Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • 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
• • 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

Definitions

• This invention relates to novel enantiomerically pure compounds of formula (I) useful in treating disorders which are characterized by an increased profileration and/or abnormal differentiation of normal, preneoplastic or neoplastic epithelial cells. These compounds are particularly useful in the field of oncology. Also disclosed are compositions containing said novel compounds, as well as methods of using the mentioned compounds to treat the mentioned disorders.
• the laevorotatory compounds of formula (I) are useful for the manufacture of a medicament for treating epithelial disorders. Further the present invention provides methods of preparing the present novel compounds.
• novel compounds subject to the present invention are the laevorotatory isomer of the compound liarozole and the pharmaceutically acceptable acid addition salts thereof.
• Liarozole is a racemic 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 compounds like liarozole in the treatment of epithelial disorders.
• EP-0,260,744 describes the use of compounds like liarozole for inhibiting or lowering androgen formation.
• EP-0,371,559 and EP-0,260,744 recognize that compounds like liarozole have stereochemically isomeric forms, no example of an enantiomerically pure form is given of liarozole.
• Chemically liarozole is ( ⁇ )-5-[3-chlorophenyl] - lH-imidazol- 1 -ylmethyl]- lH-benz- imidazole, and is represented by formula (I). As can be seen from the chemical structure, liarozole has one stereogenic center (indicated with an asterisk in formula (I)).
• the subject of this invention is the enantiomerically pure laevorotatory isomer or (-)-isomer of liarozole. Said isomer will hereinafter be referred to as (-)-liarozole.
• optically active compounds Many organic compounds exist in optically active forms, i.e. they have the ability to rotate the plane of plane-polarized light.
• the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral centers).
• the prefixes (+) and (-) or d and 1 are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is laevorotatory and with (+) or d meaning that the compound is dextrorotatory.
• the optically active isomers having an opposite sign of optical rotation are called enantiomers.
• Said enantiomers are identical except that they are mirror images of one another.
• a 1: 1-mixture of such enantiomers is called a racemic mixture.
• Stereochemical purity is of importance in the field of pharmaceuticals since the respective enantiomers may have a different potency or may have a different activity.
• the enantiomer of a beneficial isomer may even be deleterious rather that simply inert Several examples of such differences are known in the art.
• enantiomerically pure means that the product contains at least 90% by weight of one enantiomer and 10% by weight or less of the other enantiomer. In the most preferred embodiment the term “enantiomerically pure” means that the composition contains at least 99% by weight of one enantiomer and 1% or less of the other enantiomer.
• optical rotation of chemical substances is dependent upon experimental parameters.
• the values shown in the experimental part hereinunder are specific rotations and the experimental conditions such as temperature, the wavelength of the plane polarized light used, the solvent as well as the concentration of the sample are indicated in the conventional way.
• the optical rotation may vary (it may even change sign!) when for instance an acid addition salt is formed.
• the sign of the optical rotation of the base form is intended under the given experimental conditions shown hereinunder.
• the pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form.
• the latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, for example, hydrohalic acids, e.g.
• organic acids for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-o
• addition salt also comprises the hydrates and solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
• Preferred pharmaceutically acceptable acids are hydrochloric acid and (E)-2-butenedioic acid.
• Enantiomerically pure (-)-liarozole may be prepared by reacting an enantiomerically pure intermediate diamine of formula (A)-(II) with formic acid or a functional derivative thereof.
• Said functional derivative of formic acid is meant to comprise the halide, anhydride, amide and ester, including the ortho and imino ester form thereof. Also methanimidamide or an acid addition salt thereof can be used as cyclizing agent.
• the enantiomerically pure intermediate diamine of formula (A)-(II) may be prepared by reducing an intermediate of formula (A)-(III) by a stand ⁇ d nitro-to-amine reduction reaction.
• the desired enantiomer of the intermediate of formula (A)-( ⁇ i) can be prepared by fractional crystallization of a racemic mixture of the intermediate of formula (III) with an enantiomerically pure chiral acid.
• Preferred chiral acid for the above fractional crystallization is 7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-l-methanesulfonic acid (i.e. 10-camphorsulfonic acid).
• Appropriate solvents for carrying out said fractional crystallization are water, ketones, e.g. 2-propane, 2-butanone; alcohols, e.g. methanol, ethanol, 2-propanol. Mixtures of ketones and water are very suitable for the above fractional crystallization. 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. Preferred range of said ratio is 1/5 to 1/3.
• fractional crystallizations are suitably carried out below room temperature, preferably below 5°C.
• the (-)-isomer of the compound of formula (I) may be prepared by cyclizing an intermediate of formula (A)-(TV) following procedures as described above for the cyclization of intermediates of formula (A)-(II) and desulfurating the thus obtained intermediate of formula (A)-(V).
