[go: up one dir, main page]

WO2008044033A1 - Dérivés d'amide - Google Patents

Dérivés d'amide Download PDF

Info

Publication number
WO2008044033A1
WO2008044033A1 PCT/GB2007/003870 GB2007003870W WO2008044033A1 WO 2008044033 A1 WO2008044033 A1 WO 2008044033A1 GB 2007003870 W GB2007003870 W GB 2007003870W WO 2008044033 A1 WO2008044033 A1 WO 2008044033A1
Authority
WO
WIPO (PCT)
Prior art keywords
cyano
hydroxy
phenyl
trifluoromethyl
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB2007/003870
Other languages
English (en)
Inventor
Robert Hugh Bradbury
Neil James Hales
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca UK Ltd
AstraZeneca AB
Original Assignee
AstraZeneca UK Ltd
AstraZeneca AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by AstraZeneca UK Ltd, AstraZeneca AB filed Critical AstraZeneca UK Ltd
Publication of WO2008044033A1 publication Critical patent/WO2008044033A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/28—Antiandrogens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/16—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C317/18—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/28—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C07C317/46—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms

Definitions

  • This invention relates to new amide derivatives and, more particularly, to amide derivatives that modulate (or down-regulate) the androgen receptor (AR).
  • This invention also relates to methods for the preparation of such amide derivatives, and novel intermediates in the preparation thereof, to pharmaceutical compositions containing such amide derivatives, to the use of such amide derivatives in the preparation of medicines, and to the use of such amide derivatives in the treatment of androgen sensitive or mediated diseases such as prostate cancer.
  • Prostate cancer is the second most common cause of death from cancer amongst men in developed countries. Four percent of deaths amongst men over 55 can be attributed to prostate cancer. Although the death rate is relatively low, it is currently increasing yearly at a rate of about 14%.
  • tumour growth The early stages of prostate cancer tumour growth are androgen-dependent. Provided that the tumour is confined to the prostate itself, it can usually be treated by surgical removal, radiation therapy and/or by chemotherapy. In more advanced cases in which the tumour is no longer confined to the prostate, but has formed metastatic tumours elsewhere in the body, the tumour may be treated palliatively by reducing blood testosterone levels.
  • Such a reduction in blood testosterone levels may be achieved by surgical castration (orchidectomy) or medicinally by treatment with antiandrogens (Casodex, cyproterone acetate, flutamide), LHRH-Agonists (Zoladex, Buserelin), LHRH antagonists (Cetrorelix), or 5 ⁇ -reductase inhibitors (Finasteride). Since adrenal androgen synthesis is unaffected by surgical castration, a recent trend has been to combine surgical and medicinal treatment. This treatment has only temporary success since after an interval of up to 2 years renewed growth of the tumour normally occurs and this renewed tumour growth is usually not hormonally dependent (LJ. Denis and K. Griffith, Seminars in Surg. Onc, 2000, 18, 52-74). Despite extensive research on this topic during the past 50 years there is still no effective treatment for the advanced stages of prostate cancer. For patients with advanced prostate cancer the 5-year survival rate is under 15%.
  • the androgen receptor belongs to the family of steroid hormone receptors, which function as transcription factors.
  • the binding of an androgen to the androgen receptor results in the stabilisation of the receptor and protect it form undergoing a rapid proteolytic degradation.
  • the complex of androgen and androgen receptor is transported into the nucleus, where it regulates the expression of androgen responsive genes by binding to their androgen response DNA elements in the promoter region of such androgen responsive genes (DJ. Lamb et al. Vitam. Horm. 2001, 62,199-230).
  • mutated receptors can have a higher than normal affinity for androgens, can be constitutively active, can have altered ligand specificity resulting in activation by other steroid hormones or even by antiandrogens, can be activated by interaction with molecules from other growth promoting signal transduction pathways, can alter interactions with other co- factors, or can activate other target genes (J.P. EIo, T. Visakorpi, Ann. Med. 2001,33,130- 141).
  • antiandrogens that would inhibit not only the natural form of the androgen receptor but also its mutated forms and thereby so alter the receptor molecule that it became unstable would be very useful in the treatment of prostate tumours at various stages of growth. Such compounds could inhibit a recurrence of tumour growth or at least prolong the disease free interval.
  • oestrogen receptors such ligands have been identified that destabilise the receptor and lead to a reduction in the receptor content both in vitro and in vivo (S. Dauvois et al, Proc Natl. Acad. Sci. USA, 1992, 89,4037-41; R. A. McClelland et al. Eur. J. Cancer, 1996, 32A, 413-416).
  • Non-steroidal antiandrogens have been described in US5411981 (phenylimidazolidine derivatives), in WO97/00071 (specifically substituted phenyldimethyl hydantoins and their imino- and thio-derivatives), in WO00/37430 (phenylalanines, phenylhydantoins, and phenylureas), in WO01/58855 (aminopropanilides), and in EPl 122242 (substituted cyanophenylpiperazines).
  • the purpose of the present invention is the provision of a series of antiandrogenic compounds that are capable of destabilising (or down-regulating) the androgen receptor, and that are therefore potentially useful as pharmaceutical agents that inhibit the growth of androgenic responsive tumours, such as prostate tumours.
  • R 1 is selected from hydrogen or (l-4C)alkyl
  • R 2 is selected from (l-4C)alkyl or (l-4C)haloalkyl
  • R 3 is hydroxy, (l-4C)alkoxy, or (l-4C)alkanoyloxy
  • Q 1 is a linking group selected from a straight chain (4-14C)alkyl, a straight chain (4- 14C)alkenyl group or a straight chain (4-14C)alkynyl group, wherein the alkyl, alkenyl or alkynyl chain optionally comprises one to four heteroatom-containing groups selected from -S(O) 1n - (where m is 0, 1 or 2), -NR 10 - (where R 10 is selected from H, (l-4C)alkyl or (1- 4C)alkanoyl) or -O- in the chain, and one to four hydrogen atoms in the alkyl, alkenyl or alkynyl chains are optionally replaced by a substituent independently selected from (1- 4C)alkyl or (l-4C)haloalkyl;
  • X is selected from -S(O) n - (where n is 0, 1 or 2), -NR 11 -, -O-, -C(O)O-, -OC(O)-,
  • R 11 is selected from hydrogen, (l-6C)alkyl, (l-6C)alkanoyl, (2- 6C)alkenyl or (2-6C)alkynyl and one or more hydrogen atoms in the alkyl, alkanoyl, alkenyl or alkynyl groups are optionally replaced by a substituent group selected from halo, cyano, hydroxy, (l-4C)alkoxy or (l-4C)alkanoyl;
  • R 4 is selected from hydrogen, (l-lOC)alkyl, (2-10C)alkenyl, or (2-10C)alkynyl, wherein one or more hydrogen atoms in the alkyl, alkenyl or alkynyl group is optionally replaced by a substituent group selected from halo, cyano, hydroxy, or (l-4C)alkoxy; subject to the proviso that if X is -NR n -C(O)-, then R 4 is not a polyfluoro- substituted alkyl; or when X is selected from -NR 11 -, -C(O)-NR 11 -, -0-C(O)-NR 11 - or -SO 2 NR 11 , then R 11 and R 4 may be linked to so that, together with the nitrogen atom to which they are attached, they form a 4, 5, 6 or 7-membered heterocyclic ring, which optionally comprises one or two further heteroatoms selected from N, O or S, and wherein the
  • R 5 is selected from hydrogen, cyano, carbamoyl, nitro, halo, (l-4C)alkyl, (l-4C)alkoxy, (1- 4C)alkanoyl, (l-4C)alkylthio, (l-4C)alkylsulphinyl, (l-4C)alkylsulphonyl, (1- 4C)haloalkyl, (l-4C)haloalkylthio, (l-4C)haloalkylsulphinyl, (l-4C)haloalkylsulphonyl, phenylthio, phenylsulphinyl, or phenylsulphonyl;
  • R 6 is selected from cyano, carbamoyl, nitro, halo, (l-4C)alkanoyl, (l-4C)alkylthio, (1- 4C)alkylsulphinyl, (l-4C)alkylsulphonyl, (l-4C)haloalkyl, (l-4C)haloalkylthio, (1- 4C)haloalkylsulphinyl, (l-4C)haloalkylsulphonyl, phenylthio, phenylsulphinyl, or phenylsulphonyl; and
  • R 7 is hydrogen or halo; or a pharmaceutically acceptable salt thereof.
  • R 1 is selected from hydrogen or (l-4C)alkyl
  • R 2 is selected from (l-4C)alkyl or (l-4C)haloalkyl
  • R 3 is hydroxy, (l-4C)alkoxy, or (l-4C)alkanoyloxy
  • Q 1 is a linking group selected from a straight chain (4-14C)alkyl, a straight chain (4- 14C)alkenyl group or a straight chain (4-14C)alkynyl group, wherein the alkyl, alkenyl or alkynyl chain optionally comprises one to four heteroatom-containing groups selected from -S(O) 1n - (where m is 0, 1 or 2), -NR 10 - (where R 10 is selected from H, (l-4C)alkyl or (1- 4C)alkanoyl) or -O- in the chain, and one to four hydrogen atoms in the alkyl, alkenyl or alkynyl chains are optionally replaced by a substituent independently selected from (1- 4C)alkyl or (l-4C)haloalkyl;
  • X is selected from -S(O) n - (where n is 0, 1 or 2), -NR 11 -, -O-, -C(O)-NR 11 -, -NR 1 ⁇ C(O)-, - NR 1 ⁇ C(O)-NR 1 *-, -NR 11 SO 2 -, Or-SO 2 NR 11 -, where R 11 is selected from hydrogen, (1- 6C)alkyl, (l-6C)alkanoyl, (2-6C)alkenyl or (2-6C)alkynyl and one or more hydrogen atoms in the alkyl, alkanoyl, alkenyl or alkynyl groups are optionally replaced by a substituent group selected from halo, cyano, hydroxy, (l-4C)alkoxy or (l-4C)alkanoyl;
  • R 4 is selected from hydrogen, (l-lOC)alkyl, (2-10C)alkenyl, or (2-10C)alkynyl, wherein one or more hydrogen atoms in the alkyl, alkenyl or alkynyl group is optionally replaced by a substituent group selected from halo, cyano, hydroxy, or (l-4C)alkoxy; subject to the proviso that if X is -NR 1 ⁇ C(O)-, then R 4 is not a polyfluoro- substituted alkyl; R 5 is selected from hydrogen, cyano, carbamoyl, nitro, halo, (l-4C)alkyl, (l-4C)alkoxy, (1- 4C)alkanoyl, (l-4C)alkylthio, (l-4C)alkylsulphinyl, (l-4C)alkylsulphonyl, (1- 4C)haloalkyl, (l-4C)haloalkylthio,
  • R 7 is hydrogen or halo; or a pharmaceutically acceptable salt thereof.
  • the invention includes in its definition any such optically active or racemic form which possesses the above-mentioned activity.
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter. It is to be understood that certain compounds of Formula I defined above may exhibit the phenomenon of tautomerism.
  • tautomerism may affect any heterocyclic groups that bear 1 or 2 oxo substituents. It is to be understood that the present invention includes in its definition any such tautomeric form, or a mixture thereof, which possesses the above-mentioned activity and is not to be limited merely to any one tautomeric form utilised within the formulae drawings or named in the Examples.
  • alkyl unless specifically specified otherwise, includes both straight-chain and branched-chain alkyl groups such as propyl, zsopropyl and tert-butyl, and also cycloalkyl groups such as cyclopropyl and cyclobutyl, and also a cyclopropylmethyl group.
  • references to individual alkyl groups such as "propyl” are specific for the straight-chain version only, and references to individual branched-chain alkyl groups such as " ⁇ opropyl” are specific for the branched-chain version only.
  • alkenyl and “alkynyl”
  • halo is used herein to denote fiuoro, chloro, bromo and iodo.
  • novel compounds of the invention include, for example, compounds of Formula (I), or pharmaceutically-acceptable salts thereof, wherein, unless otherwise stated, each of R 1 , R 2 , R 3 , Q 1 , X, R 4 , R 5 , R 6 , and R 7 has any of the meanings defined hereinbefore or in paragraphs (1) to (46) hereinafter: - (1) R 1 is selected from hydrogen or (l-4C)alkyl;
  • R 1 is selected from hydrogen or methyl
  • R 1 is hydrogen
  • R 2 is selected from (l-4C)alkyl or (l-4C)haloalkyl;
  • R 2 is selected from (l-2C)alkyl or (l-2C)haloalkyl; (6) R 2 is selected from methyl or ethyl;
  • R 2 is methyl
  • R 3 is hydroxy or methoxy
  • R 3 is hydroxy;
  • Q 1 is a linking group selected from a straight chain (6-14C)alkyl, a straight chain (6-14C)alkenyl group or a straight chain (6-14C)alkynyl group, wherein one to four hydrogen atoms in the alkyl, alkenyl or alkynyl groups are optionally replaced by a substituent independently selected from (l-4C)alkyl or (l-4C)haloalkyl;
  • Q 1 is a linking group selected from a straight chain (7-14C)alkyl, a straight chain (7-14C)alkenyl group or a straight chain (7-14C)alkynyl group, wherein one to four hydrogen atoms in the alkyl, alkenyl or alkynyl groups are optionally replaced by a substituent independently selected from (l-4C)alkyl or (l-4C)haloalkyl;
  • Q 1 is a straight chain (4-14C)alkyl linking group, wherein one to four hydrogen atoms in the alkyl chain are optionally replaced by a substituent independently selected from (l-4C)alkyl or (l-4C)haloalkyl;
  • Q 1 is a straight chain (6-14C)alkyl linking group, wherein one to four hydrogen atoms in the alkyl chain are optionally replaced by a substituent independently selected from (l-4C)alkyl or (l-4C)haloalkyl;
  • Q 1 is a straight chain (7-14C)alkyl linking group, wherein one to four hydrogen atoms in the alkyl chain are optionally replaced by a substituent independently selected from (l-4C)alkyl or (l-4C)haloalkyl;
  • Q 1 is a straight chain (7-14C)alkyl linking group, wherein one to four hydrogen atoms are optionally replaced by a substituent independently selected from (1- 2C)alkyl or (l-2C)haloalkyl;
  • Q 1 is a straight chain (4-14C)alkyl linking group
  • Q 1 is a straight chain (6-14C)alkyl linking group;
  • Q 1 is a straight chain (7-14C)alkyl linking group;
  • X is -S(O) n - (where n is 0, 1 or 2);
