on a 8llica gel 5/CH, C1, column ( 2.8 cm, height 48 cm), After elution of 1.35 ¢ preliminary fractious, 4.10 € ol product in which the compounds desired were Con-centrated were eluted in the fornp of 10 fractions. A crystalline substance which, after isolatlon and drying, gave 2.44 g (2 32.3% yield) of pure 3)3-dimethyl-1-(3-

HHHOTOPRONYL) ~1-(4(5)-methyl-1-1midasoly1 )-5- hexen. 2-01 (6.7:3.3 mixture of 4- ang Semethylimidazole . compound) of melting point 118%; was obtained from this product after dissolving in diethyl ether/hexane. - 45 pe oo . | BAD ORIGINAL b : am :

Cy gllpsfH,0 (302.40)

Calculated: ¢ 71.49 H 7.67 F 6.28 N 9.26 %

Found : Cc 71.3 H 7.8 tt 6.3 N 9.2 9% ~xample 22 « 3,3-Dimethyl-1-(3-methoxyphenyl)-1-(4(%)-methyl- l-imidazolyl)-5-hexen-2-o0l

A solution ol 8.0. g (40 mmol) of l-(3-methoxy- bengyl)-4(5)-nethylimidazole (%:2 mixture) and 4.65 g (40 mmol) of TiwuDA in oC ml of .bsolute THF are - 10 lithiated as degscrited in bxaaple 19 using 53.5 ml of 1.5 molar n-butyllithium/hexane solution. A solution of 6.42 g of 70: purity (40 mmol) 2,2- dimethyl-4-pentenasdehyde in »0 ml of absolute {HF was then added aropwise at -70%¢, and the mix- ture was then stirred to about -70% for 20 minutes and allowed to warm to room temperature over the course of about 2.5 hours. Work-up was subsequently ef.ected as described in itxample 19. Ihe extract residue (14 g) was chromatographed as described in cxample 1J on a silica gel 5/CH,CL, column (0 2.1 cm, neight 67 cm). Alter elution of 4.4 g of preliminary ‘ fractions, 4.5 g ot product in which the compounds desired were concentrated were eluted in the form of 3 groups of fractions. From these fractions, 0.56 g ot pure crystaliine 5, 3-dime thyl-1-(3-methoxy- . - 46 = a

Ce BAD ORIGINAL 9 wn tr? 2 pnenyl)=1-(5-(4)-methyl-1-imidagolyl)-5~-hexen- 2-01, melting point 119-121°C (5-methyl:4-methyl 87:13 according to the Li ame spectrum) were obtained from diethyl ether/nexane. Ine oily lye residue 5.9 g) was again cnrownatographed in the sare way. From a group ol fractions (residue 1.6 g) containing the desired compounds in con- centrated form, a further 0.60 g of crystalline product, melting point 125-126°C (5-methyl: 4-methyl compound about Ysl) was obtained.

C)gHyglyUy (314.43)

Calculated: C 72.58 H 6.34 KH 5,91 i

Found : ¢ 73.0 qd B.4 Ho Y,0

Example 23 : ) 1-{3=Chlorophenyl)-%3sdinethyl-1-(4-methyl-1- : imidagolyl)-5-hexen-2-o0l. and 1-(3-Chlorophenyl)-3,3-dimethyl-1-(5-methyl~1- imidagolyl)-5-hexen-2~ol

A solution of 10.34 g (50 mmol) of l-(3-chloro- benzyl)-4(5)methylimidazole (3:2 mixture) in 100 ml of absolute THF wus lithiated as described in

Lxample 2 using 33,4 ml of 1.5 molar n-butyl- 1ithium/hexane solution. A solution of 6.24 g of 90% purity (50 mmol) 2,2-dimethyl-4~-pentenal in 75 ml otf absolute THF was then added dropwise at -10%¢, ) : - 47 -

Lo ; AD ORIGIN; 2) v

YY

! and the mixture was stirred at about -70%¢C for a further 40 minutes and allowed to warm to room temperaturc over tne course of about 2.5 hours.

