WO2000026173A1 - Nouveaux retinoides et techniques de leur production et utilisation - Google Patents

Nouveaux retinoides et techniques de leur production et utilisation Download PDF

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Publication number
WO2000026173A1
WO2000026173A1 PCT/IB1998/001761 IB9801761W WO0026173A1 WO 2000026173 A1 WO2000026173 A1 WO 2000026173A1 IB 9801761 W IB9801761 W IB 9801761W WO 0026173 A1 WO0026173 A1 WO 0026173A1
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hydrogen
alkyl
compound
diseases
independently
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PCT/IB1998/001761
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English (en)
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Luc J. Farmer
Lin Zhi
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Ligand Pharmaceuticals Incorporated
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Priority to AU95563/98A priority Critical patent/AU9556398A/en
Priority to PCT/IB1998/001761 priority patent/WO2000026173A1/fr
Publication of WO2000026173A1 publication Critical patent/WO2000026173A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/72—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings and other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/46—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings and other rings, e.g. cyclohexylphenylacetic acid
    • C07C57/48—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings and other rings, e.g. cyclohexylphenylacetic acid having unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/46—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings and other rings, e.g. cyclohexylphenylacetic acid
    • C07C57/50—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings and other rings, e.g. cyclohexylphenylacetic acid containing condensed ring systems

Definitions

  • the present invention relates to retinoid compounds having activity for retinoic acid receptors and/or retinoid X receptors, and to methods for the production and therapeutic use of such compounds.
  • the vitamin A metabolite, retinoic acid has long been recognized to induce a broad spectrum of biological effects.
  • retinoic acid has long been recognized to induce a broad spectrum of biological effects.
  • structural analogues of retinoic acid have been synthesized that also have been found to be bioactive.
  • retinoids have found utility as therapeutic agents for the treatment of various pathological conditions.
  • synthetic retinoids have been found to mimic many of the pharmacological actions of retinoic acid.
  • retinoids have become very interested in the therapeutic applications of retinoids. Among their uses approved by the FDA is the treatment of severe forms of acne and psoriasis. A large body of evidence also exists that these compounds can be used to arrest and, to an extent, reverse the effects of skin damage arising from prolonged exposure to the sun. Other evidence exists that these compounds may be useful in the treatment and prevention of a variety of cancerous and pre-cancerous conditions, such as melanoma, cervical cancer, some forms of leukemia, oral leukoplakia and basal and squamous cell carcinomas. Retinoids have also shown an ability to be efficacious in treating and preventing diseases of the eye, cardiovascular system, immune system, skin, respiratory and digestive tracts, and as agents to facilitate wound healing and modulate programmed cell death (apoptosis).
  • apoptosis programmed cell death
  • RARs Retinoic Acid Receptors
  • RXRs Retinoid X Receptors
  • an endogenous low-molecular-weight ligand which modulates the transcriptional activity of the RARs is all-tr «5-retinoic acid (ATRA), while an endogenous ligand for the RXRs is 9-cis retinoic acid (9-cis).
  • the receptors differ in several important aspects.
  • the RARs and RXRs are significantly divergent in primary structure (e.g., the ligand binding domains of RAR ⁇ and RXR ⁇ have only 27% amino acid identity). These structural differences are reflected in the different relative degrees of responsiveness of RARs and RXRs to various vitamin A metabolites and synthetic retinoids. In addition, distinctly different patterns of tissue distribution are seen for RARs and RXRs.
  • RXR ⁇ mRNA has been shown to be most abundant in the liver, kidney, lung, muscle and intestine.
  • RARs and RXRs have different target gene specificity.
  • response elements have recently been identified in the cellular retinal binding protein type U (CRBP ⁇ ) and Apolipoprotein Al genes which confer responsiveness to RXR, but not RAR.
  • RAR has also been recently shown to repress RXR-mediated activation through the CRBPII RXR response element (Manglesdorf et al., Cell, 66:555-61 (1991)).
  • retinoids which are more selective for the RAR subfamily or the RXR subfamily would be of great value for selectively controlling processes mediated by one or more of the RAR or RXR isoforms, and would provide the capacity for independent control of the physiologic processes mediated by the RARs or RXRs.
  • pan-agonist retinoids that activate one or more isoforms of both the RARs and RXRs would also be valuable for controlling processes mediated by both of these subfamilies of retinoid receptors.
  • retinoids which preferentially affect one or more but not all of the receptor isoforms also offer the possibility of increased therapeutic efficacy and reduced side effect profiles when used for therapeutic applications.
  • Various polyene compounds have been disclosed to be useful in the treatment of inflammatory conditions, psoriasis, allergic reactions, and for use in sunscreens in cosmetic preparations. See __g., U.S. patent numbers 4,534,979 and 5,320,833 and Australian Patent Application No. 16511/95 .
