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WO2008135824A1 - Composés d'oxyalkylpyrazole utiles en thérapie - Google Patents

Composés d'oxyalkylpyrazole utiles en thérapie Download PDF

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Publication number
WO2008135824A1
WO2008135824A1 PCT/IB2008/001048 IB2008001048W WO2008135824A1 WO 2008135824 A1 WO2008135824 A1 WO 2008135824A1 IB 2008001048 W IB2008001048 W IB 2008001048W WO 2008135824 A1 WO2008135824 A1 WO 2008135824A1
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Prior art keywords
compound
formula
alkyl
preparation
pharmaceutically acceptable
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Inventor
Paul Anthony Bradley
Kevin Neil Dack
Karl Richard Gibson
Cedric Poinsard
Alan Stobie
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Pfizer Ltd Great Britain
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Pfizer Ltd Great Britain
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with 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
    • C07D231/18—One oxygen or sulfur atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention relates to novel oxyalkylpyrazole compounds and their derivatives, which are useful in therapy, and to processes for their preparation. It also relates to intermediates used in the preparation of such compounds and derivatives, compositions containing them and their uses, for example their use in medicine.
  • a preferred use of the compounds is in the treatment of conditions alleviated by use of a progesterone receptor antagonist.
  • the compounds are useful in contraception, and the treatment of endometriosis, uterine fibroids and related conditions.
  • Endometriosis is a common gynaecological disease that affects 10-20% women of reproductive age and manifests itself in the presence of functional ectopic endometrial glands and stroma at locations outside the uterine cavity ⁇ Prentice, A. (2001). Bmj 323, 93-95. ⁇ . Patients with endometriosis may present with many different symptoms and severity. Most commonly this is dysmenorrhoea, but chronic pelvic pain, dyspareunia, dyschexia, menorrhagia, lower abdominal or back pain, infertility, bloating and pain on micturition are also part of the constellation of symptoms of endometriosis.
  • the Sampson theory proposes that the development of endometriosis is a consequence of retrograde dissemination and implantation of endometrial tissue into the peritoneal cavity during menstruation. Following attachment, the fragments of endometrium recruit a vascular supply and undergo cycles of proliferation and shedding under local and systemic hormonal controls. In women with patent fallopian tubes, retrograde menstruation appears to be a universal phenomenon ⁇ Liu, D. T. (Hitchcock, A.). British Journal of Obstetrics & Gynaecology 93, 859-862. ⁇ .
  • the disease often manifests itself as rectovaginal endometriosis or adenomyosis, ovarian cystic endometriomas and, most commonly, peritoneal endometriosis.
  • the major sites of attachment and lesion growth within the pelvis are the ovaries, broad and round ligaments, fallopian tubes, cervix, vagina, peritoneum and the pouch of Douglas.
  • endometriosis can cause profound structural modification to the peritoneal cavity, including multi-organ adhesions and fibrosis.
  • Symptomatic endometriosis can be managed medically and surgically, where the intention is to remove the ectopic lesion tissue.
  • Surgical intervention can be either conservative, aiming to preserve the reproductive potential of the patient, or comparatively radical for severe disease, involving dissection of the urinary tract, bowel, and rectovaginal septum, or total abdominal hysterectomy and bilateral salpingo-oopherectomy.
  • Medical pharmacological treatments such as the androgenic therapies, danazol and gestrinone, the constellation of GnRH agonists, buserelin, goserelin, leuprolide, nafarelin and triptorelin, GnRH antagonists, cetrorelix and abarelix, as well as the progestogens, including medroxyprogesterone acetate, induce lesion atrophy by suppressing the production of estrogen.
  • These approaches are not without unwanted side effects; danazol and gestrinone include weight gain, hirsuitism, acne, mood changes and metabolic effects on the cardiovascular system.
  • the group of GnRH agonists and antagonists are found to cause a profound suppression of estrogen leading to vasomotor effects (hot flashes) and depletion of bone mineral density, which restricts their use to only six months of therapy.
  • the group of progestogens including medroxyprogesterone acetate, suppress the gonadotropins, but do not down-regulate ovarian estrogen production to the same extent as the GnRH analogues.
  • the side effects include irregular bleeding, bloating, weight gain and metabolic effects on the cardiovascular system.
  • Steroidal progestins are commonly used in women's health, such as in contraception and hormone therapy and for the treatment of gynecological disorders. Recent studies in women and in nonhuman primates also indicate that progesterone receptor antagonists may have potential applications in contraception and for the treatment of reproductive disorders such as fibroids and endometriosis.
  • progesterone receptor agonists and antagonists are steroidal compounds. They often cause various side effects due to their functional interactions with other steroid receptors or because of effects associated with their steroidal metabolites ⁇ Winneker, Richard C. et al.; Endocrinology and Reproductive Disorders Division, Women's Health Research Institute, Collegeville, PA, USA. Seminars in Reproductive Medicine (2005), 23(1), 46-57 ⁇ .
  • Progesterone receptor antagonists [anti-progestins (APs)], including the founding members of the class mifepristone (RU-486; Roussel UCLAF, Romainville, France), onapristone (ZK 98 299; Schering AG), ZK 137 316 and ZK-230 211, are compounds that bind to the progesterone receptor (PR) and prevent progesterone- induced gene expression ⁇ Spitz, I. M. (2003). Steroids 68, 981-993. ⁇ .
  • APs anti-progestins
  • progesterone plays an essential role in the differentiation and ductal morphogenesis of endometrial tissue, but also participates in the inhibition of myometrial contractility and the polarisation of leukocyte Th1/Th2 responses that are critical for embryo implantation and the maintenance of pregnancy.
  • a number of studies have investigated the potential beneficial effects of anti-progestins on the signs and symptoms of endometriosis ⁇ Grow, D. R., et al. (1996). Journal of Clinical Endocrinology & Metabolism 81, 1933-1939.; Kettel, L. M., et al. (1996). Fertility & Sterility 65, 23-28.; Kettel, L.
  • Such anti-progestins induce amenorrhoea and endometrial compaction, and also appear to sufficiently protect against rapid oestrogen-dependent bone loss ⁇ Grow, D. R., et al. (1996). Journal of Clinical Endocrinology & Metabolism 81, 1933-1939. ⁇ .
  • GnRH analogues cause a rapid loss in bone mineral density, a clinical feature which limits their treatment duration to 6 months.
  • mifepristone is a potent anti-progestin, it also has equipotent anti-glucocorticoid activity. Outside of a palliative treatment of hypercortisolism for Cushing's syndrome ⁇ Chu, J. W., et al. (2001).
  • a further class of steroidal and non-steroidal compounds termed the progesterone receptor modulators (PRMs, or mesoprogestins), including asoprisnil (J867, benzaldehyde, 4-[(11 ⁇ , 17 ⁇ )-17-methoxy-17-(methoxymethyl)-3-oxoestra-4,9-dien- 11-yl]-, 1-oxime; Jenpharm, TAP), J912, J956, J1042, have also been described. In addition to their potential utility in hormone replacement and as contraceptives, these classes of compounds could be considered to have utility in the treatment of endometriosis and uterine leiomyoma ⁇ Chwalisz, K., et al. (2004).
  • PRMs progesterone receptor modulators
  • the compounds of the present invention have been found to have potentially useful pharmaceutical properties. They may be used to treat conditions such as endometriosis, uterine fibroids (leiomyomata) and menorrhagia, adenomyosis, primary and secondary dysmenorrhoea (including symptoms of dyspareunia, dyschexia and chronic pelvic pain), chronic pelvic pain syndrome, precocious puberty, cervical ripening, contraception (emergency), breast carcinoma, ovarian carcinoma, endometrial carcinoma, prostate carcinoma, pulmonary carcinoma, testicular carcinoma, gastric carcinoma, meningioma, anxiety, premenstrual syndrome, premenstrual dysphoric disorder, alcohol abuse and reward, or Charcot-Marie-Tooth disease.
  • endometriosis uterine fibroids (leiomyomata) and menorrhagia
  • adenomyosis adenomyosis
  • primary and secondary dysmenorrhoea including symptoms of dyspar
  • the compounds and derivatives of the present invention exhibit activity as progesterone receptor antagonists and may be useful for treatment where progesterone receptor antagonism is indicated.
  • the compounds and derivatives of the present invention may be useful for treating endometriosis and/or uterine fibroids (leiomyomata).
  • Certain of the compounds disclosed in these 5 applications may be metabolised in vivo to provide certain of the compounds (IA and IB) of this invention in vivo.
  • This invention does not include such compounds when produced in vivo by metabolism of those compounds of the 5 above-mentioned applications. Nor does this invention include prodrugs of the compounds of formula (IA and IB) which are already disclosed in the 5 above-mentioned applications.
