Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
WO 95/22541 2 1 8 2 5 8 1 P~ 91
-1-
ENANTIOMERICALLY PURE (-)-LLARO~LE
This invention relates to novel ~ y pure r Of formula a) useful in
treating disorders which are ~ by an increased l"~ and!or abnormal
of norma~ or neoplastic epithelial cells- 'rheSe r
are ~ li~ulA I iJ useful in the field of oncology. Also disclosed are c~
containimg said novel, . ', as vell as methods of using the mentioned
to treat the mentioned disorders 'rhe i~VVlU~.Vl~ 'V" 1` of formula
15 (1) are useful for the ' of a . .I;. - .. 1 for treatmg epithelial disorders.Further the present mvention provides methods of preparing the present novel
The novel . , ' subject to the present mvention are the l~vull y isomer of the
20 compound liarozole and the pl ~ lly acceptable acid addition salts thereof.
Liarozole is aracemic mixture, i.e. a mixture of its optical isomers, and is specifically
mentioned as compound 28 in EP-0,371,559. Said patent application mentionS the use
of , ' like liarozole in the treatment of epithelial disorders. EP-0,200,744
25 describes the use of compounds like liarozole for inhibiting or lowering androgen
formation. Whereas EP-0,371,559 and EP-0,200,744 recognize that ~ - r ~ like
liarozole have -~ isomeric forms, no eAxample of an ~ pure
form is given of liarozole.
30 Chemically liarozole is (~)-5-[3~Llvlupl~ l]-lH-imidazol-l-ylmethyl]-lH-benz-imidazole, amd is ~ h ~ by formula (1). As can be seen from the chemical structure,
liarozole has one stereogenic center (indicated with an asterisk in formula (I)).
H
N ~N
Cl
The subject of this invention is the I -- ~ ly pure l~,vvl~ y isomer or
wo95/22~41 2 t 8258 I P~ 91
(-)-isomer of liarozole. Said isomer will hereinafter be referred to as (-)-lia~zole.
Many organic compounds exist in optically active forms, i.e. they have the ability to
rotate the plane of plane-polatized light. In describing an optically active compound, the
5 prefixes D and L or R and S are used to denote the absolute ~ of the
molecule about its chiral center(s). The prefixes (+) and (-) or d and I are employed to
designate the sign of rotation of plane-polarized light by the compound, ~vith (-) or I
meaning that the cotnpound is 1~ ~. ~ and with (+) or d meaning that the
compound is ~- y. l~or a given chemical structure the optically active isomers
10 having an opposite sign of optical rotation are called ~ Said are
identical except that they are mirror images of one another. A l:l-mixture of such
is called a racemic mixture.
S~ purity is of impor~ance in the field of ~ - c ~ since the respective
may have a different potency or may have a different activity. The
cnantiomer of a beneficial isom may even be deleterious rather that simply inerL
Several examples of such differences are known in the arL
The term ", ., . ,1 ;.... ;. _11,~ pure" as used herein means that the product contains at least
20 90% by weight of one enantiomer and 10% by weight or less of the other ~ r
In the most preferred ' ' the term "~ "y pure" means that the
' ' contains at least 99% by weight of one enantiomer and 1% or less of the
other,
25 It should be noted that optical totation of chemical substances is dependent upon
' 1" ; - -l parametets- The values shown in the r -l,~ part l ' are
specific rotations and the ~ 1 conditions such as ~ the wavelengtb of
the plane polatized light used, the solvent as well as the c ~ ; - of the sample are
indicated in the Cul~.,...iu~ way. The optical rotation may vaty (it may even change0 sigm!) when for instance an acid addition salt is formed. When reference is made to the
y isomer of liarozole or (-)-Liarozole then the sign of the optical rotation of
the base form is intended unde} the given ~ r ' conditions shown '
It should also be noted that when a chemical teaction does not involve the ~
35 then the absolute, ~, of said ~ ~ remains the same, although the
optical rotation of the compound which results from said chemical reaction may be
different or even have an opposite sign. Hence, in order to avoid confusion, the
WO9S/22S41 2 1 8258 1 P~l/~ s~l9l
-3 -
" with the same absolute ~ ~_ of the : as the desired
enantiomer of the final product will be designated with the prefix (A) before the reference
number.
5 The ~ acceptable acid addition salts as mentioned l~ are meant to
comprise the t;~ r '- ~ aetive non-toxie acid addition salt forms which the compounds
of formula (I) are able to form. The latter ci~n .u..~, '~, be obtained by treating the base
form with. such ~ r acids as inorganic aeids, for example, hydtohalie acids, e.g.
