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WO2009153566A1 - Inhibiteurs de cyp26 - Google Patents

Inhibiteurs de cyp26 Download PDF

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WO2009153566A1
WO2009153566A1 PCT/GB2009/001533 GB2009001533W WO2009153566A1 WO 2009153566 A1 WO2009153566 A1 WO 2009153566A1 GB 2009001533 W GB2009001533 W GB 2009001533W WO 2009153566 A1 WO2009153566 A1 WO 2009153566A1
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compound according
alkyl
compound
phenyl
ester
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Claire Simons
Andrea Brancale
Mohamed Sayed Mohamed Gomaa
Ahmed Safwat Mohamed Aboraia
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Cancer Research Technology Ltd
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Cancer Research Technology Ltd
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    • 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
    • C07D233/61—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 with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
    • 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
    • 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

  • the present invention relates to compounds which act as an inhibitor of CYP26, their use and synthesis.
  • Retinoic acid is a naturally occurring retinoid, the main biologically active derivative of vitamin A (retinol). Retinoic acid regulates cell growth and differentiation in a variety of cell types. RA binds to transcription-regulatory factors in the cell nucleus known as RAR (retinoic acid receptor) and RXR (retinoid X receptor), each having subtypes ⁇ , ⁇ and ⁇ . RA controls transcription by binding to RAR/RXR dimers, which locally modifies chromatin structure.
  • RAR retinoic acid receptor
  • RXR retinoid X receptor
  • RA exists in several isomeric forms, including a ⁇ -trans retinoic acid (ATRA), 13- cis retinoic acid (13cisRA) and to a lesser extent 9-c/s retinoic acid (9cisRA).
  • ATRA is the natural ligand for the retinoic acid receptors (RARs: ⁇ , ⁇ and ⁇ ) while 9cisRA binds both RARs and retinoid X receptors (RXRs: ⁇ , ⁇ and ⁇ ). All RA isomers will readily isomerise in biological systems but conversion to ATRA is thermodynamically favoured.
  • the terms "retinoic acid” or "RA” refer to any isomeric form of retinoic acid, or a mixture thereof.
  • RA's intracellular concentrations are regulated by negative feedback controls tightly coupled to requirements for signalling in relation to cell differentiation and morphogenesis.
  • RA has been used in a number of clinical situations, including oncology, for example acute promyelocytic leukemia (Estey, E. H., ef al., M. Blood, 94, 2230 (1999); Fenaux, P.; et al., L. Blood , 94, 1192 (1999); neuroblastoma (Matthay, K.K., ef al., New England Journal of Medicine, 341, 1165-1173 (1999); Veal, G. J., et al., British Journal of Cancer, 96, 424-431 (2007)); and prostate cancer (Debruyne, F.J. M., et al., Urology, 52, 72-81 (1998)).
  • oncology for example acute promyelocytic leukemia (Estey, E. H., ef al., M. Blood, 94, 2230 (1999); Fenaux, P.; et al., L. Blood , 94, 1192 (1999
  • RA has also been used in dermatology (acne, psoriasis (Ahmad, N. and Mukhtar, H.J. Investig. Dermatol., 123, 417 (2004), Brecher, A.R. and Orlow, S.J., J. Am. Acad. Dermatol., 49, 171 (2003))).
  • RA may improve the efficacy of other treatments such as radiation, cisplatin and interferon therapies (Weiss, G. R., et al., Gynecol. Oncol., 71 , 386 (1998); Pettersson, F., et al., Pancreas, 23, 273. (2001)). Biochemical results also support lower retinoid supply, synthesis, impaired transport, and hypofunction as contributing factors to late onset Alzheimer's disease (LOAD) (Goodman, A.B. and Pardee, A.B., Proc. Nat. Acad. Sci.
  • LOAD late onset Alzheimer's disease
  • AW-trans RA has a short half-life and its potency is reduced when administered systemically, owing to metabolism by several human liver and intestine cytochrome P450 enzymes to the inactive 4-hydroxy-RA and then by dehydrogenases to the partially active 4-keto-RA and the inactive polar metabolites.
  • ATRA endogenous metabolism of ATRA occurs primarily via oxidation, with C-4 hydroxylation of the cyclohexenyl ring leading to formation of 4-hydroxy-ATRA, the most prominent metabolite.
  • a number of cytochrome P450 enzymes primarily CYP2C8, CYP3A4 and CYP2C9, can perform this oxidation but their contribution to RA metabolism may be relatively minor due to with high K m values.
  • the main route of RA catabolism likely to represent the main negative feedback control of intracellular RA concentrations, is via a family of RA-inducible P450s, P450RAI or CYP26.
  • a ⁇ -trans RA administration induces CYP26, which recognizes only RA as its substrate, and the expression of this isozyme can be induced by ATRA both in vitro and in vivo.
  • the induction of CYP26 has been reported in a wide range of cells and tissues after RA treatment and RA-treated cells transfected with full length CYP26 accumulate polar metabolites at an increased rate.
  • Evidence is growing that RA resistance is related to up- regulation of CYP26 resulting in accelerated metabolism of RA. For example, a relationship between induction of ATRA metabolism and drug resistance has been demonstrated in acute promyelocytic leukaemia (APL) patients.
  • APL acute promyelocytic leukaemia
  • CYP26A1 and CYP26B1 which metabolise ATRA in the embryo and adult, and more recently, CYP26C1 that may have a role in the specific metabolism of both a ⁇ -trans and 9-c/s isomers of RA.
  • the dose- dependent induction of CYP26 mRNA has been used as a sensitive marker of retinoid response: in SH-SY5Y neuroblastoma cells, CYP26 mRNA is normally undetectable but treatment with ATRA results in the dose-dependent induction of CYP26A1 and CYP26B1 mRNA and increased metabolism of ATRA within 24 hours.
  • CYP26 inhibitors have proven to be effective in blocking catabolic effects on ATRA and have demonstrated an increase in endogenous ATRA levels. Therefore administering a CYP26 inhibitor alone or in conjunction with exogenously administered ATRA would both be therapeutically beneficial.
  • Potentiating endogenous ATRA through inhibition of CYP26 may avoid the frequency and severity of complications associated with intensive high dose ATRA therapy and may provide an effective means of treatment following relapses in cases where resistance emerges due to CYP26 upregulation.
  • RAMBAs retinoic acid metabolism blocking agents
  • R115866 increases endogenous RA levels in rats after a single oral dose (Stoppie, P., ef a/., Journal of Pharmacology & Experimental Therapeutics, 293, 304-312 (2000)) and recent data indicate that R115866 is beneficial in the treatment of acne and psoriasis (Verfaille, CJ. ; Steijlen, P.M.; van der Kerkhof, P.C.M.; Stoppie, P.; Van Wauwe, J. P.; van Rossem, K.