  • R 1 and R 2 are independently selected from H, C- ⁇ -6 alkyl, Ci -6 alkyloxy, CN, and halo, wherein Ci -6 alkyl and Ci -6 alkyloxy are independently optionally substituted by one or more halogen;
  • R 3 is independently H or Ci -6 alkyl optionally substituted by one or more halogen
  • R 4 is independently H or Ci. 6 alkyl optionally substituted by one or more halogen; or R 3 and R 4 can be taken together with the carbon atom to which they are attached to form a C 3 -C 6 cycloalkyl ring, optionally substituted by one or more halogen;
  • R 5 is Ci -6 alkyl, Ci -6 alkyloxy, C 3-8 cycloalkyl, or halo, wherein Ci -6 alkyl and C 3- s cycloalkyl are optionally substituted by one or more fluorine and/or nitrile groups;
  • R 6 is H, Ci -6 alkyl, or C 3-S cycloalkyl, or a group of formula
  • Ci -6 alkyl and C 3-8 cycloalkyl are optionally substituted by one or more substituents independently selected from CN, halogen, Ci -4 alkoxy (optionally substituted by one or more fluorine atoms), CONR 9 R 10 , S(O) y R 8 and OH;
  • R 8 is Ci -6 alkyl or CF 3 ;
  • y is 0, 1 or 2;
  • R 9 and R 10 are each independently H, Ci_ 6 aikyl or C 3-6 cycloalkyl, X represents -C(O)- or -S(O) 2 - W represents Ci -4 alkyl or CF 3 ; m and n are independently 0, 1 , 2, or 3 provided that m + n is not more than 3;
  • M represents O 1 S, S(O) or SO 2 ;
  • p and q independently can be O, 1 , 2 or 3, provided that p + q is not more than 3; or
  • R 6 is CH 2 aryl wherein aryl is phenyl or a 5- or 6-membered heteroaryl group containing at least one ring hetero atom, selected from up to 3 N atoms, one O atom and one S atom, which phenyl or heteroaryl group is optionally substituted by up to 3 substituents independently selected from CN, halogen or Ci -4 alkyl optionally substituted by one or more halogen; and Y is H or an alcohol prodrug moiety which can cleave in vivo to release the compound of formula (IA) or (IB) where O-Y is O-H.
  • R 1 and R 2 are independently selected from H, Ci -6 alkyl optionally substituted by one or more halogen, Ci -6 alkyloxy optionally substituted by one or more halogen, CN, and halo;
  • R 3 is independently H or Ci -6 alkyl optionally substituted by one or more halogen;
  • R 4 is independently H or Ci- 6 alkyl optionally substituted by one or more halogen; or R 3 and R 4 can be taken together with the carbon atom to which they are attached to form a C 3 -C 6 cycloalkyl ring optionally substituted by one or more halogen;
  • R 5 is C- I-6 alkyl optionally substituted by one or more fluorine and/or nitrile groups,
  • R 6 is H 1 C- I-6 alkyl or C 3-S cycloalkyl (optionally substituted by one or more substituents independently selected from CN, halogen, Ci -4 alkoxy optionally substituted by one or more fluorine atoms, CONR 9 R 10 , S(O) y R 8 and OH), R 8 is Ci -6 alkyl or CF 3 , y is O, 1 or 2, R 9 and R 10 are each independently H, Ci -6 alkyl or C 3-6 cycloalkyl, or a group of formula
  • X represents -C(O)- or -S(O) 2 -
  • W represents Ci -4 alkyl or CF 3
  • m and n are independently 0, 1 , 2, or 3 provided that m+n is not more than 3, or a group of formula
  • M represents O 1 S, S(O) or SO 2 ;
  • p and q independently can be O, 1 , 2 or 3 provided that p+q is not more than 3, or
  • R 6 is CH 2 aryl wherein aryl is phenyl or a 5- or 6-membered heteroaryl group containing at least one ring heteroatom, selected from up to 3 N atoms, one O atom and one S atom, which phenyl or heteroaryl group is optionally substituted by up to 3 substituents independently selected from CN, halogen or Ci -4 alkyl optionally substituted by one or more halogen; and Y is H or an alcohol prodrug moiety which can cleave in vivo to release the compound of formula (IA') or (IB') where O-Y is O-H.
  • Alcohol prodrug moieties at the "Y" position in compounds of formula (IA) and (IB) include any group that increases solubility, and which cleaves in vivo to unmask the alcohol.
  • groups envisioned in this invention include the following:
  • Y -P(O)(OH) 2 , -P(O)O 2 Na 2 , -P(O)O 2 K 2 , -P(O)O 2 Mg, -P(O)O 2 Ca, -P(O)O 2 (NH 4 ) 2 , -P(O)(OO(OCH 2 CH 2 (NH) + S , -P(O)(OO(OCH 2 CH 2 (NMe) + S, -CH 2 OP(O)(OH) 2 or salts thereof, -SO 3 Na 2 , -SO 3 Mg, -SO 3 K 2 , -SO 3 Ca, -SO 3 (NH 4 ) 2 , -CH 2 OSO 3 Na 2 , -CH- 2 OSO 3 K 2 , , -CHO, acetyl, -C(O)CF 3 , -C(O)CH 2 CH 3 , -C(O)CH 2 CH 2 CH 3 , - C(O)CH
  • compositions comprising a compound of Formula (IA) and (IB), and the pharmaceutically acceptable salts, solvates (including hydrates), and prodrugs thereof, and a pharmaceutically acceptable carrier.
  • R 1 is H, Cl 1 Ci -3 alkyl (optionally substituted by one or more halogen) or
  • Ci- 3 alkyloxy (optionally substituted by one or more halogen).
  • R 1 is H, Cl, CH 3 , CF 3 , OCF 3 or OCH 3 .
  • R 1 is CH 3 .
  • R 2 is H, Cl, Cr -3 alkyl (optionally substituted by one or more halogen) or
  • Ci- 3 alkyloxy (optionally substituted by one or more halogen).
  • R 2 is H, Cl, CH 3 , CF 3 , OCF 3 or OCH 3 .
  • R 2 is CH 3 .
  • both R 1 and R 2 are independently selected from H, Cl, CH 3 ,
  • R 1 is H and R 2 is CH 3 , R 1 is H and R 2 is Cl,
  • R 1 is H and R 2 is CF 3 ,
  • R 1 is H and R 2 is OCH 3 , and
  • R 1 and R 2 are both CH 3 .
  • R 3 is H or Ci -6 alkyl. More preferably R 3 is H or methyl.
  • R 3 is H.
  • R 4 is H or Ci_ 6 alkyl. More preferably R 4 is H or methyl. Most preferably R 4 is H.
  • both R 3 and R 4 are H.
  • Y is H or -P(O)O 2 H 2 , -P(O)O 2 Na 2 , -P(O)O 2 K 2 . Even more preferably Y is H or P(O)(OH) 2 Most preferably Y is H.
  • R 5 is Ci_6 alkyl or C 3- s cycloalkyl. More preferably R 5 is Ci -4 alkyl or C 3-4 cycloalkyl. Yet more preferably R 5 is C 3-4 alkyl or C 3-4 cycloalkyl.
  • R 5 is isopropyl, cyclopropyl or cyclobutyl. Most preferably R 5 is cyclopropyl.
  • R 6 is H, Ci -6 alkyl or C 3-8 cycloalkyl (optionally substituted by one or more substituents independently selected from CN, halogen, Ci -4 alkoxy optionally substituted by one or more fluorine atoms, CONR 9 R 10 , S(O) y R 8 and OH), or a group of formula
  • R 6 is H, C 1-6 alkyl, CH 2 SO 2 R 8 , CH 2 CONR 9 R 10 , or a group of formula
  • R 6 is H, methyl, CH 2 SO 2 CH 3 , CH 2 CONHCH 3 , or a group of formula
  • a preferred group of compounds, pharmaceutically acceptable salts, solvates (including hydrates), and prodrugs thereof are those wherein R 1 is H, Cl, CF 3 , CH 3 , CF 3 or OCF 3 ; R 2 is H, Cl, CF 3 , CH 3 , CF 3 or OCF 3 ; R 3 is H or methyl; R 4 is H or methyl; Y is H; R 5 is isopropyl, cyclopropyi, or cyclobutyl; and
  • R 6 is H, methyl, CH 2 SO 2 CH 3 , CH 2 CONHCH 3 , or a group of formula
  • R 1 is methyl and R 2 is methyl.
  • alkyl groups containing the requisite number of carbon atoms can be unbranched or branched chain. Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Examples of alkyloxy include methoxy, ethoxy, n-propyloxy, i-propyloxy, n- butyloxy, i-butyloxy, sec-butyloxy and t-butyloxy.
  • cycloalkyl examples include cyclopropyi, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • halogen means fluoro, chloro, bromo or iodo.
  • Groups such as "alkyl optionally substituted by one or more halogen" and groups containing such, can include per-halo groups, for instance CF 3 .
  • substantially pure form is meant that the invention does not include compounds as produced by in vivo metabolism of prior art compounds, such as those prior art compounds mentioned herein. Levels of purity are preferably more than 10%, more preferably more than 90%, yet more preferably more than 95%, most preferably more than 99%.
  • a further embodiment is a purity level acceptable to good manufacturing practice (GMP) common in pharmaceutical manufacturing practice.
  • Pharmaceutically acceptable derivatives of the compounds of formula (IA and IB) according to the invention include salts, solvates, complexes, polymorphs and crystal habits thereof, prodrugs, stereoisomers, geometric isomers, tautomeric forms, and isotopic variations of compounds of formula (IA and IB).
  • pharmaceutically acceptable derivatives of compounds of formula (IA and IB) comprise salts, solvates, esters and amides of the compounds of formula (IA and IB). More preferably, pharmaceutically acceptable derivatives of compounds of formula (IA and IB) are salts, prodrugs and solvates.
  • the pharmaceutically acceptable salts of the compounds of formula (IA and IB) and their prodrugs include the acid addition and base salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, ste
  • Suitable base salts are formed from bases that form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • Hemi-salts of acids and bases may also be formed, for example, hemi-sulphate and hemicalcium salts.
  • salts of compounds of formula IA or IB may be prepared by one or more of three methods:
  • salts of prodrugs of compounds of formula IA or IB can be prepared in an analogous manner.