' ' , }~ and the like; sulfurie acid; nitrie acid; phosphorie acid and the
10 like; or orgame acids, for example, aeetic, propanoic, ~I,ydlUA~ 2 h~ .yl r
2-WUJ~ J~ , L ~ 2-b,.~ .r, (E)-2-butene-
dioic, 2-ll~h~.yl ' 2,3-dil~ul~yl " , 2-hydroxy-1,2,3-~,.~ 1 -
boxylic,T~lP-h~^s~ r~ lr~ ,4-1~1~,i.ll,y~. ~r
r 2-ll~u~yb~,l.~ic, ~amino-2 ~ V7~b~ J;C and the like acids.
15 Conversely the salt form can be converted by treatment with alkali into the free base form.
The term addition salt also eomprises the hydrates and solvent addition forms which the
- . ' of formula (I) are able to form. Examples of sueh forms are e.g. hydrates,alcoholates and the like.
20 Preferred l~ lly acceptable acids are hydrochloric acid and (E)-2-~ . t. ~ ~1;. .;.
aeid.
General preparation of struetures ineluding liarozole have bcen extensively described in
EP-0,371,559 and EP-0,260,744.
'~, pure (-)-liarozole may be prepared by reacting an; "~, pure
' diamine of formula (A)-([l) vith formic aeid or a functional derivative
thereo
~3 NH2 ~J N
(A)-(II) Cl (-)-(I)
Said funcùonal derivative of formic acid is meant to comprise the halide, anhydride,
amide and ester, including the or~ho and imino ester form thereof. Also
WO 95/22S41 2 1 8 2 5 8 1 r~
' ' or an acid addition sal~ thereof can be used as cyc izing agent.
The general reaction conditions, wor~-up procedures and cu~ ,..t;Ulldl isolationtechniques for carrying out the above and follo ving reactions are described in the prior
S alt. When more specific conditions are required they are mentioned l
The; "~, pure ~ di~unine of formula (A)-(II) may be prepared by
reducing an ' of fonnula (A)-a~) by a standard nitro-to-amine reduclion
reaction.
~NH2 ~N~
Cl (A)-(II ) Cl (A)-(II)
Tbe desired enantiomer of the of fonnula (A)-(III) can be prepared by
fractional ~ " of a racemic mrbcture of the of formula (m) with an
15 ~ ly pure chiral acid. Preferred chiral acid for the above fractional
~,ly ,~lli~liu~l is 7,7 dimethyl-2-oxobicyclo[2.2.1]heptane-1- r acid (ie.
10~ r(.- acid).
Appropriate solvents for carrying out said fractional CTyStallization are water; ketones,
20 e.g. 2-propane, 2-butanone; a7cohols, e.g. methanol, ethanol, 2-propanol. Mixtures of
ketones and water are very suitable for the above fractional ~ - Preferably a
mixture of 2-propanone and water is used.
The ratio of water/2-propanone by volume may vary from 1/10 to 1/2. ?referred range
15 f said ratio is 1/5 to 1/3.
The fractional ~ly~l _ll:, l ;....~ are suitably carried out below room L ~IA .. "" " r-, preferably
below 5C
It was also found that the subsequent reaction step can be carried out without any
30 appreciable
AlLematively the (-)-isomer of the compound of fommula (I) may be prepaTed by cyclizing
an; .. 7. ` of folmu7a (A)-(IV) foLo ving pro~edures as described above for the
W0 95/22541 2 1 8 2 5 8 ~ P~ 7v.c ~
_5_
cyclization of of fv^rmula (A)-(ll) and ~ v the thus obtained
of fonnula (A)-(V). In formulas (A)-aV) and (A)-(V) R repr~vsents
Cl 6allcyl, wherein Cl 6alkyl is a straight or branch chained saturated l~ u~
radicals having to 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl,
S butyl, pentyl, hexyl. Preferably R is methyl.
~CNHZ CN ~cN
(A)-aV) ~N H (A)-(V)
N ~ N
~IHI~ -?
Cl (-)-~
The of formula (A)-(IV) may be prepared by reacting an of
10 formula (A)-(VI) with areagent of formula (VII), alkylating the thus formed thiourea
delivative of formula (A)-(VI~ ' . l~, cyclizing the of f^vrmula (A)-
(lX), and rvducing the nitrv^ group of the " (A)-(X). In the formulas (VII),
(A)-(Vm), (A)-(IX) and (A)-(X) R represents Cl~;alkyl as defined l.v.v...~vuvc.
