EP1401427A2 - Agents gnrh non peptidiques, compositions pharmaceutiques et methodes d'utilisation de ces dernieres, procedes de preparation de ces composes - Google Patents

Agents gnrh non peptidiques, compositions pharmaceutiques et methodes d'utilisation de ces dernieres, procedes de preparation de ces composes

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Publication number
EP1401427A2
EP1401427A2 EP02739712A EP02739712A EP1401427A2 EP 1401427 A2 EP1401427 A2 EP 1401427A2 EP 02739712 A EP02739712 A EP 02739712A EP 02739712 A EP02739712 A EP 02739712A EP 1401427 A2 EP1401427 A2 EP 1401427A2
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European Patent Office
Prior art keywords
unsubstituted
nhc
group
alkyl
heteroaryl
Prior art date
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EP02739712A
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German (de)
English (en)
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EP1401427A4 (fr
Inventor
Eric T. Sun
Mark B. Anderson
Kenna Lynn Anderes
Lance Christopher Christie
Quyen-Quyen Thuy Do
Jun Feng
Thomas Goetzen
Yufeng Hong
Eugenia Anatolievna Kraynov
Haitao Li
David Robert Luthin
Genevieve D. Paderes
Ved P. Pathak
Ranjan Jagath Rajapakse
Scott Shackelford
Eileen Valenzuela Tompkins
Larry Kenneth Truesdale
Haresh Vazir
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Agouron Pharmaceuticals LLC
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Agouron Pharmaceuticals LLC
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Publication of EP1401427A2 publication Critical patent/EP1401427A2/fr
Publication of EP1401427A4 publication Critical patent/EP1401427A4/fr
Withdrawn legal-status Critical Current

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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
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom 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
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention relates generally to compounds that affect the action of human gonadotropin-releasing hormone (GnRH). More particularly, it relates to non- peptide GnRH antagonists or agonists and to their preparation. These non-peptide GnRH agents have advantageous physical, chemical, and biological properties, and are useful medicaments for diseases or conditions mediated by modulation ofthe pituitary-gonadal axis.
  • the invention also relates to methods for treating individuals needing therapeutic regulation of GnRH ⁇ i.e., methods for treating diseases and conditions mediated by GnRH regulation.
  • the invention further relates to processes for synthesizing intermediate compounds useful for making GnRH agents.
  • GnRH Gonadotropin-Releasing Hormone
  • LH-RH luteinizing hormone-releasing hormone
  • the decapeptide is released in a pulsatile manner into the pituitary portal circulation system where GnRH interacts with high-affinity receptors (7-Transmembrane G- Protein Coupled Receptors) in the anterior pituitary gland located at the base ofthe brain.
  • GnRH triggers the release of two gonadotropic hormones (gonadotropins): luteinizing hormone (LH) and follicle-stimulating hormone (FSH).
  • LH luteinizing hormone
  • FSH follicle-stimulating hormone
  • LH stimulates the production of testosterone and estradiol, respectively.
  • FSH stimulates follicle growth in women and sperm formation in men.
  • GnRH When correctly functioning, the pulse-timed release and concentration levels of GnRH are critical for the maintenance of gonadal steroidogenesis and for normal functions of reproduction related to growth and sexual development.
  • the pituitary response to GnRH varies greatly throughout life. GnRH and the gonadotropins first appear in the fetus at about ten weeks of gestation.
  • the sensitivity to GnRH declines, after a brief rise during the first three months after birth, until the onset of puberty. Before puberty, the FSH response to GnRH is greater than that of LH. Once puberty begins, sensitivity to GnRH increases, and pulsatile LH secretion ensues.
  • GnRH GnRH
  • LH responsiveness being greater than that of FSH.
  • Pulsatile GnRH release results in pulsatile LH and FSH release from the pituitary, and hence, estosterone and estradiol release from the gonads. After menopause, FSH and LH concentrations rise, and post-menopausal FSH levels are higher than those of LH.
  • GnRH agonists and antagonists Chronic administration of GnRH agonists and antagonists to animals or to man results in decreased circulating levels of both LH and FSH.
  • GnRH agonists are compounds that mimic endogenous GnRH to stimulate receptors on the pituitary gland, resulting in release of LH and FSH.
  • After a transient rise in gonadal hormone production or "flare" response chronic administration of GnRH agonists results in a down-regulation of GnRH receptors.
  • GnRH receptor down-regulation and desensitization ofthe pituitary results in a decrease of circulating levels of LH and FSH.
  • GnRH agonists have been the treatment of choice for sex-steroid-dependent pathophysiologies.
  • GnRH agonists have been used to reduce testosterone production, thereby reducing prostate volume in benign prostatic hyperplasia (BPH) and slowing tumor growth in prostate cancer.
  • BPH benign prostatic hyperplasia
  • These compounds have also been used to treat breast and ovarian cancers.
  • GnRH antagonists have become available for clinical evaluation.
  • GnRH antagonists have an immediate effect on the pituitary without the observed flare associated with agonists.
  • Use of GnRH antagonists (usually decapeptides) has been reported in the literature for treatment of breast, ovarian, and prostatic cancers.
  • Other uses of antagonists, like agonists, include endometriosis (including endometriosis with pain), uterine myoma, ovarian and mammary cystic diseases (including polycystic ovarian disease), prostatic hypertrophy, amenorrhea (e.g., secondary amenorrhea), and precocious puberty. These compounds may also be useful in the symptomatic relief of premenstrual syndrome (PMS).
  • PMS premenstrual syndrome
  • antagonists may be useful to regulate the secretion of gonadotropins in male mammals to arrest spermatogenesis (e.g., as male contraceptives), and for treatment of male sex offenders:
  • GnRH antagonists and agonists
  • GnRH antagonists have found utility in treatments where a reversible suppression ofthe pituitary-gonadal axis is desired.
  • androgen deprivation has been the most effective systematic therapy for the treatment of metastatic carcinoma ofthe prostate. The rationale is simple — the prostate gland requires androgens for proper growth, maintenance, and function.
  • prostate cancer and benign prostate hyperplasia are common in men and develop in an environment of continuous androgen exposure.
  • GnRH antagonists may have a direct effect on tumor growth by blocking receptors on the tumor cells.