  • R 4 is selected from hydrogen, (l-lOC)alkyl, (2-10C)alkenyl, or (2- 10C)alkynyl, wherein one or more hydrogen atoms in the alkyl, alkenyl or alkynyl group is optionally replaced by a substituent group selected from halo, cyano, hydroxy, or (l-4C)alkoxy; subject to the proviso that if X is
  • R 4 is not a polyfluoro-substituted alkyl
  • R 4 is selected from hydrogen or (l-lOC)alkyl, wherein one or more hydrogen atoms in the alkyl group is optionally replaced by a substituent group selected from halo, cyano, hydroxy, or (l-4C)alkoxy; subject to the proviso that if X is -NR 1 ⁇ C(O)-, then R 4 is not a polyfluoro-substituted alkyl;
  • R 4 is selected from hydrogen or (l-lOC)alkyl, wherein one or more hydrogen atoms in the alkyl group is optionally replaced by a halo atom; subject to the proviso that if X is -NR 1 ⁇ C(O)-, then R 4 is not a polyfluoro-substituted alkyl;
  • R 4 is selected from hydrogen or (l-lOC)alkyl, wherein one or more hydrogen atoms in the alkyl group is optionally replaced by a fluoro atom; subject to the proviso that if X is -NR 1 ⁇ C(O)-, then R 4 is not a polyfluoro-substituted alkyl;
  • R 4 is selected from hydrogen or (5-10C)alkyl, wherein one or more hydrogen atoms in the alkyl group is optionally replaced by a fluoro atom; subject to the proviso that if X is -NR 1 ⁇ C(O)-, then R 4 is not a polyfluoro-substituted alkyl;
  • R 4 is selected from (l-lOC)alkyl, (2-10C)alkenyl, or (2-10C)alkynyl, wherein one or more hydrogen atoms in the alkyl, alkenyl or alkynyl group is optionally replaced by a substituent group selected from halo, cyano, hydroxy, or (1- 4C)alkoxy ; subj ect to the proviso that if X is -NR 1 l -C(O)-, then R 4 is not a polyfluoro-substituted alkyl;
  • R 4 is (l-lOC)alkyl, wherein one or more hydrogen atoms in the alkyl group is optionally replaced by a substituent group selected from halo, cyano, hydroxy, or (l-4C)alkoxy; subject to the proviso that if X is -NR n -C(O)-, then R 4 is not a polyfluoro-substituted alkyl;
  • R 4 is (l-lOC)alkyl, wherein one or more hydrogen atoms in the alkyl group is optionally replaced by a halo atom; subject to the proviso that if X is -NR 11 - C(O)-, then R 4 is not a polyfluoro-substituted alkyl; (29) R 4 is (l-lOC)alkyl, wherein one or more hydrogen atoms in the alkyl group is optionally replaced by a fluoro atom; subject to the proviso that if X is -NR 11 - C(O)-, then R 4 is not a polyfluoro-substituted alkyl;
  • R 4 is (5-10C)alkyl, wherein one or more hydrogen atoms in the alkyl group is optionally replaced by a fluoro atom; subject to the proviso that if X is -NR 11 -
  • R 4 is not a polyfluoro-substituted alkyl
  • R 5 is selected from hydrogen, cyano, carbamoyl, nitro, halo, (l-4C)alkyl, (1- 4C)alkoxy, or (l-4C)haloalkyl;
  • R 5 is selected from halo or (l-4C)haloalkyl; (33) R 5 is trifluoromethyl;
  • R 6 is selected from cyano, nitro, or halo
  • R 6 is cyano
  • R 7 is hydrogen
  • R 2 is methyl or -CF 3; (38) R 2 is -CF 3 ;
  • X is selected from -S(O) n - (where n is 0, 1 or 2), -NR 11 -, -O-, -C(O)-NR 11 -, - NR ⁇ -C(O)-, -NR 11 SO 2 -, -SO 2 NR 11 -, -NR 1 ⁇ C(O)-O-, or -0-C(O)-NR 11 -, where R 11 is selected from hydrogen or (l-4C)alkyl;
  • X is selected from -S(O) n - (where n is O, 1 or 2), -NR 11 -, -0-, or -NR ⁇ -C(O)- 0-, where R 11 is selected from hydrogen or (l-2C)alkyl;
  • X is selected from -S(O) n - (where n is O, 1 or 2), -NR 11 - or -O-, where R 11 is selected from hydrogen or (l-2C)alkyl;
  • X is selected from -S(O) n - (where n is O, 1 or 2), -NR 11 -, -O-, -C(O)-NR 11 -,
  • R 11 is selected from hydrogen or (l-2C)alkyl and R 4 has any one of the defintions set out in paragraphs (21) to (30) above, or when X is selected from -NR 11 - or -C(O)-NR 11 -, then R 11 and R 4 may be linked to so that, together with the nitrogen atom to which they are attached, they form a 4, 5, or 6-membered heterocyclic ring, which optionally comprises one further heteroatom selected from N, O or S, and wherein the ring may be optionally substituted by one, two or three substituent groups selected from cyano, carbamoyl, nitro, halo, (l-4C)alkyl, (l-4C)alkoxy, (l-4C)alkanoyl, (1- 4
  • R 11 is selected from hydrogen or (l-2C)alkyl and R 4 has any one of the defintions set out in paragraphs (21) to (30) above, or when X is selected from -NR 11 - or -C(O)-NR 11 -, then R 11 and R 4 may be linked to so that, together with the nitrogen atom to which they are attached, they form a 4, 5, or 6-membered heterocyclic ring, which optionally comprises one further heteroatom selected from N, O or S, and wherein the ring may be optionally substituted by one or two substituent groups selected from cyano, carbamoyl, nitro, halo, (l-4C)alkyl, (l-4C)alkoxy, (l-4C)alkanoyl, (1- 4C)alkylthio, (l-4C)alkylsulphinyl, (l-4C)alkylsulphonyl or hydroxy(l- 4C)alkyl
  • X is selected from -S(O) n - (where n is 0, 1 or 2), -NR 11 -, or -O-, where R 11 is selected from hydrogen or (l-2C)alkyl and R 4 has any one of the defmtions set out in paragraphs (21) to (30) above, or, when X is -NR 11 -, then R 11 and R 4 may be linked to so that, together with the nitrogen atom to which they are attached, they form a saturated 4, 5, or 6- membered heterocyclic ring, which optionally comprises one further heteroatom selected from N, O or S, and wherein the ring may be optionally substituted by one or two substituent groups selected from cyano, carbamoyl, nitro, halo, (l-4C)alkyl, (l-4C)alkoxy, (l-4C)alkanoyl, (l-4C)alkylthio, (1- 4C)alkylsulphinyl, (l-4C)alkylsulphon
  • R 1 is hydrogen, methyl or ethyl. In a particular group of compounds of Formula I, R 1 is hydrogen.
  • R 2 is (l-2C)alkyl or (l-2C)haloalkyl.
  • R 2 is methyl or trifluoromethyl.
  • R 2 is methyl.
  • R 3 is hydroxy, (l-2C)alkoxy, or (l-2C)alkanoyloxy.
  • R 3 is hydroxy.
  • R 4 is hydrogen when X is O.
  • R 4 when X is S(O) n (where n is 0,1 or 2), R 4 is (l-lOC)alkyl, (2-10C)alkenyl, or (2-10C)alkynyl, wherein one or more hydrogen atoms in the alkyl, alkenyl or alkynyl group is optionally replaced by a substituent group selected from halo, cyano, hydroxy, or (l-4C)alkoxy.
  • R 4 when X is S(O) n (where n is 0, 1 or 2), R 4 is as defined in any one of paragraphs (26) to (30) above.
  • R 4 is a substituted alkyl, alkenyl or alkynyl group (particularly a substituted alkyl, alkenyl or alkynyl group as defined in any one of paragraphs (21) to (30) above).
  • R 4 is a halo-substituted (l-lOC)alkyl group.
  • R 4 is a fluoro-substituted (l-lOC)alkyl group.
  • R 4 is selected from hydrogen or a substituted alkyl, alkenyl or alkynyl group (particularly a substituted alkyl, alkenyl or alkynyl group as defined in any one of paragraphs (21) to (30) above) if X is -O- or S(O) n (where n is 0 or 1).
  • R 4 is a halo-substituted (l-lOC)alkyl or (5-10C)alkyl group if X is -O- or S(O) n (where n is 0 or 1).
  • R 4 is a fluoro-substituted (1- 10C)alkyl or (5-10C)alkyl group if X is -O- or S(O) n (where n is 0 or 1).
  • X, R 4 and R 11 are as defined in any one of paragraphs (42) to (46) above.
  • R 4 is a halo substituted (l-lOC)alkyl group.
  • R 4 is not a polyhalo-substituted alkyl.
  • Q 1 is a straight chain alkyl, it is suitably a (6-14C)alkyl group, and most suitably a (7-14C)alkyl group.
  • Q 1 is optionally substituted by one to four, more particularly 1 to 3, and especially 1 or 2, (l-4C)alkyl or (l-4C)haloalkyl groups.
  • the linking group Q 1 is unsubstituted.
  • R 4 is alkenyl it suitably has the formula
  • R 4 is alkynyl it suitably has the formula
  • R 5 is selected from hydrogen, halo or (l-4C)haloalkyl. In a particular group of compounds of formula I R 5 is trifiorormethyl.
  • R 6 is selected from cyano, carbamoyl, nitro, or halo. In a particular group of compounds of Formula I, R 6 is cyano.
  • R 7 is suitably hydrogen or fluoro. In a particular group of compounds of the invention, R 7 is hydrogen.
  • R 1 , R 2 , R 3 , Q 1 , X, R 4 , R 5 , R 6 , and R 7 each independently have any one of the definitions set out hereinbefore, or a pharmaceutically acceptable salt thereof.
  • R 1 is hydrogen
  • R 2 is methyl
  • R 3 is hydroxy, R 5 trifluoromethyl, R 6 is cyano, R 7 is hydrogen and Q 1 , X and R 4 have any one of the definitions set out hereinbefore.
  • R 1 is hydrogen
  • R 2 is methyl
  • R 3 is hydroxy
  • R 5 trifluoromethyl
  • R 6 is cyano
  • R 7 is hydrogen
  • Q 1 , X and R 4 have anyone of the definitions set out hereinbefore.
  • novel compounds of the invention include any one of the following: (2iS)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2,9-dihydroxy-2-methylnonanamide; (25)-N-[4-Cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methyl-9-[(4,4,5,5,5- pentafluoropentyl)thio]nonanamide;
  • Particular compounds of the invention include any one of the following: (25)-N-[4-Cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methyl-ll-[(4,4,5,5,5- pentafluoropentyl)thio]undecanamide; (25)-N-[4-Cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methyl-l l-[(4,4,5,5,5- pentafluoropentyl)sulfinyl]undecanamide;
  • a suitable pharmaceutically-acceptable salt of a compound of the Formula I is, for example, an acid-addition salt of a compound of the Formula I, for example an acid- addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid; or, for example, a salt of a compound of the Formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • a further suitable pharmaceutically-acceptable salt of a compound of the Formula I is, for example, a salt formed within the human or animal body after administration of a compound of the Formula I.
  • a suitable pharmaceutically-acceptable solvate of a compound of the Formula I is, for example, a hydrate such as a hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate or an alternative quantity thereof.
  • the compounds of the invention may be administered in the form of a pro-drug, that is a compound that is broken down in the human or animal body to release a compound of the invention.
  • a pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention.
  • a pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached.
  • Examples of pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the Formula I and in vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the Formula I.
  • the present invention includes those compounds of the Formula I as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the Formula I that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the Formula I may be a synthetically-produced compound or a metabolically-produced compound.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
  • pro-drug Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzvmology. Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Pro-drugs", by H. Bundgaard p. 113- 191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews. 8, 1-38 (1992); e) H.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I that possesses a carboxy group is, for example, an in vivo cleavable ester thereof.
  • An in vivo cleavable ester of a compound of the Formula I containing a carboxy group is, for example, a pharmaceutically-acceptable ester which is cleaved in the human or animal body to produce the parent acid.
  • Suitable pharmaceutically-acceptable esters for carboxy include (l-6C)alkyl esters such as methyl, ethyl and tert-hx ⁇ y ⁇ , (l-6C)alkoxymethyl esters such as methoxymethyl esters, (l-6C)alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, (3-8C)cycloalkylcarbonyloxy-(l-6C)alkyl esters such as cyclopentylcarbonyloxymethyl and l-cyclohexylcarbonyloxyethyl esters, 2-oxo-l,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-l,3-dioxolen-4-ylmethyl esters and (l-6C)alkoxycarbonyloxy-(l-6C)alkyl esters such as methoxycarbonyloxymethyl and 1 -methoxycarbonyloxyethy
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof.
  • An in vivo cleavable ester or ether of a compound of the Formula I containing a hydroxy group is, for example, a pharmaceutically-acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound.
  • Suitable pharmaceutically-acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically-acceptable ester forming groups for a hydroxy group include (1-
  • 10C)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, (l-lOC)alkoxycarbonyl groups such as ethoxycarbonyl, N,N-[di-(l- 4C)alkyl] carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups.
  • ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, N,N-dialkylaminoniethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(l-4C)alkylpiperazin-l-ylmethyl.
  • Suitable pharmaceutically-acceptable ether forming groups for a hydroxy group include ⁇ -acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a (l-4C)alkylamine such as methylamine, a di-(l-4C)alkylamine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a (l-4C)alkoxy-(2-4C)alkylamine such as 2-methoxyethylamine, a phenyl-(l-4C)alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.
  • an amine such as ammonia
  • a (l-4C)alkylamine such as methylamine
  • a di-(l-4C)alkylamine such as dimethylamine
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
  • Suitable pharmaceutically-acceptable amides from an amino group include, for example an amide formed with (l-lOC)alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.
  • ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-( 1 -4C)alkylpiperazin- 1 -ylmethyl.
  • the in vivo effects of a compound of the Formula I may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formula I. As stated hereinbefore, the in vivo effects of a compound of the Formula I may also be exerted by way of metabolism of a precursor compound (a pro-drug).
  • R 1 , R 2 , R 3 , Q 1 , X, R 4 , R 5 , R 6 , and R 7 groups are equivalent to groups R 1 , R 2 , R 3 , Q 1 , X, R 4 , R 5 , R 6 , and R 7 of Formula I respectively, and, unless otherwise specified, each group is as defined hereinbefore.
  • Yi is -OH or the group -C(O)-Yi is a reactive acid derivative; and thereafter removing any protecting groups that may be present.