  • the substances of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline.
  • the term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid.
  • Such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid.
  • a change from solid to liquid properties occurs which is characterised by a change of state, typically second order ('glass transition').
  • 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks.
  • Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order ('melting point').
  • the compounds, salts and prodrugs of the invention may also exist in unsolvated and solvated forms.
  • the term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • the term 'hydrate' is employed when said solvent is water.
  • Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules.
  • channel hydrates the water molecules lie in lattice channels where they are next to other water molecules.
  • metal-ion coordinated hydrates the water molecules are bonded to the metal ion.
  • the complex When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
  • multi-component complexes other than salts and solvates
  • complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents
  • Co-crystals may be prepared by melt crystallisation, by recrystallisation from solvents, or by physically grinding the components together - see Chem Commun, .17, 1889-1896, by O. Almarsson and M. J. Zaworotko (2004).
  • Chem Commun, .17, 1889-1896 by O. Almarsson and M. J. Zaworotko (2004).
  • the compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions.
  • the mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution).
  • Mesomorphism arising as the result of a change in temperature is described as 'thermotropic' and that resulting from the addition of a second component, such as water or another solvent, is described as 'lyotropic'.
  • Compounds that have the potential to form lyotropic mesophases are described as 'amphophilic' and consist of molecules which possess an ionic (such as -COO " Na + , -COO " K + , or -SO 3 " Na + ) or non-ionic (such as -N " N + (CH 3 ) 3 ) polar head group.
  • ionic such as -COO " Na + , -COO " K + , or -SO 3 " Na +
  • non-ionic such as -N " N + (CH 3 ) 3
  • references to compounds of formula (IA and IB) include references to salts, solvates, multi-component complexes, prodrugs, liquid crystals, etc. thereof and to solvates, multi-component complexes and liquid crystals of salts thereof, etc.
  • 'prodrugs' of the compounds of formula (IA and IB) are also within the scope of the invention.
  • certain derivatives of compounds of formula (IA or IB) which may have little or no pharmacological activity themselves, can be converted into compounds of formula IA or IB having the desired activity, for example by hydrolytic cleavage, when administered into, or onto, the body.
  • Such derivatives are referred to as 'prodrugs'.
  • Further information on the use of prodrugs may be found in "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and "Bioreversible Carriers in Drug Design", Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association).
  • Prodrugs in accordance with the invention can be produced by replacing appropriate functionalities present in the compounds of formula (IA or IB) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in "Design of Prodrugs” by H. Bundgaard (Elsevier, 1985).
  • Some examples of prodrugs in accordance with the invention include
  • the compound of formula (IA or IB) contains an alcohol functionality (for example where OY is OH), an ether thereof, for example, a compound wherein the hydrogen of the alcohol functionality of the compound of formula (IA or IB) is replaced by (Ci-C 6 )alkanoyloxymethyl; the specific alcohol ester prodrug moieties mentioned in Current Drug Metabolism, 2003, vol 4, no 6, 461-485, herein incorporated by reference; and
  • the compound of formula (IA or IB) contains a primary or secondary amino functionality (-NH 2 or -NHR where R ⁇ H), an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound of formula (IA or IB) is/are replaced by (Ci-Ci 0 )alkanoyl.
  • prodrugs may be prepared by the methods set out in Scheme 3 of the general methods and/or by the methods laid out in WO 99/33815.
  • metabolites of compounds of formula (IA or IB) that is, compounds formed in vivo upon administration of the drug.
  • the metabolites of the compounds of formula (IA or IB) when formed in vivo.
  • Compounds of formula (IA or IB) or derivative herein defined containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of formula (IA or IB) or derivative contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of formula (IA or IB) or derivative containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
  • Cisltrans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (IA or IB) or derivative contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of formula (IA or IB) or derivative contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture. When any racemate crystallises, crystals of two different types are possible.
  • the first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts.
  • the second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.
  • Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel and S. H. Wilen (Wiley, 1994).
  • the present invention includes all pharmaceutically acceptable isotopically- labelled compounds of formula (IA or IB) or derivatives herein defined, wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • isotopically-labelled compounds of formula (IA or IB) or derivative herein defined are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically-labelled compounds of formula (IA or IB) or derivatives herein defined can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopicaily- labelled reagent in place of the non-labelled reagent previously employed.
  • solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, de-acetone, d ⁇ -DMSO.
  • the compounds of formula (IA or IB) or their derivatives herein defined should be assessed for their biopharmaceutical properties, such as solubility and solution stability (across pH), permeability, ete., in order to select the most appropriate dosage form and route of administration for treatment of the proposed indication.
  • Compounds IA and IB and derivatives herein defined of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
  • the compounds IA or IB and derivatives of the invention may be administered alone or in combination with one or more other compounds or derivatives of the invention or in combination with one or more other drugs (or as any combination thereof).
  • the compounds IA and IB and derivatives of the present invention may be administered in combination with COX inhibitors.
  • a pharmaceutical product containing a progesterone receptor antagonist and one or more COX inhibitors as a combined preparation for simultaneous, separate or sequential use in the treatment of endometriosis.
  • COX inhibitors useful for combining with the compounds IA or IB and derivatives thereof of the present invention include, but are not limited to:
  • celecoxib (US Patent No. 5,466,823), valdecoxib (US Patent No. 5,633,272), deracoxib (US Patent No. 5,521 ,207), rofecoxib (US Patent No. 5,474,995), etoricoxib (International Patent Application Publication No. WO 98/03484), JTE-522 (Japanese Patent Application Publication No. 9052882), or a pharmaceutically acceptable salt or prodrug thereof;
  • Parecoxib (described in U.S. Patent No. 5,932,598), which is a therapeutically effective prodrug of the tricyclic Cox-2 selective inhibitor valdecoxib (described in U.S. Patent No. 5,633,272), in particular sodium parecoxib; (v) ABT-963 (described in International Patent Application Publication No. WO 00/24719)
  • Nimesulide (described in U.S. Patent No. 3,840,597), flosulide (discussed in J. Carter, Exp.Qpin.Ther.Patents, 8(1), 21-29 (1997)), NS-398 (disclosed in U.S. Patent No. 4,885,367), SD 8381 (described in U.S. Patent No.
  • T-614 (Toyama), D-1367 (Chiroscience), L-748731 (Merck), CT3 (Atlantic
  • the compounds of formula IA or IB and derivatives of the present invention may be administered in combination with PDE5 inhibitors.
  • a pharmaceutical product containing a compound IA or IB or derivative as herein defined and one or more PDEV inhibitors as a combined preparation for simultaneous, separate or sequential use in the treatment of endometriosis.
  • PDEV inhibitors useful for combining with compounds of formula IA or IB and derivatives herein defined of the present invention include, but are not limited to: ( i ) Preferably 5-[2-ethoxy-5-(4-methyl-1 -piperazinylsulphonyl)phenyl]-1 - methyl-3-n-propyl-1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil, e.g.
  • the PDEV inhibitor is selected from sildenafil, tadalafil, vardenafil, DA- 8159 and 5-[2-ethoxy-5-(4-ethylpiperazin-1 -ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2- methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.
  • the PDE5 inhibitor is sildenafil and pharmaceutically acceptable salts thereof. Sildenafil citrate is a preferred salt.
  • the compounds IA and IB and derivatives herein defined of the present invention may be administered in combination with a Via antagonist.
  • a pharmaceutical product containing a compound IA or IB or derivative herein defined and one or more Via antagonists as a combined preparation for simultaneous, separate or sequential use in the treatment of endometriosis.
  • vasopressin Via receptor antagonist is, for example, (4-[4-Benzyl-5-(4- methoxy-piperidin-1-ylmethyl)-4H-[1 ,2,4]triazol-3-yl]-3,4,5,6-tetrahydro-2H-
  • vasopressin Via receptor antagonist is 8-chloro-5-Methyl-1-(3,4,5,6- tetrahydro-2H-[1 ,2']bipyridinyl-4-yl)-5,6-dihydro-4H-2, 3,5,1 Ob-tetraazo- benzo[e]azulene, or a pharmaceutically acceptable salt or solvate thereof, which is Example 5 in WO 04/074291.
  • vasopressin Via receptor antagonists for use with the invention are: SR49049 (Relcovaptan), atosiban (Tractocile ® ), conivaptan (YM- 087), VPA-985, CL-385004, Vasotocin and OPC21268. Additionally, the Via receptor antagonists described in WO 01/58880 are suitable for use in the invention.
  • the compound IA or IB or derivative as herein defined of the present invention may be administered in combination with an alpha adrenergic receptor antagonist (also known as ⁇ -adrenoceptor blocker, ⁇ -receptor blocker or ⁇ -blocker).
  • an alpha adrenergic receptor antagonist also known as ⁇ -adrenoceptor blocker, ⁇ -receptor blocker or ⁇ -blocker.
  • ⁇ -i-Adrenergic receptor antagonists useful for the present invention include, but are not limited to, terazosin (US Patent No. 4,026,894), doxazosin (US Patent No. 4,188,390), prazosin (US Patent No. 3,511 ,836), bunazosin (US Patent No. 3,920,636), alfuzosin (US Patent No. 4,315,007), naftopidil (US Patent No. 3,997,666), tamsulosin (US Patent No. 4,703,063), silodosin (US Patent No. 5,387,603), phentolamine and phentolamine mesylate (US Patent No.