  • R115866 rambazole: a potential alternative for retinoids in the treatment of psoriasis. Journal of the European Academy of Dermatology and Venereology 21 : 21-21 Suppl. 1.; Bovenschen, H.J., ef a/., British Journal of Dermatology, 156, 263-270 (2007)). R116010 inhibits ATRA metabolism in neuroblastoma both in vitro and in vivo (Armstrong, J. L., ef a/., British Journal of Cancer, 92, 696-704 (2005); Armstrong ,J.L, et al., British Journal of Cancer, 96, 1675- 168 (2007)).
  • the present inventors have discovered CYP26 inhibitors which can therefore act as retinoic acid metabolism blocking agents (RAM BAs).
  • the compounds may possess improved biological activity over known CYP26 inhibitors, and/or greater selectivity for CYP26 over other CYPs.
  • the first aspect of the invention provides a compound of formula (I):
  • X is selected from O, S 1 NH or CH 2 ;
  • R d and R p are optional naphthyl group substituents
  • R Het is imidazolyl, triazolyl or pyridyl
  • R c is C 1 -4 alkyl substituted by a group selected from: hydroxy, amino, amido, carboxy, C 1-7 alkyl ester, C 5-7 aryl-C 1-2 alkyl ester, sulfonamino, sulfinamino, hydroxamino and tetrazolyl.
  • the compound of formula (I) can be of formula Ia or Ib:
  • the optional naphthyl group substituents may be selected from, but not limited to, C 1 - 7 alkyl, C 3 - 20 heterocyclyl, C 5 - 20 aryl, halo, hydroxy, ether, nitro, cyano, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thiol, thioether, sulfoxide, sulfonyl, thioamido, sulfonamino, sulfinamino and hydroxamino.
  • a second aspect of the invention provides a composition comprising a compound of the first aspect of the invention and a pharmaceutically acceptable carrier or diluent.
  • a third aspect of the invention provides a compound of the first aspect of the invention or a composition of the second aspect of the invention for use in a method of therapy.
  • a fourth aspect of the invention provides the use of a compound of the first aspect of the invention or a composition of the second aspect of the invention in the preparation of a medicament for treating diseases which are ameliorated by the inhibition of CYP26 mediated retinoic acid metabolism.
  • the fourth aspect of the invention also provides a compound of the first aspect of the invention or a composition of the second aspect of the invention for use in the treatment of diseases which are ameliorated by the inhibition of CYP26 mediated retinoic acid metabolism
  • a fifth aspect of the invention provides the use of a compound of the first aspect of the invention or a composition of the second aspect of the invention in combination with RA in the preparation of a medicament for treating diseases which are ameliorated by administration of RA.
  • the fifth aspect of the invention also provides a compound of the first aspect of the invention or a composition of the second aspect of the invention in combination with RA for use in the treatment of diseases which are ameliorated by administration of RA.
  • CYP26 mediated retinoic acid metabolism and diseases which are ameliorated by administration of RA may include, but are not limited to: (a) Cancer, e.g. acute promyelocytic leukaemia, neuroblastoma, acute myelogenous leukaemia, basal cell and squamous cell carcinomas, prostate cancer, breast cancer; which may include combination with radiotherapy, and chemotherapy;
  • Cancer e.g. acute promyelocytic leukaemia, neuroblastoma, acute myelogenous leukaemia, basal cell and squamous cell carcinomas, prostate cancer, breast cancer; which may include combination with radiotherapy, and chemotherapy;
  • Dermatological disorders e.g. acne, psoriasis, ichthyosis;
  • a sixth aspect of the invention provides an active compound as described herein for use in a method of treatment of the human or animal body, preferably in the form of a pharmaceutical composition.
  • a seventh aspect of the invention provides a method of inhibiting metabolism of retinoic acid by CYP26 in vitro or in vivo, comprising contacting a cell with an effective amount of an active compound as described herein.
  • Alkyl refers to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise specified), which may be aliphatic or alicyclic, and which may be saturated or unsaturated (e.g. partially unsaturated, fully unsaturated).
  • alkyl includes the sub-classes alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cylcoalkynyl, etc., discussed below.
  • the prefixes denote the number of carbon atoms, or range of number of carbon atoms.
  • C 1 . 4 alkyl refers to an alkyl group having from 1 to 4 carbon atoms.
  • groups of alkyl groups include Ci -4 alkyl ("lower alkyl"), Ci -7 alkyl, d. 10 alkyl and C L20 alkyl.
  • the first prefix may vary according to other limitations; for example, for unsaturated alkyl groups, the first prefix must be at least 2; for cyclic alkyl groups, the first prefix must be at least 3; etc.
  • Examples of (unsubstituted) saturated alkyl groups include, but are not limited to, methyl (C 1 ), ethyl (C 2 ), propyl (C 3 ), butyl (C 4 ), pentyl (C 5 ), hexyl (C 6 ), heptyl (C 7 ), octyl (C 8 ), nonyl (C 9 ), decyl (C 1 0), undecyl (C 11 ), dodecyl (C 12 ), tridecyl (C 13 ), tetradecyl (C 14 ), pentadecyl (C 15 ), and eicodecyl (C 20 ).
  • Examples of (unsubstituted) saturated linear alkyl groups include, but are not limited to, methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), n-butyl (C 4 ), n-pentyl (amyl) (C 5 ), n-hexyl (C 6 ), and n- heptyl (C 7 ).
  • Examples of (unsubstituted) saturated branched alkyl groups include iso-propyl (C 3 ), iso-butyl (C 4 ), sec-butyl (C 4 ), tert-butyl (C 4 ), iso-pentyl (C 5 ), and neo-pentyl (C 5 ).
  • Alkenyl refers to an alkyl group having one or more carbon-carbon double bonds. Examples of groups of alkenyl groups include C 2-4 alkenyl, C 2-7 alkenyl, C 2-2O alkenyl.
  • Alkynyl refers to an alkyl group having one or more carbon-carbon triple bonds. Examples of groups of alkynyl groups include C 2-4 alkynyl, C 2-7 alkynyl, C 2-20 alkynyl.
  • Examples of (unsubstituted) unsaturated alkynyl groups include, but are not limited to, ethynyl (ethinyl, -C ⁇ CH) and 2-propynyl (propargyl, -CH 2 -C ⁇ CH).
  • Cycloalkyl refers to an alkyl group which is also a cyclyl group; that is, a monovalent moiety obtained by removing a hydrogen atom from an alicyclic ring atom of a carbocyclic ring of a carbocyclic compound, which carbocyclic ring may be saturated or unsaturated (e.g. partially unsaturated, fully unsaturated), which moiety has from 3 to 20 carbon atoms (unless otherwise specified), including from 3 to 20 ring atoms.