S /OR
NH-C--NH--CH2-CH
NH2 ,~ NH2 S~N-CH2-CH(OR)2 ¦ ~NH2 ~OR
~CH W--NO2 ~CH~l--NO
Cl (A)-(VI) OR Cl (A)-(Vm)
NH-C=N--CH2-CH rN
~ ~CH~ ,~
Cl (A)-(IX) Cl (A)-(X)
~ (A)-(rV)
The I . - .1;. ..". . ;. .,1'~ pure ' of formula (A)-(VI) can be prepared by art-
known resolution techniques, e.g. by ~ ' v . ' ~ using chiral stationa~y phases or
WO95/22541 2 1 8258 ~ P ~ C~
by forming ~' compounds such as f~lrming an amide with an
lly pure chiral acid, e.g. ~ u~yl,., - . I;. acid (mandelic acid), or
by forming ~ ; salt foTms using " ;- ~lly pure chiral acid
5 Liarozole has retinoid mimetic effects in vivo and in vilro. This means that the
compound is thought to inhibit retinûic acid ~A) catabolism, sû that increased retinûic
acid (RA) levels lead to I ~ RA effects at the tissue or cell level. Liarowle has
also been shown to be a potent inhibitor of androgen b;v~yll~ ;s. P~cbnical and
clinical studies are ongoing showing the uility of liarowle in the field of oncology and
10 ~ ' "y.
(-)-Liarozolehas .I.. ~ .llyshownahigheractivityinceruintumormodelsthan(+)-
liarozole or the racemic liarozole. It has been sho vn that a more "urgeted" therapy is
possible in the field of oncology by A~ y pure (-)-liarozole.
15 Especially (-)-b rozole may be used to treat prosute cancers.
The use of (-)-liarozole and its ~ ly accepuble acid addition salts in the
method of the present invention is based on their useful propeny to delay the catabolism
of retinoids, such as, all-~r~ns-retinoic acid, 13-cis-retinoic acid and their derivatives.
20 The latter results in more sustained / higher tissue . . ~ - ~, ,.l ;. . ~ of retinoids and
improved control of dir~ iu.. and growth of various cell types. This action of
(-)-lia~zole is also called retinoic mimetic activity because ~,1" -~ ; "~ (-)-liarozole
causes the same effect as if retinoid would be ' ~ As such, (-)-liarozole can beused to control the rate of grûwth and ~ of normal, l ~ r ~ ;. and
25 neoplastic epithelial cells
(-)-Liarozole and its ~ , accepuble acid addition salts is therefore useful in
a method of treating disorders which are 1 , ~ by an increased l~luL~ iu~
andlor abnormal, l-rr - " of epithelial cells. (-)-Liarowle shows activity on cells of
30 which the growth and ~ rr " ' is not substantially mediated by or imsensitive to the
actions of androgens or estrogens. in panicular on cells of which the growth and,I: rr . . ; ~ . is sensitive to the actions of retinoids. (-)-Liarowle is IJ~ Li~.Llolly useful
in the treatment of tumors like head- and neck tumors, lung tumors, breast tumors,
uterine cervix tumors,, I tract tumors, skin tumors, bladder tumors and
35 prostate tumors. (-)-Iiarowle and its ~ lI y acceptable acid addition salts is
useful for the r ' of a " ,r~ for treating epithebal tumors.
wo95/225~1 218~5~1 P~l/~ s~
In gcneral it is , ' l than an effective amount to treat disorders which are
. . ;,. .1 by an excessive l ' ~ and/or abnormal ~ of tissues,
would be from 0.~01 mglkg to 20 mg/kg body weight and more preferably from 0.01
mg/kg to 10 mg/kg body weight.
The compounds of formula (I) used in the method of the invention are most preferably
applied in the form of appropriate . . As appropriate .~ there may
be cited all ~ - usually employed for ~y~ ally or topically - '
drugs. To prepale the ~,l.~. ' , of this invention, an effective
10 amount of the particular compoundl optionally in acid-addition salt form, as the active
ingredient is combmed in intimate admixture with a ~ , acceptable cartier,
which carrier may take a wide valiety of fotms depending on the form of prepa~ion
desired for ' These I ' ~ { ~ are desirable in unitaty
dosage folm suitable, IJ~uhYly~ for All~ inn c~rally, rectally, I 1,/, or
by parenteral injection. For example, in preparing the ~ .. l,n- ~;.. - in oral dosage form,
any of the usual l,l -, ~ . . ,.;. ~l media may be employed such as, for example, water,
glycols, oils, alcohols and the like in the case of oral liquid l I ~ l ;.... such as
, syrups, elixirs and solutions; or solid carriers such as starches, sugars,
kaolin, lubricants, binders, ~' , _ agents and the like in the case of powders,
20 pills, capsules, and tablets. Because of theirease in ~ tablets and capsules
represents the most ~1~ _ oral dosage unit form, in which case sohd
' carrierc are obviously employed. For parenteral c- ~ - the carrier
will usually comprise sterile water, at least in large pa~ though other in~A~ c, for
example, to aid solubility, may be inc~uded. Injectable solutions, for example, may be
25 prepated in which the carrier comprises saline solution, glucose solution or a mixture of
saline and glucose solution. Injectable . may also be prepared in which case
appropriate hquid carriers, suspending agents and the like may be employed. Alsoincluded are sobd fc)rm ~ - which are intended to be converted, shortly before
use, to liquid form ~ - In the c~ suitable forl
30 ~ ' the carrier optionally comprises a penetration enhancirlg agent atldlor asuitable wetting agent, optionally combined with suitable additives of any nature in minor
which additives do not introduce a significant deleterious effect on the skin.