  • a process for the manufacture of compounds of formula I in which R 3 OH which comprises reaction of an epoxide 2.1 with an organometallic compound 2.2 (wherein (77Or-Qi)-X-R 4 is the lower homologue OfQi-X-R 4 such that and thereafter removing any protecting groups that may be present.
  • An example of a suitable organometallic compound (/JOr-Qi)-X-R 4 Is the organocuprate formed by treating or Br-Mg-(WOr-Qi)-X-R 4 with a copper (I) complex, for instance lithium 2-thienylcyanocuprate.
  • the epoxide used as starting material may be obtained by epoxidation, for instance with a peracid, of the corresponding unsaturated anilide; or by base catalysed ring closure of the corresponding bromohydrin. Such techniques are well known in the art.
  • Metal-Qi-X-R 4 reagents include Li-Qi-X-R 4 or Br-Mg-Qi-X- R 4 , which may be obtained from the corresponding bromide Br-Qi-X-R 4 , which may themselves be obtained by methods well-known in the art from bifunctional -Q 1 - derivatives such as HO-Qi-Br or Br-Qi-Br.
  • R 3 OH, which comprises reaction of a ketoanilide 3.3 with an organometallic compound Metal-R 2 (3.4)
  • Suitable Metal-R 2 reagents include Li-R 2 or Br-Mg-R 2 , which may be obtained from the corresponding bromide Br-R 2 .
  • the alpha-ketoanilide used as starting material in each section of this process may be obtained by acylation of the corresponding aniline with a reactive derivative of the corresponding alpha-ketoacid by methods well-known in the art.
  • Suitable leaving groups Y 2 include halide, for example bromide or iodide; alkyl sulfonate esters, for example methanesulfonate; arylsulfonate esters, for example 4-toluenesulfonate; and phosphine oxides, for example triphenyl phosphine oxide.
  • Suitable leaving groups Y include halide, for example bromide or iodide; alkyl sulfonate esters, for example methanesulfonate; arylsulfonate esters, for example 4-toluenesulfonate; and phosphine oxides, for example triphenyl phosphine oxide.
  • a compound 8.1 above in which Y 5 is OH may be prepared by oxidation of the corresponding alcohol.
  • such compounds may be prepared by hydrolysis of the corresponding nitrile, which may itself be prepared by reaction of the corresponding alkylating agent with a metal cyanide.
  • suitable alkylating agents are methansulfonates or bromides.
  • suitable metal cyanides are sodium cyanide or potassium cyanide.
  • Aldehydes 9.1 may be prepared by oxidation of the corresponding alcohols.
  • X NR 11 C(O)- (10.3), said process comprising the acylation of the corresponding amine 10.1 with the corresponding acid 10.2, wherein Y 6 is OH of the group -C(O)-Y 6 is a reactive acid derivative;
  • Suitable amines 10.1 may be prepared by reductive amination of the corresponding aldehyde with the corresponding amine RnNH 2 .
  • Suitable values of Y 7 for the alkylating group 10.4 include halides, for example bromide; alkyl sulfonates, for example methane sulfonate; and arylsulfonate, for example 4-toluene sulfonate.
  • suitable metal azides include sodium azide and lithium azide.
  • a suitable reactive derivative of a sulfonic acid 11.2 is a sulfonyl halide, for instance a sulfonyl chloride.
  • Suitable amines 11.1 may be prepared by reductive amination of the corresponding aldehyde with the corresponding amine RnNH 2 .
  • suitable metal azides include sodium azide and lithium azide.
  • Suitable arylating agents include aryl bromides, aryl iodides, and aryl trifluoromethane sulfonates (i.e. Yg is Br, I or trifluoromethyl sulfonate).
  • a suitable low-valent transition metal catalyst include zerovalent palladium catalysts.
  • Amides 12.2 may be made from the corresponding acids by methods well known in the art.
  • a process for the manufacture of compounds of formula I in which R 3 is alkoxy comprises the alkylation of the corresponding compound of formula I in which R 3 is hydroxy.
  • a process for the manufacture of compounds of formula I in which R 3 is acyloxy comprises the acylation of the corresponding compound of the invention where R 3 is hydroxy.
  • a process for the manufacture of compounds of formula I in which R 3 is hydroxy comprises the deacylation of the corresponding compound of the invention in which R 3 is acyloxy.
  • Examples of suitable methods of deacylation include base catalysed hydrolysis or acid catalysed methanolysis.
  • a process for the manufacture of compounds of formula I comprises converting a functional group of one compound of the invention into another functional group using standard chemical reactions well-known to those skilled in the art to produce another compound of the invention.
  • a process for the manufacture of compounds of the invention comprises introducing a new functional group into one compound of the invention using standard chemical reactions well-known to those skilled in the art to produce another compound of the invention.
  • a process for the manufacture of compounds of the invention in the form of a single enantiomer comprises separating a racemic compound of the invention into separate enantiomers.
  • Examples of suitable methods for separating the enantiomers of a racemic compound include chromatography using a suitable chiral stationary phase; or conversion of a racemic mixture into diastereomeric derivatives, separation of the mixture of diastereomeric derivatives into two single diastereomers, and regeneration of a separate single enantiomer from each separate single diastereomer.
  • Examples of suitable methods for separating a mixture of diastereomers include fractional crystallisation, normal-phase chromatography, or reverse-phase chromatography.
  • An example of a suitable carboxylic acid is camphanic acid.
  • a process for the manufacture of a compound of the invention in the form of a single enantiomer comprises carrying out one of the processes described in the preceding sections using chiral intermediates in resolved form.
  • Any protecting groups utilised in the processes described herein may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question and may be introduced by conventional methods.
  • Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
  • protecting groups are given below for the sake of convenience, in which "lower”, as in, for example, lower alkyl, signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned is of course within the scope of the invention.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as trifluoroacetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or ⁇ -butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl or heteroaroyl group, for example picolinoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable acid such as hydrochloric, sulphuric, or phosphoric acid or trifluoroacetic acid or a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable acid such as hydrochloric, sulphuric, or phosphoric acid or trifluoroacetic acid
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a ⁇ -butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(triftuoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a ⁇ -butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a base such as sodium hydroxide
  • a ⁇ -butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
  • This immunofluorescence end point assay measures the ability of a test compound to down-regulate and reduce measured levels of the AR in the LNCaP prostate carcinoma cell line (LNCap clone FGC (CRL- 1740) obtained from the American Type Culture Collection (ATCC)). LNCaP cells were cultured in Growth Medium (phenol red free Roswell Park).
  • Cells for assay were harvested from Tl 75 stock flasks by washing once in PBS (phosphate buffered saline, pH 7.4) (Invitrogen Code no. 14190-094) and harvested using 5mls of 1 x Trypsin / ethylaminediaminetetraacetic acid (EDTA) (10 x Trypsin-EDTA, 5.0 g/L Trypsin, 2.0 g/L of EDTA « 4Na and 8.5 g/L of NaCl, without Phenol Red, Invitrogen Code no. 15400-054) diluted in PBS solution.
  • PBS phosphate buffered saline, pH 7.4
  • EDTA ethylaminediaminetetraacetic acid
  • Immunostaining was performed at room temperature. Cells were permeabilised by the addition of 35 ⁇ l of PBS containing 0.5% Tween 20 and incubated for 1 hour at room temperature. Permeabilisation solution was removed and cells were washed with 250 ⁇ l of PBST using an automated plate washer. This process was then repeated twice more. 35 ⁇ l of Blocking Solution (PBST containing 3%(w/v) Marvel dried skimmed milk (Nestle)) was added to each well and plates were incubated at room temperature for a minimum of 1 hour.
  • PBST Blocking Solution
  • mice anti-human AR monoclonal antibody (clone AR441) (immunogen - synthetic peptide corresponding to amino acids 229-315 of the human AR coupled to keyhole limpet hemocyanin, DAKO, Code No. M3562), diluted 1:500 in Blocking Solution, was added to each well and incubated for 1 hour. Then this primary antibody solution was removed from the wells followed by 3 x lOO ⁇ l PBST washes using a plate washer. Then 35 ⁇ l of Alexa- Fluor 488 goat anti-mouse IgG secondary antibody (Invitrogen, Code No. A-11001), diluted 1:500 in Blocking Solution, was added to each well.
  • Alexa- Fluor 488 goat anti-mouse IgG secondary antibody Invitrogen, Code No. A-11001
  • the Green Fluorescent AR-associated signal in each well was measured using an Acumen Explorer HTS Reader (TTP Labtech Ltd., Cambridge). AR-associated fluorescence emission can be detected at 530nm following excitation at 488nm.
  • the instrument is a laser-scanning fluorescence microplate cytometer which samples the well at regular intervals and uses threshold algorithms to identify all fluorescent intensities above the solution background without the need to generate and analyse an image. These fluorescent objects can be quantified and provide a measure of the AR levels in cells. Fluorescence dose response data obtained with each compound was exported into a suitable software package (such as Origin) to perform curve fitting analysis. Down- regulation of AR levels was expressed as a pICso value.
  • This immunofluorescence end point assay measures the ability of a test compound to down-regulate and reduce measured levels of the AR in the LNCaP prostate carcinoma cell line (LNCaP clone FGC (CRL- 1740) obtained from the American Type Culture Collection (ATCC)).
  • LNCaP cells were cultured in Growth Medium (phenol red free Roswell Park
  • Glutamine (Invitrogen Code no. 25030-024) and l%(v/v) Penicillin/Streptomycin (10000 units/ml Penicillin and 10000 ⁇ g/ml of Streptomycin utilising penicillin G (sodium salt) and streptomycin sulphate: prepared in normal saline, Invitrogen Code no. 15140122) and 10%(v/v) foetal bovine serum (FBS)) in a 5% CO 2 air incubator at 37 0 C. Cells for assay were harvested from T 175 stock flasks by washing once in PBS (phosphate buffered saline, pH 7.4) (Invitrogen Code no.
  • Cells were syringed at least twice using a sterile 18G x 1.5" (1.2 x 40mm) broad gauge needle and cell density was measured using a haemocytometer. Cells were further diluted in Growth Medium plus charcoal stripped FBS and seeded at a density of 6.5x10 3 cells per well (in 9OuI) into transparent , black, tissue culture treated 96 well plates (Packard, No. 6005182).
  • mice anti-human AR monoclonal antibody (clone AR441) (immunogen - synthetic peptide corresponding to amino acids 229-315 of the human AR coupled to keyhole limpet hemocyanin, DAKO, Code No. M3562), diluted 1:500 in Blocking Solution, was added to each well and incubated for 1 hour. Then this primary antibody solution was removed from the wells followed by 3 x lOO ⁇ l PBST washes using a plate washer. Then 35 ⁇ l of Alexa- Fluor 488 goat anti-mouse IgG secondary antibody (Invitrogen, Code No. A-11001), diluted 1:500 in Blocking Solution, was added to each well.
  • Alexa- Fluor 488 goat anti-mouse IgG secondary antibody Invitrogen, Code No. A-11001
  • the Green Fluorescent AR-associated signal in each well was measured using an Acumen Explorer HTS Reader (TTP Labtech Ltd., Cambridge). AR-associated fluorescence emission can be detected at 530nm following excitation at 488nm.
  • the instrument is a laser-scanning fluorescence microplate cytometer which samples the well at regular intervals and uses threshold algorithms to identify all fluorescent intensities above the solution background without the need to generate and analyse an image. These fluorescent objects can be quantified and provide a measure of the AR levels in cells. Fluorescence dose response data obtained with each compound was exported into a suitable software package (such as Origin) to perform curve fitting analysis. Down- regulation of AR levels was expressed as an IC 50 value. This was determined by calculation of the concentration of compound that was required to give a 50% reduction of the AR signal. In the table presented herein providing data for the examples, the IC 5 0 is presented as pICso data.
  • the pharmacological properties of the compounds of the formula I vary with structural change as expected, in general activity possessed by compounds of the Formula I may be demonstrated in the aforementioned down-regulation assays, and such compounds typically exhibit an IC 5O in the range of, for example, ⁇ 30 ⁇ M.
  • Particular compounds of Formula I have a pIC 5 o value of 4.5 or above, and especially 5 or above, or a maximum percentage inhibition at 30 ⁇ M of 50% or above, and especially 80% or above.
  • a pharmaceutical composition which comprises a compound of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier.
  • the composition may be in a form suitable for oral administration, for example as a tablet or capsule; for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion; for topical administration as an ointment or cream; or for rectal administration as a suppository.