  • antagonists should be effective in slowing tumor growth by these two mechanisms. Since GnRH receptors are present on many prostate and breast cancer cells, it has recently been speculated that GnRH antagonists may also be effective in treating non-hormone-dependent tumors. Recent literature examples indicate that GnRH receptors are present on a number of cancer cell lines, including:
  • prostate cancer GnRH agonists exert both in vitro, and in vivo, a direct inhibitory action on the growth of both androgen-dependent (LNCaP) and androgen-independent (DU 145) human prostatic cancer cell lines
  • breast cancer Breast cancer is the most common type of cancer in women over the age of forty and is the leading cause of cancer-related death in women.
  • Systematic endocrine intervention represents a major treatment option for the management of advanced breast cancer, especially with estrogen-dependent cancers.
  • the genes for gonadotropin-releasing hormone and its receptor are expressed in human breast with fibrocystic disease and cancer [Kottler et al., Int. J. Cancer, 71(4), 595-599 (1997)].
  • GnRH agents may also be useful in treating cancer through generation of thymus re-growth and therefore induction ofthe development of new T-cells. See Norwood Abbey press release dated March 5, 2001.
  • GnRH agents may be useful for treating HIV infection or acquired immune deficiency syndrome (AIDS). Additionally, GnRH agents may be useful in combating infection in tissue-transplant patients where immunosuppressive drugs, which remove T-cells, are being administered to counteract rejection ofthe transplanted tissue.
  • GnRH agents may be useful in treating cancer.
  • GnRH agents may be useful for treating autoimmune diseases such as multiple sclerosis (MS), where T-cells are produced that react against a molecule surrounding nerve cells.
  • MS multiple sclerosis
  • GnRH antagonists have primarily been peptide analogs of GnRH. See, e.g., International Publication Nos. WO 93/03058, WO 99/50276, WO 00/12521, and WO 00/12522; Koppan et al., Prostate, 38(2),151-8 (1999); and Nagy et al, Proc Natl Acad Sci USA, 97(2),829-34 (2000).
  • peptide antagonists of peptide hormones are often quite potent, the use of peptide antagonists is typically associated with problems because peptides are degraded by physiological enzymes and often poorly distributed within the organism being treated.
  • the first non-peptide antagonist ofthe human leuteinizing hormone-releasing hormone (LHRH) receptor was reported by Cho et al. (JMed Chem, 41(22), 4190 (1998). Since then, other non-peptide GnRH antagonists have been reported in the literature. For example, quinolone-6-carboxamides were reported by Walsh et al. in Bioorg & Med Chem Ltrs., 10, 443-447 (2000). Tricyclic diazepines and cyclic pentapeptides were reported in International Publication Nos. WO 96/38438 and WO 96/34012, respectively. Tetrahydroisoquinoline derivatives were reported in U.S. Patent No. 5,981,521.
  • non-peptide GnRH antagonists see International Publication Nos. WO 97/21435, WO 97/21703, WO 97/21704, WO 97/21707, WO 99/44987, WO 00/04013, WO 00/12522, WO 00/12521, WO 00/04013, and WO 00/20358.
  • non-peptide antagonists ofthe peptide hormone GnRH with desirable properties.
  • non-peptide GnRH agents having advantageous physical, chemical and biological properties compared to peptides, which are useful medicaments for treating diseases mediated via the pituitary-gonadal axis and by directly targeting the receptor on tumor cells.
  • GnRH agents that act upon these receptors to treat both hormone-dependent and hormone-independent cancers.
  • the invention is directed to compounds represented by the following Formula I:
  • the invention is also directed to pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of such compounds, and pharmaceutically acceptable salts of such metabolites.
  • Such compounds, salts, prodrugs and metabolites are at times collectively referred to herein as "GnRH agents.”
  • the invention also relates to pharmaceutical compositions each comprising a therapeutically effective amount of a GnRH agent ofthe invention in combination with a pharmaceutically acceptable carrier or diluent. Moreover, the invention relates to methods for regulating the secretion of gonadotropins in mammals, comprising administering therapeutically effective amounts of GnRH agents ofthe invention.
  • alkyl refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms in the chain.
  • exemplary alkyl groups include methyl (Me, which also may be structurally depicted by I), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and the like.
  • heteroalkyi refers to a straight- or branched-chain alkyl group having from 2 to 12 atoms in the chain, one or more of which is a heteroatom selected from S, O, and N.
  • exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, alkyl suifides, and the like.
  • alkenyl refers to a straight- or branched-chain alkenyl group having from 2 to 12 carbon atoms in the chain.
  • Illustrative alkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, and the like.
  • alkynyl refers to a straight- or branched-chain alkynyl group having from 2 to 12 carbon atoms in the chain.
  • Illustrative alkynyl groups include prop-2-ynyl, but-2-ynyl, but-3-ynyl, 2-methylbut-2-ynyl, hex-2-ynyl, and the like.
  • aryl refers to a monocyclic, or fused or spiro polycyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) having from 3 to 12 ring atoms per ring.
  • aryl groups include the following moieties:
  • heteroaryl refers to a monocyclic, or fused or spiro polycyclic, aromatic heterocycle (ring structure having ring atoms selected from carbon atoms as well as nitrogen, oxygen, and sulfur heteroatoms) having from 3 to 12 ring atoms per ring.
  • aryl groups include the following moieties:
  • cycloalkyl refers to a saturated or partially saturated, monocyclic or fused or spiro polycyclic, carbocycle having from 3 to 12 ring atoms per ring.
  • Illustrative examples of cycloalkyl groups include the following moieties:
  • heterocycloalkyl refers to a monocyclic, or fused or spiro polycyclic, ring structure that is saturated or partially saturated and has from 3 to 12 ring atoms per ring selected from C atoms and N, O, and S heteroatoms.
  • ring atoms per ring selected from C atoms and N, O, and S heteroatoms.
  • heterocycloalkyl groups include:
  • halogen represents chlorine, fluorine, bromine or iodine.
  • 'halo represents chloro, fluoro, bromo or iodo.
  • substituted means that the specified group or moiety bears one or more substituents.
  • unsubstituted means that the specified group bears no substituents.
  • optionally substituted means that the specified group is unsubstituted or substituted by one or more substituents.
  • Preferred GnRH agents ofthe invention include those having a Ki value of about 10 ⁇ M or less. Especially preferred GnRH agents are those having a K; value in the nanomolar range.