As appropriate ~ : - for topical application there may be cited all
usually employed for topically ~ drugs, e.g., crearns, gellies, dressings,
35 shampoos, tinctures, pastes, ointments, salves, powders, liquid or semi-liquid
r ,-, ~ ,- ..- and the like. Application of said ~ may be by aerosol e.g. with apropellent such as nitrogen carbon dioxide, a freon, or without a propellent such as a
wo 9~/22541 2 l 8 2 5 8 1
-8-
pump spray, diY~ps7 lotions, or a semisolid sueh as a thiekened c~ whieh ean
be applied by a swab. In partieular ~ semisold , ~ sueh as salves,
ercams, pastes, gellies, ointmenis and the like will cu..v, l~, be used.
S It is espeeially ,q.~iy-~ ''` to fc~rmulaAe the ~
''' in closage unit form for case of q~ and uniformity of dosage.
Dosage umit form as used in ihe ~ and elaims herein refers to physieaOy
disercate units suitable as unitary dosages, eaeh unit eontainimg a I ~ ' quantity
of aetive imgredient ealeulated to produee the desi~d therapeutie effect in assoeiation with
10 the required ~ t;~ rl earrier. Examples of sueh dosage unit forms are tablets(ineluding seored oreoated tablets), eapsules, piOs, powders packets, wafers, injectable
solutions or ~ , A ~ c~ r~ c~ r~lc and ihe like, and segregaAqd
multiples thereof.
15 Other 1 are I~lC~ iU..D of the eosmetic typc, such as toilet waters, packs,
lûtions, skin miOcs or milky lotions. Said l ~ contain, besides the active
ingredient, ~ 1 usually employed in such l~ Examples of such
J ~ are oils, fats, waces, surfactants, h~m~ rtq~tc, thickening agents,
..1;..~;.1 ---~ viscosity stabiiizers, chelating agents, buffers, ~ UU~ perfumes,
2v dyestuffs, lower aikanols, and the like. If desirecl, further ingredients may be
~ r ' ~ imthe~ .e.g.: ~ yagents". .l;l.--.. ;~lc :~ntifiln~plc
~' ' vitamins, sunsereens, antibioties, or other amti-aene agents.
In a further aspcet of the invention there are provided particular ~.l, " ,, . , l;, l or
25 eosmetical ~ ; which comprise an inert earrier, an effective amount of
(-)-liarozole or an acid addition salt form thereof and an effective amount of a retinoic
acid, a derivative thereof or a ~ r i~ lly isomeric form thereo
It ean be ~' ' that the retinoie acids and the derivatives thereof, in partieular
30 retinol, and (-)-liarozole act in a synergistie manner. Indeed, the eombined effect of both
subst4nces is greater than the sum of their respective effeets when qfiminict~d
separately. The above deseribed retinoie acid eontaining ~ c are partieularly
useful for treating aene or for retarding the effects of aging of the skin and generally
improve the quality of the skin, particul4rly human facial skin. A r~ ' or
35 eosmetieal . ~. ..l,~.- ~;.~.~ eontaining retinoie acid vr a derivative thereof as the aetive
ingredient in intima~Ae admixture with a ~ ly aeceptable earriercan be
prepared aecording to ~UII~.. iV113~ C; techniques, sueh as those known for
W095/22541 218253 ~ r~l,~ 151
topical applicalion of retinoic acid and its derivatives, optionaUy in admixture with
or derivatives thereof known in the art. Preferred ~ : .. . for topical
application are in form of a cream, ointment or lotion rnmrnC; A,g from 0.0()1 to 05%
(r ' 1!1 from 0.01 to Ql%) all-~-retmoic acid, 13-c~s-retinoic acid or a derivative thereof, in particular retinol, and from 0.1 to 5% of a (-)-liarozole or a
acceptable acid addition salt thereof, in a semi-solid or liquid diluent or
canier.
These preferred ~.. l,.. - ~;.. ~ should preferably be non-initating and as far as possible
they should be odorless and non-toxic. For f~..v.,..i~ .,c in applying to the skin, the
10 ~ usually contain, besides water or an organic solvent, several of certain
organic emoUients, emulsifiers for the aqueous andlor non aqueous phases of the
wetting agents lu~ ~ vaL;~ and agents that facilitate the penetration and
l~,."al...,.,.,e of the active agents in the skin.
15F IRaTt
A. Pre~arationofthe
ExaTnple I
a) A mixture of (4-amino-3 ~ lyl) (3-~ (50 g), formamide
(375 ml) and formic acid (63 ml) was stiTred and refluxed for 17 hour,. After cooling,
20 the mixture was poured on ice. TTTe precipitate was filtered offand dried, yielding 55 g
(99A%) of (i)-N-[(4-amino-3 u~ l) (3~hlnn~rT~nyl)methyl] r( ., . - ..;.1~ (interm.