  • parenteral injection including intravenous, subcutaneous, intramuscular, intravascular or infusion
  • a sterile solution, suspension or emulsion for topical administration as an ointment or cream
  • rectal administration as a suppository.
  • the compositions of the invention are particularly suited to parenteral injection.
  • compositions may be prepared in a conventional manner using conventional excipients.
  • the compound of formula I will normally be administered to a warm-blooded animal at a unit dose within the range 5-5000 mg/m 2 body area of the animal, i.e. approximately 0.1-100 mg/kg, and this normally provides a therapeutically-effective dose.
  • a unit dose form such as a tablet or capsule will usually contain, for example 1-250 mg of active ingredient.
  • Preferably a daily dose in the range of 1-50 mg/kg is employed.
  • the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
  • the compounds defined in the present invention are effective androgen-receptor downregulators. Accordingly, the compounds of the present invention are expected to be potentially useful agents in the treatment of diseases or medical conditions mediated alone or in part by the stimulation of androgen receptors. This includes the treatment of androgen-sensitive diseases or disorders whose progress or onset is aided by activation of the androgen receptor or androgen receptor modulators.
  • Examples of particular androgen-sensitive diseases or disorders include, but are not limited to, androgen-sensitive cancers such as prostate cancer, benign prostatic hyperplasia and prostamegaly, acne (acne vulgaris), seborrhoea, hirsutism (hypertrichosis), androgenic alopecia and male pattern baldness, precocious puberty, polycystic ovarian syndrome, sexual perversion, virilisation, and the like.
  • Compounds of the invention may also be used to improve ovulation in a domestic animal.
  • the present invention relates to a method of treating any one of the aforementioned androgen-sensitive diseases or disorders in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
  • the present invention relates to the use of compound of formula I, or a pharmaceutically acceptable salt thereof, as hereinbefore defined in the manufacture of a medicament for the treatment of any one of the aforementioned androgen-sensitive diseases or disorders.
  • a compound of the formula I or a pharmaceutically acceptable salt or pro-drug thereof, as defined hereinbefore for use in the treatment of any one of the aforementioned androgen-sensitive diseases or disorders.
  • a compound of the formula I or a pharmaceutically acceptable salt or pro-drug thereof, as defined hereinbefore in the manufacture of a medicament for use in the production of an anti-androgenic effect in a warm-blooded animal such as man.
  • a method for producing an anti-androgenic effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
  • anti-androgenic effect is used herein to mean the inhibition and/or down regulation of androgen receptors.
  • a method for producing an anti-cell-proliferation effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
  • a method of treating androgen-sensitive cancers in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
  • a compound of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in the treatment of androgen-sensitive cancers According to a further feature of the invention there is provided the use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of androgen- sensitive cancers.
  • a method of treating prostate cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
  • a compound of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in the treatment of prostate cancer is provided.
  • a method of treating any one of the following conditions benign prostatic hyperplasia, prostamegaly, acne (acne vulgaris), seborrhoea, hirsutism (hypertrichosis), androgenic alopecia and male pattern baldness, precocious puberty, polycystic ovarian syndrome, sexual perversion, or virilisation; in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
  • a compound of the formula I or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of any one of the following conditions: benign prostatic hyperplasia, prostamegaly, acne (acne vulgaris), seborrhoea, hirsutism (hypertrichosis), androgenic alopecia and male pattern baldness, precocious puberty, polycystic ovarian syndrome, sexual perversion, or virilisation.
  • the size of the dose required for the therapeutic or prophylactic treatment of a particular cell-proliferation disease will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated.
  • a unit dose in the range, for example, 1-100 mg/kg, preferably 1-50 mg/kg is envisaged.
  • the androgen receptor down-regulator compounds of the present invention may be applied as a sole therapy or may involve, in addition to a compound of the invention, one or more other substances and/or treatments.
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment.
  • the other component(s) of such conjoint treatment in addition to the cell cycle inhibitory treatment defined hereinbefore, may be: surgery, radiotherapy or chemotherapy.
  • Such chemotherapy may include one or more of the following categories of anti-tumour agents:
  • antiproliferative/antineoplastic drugs and combinations thereof as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin- C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblast
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti-erbBl antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. Critical reviews in oncology/haematology, 2005, Vol.
  • inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-mo ⁇ holinopropoxy)quinazolin-4-amine (gef ⁇ tinib, ZDl 839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3- morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib, inhibitors of the hepatocyte growth factor family, inhibitor
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (AvastinTM) and VEGF receptor tyrosine kinase inhibitors such as 4-(4- bromo-2-fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline (ZD6474; Example 2 within WO 01/32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6- methoxy-7-(3-pyrrolidin-l-ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00/47212), vatalanib (PTK787; WO 98/35985) and SUl 1248 (sunitinib; WO 01/60814), compounds such as those disclosed in International Patent Applications WO97/22596, WO 97,
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy;
  • GDEPT gene-directed enzyme pro-drug therapy
  • immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies; and
  • cell cycle inhibitors including for example CDK inhibitiors (eg flavopiridol) and other inhibitors of cell cycle checkpoints (eg checkpoint kinase); inhibitors of aurora kinase and other kinases involved in mitosis and cytokinesis regulation (eg mitotic kinesins); and histone deacetylase inhibitors.
  • the compounds of the invention may be used for the treatment of various hormone dependent cancers including without limitation prostate cancer in combination with one or more of the following agents: gonadotrophin agonists (GnRH) (LH-RH agonists); inhibitors of gonadotrophin secretion; 5-alpha reductase inhibitors; antiprogestins; antiestrogens; aromatase inhibitors; progestins; estrogens; cytostatic agents; cytotoxic agents; inhibitors of cell growth signalling pathways, including without limitation kinase inhibitors such as VEGF kinase inhibitors; antibodies including without limitation antibodies directed at cell-growth signalling factors such as EGF antibodies; antisense oligonucleotides; immunological modifiers such as interferons, interleukins, growth hormones, and other cytokines; and other hormonal therapies.
  • gonadotrophin agonists GnRH
  • LH-RH agonists LH-RH agonists
  • the compounds of the invention man also be used for the treatment of various hormone dependent diseases and disorders, such as prostate cancer in combination with one or more of the following agents: antibiotics; anti-inflammatory agents; potassium channel openers; synthetic thyroid hormone replacements; protein kinase C inhibitors (PKC inhibitors); and immunophilin inhibitors or antagonists.
  • antibiotics antibiotics
  • anti-inflammatory agents potassium channel openers
  • synthetic thyroid hormone replacements synthetic thyroid hormone replacements
  • PKC inhibitors protein kinase C inhibitors
  • immunophilin inhibitors or antagonists immunophilin inhibitors or antagonists.
  • the compounds of formula I and their pharmaceutically acceptable salts thereof are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of cell cycle activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
  • Example 4 The procedure described in Example 4 was repeated using (25)-N-[4-cyano-3- (trifluoromethyl)phenyl]-2-hydroxy-2-methyl-9-(pentylthio)nonanamide to give the title compound in 80% yield; ⁇ MR spectrum (CDCl 3 ) 0.91 (t, 3H), 1.18 - 1.57 (m, 14H), 1.61 - 1.85 (m, 6H), 1.88 - 2.00 (m, IH), 2.60 - 2.83 (m, 4H), 3.93 (s, IH), 7.78 (d, IH), 7.94 - 7.98 (m, IH), 8.10 (d, IH), 9.20 (s, IH); Mass spectrum MK 475.
  • Example 4 The procedure described in Example 4 was repeated using (25 ⁇ -N-[4-cyano-3- (trifluoromethyl)phenyl]-2-hydroxy-2-methyl-9-[(4,4,5,5,5- pentafluoropentyl)thio]nonanamide (obtained as described in Example 2) to give the title compound in 89% yield; ⁇ MR spectrum (CDCl 3 ) 1.18 - 1.56 (m, 10H), 1.61 - 1.71 (m, IH), 1.73 - 1.83 (m, 2H), 1.92 - 2.01 (m, IH), 2.10 - 2.33 (m, 5H), 2.62 - 2.93 (m, 4H), 3.60 - 4.08 (m, IH), 7.78 (d, IH), 7.93 - 7.97 (m, IH), 8.10 (d, IH), 9.14 (s, IH); Mass spectrum MH + 565.
  • Example 10 The procedure described in Example 4 was repeated using (25)-N-[4-cyano-3- (trifluoromethyl)phenyl]-9-[(3,3,4,4,5,5,5-heptafluoropentyl)thio]-2-hydroxy-2- methylnonanamide (obtained as described in Example 3) to give the title compound in 79% yield; ⁇ MR spectrum (CDCl 3 ) 1.18 - 1.60 (m, HH), 1.60 - 1.70 (m, IH), 1.70 - 1.84 (m, 2H), 1.92 - 2.01 (m, IH), 2.52 - 3.01 (m, 6H), 3.32 (s, IH), 7.78 (d, IH), 7.93 - 7.97 (m, IH), 8.09 (d, IH), 9.14 (s, IH); Mass spectrum MH + 601.
  • Example 10 Example 10
  • Example 12 The procedure described in Example 10 was repeated using (2S)-N-[4-cyano-3- (trifluoromethyl)phenyl]-2-hydroxy-2-methyl-9-(pentylthio)nonanamide (obtained as described in Example 5) to give the title compound in 75% yield; ⁇ MR spectrum (CDCl 3 ) 0.91 (t, 3H), 1.16 - 1.70 (m, 17H), 1.78 - 1.87 (m, 4H), 1.93 - 2.03 (m, IH), 2.88 - 2.95 (m, 4H), 7.79 (d, IH), 7.93 - 7.97 (m, IH), 8.09 (d, IH), 9.08 (s, IHi: Mass spectrum MH + 491.
  • Example 12 Example 12
  • Example 10 The procedure described in Example 10 was repeated using (2S)-N-[4-cyano-3- (trifluoromethyl)phenyl] -9-(hexylthio)-2-hydroxy-2-methylnonanamide (obtained as described in Example 6) to give the title compound in 51% yield; NMR spectrum (CDCl 3 ) 0.88 (t, 3H), 1.20 - 1.50 (m, 15H), 1.53 (s, 3H), 1.60 - 1.70 (m, IH), 1.77 - 2.03 (m, 5H), 2.87 - 2.96 (m, 4H), 7.79 (d, IH), 7.93 - 7.97 (m, IH), 8.10 (d, IH), 9.08 (s, IH); Mass spectrum MH + 505.
  • Example 14 The procedure described in Example 10 was repeated using (2S)-N- [4-cyano-3- (trifluoromethyl)phenyl]-9-(heptylthio)-2-hydroxy-2-methylnonanamide (obtained as described in Example 7) to give the title compound in 66% yield; ⁇ MR spectrum (CDCl 3 ) 0.87 (t, 3H), 1.17 - 1.48 (m, 17H), 1.52 (s, 3H), 1.59 - 1.70 (m, IH), 1.77 - 1.89 (m, 4H), 1.92 - 2.04 (m, IH), 2.86 - 2.95 (m, 4H), 7.79 (d, IH), 7.93 - 7.96 (m, IH), 8.09 (s, IH), 9.06 (s, IH); Mass spectrum MH + 519.
  • Example 14 Example 14
  • Example 10 The procedure described in Example 10 was repeated using (2S)-N-[4-cyano-3- (trifluoromethyl)phenyl]-2-hydroxy-2-methyl-9-[(4,4,5,5,5- pentafluoropentyl)thio]nonanamide (obtained as described in Example 2) to give the title compound in 34% yield; ⁇ MR spectrum (CDCl 3 ) 1.30 - 1.51 (m, 9H), 1.54 (s, 3H), 1.59 - 1.70 (m, IH), 1.79 - 1.89 (m, 2H), 1.92 - 2.03 (m, IH), 2.09 - 2.38 (m, 4H), 2.94 - 3.06 (m, 4H), 7.79 (d, IH), 7.93 - 7.96 (m, IH), 8.08 (s, IH), 9.06 (s, IH); Mass spectrum MH + 581.
  • Example 16 (2S)-N-[4-cyano-3- (trifluoromethyl)phenyl]-9-[(3 ,3 ,4,4,5,5, 5-heptafluoropentyl)thio]-2-hydroxy-2- methylnonanamide (obtained as described in Example 3) to give the title compound in 54% yield; ⁇ MR spectrum (CDCl 3 ) 1.18 - 1.51 (m, 7H), 1.54 (s, 3H), 1.57 - 1.70 (m, 3H), 1.79 - 1.91 (m, 2H), 1.91 - 2.03 (m, IH), 2.57 - 2.74 (m, 2H), 3.00 - 3.06 (m, 2H), 3.14 - 3.24 (m, 2H), 7.79 (d, IH), 7.93 - 7.97 (m, IH), 8.08 (s, IH), 9.07 (s, IH); Mass spectrum MH + 617.
  • Example 16 (2S)-N-[4-Cyano-3
  • Example 4 The procedure described in Example 4 was repeated using (2S)-N-[4-cyano-3- (trifluoromethyl)phenyl]-2-hydroxy-2-methyl-10-[(4,4,4-trifluorobutyl)thio]decanamide (obtained as described in Example 17) to give the title compound in 90% yield; NMR spectrum (CDCl 3 ) 1.28 (8H, d), 1.44 (2H, t), 1.52 (3H, s), 1.62 - 1.78 (3H, m), 1.96 (IH, d), 2.13 (2H, q), 2.27 - 2.32 (2H, m), 2.71 (IH, t), 2.76 - 2.84 (2H, m), 2.86 - 2.88 (IH, m), 3.21 (IH, s), 7.79 (IH, d), 7.93 - 7.97 (IH, m), 8.09 (IH, d), 9.12 (IH, s); Mass spectrum MH + 529.
  • Example 4 The procedure described in Example 4 was repeated using (2S)-N-[4-cyano-3- (trifluoromemyl)phenyl]-2-hydroxy-2-methyl-10-[(4,4,5,5,5- pentafluoropentyl)thio]decanamide (obtained as described in Example 18) to give the title compound in 79% yield; NMR spectrum (CDCl 3 ) 1.24 (IH, s), 1.31 (7H, s), 1.44 (IH, t), 1.52 (5H, s), 1.61 - 1.70 (IH, m), 1.70 - 1.83 (2H, m), 1.92 - 2.00 (IH, m), 2.10 - 2.35 (4H, m), 2.67 - 2.76 (IH, m), 2.81 (IH, t), 2.86 - 2.93 (IH, m), 3.55 (IH, s), 7.79 (IH, d), 7.93 - 7.97 (IH, m), 8.10 (IH,