  • a compound of Formula I, II or III may exist as an "E” or “Z” configurational isomer, or a mixture of E and Z isomers. It is therefore to be understood that a formula is intended to represent any configurational form ofthe depicted compound and is not to be limited merely to a specific compound form depicted by the formula drawings.
  • inventive compounds may exist as single stereoisomers (i.e., essentially free of other stereoisomers), racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention.
  • inventive compounds that are optically active are used in optically pure form.
  • an optically pure compound having one chiral center is one that consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure.
  • the compounds ofthe present invention are used in a form that is at least 90% optically pure, that is, a form that contains at least 90% of a single isomer (80% enantiomeric excess ("e.e.") or diastereomeric excess (“d.e.”)), more preferably at least 95% (90% e.e.
  • GnRH agents in accordance with the invention also include active tautomeric and stereoisomeric forms ofthe compounds of Formula I, II or III, which may be readily obtained using techniques known in the art.
  • optically active (R) and (S) isomers may be prepared via a stereospecific synthesis, e.g., using chiral synthons and chiral reagents, or racemic mixtures may be resolved using conventional techniques.
  • Formulas I, II, and ni are intended to cover, where applicable, solvated as well as unsolvated forms ofthe compounds.
  • each formula includes compounds having the indicated structure, including the hydrated as well as the non- hydrated forms.
  • the GnRH agents of the invention include pharmaceutically acceptable salts, prodrugs, and active metabolites of such compounds, and pharmaceutically acceptable salts of such metabolites.
  • Such non-peptide agents are pharmaceutically advantageous over peptide agents since they provide better biodistribution and tolerance to degradation by physiological enzymes.
  • a “prodrug” is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a pharmaceutically acceptable salt of such compound.
  • An “active metabolite” is a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. Prodrugs and active metabolites of a compound may be identified using routine techniques known in the art. See, e.g., Bertolini et al., J. Med. Chem., 40, 2011-2016 (1997); Shan et al., J. Pharm. Sci., 86 (7), 765-767; Bagshawe, Drug Dev.
  • pharmaceutically acceptable salts refers to salt forms that are pharmacologically acceptable and substantially non-toxic to the subject being administered the GnRH agent.
  • Pharmaceutically acceptable salts include conventional acid-addition salts or base-addition salts formed from suitable non-toxic organic or inorganic acids or inorganic bases.
  • Exemplary acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, methanesulfonic acid, ethane-disulfonic acid, isethionic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, 2-acetoxybenzoic acid, acetic acid, phenylacetic acid, propionic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, ascorbic acid, maleic acid, hydroxymaleic acid, glutamic acid, salicylic acid, sulfanilic acid, and fumaric acid.
  • inorganic acids such as hydrochloric acid, hydro
  • Exemplary base-addition salts include those derived from ammonium hydroxides (e.g., a quaternary ammonium hydroxide such as tetramethylammonium hydroxide), those derived from inorganic bases such as alkali or alkaline earth-metal (e.g., sodium, potassium, lithium, calcium, or magnesium) hydroxides, and those derived from organic bases such as amines, benzylamines, piperidines, and pyrrolidines.
  • ammonium hydroxides e.g., a quaternary ammonium hydroxide such as tetramethylammonium hydroxide
  • inorganic bases such as alkali or alkaline earth-metal (e.g., sodium, potassium, lithium, calcium, or magnesium) hydroxides
  • organic bases such as amines, benzylamines, piperidines, and pyrrolidines.
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
  • an inorganic acid such as hydrochloric acid
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment ofthe free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • Ligand- binding assays are used to determine interaction with the receptor of interest. Where binding is of interest, a labeled receptor may be used, where the label is a fluorescer, enzyme, radioisotope, or the like, which registers a quantifiable change upon the binding ofthe receptor. Alternatively, the artisan may provide for an antibody to the receptor, where the antibody is labeled, which may allow for amplification of the signal. Binding may also be determined by competitive displacement of a ligand bound to the receptor, where the ligand is labeled with a detectable label.
  • agonist and/or antagonist activity is of interest
  • an intact organism or cell may be studied, and the change in an organismic or cellular function in response to the binding ofthe compound of interest may be measured.
  • Various devices are available for detecting cellular response, such as a microphysiometer available from Molecular- Devices, Redwood City, California.
  • In vitro and in vivo assays useful in measuring GnRH antagonist activity are known in the art. See, e.g., Bowers et al., "LH suppression in cultured rat pituitary cells treated with 1 ng of LHRH," Endocrinology, 1980, 106:675-683 (in vitro,) and Corbin et al., "Antiovulatory activity (AOA) in rats," Endocr. Res. Commun., 2:1-23 1975.. Particular test protocols that may be used are described below.
  • GnRH-receptor antagonists may be functionally assessed by measurement of change in extracellular acidification rates as follows. The ability of compounds to block the extracellular rate of acidification mediated by GnRH in HEK 293 cells expressing human GnRH receptors is determined as a measure of the compound's antagonist activity in vitro. Approximately 100,000 cells/chamber are immobilized in agarose suspension medium (Molecular Devices) and perfused with unbuffered MEM media utilizing the Cytosensor ® Microphysiometer (Molecular Devices). Cells are allowed to equilibrate until the basal acidification rate remains stable (approximately one hour). Control dose-response curves are performed to GnRH (10 " ⁇ M to 10 "7 M).
  • Compounds are allowed to incubate 15 minutes prior to stimulation with GnRH, and are assessed for antagonist activity. After incubation with test compounds, repeat dose-response curves to GnRH in the presence or absence of various concentrations of the test compounds are obtained. Schild regression analysis is performed on compounds to determine whether compounds antagonize GnRH-mediated increases in extracellular acidification rates through a competitive interaction with the GnRH receptor.
  • accumulation of total inositol phosphates may be measured by formic acid extraction from cells, followed by separation ofthe phosphates on Dowex columns.
  • Cells are split using trypsin into two 12-well plates and pre-labeled with 3 H-myoinositol (0.5 Ci to 2 mCi per mL) for 16-18 hours in inositol-free medium.
  • the medium is then aspirated and the cells rinsed with either IX HBSS, 20 mM HEPES (pH 7.5), or serum-free DMEM, IX HBSS, 20mM HEPES (pH 7.5) containing test compound, and 20 mM LiCl is then added and the cells are incubated for the desired time.