  • trienediolates of hexadienoic acids have proved useful in the synthesis of retinoic and nor-retinoic acids. See M J. Aurell, et al., 49
  • the present invention provides novel dienoic retinoid compounds that have selective activity as RXR agonists or pan-agonist activity on one or more of each of the RAR and RXR isoforms.
  • the present invention also provides pharmaceutical compositions incorporating these novel dienoic compounds and methods for the therapeutic use of such compounds and pharmaceutical compositions.
  • alkyl refers to straight-chain, branched-chain, cyclic structures, and combinations thereof.
  • aryl refers to an optionally substituted six-membered aromatic ring.
  • heteroaryl refers to an optionally substituted five-membered or six- membered heterocyclic ring containing one or two heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and more preferably one heteroatom selected from the group consisting of oxygen, nitrogen and sulfur.
  • 'aryl' and 'heteroaryl' also encompass bi- and tri-aryls, bi- and tri-heteroaryls and any combination of up to three rings including at least one aryl fused to at least one heteroaryl, e.g., biphenyl, naphtyl, anthracenyl, furyl, pyrralyl, pyrralidinyl, thienyl, pyridyl, piperidyl, indolyl and quinolyl.
  • heteroaryl e.g., biphenyl, naphtyl, anthracenyl, furyl, pyrralyl, pyrralidinyl, thienyl, pyridyl, piperidyl, indolyl and quinolyl.
  • retinoid or retinoids refer to compound(s) that bind and/or activate one or more retinoid receptors, thereby affecting the transcriptional activity of a target gene to which the activated receptor and compound complex binds.
  • pan-agonist refers to a retinoid that activates at least one member of both the RAR subfamily (i.e., RAR ⁇ , RAR ⁇ , or RAR ⁇ ) and the RXR subfamily (i.e., RXR ⁇ , RXR ⁇ , or RXR ⁇ ).
  • RAR ⁇ , RAR ⁇ , or RAR ⁇ the RAR subfamily
  • RXR ⁇ , RXR ⁇ , or RXR ⁇ the RXR ⁇
  • pan-agonist retinoids activate all members of both the RAR and RXR subfamilies of retinoid receptors.
  • Rl is hydrogen or a C1-C10 alkyl, F or OR4, where R4 has the definition given below;
  • R 2 is hydrogen, CH 3 , OCH 3 or NO 2 ;
  • R3 is hydrogen, F, a -C12 alkyl, CF3, NO2, OR4 or NR5R6, where R4 is
  • hydroxyalkyl or taken together are a C3-C6 cycloalkyl, provided that R5 must be a
  • Rg is aryl or hydroxyaryl
  • R7 and Rg each independently are hydrogen or a C ⁇ -C6 alkyl
  • R9 is hydrogen or a Ci-C ⁇ alkyl or CF3;
  • RlO is OR11 or NR12R13, where Rn is hydrogen, a C ⁇ -C6 alkyl, with R12 and R13 each independently being hydrogen, a Cj-Cg alkyl, aryl or ortho-, meta- and para- substituted hydroxy aryl;
  • R14-R15 each independently are hydrogen, a -C12 alkyl, C7- 5 arylalkyl or
  • Rl6-Rl9 each independently are hydrogen, a -C12 alkyl, C7-C15 arylalkyl, CF3,
  • Rig and R17, R ⁇ g and R19, ⁇ _ and R19, R17 and Rjg are epoxy or cyclopropyl
  • R21 and R22 each independently are hydrogen, a -C6 alkyl or a C7-C15 arylalkyl;
  • R23 is hydrogen, NO2, a Cj-Cg alkyl or OR20, where R20 has the definition given above;
  • R24-R27 each independently are hydrogen, a -C12 alkyl, C7-C15 arylalkyl, CF3, OR20 or NR5R6, where R5, Rg and R20 have the definitions given above;
  • R28- 33 each independently are hydrogen, a -C12 alkyl, C7-C15 arylalkyl or
  • V, M and W independently represent C, O, S, N, SO or SO2, provided, however,
  • X represents C, O, N or CF2
  • n 1, 2, 3 or 4
  • the dotted lines in structures I and III represent optional double bonds
  • the wavy lines represent olefin bonds that are either in the cis (Z) or trans (E) configuration, provided, however, that the double bonds cannot be contiguous, and further provided that when such optional double bonds exist then the substitution patterns around such bonds cannot violate double bond valency.
