CA2182581A1 - Enantiomerically pure(-)-liarozole - Google Patents
Enantiomerically pure(-)-liarozoleInfo
- Publication number
- CA2182581A1 CA2182581A1 CA002182581A CA2182581A CA2182581A1 CA 2182581 A1 CA2182581 A1 CA 2182581A1 CA 002182581 A CA002182581 A CA 002182581A CA 2182581 A CA2182581 A CA 2182581A CA 2182581 A1 CA2182581 A1 CA 2182581A1
- Authority
- CA
- Canada
- Prior art keywords
- compound
- acid
- formula
- enantiomerically pure
- liarozole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
This invention relates to the novel enantiomer-ically pure laevorotatory isomer of liarozole of for-mula (I) and the pharmaceutically acceptable acid addition salt forms thereof. These compounds are particularly useful in treating disorders which are characterized by an increased proliferation and or abnormal differentiation of normal, preneoplastic or neoplastic epithelial cells. The compounds of for-mula (I) are particularly useful in the field of oncology. Also disclosed are compositions containing said novel compounds, methods of preparing said novel compounds as well as methods of using the mentioned compounds to treat the mentioned disorders.
Description
2 1 8 2 5 8 1 P~ 91 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
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
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 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 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 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 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 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~
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 .~
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
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 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 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 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 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 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~
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 .~
Claims (11)
1. The laevorotarory compound of formula (I) (I) or a pharmaceutically acceptable acid addition salt thereof.
2. A compound according to claim 1, wherein the compound is (-)-5-[3-chlorophenyl]-1H-imidazol-1-ylmethyl]-1H-benzimidazole hydrochloride (1:1).
3. A compound according to claim 1, wherein the compound is (-)-5-[3-chlorophenyl]-1H-imidazol-1-ylmethyl]-1H-benzomodazole (E)-2-butenedioate(3:2).
4. A composition for treating epithelial tumors comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound as claimed in any of claims 1 to 3.
5. A composition as claimed in claim 4 wherein said composition is in a form suitable for systemic administration.
6. A composition according to claim 5 wherein said composition also comprises aneffective amount of a retinoic acid, a derivative thereof or a stereochemically isomeric form thereof.
7. Use of a compound as claimed in any of claims 1 to 3 as a medicine.
8. Use of a compound for the manufacture of a medicament for treating epithelial tumors.
9. Use of a compound for the manufacture of a medicament for treating prostatic tumors.
10. An enantiomerically pure intermediate of formula (A)-(II) (A)-(II) or an acid addition salt thereof.
11. A process for preparing a compound as claimed in claim 1, characterized by a) resolving an intermediate of formula (III) with an enantiomerically pure chiral acid, such as7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanessulphonic acid, in an appropriate solvent;
b) reducing the thus obtained enantiomerically pure intermediate of formula (A)-(III);
? (A)-(III) (A)-(II) c) cyclizing the enantiomerically pure intermediate of formula (A)-(II), with methanimidamide, formic acid; functional derivatives thereof, yielding an enantiomerically pure compound of formula (I);
? (A)-(II) (-)-(I) and if desired, converting the compound of formula (I) into a pharmaceutically acceptable acid addition salt form thereof by treatment with an appropriate acid or, conversely, converting the acid-addition salt into the free base form with alkal;
b) reducing the thus obtained enantiomerically pure intermediate of formula (A)-(III);
? (A)-(III) (A)-(II) c) cyclizing the enantiomerically pure intermediate of formula (A)-(II), with methanimidamide, formic acid; functional derivatives thereof, yielding an enantiomerically pure compound of formula (I);
? (A)-(II) (-)-(I) and if desired, converting the compound of formula (I) into a pharmaceutically acceptable acid addition salt form thereof by treatment with an appropriate acid or, conversely, converting the acid-addition salt into the free base form with alkal;
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002182581A CA2182581A1 (en) | 1994-02-18 | 1995-02-10 | Enantiomerically pure(-)-liarozole |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP94200418.5 | 1994-02-18 | ||
| CA002182581A CA2182581A1 (en) | 1994-02-18 | 1995-02-10 | Enantiomerically pure(-)-liarozole |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2182581A1 true CA2182581A1 (en) | 1995-08-24 |
Family
ID=4158693
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002182581A Abandoned CA2182581A1 (en) | 1994-02-18 | 1995-02-10 | Enantiomerically pure(-)-liarozole |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2182581A1 (en) |
-
1995
- 1995-02-10 CA CA002182581A patent/CA2182581A1/en not_active Abandoned
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