WOork-up wag gubseyuently eilecied as described in oxample 1.0 & oi crystaliine product (melting point 136-1370) (1-(3-chlorophenyl)-3,3-dimethyl- 1-(5(4)-methyl-1-imidazolyl)=-5-hexen-2-0l accord- : ing to the 11 dik; H-methyl:4-methyl compound 16:14) were obtained in addition to 11.6 g ol oily ether extract residue. The latter was chroma- tographed as described in kxample 19 (column: @ ».6 cm, heignt 95 em). After 1.0 8 preliminary frac=- : tions, groups ot jractions were obtained which, according to TLC and 1a Nd, contain the desired compounds in concentrated form (5.8 g). From these groups of iractions, crystalline product was obtained, in each case irom diethyl ether/hexane golutions. 1.39 g of crystals (4-methyl :5-methyl compound 75:25) were obtained from the first-eluted group of fractions (2.33 g), and 0.94 g of crystals (5-methyl:4-methyl coapound aboub 1:1) from the subsequently eluted groul. 0.46 2 of crystals, pure

Lo (3-chlorophenyL)-3, 3-dinethyl=l=(o=methyl=i- imidazolyl)->-hexen-2-ol, according to ly NR, melting point 142-143°C was obtained from the iinal group of iractions (2.93 8).

C\ gilp 51 Np0 (318.86) . - 48 - | / : [EAD ORIGINAL 9

“ } a7 7

Calculated: C 67.80 H 7.27 C1 11.12 K 8.79 %

Found : c 67.5 Hd 7.3 C1 11.0 HK 5.0 %

The 0.94 g of product (5-methyl:4-methyl compound : about 1:1) waa recrystallized from ethyl acetate/ diethyl ether/aiisopropyl ether. Up doing this, 0.42 g oi crystsls with a 62x proportion of 5-methyl : compound was obtained. The residue from the mother liquors (75a of 4- methyl compound) (0.5 g) was combined with the 1,35 g of product {75% of 4-methyl compound) obtained above, and this component was recrystallized as described above. From this pro- cedure, 0.31 g >I pure 1-(3-chlorophenyl)=3¢3- : dimethyl-l-(4-rethyl-l-imidazolyl)-5-hexen-2-ol, according to 1a NMR, melting point 126-127, was obtained. :

C1 gflp3CLl¥,0(310.86) | ‘

Found: C 67.6 H 7.2 Cl 11.0 § 8.9 %

The 4-methyl- and 5-methyl-l-imldazolyl compounds difier, inte: alia, clearly in the position of the ly NiMR signal for the proton in the 2-position of the imidazole radical (measured in CDCl uging TiS as the internal standard). This signal is at 7.43 s in the case of the 4-methyl-l-imidazolyl compound, and, in contrast, at 6.16 6 in the case of the y-methyl-l-imidazolyl compound. . - 49 = .

BAD ORIGINAL 9

Ilxample 24 543=Dimethyl-l-(4~-diphenyl)-1-(4~methyl-1l-imidazo- lyl)-5-hexen-2-ol 25 mmol ‘of 1-(4-diphenylmethyl)=-4(5)-methylimi- dazole in 50 ml of absolute THF were lithiated as descrited in bxample 2 using 2% mmol of n-butylli- thium, dissolved in hexzne (1.5 molar). As de- scribed in Lxample 23, a solution of 3,12 g of 90% purity (25 mmol) 2,2-dimethyl-4-pentenal in 35 ul of absolute [HF was then added dropwise. Further treatment took piace analogously to lxample 23 or vxample 19, 1.0 ¢ of a viscous 211 were obtained as the rovidue irom the ether extract and were chromatographed as described in cxample 19 (column: io 2.8 cm, height 36 cm,. After elution of 2.2 g sreiiminary 1lractions, ww tractions (6.10 g) were eluted which cornitained the desired compounds (4- and b-methylimidazolyl compounds) in highly con- centrated form, J3onme of this product crystallized from acetonitrile, Alter isolation, 0.81 g of, according to 1y NAR, pure 5,3-dimeth, L-1-(4-di- phenyl )-1~(4-methyl-i-imidazolyl)-5-nexen-2-0l, melting point 159-1607¢, was obtained.