  • the medium is aspirated and the reaction stopped by addition of ice-cold 10 mM formic acid, which also serves to extract cellular lipids.
  • Inositol phosphates are separated by ion-exchange chromatography on Dowex columns, which are then washed with 5 mL of 10 mM myoinositol and 10 mM formic acid. The columns are then washed with 10 mL of 60 mM sodium formate and 5 mM borax, and total inositol phosphates are eluted with 4.5 mL IM ammonium formate, 0.1M formic acid.
  • an exemplary daily dose generally employed will be from about 0.001 to about 1000 mg/kg of body weight, with courses of treatment repeated at appropriate intervals.
  • Administration of prodrugs may be dosed at weight levels that are chemically equivalent to the weight levels ofthe fully active compounds.
  • a pharmaceutical composition ofthe invention is administered in a suitable formulation prepared by combining a therapeutically effective amount (i.e., a GnRH modulating, regulating, or inhibiting amount effective to achieve therapeutic efficacy) of at least one GnRH agent of the invention (as an active ingredient) with one or more pharmaceutically suitable carriers, which may be selected from diluents, excipients and auxiliaries that facilitate processing of the active compounds into the final pharmaceutical preparations.
  • a therapeutically effective amount i.e., a GnRH modulating, regulating, or inhibiting amount effective to achieve therapeutic efficacy
  • one GnRH agent of the invention as an active ingredient
  • pharmaceutically suitable carriers which may be selected from diluents, excipients and auxiliaries that facilitate processing of the active compounds into the final pharmaceutical preparations.
  • one or more additional active ingredients such as a second GnRH agent, may be employed in a pharmaceutical composition according to the invention.
  • the pharmaceutical carriers employed may be either solid or liquid.
  • Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • Exemplary liquid carriers are syrup, peanut oil, olive oil, water and the like.
  • the inventive compositions may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate or the like. Further additives or excipients may be added to achieve the desired formulation properties.
  • a bioavaliability enhancer such as Labrasol, Gelucire or the like, or formulator, such as CMC (carboxymethylcellulose), PG (propyleneglycol), or PEG (polyethyleneglycol), may be added.
  • CMC carboxymethylcellulose
  • PG propyleneglycol
  • PEG polyethyleneglycol
  • Gelucire ® a semi-solid vehicle that protects active ingredients from light, moisture and oxidation, may be added, e.g., when preparing a capsule formulation.
  • the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
  • the amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g.
  • the preparation may be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or nonaqueous liquid suspension.
  • a semi-solid carrier is used, the preparation may be in the form of hard and soft gelatin capsule formulations.
  • the inventive compositions are prepared in unit-dosage form appropriate for the mode of administration, e.g., parenteral or oral administration.
  • a pharmaceutically acceptable salt of an inventive agent may be dissolved in an aqueous solution of an organic or inorganic acid, such as 0.3 M solution of succinic acid or citric acid. If a soluble salt form is not available, the agent may be dissolved in a suitable cosolvent or combinations of cosolvents. Examples of suitable cosolvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0-60% of the total volume.
  • a compound of Formula I, II, or III is dissolved in DMSO and diluted with water.
  • the composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.
  • the agents of the invention may be formulated into aqueous solutions, preferably in physiologically compatible buffers such as Hanks solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • disintegrating agents may be added, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate, and, optionally, stabilizers.
  • the active agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • the compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit-dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active agents may be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • a GnRH agent may be delivered in a pharmaceutically acceptable ophthalmic vehicle such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the corneal and internal regions of the eye, including, for example, the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris/cilary, lens, choroid/retina and selera.
  • the pharmaceutically acceptable ophthalmic vehicle may be an ointment, vegetable oil, or an encapsulating material.
  • a compound ofthe invention may also be injected directly into the vitreous and aqueous humor.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g, containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • the cosolvent system may be a VPD co-solvent system.
  • VPD is a solution of 3% w/v benzyl alcohol, 8% w/v ofthe nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the VPD co-solvent system (VPD: 5W) contains VPD diluted 1:1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
  • the proportions of a co-solvent system may be suitably varied without destroying its solubility and toxicity characteristics.
  • identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose.
  • hydrophobic pharmaceutical compounds may be employed.
  • Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs.
  • Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.
  • compositions also may comprise suitable solid- or gel- phase carriers or excipients.
  • suitable solid- or gel- phase carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • Some of the compounds of the invention may be provided as salts with pharmaceutically compatible counter ions.
  • Pharmaceutically compatible salts may be formed with many acids, including hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free-base forms.
  • the compounds of Formulas I, H and ITI and their intermediates may be prepared by advantageous processes described below.
  • Preferred intermediates useful for synthesizing the inventive compounds include 5-(2-methylphenoxy)-2-furoic acid, 5-[2-bromo-5-(tert-butyl)phenoxy]-2-furoic acid, 5-[(3,3,6-trimethyl-2,3-dihydro-lH- inden-5-yl)oxy]-2-furoic acid, 5-(4-chloro-5-isopropyl)-2-methylphenoxy)-2-furoic acid, 5-[(4-bromo-3,3,6-trimethyl-2,3-dihydro-lH-inden-5-yl)oxy]-2-furoic acid, and 6-methyl-2-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-4- pyrimidinecarboxylic acid. Additional preferred nitro and amine intermediates useful for synthes
  • nitration process of the present invention comprises forming a nitrating reagent by adding trifluoromethanesulfonic anhydride to 2-tetramethylammonium nitrate in a polar solvent and reacting the nitrating reagent with an aryl or heteroaryl compound.
  • Advantages of the present method are, e.g.: a) simplified and more rapid aqueous work-up, thereby eliminating chromatographic column separation and/or plug filtration; b) improved reactant solubility and reduced byproduct formation as a result of organic solvents rather than aqueous or easily hydrolyzed, corrosive anhydride solvents; c) facilitated synthesis of regioisomeric nitrated products sometimes not available when using other nitration procedures; d) enables the preparation of novel nitroaromatic and nitroheterocyclic compounds; e) achieves selective and exclusive mono-nitration from mild reaction conditions; f) provides higher product yields than many conventional nitration procedures; g) higher crude nitrated product purity; and h) scaleable over a wide range to provide small or large product quantities.