  • R is hydrogen, CH3 or OCH3 ;
  • R2 is hydrogen, CH3 or OCH3;
  • R3 is hydrogen, F, a C1-C2 alkyl, NO2 or OR4, where R4 is a C1-C3 alkyl;
  • R7 and Rg each independently are hydrogen or a C1-C2 alkyl
  • R 9 is a C ⁇ -C 2 alkyl or CF 3 ;
  • RlO is OR11, where Rn is hydrogen, a C1-C2 alkyl or Na or Ca;
  • R14-R22 eac h independently are hydrogen or a C -C2 alkyl
  • R23 is hydrogen or a C1-C3 alkyl
  • R24-R33 each independently are hydrogen or a C1-C2 alkyl; V, M and W independently represent C, S or N;
  • the compounds of structure I are retinoid compounds of the formula:
  • Rl and R3 each independently are hydrogen or a C1-C10 alkyl, F or OR4, where R4 has the definition given above;
  • R 2 is hydrogen, NO 2 , CH 3 or OCH 3 ;
  • R7 and Rg each independently are hydrogen or a C1-C-6 alkyl
  • R9 is hydrogen or a Ci-Cg alkyl or CF3;
  • RlO is ORn or NR12R13, where Rn is hydrogen, a C -Cg alkyl, and with R12 and
  • R13 each independently being hydrogen, a C -Cg alkyl, aryl or ortho-, meta- and para- substituted hydroxy aryl;
  • Rl4, R15, R21 and R22 each independently are hydrogen, a Ci-Cg alkyl or a C7- C15 arylalkyl;
  • R 6 through R19 each independently are hydrogen, a C -C2 alkyl or OR23, where
  • R23 is hydrogen or a C1-C10 alkyl, or R16-R19 taken together are keto or Ri6 and R17, Rl8 and R19, R 5 and R19, R17 and R ⁇ are epoxy or cyclopropyl; V and W independently represent C, O, S, N, SO or SO2, provided, however, that
  • the retinoid compounds of structure II are compounds of the formula:
  • Rl is hydrogen or a C1-C10 alkyl
  • R3 and R24 each independently are hydrogen, a C1-C6 alkyl, branched alkyl, CF3
  • R24 and R25 are C1-C4 alkyls
  • R7 and Rg are hydrogen or a C1-C6 alkyl
  • R9 is a hydrogen or a -CO alkyl or CF3;
  • RlO is OR or NR12R13, where Rn is hydrogen, a C -C ⁇ alkyl, and with R12 and
  • R13 each independently being hydrogen, a Ci-C ⁇ alkyl, aryl or ortho-, meta- and para- substituted hydroxy aryl;
  • R23 is hydrogen, NO2, a Ci-C ⁇ alkyl or OR20, where R20 has the definition given above;
  • R25 is hydrogen, -Cs alkyl and OR26 with R26 being a C C 7 alkyl or benzyl;
  • the retinoid compounds of structure III are compounds of the formula:
  • Rl is hydrogen
  • R26-R27 each independently are hydrogen, a C1-C 2 alkyl, C7-C15 arylalkyl, CF3,
  • R28-R33 each independently are hydrogen, a C1-C12 alkyl, C7-C15 arylalkyl or CF 3 ;
  • R7 and Rg each independently are hydrogen or a C1-C6 alkyl
  • R9 is a hydrogen or a Ci-C ⁇ alkyl or CF3;
  • RlO is ORn or NR 2R13, where Rn is hydrogen, a Ci-C ⁇ alkyl, and with R 2 and
  • Rl3 each independently being hydrogen, a Ci-C ⁇ alkyl, aryl or ortho-, meta- and para- substituted hydroxyaryl;
  • the compounds of the present invention also include all pharmaceutically acceptable salts, as well as esters and amides. Preferably, such salts, esters and amides, will be formed at the R o position.
  • pharmaceutically acceptable salts include, but are not limited to: pyridine, ammonium, piperazine, diethylamine, nicotinamide, formic, urea, sodium, potassium, calcium, magnesium, zinc, lithium, cinnamic, methylamino, methanesulfonic, picric, tartaric, triethylamino, dimethylamino, and tris(hydoxymethyl)aminomethane. Additional pharmaceutically acceptable salts are known to those skilled in the art.
  • the compounds of the present invention are particularly useful in the treatment of skin-related diseases, including, without limitation, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical anti- microbial, as skin pigmentation agents and to treat and reverse the effects of age and photo damage to the skin.
  • skin-related diseases including, without limitation, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen plan
  • the compounds are also useful for the prevention and treatment of cancerous and pre-cancerous conditions, including, premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposi sarcoma.
  • premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposi sar
  • the present compounds can be used as agents to treat diseases of the eye, including, without limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and other corneopathies, as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associ- ated with lipid metabolism such as dyslipidemias, prevention of restenosis and as an agent to increase the level of circulating tissue plasminogen activator (TPA).
  • PVR proliferative vitreoretinopathy
  • TPA tissue plasminogen activator
  • papilloma virus including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn's disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Amyotrophic Lateral Sclerosis (ALS), improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and inhibition of T-Cell activated apoptosis, restoration of hair growth, including
  • HPV human papilloma virus
  • various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn's disease
  • neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Amyotrophic Lateral Sclerosis (ALS)
  • improper pituitary function including insufficient production of growth hormone
  • modulation of apoptosis including both the induction of apoptosis and inhibition of T-Cell activated apopto
  • the compounds of the present invention can be used in a wide variety of combination therapies to treat the conditions and diseases described above.
  • the compounds of the present invention can be used in combination with other therapies, including, without limitation, chemotherapeutic agents such as cytostatic and cytotoxic agents, immunological modifiers such as interferons, interleukins, growth hormones and other cytokines, hormone therapies, surgery and radiation therapy.