  • Example 4 The procedure described in Example 4 was repeated using (2S)-N-[4-cyano-3- (trifluoromethyl)phenyl]-10-[(3,3,4,4,5,5,5-heptafluoropentyl)thio]-2-hydroxy-2- methyldecanamide (obtained as described in Example 19) to give the title compound in 78% yield; NMR spectrum (CDCl 3 ) 1.33 (9H, d), 1.46 (IH, d), 1.52 (3H, s), 1.60 - 1.71 (IH, m), 1.79 (2H, t), 1.91 - 2.02 (IH, m), 2.59 (IH, s), 2.65 - 2.80 (2H, m), 2.88 - 2.97 (IH, m), 2.99 (2H, q), 4.29 (IH, s), 7.79 (IH, d), 7.93 - 7.97 (IH, m), 8.09 (IH, d), 9.13 (IH, s); Mass spectrum MH +
  • Example 10 The procedure described in Example 10 was repeated using (2S)-N-[4-cyano-3- (trifluorometliyl)phenyl]-2-hydroxy-2-methyl-10-[(4,4,4-trifluorobutyl)thio]decanamide (obtained as described in Example 17) to give the title compound in 92% yield; NMR spectrum (CDCl 3 ) 1.24 (IH, d), 1.31 (6H, s), 1.43 (3H, q), 1.53 (3H, s), 1.61 - 1.70 (IH, m), 1.83 (3H, t), 1.94 - 2.03 (IH, m), 2.09 - 2.19 (2H, m), 2.29 - 2.39 (2H, m), 2.93 - 3.05 (4H, m), 7.79 (IH, d), 7.93 - 7.97 (IH, m), 8.09 (IH, d), 9.08 (IH, s); Mass spectrum MH- 544.
  • Example 10 The procedure described in Example 10 was repeated using (2S)-N-[4-cyano-3- (trifluoromethyl)phenyl]-2-hydroxy-2-methyl-10-[(4,4,5,5,5- pentafluoropentyl)thio]decanamide (obtained as described in Example 18) to give the title compound in 75% yield; NMR spectrum (CDCl 3 ) 1.31 (7H, s), 1.43 (2H, q), 1.53 (4H, s), 1.60 - 1.70 (IH, m), 1.78 - 1.88 (2H, m), 1.93 - 2.03 (IH, m), 2.10 - 2.36 (5H, m), 2.97 - 3.07 (4H, m), 7.79 (IH, d), 7.94 - 7.97 (IH, m), 8.10 (IH, d), 9.10 (IH, s); Mass spectrum MH- 593.
  • Example 10 The procedure described in Example 10 was repeated using (2S)-N-[4-cyano-3- (trifluoromethyl)phenyl]-10-[(3,3,4,4,5,5,5-heptafluoropentyl)thio]-2-hydroxy-2- methyldecanamide (obtained as described in Example 19) to give the title compound in 78% yield; NMR spectrum (CDCl 3 ) 1.32 (7H, s), 1.45 (3H, t), 1.53 (3H, s), 1.60 - 1.70 (IH, m), 1.81 - 1.89 (2H, m), 1.94 - 2.03 (IH, m), 2.24 (IH, s), 2.56 - 2.75 (2H, m), 3.00 3.07 (2H, m), 3.17 - 3.23 (2H, m), 7.79 (IH, d), 7.94 - 7.97 (IH, m), 8.09 (IH, d), 9.09 (IH, s); Mass spectrum MH- 629.
  • Example 10 The procedure described in Example 10 was repeated using (2S)-10-(butylthio)-N- [4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methyldecanamide (obtained as described in Example 23) to give the title compound in 77% yield; NMR spectrum (CDCl 3 ) 0.96 (3H, t), 1.30 (8H, s), 1.42 (IH, s), 1.44 (3H, t), 1.51 (3H, d), 1.60 - 1.70 (IH, m), 1.74 - 1.86 (4H, m), 1.92 - 2.00 (IH, m), 2.29 (IH, s), 2.90 - 2.97 (4H, m), 7.79 (IH, d), 7.94 - 7.98 (IH, m), 8.11 (IH, d), 9.13 (IH, s>: Mass spectrum MH ' 489.
  • Example 10 The procedure described in Example 10 was repeated using (2S)-N-[4-cyano-3- (trifluoromethyl)phenyl]-2-hydroxy-2-methyl-10-(pentylthio)decanamide (obtained as described in Example 24) to give the title compound in 86% yield; NMR spectrum (CDCl 3 ) 0.92 (3H, t), 1.30 (7H, s), 1.39 - 1.42 (IH, m), 1.35 - 1.48 (6H, m), 1.53 (3H, s), 1.60 - 1.70 (IH, m), 1.76 - 1.88 (4H, m), 1.92 - 2.00 (IH, m), 2.20 (IH, s), 2.90 - 2.96 (4H, m), 7.79 (IH, d), 7.94 - 7.98 (IH, m), 8.11 (IH, d), 9.12 (IH, s); Mass spectrum MH ' 503.
  • Example 10 The procedure described in Example 10 was repeated using (2S)-N-[4-cyano-3- (trifluoromethyl)phenyl]-10-(hexylthio)-2-hydroxy-2-methyldecanamide (obtained as described in Example 25) to give the title compound in 61% yield; NMR spectrum (CDCl 3 ) 0.90 (3H, t), 1.31 (3H, s), 1.32 (8H, t), 1.36 - 1.37 (IH, m), 1.43 (2H, d), 1.46 (2H, t), 1.53 (3H, s), 1.60 - 1.70 (IH, m), 1.76 - 1.87 (4H, m), 1.96 - 2.02 (IH, m), 2.08 (IH, s), 2.90 - 2.96 (4H, m), 7.79 (IH, d), 7.94 - 7.98 (IH, m), 8.10 (IH, d), 9.12 (IH, s); Mass spectrum MH " 517.
  • Example 10 The procedure described in Example 10 was repeated using (2S)-N-[4-cyano-3- (trifluoromethyl)phenyl] - 10-(heptylthio)-2-hydroxy-2-methyldecanamide (obtained as described in Example 26) to give the title compound in 71% yield; NMR spectrum (CDCl 3 ) 0.89 (3H, t), 1.30 (13H, d), 1.37 (2H, d), 1.43 (3H, d), 1.52 (3H, s), 1.60 - 1.70 (IH, m), 1.76 - 1.82 (3H, m), 1.83 - 1.87 (IH, m), 1.92 - 2.00 (IH, m), 2.16 (IH, s), 2.90 - 2.96 (4H, m), 7.79 (IH, d), 7.94 - 7.98 (IH, m), 8.11 (IH, d), 9.13 (IH, s); Mass spectrum MH " 531.
  • (2S)-ll-(Butylthio)- ⁇ -[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2- methylundecanamide was prepared by the procedure described in Intermediate Example 3 using butyl imidothiocarbamate hydrobromide and (10S)-I l- ⁇ [4-cyano-3- (trifluoromethyl)phenyl] amino ⁇ - 10-hy droxy- 10-methyl- 11 -oxoundecyl methanesulfonate to give (2S)-I l-(butylthio)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2- methylundecanamide in 26% yield; NMR spectrum (CDCl 3 ) 0.90 (t, 3H), 1.21 - 1.51 (m, 16H), 1.53 (s, 3H), 1.56 - 1.71 (m, 3H), 1.93 - 2.02 (m, IH), 2.46 - 2.5
  • Example 4 The procedure described in Example 4 was repeated using (2S)-JV- [4-cyano-3- (trifluoromethyl)phenyl] -2-hydroxy-2 -methyl- 11 -[(4,4,4-trifluorobutyl)thio]undecanamide (obtained as described in Example 35) to give the title compound in 88% yield; NMR spectrum (CDCl 3 ) 1.18 - 1.39 (m, 8H), 1.42 - 1.49 (m, 2H), 1.52 (s, 3H), 1.61 - 1.70 (m, IH), 1.73 - 1.83 (m, 2H), 1.92 - 2.01 (m, IH), 2.06 - 2.16 (m, 2H), 2.23 - 2.39 (m, 2H), 2.63 - 3.14 (m, 7H), 7.78 (d, IH), 7.94 - 7.97 (m, IH), 8.09 (d, IH), 9.13 (s, IH); Mass spectrum MH + 543.
  • Example 4 The procedure described in Example 4 was repeated using (2S)-N-[4-cyano-3- (trifluoromethyl)phenyl]-2-hydroxy-2 -methyl- 11 -[(5,5,5- trifluoropentyl)thio]undecanamide (obtained as described in Example 36) to give the title compound in 97% yield; ⁇ MR spectrum (CDCl 3 ) 1.18 - 1.34 (m, 8H), 1.39 - 1.49 (m, 2H), 1.52 (s, 3H), 1.61 - 2.01 (m, 8H), 2.08 - 2.23 (m, 2H), 2.62 - 2.74 (m, 2H), 2.79 - 2.88 (m, 2H), 3.58 - 3.94 (m, 3H), 7.78 (d, IH), 7.94 - 7.97 (m, IH), 8.09 (s, IH), 9.16 (s, IH); Mass spectrum MH + 557.
  • Example 4 The procedure described in Example 4 was repeated using (25)-N-[4-cyano-3- (trifluoromethyl)phenyl]-2-hydroxy-2-methyl-ll-[(4,4,5,5,5- pentafluoropentyl)thio]undecanamide (obtained as described in Example 37) to give the title compound in 96% yield; ⁇ MR spectrum (CDCl 3 ) 1.19 - 1.38 (m, 8H), 1.39 - 1.50 (m, 2H), 1.52 (s, 3H), 1.59 - 1.70 (m, IH), 1.73 - 1.83 (m, 2H), 1.89 - 2.01 (m, IH), 2.09 - 2.36 (m, 4H), 2.61 - 3.03 (m, 7H), 7.78 (d, IH), 7.95 (d, IH), 8.09 (s, IH), 9.13 (s, IH); Mass spectrum MH + 593.
  • Example 4 The procedure described in Example 4 was repeated using (2S)-N- [4-cyano-3- (trifluoromemyl)phenyl]- 11 -[(3 ,3 ,4,4,5,5,5-heptafluoropentyl)thio]-2-hydroxy-2- methylundecanamide (obtained as described in Example 38) to give the title compound in 88% yield; ⁇ MR spectrum (CDCl 3 ) 1.19 - 1.39 (m, 8H), 1.39 - 1.47 (m, 2H), 1.52 (s, 3H), 1.60 - 1.70 (m, IH), 1.74 - 1.84 (m, 2H), 1.92 - 2.01 (m, IH), 2.53 - 3.15 (m, 9H), 7.78 (d, IH), 7.94 - 7.97 (m, IH), 8.09 (s, IH), 9.13 (s, IH); Mass spectrum MH + 629.
  • Example 10 The procedure described in Example 10 was repeated using (2.S r )-N-[4-cyano-3- (trifluoromethyl)phenyl]-2-hydroxy-2-methyl-ll-[(4,4,4-trifluorobutyl)thio]undecanamide (obtained as described in Example 35) to give the title compound in 89% yield; NMR spectrum TCDClQ 1.16 - 1.36 (m, 9H), 1.37 - 1.49 (m, 2H), 1.53 (s, 3H), 1.58 - 1.88 (m, 4H), 1.93 - 2.03 (m, IH) 5 2.09 - 2.19 (m, 2H), 2.26 - 2.41 (m, 2H), 2.93 - 3.05 (m, 4H), 7.79 (d, IH), 7.93 - 7.97 (m, IH), 8.09 (d, 2H), 9.07 (s, IH); Mass spectrum MH + 559.
  • Example 10 The procedure described in Example 10 was repeated using (25)-N-[4-cyano-3- (trifluoromethyl)phenyl]-2-hydroxy-2-methyl-l 1 -[(5,5,5- trifluoropentyl)thio]undecanamide (obtained as described in Example 36) to give the title compound in 86% yield; ⁇ MR spectrum (CDCl 3 ) 1.20 - 1.36 (m, 8H), 1.37 - 1.49 (m, 4H), 1.53 (s, 3H), 1.61 - 1.85 (m, 7H), 1.87 - 2.02 (m, 2H), 2.07 - 2.23 (m, 2H), 2.92 - 2.99 (m, 4H), 7.79 (d, IH), 7.93 - 7.97 (m, IH), 8.09 (d, IH), 9.08 (s, IH); Mass spectrum MH + 573.
  • Example 10 The procedure described in Example 10 was repeated using (25)-N-[4-cyano-3- (trifluoromethyl)phenyl]-2-hydroxy-2-methyl-ll-[(4,4,5,5,5- pentafluoropentyl)thio]undecanamide (obtained as described in Example 37) to give the title compound in 91% yield; NMR spectrum (CDCl 3 ) 1.17 - 1.38 (m, 8H), 1.39 - 1.50 (m, 4H), 1.53 (s, 3H), 1.55 - 1.74 (m, 2H), 1.78 - 1.88 (m, 2H), 1.93 - 2.05 (m, IH), 2.11 - 2.37 (m, 4H), 2.94 - 3.06 (m, 4H), 7.79 (d, IH), 7.93 - 7.97 (m, IH), 8.09 (d, IH), 9.07 (s, IH); Mass spectrum MH + 609.
  • Example 10 The procedure described in Example 10 was repeated using (2S)-I l-(butylthio)-N- [4-cyano-3-(trifluoromethyl) ⁇ henyl]-2-hydroxy-2-methylundecanamide (obtained as described in Example 40) to give the title compound in 65% yield; NMR spectrum (CDCl 3 ) 0.95 (t, 3H), 1.17 - 1.49 (m, 15H), 1.53 (s, 3H), 1.60 - 1.70 (m, IH), 1.74 - 1.87 (m, 4H), 1.92 - 2.02 (m, IH), 2.90 - 2.97 (m, 4H) 5 7.79 (d, IH), 7.94 - 7.98 (m, IH), 8.10 (d, IH), 9.11 (s, IH): Mass spectrum MH + 503.
  • Example 10 The procedure described in Example 10 was repeated using (2iS)-N-[4-cyano-3- (trifluoromethyl)phenyl]-2-hydroxy-2-methyl-l l-(pentylthio)undecanamide (obtained as described in Example 41) to give the title compound in 79% yield; ⁇ MR spectrum (CDCl 3 ) 0.91 (t, 3H), 1.19 - 1.48 (m, 17H), 1.52 (s, 3H),1.60 - 1.70 (m, IH), 1.73 - 1.88 (m, 4H), 1.88 - 2.00 (m, IH), 2.90 - 2.97 (m, 4H), 7.78 (d, IH), 7.95 - 7.98 (m, IH), 8.12 (d, IH), 9.18 (s, IH); Mass spectrum MH + 519.
  • Example 10 The procedure described in Example 10 was repeated using (25)-N-[4-cyano-3- (trifluoromethyl)phenyl]-l l-(hexylthio)-2-hydroxy-2-methylundecanamide to give the title compound in 75% yield; ⁇ MR spectrum (CDCl 3 ) 0.88 (t, 3H), 1.23 - 1.49 (m, 19H), 1.52 (s, 3H), 1.60 - 1.70 (m, IH), 1.76 - 1.87 (m, 4H), 1.91 - 2.00 (m, IH), 2.90 - 2.97 (m, 4H), 7.78 (d, IH), 7.95 - 7.98 (m, IH), 8.12 (d, IH), 9.17 (s, IH); Mass spectrum MH + 533.
  • the (2S)-12-(butylthio)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2- methyldodecanamide used as starting material was prepared as follows: (1 lS)-12- ⁇ [4-Cyano-3-(trifluoromethyl)phenyl]amino ⁇ -l 1-hydroxy-l l-methyl-12- oxododecyl methanesulfonate was prepared as described in Intermediate Example 3 (preparation of starting materials) using (2S)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2,12- dihydroxy-2-methyldodecanamide (prepared as described in Example 54) in 86% yield; NMR spectrum (CDCl 3 ) 1.17 - 1.48 (m, 13H), 1.53 (s, 3H), 1.56 - 1.77 (m, 5H), 1.89 - 2.02 (m, IH), 3.00 (s, 3H), 4.20 (t, 2H),
  • (2S)-12-(butylthio)-N-[4-cyano-3-(trifiuoromethyl)phenyl]-2-hydroxy-2- methyldodecanamide was prepared by the procedure described in Intermediate Example 3 using butyl imidothiocarbamate hydrobromide and (115)-12- ⁇ [4-cyano-3- (trifluoromethyl)phenyl]amino ⁇ -l 1-hydroxy-l 1 -methyl- 12-oxododecyl methanesulfonate to give (2S)-12-(butylthio)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2- methyldodecanamide in 61% yield; NMR spectrum (CDCl 3 ) 1.19 - 1.51 (m, 16H), 1.53 (s, 3H), 1.56 - 1.71 (m, 4H), 1.93 - 2.05 (m, IH), 2.47 - 2.65 (m, 6H), 7.79 (d, I
  • Example 4 The procedure described in Example 4 was repeated using (2S)-N-[4-cyano-3- (trifluoromethyl)phenyl]-2-hydroxy-2-methyl-12-[(4,4,4-trifluorobutyl)thio]dodecanamide (obtained as described in Example 55) to give the title compound in 88% yield; NMR spectrum (CDCl 3 ) 1.27 (1OH, s), 1.34 (2H, d), 1.39 - 1.47 (2H, m), 1.52 (3H, s), 1.62 - 1.70 (IH, m), 1.72 - 1.83 (2H, m), 1.92 - 2.00 (IH, m), 2.06 - 2.17 (2H, m), 2.24 - 2.36 (2H, m), 2.65 - 2.74 (2H, m), 2.82 - 2.91 (2H, m), 3.38 (IH, s), 7.79 (IH, d), 7.94 - 7.97 (IH, m), 8.09 (IH,
  • Example 4 The procedure described in Example 4 was repeated using (2S)-N-[4-cyano-3- (trifluoromethyl)phenyl]-2-hydroxy-2-methyl-12-[(4,4,5,5,5- pentafluoropentyl)thio]dodecanamide (obtained as described in Example 56) to give the title compound in 83% yield; NMR spectrum (CDCl 3 ) 1.28 (9H, s), 1.34 (2H, d), 1.45 (IH, t), 1.52 (4H, s), 1.73 - 1.83 (2H, m), 1.92 - 2.00 (IH, m), 2.10 - 2.19 (2H, m), 2.20 - 2.23 (IH, m), 2.64 - 2.73 (IH, m), 2.76 - 2.84 (IH, m), 2.79 - 2.86 (3H, m), 2.88 (3H, d), 7.78 (IH, d), 7.94 - 7.97 (IH, m), 8.09 (IH
  • Example 4 The procedure described in Example 4 was repeated using (2S)-N-[4-cyano-3- (trifluoromethyl)phenyl]-12-[(3,3,4,4,5,5,5-heptafluoropentyl)thio]-2-hydroxy-2- methyldodecanamide (obtained as described in Example 57) to give the title compound in 80% yield; NMR spectrum (CDCl 3 ) 1.27 (1OH, s), 1.36 (IH, s), 1.43 (IH, t), 1.48 (IH, s), 1.52 (4H, s), 1.62 - 1.70 (IH, m), 1.74 - 1.84 (2H, m), 1.92 - 2.00 (IH, m), 2.58 - 2.65 (IH, m), 2.68 - 2.78 (2H, m), 2.86 (IH, t), 2.91 - 3.00 (2H, m), 3.28 (IH, s), 7.79 (IH, d), 7.94 - 7.97 (
  • Example 66 The procedure described in Example 10 was repeated using (2S)-12-(butylthio)-N- [4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methyldodecanamide (obtained as described in Example 58) to give the title compound in 82% yield; NMR spectrum (CDCl 3 ) 0.95 (t, 3H), 1.17 - 1.49 (m, 16H), 1.52 (s, 3H), 1.62 - 1.71 (m, IH), 1.76 - 1.87 (m, 4H), 1.92 - 2.01 (m, IH), 2.67 (s, IH), 2.91 - 2.98 (m, 4H), 7.79 (d, IH), 7.95 - 7.98 (m, IH), 8.11 (d, IH), 9.15 (s, IH); Mass spectrum MH ' 517.
  • Example 66 Example 66
  • Example 10 The procedure described in Example 10 was repeated using (2S)-N-[4-cyano-3- (trifluorometliyl)phenyl]-2-liydroxy-2-methyl-12-(pentyltliio)dodecanamide (obtained as described in Example 59) to give the title compound in 67% yield; NMR spectrum (CDCl 3 ) 0.91 (t, 3H), 1.20 - 1.50 (m, 18H), 1.52 (s, 3H), 1.59 - 2.01 (m, 6H), 2.81 (s, IH), 2.88 - 2.97 (m, 4H), 7.79 (d, IH), 7.95 - 7.98 (m, IH), 8.11 (d, IH), 9.15 (s, IH); Mass spectrum MH ' 531.
  • Example 10 The procedure described in Example 10 was repeated using (2S)-N-[4-cyano-3- (trifluoromethyl)phenyl] - 12-(hexylthio)-2-hydroxy-2-methyldodecanamide (obtained as described in Example 59) to give the title compound in 89% yield; NMR spectrum (CDCl 3 ) 0.88 (t, 3H), 1.20 - 1.49 (m, 20H), 1.52 (s, 3H), 1.62 - 1.71 (m, IH), 1.76 - 1.87 (m, 4H), 1.92 - 2.01 (m, IH), 2.27 (s, 4H), 2.90 - 2.97 (m, IH), 7.79 (d, IH), 7.95 - 7.98 (m, IH), 8.11 (d, IH), 9.14 (s, IHI: Mass spectrum MH ' 545.