  • This nitration method described herein may be used to provide nitrated benzene derivatives (e.g., Compound II) and aromatic heterocyclic intermediates. Such nitrated intermediates are reduced (e.g., Compound II to Compound IH) to provide intermediates useful for preparing final GnRH agents of the invention (e.g., Compound V ⁇ the compound of Example B52).
  • the aromatic substrate 7.50 mmol of in 10 mL DCM, was added dropwise to the stirred nitronium triflate suspension keeping the reaction temperature at -65.0°C or less.
  • the addition funnel was then rinsed with 2 mL anhyd. DCM; this rinse also was added to the stirred reaction suspension.
  • the dry ice/acetone bath could then be removed; however, many reactions proceeded more cleanly if the bath was kept in place 30 to 60 minutes and was then allowed to warm unattended to room temperature over the next 15 to 48 hours. In several reactions, the acetone bath was kept in place one hour and then was replaced with a dry ice/acetonitrile cold bath.
  • the reaction contents were transferred with 25 mL DCM and 50 mL H 2 O. The lower
  • the reaction was stirred for two and one-half hours in a room temperature environment.
  • the reaction suspension was suction filtered, and the isolated iron powder was washed with 2 x 25 mL of ethanol, followed by 3 x 25 mL of ethyl acetate. Too the organic filtrate was added 200 mL water and 50 mL more ethyl acetate to effect separation.
  • the upper organic layer was separated, and the lower aqueous layer was extracted with 3 x 50 mL of ethyl acetate. All ethyl acetate portions were combined and dried over anhydrous magnesium sulfate.
  • VI VII The synthesis of VH was also achieved by direct nitronium triflate nitration of VI in a 73% crude yield with 85% crude yield purity. This represents the first synthesis of VH by direct nitration.
  • Use of the acetic anhydride/nitric acid nitration procedure gave several byproducts plus VII in only 16% purity.
  • the only other literature preparation appearing in the Beilstein electronic data base for V produced it from VI and gave a 66% yield [Cherkasov, V. M.; Remennikov, G. Ya.; Kisilenko, A. A. Chem. Heterocycl Compd. (Engl. Transl.); EN; 526 (1982)].
  • the addition funnel was rinsed with a small amount of DCM, and this rinse was added to the stirred reaction suspension.
  • the resultant suspension was stirred at room temperature for 1.5 hours.
  • the addition funnel was charged with 76.9 g (0.452 mole) dissolved in a minimum amount of DCM and was added dropwise at room temperature over 85 minutes such that the reaction temperature did not rise more than 5 °C, and a bright crimson red suspension resulted.
  • the reaction was stirred overnight at room temperature. Work up entailed adding 5 kg of ice to the stirred reaction suspension followed by 10% NaHCO 3 solution until a pH 8 was reached and the reaction turned from a burgundy to purple to blue to green to yellow color change.
  • Compound VLH represents another class of aromatic heterocycle product that was obtained by the above mentioned nitronium triflate method and demonstrates that a pendant ester group also is not attacked nor modified by these nitration conditions.
  • Nitration of non-heterocyclic aromatic compounds are also achieved with this anhydrous, one-pot, two-step method in which the nitronium triflate XVI nitrating reagent is generated in-situ under a static nitrogen gas blanket from tetramethylammonium nitrate XIV and trifluoromethanesulfonic anhydride (triflic anhydride) XV.
  • the aromatic compound to be nitrated is then introduced XVTI. Nitration occurs to produce the desired product XVHI plus the tetramethylammonium tiflate salt byproduct XIX.
  • the resulting salt byproduct XTX is water soluble and is removed during an aqueous work-up leaving only the desired nitrated product XVHI after drying.
  • higher homologues of XTV e.g. tetra-n-butylammonium nitrate and tetraethylammonium nitrate
  • XTV e.g. tetra-n-butylammonium nitrate and tetraethylammonium nitrate
  • the one lower homolog, ammonium nitrate, gives irreproducible results under analogous nitration conditions.
  • nitronium triflate From 1.05 to 1.50 equivalents of nitronium triflate have been used for mononitration ofthe aromatic or heterocyclic reactant with excess reagent having no deleterious effect. The less reactive the reactant, the larger the excess of nitronium triflate is needed for complete conversion. More than 1.5 equivalents of nitronium triflate could be used; no upper limit has been determined.
  • aromatic alkylsulfides 31 are cleanly oxidized to their analogous sulfoxide 32, and the sulfoxide 32 is then oxidized to a sulfone 33 in an apparent stepwise fashion. Once the fully oxidized sulfone 33 is obtained, nitration can then occur to provide the mono-nitrated sulfone 34. This is illustrated by the three following non- optimized reactions.
  • Reactant 14 (Table 2): the first two runs were conducted by removing the dry ice/acetone bath as described in the General Procedure. The best small-scale result with 14 used a slower warming profile by replacing the dry ice/acetone cooling bath with a dry ice/acetonitrile cold bath fro 2.5 hours (-49.6°C to -35.0°C), allowing the bath to warm to 9.0°C over the next 2.5 hours (-35.0°C-9.0°C), then removing the bath completely and stirring for 48 hours. This led to the following temperature warming modification for the large-scale nitrations with reactants 14, 25, and 27.
  • the reaction was kept one hour in the dry ice/acetone bath; then, it was then replaced with a dry ice/acetonitrile bath (ca. -45°C) for three hours, after which, the bath was permitted gradually to warm unattended to room temperature (RT) over the nexr 48 hours.
  • RT room temperature
  • the dry ice/acetone bath was removed as soon as addition was complete and was stirred in a RT environment for 24 hours.
  • the dry ice/acetone bath was not removed following its addition, but was left in place to warm gradually, unattended to RT over the next 23 hours.
  • inventive agents may be prepared using the reaction routes and synthesis schemes as described below, employing the techniques available in the art using starting materials that are readily available.
  • the preparation of preferred compounds of the present invention is described in detail in the following examples, but the artisan will recognize that the chemical reactions described may be readily adapted to prepare a number of other protein kinase inhibitors ofthe invention.
  • the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions.
  • other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds ofthe invention.