C, 4 Hy gh ,0 (360.50) 29 calculated: CC {39.6 il T.&3 NK 7.77 % . found : : CC &0.l i w.l HN 7.6 }% - 00 ~ I IN - : BAD CRIGIMNE!

. oo 2

Example 25 . 2-(3-Chlorophenyl )~-2-(1-imidagolyl)-1-(3-methyl-

S-oxetanyl)-ethznol

A solution of 3.85 g (20 mmol) of 1-(3~-chlorobenzyl)- lmidazole in 40 ml of absolute THFi were lithiated a8 desc ribed in bxample 2 using 14.7 wl of 1.5 molar n-butyllichium/bhexane solution. A solution of ¢.,10 g (21 mmol) ot 3-methyloxetan-3-zldehyde (see below) in 2H ml of ab-solule LHF . . was then added dropwise over the .ourse of about 30 minutes at -70%¢, and the wixture was stireced at about -70": ior rurther 30 minutes and allowed to warm to room temperature over the course of about 3 nours., lhe mixture was subseyuently cooled to -10%, 200 nl af water were addcd dropwise, and the mixture was stirred ior = iurther 30 minutes while cooling in an ice bath. Lhe pneges were then scpurated an! the agueous phuse wus extracted three times with ¢tner. After duryi... , tiltration and gvaporation co! the solvents, the ombincd ori-nic phases gave 5.10 of an oily residue, some of which crystal- lized from scetonilrile igolation of the crystal- line subetance gave 0.50g0f pure 23-(3-chloro=- phenyl)-2-(l=-inidagolyl)-1-(3~methyl-3-oxctanyl)- ethanol, melting point 223-229°C, diastereomer A, (& 8.5% yield). !

Uy gil) gCIN,0,(232. 77) - bL - : aso orca. J y37 >t

Calculated: UU 6€l.54 i 5.85 Cl 12.11 § 9,57 %

Found : Cc 61.8 n 6.0 c1 11.7 N 9.5 4%

The residue from the mother liquors (4.6 g) was chromatographed as described in Example 19 on a gilica gel 3/¢H,Ll, column ( 2.8 cm, height 28 cm)

CH,CL,/C,H 0H mixtures with an increasing C,oH,0H content, to a maximum of Sk by volume), After elution of 1.10 g of preliminary fractions, 1.20 g of product were eluted, from which 0.37 g of the " desired compound, diastereomer B, melting point 145-146°C, crystallized out from a» solution in acetonitrile. A :urther four subsequent frattions contained 1.5 g as eluate residue, wnich gave 0.96 g of 2-(3-chiorophenyl)-2-(1-imidazolyl)-1- : (3-meth,l-3-oxwtanyl)-ethanol, diastereomer B, melting point 145-146°C, from acetonitrile solu-

Co tion. lp total 1.33 ¢ of diestereomer B were isolated in crystalline form (melting point 145-146°C) (8 22.7% yield). a0 Cg CINy0, (252.77) calculated: C 61.54 H 5.85 C1 12.11 RN. 3.57% found ¢C 61.8 il 5.6 Cl 12.4 N 9.5 HK

Preparation of 3“methyloxetan-3-aldehyde (starting material for the compounds of txample 25): ah 9.84 g (120 mmol) of powdered anhydrous sodium ’ acetate were added to a solution of 37.05 g (172 mmol) - 52 = -

BAD ORIGINAL A oe sf pyridinium chlorochromate in 300 ml of CH,CL,.