  • Example 68 Example 68
  • Example 10 The procedure described in Example 10 was repeated using (2S)-N-[4-cyano-3- (trifluoromethyl)phenyl]-12-(heptylthio)-2-hydroxy-2-methyldodecanamide (obtained as described in Example 61) to give the title compound in 100% yield; NMR spectrum (CDCl 3 ) 0.87 (t, 3H), 1.20 - 1.49 (m, 22H), 1.53 (s, 3H), 1.61 - 1.71 (m, IH), 1.76 - 1.88 (m, 4H), 1.92 - 2.01 (m, IH), 2.46 (s, IH), 2.91 - 2.97 (m, 4H), 7.79 (d, IH), 7.94 - 7.98 (m, IH), 8.10 (d, IH), 9.13 (s, IH); Mass spectrum MH ' 559.
  • Example 10 The procedure described in Example 10 was repeated using (2S)-N-[4-cyano-3- (trifluoiOmethyl)phenyl]-2-hydroxy-2-methyl-12-[(4,4,4-trifluorobutyl)thio]dodecanamide (obtained as described in Example 55) to give the title compound in 96% yield; NMR spectrum (CDCl 3 ) 1.19 - 1.49 (m, 14H), 1.53 (s, 3H), 1.62 - 1.70 (m, IH), 1.78 - 1.88 (m, 2H), 1.93 - 2.02 (m, IH), 2.02 - 2.19 (m, 3H), 2.26 - 2.41 (m, 2H), 2.96 (t, 2H), 3.04 (t, 2H), 7.79 (d, IH), 7.94 - 7.97 (m, IH), 8.09 (d, IH), 9.09 (s, IH); Mass spectrum MH " 971.
  • Example 12 (2S)-N-[4-cyano-3- (trifluoromethyl)phenyl]-12-[(3,3,4,4,5,5,5-heptafluoropentyl)thio]-2-hydroxy-2- methyldodecanamide (obtained as described in Example 57) to give the title compound in 93% yield; NMR spectrum (CDCl 3 ) 1.16 - 1.47 (m, 14H), 1.53 (s, 3H), 1.62 - 1.70 (m, IH), 1.81 - 2.05 (m, 3H), 2.46 - 2.75 (m, 3H), 3.01 - 3.07 (m, 2H), 3.15 - 3.23 (m, 2H), 7.79 (d, IH), 7.94 - 7.97 (m, IH), 8.09 (d, IH), 9.10 (s, IH); Mass spectrum MH ' 657.
  • Example 72 (2 1 S)-7V-[4-Cyano-3-(trifluoromethyl)phenyl]-2
  • Example 4 The procedure described in Example 4 was repeated using (25)-N-[4-cyano-3- (trifiuoromethyl)phenyl]-2-hydroxy-2-methyl-13-(pentylthio)tridecanamide to give the title compound in 74% yield; ⁇ MR spectrum (CDCl 3 ) 0.91 (t, 3H), 1.13 - 1.48 (m, 20H), 1.51 (s, 3H), 1.62 - 1.86 (m, 5H), 1.91 - 2.00 (m, IH), 2.63 - 2.86 (m, 4H), 4.15 (s, IH), 7.78 (d, IH), 7.94 - 7.98 (m, IH), 8.10 (d, IH), 9.21 (s, IH): Mass spectrum MH + 531.
  • Example 4 The procedure described in Example 4 was repeated using (2S)-N- [4-cyano-3- (trifluoromethyl)phenyl]-2-hydroxy-2-methyl-13-[(4,4,5 3 5,5- pentafluoropentyl)thio]tridecanamide (obtained as described in Example 73) to give the title compound in 83% yield; NMR spectrum (CDCl 3 ) 1.18 - 1.49 (m, 16H), 1.51 (s, 3H), 1.62 - 1.82 (m, 3H), 1.91 - 2.01 (m, IH), 2.10 - 2.34 (m, 4H), 2.65 - 2.92 (m, 4H), 3.79 (s, IH), 7.78 (d, IH), 7.94 - 7.97 (m, IH), 8.10 (d, IH), 9.17 (s, IH); Mass spectrum MH + 621.
  • Example 84 The procedure described in Example 4 was repeated using (2!S)-N-[4-cyano-3- (trifluoromethy l)pheny 1] - 2-hy droxy-2 -methyl- 13 - [(5 , 5 , 5 - trifluoropentyl)thio]tridecanamide (obtained as described in Example 75) to give the title compound in 81% yield; ⁇ MR spectrum (CDCl 3 ) 1.15 - 1.48 (m, 16H), 1.51 (s, 3H), 1.60 2.00 (m, 8H), 2.08 - 2.23 (m, 2H), 2.64 - 2.74 (m, 2H), 2.78 - 2.88 (m, 2H), 3.91 (s, IH), 7.78 (d, IH), 7.94 - 7.97 (m, IH), 8.10 (d, IH), 9.19 (s, IH); Mass spectrum MH + 585.
  • Example 84 Example 84
  • Example 4 The procedure described in Example 4 was repeated using (2S)-N-[4-cyano-3- (trifluoromethyl)phenyl]-2-hydroxy-2-methyl-13-[(4,4,4-trifluorobutyl)thio]tridecanamide (obtained as described in Example 76) to give the title compound in 83% yield; ⁇ MR spectrum (CDCl 3 ) 1.15 - 1.49 (m, 16H), 1.52 (s, 3H), 1.62 - 1.82 (m, 3H), 1.92 - 2.01 (m, IH), 2.06 - 2.16 (m, 2H), 2.23 - 2.39 (m, 2H), 2.64 - 2.92 (m, 4H), 3.32 (s, IH), 7.78 (d, IH), 7.94 - 7.97 (m, IH), 8.09 (d, IH), 9.14 (s, IH): Mass spectrum MH + 571.
  • Example 86 The procedure described in Example 10 was repeated using (25)-13-(butylthio)-N- [4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methyltridecanamide (obtained as described in Example 77) to give the title compound in 77% yield; ⁇ MR spectrum (CDCl 3 ) 0.95 (t, 3H), 1.18 - 1.49 (m, 18H), 1.52 (s, 3H), 1.62 - 1.71 (m, IH), 1.76 - 1.87 (m, 4H), 1.90 - 2.02 (m, IH), 2.25 (s, IH), 2.88 - 2.97 (m, 4H), 7.79 (d, IH), 7.94 - 7.98 (m, IH), 8.10 (d, IH), 9.13 (s, IH); Mass spectrum MH + 533.
  • Example 86 Example 86
  • Example 10 The procedure described in Example 10 was repeated using (2jS)-iV-[4-cyano-3- (trifluoromethyl)plienyl]-2-hydroxy-2-methyl-13-(pentylthio)tridecanamide (obtained as described in Example 78) to give the title compound in 72% yield; NMR spectrum (CDCl 3 ) 0.91 (t, 3H), 1.17 - 1.52 (m, 20H), 1.52 (s, 3H), 1.59 - 1.71 (m, IH), 1.74 - 1.87 (m, 4H), 1.88 - 2.01 (m, IH), 2.32 (s, IH), 2.91 - 2.98 (m, 4H) 5 7.78 (d, IH), 7.94 - 7.98 (m, IH), 8.10 (d, IH), 9.14 (s, Iff): Mass spectrum MH + 545.
  • Example 10 The procedure described in Example 10 was repeated using (2 ⁇ S)-iV-[4-cyano-3- (trifluoromethyl)phenyl]- 13 -(hexylthio)-2-hydroxy-2-methyltridecanamide (obtained as described in Example 79) to give the title compound in 98% yield; NMR spectrum (CDCl 3 ) 0.88 (t, 3H), 1.16 - 1.52 (m, 22H), 1.52 (s, 3H), 1.62 - 1.73 (m, IH), 1.76 - 1.87 (m, 4H), 1.87 - 2.04 (m, IH), 2.04 (s, IH), 2.86 - 2.97 (m, 4H), 7.78 (d, IH), 7.94 - 7.98 (m, IH), 8.11 (d, IH), 9.14 (s, IH); Mass spectrum MH + 561.
  • Example 88 NMR spectrum (CDCl 3 ) 0.88 (t, 3H), 1.16 - 1.52 (m, 22H), 1.52 (
  • Example 10 The procedure described in Example 10 was repeated using (2S)-N- [4-cyano-3- (trifluoromethyl)phenyl] - 13 -(heptylthio)-2-hydroxy-2-methyltridecanamide (obtained as described in Example 80) to give the title compound in 82% yield; ⁇ MR spectrum (CDCl 3 ) 0.87 (t, 3H), 1.17 - 1.48 (m, 24H), 1.52 (s, 3H), 1.62 - 1.71 (m, IH), 1.77 - 1.88 (m, 4H), 1.92 - 2.01 (m, IH), 2.01 (s, IH), 2.91 - 2.96 (m, 4H), 7.78 (d, IH), 7.94 - 7.98 (m, IH), 8.11 (d, IH), 9.13 (s, IHV Mass spectrum MH + 575.
  • Example 90 The procedure described in Example 10 was repeated using (2S)-N- [4-cyano-3- (t ⁇ fluoromethyl)phenyl] -2-hydroxy-2-methyl- 13 -[(4,4,5 ,5 ,5- pentafluoropentyl)thio]tridecanamide (obtained as described in Example 73) to give the title compound in 71% yield; ⁇ MR spectrum (CDCl 3 ) 1.17 - 1.53 (m, 15H), 1.53 (s, 3H), 1.57 - 1.74 (m, 3H), 1.78 - 1.89 (m, 2H), 1.93 - 2.03 (m, IH), 2.14 - 2.37 (m, 4H), 2.95 - 3.07 (m, 4H), 7.79 (d, IH), 7.93 - 7.97 (m, IH), 8.09 (d, IH), 9.08 (s, IH); Mass spectrum MH + 637.
  • Example 90 Example 90
  • Example 10 The procedure described in Example 10 was repeated using (2»S)-N-[4-cyano-3- (trifluoromethyl)phenyl]-13-[(3,3,4,4,5,5,5-heptafluoropentyl)thio]-2-hydroxy-2- methyltridecanamide (obtained as described in Example 74) to give the title compound in 79% yield; ⁇ MR spectrum (CDCl 3 ) 1.21 - 1.48 (m, 14H), 1.53 - 1.70 (m, 4H), 1.53 (s, 3H), 1.81 - 1.92 (m, 2H), 1.92 - 2.03 (m, IH), 2.58 - 2.75 (m, 2H), 3.01 - 3.07 (m, 2H), 3.17 - 3.23 (m, 2H), 7.79 (d, IH), 7.93 - 7.97 (m, IH), 8.08 (s, IH), 9.06 (s, IH); Mass spectrum MH + 673.
  • Example 10 The procedure described in Example 10 was repeated using (2,S)-N- [4-cyano-3- (trifluoromethyl)phenyl] -2 -hy droxy-2 -methyl- 13 - [(5 , 5 , 5 - trifluoropentyl)thio]tridecanamide (obtained as described in Example 75) to give the title compound in 70% yield; ⁇ MR spectrum (CDCl 3 ) 1.17 - 1.50 (m, 15H), 1.53 (s, 3H), 1.58 1.88 (m, 7H), 1.88 - 2.02 (m, 3H), 2.07 - 2.23 (m, 2H), 2.89 - 2.99 (m, 4H), 7.79 (d, IH), 7.94 - 7.97 (m, IH), 8.09 (d, IH), 9.09 (s, IH); Mass spectrum MH + 601. - Ill -
  • Example 96 The procedure described in Example 10 was repeated using (2R)-N- [4-cyano-3- (trifluoromethyl)phenyl]-2-hydroxy-2-methyl-12-[(4,4,5,5,5- pentafluoropentyl)thio]dodecanamide (obtained as described in Example 93) to give the title compound in 75% yield; NMR spectrum (CDCl 3 ) 1.36 (s, 1 IH), 1.38 - 1.50 (m, 3H), 1.53 (s, 3H), 1.65 (d, IH), 1.77 - 1.89 (m, 2H), 1.90 - 2.03 (m, IH), 2.06 - 2.39 (m, 6H), 2.98 (t, 2H), 3.05 (t, 2H), 7.79 (d, IH), 7.95 (dd, IH), 8.10 (d, IR): Mass spectrum MH + 640.
  • Example 96 Example 96
  • the 2-hydroxy-l l-[(4,4,5,5,5-pentafluoropentyl)thio]-2-(trifluoromethyl)undecanoic acid used as starting material was prepared as follows: A few crystals of iodine were added to magnesium ribbon (1.36g, 56.35mmol) in dry THF (30ml) and heated to 45 0 C. 1-Bromo- 9-(4,4,5,5,5-pentafluoropentylthio)nonane (15g, 39.44mmol) was added to the mixture to initiate formation of the corresponding Grignard reagent and the reaction mixture was heated at 45 0 C for a further 2 hours.
  • the cool reaction mixture was added dropwise to a solution of ethyl 3,3,3-trifluoropyruvate (4.99ml, 37.56mmol) in dry THF (10ml) at -78 0 C.
  • the reaction mixture stirred at -78 0 C for 2 hours and then quenched with saturated ammonium chloride solution.
  • the reaction mixture was allowed to warm to room temperature and then extracted with ethyl acetate (3 x 150ml) and the combined extract was dried (MgSO 4 ) and concentrated under reduced pressure.
  • the iV-[4-cyano-3-(trifluoromethyl)plienyl]-2-(trifluoromethyl)oxirane-2-carboxamide used as starting material was prepared as follows: To a stirred solution of 2- (trifluoromethyl)-acrylic acid (4.91g, 25mM) in DCM (50ml) was added oxalyl chloride (4.89g, 38.5mM, 3.37ml) followed by DMF (2 drops). A further 2 drops of DMF were added after 30mins and again after lhr and the reaction mixture was stirred for a total of 2hrs. The reaction mixture was diluted with DCM (100ml) and cooled to 0-4 0 C.
  • the ethyl acetate layer was washed with brine, dried over magnesium sulphate, filtered, and evaporated under reduced pressure to give the crude product as a pale brown gum.
  • the crude product was purified by preparative LCMS on an Xterra column (19 x 100mm) using decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile (49-69%) as eluents.
  • N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methyl-ll-(tetrahydropyran-2- yloxy)undecanamide used as starting material was prepared as follows: To freshly distilled dry THF (3 mis) under a nitrogen atmosphere were added small pieces of magnesium ribbon (134 mg) and a crystal of iodine. A solution of 2-(8-bromooctyloxy)tetrahydropyran (1.41 g) in THF (2 mis) was added dropwise and the reaction mixture stirred until the iodine colour disappeared. The reaction mixture was heated at 50 0 C for 1 hour.
  • reaction mixture was diluted with THF (10 ml), cooled to -55 °C and lithium 2- thienylcyanocuprate (0.25m soln in THF) (19.24 ml) added dropwise.
  • the reaction mixture was stirred at -55 0 C for a further 30 minutes and a solution of N-[4-cyano-3- (trifluoromethyl)phenyl]-2-methyl-oxirane-2-carboxamide (0.5 g) in THF (5 ml) was added.
  • the mixture was slowly warmed to 20 0 C and stirred for 18 hours at this temperature.
  • a 10% solution of ammonium hydroxide in saturated aqueous ammonium chloride (20 mis) was added dropwise and the product extracted with EtOAc (x4).
  • N-methyl-9-(4,4,5,5,5-pentafluoropentylthio)nonan-l-amine hydrochloride used as starting material was prepared as follows: A solution of ter/-butyl ⁇ - methylcarbamate (0.395 g, 3.01 mmol) in dry DMF (10 mL) at 0 0 C under an atmosphere of nitrogen was treated with sodium hydride (60% dispersion in mineral oil, 0.122 g, 3.01 mmol) portionwise.
  • the 9-(4,4,5,5,5-pentafluoropentylthio)nonan-l-ol used as starting material was prepared as follows: A solution of l-bromo-9-(4,4,5,5,5-pentafluoropentylthio)nonane (0.5 g, 1.25 mmol) in THF (15 mL) was treated with MP-carbonate (2.73 mmol/g, 4.57 g, 12.5 mmol) and the mixture was heated at reflux for 7 h. Further THF (10 mL) was added and the mixture heated at reflux for 18 h.
  • the 9-(4,4,5,5,5-pentafluoropentylthio)non-l-ylamine used as starting material was prepared as follows: A solution of di-fer ⁇ butyliminodicarboxylate (0.635 g, 3.01 mmol) in dry DMF (20 mL) at 0 0 C under an atmosphere of nitrogen was treated with sodium hydride (60% dispersion in mineral oil, 0.122 g, 3.01 mmol) portionwise. After stirring for 1 hour at 0 °C, the mixture was treated dropwise with a solution of l-bromo-9-(4,4,5,5,5- pentafluoropentylthio)nonane (0.8 g, 2 mmol) in dry DMF (10 mL).
  • the (2S)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-3-(N-7-hydroxyheptyl- N-methyl-amino)-2-methyl-propanamide used as starting material was prepared as follows: A solution of 2-(7-iodohept-l-yloxy)tetrahydropyran (0.5 g, 1.53 mmol) in THF (5 mL) was treated with 40% aqueous methylamine solution (1.19 mL, 15.33 mmol) and was stirred vigorously for 18 h. The solvent was evaporated and diethyl ether (15 mL) was added to the residue followed by 2 N aqueous NaOH solution.
  • the mixture was cooled to room temperature, treated with sodium iodide (144 mg, 0.96 mmol) and then heated at 65 0 C for 24 h.
  • the mixture was cooled to room temperature, treated with DMF (2 mL), sodium iodide (78 mg, 0.52 mmol) and DIPEA (0.45 mL, 0.53 mmol) and was then heated at 65 0 C for 18 h.
  • the mixture was cooled to room temperature, treated with MeOH (2 mL) and was applied to an SCX-2 column (10 g) eluting first with methanol then with 1% ammonia in methanol solution. The latter fractions were combined and evaporated to afford a gum.
  • N-[4-cyano-3-(trii ⁇ uoromethyl)phenyl]-2,8-dihydroxy-2- methyloctanamide (0.50 g, 1.40mmol) in DCM (20ml) was added triethylamine (0.234ml, 1.67mmol) and methanesulfonyl chloride (0.130ml, 1.67mmol).
  • the mixture was stirred for 2h, washed with 2N HCl, dried (MgSO 4 ) and concentrated to give N-[4-cyano-3- (trifluoromethyl)phenyl]-2-hydroxy-2-methyl-8-methylsulfonyloxy-octanamide as an oil.
  • N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methyl-8- methylsulfonyloxy-octanamide prepared from N-[4-cyano-3-(trifluoromethyl)phenyl]-2,8- dihydroxy-2-methyloctanamide (500mg, 1.40mmoi), see above