  • Reagents useful for synthesizing compounds may be obtained or prepared according to techniques known in the art. For example, the preparation of free amines from common salt forms and stock reagent solutions can be useful for small-scale reactions. See also Abdel-Magid et al, "Reductive Animation of Aldehydes and Ketones with Sodium Triacetoxyborohydride,” J. Org. Chem. 61: 3849 (1996).
  • Methanolic solutions of the free bases can be prepared from hydrochloride, dihydrochloride, hydrobromide, or other salts when the free base is soluble in methanol.
  • a 10-mL quantity of a 0.1M solution of a free base in methanol may be prepared as follows. Weigh 1.0 mmol of a monohydrochloride salt into a tared Erlenmeyer flask containing a stirring bar, and add 7 mL of methanol.
  • a 0.5 M solution of sodium borohydride in ethanol may be prepared as follows. Sodium borohydride (520 mg, 13.8 mmol) is stirred in pure (non-denatured) anhydrous ethanol (25 mL) for ⁇ 2-3 minutes. The suspension is filtered through a medium fritted glass funnel to remove a small amount of undissolved solid (typically about 5% ofthe total mass of borohydride, or 25 mg). The filtrate should appear as a colorless solution that evolves only a little hydrogen. This solution should be used immediately, as it decomposes significantly over a period of a few hours, resulting in the formation of a gelatinous precipitate.
  • Sodium borohydride is hygroscopic, so avoid exposure to air by making the solution at once after weighing the solid.
  • Sodium borohydride has a solubility of about 4% in ethanol at room temperature. This corresponds to a little over 0.8 M. However, sometimes a small percentage of the solid remains undissolved regardless of the concentration being prepared, even after stirring for > 5 minutes.
  • Potassium phenoxide 10 A mixture of potassium hydroxide (2.55g, 44.8 mmol) and the appropriate phenol 9 (52.9 mmol) was heated in an oil bath at 150-155 °C for 1-2 hours. The dark colored liquid was then evacuated at 130-140 °C to remove water. The residue (potassium phenoxide 10) was dried in vacuo overnight.
  • the phenoxide 10 may be prepared by reaction with potassium t- butoxide in tetrahydrofuran.
  • Condensation 12 A mixture of potassium phenoxide 10 (7 mmol), prepared as described above, and methyl 5-bromo-2-furoate 11 (5.8 mmol) in DMSO (10 mL) was heated at 85 °C under nitrogen atmosphere. The reaction mixture was then diluted with water, and the aqueous mixture was acidified with concentrated HCl, and then extracted with diethyl ether. The combined ether extracts were concentrated and the product 12 was purified by silica gel chromatography, eluting with a mixture of ethyl acetate and hexanes (1:5 to 1:1 v/v). Yield was in the range of 50-80%.
  • Saponification 13 The methyl ester 12 obtained from above was dissolved in methanol (4 mmol in 15 mL of solvent). An aqueous solution of sodium hydroxide (0.7g in 5 mL water) was added. The mixture was monitored by TLC for completion of reaction. It was concentrated, diluted with water, and extracted with diethyl ether. The aqueous layer was then acidified with concentrated HCl, and extracted with ethyl acetate. The ethyl acetate extracts were washed with brine, dried over magnesium sulfate and concentrated to give a solid residue. The product 5-substituted-2-furoic acid 13 may be purified, if necessary, by silica gel chromatography. Yield was greater than 90%.
  • the appropriate amide 15 may be prepared via carboxylic acid chloride 14.
  • a suspension of 13 (300mmol) in anhydrous benzene (lOOmfi containing a ew drops of anhydrous DMF was heated to relux under nitrogen as thionyl chloride(l.l eq.) in benzene (35ml) was added dropwise.
  • the solution was refluxed for 10 hours and then cooled to room temperature and concentrated under vacuum to give 14.
  • Example A5 5-[(l-bromo-3,8,8-trimethyI-5,6,7,8-tetrahydronaphthalen-2- yl)oxy]-N-(2,4,6-trimethoxypyrimidm-5-yl) ⁇ 2-furamide
  • Example A7 5-[(l-bromo-3,8,8-trimethyI-5,6,7,8-tetrahydronaphthalen-2- yl)oxy]-N-(2,6-dimethoxyphenyl)-2-furamide
  • Example A8 5-[(3-bromo-5,5,8,8-tetramethyI-5,6,7,8-tetrahydro-2- naphthalenyl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furami ⁇ e
  • 6-bromo-7-methoxy-l,l ? 4,4-tetramethyl-l,2,3,4-tetrahydronaphthaIene (i): A solution of 2-bromoanisole, 2,5-dichloro-2,5-dimethylhexane (1.1 equiv.) in dichloromethane (2 mL/mmol) was stirred at 0 °C under nitrogen as anhydrous A1C1 3 (7.5 mol%) was added portionwise while keeping the temperature below 5 °C. The suspension was allowed to warm to room temperature and further stirred for about 15 hours.
  • Example A12 5-[(7-chloro-l,4,4-trimethyI-2-oxo-l,2,3,4-tetrahydro-6- quinolinyl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide
  • Example A15 5-[(l-methoxy-3,8,8-trimethyl-5,6,7,8-tetrahydronaphthaIen-2- yl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide
  • Example A17 5-[(l-bromo-3,8,8-trimethyI-5,6,7,8-tetrahydronaphthalen-2- yl)oxy]-N-(2,4,6-trimethoxyphenyI)-2-furamide
  • Scheme B is a modification of Scheme A. Numbered compounds and identified reagents of Scheme B are analogous to those similarly identified compounds and reagents of Scheme A.
  • Example Bl N-(2,4,6-trimethoxyphenyl)-5- [(3,8,8-trimethyI-5,6,7,8-tetrahydro- 2-naphthaIenyl)oxy] -2-f iiramide
  • 3,8,8-trimethyl-5,6,7,8-tetrahydro-2-naphthalenoI 30 7-methoxy-l,l,6- trimethyl- 1,2,3 ,4-tetrahydronaphthalene (1.0 eq, 5.67 g, 27.8 mmol) was dissolved in methylene chloride (0.2 M) and cooled to -78°C. To this solution, BBr 3 (1.0 eq, 1 M, 27 mL) was added at once and stirred overnight slowly bringing the solution to room temperature. The solution was then quenched with methanol and passed through a silicagel plug to yield 3,8,8-trimethyl-5,6,7,8-tetrahydro-2-naphthalenol 30 (4.68 g, 88%).