• R represents C ⁇ -6alkyl, wherein Ci ⁇ alkyl is a straight or branch chained saturated hydrocarbon radicals having to 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl.
• R is methyl.
• the intermediates of formula (A)-(TV) may be prepared by reacting an intermediate of formula (A)-(VI) with a reagent of formula (VII), alkylating the thus formed thiourea derivative of formula (A)-(VHI) subsequently cyclizing the intermediate of formula (A)- (IX), and reducing the nitro group of the intermediate (A)-(X).
• a reagent of formula (VII) alkylating the thus formed thiourea derivative of formula (A)-(VHI) subsequently cyclizing the intermediate of formula (A)- (IX), and reducing the nitro group of the intermediate (A)-(X).
• formulas (VII), (A)-(Vi ⁇ ), (A)-(IX) and (A)-(X) R represents Ci ⁇ alkyl as defined hereinabove.
• the enantiomerically pure intermediate of formula (A)-(VI) can be prepared by art- known resolution techniques, e.g. by chromatography using chiral stationary phases or by forming diastereomeric compounds such as forming an amide with an enantiomerically pure chiral acid, e.g. ⁇ -hydroxybenzeneacetic acid (mandelic acid), or by forming diastereomeric salt forms using enantiomerically pure chiral acid.
• Liarozole has retinoid mimetic effects in vivo and in vitro. This means that the compound is thought to inhibit retinoic acid (RA) catabolism, so that increased retinoic acid (RA) levels lead to pronounced RA effects at the tissue or cell level. Liarozole has also been shown to be a potent inhibitor of androgen biosynthesis. Preclinical and clinical studies are ongoing showing the utility of liarozole in the field of oncology and dermatology.
• (-)-Liarozole has unexpectedly shown a higher activity in certain tumor models than (+)- liarozole or the racemic liarozole. It has been shown that a more "targeted” therapy is possible in the field of oncology by administering enantiomerically pure (-)-liarozole. Especially (-)-liarozole may be used to treat prostate cancers.
• (-)-liarozole and its pharmaceutically acceptable acid addition salts in the method of the present invention is based on their useful property to delay the catabolism of retinoids, such as, all-tr /u-retinoic acid, 13-cw-retinoic acid and their derivatives. The latter results in more sustained / higher tissue concentrations of retinoids and improved control of differentiation and growth of various cell types.
• This action of (-)-liarozole is also called retinoic mimetic activity because administering (-)-liarozole causes the same effect as if retinoid would be administered.
• (-)-liarozole can be used to control the rate of growth and differentiation of normal, preneoplastic and neoplastic epithelial cells.
• (-)-Liarozole and its pharmaceutically acceptable acid addition salts is therefore useful in a method of treating disorders which are characterized by an increased proliferation and/or abnormal differentiation of epithelial cells.
• (-)-Liarozole shows activity on cells of which the growth and differentiation is not substantially mediated by or insensitive to the actions of androgens or estrogens, in particular on cells of which the growth and differentiation is sensitive to the actions of retinoids.
• (-)-Liarozole is particularly useful in the treatment of tumors like head- and neck tumors, lung tumors , breast tumors, uterine cervix tumors, gastrointestinal tract tumors, skin tumors, bladder tumors and prostate tumors.
• (-)-Liarozole and its pharmaceutically acceptable acid addition salts is useful for the manufacture of a medicament for treating epithelial tumors.
• an effective amount to treat disorders which are characterized by an excessive proliferation and/or abnormal differentiation of tissues would be from 0.001 mg/kg to 20 mg kg body weight and more preferably from 0.01 mg/kg to 10 mg kg body weight.
• compositions there may be cited all compositions usually employed for systemically or topically administering drugs.
• an effective amount of the particular compound, optionally in acid-addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
• a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
• These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection.
• any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represents the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.
• the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
• Injectable solutions may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
• Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations.
• the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin.
• compositions usually employed for topically administering drugs e.g., creams, gellies, dressings, shampoos, tinctures, pastes, ointments, salves, powders, liquid or semi-liquid formulation and the like.
• Application of said compositions may be by aerosol e.g. with a propellent such as nitrogen carbon dioxide, a freon, or without a propellent such as a pump spray, drops, lotions, or a semisolid such as a thickened composition which can be applied by a swab.
• a propellent such as nitrogen carbon dioxide, a freon
• a propellent such as a pump spray
• drops lotions
• a semisolid such as a thickened composition which can be applied by a swab.
• semisold compositions such as salves, creams, pastes, gellies, ointments and the like will conveniently be used.
• Dosage unit form as used in the specification and claims herein refers to physically discreate units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets
• compositions of the cosmetic type, such as toilet waters, packs, lotions, skin milks or milky lotions.
• Said preparations contain, besides the active ingredient, components usually employed in such preparations.
• components usually employed in such preparations.
• further ingredients may be incorporated in the compositions, e.g. antiinflamatory agents, antibacterials, antifungals, disinfectants, vitamins, sunscreens, antibiotics, or other anti-acne agents.