  • WO 03/076427 in particular 5-cyclopropyl-7-methoxy-2-(2- morpholin-4-ylmethyl-7,8-dihydro[1 ,6]-naphthyridin-6(5H)-yl)-4(3H)-quinazolinone (example 11), and the compounds disclosed in International Application Publication No. WO 98/30560 in particular 4-amino-6,7-dimethoxy-2-(5- methanesulfonamido-1 ,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline
  • ⁇ - adrenergic receptor antagonists are doxazosin, 5-cyclopropyl-7-methoxy-2-(2- morpholin-4-ylmethyl-7,8-dihydro[1 ,6]-naphthyridin-6(5H)-yl)-4(3H)-quinazolinone and 4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1 ,2,3,4-tetrahydroisoquinol- 2-yl)-5-(2-pyridyl)quinazoline and pharmaceutically acceptable derivatives thereof.
  • ⁇ 2 -Adrenergic receptor antagonists suitable for the present invention include dibenamine (DE 824208), tolazoline (US Patent No. 2,161 ,938), trimazosin (US Patent No. 3,669,968), efaroxan (EP 71368), yohimbine (MR Goldberg et al, Pharmacol. Rev. 35, 143-180 (1987)), idazoxan (EP 33655), and clonidine (US Patent No. 3,202,660);
  • Non-selective ⁇ -adrenergic receptor antagonists suitable for the present invention include dapiprazole (US Patent No. 4,252,721 );
  • the compound IA or IB or derivative as herein defined may be administered in combination with an 5-alpha reductase inhibitor.
  • a pharmaceutical product containing a compound IA or IB or derivative as herein defined and one or more 5-alpha reductase inhibitors as a combined preparation for simultaneous, separate or sequential use in the treatment of endometriosis.
  • 5-alpha reductase inhibitors include inhibitors of 5-alpha reductase isoenzyme 2.
  • Suitable compounds for use in the present invention are PROSCAR ® (also known as finasteride, US Patent 4,377,584 and 4,760,071), compounds described in WO 93/23420, EP0572166, WO 93/23050, WO 93/23038, WO 93/23048, WO 93/23041 , WO 93/23040, WO 93/23039, WO 93/23376, WO 93/23419, EP0572165, and WO 93/23051.
  • the compound IA or IB or derivative as herein defined of the present invention may be administered in combination with an agent which lowers estrogen levels, or which antagonises the estrogen receptor.
  • an agent which lowers estrogen levels, or which antagonises the estrogen receptor may be administered in combination with an agent which lowers estrogen levels, or which antagonises the estrogen receptor.
  • a pharmaceutical product containing a compound IA or IB or derivative as herein defined and one or more agents which lower estrogen levels, or antagonise the estrogen receptor, as a combined preparation for simultaneous, separate or sequential use in the treatment of endometriosis.
  • Agents which lower estrogen levels include gonadotropin releasing hormone (GnRH) agonists, GnRH antagonists and estrogen synthesis inhibitors.
  • Agents which antagonise the estrogen receptor, i.e. estrogen receptor antagonists, include anti-estrogens.
  • GnRH agonists suitable for the present invention include leuprorelin (Prostap - Wyeth), buserelin (Suprefact - Shire), goserelin (Zoladex - Astra Zeneca), triptorelin (De-capeptyl - Ipsen), nafarelin (Synarel - Searle), deslorelin (Somagard - Shire), and histrelin/supprelin (Ortho Pharmaceutical Corp/Shire).
  • GnRH antagonists suitable for the present invention include teverelix (also known as antarelix), abarelix (Plenaxis - Praecis Pharmaceuticals Inc.), cetrorelix (Cetrotide - ASTA Medica), and ganirelix (Orgalutran - Organon).
  • Anti-estrogens suitable for the present invention include tamoxifen, Faslodex (Astra Zeneca), idoxifene (see Coombes et al. (1995) Cancer Res. 55, 1070- 1074), raloxifene or EM-652 (Labrie, F et al, (2001) J steroid Biochem MoI Biol, 79, 213).
  • Estrogen synthesis inhibitors suitable for the present invention include aromatase inhibitors.
  • aromatase inhibitors include Formestane (4-OH androstenedione), Exemestane, Anastrozole (Arimidex) and Letroxole.
  • the compound IA or IB or derivative as herein defined of the present invention may be administered in combination with an alpha-2-delta ligand.
  • a pharmaceutical product containing a compound IA or IB or derivative as herein defined and one ore more alpha-2-delta ligands, as a combined preparation for simultaneous, separate or sequential use in the treatment of endometriosis.
  • aipha-2-delta ligands for use in the present invention are those compounds, or pharmaceutically acceptable salts thereof, generally or specifically disclosed in US4024175, particularly gabapentin, EP641330, particularly pregabalin, US5563175, WO-A-97/33858, WO-A-97/33859, WO-A-99/31057, WO- A-99/31074, WO-A-97/29101 , WO-A-02/085839, particularly [(1 R,5R,6S)-6- (aminomethyl)bicyclo[3.2.0]hept ⁇ 6-yl]acetic acid, WO-A-99/31075, particularly 3- (1 -aminomethyl-cyclohexylmethyl)-4H-[1 ,2,4]oxadiazoI-5-one and C-[1 -(1 H- tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, WO-A-99/218
  • Preferred alpha-2-delta ligands for use in the combination of the present invention include: gabapentin, pregabalin, [(1 R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6- yl]acetic acid, 3-(1-aminomethyl-cyclohexylmethyl)-4H-[1 ,2,4]oxadiazol-5-one, C-
  • alpha-2-delta ligands for use in the combination of the present invention are (3S,5R)-3-amino-5-methyloctanoic acid, (3S,5R)-3-amino-5- methylnonanoic acid, (3R,4R,5R)-3-amino-4,5-dimethylheptanoic acid and (3R,4R,5R)-3-amino-4,5-dimethyloctanoic acid, and the pharmaceutically acceptable salts thereof.
  • alpha-2-delta ligands for use in the combination of the present invention are selected from gabapentin, pregabalin, (1 ⁇ ,3 ⁇ ,5 ⁇ )(3-amino- methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (2S,4S)-4-(3-chlorophenoxy)proline and (2S,4S)-4-(3-fluorobenzyl)proline or pharmaceutically acceptable salts thereof.
  • the compound IA or IB or derivative as herein defined of the present invention may be administered in combination with an oxytocin receptor antagonist.
  • a pharmaceutical product containing a compound IA or IB or derivative as herein defined and one or more oxytocin antagonists, as a combined preparation for simultaneous, separate or sequential use in the treatment of endometriosis.
  • oxytocin receptor antagonists suitable for the present invention are atosiban (Ferring AB), barusiban (Ferring AB), TT-235 (Northwestern University), and AS-602305 (Serono SA).
  • the compounds of the present invention may also be administered in combination with any one or more of the following
  • Aromatase inhibitor (i) Aromatase inhibitor; (ii) Estrogen receptor agonist;
  • Microtubule modulator e.g. Microtubule stabilizer
  • Topoisomerase I inhibitor e.g. Topoisomerase I inhibitor
  • Metalloprotease inhibitor e.g. Metalloprotease inhibitor
  • Progesterone modulator e.g. Progesterone modulator.
  • Microtubule modulator e.g. Microtubule stabilizer
  • compounds IA or IB or derivatives as herein defined of the invention will be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • excipient is used herein to describe any ingredient other than the compound(s) of the invention.
  • the choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • compositions suitable for the delivery of compounds IA or IB or derivatives as herein defined of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in "Remington's Pharmaceutical Sciences", 19th Edition (Mack Publishing Company, 1995).
  • the compounds IA or IB or derivatives as herein defined of the invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid, semi-solid and liquid systems such as tablets; soft or hard capsules containing multi- or nano- particulates, liquids, or powders; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesive patches.
  • Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the compounds IA or IB or derivatives as herein defined of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, IJ. (6), 981-986, by Liang and Chen (2001).
  • the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form.
  • tablets generally contain a disintegrant.
  • disintegrants examples include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate.
  • the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • lactose monohydrate, spray-dried monohydrate, anhydrous and the like
  • mannitol xylitol
  • dextrose sucrose
  • sorbitol microcrystalline cellulose
  • starch dibasic calcium phosphate dihydrate
  • Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • surface active agents such as sodium lauryl sulfate and polysorbate 80
  • glidants such as silicon dioxide and talc.
  • surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.
  • Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet.
  • ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.
  • Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.
  • Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting.
  • the final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.
  • Consumable oral films are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound IA or IB or derivative as herein defined, a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one function.
  • the film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %.
  • ingredients include anti-oxidants, colorants, flavourings and flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents.
  • Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze- drying or vacuuming.
  • Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in "Pharmaceutical Technology On-line", 25(2), 1-14, by Verma et a/ (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.
  • the compound IA or IB or derivative as herein defined of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle- free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9)
  • a suitable vehicle such as sterile, pyrogen-free water.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • the solubility of compounds IA or IB or derivatives as herein defined used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • compounds of the invention may be formulated as a suspension or as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and semi-solids and suspensions comprising drug-loaded poly(d/-lactic-coglycolic)acid (PGLA) microspheres.
  • PGLA poly(d/-lactic-coglycolic)acid
  • the compounds IA or IB or derivatives as herein defined of the invention may also be administered topically, (intra)dermally, or transdermal ⁇ to the skin or mucosa.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999).
  • topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. PowderjectTM, BiojectTM, etc.) injection.
  • Formulations for topical administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds IA or IB or derivatives as herein defined of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler, as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3- heptafluoropropane, or as nasal drops.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 ⁇ g to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 ⁇ l to 100 ⁇ l.