  • Example B4 N-(2,6-dimethoxyphenyI)-5-[(5,5,8,8-tetramethyl-5,6,7,8- tetrahydro-2-naphtha!enyl)oxy]-2- uramide
  • Example B5 ethyl 4-[(5- ⁇ [5-(4-chIoro-3-isopropyl-2-methoxy-6-methylphenoxy)- 2-furoyl]amino ⁇ -4,6-dimethoxy-2-pyrimidinyl)amino]butanoate
  • Example B6 4-bromo-5- [(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2- naphthalenyl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide
  • Example B7 4-bromo-5- [(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2- naphthalenyl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide
  • Example B9 5-[(2,2,5,7,8-pentamethyl-3,4-dihydro-2h-chromen-6-yl)oxy]-n- (2,4,6-trimethoxyphenyl)-2-furamide
  • Example B12 N-[(5-methyl-2-pyrazinyl)methyl]-5-[(4,4,7-trimethyl-3,4-dihydro- 2H-chromen-6-yl)oxy]-2-furamide
  • Example B16 5-[(3-isopropyI-l,l,2,6-tetramethyl-2,3-dihydro-lH-inden-5- yl)oxy]-N-(2,4,6-trimethoxy-5-pyrimidinyI)-2-furamide
  • Compound B17 was synthesized from Compound B5.
  • Compound B5 (53 mg, 0.089 mmol) was dissolved in ethanol (1 mL) and an aqueous solution of sodium hydroxide (2 equivalents) was added. The reaction was monitored by TLC
  • Example B18 5-[(3-isopropyl-l,l 5 2,6-tetramethyl-2,3-dihydro-lH-inden-5- yl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide
  • Example B20 N-[2-(2,4-difluorophenoxy)-3-pyridinyl]-5-[(3-isopropyl-l,l,2,6- tetramethyl-2,3-dihydro-lH-inden-5-yl)oxy]-2-furamide
  • Example B21 4-bromo-5-[(3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydro-2- naphthalenyl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide
  • Example B23 4-bromo-5-[(3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydro-2- naphthalenyl)oxy]-N-(2,4,6-trimethoxy-5-pyrimidinyl)-2-furamide
  • Example B24 4-bromo-N-(2,4,6-trimethoxyphenyI)-5-[(3,3,6-trimethyl-l,3- dihydro-2-benzofuran-5-yl)oxy]2-furamide
  • NMR and mass spectrometry data consistent with the desired title product were as follows: l H (300 MHz, CDC1 3 ): ⁇ 1.46 and 2.37 (2s, 6H and 3H respectively), 3.81 (s, 6H), 3.99 (s, 3H), 5.01, 6.16 (2s, 2H each), 6.62 and 7.05 (2s, IH each), 7.09 (brs, IH), 7.20 (s, IH), APCI-MS m/z 533 and 534 (M+H) + .
  • Example B25 4 ⁇ bromo-N-methyl-N-(2,4,6-trimethoxyphenyI)-5-[(3,3,6- trimethyl-l,3-dihydro-2-benzofuran-5-yI)oxy]-2-furamide
  • Example B29 N- ⁇ 4,6-dimethoxy-2-[(2-morpholin-4-ylethyl)amino]pyrimidin-5- yl ⁇ -5-[(3,3,6-trimethyI-2,3-dihydro-lH-inden-5-yl)oxy]-2-furamide
  • Example B31 N-(2,4,6-trimethoxyphenyl)-5-[(3,3,6-trimethyl-2,3-dihydro-lH- inden-5-yI)oxy]-2-furamide
  • Example B32 N-(2,6-dimethoxyphenyl)-5-[(l,l,3,3,6-pentamethyl-2,3-dihydro- lH-inden-5-yl)oxy]-2-furamide
  • Example B34 N-(4,6-dimethoxy-2- ⁇ [3-(4-methylpiperazin-l- yl)propyl]amino ⁇ pyrimidin-5-yl)-5-[(3,8,8-trimethyl-5,6,7,8- tetrahydronaphthalen-2-yl)oxy]-2-furamide
  • Example B36 N-(2,4,6-trimethoxy-5-pyrimidinyl)-5-[(3,3,6-trimethyl-2,3- dihydro-lH-inden-5-yl)oxy]-2-furamide
  • Example B40 ⁇ -(2- ⁇ [3-(dimethyIamino)propyl]amino ⁇ -4,6- dimethoxypyrimidin-5-yl)-5-[(3,8,8-trimethyl-5,6,7,8-tetrahydronaphthalen- 2-yl)oxy] -2-furamide
  • Example B48 5-(5-Chloro-l,l,7-trimethyl-indan-4-yloxy)-furan-2-carboxylic acid [2-(3-dimethylamino-propylamino)-4,6-dimethoxy- ⁇ yrimidin-5-yl]-amide acetic acid salt
  • Example B50 5-[(3-isopropyl-l,l,4,6-tetramethyl-2,3-dihydro-lH-inden-5- yl)oxy]-N-(2,4,6-trimethoxypyrimidin-5-yl)-2-furamide
  • Example B52 N- ⁇ 4,6-dimethoxy-2- [(3-morpholin-4-ylpropyl)amino] py rimidin-5- ylJ-S-P ⁇ -trimthyl ⁇ j S-dih dro-Zfl-inden-S-y oxyl ⁇ -furamide
  • 5-hydroxy-3,3,6-trimethyl-l-indanone 62 To a three-necked round bottom flask assembled with a condenser, thermometer and mechanic stirrer under nitrogen, o-cresol (1197 mmol, 124 ml) and 3,3-dimethylacrylic acid (1520 mmol, 154 g) were added. The mixture was gently stirred and heated at 40 °C while adding polyphosphoric acid (3.9 L). After the addition of polyphosphoric acid was completed, the contents were rapidly heated to 105 °C, and the heating mantel was removed. The reaction mixture was monitored by TLC (1:3 ethyl acetate: hexane) showing no starting materials.