1)-
b) A mixture of ' (1) (50.7 g), lly~ acid 6N (350 ml) and
2-propanol (70 ml) was stirred and refluxed for 17 hours. The resulting precipitate was
filtered off and dried in vacuo, yielding 51 g (97.8%) of (i)-4-amino--(3-chloro-
phenyl)-3 I 1 ' ~ ..JII~ . ;f~., mp. 263C (intenm. 2).
c) N~N~ llyl ,' - -; -- (13.8 g) was adfled to a solution of : ' (2) (43 g) in
' .~,' ~ (400 ml) and stirred at room ~ (R)-(-)--hydroxy-
;f acid (20.8 g) was aflde(i A solution of l-l.~d.~ u. ...~ (22.2 g)
30 in ~,IL.~.l-, ~ (200 ml) was a~ded, foUowed by a solution of l~[.N'-" Ih - - I. ~. A.~l_
, k ' (33.9 g) in .' ~ ' (300 ml). The reaction mixture was
stirred for 2 hours at room 1~ r D, ~1.. ,.. 1l. -. ~r (400 ml) was af~ded and
~-d;~V~ A.~ - was filtered off. The filtrate was washed with a 10% aqueous
potassium carbonate solution and the organic layer was dried (MgSO4), filtered aTid the
35 solvent was evaporated, yielding 60 g ~1) (mixture of f~ u ~ ~). The same
experiment staTting from ' ~2) (16 g) resulted in a yield of 26 g (lI) (mixture
of diA~.~ ). Fractions (I) and ~I~ were combined and purified by high-
WO95/2~541 2 1 82~8 1 P~,ll~ 5~ 19l
-10-
liquid, ' ,, . ' ~ (eluent CH2C121ethyl acetate 90110). Two fraction
grr)ups were collected. The solvent of the fraction group with higher Rf value was
~r a, yieloing 27 g of (-)-(R.A)-~-[(4-amino-3-~ lu~ ..yl)(3-
~LIuluyll~ yl)methyl]- h~Lu,.~ ~ (interm. 3)
d) A mixture of - - (3) (27 g) in ~,JLULI.Iuli., acid 12N (300 ml) and
1-propanol (100 ml) was stirred and refluxed for 18 hours. The cooled reaction mixture
was poured on ice. This mixturG was allcali~cd with ammonium hydroxide and extracted
with ~ The separated organic layer was dried (MgSO4), filtered and the
solvent was evaporat~ The residue (19 g) was purified by column, ' - ,, . ' J
over silica gel (eluent: CH2C12/CH3OH 98n). The pure fractions were collected and the
solvent was cv, r 1~ yielding 6 g (33%) of (-)-(A)~amino-c~-(3-, ' '( I ' .y1)-3-
- ~ ' [(1]2 =_27.00(c=1%inmethanol)~mterm.4).
e) A mixture of - (4) (11.6 g) arld 1,1~imethoxy-2-i~u~h;u,,~. cthane
(7.3 g) in methanol (120 ml) was stirred and refluxed for 2 hours. The solvent was
~,v, 1, yielding Ih~lG~lly 17.8 g of (-)-(A)-N-[(4-amino-3-~ .u~,l.v,.yl)(3
.,III(,I, I ' Jl)methyl]-N'-(2,2--li..._.l.u~ tllyl)thiourea (interm. 5).
f) Potassium carbonate (6.95 g) was added to a solution of (5) (17.8 g) in
2-propanone (200 ml). I ' ' (3.1 ml) waC added and the reaction mixture was
stirred for 48 hours at room . The solvent was evaporated and the residue
was stirred in 1- ' ' ' The organic layer was separated, washed with water,
dried (MgSO4), filtered and the solvent was ~,v, - i, yielding 17 g (92%) (-)-S-methyl (A)-N-[(4-amino-3 - .' Jl)(3~ 1)methyl]-~-(2,2-
d;lll~llU~ ' - (interm. 6).
g) T ------ '~ (6) (16 g) was cooled to O C and sulfu~ic acid (cooled to 5 C) was
added. The mixture was stirrGd at 5 C to complete ~iiccnlllti~n The solution was
warmed to room i ~ - c, then stirr~d for 2 hours. The solution was poured on iceand aLkalized with ammonium llydroxide. The aqueous solution was extracted with ethyl
acetate. The æparated orgaluc layer wæ dried (MgSO4), filtered and the solvent was
~v, - ' The residue (16 g) was purified by column ~ over silica gel
(eluent: CH2C12/CH30H 98~2). The pure fractions were collected and the solvent was
- 1 yidding10g(74%)(-)-(A)~[(3~'' ~ 1)[2-(methylthio)-111-
imidazol-l-yl]methyl]-2~ -ul, --.;... Cmterm.7).
h) A mixture of (7) (10 g) in methanol (200 ml) was l.~/dl.o ' for 2
hours at room i . (2-bar pressure; Parr apparatus) with Raney nickel (10 g) as a35 catalyst. After uptake of hydrogen (3 eq.), the catalyst was filtered off and the filtrate
was evaporated, yielding tl "~/ 9.3 g of (-)-(A)-4-[(3-~ lu~u~ 1)[2-
(.. ~,I,jlll,io)-1_-imidazol-1-yl]methyl]-1,2-1 ' (interm. 8).