  • Representative retinoids of the present invention include, without limitation, (2E, 4E)-6-[l-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphtha-len-2-yl) cyclopropanyl]-3-methyl hexadienoic acid (Compound 101); (2E, 4E)-6-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahy- dronaphthalen-2-yl) cyclopropan-l-yl]-3-methyl hexadienoic acid (Compound 102); (2E, 4E)-6-[(5,5,8,8-Tetramethyl-3-methoxy-5,6,7,8-tetrahydronaphtha- len-2-yl) cyclopropan-l- yl]-3-methyl hexadienoic acid (Compound 103); (2E, 4E)-6-[(5,5,8,8-Tetramethyl-3-e
  • the compounds of the present invention can be obtained by modification of the compounds disclosed or by a total synthesis approach, by techniques known to those skilled in the art.
  • the synthesis of the compounds of the present invention often follow established retinoid synthesis schemes and techniques as described in M.I. Dawson and W.H. Okamura, "Chemistry and Biology of Synthetic Retinoids", Chapters 3, 8, 14 and 16, CRC Press, Inc., Florida (1990); M.I. Dawson and P.D. Hobbs, The Synthetic Chemistry of Retinoids, In Chapter 2: "The Retinoids, Biology, Chemistry and Medicine", M.B. Sporn et al., Eds. (2nd ed.), Raven Press, New York, New York, pp.
  • the bicyclic derivatives of the present invention may be prepared in accordance with Scheme I.
  • Halogen-metal exchange of an appropriately substituted tetrahydrotetramethylnaphthalene such as 2-bromo-5,5,8,8- tetramethyl-5,6,7,8-tetrahydronaphthalene with a base, such as rc-Buli
  • a base such as rc-Buli
  • treatment with trimethyl borate and acidification with aqueous 10% hydrochloric acid provides the boronic acid precursor 1.
  • the dienoic acid side chain precursor was introduced by the Suzuki coupling of boronic acid 1 with 3-bromo-3-butene-l-ol in the presence of tetrakis triphenylphosphine palladium (0) and a base, such as sodium carbonate, in toluene at 100°C to provide compound 2.
  • Cyclopropanation of homoallylic alcohol 2 with reagents such as diethyl zinc and chloroiodomethane in dichloroethane provides the cyclopropane compound 3.
  • Oxidation of alcohol 3 with a reagent such as PCC in dichloromethane provides aldehyde 4.
  • This aldehyde 4 can be treated with a phosphonate, such as the lithium salt of diethyl 3-ethoxycarbonyl-2-methylprop-2-enylphosphonate (mixture of double bond iso- mers) in THF at reduced temperatures in a Horner-Wadsworth-Emmons olefination reaction to provide the dienoate esters 5.
  • a phosphonate such as the lithium salt of diethyl 3-ethoxycarbonyl-2-methylprop-2-enylphosphonate (mixture of double bond iso- mers) in THF at reduced temperatures in a Horner-Wadsworth-Emmons olefination reaction to provide the dienoate esters 5.
  • the olefination reaction is preferably conducted in the presence of l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU).
  • the acids and salts 6 are readily obtainable from the corresponding esters by hydrolysis in an alkanol solvent at ambient temperature with about a three molar excess of base, for example, potassium hydroxide.
  • the ethyl esters may be hydrolyzed in THF/water or acetone/water at ambient temperature with, for example, excess lithium hydroxide.
  • the hydrolysis solution is acidified and the hydrolysate recovered by conventional means to give as the major product the (2E, 4E)-bicyclic diene carboxylic acid derivatives of structure 6.
  • the polysubstituted benzene derivatives of the present invention may be prepared in accordance with Scheme II.
  • Compound 8 was then elaborated by the same processes as employed in the preparation process of Scheme I, to afford dienoic acid 12.
  • Scheme III Synthesis of Compounds of Structure (III):
  • Dienoic acid derivatives such as compound 20 can be obtained in accordance with the reaction Scheme III.
  • Bayer- Villager oxidation of ketone 13 with an oxidant such as MCPBA in dichloromethane gave compound 14.
  • Hydrolysis in an alkanol solvent at ambiant temperature with a base such as sodium carbonate, followed by a treatment with for example, triflic anhydride in pyridine provided triflate 15.
  • Compound 15 was then elaborated by the same processes as employed in the preparation process of Scheme II, to afford dienoic acid 20.
  • the dienoic acids of the present invention may be prepared in accordance with reaction Scheme IV. Cyanation of benzyl bromide of general structure 21 with, for example, tetraethyl ammoniun cyanide in acetonitrile afforded compound 22. Cyclopentannulation with 1,4-dibromobutane with a base, such as sodium hydride, in DMF followed by reduction with a reducing agent like diisobutyl aluminium hydride gave compound 23.