A solution of 12.27 g (120 mmol) of 3-methyl-3-hydro- xymethyloxetane was added dropwise to this mixture over the course of 30 minutes at 7-10°C while gtirring. The mixture was stireed tor a further 3 hours at 8-12%z. The reaction mixture was then poured into 900 ml of pentane, a viscous; dark resinous material depositing. After pouring of. the pentane solution, ti.ig material was worked . thoroughly several tiie® with pentane; The pentane componeuts were clarified through a filtration aid, washed by shaking .nce with saturated NaHCO4/!,0 golution, dried over MeS0, and, after filtration, concentrated on a 40 cm Vigreux column at a tath = 19 temperature of 50-60°C. The residue was subjccted to fractional distillation, initially at atuospheric pressure tnen snder reduced pressure. A fraction (4.10 g 2 34% yield) of boiling point 117-122°7 at 200 mbar was about 90% purity 3-methyl-oxetan-3- <0 aldehyde accordlug to the ly NMR spectrum and was used in this form ior the synthesis described in

Lxample 25. nxample 26 1-(4-Diphenyl)-3,3-dimethyl-1-(1-imidazolyl)-2- hexanol 170 mg of %% platinum on activated charcoal was ) added ag catalyst to a solution of 1.733 & (5 mmol) - 53 - oo ¢

BAD ORIGINAL 9 of 1-(4-lipnenyl)-3,3-dimethyl-1-(l-imidazolyl)-5- hexeun-2-0l (compound according to Example 16) in 80 ml of methanol and mixed vigorously under a hydro- cen atmosphere at a slight excess pressure of hydro- p sen at 24°C and aa atospeeric presygure of 984 wbar.

After 1 nour, 120 ul of nydrogen had been tazen up. 40e suspension was liltered under suction tnrough a illtration aid and the filtrate was sub- reyuently evaporated in vacuo. ihe crystalline regidue remaining (1.75 g¢) was toiled triefly with r+ ml of diisopropyl ether, cooled in an ice bath, i1ltered off unuer suction and dried. 1.63 g (£ 93.76 yield) of pure 1-(4-diphenyl)-5,3-di- nethyl-l-(l4midazolyl)-2-uexanol of rnelting point 1H 171% were obtained.

Chip, 150 (34.49)

Calculated: © 79.27 u ©.,10 i «.,04 found Cc 712.9 dB. dA T7.9 cxample 27 1-(3-Chlorophenyl)=-3,3-dimeth,1-1~(l-imidazolyl)- 2-hexanol in the same fashion as described in Example 26, 1.43 g of 1-(3-chlorophenyl)-3,3-dimethyl-l~(1- o imidazolyl)-2-hexanol of melting point 97 °C were obtained througn nydrogenation on a 5 mmol scale - --04 = [sting

BAD ORIGINAL 2) =

Co. op J 7 of 1-(3-chlorophenyl)-5,3-dimethyl-1-(1-imidagolyl)= s~hexen~-2-01 (compound according to cxample 2) with 200 mg of sulfidized 5x platinum on activated charcoal as catalyst.

Cj qty3C1a,0 (300.84)

Calculated: 6¢.54 il [.56 C1 11.5% N 9.13 %

Found : C 66.3 h T.4 1 11.7 N 9.0 %

Lxanple 28 : 1-(3-Chlorophenyl)-3, 3-dimethyl-1-(4-methyl-1- imidazolyl)-2~hexanol

In the same fashion as described in ixample 26 through hydrogenation ol 1.27 g (4 mmol) of 1-(3- chlorophenyl)-3,3-dimethyl-1-(4-pethyl-1l-imidagolyl)- 5-hexen-2-0l (cowpound of bxample 23) in 70 ml of methanol using l80 mg of sulfidized 5% platinum on activated charcoal as catalyst, 1.27 g of 1-(3- chlorophenyl)-3,3-dimethyl-1-(4-nethyl-l-imidazolyl)=- 2-hexanol, melting puint 123-122, were obtained.