  • 1- ethylsulphonylpiperazine (245r ⁇ g, 1.37mmol) in DMF (2ml) was heated at 70°C for 2h, cooled and absorbed onto an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated.
  • the N-[4-cyano-3-(trifluoromethyl)phenyl]-2,8-dihydroxy-2-methyloctanamide used as starting material was prepared as follows: 2-[(5-Bromopentyl)oxy]tetrahydro-2H-pyran (1.17g, 4.63mmol) was slowly added to magnesium turnings (0.134 g, 5.55mmol) in T ⁇ F (5ml) containing a few crystals of iodine. The reaction mixture was heated at 50 0 C for Ih. The reaction mixture was transferred via cannular to a new flask with the remaining magnesium being washed with T ⁇ F (10ml). The mixture was cooled to -55 0 C.
  • Lithium 2- thienylcyanocuprate (18.5ml of a 0.25M solution in T ⁇ F, 4.63mmol) was slowly added and the mixture stirred for 0.5h.
  • N-[4-Cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methyl-8-(tetrahydro-2H-pyran-2- yloxy)octanamide 400mg, 0.90mmol was dissolved in methanol (10ml) and Dowex 50 (pre-washed with water and methanol) was added. The mixture was heated at 5O 0 C for 3h, cooled, filtered and the filtrate concentrated.
  • N-[4-cyano-3-(trifluoromethyl)phenyl]-2,9-dihydroxy-2-methylnonanamide used as starting material was prepared as follows: 2-[(6-bromohexyl)oxy]tetrahydro-2H-pyran was reacted with N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methyloxirane-2-carboxamide according to the procedure described in Example 108 to give N-[4-cyano-3- (trifluoromethyl)phenyl]-2-hydroxy-2-niethyl-9-(tetrahydro-2H-pyran-2- yloxy)nonanamide in 85% yield as a viscous, pale brown oil; ⁇ MR spectrum (CDCI 3 ) 1.25 (m, 7 ⁇ ), 1.36-1.49 (m, 10H+H2O), 1.55-1.67 (m, 2H) 5 1.72-1.78 (m, IH), 1.87-1.94 (m, IH), 2.1
  • N-[4-Cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methyl-9-(tetrahydro-2H-pyran-2- yloxy)nonanamide was deprotected according to the procedure described in Example 108 to give N-[4-cyano-3-(trifluoromethyl)phenyl]-2,9-diliydroxy-2-methylnonanamide in 97% yield as a colourless oil; ⁇ MR spectrum (CDCl 3 ) 1.15-1.29 (m, 8 ⁇ ), 1.40-1.47 (m, 6H+H2O), 1.87-1.96 (d, IH), 2.07 (s, IH), 3.56 (t, 2H), 7.72 (d, IH), 7.87-7.89 (m, IH), 8.01 (d, IH), 8.99 (s, IH); Mass spectrum MH ' 371.
  • Example 108 The procedure described in Example 108 was repeated using N-[4-cyano-3- (trifluoromethyl)phenyl]-2,10-dihydroxy-2-methyldecanamide to give N-[4-cyano-3- (trifluoromethyl)phenyl]- 10-[4-(ethylsulfonyl)piperazin- 1 -yl]-2-hydroxy-2- methyldecanamide in 50% yield as a gum; ⁇ MR spectrum (CDCl 3 ) 1.19- 1.32 (m, 12H), 1.34-1.49 (m, 6H+D2O), 1.54-1.64 (m, IH), 1.88-1.93 (m, IH), 2.03 (s, IH), 2.28 (q, 2H), 2.42 (t, 4H), 2.88 (q, 2H), 3.24 (t, 4H), 7.72 (d, IH), 7.86-7.89 (m, IH), 8.02 (d, IH), 8.99 (s, IH); Mass spectrum MH + 547.
  • N-[4-cyano-3-(trifluoromethyl)phenyl]-2, 10-dihydroxy-2-methyldecanamide used as starting material was prepared as follows: 2-[(7-Bromoheptyl)oxy]tetrahydro-2H-pyran was reacted with N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methyloxirane-2-carboxamide according to the procedure described in Example 108 to give N-[4-cyano-3- (trifluoromethyl)phenyl]-2-hydroxy-2-methyl-10-(tetrahydro-2H-pyran-2- yloxy)decanamide in 44% yield as a viscous, pale brown oil; ⁇ MR spectrum (CDCl 3 )
  • N-[4-Cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methyl-10-(tetrahydro-2H-pyran-2- yloxy)decanamide was deprotected according to the procedure described in Example 108 to give N-[4-cyano-3-(trifluoromethyl)phenyl]-2,10-dihydroxy-2-methyldecanamide in 61% yield as a colourless oil; ⁇ MR spectrum (CDCl 3 ) 1.11-1.30 (m, 10 ⁇ ), 1.37-1.52 (m, 6 ⁇ + ⁇ 2O), 1.54-1.62 (m, IH), 1.88-1.96 (m, IH), 1.97 (s, IH), 3.55-3.57 (m, 2H), 7.72 (d, IH), 7.87-7.89 (m, IH) 5 8.01 (d, IH), 8.98 (s, IH): Mass spectrum MH ' 385.
  • Example 111 iV-[4-Cyano-3-(trifluoromethyl)phenyl]-12-[4-(ethylsulfonyl)piperazin-l-yl]-2- hydroxy-2-methyldodecanamide
  • Example 108 The procedure described in Example 108 was repeated using N-[4-cyano-3- (trifluoromethyl)phenyl]-2,12-dihydroxy-2-methyldodecanamide to give N-[4-Cyano-3- (trifluoromethyl)phenyl]-12-[4-(ethylsulfonyl)piperazin-l-yl]-2-hydroxy-2- methyldodecanamide in 33% yield as a gum; ⁇ MR spectrum (CDCl 3 ) 1.14-1.19 (m, 14H), 1.30 (t, 3H), 1.34-1.49 (m, 5H+H2O), 1.54-1.62 (m, IH), 1.88-1.94 (m, IH), 2.10 (s, IH), 2.28 (t, 2H), 2.43 (t, 4H), 2.88 (q, 2H), 3.24 (t, 4H), 7.72 (d, IH), 7.87-7.90 (m, IH), 8.02 (d, IH), 9.00
  • N-[4-cyano-3-(trifluoromethyl)phenyl]-2, 12-dihydroxy-2-methyldodecanamide used as starting material was prepared as follows: 2-[(9-bromononyl)oxy]tetrahydro-2H-pyran was reacted with N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methyloxirane-2-carboxamide according to the procedure described in Example 108 to give N-[4-cyano-3- (trifluoromethyl)phenyl]-2-hydroxy-2-methyl-12-(tetrahydro-2H-pyran-2- yloxy)dodecanamide in 42% yield as a viscous, pale brown oil; ⁇ MR spectrum (CDCl 3 ) 1.14-1.28 (m, 14 ⁇ ), 1.36-1.68 (m, 11H+H2O), 1.73-1.77 (m, IH), 1.87-1.94 (m, IH), 2.18 (d, IH), 3.28-3.33 (m, I
  • N-[4-Cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methyl-12-(tetrahydro-2H-pyran-2- yloxy)dodecanamide was deprotected according to the procedure described in Example 108 to give N-[4-cyano-3-(trifluoromethyl)phenyl]-2,12-dihydroxy-2-methyldodecanamide in 82% yield as a colourless oil; NMR spectrum (CDCl 3 ) 1.14-1.29 (m, 14 ⁇ ), 1.36-1.62 (m, 6H+H2O), 1.86-1.94 (m, IH), 2.22 (s, IH), 3.56 (s, 2H), 7.72 (d, IH), 7.87-7.89 (m, IH), 8.02 (d, IH), 9.01 (s, IH); Mass spectrum MH ' 413.
  • N-[4-cyano-3-(trifluoromethyl)phenyl]-2,7-dihydroxy-2-methylheptanamide used as starting material was prepared as follows: 50% w/v Aqueous sodium hydroxide (13.8ml) was added to 4-methoxybenzyl alcohol (5g, 36.19mmol) and tetrabutylammonium bromide (234mg, 0.72mmol) in 1,4-dibromobutane (13ml, 108.56mmol) and stirred at room temperature over night. The mixture was diluted with water (200ml) and extracted with DCM (x2). The combined extracts were washed with brine, dried (MgSO 4 ) and concentrated.
  • Example 108 The procedure described in Example 108 was repeated using N-[4-cyano-3- (trifluoromethyl)phenyl]-2,l l-diliydroxy-2-methylundecanamide and (25)-prolinamide to give 1-(1 l- ⁇ [4-cyano-3-(trifluoromethyl)phenyl]amino ⁇ -10-hydroxy-10-methyl-l 1- oxoundecyl)-(25)-prolinamide in 44% yield as a gum; ⁇ MR spectrum (CDCl 3 + D 2 O) 1.17-1.27 (s, HH), 1.38-1.45 (m, 6H), 1.54-1.62 (m, IH), 1.65-1.75 (m, 2H), 1.77-1.92 (m, 2H), 2.05-2.13 (m, IH), 2.21-2.27 (m, IH), 2.34-2.41 (m, IH), 2.48-2.56 (m, IH), 2.89-2.93 (m, IH), 3.10 (
  • N-[4-cyano-3-(trifluoromethyl)phenyl]-2,l l-dihydroxy-2-methylundecanamide used as starting material was prepared as follows: 2-[(8-bromooctyl)oxy]tetrahydro-2H-pyran was reacted with N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methyloxirane-2-carboxamide according to the procedure described in Example 108 to give N-[4-cyano-3- (trifluoromethyl)phenyl]-2-hydroxy-2-methyl-ll-(tetrahydro-2H-pyran-2- yloxy)undecanamide in 70% yield as a viscous, pale brown oil; ⁇ MR spectrum (CDCl 3 ) 1.13-1.29 (m, 12 ⁇ ), 1.36-1.67 (m, 11H+H2O), 1.73-1.78 (m, IH), 1.86-1.94 (m, IH), 2.17 (d, IH), 3.27-3.33
  • Example 108 The procedure described in Example 108 was repeated using JV-[4-cyano-3- (trifluoromethyl)phenyl]-2,12-dihydroxy-2-methyldodecanamide (obtained as described in Example 111) and (i?)-prolinol to give N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy- 12-[(2R)-2-(hydroxymethyl)pyrrolidin-l-yl]-2-methyldodecanamide in 36% yield as a gum; NMR spectrum (CDCl 3 ) 1.26-1.79 (m, 24H+H2O), 1.83-2.00 (m, 2H), 2.20-2.28 (m, 2H), 2.55-2.60 (m, IH), 2.65-2.83 (m, 2H), 3.15-3.19 (m, IH), 3.37 (d, IH), 3.60-3.64 (m, IH), 7.78 (d, IH), 7.94-7.97 (m, IH), 8.08 (d,
  • Example 108 The procedure described in Example 108 was repeated using -[4-cyano-3- (trifluoromethyl)phenyl]-2,12-dihydroxy-2-methyldodecanamide (obtained as described in Example 111) and (S)-prolinol to give N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy- 12-[(2>S)-2-(hydroxymethyl) pyrrolidin-l-yl]-2-methyldodecanamide in 70% yield as a gum; ⁇ MR spectrum (CDCl 3 ) 1.26-1.79 (m, 24H+H2O), 1.83-2.00 (m, 2H), 2.20-2.28 (m, 2H), 2.55-2.60 (m, IH), 2.65-2.83 (m, 2H), 3.15-3.19 (m, IH), 3.37 (d, IH), 3.60-3.64 (m, IH), 7.78 (d, IH), 7.94-7.97 (m, IH), 8.08 (d
  • Example 4 The procedure described in Example 4 was repeated using N-[4-cyano-3- (trifluoromethyl)phenyl]-2-hydroxy-2-methyl-8-(4,4,5,5,5-pentafluoropentylthio) octanamide (obtained as described in Example 116, above) to give N-[4-cyano-3- (trifluoromethyl)phenyl]-2-hydroxy-2-methyl-8-(4,4,5,5,5- pentafluoropentylsulfinyl)octanamide)sulfmyl]octanamide in 61% yield; Mass spectrum MH + 551
  • Example 10 The procedure described in Example 10 was repeated using N-[4-cyano-3- (trifluoromemyl)phenyl]-2-hydroxy-2-methyl-8-(4,4,5,5,5- pentafluoropentylthio)octanamide (obtained as described in Example 116, above) and purified using 5%ethyl acetate/dicloromethane increasing to 20% ethyl acetate dichloromethane to give N-[4-cyano-3-(trifluoromethyl) ⁇ henyl]-2-hydroxy-2-methyl-8- (4,4,5,5,5-pentafluoropentylsulfonyl)octanamide in 74% yield; NMR spectrum (CDCl 3 0.3- 0.7 (m,12H) 0.6 (m,lH) 0.9 (m,2H)l.l (m,lH) 1.2-1.5 (m,4H) 2.05 (t,2H) 2.2 (t,2H) 6.9 (d,lH) 7.
  • Example 10 The procedure described in Example 10 was repeated using N-[4-cyano-3- (trifluoromethyl)phenyl]-2-hydroxy-2-methyl-7-(4,4,5,5,5- pentafluoropentylthio)heptanamide (obtained as described in Example 119, above) and purified using 5%ethyl acetate/dicloromethane increasing to 20% ethyl acetate dichloromethane to give N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methyl-7- (4,4,5,5,5-pentafluoropentylsulfonyl)heptanamide in 74% yield; NMR spectrum (CDCl 3 1.2-1.6 (m,6H) 1.7 (m,lH)2.85 (m,2H) 2.0 (m,lH) 2.1-2.35 (m,5H) 3.0 (m,4H) 7.8 (d,lH) 7.95 (d,lH) 8.1 (s,lH)
  • reaction mixture was stirred until the iodine colour disappeared and a reaction set in. An exotherm was noted as the reaction progressed.
  • the reaction mixture was heated at 50°C for 1 hour by which time almost all of the magnesium had reacted.
  • the reaction mixture was then diluted with more THF (50 ml), cooled to -55 0 C and a solution of lithium 2 - thienylcyanocuprate in THF (0.25M, 100 ml, 25 mmol) added dropwise.
  • N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methyl-l 1 -methylsulfonyloxy- undecanamide used as starting material was prepared as follows: To a stirred solution of N-[4-cyano-3-(trifluoromethyl)phenyl]-2,l l-dihydroxy-2-methyl-undecanamide (2.5 g, 6.24 mmol) (obtained by the process described in Example 121), and triethylamine (1.04 ml, 7.49 mmol) in dichloromethane (30 ml) was added dropwise a solution of methane sulfonyl chloride (0.58 ml, 7.49 mmol) in dichloromethane and the mixture stirred for 3 hours.
  • Example 121 The procedure described in Example 121 was repeated using 2-hydroxy-2 ⁇ methyl-N-[4- nitro-3-(trifluoromethyl)phenyl]- 11 -(tetrahydropyran-2-yloxy)undecanamide to give 2,11- dihydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]undecanamide in 80% yield.
  • the 2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-l l-(tetrahydropyran-2- yloxy)undecanamide used as starting material was prepared as follows: The procedure described for the synthesis of the starting material in Example 121 was repeated with 2- methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]oxirane-2-carboxamide and l-bromo-8- (tetrahydropyranyloxy)octane to give 2-hydroxy-2-methyl-N-[4-nitro-3- (trifluoromethyl)phenyl]- 11 -(tetrahydropyran-2-yloxy)undecanamide in 27% yield.
  • Example 121 The procedure described in Example 121 was repeated using N-(3-chloro-4-cyano ⁇ phenyl)-2-hydroxy-2 -methyl- 11 -(tetrahydropyran-2-yloxy)undecanamide to give N-(3 - chloro-4-cyano-phenyl)-2,ll-dihydroxy-2-methyl-undecanamide in 57% yield; NMR spectrum: (CDClQ 1.17 - 1.37 (m, 10H), 1.40 - 1.75 (m, 8H), 1.92 - 2.02 (m, IH), 3.65 (t, 2H), 7.54 (dd, IH), 7.62 (d, IH), 7.97 (d, IH), 8.98 (s, IH), 2 OH protons not seen: Mass spectrum MH " 365
  • N-(3 -chloro-4-cyano-phenyl)-2-hydroxy-2 -methyl- 11 -(tetrahydropyran-2- yloxy)undecanamide used as starting material was prepared as follows: m- Chloroperoxybenzoic acid (3.46 g, 20 mmol) was added in portions to a refluxing suspension of N-(3-chloro-4-cyano- ⁇ henyl)-2-methyl-prop-2-enamide (2.21 g, 10 mmol) and 4-memyl-2,6-di-tert-butyl-phenol (0.035 g, 0.16 mmol) in 1,1,1-trichloroethane (65 ml) and the mixture stirred at reflux for 4 hours.
  • the mixture was cooled, diluted with dichloromethane and washed sequentially with aqueous sodium sulphite solution, saturated aqueous sodium bicarbonate solution and brine.
  • the dichloromethane solution was filtered through phase separating paper and evaporated under reduced pressureto give an oil.
  • the data for certain examples is shown in the Table below.
  • the data presented is one or more of the pICso obtained using Assay A or Assay B described above, or the maximum percentage inhibition obtained at 30 ⁇ M using Assay A.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés amides représentés par la formule I dans laquelle les groupes R1, R2, R3, Q1, X, R4, R5, R6, et R7 sont tels que définis dans la description. La présente invention porte également sur des procédés pour la préparation de tels composés, sur des compositions pharmaceutiques les contenant et sur leur utilisation dans la fabrication d'un médicament destiné à être utilisé en tant qu'agent antiprolifératif dans la prévention ou le traitement de tumeurs sensibles aux androgènes ou autres conditions prolifératives qui sont sensibles à la régulation négative du récepteur d'androgène.
PCT/GB2007/003870 2006-10-11 2007-10-11 Dérivés d'amide Ceased WO2008044033A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US82899106P 2006-10-11 2006-10-11
US60/828,991 2006-10-11