  • cycloalkyl includes the sub-classes cycloalkenyl and cycloalkynyl.
  • each ring has from 3 to 7 ring atoms.
  • groups of cycloalkyl groups include C 3 . 2 o cycloalkyl, C 3-15 cycloalkyl, C 3-10 cycloalkyl, C 3-7 cycloalkyl.
  • cycloalkyl groups include, but are not limited to, those derived from: saturated monocyclic hydrocarbon compounds: cyclopropane (C 3 ), cyclobutane (C 4 ), cyclopentane (C 5 ), cyclohexane (C 6 ), cycloheptane (C 7 ), methylcyclopropane (C 4 ), dimethylcyclopropane (C 5 ), methylcyclobutane (C 5 ), dimethylcyclobutane (C 6 ), methylcyclopentane (C 6 ), dimethylcyclopentane (C 7 ), methylcyclohexane (C 7 ), dimethylcyclohexane (C 8 ), menthane (C 10 ); unsaturated monocyclic hydrocarbon compounds: cyclopropene (C 3 ), cyclobutene (C 4 ), cyclopentene (C 5 ), cyclohexene (C 6 ), methylcyclopropene
  • Heterocyclyl refers to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 3 to 20 ring atoms (unless otherwise specified), of which from 1 to 10 are ring heteroatoms.
  • each ring has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms.
  • the prefixes e.g. C 3 . 2 o, C 3-7 , C 5-6 , etc.
  • the prefixes denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms.
  • the term "C 5 - 6 heterocyclyl”, as used herein, pertains to a heterocyclyl group having 5 or 6 ring atoms.
  • groups of heterocyclyl groups include C 3-2O heterocyclyl, C 5-20 heterocyclyl, C 3 .i 5 heterocyclyl, C 5 .i 5 heterocyclyl, C 3-I2 heterocyclyl, C 5-I2 heterocyclyl, C 3-10 heterocyclyl, C 5- i 0 heterocyclyl, C 3-7 heterocyclyl, C 5-7 heterocyclyl, and C 5 . 6 heterocyclyl.
  • monocyclic heterocyclyl groups include, but are not limited to, those derived from:
  • Ni aziridine (C 3 ), azetidine (C 4 ), pyrrolidine (tetrahydropyrrole) (C 5 ), pyrroline (e.g.,
  • O 1 oxirane (C 3 ), oxetane (C 4 ), oxolane (tetrahydrofuran) (C 5 ), oxole (dihydrofuran) (C 5 ), oxane (tetrahydropyran) (C 6 ), dihydropyran (C 6 ), pyran (C 6 ), oxepin (C 7 );
  • N 2 imidazolidine (C 5 ), pyrazolidine (diazolidine) (C 5 ), imidazoline (C 5 ), pyrazoline
  • NiS 1 thiazoline (C 5 ), thiazolidine (C 5 ), thiomorpholine (C 6 ); N 2 Oi: oxadiazine (C 6 );
  • UIS 1 oxathiole (C 5 ) and oxathiane (thioxane) (C 6 ); and, N 1 O 1 Si: oxathiazine (C 6 ).
  • substituted (non-aromatic) monocyclic heterocyclyl groups include those derived from saccharides, in cyclic form, for example, furanoses (C 5 ), such as arabinofuranose, lyxofuranose, ribofuranose, and xylofuranse, and pyranoses (C 6 ), such as allopyranose, altropyranose, glucopyranose, mannopyranose, gulopyranose, idopyranose, galactopyranose, and talopyranose.
  • furanoses C 5
  • arabinofuranose such as arabinofuranose, lyxofuranose, ribofuranose, and xylofuranse
  • pyranoses C 6
  • allopyranose altropyranose
  • glucopyranose glucopyranose
  • mannopyranose gulopyranose
  • idopyranose galactopyr
  • C 5-20 aryl as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of a C 5 . 2 o aromatic compound, said compound having one ring, or two or more rings (e.g., fused), and having from 5 to 20 ring atoms, and wherein at least one of said ring(s) is an aromatic ring.
  • each ring has from 5 to 7 ring atoms.
  • the ring atoms may be all carbon atoms, as in "carboaryl groups” in which case the group may conveniently be referred to as a "C 5-20 carboaryl” group.
  • C 5-20 aryl groups which do not have ring heteroatoms include, but are not limited to, those derived from benzene (i.e. phenyl) (C 6 ), naphthalene (Ci 0 ), anthracene (Ci 4 ), phenanthrene (C1 4 ), and pyrene (Ci 6 ).
  • the ring atoms may include one or more heteroatoms, including but not limited to oxygen, nitrogen, and sulfur, as in “heteroaryl groups".
  • the group may conveniently be referred to as a "C 5-20 heteroaryl” group, wherein “C 5-20 " . denotes ring atoms, whether carbon atoms or heteroatoms.
  • each ring has from 5 to 7 ring atoms, of which from 0 to 4 are ring heteroatoms.
  • C 5-20 heteroaryl groups include, but are not limited to, C 5 heteroaryl groups derived from furan (oxole), thiophene (thiole), pyrrole (azole), imidazole (1 ,3-diazole), pyrazole (1 ,2-diazole), triazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, tetrazole and oxatriazole; and C 6 heteroaryl groups derived from isoxazine, pyridine (azine), pyridazine (1 ,2-diazine), pyrimidine (1 ,3-diazine; e.g., cytosine, thymine, uracil), pyrazine (1 ,4-diazine) and triazine.
  • C 5 heteroaryl groups derived from furan (oxole), thiophene (thiole
  • the heteroaryl group may be bonded via a carbon or hetero ring atom.
  • C 5 . 2 o heteroaryl groups which comprise fused rings include, but are not limited to, C 9 heteroaryl groups derived from benzofuran, isobenzofuran, benzothiophene, indole, isoindole; C 10 heteroaryl groups derived from quinoline, isoquinoline, benzodiazine, pyridopyridine; d 4 heteroaryl groups derived from acridine and xanthene.
  • Halo -F, -Cl, -Br, and -I.
  • Ether -OR, wherein R is an ether substituent, for example, a C 1-7 alkyl group (also referred to as a C 1-7 alkoxy group), a C 3 . 2 o heterocyclyl group (also referred to as a C 3-2 O heterocyclyloxy group), or a C 5-2O aryl group (also referred to as a C 5-2 O aryloxy group), preferably a Ci -7 alkyl group.
  • R is an ether substituent, for example, a C 1-7 alkyl group (also referred to as a C 1-7 alkoxy group), a C 3 . 2 o heterocyclyl group (also referred to as a C 3-2 O heterocyclyloxy group), or a C 5-2O aryl group (also referred to as a C 5-2 O aryloxy group), preferably a Ci -7 alkyl group.