  • a typical formulation may comprise a compound IA or IB or derivative as herein defined, propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
  • Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds IA or IB or derivatives as herein defined of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds IA or IB or derivatives as herein defined of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
  • Drug-cyclodextrin complexes are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.
  • compositions at least one of which contains a compound IA or IB or derivative as herein defined in accordance with the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions.
  • the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound IA or IB or derivative as herein defined in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • a container, divided bottle, or divided foil packet An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
  • the kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit typically comprises directions for administration and may be provided with a so-called memory aid.
  • the total daily dose of the compound IA or IB or derivative as herein defined of the invention is typically in the range ⁇ 1mg to 1000 mg depending, of course, on the mode of administration.
  • oral administration may require a total daily dose of from ⁇ 1 mg to 1000 mg, while an intravenous dose may only require from ⁇ 1 mg to 500 mg.
  • the total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein.
  • These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
  • treating means to alleviate symptoms, eliminate the causation either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms.
  • treatment includes alleviation, elimination of causation (either on a temporary or permanent basis) of, or prevention of symptoms and disorders associated with endometriosis and/or uterine leiomyoma.
  • the treatment may be a pre-treatment as well as a treatment at the on-set of symptoms.
  • the compounds of the present invention should be useful for the treatment of gynaecological symptoms of painful menstruation (dysmenorrhoea), painful intercourse (dyspareunia), painful defaecation (dyzchexia) or micturition (dysuria) provoked by menstruation, chronic pelvic pain (constant or cyclic painful symptoms present for more than six months), excessive menstrual blood loss (menorrhagia), frequent periods (polymenorrhagia) or infrequent or irregular periods (oligoamenorrhoea or amenorrhoea) either occurring in the absence of specific pathology (dysfunctional uterine bleeding and/or primary dysmenorrhoea), or in association with endometriosis, adenomyosis, polycystic ovarian syndrome, or uterine fibroids (leiomyomata).
  • treatment encompasses not only the management of the pain symptoms associated with the abovementioned conditions, but also modification of the disease progression itself, i.e. a clinically meaningful benefit to the patients is achieved.
  • Modification of disease progression may result in reduction or elimination of pain. More preferably, modification of disease progression may result in reduction or elimination of pain, and prolonged intervals to symptom onset. Even more preferably, modification of disease progression may result in reduction or elimination of pain, prolonged intervals to symptom onset, and reduction in the need for surgery. Most preferably, modification of disease progression may result in reduction or elimination of pain, prolonged intervals to symptom onset, a reduction in the need of surgery, and preserved and/or improved fertility.
  • the compounds IA or IB or derivatives as herein defined of the present invention may be tested in the screens set out below:
  • the assay for PR antagonism takes advantage of the extensively reported modulation of alkaline phosphatase (AP) expression in human breast T47D mammary carcinoma cells ⁇ Beck et al., D. P. (1993).
  • the progesterone antagonist RU486 acquires agonist activity upon stimulation of cAMP signalling pathways. Proc Natl Acad Sci USA 90, 4441-4445; Fensome et al. (2002). New progesterone receptor antagonists: 3,3-disubstituted-5-aryloxindoles. Bioorg Med Chem Lett 12, 3487-3490; Zhang et al., (2002a).
  • 6-Aryl-1 ,4-dihydro-benzo d 1 ,3 oxazin- 2-ones a novel class of potent, selective, and orally active nonsteroidal progesterone receptor antagonists. Journal of Medicinal Chemistry 45, 4379-4382; Zhang et al., (2003). Novel 6-aryl-1,4-dihydrobenzo d oxazine-2-thiones as potent, selective, and orally active nonsteroidal progesterone receptor agonists. Bioorganic & Medicinal Chemistry Letters 13, 1313-1316; Zhang et al., (2002b). Potent nonsteroidal progesterone receptor agonists: synthesis and SAR study of 6-aryl benzoxazines.
  • Assay medium DMEM - Red (31053-028)
  • T47D cells are grown by propagating in DMEM with phenol red + 10% FCS + 2 mM Glutamine at 37°C/5% CO 2 .
  • the media is exchanged for phenol red free DMEM + 5% CS-FCS (Assay media).
  • Cells are incubated overnight in assay media then harvested and frozen in assay media containing 10% DMSO at 1.5e7 cells/mL in 2 mL aliquots using a Planer and immediately stored in liquid nitrogen. Vials are removed from liquid nitrogen storage and immediately thawed in a water bath at 37 0 C.
  • the cell suspension is added dropwise to 20 ml_ of assay media, then the tube centrifuged at 1000 rpm for 4 minutes, the supernatant is discarded and the pellet re-suspended in 20 ml_ assay media.
  • T47D cells are then plated at 8750 cells/well in 35 ⁇ L assay media in sufficient white solid 384 well TC plates for the assay.
  • For the agonist format assay a further 10 ⁇ L of assay media is added to each well. These plates are then cultured for 3-6 hours at 37°C/5% CO 2 before compound addition.
  • Test substances are prepared by in 100% DMSO 1 half log concentrations from 4 mM in 384 well plates 5 ⁇ L / well (referred to here as 'grandmother plates').
  • Progesterone is 100 ⁇ M made up in ethanol and PBS (i.e. add 1 mL ethanol to progesterone initially to help dissolving) and stored in 0.5-1 mL aliquots at -20 0 C.
  • Max's & Min's are prepared as below in Falcon tubes and then 100 ⁇ L is transferred to the appropriate wells of a 384 well plate:
  • Agonist Max (solid block on plate map) 10 uM progesterone (FAC 1 ⁇ M)
  • Antagonist Max (solid block on plate map) Diluent
  • Antagonist Min (checker pattern on plate map) 1 ⁇ M RU-486 (FAC 0.1
  • the PlateMate Plus was used to add 5 ⁇ L MAX/MIN to cell plates
  • test substances are added from the mother p ⁇ ate(after removing max/min PlateMate tips : columns 1 and 24)
  • the cell plates are incubated @ 37 0 C, 5% CO 2 overnight (at least 16 hours). Then:
  • results are expressed as alkaline phosphatase induction (% of maximal progesterone response) by the test substances is achieved and an EC 5 O is determined.
  • results are expressed as alkaline phosphatase inhibition by the test compounds and an IC 5O is determined
  • the EC 50 value is defined as the drug concentration required to produce a 50% induction of AP activity compared with 5 nM progesterone alone. Test substances with full agonism achieve 100% of the response of progesterone whereas partial agonists induce AP activity to a level which is sub-maximal to that induced by progesterone.
  • the IC 50 value is defined as the drug concentration required to produce a 50% inhibition of AP activity compared with 5 nM progesterone alone.
  • IC 50 values are less than 5 ⁇ M. In a preferred embodiment, the IC 50 value is less than 500 nM. In a more preferred embodiment, the IC 50 is less than 50 nM.
  • the present invention also encompasses any one or more of these processes for preparing the compounds of formula IA or IB or derivative as herein defined, in addition to any novel intermediates used therein.
  • the substituents are as previously defined for a compound of formula IA or IB or derivative as herein defined unless otherwise stated.
  • R15 is a C 1-4 alkyl group such as methyl or ethyl.
  • a solution of compound of formula (HA) in a suitable solvent is treated with a hydride based reducing agent.
  • a solution of a compound of formula (HA) in tetrahydrofuran is treated with lithium borohydride at room temperature.
  • compounds of formula (IB) may be prepared by corresponding reduction of compounds of formula (HB) using similar procedures.
  • a solution of compound of formula (HA) in a suitable solvent is treated with an alkyl Grignard of formula R 3 MgBr/R 4 MgBr.
  • R 3 MgBr/R 4 MgBr an alkyl Grignard of formula
  • a solution of a compound of formula (HA') in 2-methyltetrahydrofuran is treated with 2.6 equivalents of methylmagnesium bromide at room temperature.
  • compounds of formula (IB) may be prepared by corresponding reaction of compounds of formula (MB) using similar procedures.
  • compounds of formula (IB) may be prepared by corresponding reaction of compounds of formula (UB) using similar procedures.
  • Compounds of formula (UA) and (HB) may be prepared by alkylation of a compound of formula (III) with a suitable "alkylating agent" of formula (IV) where X2 is a suitable leaving group such as Cl, I or Br.
  • a solution of the compound of formula (III) in a suitable solvent is treated with a strong base and then a compound of formula (IV) at a temperature between room temperature and 200 0 C.
  • a solution of the compound of formula (III) in 1 ,2- dimethoxyethane was treated with potassium te/f-butoxide followed by a compound of formula (IV) R6-X2 wherein X2 is chlorine at room temperature.
  • a solution of the compound of formula (III) in a suitable solvent is treated with a weak base or no base and then a compound of formula (IV) at a temperature between room temperature and 200 0 C.
  • a solution of the compound of formula (III) in 1 ,2-dimethoxyethane is treated with triethylamine and a compound of formula (IV) at room temperature to 60 0 C.
  • this step may be omitted.
  • Compounds of formula (III) can be prepared by a carbonylation reaction of compounds of formula (V) where X is a suitable leaving group such as iodo, bromo or trifluoromethanesulfonyl.
  • X is a suitable leaving group such as iodo, bromo or trifluoromethanesulfonyl.
  • a compound of formula (V) is treated with a palladium catalyst with a phosphine ligand, carbon monoxide and base in a suitable alcoholic solvent R15OH where R15 is a Ci -4 alkyl group such as methyl or ethyl which is incorporated into the ester product of formula (III) at a pressure of between atmospheric pressure and 150 psi and a temperature between room temperature and 150 0 C.