  • a base such as sodium hydride
  • aldehyde 24 One carbon homologation with (methoxymethyl) triphenylphosphonium bromide-mixture with sodium amide in toluene at reflux in a Wittig olefination reaction provided after hydrolysis, for example with HC1 10% in THF, aldehyde 24.
  • This aldehyde 24 can be treated with a phosphonate, such as the lithium salt of diethyl 3-ethoxycarbonyl-2-methylprop-2-enylphosphonate (mixture of double bond isomers) in THF at reduced temperatures in a Horner-Wadsworth.-Emmons olefination reaction to provide the dienoate esters 25.
  • a phosphonate such as the lithium salt of diethyl 3-ethoxycarbonyl-2-methylprop-2-enylphosphonate (mixture of double bond isomers) in THF at reduced temperatures in a Horner-Wadsworth.-Emmons olefin
  • the olefination reaction is preferably conducted in the presence of l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU).
  • DMPU l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone
  • the acids and salts 26 are readily obtainable from the corresponding esters by hydrolysis in an alkanol solvent at ambient temperature with about a three molar excess of base, for example, potassium hydroxide.
  • the ethyl esters may be hydrolyzed in THF/water or acetone/water at ambient temperature with, for example, excess lithium hydroxide.
  • the hydrolysis solution is acidified and the hydrolysate recovered by conventional means to give as the major product the (2E, 4E)-bicyclic diene carboxylic acid derivatives of structure 26.
  • the compounds of the present invention may also be produced in the form of the corresponding amides or esters, or pharmaceutically acceptable salts.
  • the retinoid compounds of the present invention are combined in a mixture with a pharmaceutically acceptable carrier to provide pharmaceutical compositions useful for treating the biological conditions or disorders noted herein in mammalian, and more preferably, in human patients.
  • a pharmaceutically acceptable carrier employed in these pharmaceutical compositions may take a wide variety of forms depending upon the type of administration desired, e.g., intravenous, oral, topical, suppository or parenteral.
  • typical pharmaceutical media such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be employed.
  • oral solid dosage forms e.g., powders, tablets and capsules
  • carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like will be employed. Due to their ease of administration, tablets and capsules represent the most advantageous oral dosage form for the pharmaceutical compositions of the present invention.
  • the carrier will typically comprise sterile water, although other ingredients that aid in solubility or serve as preservatives, may also be included.
  • injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like will be employed.
  • the compounds of the present invention may be formulated using bland, moisturizing bases, such as ointments or creams.
  • suitable ointment bases are petrolatum, petrolatum plus volatile silicones, lanolin, and water in oil emulsions such as EucerinTM (Beiersdorf).
  • suitable cream bases are NiveaTM Cream (Beiersdorf), cold cream (USP), Purpose CreamTM (Johnson & Johnson) hydrophilic ointment (USP), and Lubriderm TM (Warner-Lambert).
  • compositions and compounds of the present invention will gen- erally be administered in the form of a dosage unit (e.g., tablet, capsule etc.) at from about 1 ⁇ g/kg.of body weight to about 500 mg/kg of body weight, more preferably from about 10 ⁇ g/kg to about 250 mg kg, and most preferably from about 20 ⁇ g/kg to about 100 mg/kg.
  • a dosage unit e.g., tablet, capsule etc.
  • the particular quantity of pharmaceutical composition according to the present invention administered to a patient will depend upon a number of factors, including, without limitation, the biological activity desired, the condition of the patient, and tolerance for the drug.
  • the compounds of this invention also have utility when labeled and used in assays to determine the presence of RARs and RXRs. They are particularly useful due to their ability to selectively bind to members of the RAR and RXR subfamilies and can therefore be used to determine the presence of RAR and RXR isoforms in the presence of other retinoid receptors or related intracellular receptors. Due to the selective specificity of the compounds of this invention for retinoid receptors, these compounds can also be used to purify samples of RARs and RXRs in vitro.
  • Such purification can be carried out by mixing samples containing retinoid receptors with one of more of the compounds of the present invention, so that the com- pound (ligand) binds to the receptor, and then separating out the bound ligand/ receptor combination by separation techniques which are known to those of skill in the art. These techniques include column separation, filtration, centrifugation, tagging and physical separation, and antibody complexing, among others.
  • the compounds of the present invention also include racemate, individual stereoiso- mers and mixtures thereof. These isomers are then isolated by standard resolution techniques, including fractional crystallization and reverse phase and chiral column chromatography.
  • the compounds and pharmaceutical compositions of the present invention can advantageously be used in the treatment of the diseases and conditions described herein.
  • the compounds and compositions will prove particularly useful in the treatment of skin-related diseases and conditions, such as acne, psoriasis, and photo damage, cancerous and precancerous conditions, diseases of the eye, cardiovascular diseases, inflammatory and neurodegenerative diseases, diseases associated with human papilloma virus, improper pituitary function, modulation of apoptosis, diseases of the immune system, wound healing and restoration of hair growth.
  • the compounds and pharmaceutical compositions of the present invention possess a number of advantages over previously identified retinoid compounds.