  • R is an acyl substituent, for example, H, a C 1-7 alkyl group (also referred to as Ci -7 alkylacyl or Ci. 7 alkanoyl), a C 3-2O heterocyclyl group (also referred to as C 3 . 20 heterocyclylacyl), or a C 5-2 O aryl group (also referred to as C 5-20 arylacyl), preferably a C 1 .7 alkyl group.
  • R is an acyl substituent, for example, H, a C 1-7 alkyl group (also referred to as Ci -7 alkylacyl or Ci. 7 alkanoyl), a C 3-2O heterocyclyl group (also referred to as C 3 . 20 heterocyclylacyl), or a C 5-2 O aryl group (also referred to as C 5-20 arylacyl), preferably a C 1 .7 alkyl group.
  • Ester (carboxylate, carboxylic acid ester, oxycarbonyl): -C( O)OR, wherein R is an ester substituent, for example, a Ci_ 7 alkyl group, a C 3 . 2 o heterocyclyl group, or a C 5 . 20 aryl group, preferably a C 1-7 alkyl group.
  • R is a C 1-2 alkyl group substituted by a C 5 . 6 aryl group
  • the ester is termed a C 5-6 aryl-Ci. 2 alkyl ester.
  • R 1 and R 2 together with the nitrogen atom to which they are attached, form a heterocyclic structure as in, for example, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, and piperazinylcarbonyl.
  • R 1 and R 2 are independently amino substituents, for example, hydrogen, a Ci -7 alkyl group (also referred to as C ⁇ alkylamino or di-C ⁇ alkylamino), a C 3 . 20 heterocyclyl group, or a C 5-20 aryl group, preferably H or a C 1-7 alkyl group, or, in the case of a "cyclic" amino group, R 1 and R 2 , taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms.
  • a Ci -7 alkyl group also referred to as C ⁇ alkylamino or di-C ⁇ alkylamino
  • C 3 . 20 heterocyclyl group or a C 5-20 aryl group, preferably H or a C 1-7 alkyl group, or, in the case of a "cyclic" amino group, R 1 and R 2 , taken together with the nitrogen atom to which they are attached, form a heterocyclic
  • amino groups include, but are not limited to, -NH 2 , -NHCH 3 , -NHCH(CH 3 ) 2 , -N(CH 3 J 2 , -N(CH 2 CH 3 ) 2 , and -NHPh.
  • cyclic amino groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperazinyl, perhydrodiazepinyl, morpholino, and thiomorpholino.
  • the cylic amino groups may be substituted on their ring by any of the substituents defined here, for example carboxy, carboxylate and amido.
  • R 1 is an amide substituent, for example, hydrogen, a Ci -7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably H or a C 1-7 alkyl group, most preferably H
  • R 2 is an acyl substituent, for example, a Ci -7 alkyl group, a C 3-20 heterocyclyl group, or a C
  • R 1 and R 2 may together form a cyclic structure, as in, for example, succinimidyl, maleimidyl, and phthalimidyl: succinimidyl maleimidyl
  • R 2 and R 3 are independently amino substituents, as defined for amino groups, and R1 is a ureido substituent, for example, hydrogen, a C 1-7 alkyl group, a C 3 .2oheterocyclyl group, or a C 5 - 2 oaryl group, preferably hydrogen or a Ci -7 alkyl group.
  • Acyloxy (reverse ester): -OC( O)R, wherein R is an acyloxy substituent, for example, a Ci -7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a C 1-7 alkyl group.
  • R is an acyloxy substituent, for example, a Ci -7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a C 1-7 alkyl group.
  • Ci -7 alkylthio groups include, but are not limited to, -SCH 3 and -SCH 2 CH 3 .
  • R is a sulfoxide substituent, for example, a Ci -7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a C 1-7 alkyl group.
  • Sulfonyl (sulfone): -S( 0) 2 R, wherein R is a sulfone substituent, for example, a Ci- 7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a Ci -7 alkyl group.
  • R is a sulfone substituent, for example, a Ci- 7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a Ci -7 alkyl group.
  • Thioamido (thiocarbamyl): -C( S)NR 1 R 2 , wherein R 1 and R 2 are independently amino substituents, as defined for amino groups.
  • R 1 is an amino substituent, as defined for amino groups
  • R is a sulfonamino substituent, for example, a Ci- 7 alkyl group, a C 3 . 2oheterocyclyl group, or a C 5 -2oaryl group, preferably a d- 7 alkyl group.
  • R 1 is an amino substituent, as defined for amino groups
  • R is a sulfinamino substituent, for example, a C ⁇ alkyl group, a C 3 . 20 heterocyclyl group, or a C 5 - 2 oaryl group, preferably a C ⁇ alkyl group.
  • Hydroxamino (hydroxamic acid): -C( O)NR 1 OH, wherein R 1 is an amide substituent, for example, hydrogen, a Ci -7 alkyl group, a C 3 . 2 o heterocyclyl group, or a C 5-20 aryl group, preferably H or a Ci -7 alkyl group, most preferably H.
  • R 1 is an amide substituent, for example, hydrogen, a Ci -7 alkyl group, a C 3 . 2 o heterocyclyl group, or a C 5-20 aryl group, preferably H or a Ci -7 alkyl group, most preferably H.
  • the groups that form the above listed substituent groups e.g. C 1 . ? alkyl, C 3 . 2 o heterocyclyl and C 5-20 aryl, may themselves be substituted.
  • the above definitions cover substituent groups which are substituted.
  • X is O. In other embodiments, X is S. In other embodiments, X is NH. In further embodiments, X is CH 2 .
  • Naphthyl group substituents R d and R p are optional naphthyl group substituents. There can be one, two or three R p groups on the proximal naphthyl ring, which may be the same or selected independently from the possible substituent groups. The substituents may be at any available ring position. In some embodiments, there are no substituents on the proximal naphthyl ring. In other embodiments, there is a single substituent on the proximal naphthyl ring, which may be in any available ring position.
  • R d groups on the distal naphthyl ring there can be one, two, three or four R d groups on the distal naphthyl ring, which may be the same or selected independently from the possible substituent groups. In some embodiments, there are no substituents on the distal naphthyl ring. In other embodiments, there is a single substituent on the distal naphthyl ring, which may be in any available ring position. In further embodiments, there are two substituents on the distal naphthyl ring, which may be in any available ring position.
  • the optional naphthyl group substituents may be selected from, but not limited to, Ci -7 alkyl, C3-20 heterocyclyl, C5- 2 0 aryl, halo, hydroxy, ether, nitro, cyano, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thiol, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino.
  • the optional naphthyl group substituents may be selected from C 1 - 4 alkyl, C 5-6 aryl, halo, hydroxy, C 1-4 alkyl ether, C 1-4 alkyl acyl, C 1 . 4 alkyl ester, amino, Ci -4 alkylamino and diC 1-4 alkylamino.