  • Compounds of formula (V) where X is iodine or bromine may be prepared by electrophilic halogenation of compounds of formula (Vl) in a suitable solvent.
  • a solution of a compound of formula (Vl) in a suitable solvent is treated with an N-halosuccinimide at a temperature between room temperature and the reflux temperature of the solvent.
  • a solution of a compound of formula (Vl) in acetonitrile is treated with N-iodosuccinimide at reflux.
  • Compounds of formula (Vl) may be prepared by condensation of a compound of formula (VII) with hydrazine, or a salt or hydrate thereof, optionally in the presence of an acid or a base (the base preferably being a tertiary amine base, such as triethylamine, and the acid preferably being acetic acid).
  • a solution of the compound of formula (VII), in acetic acid is treated with hydrazine, or the salt or hydrate thereof, at a temperature between room temperature to the reflux temperature of the solvent.
  • the reaction is conducted with hydrazine hydrate in acetic acid at room temperature.
  • Compounds of formula (VII) may be prepared by the condensation of a compound of formula (VIII) with an acetal of dimethylformamide at an elevated temperature, between 50 0 C and 120 0 C. In a preferred procedure a compound of formula (VIII) is heated in dimethylformamide dimethylacetal at 100 0 C.
  • Compounds of formula (VIIl) are either commercially available or may be prepared by the reaction of a compound of formula (IX) with a phenol of formula (X).
  • a suitable base such as caesium carbonate
  • the reaction mixture is heated, for example under reflux.
  • a nucleophilic catalyst such as sodium iodide or tetrabutylammonium iodide, may be added.
  • Compounds of formula (IX) are either commercially available or readily available from procedures described in the Science of Synthesis 2005, 26, 869- 969.
  • a solution of compound of formula (HA') in a suitable solvent is treated with a hydride based reducing agent.
  • a solution of a compound of formula (UA') in tetrahydrofuran is treated with lithium borohydride at room temperature.
  • a solution of compound of formula (HA') in a suitable solvent is treated with an alkyl Grignard agent of formula R 3 MgBr.
  • a solution of a compound of formula (HA') in 2- methyltetrahydrofuran is treated with 2.6 equivalents of methyimagnesium bromide at room temperature.
  • a solution of a compound of formula (HA") where R6 CH 2 SCH 3 in methanol and water is treated with OxoneTM at 60 0 C.
  • a solution of the compound of formula (111) in 1 ,2-dimethoxyethane was treated with potassium ferf-butoxide followed by chloromethyl methylsulfide at room temperature.
  • a solution of the compound of formula (III) in a suitable solvent is treated with an amine base or no base and then chloromethyl methylsulfide at a temperature between room temperature and 200 0 C.
  • a solution of the compound of formula (III) in 1 ,2- dimethoxyethane was treated with triethylamine and a compound of formula (IV) at room temperature to 60 0 C.
  • a suitable phosphoroamidite for example dibenzyl diisopropylphosphoroamidite
  • an acid for example tetrazole or trifluoroacetic acid.
  • a pharmaceutically acceptable salt of a compound of the formula (I) may be readily prepared by mixing together solutions of a compound of the formula (I) and the desired acid as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of three methods:
  • the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.
  • the invention includes all polymorphs of the compounds of Formula (I) and crystal habits thereof.
  • the compounds of the invention may have the advantage that they are more potent, have a longer duration of action, have a broader range of activity, are more stable, have fewer side effects or are more selective, or have other more useful properties than the compounds of the prior art.
  • the invention provides:
  • a method of treatment of a mammal to treat endometriosis, uterine fibroids (leiomyomata), menorrhagia, adenomyosis, primary and secondary dysmenorrhoea (including symptoms of dyspareunia, dyschexia and chronic pelvic pain), chronic pelvic pain syndrome including treating said mammal with an effective amount of compound
  • TLC thin layer chromatography
  • R f represents the distance travelled by a compound divided by the distance travelled by the solvent front on a TLC plate.
  • LCMS liquid chromatography mass spectroscopy
  • LCMS high performance liquid chromatography mass spectroscopy
  • LRMS low resolution mass spectroscopy
  • Certain compounds of the Examples and Preparations were purified using Automated Preparative High Performance Liquid Chromatography (HPLC). Reversed-phase HPLC conditions were on FractionLynx systems. Samples were submitted dissolved in 1mL of DMSO. Depending on the nature of the compounds and the results of a pre-analysis, the purification was performed under either acidic conditions or basic conditions at ambient temperature. Acidic runs were carried out on a Sunfire Prep C18 OBD column (19 x 50mm, 5 ⁇ m), basic runs were carried out on a Xterra Prep MS C18 (19 x 50mm, 5 ⁇ m), both from Waters.
  • HPLC Automated Preparative High Performance Liquid Chromatography
  • a flow rate of 18mL/min was used with mobile phase A: water + 0.1 % modifier (v/v) and B: acetonitrile + 0.1 % modifier (v/v).
  • mobile phase A water + 0.1 % modifier (v/v)
  • B acetonitrile + 0.1 % modifier (v/v).
  • the modifier was formic acid, for basic run the modifier was diethylamine.
  • a Waters 2525 binary LC pump supplied a mobile phase with a composition of 5%B for 1 min then ran from 5% to 98%B over 6 min followed by a 2 min hold at 98%B.
  • Detection was achieved using a Waters 2487 dual wavelength absorbance detector set at 225nm followed in series by a Polymer Labs PL-ELS 2100 detector and a Waters ZQ 2000 4 way MUX mass spectrometer in parallel.
  • the PL 2100 ELSD was set at 3O 0 C with 1.6L/min supply of Nitrogen.
  • the Waters ZQ MS was tuned with the following parameters:
  • the fraction collection was triggered by both MS and ELSD. Quality control analysis was performed using a LCMS method orthogonal to the preparative method. Acidic runs were carried out on a Sunfire C18 (4.6 x 50mm, 5 ⁇ m), basic runs were carried out on a Xterra C18 (4.6 x 50mm, 5 ⁇ m), both from Waters. A flow rate of 1.5mL/min was used with mobile phase A: water + 0.1 % modifier (v/v) and B: acetonitrile + 0.1 % modifier (v/v). For acidic runs the modifier was formic acid, for basic run the modifier was diethylamine.
  • a Waters 1525 binary LC pump ran a gradient elution from 5% to 95%B over 3 min followed by a 1 min hold at 95%B. Detection was achieved using a Waters MUX UV 2488 detector set at 225nm followed in series by a Polymer Labs PL-ELS 2100 detector and a Waters ZQ 2000 4 way MUX mass spectrometer in parallel.
  • the PL 2100 ELSD was set at 30 0 C with 1.6L/min supply of Nitrogen.
  • the Waters ZQ MS was tuned with the following parameters: ES+ Cone voltage: 25 v Capillary: 3.30 kv ES- Cone voltage:-30 v Capillary:-2.50 kv Desolvation gas: 800 L/hr Source Temp: 150 0 C. Scan range 160-900 Da
  • reaction times, number of equivalents of reagents and reaction temperatures may be modified for each specific reaction, and that it may nevertheless be necessary or desirable to employ different work-up or purification conditions.
  • the benzonitrile of Preparation 2 (11.19 g, 39.3 mmol) was dissolved in acetic acid (62 ml). Hydrazine hydrate (2.11 ml, 43.6 mmol) was added, and the mixture was stirred at room temperature for 12 hours, under nitrogen. The reaction mixture was then concentrated under reduced pressure, and the residue was partitioned between water (100 ml) and diethyl ether (150 ml). The organic layer was dried over magnesium sulphate, filtered and concentrated under reduced pressure to provide the title compound (9.71 g, 98%) as a solid.
  • N-lodosuccinimide (5.76 g, 25.6 mmol) was added to a solution of the compound of preparation 3 (5.4 g, 31.32 mmol) in acetonitrile (43 ml_). The mixture was heated at reflux for 3 hours before cooling to room temperature. The mixture was evaporated in vacuo to low volume and purified by flash chromatography eluting with 20% ethyl acetate in pentane to 100% ethyl acetate to afford the title compound as a foam (6.47 g, 75%).
  • Triethylamine (2.04 mL, 14.6 mmol) and palladium(ll)diphenylphosphinoferrocene dichloride (795 mg, 0.98 mmol) were added to a solution of the compound of preparation 4 (3.7 g, 9.76 mmol) in ethanol (98 mL).
  • the reaction mixture was placed in a pressure reactor and treated with carbon monoxide at 100 psi and 9O 0 C for 16 hours.
  • the reaction mixture was allowed to cool to room temperature and filtered through Arbocel and the solvent was removed in vacuo.
  • Chloromethyl methylsulfide (0.31 mL, 3.69 mmol) was added to a solution of the compound of preparation 5 (1000 mg, 3.07 mmol) and N-ethyldiisopropylamine (1.06 mL, 6.15 mmol) in 1 ,2-dimethoxyethane (15 mL), under nitrogen, and the mixture was stirred at 40 0 C for 64 hours. It was then allowed to cool and partitioned between saturated sodium bicarbonate solution (100 mL) and dichloromethane (100 mL). The layers were separated and the organic phase was dried with magnesium sulphate, filtered and concentrated in vacuo.
  • OxoneTM 64 mg, 0.104 mmol was added to a solution of the compound of preparation 6 (20 mg, 0.502 mmol) in methanol (2 mL) and water (0.6 mL) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to a small amount of solvent, and then water (15 mL) was added. The resulting mixture was extracted with dichloromethane 2 x 10 mL) on a hydrophobic membrane and concentrated in vacuo to afford the title compound as a solid (14 mg, 65%).