~ WO95/22541 182581 r ./..~ cc-lsl
i) A mixture of ' (8) (9.3 g) and - ' acetate (8.4 g) in methanol
(200 ml) was stirred and refluxed for 3 hours. The solvent was evaporated and the
esidue was dissolved in lil~hh~ . The organic solution was washed with a
10% NaHCO3 solution, dlied (MgSO4), filtered and the solvent was ~,v r ' ~i The
5 oily residue (10 g) was purified by column ~' O , ' Y over siiica gel (duent:
CH2C12/CH3OH 95/5). The pure fractions were collected and the solvent was
~'~`-r ' ~ yielding 6-2 g (65%) of (-)-(A)-5-[(3-- ' ' , ' .~1)[2-(1ll~,~l.y' ' )-1
imidazol-l-yl]methyl]-lE i~ .-:---..1~,.,1 (interm. 9).
Example 2
a) Amixtureof(_)-4-[(3- ' ,' yl)-lH-imidazol-l-ylmethyl]-2-
(500 g) and (+)-(lS)-7,7-dimethyl-2-oxo-bicyclo[2.2.1]heptane-1-, ' '' acid
(353.3 g) in 2-propanone (2000 ml) was stirred at 20 C until it became l~
Crystallization rapidly resulted. Water (100 ml) was added and the mixture was warmed
15 to 38 C. The mixture became i~ and was seeded with crystals. The
compound was aUowed to crystalliæ out duling a 20-hour stir~ing at 20 C followed by
a 2-hour stirring at 0 C The precipitate was filtered off, washed with
2-1,l~ .. 95/5 (250 ml), then dried (50 C), yielding 288.90 g (33.86~o;
67.7% in relation with the ellallLivlll~) of (-)-(A) ~i [(3~hlvlv~)1l~,.l.yl)-1~-imidazol-1-
ylmethyl]-2 ~ (lS)-7,7-dimethyl-2~,.~;~y~1O[2.2.1]heptane-1-
:l . .l r, . - ~ . mp. 158.8C; t]D = -22.70 (c = 0.5% in methamol) (intelrn. 10).
b) A mixnlre of " (10) (167.7 g) in methanol (615 ml) and methanoV
arnmonia (30.7 ml) was l.~, " ' at 20-25 C with platinum on activated carbon
(5%) (12.3 g) as a catalyst in the presence of thiophene (0.5 g). After uptaice of
hydrogen (3 eq.); the catalyst was filtered off and washed with 2-propanol (30 ml).
Ily~' ' acid in 2-propanol (487 ml) was added to the filtrate at < 30 C The
mixture was slirred for 18 hours at 20 C then for 3 hours at 0 C The resultingprecipitate was filtered off, washed with methanol (100 ml) and dried (50 C), yielding
180.40 g of product (86.7%). The mother layer was evaporated, yielding 25.12 g (12.1
%) of product. The total yield was 205.52g (98.8%) of (-)-(A)-4-[(3-.1.l,.".l,1.. ~1)-1_-
imidazol-l-ylmethyl]-1,2-l~ .' '' ' (interrn. 11).
B. Pre~aration of the final l .
Example 3
A mixture of ' (9) (6.2 g) in ethanol (100 ml) was stirred and refluxed for 24
hours with Raney nickel (6 g) as a catalyst. The mixture was stirred and refluxed for 5
days and every day an additional amount of Raney nickel (6 g/adciition) was added.
2l825
wog~n2541 81 r~l"l ~cls
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Then, the catalyst was filtued off and the filter residue was rinsed with ~1.. I I .,, . :1 .,
The filtrate w2s ,. ' The residue (4 g) was purified by column ~ ' ~, , ' .y
over silica gel (eluent CH2Clz/CH30H 9S/S and CHzClz/CH30H/NH40H 80/20/3).
The pure fractions were collected and the solvent was evaporated. The residue (2.58 g
S free basc) was dissolved in 2-propanol and converted into the l~ dlU~IIIU~ acid salt (1:1)
with HCVeth~nol. Crys~s~ n was induced by addition of methyl ethyl ketone. The
precipitate was filtered off and dried, yielditlg 2.3 g (38%) of (-)-(A)-5-[(3-chloro-
phenyl)-l~-imidazol-1-ylmethyl]-lH-1 ' '- ~ y,l"~ I,l~lTi~i.~ mp. 207.7C;
[a]D = 42.43 (c = 1% irl methanol) (comp. 1).