  • the optional naphthyl group substituents may be selected from hydroxy and Ci -4 alkyl ether.
  • R Het is imidazolyl. In other embodiments, R Het is triazolyl. In further embodiments, R Het is pyridyl.
  • R c is methyl, which is substituted.
  • R c is ethyl, which is substituted.
  • the substituent may be ⁇ to the point at which R c is bound to the remainder of the compound, i.e. attached to the carbon atom which is attached to the remainder of the molecule.
  • R c is propyl, which is substituted.
  • the propyl group may be branched, i.e. iso-propyl, and the substituent may be ⁇ to the point at which R c is bound to the remainder of the compound, i.e. attached to the carbon atom which is attached to the remainder of the molecule.
  • the substituent for R c is selected from hydroxy, amino, amido, carboxy, C 1-7 alkyl esters, C 5- 7 aryl-C ⁇ . 2 alkyl esters, sulfonamino, sulfinamino, hydroxamino and tetrazolyl. In some embodiments, the substituent for R c is selected from carboxy, amido and sulfonamino. In further embodiments, the substituent for R c is selected from hydroxy, carboxy, Ci. 7 alkyl esters, C 5-7 aryl-Ci. 2 alkyl esters and amido. In other embodiments, the substituent for R c is selected from carboxy, Ci -7 alkyl esters, Cs -7 aryl-Ci-2 alkyl esters and amido.
  • the amino substituents may be selected from H and C 1-4 alkyl (e.g. methyl, ethyl).
  • the amino substituents may also, along with the nitrogen atom to which they are attached, form a heterocyclic ring, such that the optional substituent is e.g. morpholino, piperazinyl, piperidinyl.
  • the amino substituents may be selected from H and Ci -4 alkyl (e.g. methyl, ethyl).
  • the amino substituents may also, along with the nitrogen atom to which they are attached, form a heterocyclic ring, such that the optional substituent is e.g. morpholinocarbonyl, piperazinylcarbonyl, piperidinylcarbonyl.
  • the substituent is sulfonamino
  • the amino substituent may be selected from H and Ci -4 alkyl (e.g. methyl, ethyl).
  • the sulfonamino substituent may be selected from C 1-4 alkyl (e.g. methyl, ethyl) or a C 5-6 aryl group (e.g. phenyl, pyridyl, furanyl, thiophenyl).
  • the amino substituent may be selected from H and Ci -4 alkyl (e.g. methyl, ethyl).
  • the sulfinamino substituent may be selected from Ci -4 alkyl (e.g. methyl, ethyl) or a C 5-6 aryl group (e.g. phenyl, pyridyl, furanyl, thiophenyl).
  • the amide substituent may be selected from H and Ci. 4 alkyl (e.g. methyl, ethyl).
  • the C 1-7 alkyl group may in some embodiments be a C 1-4 alkyl ester, in which case the alkyl group may be methyl, ethyl, propyl and butyl. If the alkyl group is a C 1-7 alkyl group, it may also be, for example, a C 5 alkyl group, i.e. pentyl.
  • the alkyl group may be methyl or ethyl. In some embodiments, the group is methyl.
  • the C 5-7 aryl group may be phenyl, pyridyl, furanyl or thiophenyl. In some embodiments, the C 5-7 aryl group is phenyl.
  • Compounds of particular interest include:
  • a reference to carboxylic acid (-COOH) also includes the anionic (carboxylate) form (-COO ' ), a salt or solvate thereof, as well as conventional protected forms.
  • a reference to an amino group includes the protonated form (-N + HR 1 R 2 ), a salt or solvate of the amino group, for example, a hydrochloride salt, as well as conventional protected forms of an amino group.
  • a reference to a hydroxyl group also includes the anionic form (-0 ), a salt or solvate thereof, as well as conventional protected forms of a hydroxyl group.
  • Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and transforms; E- and Z-forms; c-, f-, and ⁇ -forms; endo- and exo-forms; R-, S-, and meso-forms; D- and /.-forms; d- and /-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; ⁇ - and ⁇ - forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers” (or "isomeric forms").
  • the compound is in crystalline form, it may exist in a number of different polymorphic forms.
  • isomers are structural (or constitutional) isomers (i.e. isomers which differ in the connections between atoms rather than merely by the position of atoms in space).
  • a reference to a methoxy group, -OCH 3 is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH 2 OH.
  • a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta- chlorophenyl.
  • a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., C ⁇ alkyl includes n-propyl and /so-propyl; butyl includes n-, iso-, sec-, and terf-butyl; methoxyphenyl includes ortho-, meta-, and para- methoxyphenyl).
  • C ⁇ alkyl includes n-propyl and /so-propyl
  • butyl includes n-, iso-, sec-, and terf-butyl
  • methoxyphenyl includes ortho-, meta-, and para- methoxyphenyl
  • keto-, enol-, and enolate-forms as in, for example, the following tautomeric pairs: keto/enol, imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N- nitroso/hyroxyazo, and nitro/aci-nitro.
  • H may be in any isotopic form, including 1 H, 2 H (D), and 3 H (T); C may be in any isotopic form, including 12 C, 13 C, and 14 C; O may be in any isotopic form, including 16 O and 18 O; and the like.
  • a reference to a particular compound includes all such isomeric forms, including (wholly or partially) racemic and other mixtures thereof. Methods for the preparation (e.g. asymmetric synthesis) and separation (e.g. fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner. Unless otherwise specified, a reference to a particular compound also includes ionic, salt, solvate, and protected forms of thereof, for example, as discussed below, as well as its different polymorphic forms.
  • a corresponding salt of the active compound for example, a pharmaceutically-acceptable salt.
  • a pharmaceutically-acceptable salt examples are discussed in Berge, et a/., “Pharmaceutically Acceptable Salts", J. Pharm. ScL, 66, 1-19 (1977).
  • a salt may be formed with a suitable cation.
  • suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as Al 3+ .
  • Suitable organic cations include, but are not limited to, ammonium ion (i.e., NH 4 + ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R 2 + , NHR 3 + , NR 4 + ).
  • suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
  • An example of a common quaternary ammonium ion is N(CH 3 )/.
  • a salt may be formed with a suitable anion.
  • suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
  • Suitable organic anions include, but are not limited to, those derived from the following organic acids: acetic, propionic, succinic, gycolic, stearic, palmitic, lactic, malic, pamoic, tartaric, citric, gluconic, ascorbic, maleic, hydroxymaleic, phenylacetic, glutamic, aspartic, benzoic, cinnamic, pyruvic, salicyclic, sulfanilic, 2-acetyoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanesulfonic, ethane disulfonic, oxalic, isethionic, valeric, and gluconic.