  • OxoneTM (1.59 g, 2.58 mmol) was added to a solution of the compound of preparation 7 (497 mg, 1.29 mmol) in a mixture of methanol (25.8 ml_) and water (8.6 ml_), and the mixture was stirred at 60 0 C for 2 hours.
  • the reaction mixture was evaporated to 1/3 volume, then diluted with water (50 mL) and the product was extracted with dichloromethane (50 mL).
  • the combined organic extracts were dried with magnesium sulfate, filtered and the solvent was removed in vacuo to afford a white foam.
  • the crude product was purified by flash chromatography eluting with 25% ethyl acetate in pentane to afford the title compound as a white solid (401 mg, 75%).
  • Potassium te/f-butoxide (90 mg, 0.80 mmol) was added to a solution of the compound of preparation 5 (200 mg, 0.61 mmol) in 1 ,2-dimethoxyethane (10 ml_) under nitrogen and the mixture was stirred for 10 minutes, lodomethane (0.043 mL, 0.69 mmol) was then added, and the reaction mixture was heated at 60 0 C for 16 hours. The reaction was allowed to cool, quenched with water (20 mL) and extracted with dichloromethane (2x30 mL).
  • N-Ethyldiisopropylamine (241 ⁇ L, 1.38 mmol), bromoethane (260 ⁇ L, 3.6 mmol) and potassium iodide (10 mg, 0.06 mmol) were added to a solution of the compound of preparation 5 (150 nig, 0.46 mmol) in 1,2-dimethoxyethane (5 ml_) and the mixture was heated by microwave at 150 0 C for 40 minutes. It was then diluted with dichloromethane (30 ml_) and washed with water (3 x 50 ml_). The organic phase was collected through a hydrophobic cartridge and evaporated to dryness.
  • N-Ethyldiisopropylamine (322 ⁇ L, 1.85 mmol), bromo-2-methoxyethane (868 ⁇ l_, 9.23 mmol) and potassium iodide (10 mg, 0.06 mmol) were added to a solution of the compound of preparation 5 (150 mg, 0.46 mmol) in 1 ,2-dimethoxyethane (2 mL) and N-methylpyrrolidinone (0.5 mL).
  • the reaction mixture was heated by microwave at 150 0 C for 120 minutes. Potassium terf-butoxide (155 mg, 1.38 mmol) was then added and the mixture was subjected to further microwave heating at 150 0 C for 120 minutes.
  • the title compound may be prepared using a procedure similar to that described for Preparation 1 starting with 3-methyl-butan-2-one in place of cyclopropylmethyl ketone (1.45 g, 47%).
  • the title compound may be prepared using a procedure similar to that described for Preparation 2 using the title compound of Preparation 14 in place of the title compound of Preparation 1 (1.78 g, 99%).
  • LRMS APCI + : 287 [MH + ].
  • the title compound may be prepared using a procedure similar to that described for Preparation 3 using the title compound of Preparation 15 in place of the title compound of Preparation 2 (1.59 g, 88%).
  • the title compound may be prepared using a procedure similar to that described for Preparation 4 using the title compound of Preparation 16 in place of the title compound of Preparation 3 (2.09 g, 48%).
  • the title compound may be prepared using a procedure similar to that described for Preparation 5 using the title compound of Preparation 17 in place of the title compound of Preparation 4 (0.86 g, 75%).
  • the title compound may be prepared using a procedure similar to that described for Preparation 7 using the title compound of Preparation 18 in place of the title compound of Preparation 5 (0.45 g, 39%).
  • the title compound may be prepared using a procedure similar to that described for Preparation 9 using the title compound of Preparation 18 in place of the title compound of Preparation 7 (0.56 g, 100%).
  • the title compound may be prepared using a procedure similar to that described for Preparation 1 starting with cyclobutylmethyl ketone in place of cyclopropylmethyl ketone (4.5 g, 33%).
  • the title compound may be prepared using a procedure similar to that described for Preparation 2 using the title compound of Preparation 21 in place of the title compound of Preparation 1 (5.6 g, 100%).
  • the title compound may be prepared using a procedure similar to that described for Preparation 3 using the title compound of Preparation 22 in place of the title compound of Preparation 2 (3.4 g, 83%).
  • LRMS APCI + : m/z 268 [MH + ]; APCr : ' m/z 266 [M-H]-
  • the title compound may be prepared using a procedure similar to that described for Preparation 4 using the title compound of Preparation 23 in place of the title compound of Preparation 3 (1.6 g, 54%).
  • 1 H-NMR (400MHz, CDCI 3 ): ⁇ 1.80-2.05(m, 2H), 2.18-2.30(m, 4H), 2.44(s, 6H), 3.44(quintet, 1 H), 6.60(s, 2H), 10.70(brs, 1 H); LRMS ES + m/z 394 (MH + ) ES " 392 (M-H)-
  • the title compound may be prepared using a procedure similar to that described for Preparation 5 using the title compound of Preparation 24 in place of the title ' compound of Preparation 4 (1.20 g, 87%).
  • the title compound may be prepared using a procedure similar to that described for Preparation 7 using the title compound of Preparation 25 in place of the title compound of Preparation 5 (130 mg, 22%).
  • the title compound may be prepared using a procedure similar to that described for Preparation 9 using the title compound of Preparation 26 in place of the title compound of Preparation 7 (135 mg, 96%).
  • the title compound may be prepared using a procedure similar to that described for Preparation 1 starting with 4-hydroxy ⁇ 2methylbenzonitrile (prepared according to WO 2006111856) in place of 4-hydroxy-2,6-dimethylbenzonitrile (3.3 g, 50%).
  • LRMS APCI + : 216 [MH + ]
  • the title compound may be prepared using a procedure similar to that described for Preparation 3 using the title compound of Preparation 29 in place of the title compound of Preparation 2 (1.7 g, 65%).
  • the title compound may be prepared using a procedure similar to that described for Preparation 4 using the title compound of Preparation 30 in place of the title compound of Preparation 3 (1.22 g, 47%).
  • the title compound may be prepared using a procedure similar to that described for Preparation 5 using the title compound of Preparation 31 in place of the title compound of Preparation 4 (0.33 g, 65%).
  • the title compound may be prepared using a procedure similar to that described for Preparation 7 using the title compound of Preparation 32 in place of the title compound of Preparation 5 (200 mg, 56%).
  • the title compound may be prepared using a procedure similar to that described for Preparation 9 using the title compound of Preparation 33 in place of the title compound of Preparation 7 (202 mg, 93%).
  • the title compound may be prepared using a procedure similar to that described for Preparation 1 starting with 4-hydroxy-2-chlorobenzonitrile (prepared according to WO 2006111856) in place of 4-hydroxy-2,6-dimethylbenzonitrile (8.3 g, 64%).
  • the title compound may be prepared using a procedure similar to that described for Preparation 2 using the title compound of Preparation 35 in place of the title compound of Preparation 1 (9.31 g, 99%).
  • the title compound may be prepared using a procedure similar to that described for Preparation 3 using the title compound of Preparation 36 in place of the title compound of Preparation 2 (8.45 g, 98%).
  • LRMS ES “ : m/z 258, 260 [M-H] "
  • the title compound may be prepared using a procedure similar to that described for Preparation 4 using the title compound of Preparation 37 in place of the title compound of Preparation 3 (3.7 g, 42%).
  • the title compound may be prepared using a procedure similar to that described for Preparation 5 using the title compound of Preparation 38 in place of the title compound of Preparation 4 (1.54 g, 53%).
  • the title compound may be prepared using a procedure similar to that described for Preparation 7 using the title compound of Preparation 39 in place of the title compound of Preparation 5 (1.34 g, 76%).
  • the title compound may be prepared using a procedure similar to that described for Preparation 9 using the title compound of Preparation 40 in place of the title compound of Preparation 7 (0.62 g, 93%).
  • Lithium borohydride solution (0.1 mL, 2M in tetrahydrofuran, 0.2 mmol) was added dropwise to a solution of the compound of preparation 5 (30 mg, 0.092 mmol) in tetrahydrofuran (2 mL). After 16 hours at room temperature, a further aliquot of lithium borohydride solution (0.2 mL, 2M in tetrahydrofuran, 0.4 mmol) was added, and after an additional 90 minutes the reaction was quenched by dropwise addition of water (1 mL), followed by ammonium chloride solution (2 mL, sat. aqueous). It was then stirred at room temperature for 2 hours.
  • Lithium borohydride (0.66 mL, 2M in tetrahydrofuran, 1.32 mmol) was added dropwise to a solution of the compound of preparation 9 (250 mg, 0.6 mmol) in tetrahydrofuran (6 mL), under nitrogen, and the resulting mixture was stirred at room temperature for 16 hours. It was then carefully diluted with methanol (25 mL) and stirred for 30 minutes. The solvent was removed in vacuo and the residue was azeotroped with methanol (25 mL). The resulting solid was purified by flash chromatography eluting with 20-70% ethylacetate in pentane to afford the title compound as a white foam (168 mg, 75%).
  • the title compound may be prepared using a procedure similar to that described for Example 2 starting with 3-methyl-butan-2-one in place of cyclopropylmethyl ketone as described in Preparation 1.
  • the title compound may be prepared using a procedure similar to that described for Example 3 using the title compound of Preparation 27 in place of the title compound of Preparation 9 (75 mg, 62%).