Iû
Examvle 4
Amixtureof -' (11)(177.35g)inwater(491ml), I~Lu~,Llul;~, acid(277ml)
and formic acid (70.6 ml) was heated to 50-55 C The reaction mixture was stirred for 3
hours at SS C The mixture was cooled to 20 C. Dh,hlululll~,ll~.~, (1173 ml) was
IS added. Ammonium hydroxide (700 ml) was added (pH > 9) while cooling. The mixture
was stirred for 30 min~tes al 20 C The organic layer w2s separated, washed with water
(500 ml), dried, filtered and the solvent was evapor2tçd at 45-50 C, yielding 134.16 g
(100%) of (-)-(A)-5-[(3~ ' ' . ' .~1)-1_-imidazol-1-ylmethyl]-lH-' ' ' mp.
132.7C; [a]D = -45.30 (c = 1% in methanol) (comp. 2)
Examplç 5
A mixturc of compound (2) (2.66 g) in ethanol (28.5 ml) was stirred at 20 C until it
bçcame l~-~."n~ (E)-2-L ' acid (2 g) was added and the mixture became
after 10 mirlutes. The product was allowed to crystallize out over a 20-
25 hour period. The precipit2te was filtercd off, washed with ethamol (S ml) and dried,yielding 1.72 g (41.4%) of (-)-(A)-5-[(3-chlorophenyl)-lH-imidazol-l-ylmethyl]-l~-
E)-2-~ );mp.116.7C;[a]D=-29.20(c=0.5%in
methanol) (comp. 3).
30 E~xample 6
Compound (2) (114.5 g) was dissolved in 2-but2none (1854 ml). A mixture of
llydl~llluli~: acid in 2-proparlol (68.5 ml) in 2-butanone (556 ml) was 2d~ed ovçr a
2-hour period at 20 C. The reaction mixture w2s stirred for 16 hours at 20 C. The
precipit2te w2s filterçd off, washed with 2-butanone (185 ml) and dried (vacuum; 80 C),
yielding 122.6 g (99.5%) of (-)-(A)-5-[(3-~,Llv u~l.. ,.. yl)-l~l-imidazol-l-ylmethyl]~
y.l., ~ l ~ . ;fil~ mp. 216.4C;[a]D = -37.90 (c = 1% in methanol)
(comp. 1).
WO 95/22541 218 2 5 81 r .,~ 191
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C Co~rosinnnExamples
The following r ' ' exemplify typical ~ suitable for
systemic or topical: to animal and human subjects in accordance with the
5 present invention.
"Active ing~dient" (A.L) as used throughout these examples relates to a compound of
formula (I) or a ~,l , , . ..: lly acceptable acid addiLion salt form thereof.
F~ 7: 0~1 drops
500 g of the A.I. was dissolved in 0.51 of 2-hy~uA~ u~ ic acid and 1.51 of the
~ly~ glycol at 60~80C After cooling to 30~40C there were added 35 1 of
I~,LI~ glycol and the mixture was stirred well. Then there was added a solution of
175û g of sodium saccharin in 2.51 of purified vater and while stirring there were added
2.51 of cocoa flavor and ~I~ yl~ e glycol q.s. to a volume of 501, providing an oral
15 drop solution comprising 10 mg/ml of A.I. The resulting solution was filled into suitable
containers.
Exam~le 8: Oral solution
9 g of methyl 4-1l1J.UA~; and I g of propyl 4-llyLuAyl were dissolved
20 in 41 of boiling purified water. In 31 of this solution were dissolved first lû g of
2,3~1i;.JLUAy~ acid and thereafter 20 g of the A.I. The latter solution was
combined with the remaining part of the former solution and 121 1,2,3-l . -.~.~. .. l . ;.~l and
31 of sorbitol 70% solution were added thereto. 40 g of sodium saccharin were
dissolved in 0.51 of water and 2 ml of raspberry and 2 ml of gooseberry essence were
added. The latter solution was combmed with the former, water was added q.s. to a
volume of 201 providing am oral solution comprising 5 mg of the A.I. per r '
(S ml). The resulting solution was filled in suitable containers.
Example 9: Capsules
20 g of the A.I., 6 g sodium lauryl sulfate, 56 g starch, 56 g lactose, 0.8 g colloidal
silicon dioxide. and 1.2 g ,, stearate were vigorously sti~red together. The
resulLing mixture was . '!~ filled into 1000 suitable hardened gelatin capsules,
each comprising 20 mg of the A.I.