  • the compounds are extremely potent activators of RARs and RXRs, preferably displaying 50% maximal activation of one or more of the retinoid receptors at a concentra- tion of less than 100 nM, more preferably at a concentration of less than 50 nM, more preferably yet at a concentration of less than 20 nM, and most preferably at a concentration of less than 10 nM.
  • the RAR and RXR selective compounds of the present invention preferentially activate one subfamily of retinoid receptors at a level at least 2 times greater, preferably at least 5 times greater, more preferably at least 10 times greater, and most preferably at least 100 times greater than the other subfamily of retinoid receptors.
  • the compounds of the present invention also are easier to synthesize, provide greater stability and bioavailability, and appear to be less teratogenic in comparison to all-trans retinoic acid and 9-cis retinoic acid, known RAR and RXR active compounds, respectively.
  • the top of the condenser is connected to a gas-absorption trap containing 10% Na 2 CO 3 .
  • Mixture is stirred and cooled in an ice-salt mixture.
  • Bromine is added dropwise over a 30 min. period. (During this time, internal temp, is maintained at 0° C to -5° C.) Temperature higher than 10° C will increase amount of dibromo compound formed. After all the bromine has been added, the reaction mixture is allowed to stand overnight.
  • the crude boronic acid was carried on to the next step without further purification.
  • the above unsaturated alcohol 8 (930 mg, 4.55 mmol) was converted to the cyclopropyl alcohol as described in Example 1 to give 900 mg of [l-(3,4-diethyl benzene)- cyclopropylj-ethanol (9) as a pale yellow oil in 91% yield.
  • the above cyclopropyl alcohol (900 mg, 4.12 mmol) was oxidized as described in Example 1 to give 520 mg of l-(3,4- diethyl benzene) cyclopropaneacetaldehyde (10) as a clear oil in 58% yield.
  • the above unsaturated alcohol (16) (30 mg, 0.16 mmol) was converted to the cyclopropyl alcohol as described in Example 1 to give 33 mg of [l-(6-t-butyl-l,l-dimethyl- indan-4-yl)-cyclopropyl]-ethanol (17) as a pale yellow oil in 67% yield that was used directly for the next step.
  • the above cyclopropyl alcohol (33 mg, 0.15 mmol) was oxidized as described in Example 1 to give 32 mg of l-(6-t-butyl-l,l-dimethyl-indan-4-yl)- cyclopropaneacetaldehyde (18) as a clear oil in 100% yield.
  • the co-transfection assay provides a method for identifying functional agonists which mimic, or antagonists which inhibit, the effect of native hormones, and quantifying their activity for responsive IR proteins.
  • the co-transfection assay mimics an in vivo system in the laboratory.
  • activity in the co-transfection assay correlates very well with known in vivo activity, such that the co-transfection assay functions as a qualitative and quantitative predictor of a tested compounds in vivo pharmacology. See, e. g .. T. Berger et al. 41 J. Steroid Biochem. Molec. Biol. 773 (1992), the disclosure of which is herein incorporated by reference.
  • a cloned cDNA for an IR e.g., human RAR ⁇ , RAR ⁇ , RXR ⁇
  • a constitutive promoter e.g., the SV 40 promoter
  • transfection a procedure to induce cells to take up foreign genes
  • This introduced gene directs the recipient cells to make the IR protein of interest.
  • a second gene is also introduced (co-transfected) into the same cells in conjunction with the IR gene.
  • This second gene comprising the cDNA for a reporter protein, such as firefly luciferase (LUC), controlled by an appropriate hormone responsive promoter containing a hormone response element (HRE).
  • This reporter plasmid functions as a reporter for the transcription-modulating activity of the target IR.
  • the reporter acts as a surrogate for the products (mRNA then protein) normally expressed by a gene under control of the target receptor and its native hormone.
  • the co-transfection assay can detect small molecule agonists or antagonists of target IRs. Exposing the transfected cells to an agonist ligand compound increases reporter activity in the transfected cells. This activity can be conveniently measured, e.g., by increasing luciferase production, which reflects compound-dependent, IR-mediated increases in reporter transcription.
  • the co-transfection assay is carried out in the presence of a constant concentration of an agonist to the target IR (e.g., all-tr ⁇ ns retinoic acid for RAR ⁇ ) known to induce a defined reporter signal. Increasing concentrations of a suspected antagonist will decrease the reporter signal (e.g., luciferase production).
  • the co-transfection assay is therefore useful to detect both agonists and antagonists of specific IRs. Furthermore, it determines not only whether a compound interacts with a particular IR, but whether this interaction mimics (agonizes) or blocks (antagonizes) the effects of the native regulatory molecules on target gene expression, as well as the specificity and strength of this interaction.
  • the activity of the retinoid compounds of the present invention were evaluated utilizing the co-transfection assay according to the following illustrative Example.