  • the title compound may be prepared using a similar procedure to that described for Example 2 starting with cyclobutylmethylketone in the place of cyclopropylmethyl ketone as described in Preparation 1.
  • Lithium borohydride solution (52 ⁇ l_, 2M in tetrahydrofuran, 0.104 mmol) was added dropwise to a solution of the compound of preparation 10 (14 mg, 0.041 mmol) in tetrahydrofuran (2 mL), under nitrogen, and the resulting mixture was stirred at room temperature.
  • An additional aliquot of lithium borohydride (52 ⁇ l_, 2M in tetrahydrofuran, 0.104 mmol) was added and the reaction was stirred for a further 2 hours at room temperature. It was then quenched with water (2 mL) and diluted with hydrochloric acid (5 mL, 2N aqueous). The resulting mixture was extracted with dichloromethane (2 x 10 mL), with the organic phases collected through a hydrophobic cartridge, and then evaporated to dryness to afford the title compound as a white solid (12mg, 100%).
  • Lithium borohydride solution (1.15 mL, 2M in tetrahydrofuran, 2.30 mmol) was added dropwise to a solution of the compound of preparation 11 (130 mg, 0.38 mmol), in tetrahydrofuran (4 mL), under nitrogen, and the resulting reaction mixture was stirred for 16 hours at room temperature. It was then quenched by the addition of water (4 mL) and diluted with aqueous hydrochloric acid (10 mL,
  • Methylmagnesium bromide solution (0.60 mL, 1.4M in tetrahydrofuran, 0.84 mmol) was added to a solution of the compound of preparation 9 (134 mg, 0.32 mmol) in
  • Example 12 4-[3-Cyclopropyl-5-hydroxymethyl-1-(2-methoxy-ethyl)-1H-pyrazol-4- yloxy]-2,6-dimethyl-benzonitrile
  • the title compound may be prepared using the same method as described for Example 11 using the title compound of Preparation 13 as the starting material. (59 mg, 100%).
  • 1H-NMR (400MHz, CDCI 3 ): ⁇ 0.74-0.83(m, 4H), 1.62(m, 1H), 2.47(s, 6H), 3.36(s, 3H),. 3.74(m, 2H), 4.25(m, 2H), 4.39(s, 2H), 6.68(s, 2H); MS m/z ES + 341 (MH + ).
  • Example 13 4-(3-Cyclopropyl-5-hydroxymethyl-1-methanesulfonylmethyl-1 H- pyrazol-4-yloxy)-2-methyl-benzonitrile
  • the title compound may be prepared using a procedure similar to that described for Example 3 using the title compound of Preparation 34 in place of the title compounds of Preparation 9. (75 mg, 36%).
  • the title compound may be prepared using a procedure similar to that described for Example 3 using the title compound of Preparation 41 in place of the title compounds of Preparation 9. (140 mg, 82%).
  • the title compound may be prepared using a similar procedure to that described for Example 3 starting with cyclobutylmethyl ketone in the place of cyclopropylmethyl ketone and 2-methyl-4-hydroxybenzonitrile in the place of 2,6- dimethyl-4-hydroxybenzonitrile as described in Preparation 1.
  • the title compound may be prepared using a similar procedure to that described for Example 3 starting with 2-chloro-4-hydroxybenzonitrile in the place of 2,6- dimethyl-4-hydroxybenzonitrile as described in Preparation 1.
  • the title compound may be prepared from an intermediate such as the title compound of Preparation 9 using the chemistry described in Scheme 2 of the general methods.
  • Example 20 4-[3-Cyclopropyl-1-(1 ,1-dioxo-1lambda*6*-thietan-3-yl)-5-hydroxy methyl-1H-pyrazol-4-yloxy]-2,6-dimethyl-benzonitriie
  • Examples 18 to 20 may be prepared in an analogous fashion to Examples 3 and 4 using the chemistry described in Scheme 1 of the general methods and the compound of Preparation 5.
  • Example 21 4-[1-(1 ,1-Dioxo-1 lambda*6*-thietan-3-yl)-5-hydroxymethyl-3- isopropyl-1 H-pyrazol-4-yloxy]-2,6-dimethyl-benzonitrile
  • Example 22 4-[1-(1 ,1-Dioxo-1lambda*6*-thietan-3-yl)-5-hydroxymethyl-3- cyclobutyl-1 H-pyrazol-4-yloxy]-2,6-dimethyl-benzonitrile
  • Examples 21 and 22 may be prepared in an analogous fashion to Example 3 using the chemistry described in Scheme 1.
  • Example 23 Phosphoric acid mono-[4-(4-cyano-3,5-dimethyl-phenoxy)-5- cyclopropyl-2-methanesulfonylmethyl-2H-pyrazol-3-ylmethyl] ester
  • the title compound may be prepared from the title compound of Example 3 using the methods outlined in Scheme 3 of the general methods section.
  • the title compound may be prepared from the title compound of Example 13 using the methods outlined in Scheme 3 of the general methods section.
  • Example 26 Phosphoric acid mono-[4-(3-lsopropyl-5-hydroxymethyl-1- methanesulfonylmethyl-1 H-pyrazol-4-yloxy)-2,6-dimethyl-benzonitrile]ester
  • the title compound may be prepared from the title compound of Example 5 using the methods outlined in Scheme 3 of the general methods section.
  • Example 27 Phosphoric acid mono-[4-(3-cylobutyl-5-hydroxymethyl-1 -methane sulfonylmethyl-1 H-pyrazol-4-yloxy)-2,6-dimethyl-benzonitrile]ester
  • the title compound may be prepared from the title compound of Example 6 using the methods outlined in Scheme 3 of the general methods section.
  • Example 28 Phosphoric acid mono-[4-(3-Cyclobutyl-5-hydroxymethyl-1 -methane sulfonylmethyl-1 H-pyrazol-4-yloxy)-2-methyl-benzonitrile]ester
  • Example 29 Phosphoric acid mono-[2-Chioro-4-(3-cyclobutyl-5-hydroxymethyI-1- methanesulfonylmethyl-1 H-pyrazol-4-yloxy)-benzonitrile]ester
  • the title compound may be prepared from the title compound of Example 16 using the methods outlined in Scheme 3 of the general methods section.
  • Example 30 Phosphoric acid mono-[4-[1-(1 ,1-dioxo-1 lambda*6*-thietan-3-yl)-5- hydroxymethyl-3-isopropyl-1 H-pyrazol-4-yloxy]-2,6-dimethyl-benzonitrile]ester
  • the title compound may be prepared from the title compound of Example 21 using the methods outlined in Scheme 3 of the general methods section.
  • Example 31 Phosphoric acid mono-[4-[1-(1 ,1-dioxo-1lambda*6*-thietan-3-yl)-3- hydroxymethyl-5-cylobutyl-1 H-pyrazol-4-yloxy]-2,6-dimethyl-benzonitrile]ester
  • the title compound may be prepared from the title compound of Example 22 using the methods outlined in Scheme 3 of the general methods section.

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Abstract

L'invention concerne un composé de formule (IA) ou (IB) ou un sel pharmaceutiquement acceptable, un solvate (y compris un hydrate) dudit composé et sel ou un promédicament dudit composé, ou un sel pharmaceutiquement acceptable ou un solvate dudit promédicament (Formule IA, IB) (IA) (IB) dans laquelle les substituants sont tels que définis dans le présent document. Le composé selon l'invention peut être utile en thérapie, par exemple pour le traitement de l'endométriose, des fibromes utérins (léiomyome), de la ménorragie, de l'adénomyose, de la dysménorrhée primaire et secondaire (y compris les symptômes de la dyspareunie, de la dyschexie et les douleurs pelviennes chroniques) ou du syndrome des douleurs pelviennes chroniques.
PCT/IB2008/001048 2007-05-02 2008-04-24 Composés d'oxyalkylpyrazole utiles en thérapie Ceased WO2008135824A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10647675B2 (en) 2015-09-18 2020-05-12 Kaken Pharmaceutical Co., Ltd. Biaryl derivative and medicine containing same
WO2025168620A1 (fr) 2024-02-07 2025-08-14 Bayer Aktiengesellschaft 4,5-dihydro-1h-2,4,5-oxadiazines substituées par hétéroaryle utilisées en tant que nouveaux fongicides

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002085860A1 (fr) * 2001-04-10 2002-10-31 Pfizer Limited Derives de pyrazole pour le traitement de vih
WO2006111856A1 (fr) * 2005-04-20 2006-10-26 Pfizer Limited Derives de pyrazole tenant lieu d'antagonistes du recepteur de la progesterone
WO2007054770A2 (fr) * 2005-11-08 2007-05-18 Pfizer Limited Composes utiles en therapie

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002085860A1 (fr) * 2001-04-10 2002-10-31 Pfizer Limited Derives de pyrazole pour le traitement de vih
WO2006111856A1 (fr) * 2005-04-20 2006-10-26 Pfizer Limited Derives de pyrazole tenant lieu d'antagonistes du recepteur de la progesterone
WO2007054770A2 (fr) * 2005-11-08 2007-05-18 Pfizer Limited Composes utiles en therapie

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10647675B2 (en) 2015-09-18 2020-05-12 Kaken Pharmaceutical Co., Ltd. Biaryl derivative and medicine containing same
WO2025168620A1 (fr) 2024-02-07 2025-08-14 Bayer Aktiengesellschaft 4,5-dihydro-1h-2,4,5-oxadiazines substituées par hétéroaryle utilisées en tant que nouveaux fongicides

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