Publications (1)

Publication Number Publication Date
WO2008044033A1 true WO2008044033A1 (fr) 2008-04-17

Family

ID=38819574

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2007/003870 Ceased WO2008044033A1 (fr) 2006-10-11 2007-10-11 Dérivés d'amide

Country Status (1)

Country Link
WO (1) WO2008044033A1 (fr)

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8067448B2 (en) 2008-02-22 2011-11-29 Radius Health, Inc. Selective androgen receptor modulators
US8258140B2 (en) 2009-02-10 2012-09-04 Astrazeneca Ab Chemical compounds—643
US8268872B2 (en) 2008-02-22 2012-09-18 Radius Health, Inc. Selective androgen receptor modulators
US8642632B2 (en) 2010-07-02 2014-02-04 Radius Health, Inc. Selective androgen receptor modulators
US8987319B2 (en) 2010-02-04 2015-03-24 Radius Health, Inc. Selective androgen receptor modulators
WO2015089634A1 (fr) 2013-12-19 2015-06-25 Endorecherche, Inc. Antiandrogènes non stéroïdiens et modulateurs de récepteur d'androgène sélectifs avec un fragment pyridyle
US9133182B2 (en) 2010-09-28 2015-09-15 Radius Health, Inc. Selective androgen receptor modulators
US9555014B2 (en) 2010-05-12 2017-01-31 Radius Health, Inc. Therapeutic regimens
US10071066B2 (en) 2014-03-28 2018-09-11 Duke University Method of treating cancer using selective estrogen receptor modulators
CN109310664A (zh) * 2016-06-10 2019-02-05 田纳西大学研究基金会 选择性雄激素受体降解剂(sard)配体和其使用方法
US10385008B2 (en) 2017-01-05 2019-08-20 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCL
US10420734B2 (en) 2014-03-28 2019-09-24 Duke University Method of treating cancer using selective estrogen receptor modulators
US11230531B2 (en) 2016-06-10 2022-01-25 University Of Tennessee Research Foundation Selective androgen receptor degrader (SARD) ligands and methods of use thereof
US11230523B2 (en) 2016-06-10 2022-01-25 University Of Tennessee Research Foundation Selective androgen receptor degrader (SARD) ligands and methods of use thereof
US11591290B2 (en) 2015-04-21 2023-02-28 University Of Tennessee Research Foundation Selective androgen receptor degrader (SARD) ligands and methods of use thereof
RU2795431C2 (ru) * 2016-06-10 2023-05-03 Юниверсити Оф Теннесси Рисёрч Фаундейшн Лиганды, селективно разрушающие андрогенные рецепторы (sard), и способы их применения
US11643385B2 (en) 2018-07-04 2023-05-09 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCl
US11648234B2 (en) 2015-04-21 2023-05-16 University Of Tennessee Research Foundation Selective androgen receptor degrader (SARD) ligands and methods of use
US11771682B2 (en) 2016-06-22 2023-10-03 Ellipses Pharma Ltd. AR+ breast cancer treatment methods
US11819480B2 (en) 2015-04-29 2023-11-21 Radius Pharmaceuticals, Inc. Methods for treating cancer
US11873282B2 (en) 2015-04-21 2024-01-16 University Of Tennessee Research Foundation Selective androgen receptor degrader (SARD) ligands and methods of use thereof
US12128026B2 (en) 2015-04-21 2024-10-29 University Of Tennessee Research Foundation Selective androgen receptor degrader (SARD) ligands and methods of use thereof
US12202815B2 (en) 2018-09-05 2025-01-21 University Of Tennessee Research Foundation Selective androgen receptor degrader (SARD) ligands and methods of use thereof
WO2025067483A1 (fr) * 2023-09-28 2025-04-03 中国药科大学 Composés amides

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0100172A1 (fr) * 1982-07-23 1984-02-08 Imperial Chemical Industries Plc Dérivés d'amides
WO2000037430A2 (fr) * 1998-12-18 2000-06-29 Biophysica, Inc. Utilisation de suppresseurs du recepteur androgenique
WO2001058855A1 (fr) * 2000-02-11 2001-08-16 Biophysica, Inc Suppresseurs du recepteur androgene dans la therapie et le diagnostic du cancer de la prostate, l'alopecie et d'autres syndromes hyper-androgeniques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0100172A1 (fr) * 1982-07-23 1984-02-08 Imperial Chemical Industries Plc Dérivés d'amides
WO2000037430A2 (fr) * 1998-12-18 2000-06-29 Biophysica, Inc. Utilisation de suppresseurs du recepteur androgenique
WO2001058855A1 (fr) * 2000-02-11 2001-08-16 Biophysica, Inc Suppresseurs du recepteur androgene dans la therapie et le diagnostic du cancer de la prostate, l'alopecie et d'autres syndromes hyper-androgeniques

Cited By (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8268872B2 (en) 2008-02-22 2012-09-18 Radius Health, Inc. Selective androgen receptor modulators
US8455525B2 (en) 2008-02-22 2013-06-04 Radius Health, Inc. Selective androgen receptor modulators
US8629167B2 (en) 2008-02-22 2014-01-14 Radius Health, Inc. Selective androgen receptor modulators
US8067448B2 (en) 2008-02-22 2011-11-29 Radius Health, Inc. Selective androgen receptor modulators
US8258140B2 (en) 2009-02-10 2012-09-04 Astrazeneca Ab Chemical compounds—643
US8987319B2 (en) 2010-02-04 2015-03-24 Radius Health, Inc. Selective androgen receptor modulators
US9555014B2 (en) 2010-05-12 2017-01-31 Radius Health, Inc. Therapeutic regimens
US8642632B2 (en) 2010-07-02 2014-02-04 Radius Health, Inc. Selective androgen receptor modulators
US9133182B2 (en) 2010-09-28 2015-09-15 Radius Health, Inc. Selective androgen receptor modulators
US9920044B2 (en) 2010-09-28 2018-03-20 Radius Pharmaceuticals, Inc. Selective androgen receptor modulators
US9682960B2 (en) 2013-12-19 2017-06-20 Endorecherche, Inc. Non-steroidal antiandrogens and selective androgen receptor modulators with a pyridyl moiety
WO2015089634A1 (fr) 2013-12-19 2015-06-25 Endorecherche, Inc. Antiandrogènes non stéroïdiens et modulateurs de récepteur d'androgène sélectifs avec un fragment pyridyle
US11779552B2 (en) 2014-03-28 2023-10-10 Duke University Method of treating cancer using selective estrogen receptor modulators
US10071066B2 (en) 2014-03-28 2018-09-11 Duke University Method of treating cancer using selective estrogen receptor modulators
US12263142B2 (en) 2014-03-28 2025-04-01 Duke University Method of treating cancer using selective estrogen receptor modulators
US11951080B2 (en) 2014-03-28 2024-04-09 Duke University Method of treating cancer using selective estrogen receptor modulators
US10420734B2 (en) 2014-03-28 2019-09-24 Duke University Method of treating cancer using selective estrogen receptor modulators
US11873282B2 (en) 2015-04-21 2024-01-16 University Of Tennessee Research Foundation Selective androgen receptor degrader (SARD) ligands and methods of use thereof
US11648234B2 (en) 2015-04-21 2023-05-16 University Of Tennessee Research Foundation Selective androgen receptor degrader (SARD) ligands and methods of use
US12128026B2 (en) 2015-04-21 2024-10-29 University Of Tennessee Research Foundation Selective androgen receptor degrader (SARD) ligands and methods of use thereof
US11591290B2 (en) 2015-04-21 2023-02-28 University Of Tennessee Research Foundation Selective androgen receptor degrader (SARD) ligands and methods of use thereof
US12263141B2 (en) 2015-04-29 2025-04-01 Radius Pharmaceuticals, Inc. Methods for treating cancer
US11819480B2 (en) 2015-04-29 2023-11-21 Radius Pharmaceuticals, Inc. Methods for treating cancer
US11230523B2 (en) 2016-06-10 2022-01-25 University Of Tennessee Research Foundation Selective androgen receptor degrader (SARD) ligands and methods of use thereof
RU2795431C2 (ru) * 2016-06-10 2023-05-03 Юниверсити Оф Теннесси Рисёрч Фаундейшн Лиганды, селективно разрушающие андрогенные рецепторы (sard), и способы их применения
JP2021138780A (ja) * 2016-06-10 2021-09-16 ユニバーシティ オブ テネシー リサーチ ファウンデーション 選択的アンドロゲン受容体分解剤（ｓａｒｄ）リガンドおよびその使用方法
US11230531B2 (en) 2016-06-10 2022-01-25 University Of Tennessee Research Foundation Selective androgen receptor degrader (SARD) ligands and methods of use thereof
CN109310664A (zh) * 2016-06-10 2019-02-05 田纳西大学研究基金会 选择性雄激素受体降解剂(sard)配体和其使用方法
EP3468552A4 (fr) * 2016-06-10 2020-07-08 University of Tennessee Research Foundation Ligands de sard - composés de dégradation sélectifs de récepteurs des androgènes - et méthodes d'utilisation
JP7382987B2 (ja) 2016-06-10 2023-11-17 ユニバーシティ オブ テネシー リサーチ ファウンデーション 選択的アンドロゲン受容体分解剤（ｓａｒｄ）リガンドおよびその使用方法
US12215086B2 (en) 2016-06-10 2025-02-04 University Of Tennessee Research Foundation Selective androgen receptor degrader (SARD) ligands and methods of use thereof
JP2019522644A (ja) * 2016-06-10 2019-08-15 ユニバーシティ オブ テネシー リサーチ ファウンデーション 選択的アンドロゲン受容体分解剤（ｓａｒｄ）リガンドおよびその使用方法
US11771682B2 (en) 2016-06-22 2023-10-03 Ellipses Pharma Ltd. AR+ breast cancer treatment methods
US12329746B2 (en) 2016-06-22 2025-06-17 Ellipses Pharma Ltd AR+breast cancer treatment methods
US12398094B2 (en) 2017-01-05 2025-08-26 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCL
US10385008B2 (en) 2017-01-05 2019-08-20 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCL
US11708318B2 (en) 2017-01-05 2023-07-25 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCL
US11643385B2 (en) 2018-07-04 2023-05-09 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCl
US12202815B2 (en) 2018-09-05 2025-01-21 University Of Tennessee Research Foundation Selective androgen receptor degrader (SARD) ligands and methods of use thereof
WO2025067483A1 (fr) * 2023-09-28 2025-04-03 中国药科大学 Composés amides

Similar Documents

Publication Publication Date Title
WO2008044033A1 (fr) Dérivés d'amide
KR101227738B1 (ko) 유기 화합물
Amr et al. Anti-inflammatory profile of some synthesized heterocyclic pyridone and pyridine derivatives fused with steroidal structure
KR102616970B1 (ko) Ｐｒｍｔ５-매개성 질환의 치료 또는 예방에 유용한 화합물
AU2014234990B2 (en) Organic compounds
EP3053926B1 (fr) Composé de pyrimidine condensée, intermédiaire, procédé de préparation s'y rapportant et composition et application correspondantes
NZ522181A (en) 3-nitrogen-6,7-dioxygen steroids and uses related thereto
EP4368620A1 (fr) Composé servant d'inhibiteur de kat6
KR101070025B1 (ko) 신규의 17β-히드록시스테로이드 탈수소효소타입Ⅰ억제제들
DE102011083725A1 (de) Estra-1,3,5(10),16-tetraen-3-carboxamid-Derivate, Verfahren zu ihrer Herstellung, pharmazeutische Präparate die diese enthalten, sowie deren Verwendung zur Herstellung von Arzneimitteln
BR112015017963A2 (pt) composto de fenil amino pirimidina deuterado, método para preparar a composição farmacêutica, composição farmacêutica e uso do composto
CA2443721A1 (fr) Derives de sulfonamide
WO2024189598A2 (fr) Inhibiteurs de kat6a de type acylsulfonamides
CN111770924B (zh) 用于治疗乳腺癌的雌激素受体降解剂
CN107207561B (zh) 17β-HSD1–抑制剂的前药
CN107501279B (zh) 呋喃并喹啉二酮类化合物及其医药用途
WO2021179884A1 (fr) Dérivé d'acide oléanolique ayant un cycle c à structure diénique conjuguée, son procédé de préparation et son utilisation
JP2025520909A (ja) 二官能性化合物、該二官能性化合物を含む医薬組成物、およびこれらを使用したアンドロゲン受容体関連疾患の治療方法
WO2025091011A1 (fr) Composés organiques
WO2025091010A1 (fr) Composés organiques
JP7417608B2 (ja) １７－ｈｓｄ１阻害剤としての１６（１７）位でピラゾール環と縮合しているエストラ－１，３，５（１０）－トリエン化合物
JP2008538099A (ja) 新規なアデノシンａ３受容体調節剤
WO2025091037A1 (fr) Composés organiques
WO2024127343A1 (fr) Inhibiteurs de l'ectonucléotide pyrophosphatase/phosphodiestérase 1 (enpp-1)
US20080269266A1 (en) Novel compounds 747

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07824124

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07824124

Country of ref document: EP

Kind code of ref document: A1