  • CV-1 cells African green monkey kidney fibroblasts
  • DMEM Dulbecco's Modified Eagle Medium
  • charcoal resin- stripped fetal bovine serum then transferred to 96-well microtiter plates one day prior to transfection.
  • the CV-1 cells were transiently transfected by calcium phosphate coprecipitation according to the procedure of Berger et al., 41 . Steroid Biochem. Mol. Biol, 733 (1992) with the following receptor expressing plasmids: pRShRAR ⁇ : Giguere et al., 330 Nature, 624 (1987); pRShRAR ⁇ and pRShRAR ⁇ , Ishikawa et al, 4 Mol.
  • Each of these receptor expressing plasmids was co-trans- fected at a concentration of 5 ng/well, along with a basal reporter plasmid at 100 ng/well, the internal control plasmid pRS- ⁇ -Gal at 50 ng/well and filler DNA , pGEM at 45 ng/well.
  • the basal reporter plasmid D-MTV-LUC (Hollenberg and Evans, 55 Cell, 899 (1988), the disclosure of which is herein incorporated by reference) containing two copies of the TRE-palindromic response element described in Umesono et al, 336 Nature, 262 (1988), the disclosure of which is herein incorporated by reference, was used in transfec- tions for the RARs, and the reporter plasmid CRBPIIFKLUC, which contains an RXRE (retinoid X receptor response element, as described in Mangelsdorf et al., 66 Cell, 555 (1991), the disclosure of which is herein incorporated by reference), was used in transfec- tions for the RXRs.
  • D-MTV-LUC Hollenberg and Evans, 55 Cell, 899 (1988), the disclosure of which is herein incorporated by reference
  • Each of these reporter plasmids contains the cDNA for firefly luciferase (LUC) under constitutive promoter containing the appropriate RAR or RXR response ele- ment.
  • LOC firefly luciferase
  • pRS- ⁇ -Gal coding for constitutive expression of E. coli ⁇ - galactosidase ( ⁇ -Gal) was included as an internal control for evaluation of transfection efficiency and compound toxicity.
  • NR normalized response
  • ⁇ -Gal rate ⁇ -Gal-lxlO- 5 / ⁇ -Gal incubation time.
  • the mean and standard error of the mean (SEM) of the NR were calculated. Data was plotted as the response of the compound compared to the reference compounds over the range of the dose-response curve.
  • the effective concentration that produced 50% of the maximum response (EC50) was quantified.
  • the potency (nM) of selected retinoid compounds of the present invention are in
  • Table 1 Potency (nM) of selected retinoid compounds of the present invention on RAR ⁇ , ⁇ , ⁇ and RXR ⁇ , ⁇ , ⁇ , in comparison to the known RAR- active retinoid compound all-tr ⁇ ns retinoic acid (ATRA) and RXR-active retinoid compound 9-cis retinoic acid (9-cis-RA).
  • ATRA all-tr ⁇ ns retinoic acid
  • 9-cis-RA 9-cis retinoic acid
  • Compounds 101 and 105 are pan-agonists that display superior potency profiles to that of the known pan-agonist compound 9-cis retinoic acid.
  • Non-specific binding was defined as that binding remaining in the presence of 500 nM of the appropriate unlabelled compound. At the end of the incubation period, bound from free ligand were separated. The amount of bound tritiated retinoids was determined by liquid scintillation counting of an aliquot (700 mL) of the supernatant fluid or the hydroxylapatite pellet.
  • IC50 values were determined.
  • the IC50 value is defined as the concentration of competing ligand needed to reduce specific binding by 50%.
  • the IC50 value was determined graphically from a log-logit plot of the data.
  • the Kj values were determined by application of the Cheng-Prussof equation to the IC50 values, the labeled ligand concentration and the K of the labeled ligand.
  • Table 2 Binding (Kd in nM) of selected retinoid compounds of the present invention on RAR ⁇ , ⁇ , ⁇ and RXR ⁇ , ⁇ , ⁇ proteins in comparison to the known RAR-active retinoid compound all-tr ⁇ ns retinoic acid (ATRA) and RXR-active retinoid compound 9-cis retinoic acid (9-cis-RA).
  • ATRA all-tr ⁇ ns retinoic acid
  • 9-cis-RA 9-cis retinoic acid
  • na not active (Kd of >5,000)
  • RPMI 8226 is a human hematopoietic cell line obtained from the peripheral blood of a patient with multiple myeloma, and as such is a recognized model for multiple myelomas and related malignancies.
  • Y. Matsuoka, G.E. Moore, Y. Yagi and D. Pressman "Production of free light chains of immunoglobulin by a hematopoietic cell line derived from a patient with multiple myeloma", 125 Proc. Soc. Exp.
  • RPMI 8226 cells were grown in RPMI medium (Gibco) supplemented with 10% fetal bovine serum, glutamine and antibiotics. The cells were maintained as suspension cultures grown at 37°C in a humidified atmosphere of 5% CO2 in air. The cells were diluted to a concentration of 1 x lO ⁇ /mL twice a week.