  • Suitable polymeric anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose. It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the active compound.
  • solvate is used herein in the conventional sense to refer to a complex of solute (e.g. active compound, salt of active compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.
  • chemically protected form pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions, that is, are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group).
  • a protected or protecting group also known as a masked or masking group or a blocked or blocking group.
  • the aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
  • an amine group may be protected, for example, as an amide or a urethane, for example, as: a methyl amide (-NHCO-CH 3 ); a benzyloxy amide (-NHCO-OCH 2 C 6 H 5 , -NH- Cbz); as a t-butoxy amide (-NHCO-OC(CH 3 ) 3 , -NH-Boc); a 2-biphenyl-2-propoxy amide (- NHCO-OC(CHs) 2 C 6 H 4 C 6 H 5 , -NH-Bpoc), as a 9-fluorenylmethoxy amide (-NH-Fmoc), as a 6- nitroveratryloxy amide (-NH-Nvoc), as a 2-trimethylsilylethyloxy amide (-NH-Teoc), as a 2,2,2-trichloroethyloxy amide (-NH-Troc), as an allyloxy amide (-NH-NH-
  • a carboxylic acid group may be protected as an ester for example, as: an C 1-7 alkyl ester (e.g. a methyl ester; a f-butyl ester); a Ci. 7 haloalkyl ester (e.g. a Ci. 7 trihaloalkyl ester); a triCi- 7 alkylsilyl-C-i. 7 alkyl ester; or a C 5-2O aryl-Ci -7 alkyl ester (e.g. a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.
  • an C 1-7 alkyl ester e.g. a methyl ester; a f-butyl ester
  • a Ci. 7 haloalkyl ester e.g. a Ci. 7 trihaloalkyl ester
  • prodrug refers to a compound which, when metabolised (e.g. in vivo), yields the desired active compound.
  • the prodrug is inactive, or less active than the active compound, but may provide advantageous handling, administration, or metabolic properties.
  • some prodrugs are esters of the active compound (e.g. a physiologically acceptable metabolically labile ester).
  • Examples of such metabolically labile esters include those wherein R is C 1-2O alkyl (e.g. -Me, -Et); d ⁇ aminoalkyl (e.g.
  • acyloxy-Ci. 7 alkyl e.g. acyloxy methyl; acyloxyethyl; e.g.
  • pivaloyloxymethyl acetoxymethyl; 1-acetoxyethyl; 1-(1-methoxy-1- methyl)ethyl-carbonxyloxyethyl; 1-(benzoyloxy)ethyl; isopropoxy-carbonyloxymethyl; 1-isopropoxy-carbonyloxyethyl; cyclohexyl-carbonyloxymethyl; 1-cyclohexyl- carbonyloxyethyl; cyclohexyloxy-carbonyloxymethyl; 1-cyclohexyloxy-carbonyloxyethyl; (4- tetrahydropyranyloxy) carbonyloxy methyl; 1 -(4-tetrahydropyranyloxy)carbonyloxyethyl; (4-tetrahydropyranyl)carbonyloxymethyl; and 1 -(4-tetrahydropyranyl)carbonyloxyethyl).
  • prodrug forms include phosphonate and glycolate salts.
  • Such a group can be cleared by phosphotase enzymes during metabolism to yield the active drug with the hydroxy group.
  • some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound.
  • the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
  • Prodrugs of particular interest in the present invention are of formula (II):
  • R c is a C 1-4 alkyl ester.
  • R c may also be a group a selected from C 1 . 7 alkyl ester and C 5 - 7 aryl-
  • R c is a Ci -4 alkyl group, it may be methyl ester, ethyl ester, propyl ester and butyl ester.
  • Formula 3 by reacting with R Het -H and an activating agent, such as 1 ,1 '-carbonydiimidazole, thionyl chloride or triazole.
  • an activating agent such as 1 ,1 '-carbonydiimidazole, thionyl chloride or triazole.
  • the napthyl group may derivatised as in the final product or may bear precursor groups that are derived at an appropriate stage. The same may apply to the RC group, which may, in particular, be protected during the transformations described above.
  • the compound of Formula 3 may be formed initially as a ketone and then reduced to the alcohol - the ketone would be formed from a ketone version of a compound of Formula 4.
  • the compounds of the present invention are capable of inhibiting the activity of CYP26, and consequently acting as an RA metabolism blocking agent (RAMBA).
  • the present invention provides a method of inhibiting CYP26 in cells either in vivo or in vitro.
  • treatment pertains generally to treatment and therapy, whether of a human or an animal (e.g. in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, amelioration of the condition, and cure of the condition.
  • Treatment as a prophylactic measure i.e. prophylaxis is also included.
  • Active compounds may also be used as part of an in vitro assay, for example, in order to determine whether a candidate host is likely to benefit from treatment with the compound in question.
  • the active compound or pharmaceutical composition comprising the active compound may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or at the site of desired action, including but not limited to, oral (e.g. by ingestion); topical (including e.g. transdermal, intranasal, ocular, buccal, and sublingual); pulmonary (e.g. by inhalation or insufflation therapy using, e.g. an aerosol, e.g.
  • vaginal parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot, for example, subcutaneously or intramuscularly.
  • the subject may be a eukaryote, an animal, a vertebrate animal, a mammal, a rodent (e.g. a guinea pig, a hamster, a rat, a mouse), murine (e.g. a mouse), canine (e.g. a dog), feline (e.g. a cat), equine (e.g. a horse), a primate, simian (e.g. a monkey or ape), a monkey (e.g. marmoset, baboon), an ape (e.g. gorilla, chimpanzee, orangutang, gibbon), or a human.
  • a rodent e.g. a guinea pig, a hamster, a rat, a mouse
  • murine e.g. a mouse
  • canine e.g. a dog
  • feline e.g. a cat
  • compositions comprising at least one active compound, as defined above, together with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilisers, preservatives, lubricants, or other materials well known to those skilled in the art and optionally other therapeutic or prophylactic agents.
  • the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising admixing at least one active compound, as defined above, together with one or more pharmaceutically acceptable carriers, excipients, buffers, adjuvants, stabilisers, or other materials, as described herein.
  • pharmaceutically acceptable refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of a subject (e.g. human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • a subject e.g. human
  • Each carrier, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
  • Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts. See, for example, “Handbook of Pharmaceutical Additives”, 3 rd Edition (eds. M. Ash and I. Ash), 2007 (Synapse Information Resources, Inc.), “Remington's Pharmaceutical Sciences”, 21 st edition, 2005 (Lippincott, Williams & Wilkins); and “Handbook of Pharmaceutical Excipients", 5 th edition (eds. R. Rowe, P. Sheskey, S. Owen), 2005 (Pharmaceutical Press)
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active compound with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • Formulations may be in the form of liquids, solutions, suspensions, emulsions, elixirs, syrups, tablets, losenges, granules, powders, capsules, cachets, pills, ampoules, suppositories, pessaries, ointments, gels, pastes, creams, sprays, mists, foams, lotions, oils, boluses, electuaries, or aerosols.
  • Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; as a bolus; as an electuary; or as a paste.
  • a tablet may be made by conventional means, e.g. compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g. povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g. lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc, silica); disintegrants (e.g.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile.
  • Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
  • Formulations suitable for topical administration may be formulated as an ointment, cream, suspension, lotion, powder, solution, past, gel, spray, aerosol, or oil.
  • a formulation may comprise a patch or a dressing such as a bandage or adhesive plaster impregnated with active compounds and optionally one or more excipients or diluents.
  • Formulations suitable for topical administration in the mouth include losenges comprising the active compound in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active compound in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active compound in a suitable liquid carrier.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active compound.
  • Formulations suitable for nasal administration wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid for administration as, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser include aqueous or oily solutions of the active compound.
  • Formulations suitable for administration by inhalation include those presented as an aerosol spray from a pressurised pack, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.
  • a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.
  • Formulations suitable for topical administration via the skin include ointments, creams, and emulsions.
  • the active compound When formulated in an ointment, the active compound may optionally be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active compounds may be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydhc alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1 ,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.
  • the oily phase may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • an emulsifier otherwise known as an emulgent
  • a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax
  • the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulphate.
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di- isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active compound, such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and nonaqueous isotonic, pyrogen-free, sterile injection solutions which may contain anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents, and liposomes or other microparticulate systems which are designed to target the compound to blood N components or one or more organs.
  • Suitable isotonic vehicles for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection.
  • concentration of the active compound in the solution is from about 1 ng/ml to about 10 ⁇ g/ml, for example from about 10 ng/ml to about 1 ⁇ g/ml.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
  • Formulations may be in the form of liposomes or other microparticulate systems which are designed to target the active compound to blood components or one or more organs.
  • appropriate dosages of the active compounds, and compositions comprising the active compounds can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the treatments of the present invention.
  • the selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient.
  • the amount of compound and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
  • Administration in vivo can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician.
  • a suitable dose of the active compound is in the range of about 100 ⁇ g to about 250 mg per kilogram body weight of the subject per day. Where the active compound is a salt, an ester, prodrug, or the like, the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.
  • Pd/C catalyst 100 mg was added to a solution of 3-hydroxy-2,2-dimethyl-3-(4-nitrophenyl)- propionic acid methyl ester (1)(1 g, 3.95 mmol) dissolved in EtOH (20 mL) and then the reaction was stirred under a H 2 atmosphere. After 30 minutes the hydrogen balloon was removed and the mixture was filtered through Celite. The solvent was then removed under reduced pressure and the oil formed was extracted with CH 2 CI 2 (100 mL), washed with H 2 O (2 x 50 mL) and dried (MgSO 4 ), filtered and evaporated in vacuo.
  • 3-lmidazol-1-yl-2,2-dimethyl-3-[4-(naphthalen-2-ylamino)-phenyl]-propionic acid (12) 3-lmidazol-1-yl-2,2-dimethyl-3-[4-(naphthalen-2-ylamino)-phenyl]-propionic acid methyl ester (4) (0.4 g, 1.01 mmol) in EtOH (20 mL) was saponified with KOH (0.23 g, 1.05 mmol) under reflux for 72 h. The solvent was removed under reduced pressure, H 2 O (100 mL) was added and the unreacted starting materials were extracted with ether (3 X 50 mL).
  • MCF-7 cells were seeded in 12-well cell culture plates (Comings Inc. New York, USA) at 2.5 x 10 5 cells per well in a total volume of 1.5ml_. Cells were allowed to adhere to the well for 24 hours. After 24 hours, the medium from each well was removed, washed once with Phosphate Buffer Saline (PBS) and replaced by fresh medium plus 10 ⁇ L inhibitor/solvent (acetonitrile) and 10 ⁇ L of ATRA (to give final concentration of 1x 10 '7 M ATRA and 0.1 ⁇ Ci [11 ,12- 3 H] a ⁇ -trans retinoic acid). The plates were foil wrapped and incubated at 37°C for 9 hours. Each treatment was performed in duplicate.
  • PBS Phosphate Buffer Saline
  • SH-SY5Y cell assay was used to determine IC 50 values. SH-SY5Y cells were seeded in 96-well plates at a density of 1000 cells well "1 and allowed to attach overnight. ATRA (0.01 ⁇ M), 13cisRA (0.1 ⁇ M), compound 4 or R116010 (1 ⁇ M) were added alone or in combination and cell growth determined after 6 days using the SRB assay as described previously (Skehan P, 1990 J Natl Cancer Inst 82, 1107-1112).
  • CYP26B1 mRNA was chosen as it is a more responsive marker than CYP26A1.
  • Cell line SH-SY5Y neuroblastoma cells where cultured at 37°C in RPMI 1640 medium containing foetal calf serum (10%) and l-glutamine (2nM) in a humidified atmosphere of 5% CO 2 in air.
  • the thermocycling program consisted of one cycle at 50 0 C for 2min followed by 95°C for 10 min and 40 cycles at 95°C (15s) and 60 0 C (1 min).
  • the comparative C 1 method (2 ⁇ Ct ) was used for relative quantification of gene expression.
  • the values derived from 2 experiments are expressed as expression relative to cells treated with 0.01 ⁇ M ATRA at the 1-day time point, and normalised to ⁇ -actin expression.
  • R116010 has an IC 50 value in the same assay of about 10 nM.
  • Compound 4 shows a 3-fold greater efficacy at 6 days compared to R116010.
  • MCF-7 breast cancer cells were grown in the presence of 1 ⁇ M all-frans-retinoic acid (ATRA) for 24 hours to induce expression of CYP26.
  • the cells were harvested by treatment with trypsin/EDTA, followed by being centrifuged at 4°C, for 5 minutes at 1500 rpm. The resulting pellet was washed twice with PBS and centrifuged as before. The cell pellet was then stored in the freezer (-20 0 C) until microsome extraction.
  • ATRA all-frans-retinoic acid
  • the cell pellets were defrosted on ice and re-suspended in homogenisation buffer (10 mM Tris (pH 7.4); 1 mM EDTA; 0.5 M sucrose; 1 mM PMSF; 0.1 ⁇ g/ml leupeptin; 0.04 U/ml aprotinin).
  • the cells were homogenised in a Dounce homogeniser (10 strokes), and the homogenate was diluted with an equal volume of Tris/EDTA.