C,gliygC1N,0(320.87) : cnlculated: C 67.38% H 7.85 Cl 11.05 HN 8.73 %

Found : Cc 67.2 H 8.0 cl 11.1 N 8.8 %

B Iharmacological test }

Tegt tor influence on tetrabenazime-induced ptosis : method ; - 55 =

CE BAD ORIGINAL 9 } ~m.

yb ~

Cale aice (oiw=Tl, Kr¥:NIAL) weighing 18-22 g were alloted al random to treatment groups of 6 animals. The test substances were suspended in 1% strength nethylhydroxyethyicellulose (MH) /water o and administered orally at lO ml/kg of body weight. 4 control group was clven the anlvent (1 strength “H), and the standard group was given 10 mg/kg p.o. of nomifensine (in 1: strength MH). The tetra- : Lbenazine solution used wag prepared trom methane- sulfonate (2 76.86. of base), and an amount correspond- ing to 40 hg/ke oli tetrabenavine base was admin- istered intrapevitonezlly in minutee after the test substances. The ptosis was assessed accord- ing to the following scale 30 minutes after admin- 1h 1gtration of tetrabenazine:

Ptogis score iyes closed 4 nyea 3/4 closed 3

Lyes 1/2 closed 2 Bb

Lyes 1/4 closed 1 wyes open 0

The ptosis scores were cumulated and the result of the groups related to the maximum score achiev- "able (6 x 4 = 100%). Ly means of linear regres- sion, the Ble (ng/kg) was determined :as the dose at whicn the degree of ptosis is 50% of the value . determined in the control group. - 56 - . \ ~ BAD ORIGINAL J

- ? 7 2650.

IU

The lollowing results were obtained:

Compound according sDg, (coniidence limit 95%) to example _ _ mg/kg p.0, 2 2.0 (0.5~-8.8) 9 13 1.3 (0.1-26.8) 4.6 (2.2-9.7) 1 3.9 (2.1-7.3) 26 1.2 (0.3-5.4)

Standard nomifeusine l.2 (0.,7-2.0) 10 The substances mentioned exhibited a strong action in the model of tetrabenazine-induced ptosis in mice, wnich applies as predictive for an anti- : depressive action in humans. ! - 57 =

BAD ORIGINAL 9 - | '

Claims (2)

Ale? wlaims:

1. A jrocess for the preparation of a compound of the formula 1 4 d J" Rb: doa =i? I } nn RO 1 Y > W . W J N 5 in which A denntes ‘i, phenyi, ¥, Cl, Br, I or (C,-C4)-alkoxy, yf denotes H, t, Cl, Br or (c,-C,)-alkoxy W denotes H, or OClis, i denotes il, (0,mC,)-aliyl, (Cp=0y)-alrenyl, (C4-Cy)-cycloalkyl, (¢,-C,)-alkoxymethyl, Q- (Uy-Ug)-alkyl or 5 it n - 58 - t 3 . BAD ORIGINAL Pp)

2? 7 : ye YEG BA 26337 ' L&E Qr CH = Cif = Ch, in which

: Rg denotes F, Cl, Br and n denotes 0, J and, .

2 Y " ¥ Al 1 : a7 denotes (C=C, )-alkyl or (C3-Cy)-alkenyl, D io denotes (c;-C4)-alkyl or ’ Lo at and RO or R® and RS, together with the carbon atom to which they are bound, denote (Cx=Cq)= cycloalkyl, Cq-bicycloalkyl, or Co-bicyclo- alkenyl which is in each case unsubstituted or substituted by 1 or 2 Cily and in which bicycloairkenyl radicals the C = C double bond is uot in the l-position, or (oxa-J’,- Cgl-aycloalkydl, and 2 denotes H or Cily in the 4- and/or S-position, which comprises nucleophically opening an oxirane. olf the Formula I1 : ! - 59 =~ a ’ f JE Cree A DAL TIL ae Mate

. . oo . a 37 ie Xi aN at ) di — = —#° 11 Y AY !

w . , i 1 2 3 in which X, ¥, », ho, 2° and i” have the meanings as mer.tioned above by reacting said oxirane compound of the formula III N N AN | 111 pr Q / : N in which 4 denoteeg hydrogen or an alkali metal or alkaline-earth setal, and Q has the meanings as mentioned above at a temperature between -20°¢ and 150°C in a polar solvent and a protonic acld ie

JL.O then added, and the compounds sf the formula i are converted, if appropriate, into their physio- logically acceptable acid-addition malts using ln- organic or organic acids, and a compound is resolved, if appropriate, into its stereoisomers and/or its optically active enantiomers. ) ’ - 50 - : v ‘BAD ORIGINAL IP LL