35 Example 10: Film-coated tablets
prr.~ finn t)f ~~ t t~t~
A mixture of 100 g of the A.L, 570 g lactose and 200 g starch was mixed well and
W095122541 2182581 1
-14-
Lhereafter humidified ~vith a solution of 5 g sociium dodecyl sulfaoe and 10 g
pul.~ ' (Kollidon-K 90 ~9) in about 200 ml of water. The wet powder
mixL~re was sieved, d~ied and sieved again. Then there was added 100 g l.l;.,l~ ~ .,~lli.,
cellulose (Avicel ~9) and 15 g ~J.", ' vegetable oil (Sterotex (!~)). The whole was
mixed well and ~ into LableLs, giving 10.000 tableLs, each comprising 10 mg
of the active ingreciienL
.~Qa~D
To a soluion of 10 g methyl cellulose (MeLhocel 60 HG ~) im 75 ml of l' '
eLhanol there was added a solution of S g of eLhyl cellulose (Ethocel 22 cps ~9) in 150 ml
of ~ ' Then tilere were added 75 ml of .l; ~ and 2.5 ml
1,2,3-~u~ ,Lliol. 10 g of p~ ,LIlyl~ , glycol was molten and dissolved in 75 ml of
~i ;~ l ~ ., . ." .. l l ~ . .. The iatter solution was added to the former and then there werc added
2.5 g of magnesium ~ ' 5 g of ~oly v ;~ ylluiidOl~c and 30 ml of
' color suspension (Opaspray K- 1-2109 (ID) and the whole was i
The tablet cores were coated wiLh Lhe thus obtained mixture in a coating apparatus.
Example 11: Injectable solution
1.8 g methyl 4-l~yLu~y' and Q2 g pwpyl 4-IIJ~U~Y; were dissolved in
about Q5 1 of boiiing water for injecLion. After cooling to about 50C there were added
while sLi~ring 4 g lactic acid, 0.05 g propylene glycol and 4 g of the A.L The solution
was cooled to wom t~ . and ~ with water for injecLion q.s. ad 1 1
volume, giving a solution of 4 mg/ml of A.I. The solution was sterilized by filtraLion
(U.S.P. XVU p. 811) and filled in sterile conL~iners.
Example 12: S,, ~
3 g A.L was cissolved in a solution of 3 g 2,3-dihydroxy-1, ~ acid in 25 ml
l~ul.~ yl~,lle glycol 400. 12 G surfacL~mt (SPAN (!~)) and l.iOly.,.,lides (Witepsol 555 ~i)
q.s. ad 3(i0 g were molten together. The iattcr mixture was mixed wdl with the former
solution. The thus obtained mixture was poured into mouids at a l of 37-38C
to form 100 ~ each containing 30 mg of the aCLive ing~edienL
FY~Tr~r11F~ 13 29~o topical ~el
To a soludon of 200 mg l~Lu~y~lu~ ' ' in purified water is added 20 mg
of A.l. while sdlring. Il~l' ' ' acid is added until complete dissoludon and then
sodium l1ydroxide is addcd undl pH 6Ø This soludon is added to a dispersion of 10 mg
PJ in 50 mg propylene glycol while mixing. While mixing slowly, the
mixL~lre is heated to 50DC and allowed to cool to about 35C whereupon 50 mg ethyl
W0 95/22541 2 1 8 2 5 8 1 P~
-15-
alcohol 95% (v/v) is added. The rest of the purif1ed water q.s. ad I g is added and the
mixture is mixed to 1~
Exam~le 15: Aerosols
a) To a solution of 0.1 g of IIJdI~JAY~ JYI ~l~Uyul~L~A~ l (MS = 0.43) in 0.7 ml of
distilled waterwere added 730 llg of a Ql N h~ ` acid solution and 2.5 mg
A.L. After stirnng for 10 minutes at room i , the pH of the thus obtained
solution was adjusted to pH 5.5 by adding a 0.1 N sodium hydroxide solution. Then
there were added ~u~ 4 mg of sodium chloride and 0.15 mg of phenyl mercuri
10 acetate and the whole was stirred to produce complete rlicct~ n Distilled water was
then added to a volume of 1.0 ml. The whole was filled in a glass bottle closed with a
m~chanical pump delivering 0.1 ml perpuffupon ..I~
b) To a solution of 0.1 g of dimethyl ~B-uy~ LALlill in 0.7 ml of distilled water were
added 600 ~Lg of a 0.1 N llyJI~ ' acid solution and 2 mg A.I.. After stirring for 10
15 minutes at room . ~ 10 mg of poly ~ .~' ' ` was dissolved in the mixture
and the pH of the thus obtained solution was adjusted to pH 5.5 by adding a 0.1 N
sodium hydroxide solution. Then there were added ~u~ ,ly 4 mg of sodium
chloride and 2 mg of l~h~lyL,Il~yl alcohol and the whole was stilred to produce complete
dissolution. Distilled water was added to produce a volume of 1.0 ml which was filled in
20 a glass bottle closed with a ' pump delivering 0.1 ml per puff upon
.~