  • the diluted homogenate laid over V. (original) volume homogenisation buffer in ultra-centrifuge tubes, and then centrifuged at 4°C for 10 minutes at approximately 13 500 rpm. The supernatant was re-spun as above.
  • the supernatant was then spun at 4°C for 60 minutes at 100 000g.
  • the small resultant "ghost" pellet was re- suspended in storage buffer, homogenised, aliquotted and stored at -80 0 C until use.
  • the storage buffer was identical to homogenisation buffer except the sucrose molarity reduced to 0.25 M. 3 H ATRA metabolism microsome assay
  • the assay buffer comprised: 50 mM Tris (pH 7.4), 150 mM KCI, 10 mM MgCI 2 , and 0.02 % w /v BSA.
  • the reaction components were: 50 ⁇ g microsomal protein (defrosted on ice), +/- inhibitor solution (diluted in assay buffer), 10 nM ATRA (diluted in assay buffer), 0.1 ⁇ Ci 3 H ATRA (10 ⁇ l in ethanol), 2 mM NADPH (20 ⁇ l in 0.01 M NaOH), assay buffer to give total volume of 200 ⁇ l.
  • Microsomal protein and assay buffer were aliquotted into small amber eppendorf tubes, flick mixed and centrifuged briefly.
  • the test compound, ATRA and 3 H ATRA were added and flick mixed.
  • the eppendorfs were incubated in a water bath at 37 0 C for 10 minutes with shaking (75 shakes/min). NADPH was added, flick mixed and centrifuged briefly.
  • the tubes were then incubated in a water bath at 37°C for 60 minutes with shaking.
  • the reaction was quenched with 200 ⁇ l ice-cold acetonitrile, and the eppendorfs centrifuged at 4 0 C for 5 minutes at 18 000g. 200 ⁇ l supernatant was then transferred to HPLC vials for analysis, and the HPLC sample chamber maintained at 4°C.
  • %metabolites in uninhibited samples 100 x (activity of metabolite peaks/total activity of injection)

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Abstract

L’invention concerne un composé représenté par la formule (I) dans laquelle X est choisi parmi O, S, NH ou CH2 ; Rd et Rp sont éventuellement des substituants du groupe naphtyle ; RHet est imidazolyle, triazolyle ou pyridyle ; et Rc est alkyle C1-C4 substitué par un groupe choisi parmi hydroxyle, amino, amido, carboxyle, ester d’alkyle C1-C7, aryle C5-C7-ester d’alkyle C1-2, sulfonamino, sulfinamino, hydroxamino et tetrazolyle.
PCT/GB2009/001533 2008-06-17 2009-06-17 Inhibiteurs de cyp26 Ceased WO2009153566A1 (fr)

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US8513291B2 (en) 2010-06-01 2013-08-20 Angion Biomedica Corp. Cytochrome P450 inhibitors and uses thereof
WO2014093960A1 (fr) * 2012-12-16 2014-06-19 Angion Biomedica Corp. Compositions et méthodes de traitement de maladie
WO2016031928A1 (fr) * 2014-08-29 2016-03-03 東京応化工業株式会社 Composé d'imidazole, liquide de traitement de surface métallique, procédé de traitement de surface métallique et procédé de production de stratifié
WO2017137770A1 (fr) * 2016-02-12 2017-08-17 C26 Bioscience Ab Dérivés de tétrazole comme inhibiteurs du cytochrome p450
US9988374B2 (en) 2014-08-11 2018-06-05 Angion Biomedica Corp. Cytochrome P450 inhibitors and uses thereof
US10414760B2 (en) 2016-11-29 2019-09-17 Angion Biomedica Corp. Cytochrome P450 inhibitors and uses thereof
US11434234B2 (en) 2014-12-31 2022-09-06 Angion Biomedica Corp. Methods and agents for treating disease

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US8513291B2 (en) 2010-06-01 2013-08-20 Angion Biomedica Corp. Cytochrome P450 inhibitors and uses thereof
US8865752B2 (en) 2010-06-01 2014-10-21 Angion Biomedica Corp. Cytochrome P450 inhibitors and uses thereof
WO2014093960A1 (fr) * 2012-12-16 2014-06-19 Angion Biomedica Corp. Compositions et méthodes de traitement de maladie
US10556893B2 (en) 2014-08-11 2020-02-11 Angion Biomedica Corp. Cytochrome P450 inhibitors and uses thereof
US9988374B2 (en) 2014-08-11 2018-06-05 Angion Biomedica Corp. Cytochrome P450 inhibitors and uses thereof
US11459319B2 (en) 2014-08-11 2022-10-04 Angion Biomedica Corp. Cytochrome P450 inhibitors and uses thereof
EP3514145A1 (fr) * 2014-08-29 2019-07-24 Tokyo Ohka Kogyo Co., Ltd. Composé d'imidazole, liquide de traitement de surface métallique, procédé de traitement de surface métallique et procédé de production de stratifié
JP2018039837A (ja) * 2014-08-29 2018-03-15 東京応化工業株式会社 イミダゾール化合物
CN107540617A (zh) * 2014-08-29 2018-01-05 东京应化工业株式会社 咪唑化合物、金属表面处理液、金属的表面处理方法、及层合体的制造方法
US10336708B2 (en) 2014-08-29 2019-07-02 Tokyo Ohka Kogyo Co., Ltd. Imidazole compound, metal surface treatment liquid, metal surface treatment method, and laminate production method
CN106687447A (zh) * 2014-08-29 2017-05-17 东京应化工业株式会社 咪唑化合物、金属表面处理液、金属的表面处理方法、及层合体的制造方法
WO2016031928A1 (fr) * 2014-08-29 2016-03-03 東京応化工業株式会社 Composé d'imidazole, liquide de traitement de surface métallique, procédé de traitement de surface métallique et procédé de production de stratifié
CN106687447B (zh) * 2014-08-29 2020-06-02 东京应化工业株式会社 咪唑化合物、金属表面处理液、金属的表面处理方法、及层合体的制造方法
CN107540617B (zh) * 2014-08-29 2020-12-18 东京应化工业株式会社 咪唑化合物、金属表面处理液、金属的表面处理方法、及层合体的制造方法
US11434234B2 (en) 2014-12-31 2022-09-06 Angion Biomedica Corp. Methods and agents for treating disease
US10577333B2 (en) 2016-02-12 2020-03-03 C26 Bioscience Ab Tetrazole derivatives as cytochrome P450 inhibitors
WO2017137770A1 (fr) * 2016-02-12 2017-08-17 C26 Bioscience Ab Dérivés de tétrazole comme inhibiteurs du cytochrome p450
US10414760B2 (en) 2016-11-29 2019-09-17 Angion Biomedica Corp. Cytochrome P450 inhibitors and uses thereof

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