• compositions which comprise an inert carrier, an effective amount of
• retinoic acids and the derivatives thereof, in particular retinol, and (-)-liarozole act in a synergistic manner. Indeed, the combined effect of both substances is greater than the sum of their respective effects when administered separately.
• the above described retinoic acid containing compositions are particularly useful for treating acne or for retarding the effects of aging of the skin and generally improve the quality of the skin, particularly human facial skin.
• a pharmaceutical or cosmetical composition containing retinoic acid or a derivative thereof as the active ingredient in intimate admixture with a dermatologically acceptable carrier can be prepared according to conventional compounding techniques, such as those known for topical application of retinoic acid and its derivatives, optionally in admixture with cyclodextrines or derivatives thereof known in the art.
• composition for topical application are in form of a cream, ointment or lotion comprising from 0.001 to 0.5% (particularly from 0.01 to 0.1%) all-tr ⁇ ns-retinoic acid, 13-cis-retinoic acid or a derivative thereof, in particular retinol, and from 0.1 to 5% of a (-)-liarozole or a dermatologically acceptable acid addition salt thereof, in a semi-solid or liquid diluent or carrier.
• compositions should preferably be non-irritating and as far as possible they should be odorless and non-toxic.
• the composition usually contain, besides water or an organic solvent, several of certain organic emollients, emulsifiers for the aqueous and or non aqueous phases of the compositions, wetting agents preservatives and agents that facilitate the penetration and remainence of the active agents in the skin.
• Example 1 Preparation of the intermediates Example 1 a) A mixture of (4-amino-3-nitrophenyl) (3-chlorophenyl)methanone (50 g), formamide (375 ml) and formic acid (63 ml) was stirred and refluxed for 17 hours. After cooling, the mixture was poured on ice. The precipitate was filtered off and dried, yielding 55 g (99.4%) of ( ⁇ )-N-[(4-amino-3-nitrophenyl) (3-chlorophenyl)methyl] formamide (interm.
• Example 3 A mixture of intermediate (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/addition) was added. Then, the catalyst was filtered off and the filter residue was rinsed with dichloromethane. The filtrate was evaporated. The residue (4 g) was purified by column chromatography over silica gel (eluent CH2CI2/CH3OH 95/5 and CH2CI2/CH3OH/NH4OH 80/20/3). The pure fractions were collected and the solvent was evaporated.
• compositions suitable for systemic or topical administration to animal and human subjects in accordance with the present invention.
• Active ingredient as used throughout these examples relates to a compound of formula (I) or a pharmaceutically acceptable acid addition salt form thereof.
• Example 7 Oral drops 500 g of the A.I. was dissolved in 0.5 1 of 2-hydroxypropanoic acid and 1.5 1 of the polyethylene glycol at 60 ⁇ 80°C. After cooling to 30 ⁇ 40°C there were added 351 of polyethylene glycol and the mixture was stirred well. Then there was added a solution of 1750 g of sodium saccharin in 2.5 1 of purified water and while stirring there were added 2.5 1 of cocoa flavor and polyethylene glycol q.s. to a volume of 501, providing an oral drop solution comprising 10 mg/ml of A.I. The resulting solution was filled into 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 magnesium stearate were vigorously stirred together. The resulting mixture was subsequently filled into 1000 suitable hardened gelatin capsules, each comprising 20 mg of the A.I.
• Example 10 Film-coated tablets Jtep &Qn.Qi til&.QOJ ⁇ A mixture of 100 g of the A.I., 570 g lactose and 200 g starch was mixed well and thereafter humidified with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone (Kollidon-K 90 ®) in about 200 ml of water. The wet powder mixture was sieved, dried and sieved again. Then there was added 100 g microcrystalline cellulose (Avicel ®) and 15 g hydrogenated vegetable oil (Sterotex ®). The whole was mixed well and compressed into tablets, giving 10.000 tablets, each comprising 10 mg of the active ingredient .Coating
• 1,2,3-propanetriol 10 g of polyethylene glycol was molten and dissolved in 75 ml of dichloromethane. The latter solution was added to the former and then there were added 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of concentrated color suspension (Opaspray K- 1-2109 ®) and the whole was homogenated. The tablet cores were coated with the thus obtained mixture in a coating apparatus.
• Example 11 Injectable solution
• Example 12 Suppositories
• Example 13 2% topical gel

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• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
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• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Public Health (AREA)
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• Engineering & Computer Science (AREA)
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Citations (2)

• 1995
  • 1995-02-10 SG SG1996009264A patent/SG47122A1/en unknown
  • 1995-02-10 TW TW084101154A patent/TW418203B/zh active
  • 1995-02-10 MX MX9603510A patent/MX9603510A/es unknown
  • 1995-02-10 AU AU15788/95A patent/AU688852B2/en not_active Expired - Fee Related
  • 1995-02-10 EP EP95907663A patent/EP0745078A1/en not_active Withdrawn
  • 1995-02-10 NZ NZ279228A patent/NZ279228A/en unknown
  • 1995-02-10 CN CN95191667A patent/CN1141041A/zh active Pending
  • 1995-02-10 WO PCT/EP1995/000491 patent/WO1995022541A1/en not_active Application Discontinuation
  • 1995-02-10 JP JP7521564A patent/JPH09508915A/ja active Pending
  • 1995-02-17 ZA ZA951342A patent/ZA951342B/xx unknown
  • 1995-02-17 IL IL11268995A patent/IL112689A0/xx unknown

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