  • ME 180 is a human epidermoid carcinoma cell line derived from the cervix, and as such is a recognized model for squamous cell carcinomas and related malignancies.
  • the tumor was a highly invasive squamous cell carcinoma with irregular cell clusters and no significant keratinization.
  • ME 180 cells were grown and maintained in McCoy's 5a medium (Gibco) supplemented with 10% fetal bovine serum, glutamine and antibiotics. The cells were maintained as monolayer cultures grown at 37 °C in a humidified atmosphere of 5% CO2 in air.
  • McCoy's 5a medium Gibco
  • the cells were maintained as monolayer cultures grown at 37 °C in a humidified atmosphere of 5% CO2 in air.
  • the AML-193 cell line was established from the blast cells of a patient with leukemia and was classified as M5 Acute Monocytic Leukemia, and as such is a recognized model for leukemias and related malignancies. G. Rovera, et al., 139 J. Immunol, 3348 (1987), the disclosure of which is herein incorporated by reference. Over 75% of these cells are positive by immunofluorescence for the myelomonocytic antigen CS15. The cells were grown in Iscove's modified Dulbeccos's medium with 5 ⁇ g/mL transferring, 5 ⁇ g/mL insu- lin and 2 ng/mL rh GM-CSF. The cells were maintained as suspension cultures grown at 37 °C in a humidified atmosphere of 5% CO2 in air. The cells were diluted to a concentration of 1 x 10-5/mL twice a week.
  • retinoid test compounds were added at the final concentrations indicated for a final volume of 150 ⁇ L/well.
  • the plates were incubated for 96 hours at 37 °C in a humidified atmosphere of 5% CO2 in air. Subsequently, 1 ⁇ Ci of [5'-3H]-thymidine (Amersham, U.K, 43 Ci/mmol specific activity) in 25 ⁇ L culture medium was added to each well and the cells were incubated for an additional six hours. The cultures were further processed as described below.
  • ME 180 cells harvested by trypsinization were plated in a 96 well flat bottom microtiter plate (Costar) at a density of 2,000 cells/well. The cultures were treated as described above for RPMI 8226 with the following exceptions. After incubation, the supernatant was carefully removed, and the cells were washed with a 0.5 mM solution of thymidine in phosphate buffered saline. ME 180 cells were briefly treated with 50 ⁇ L of 2.5% trypsin to dislodge the cells from the plate.
  • Table 4 Inhibitory concentration required to inhibit 50% of the maximally observed radiolabeled thymidine (TdR IC50) in nM for Compound 101 of the present invention and reference compounds ATRA, TTNBP and 9- ' s-RA on the RPMI 8226, ME 180 and AML-193 cell lines.
  • TdR IC50 radiolabeled thymidine
  • Hard gelatin capsules are prepared using the following ingredients:
  • the above ingredients are mixed and filled into hard gelatin capsules in 250 mg quantities.
  • a tablet is prepared using the ingredients below:
  • Compound 101b 140 Cellulose, microcrystalline 200 Silicon dioxide, fumed 10 Stearic acid JO
  • the active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly.
  • the solution of PVP is mixed with the resultant powders, which are then passed through a No. 14 mesh U.S. sieve.
  • the granules so produced are dried at 50°C and passed through a No. 18 mesh U.S. sieve.
  • the SCMS, magnesium stearate, and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
  • Suppositories each containing 225 mg of active ingredient, may be made as follows: Compound 101b 225 mg
  • the active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of normal 2g capacity and allowed to cool.
  • An intravenous formulation may be prepared as follows:
  • Isotonic saline 1,000 ml Glycerol 100 ml
  • the compound is dissolved in the glycerol and then the solution is slowly diluted with isotonic saline.
  • the solution of the above ingredients is then administered intravenously at a rate of 1 ml per minute to a patient.

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Abstract

L'invention concerne des rétinoïdes dienoïques ayant une activité pour les récepteurs de rétinoïdes X ou qui sont des pan-agonistes sur des récepteurs d'acide rétinoïque et des récepteurs de rétinoïdes X. L'invention concerne également des compositions pharmaceutiques renfermant de tels composés, ainsi que des techniques de leur utilisation thérapeutique.
PCT/IB1998/001761 1998-11-03 1998-11-03 Nouveaux retinoides et techniques de leur production et utilisation WO2000026173A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106831445A (zh) * 2016-11-22 2017-06-13 斯芬克司药物研发（天津）股份有限公司 一种茚基胺化合物的制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997012853A1 (fr) * 1995-10-06 1997-04-10 Ligand Pharmaceuticals Incorporated Modulateurs rxr selectifs pour les dimeres et leurs methodes d'utilisation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997012853A1 (fr) * 1995-10-06 1997-04-10 Ligand Pharmaceuticals Incorporated Modulateurs rxr selectifs pour les dimeres et leurs methodes d'utilisation

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106831445A (zh) * 2016-11-22 2017-06-13 斯芬克司药物研发（天津）股份有限公司 一种茚基胺化合物的制备方法

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