  • 3,3,6-trimethyI-5-indanol 63 A solution of 5-hydroxy-3,3,6-trimethyl-l- indanone (21.5 mmol, 4.1 g) and sulfuric acid (290 ul) in methanol (150 ml) were degassed with nitrogen for at least twenty minutes following by the addition of catalyst palladium on carbon (4.3 mmol, 0.63 g). The ketone was reduced under 40 psi of H 2 overnight. The contents were filtered over celite. Methanol was removed in vacuum to give brown oil residue that was redissolved in ethyl acetate and washed with water until neutral and brine. The organic layer was dried over sodium sulfate and brought to dryness given light yellow oil.
  • Methyl 5-[(3,3,6-trimethyI-2,3-dihydro-lH-inden-5-yl)oxy]-2-furoate 65 In a one-necked round-bottom flask assembled with a condenser and gas outlet, a solution of 63 (22.73 mmol, 4.0 g), 64 (17.6 mmol, 3.6 g) and cesium carbonate ( 22.8 mmol, 7.4 g) in DMF ( 45 mL) was degassed with nitrogen gas for 20 minutes then heated to 100 C for 7 hours under N 2 . The mixture was cooled down to room temperature and quenched with IM HCl. The content was extracted with ethyl acetate, water and brine.
  • 2-chloro-4,6-dimethoxy-5-nitropyrimidine 24 In a 12-L flask assembled with an overhead stirrer, thermometer, N 2 inlet and addition funnel, tetramethylammonium nitrate (587 g, 4.31 moi) and dichloromethane (4 L) were added. The contents were stirred under N 2 for 1 hour at room temperature (20°C). Triflic anhydride (1.216 g, 4.31 moi, 725 ml) was added dropwise over a period of 45 minutes so that the temperature remained below 25°C. The addition funnel was rinsed with 100 ml of dichloromethane, and the dichloromethane was added to the reaction. The contents were stirred at room temperature under N 2 for 2 hours.
  • the reaction mixture was then cooled to -78°C in a dry ice/acetone bath.
  • the 2-chloro-4,6- dimethoxypyrimidine 73 (500 g, 2.87 moi) was dissolved in minimal amount of dichloromethane (3L).
  • the solution of 73 was added dropwise over a period of 1.5 hours. The addition rate was important to ensure the temperature did not rise above 5°C.
  • the addition funnel was rinsed with 100 ml of dichloromethane and the rinse was added to the reaction. The acetone/dry bath was removed and the reaction was stirred for 38 hours under N2 as it warmed to room temperature.
  • N-(5-amino-4,6-dimethoxy-2-pyrimidinyl)-N-(3-(4- morpholinyl)propyl]amine 67 A solution of 4,6-dimethoxy-N-(3-morpholin-4- ylpropyl)-5-nitropyrimidine-2-amine 75 (55 mmol, 18 g) in methanol (500 ml) was degassed for 15 minutes followed by the addition of catalyst Pd/C (5.5 mmol, 0.8 g).
  • Example B55 5-[(4-bromo-3,3,6-trimethyl-2,3-dihydro-lH-inden-5-yl)oxy]-N- (4,6-dimethoxy-2- ⁇ [3-(4-methylpiperazin-l-yl)propyI]amino ⁇ pyrimidin-5-yI)-2- furamide
  • Example B56 5-[(4-bromo-3,3,6-trimethyl-2,3-dihydro-lH-inden-5-yl)oxy]-N- ⁇ 4,6-dimethoxy-2-[(3-morpholin-4-ylpropyl)amino]pyrimidin-5-yl ⁇ -2-furamide
  • Example B57 5-(2-bromo-5-tert-butylphenoxy)-N-(4,6-dimethoxy-2- ⁇ [3-(4- methylpiperazin-l-yl)propyI]amino ⁇ pyrimidin-5-yl)-2-furamide
  • Example B58 5-[(l-Methoxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2- naphthalenyl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide
  • Example B60 5-[(l-methoxy-3,5,5,8,8-pentamethyl-5,6,7,8- tetrahydronaphthalen-2-yl)oxy]-N-(2,4,6-trimethoxypyrimidin-5-yl)-2-furamide
  • Example B61 5-[5-(tert-butyl)-2-methylphenoxy]-N-(4,6-diemthoxy-2- ⁇ [3-(4- methyl-l-piperazinyl)propyl]amino ⁇ -5-pyrimidinyl)-2-furamide
  • Example B66 5-[(3,6,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-N- (2,4,6-trimethoxyphenyl)-2-furamide
  • Example B71 5-(4-chIoro-5-isopropyI-2-methyIphenoxy)-N-(4,6-dimethoxy-2- phenoxypyrimidin-5-yl)-2-furamide
  • Example B73 5-(4-chloro-3-isopropyl-2-methoxy-6-methylphenoxy)-N-(4,6- d ⁇ methoxy-2- ⁇ [3-(4-methyl-l-piperazinyl)propyl]amino ⁇ -5-pyrimidinyl)-2- furamide
  • Example B77 4-bromo-N-(2,6-dimethoxyphenyl)-5-[(3,5,5,8,8-pentamethyl- 5,6,7,8-tetrahydro-2-naphthalenyl)oxy] -2-furamide
  • Example B78 N-(4,6-dimethoxy-2- ⁇ [3-(4-methyl-l-piperazinyl)propyl]amino ⁇ -5- pyrimidinyI)-5-[(2,2,4,6-tetramethyl-2,3-dihydro-l-benzofuran-7-yl)oxy]-2- furamide
  • Example B80 N- ⁇ 4,6-dimethoxy-2-[(3-morpholin-4-ylpropyl)amino]pyrimidin-5- yl ⁇ -5-[(3,3,6-trimethyl-2,3-dihydro-lH-inden-5-yl)oxy]-2-furamide acetate
  • Example B82 5-[(3-methoxy-l,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2- naphthalenyl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide
  • Example B83 5-[(3-methoxy-l,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2- naphthalenyl)oxy]-N-(2,4,6-trimethoxy-5-pyrimidinyI)-2-furamide
  • Example B87 5-[(4,6-dibromo-2,2-dimethyl-2,3-dihydro-l-benzofuran-7-yl)oxy]- N-(4,6-dimethoxy-2- ⁇ [3-(4-methyIpiperazin-l-yl)propyl]amino ⁇ pyrimidin-5-yl)-2- furamide
  • Example B89 N-(4,6-dimethoxy-2- ⁇ [3-(4-methyIpiperazin-l- yl)propyl]amino ⁇ pyrimidin-5-yl)-5-[(3.3.6-trimethyl-2,3-dihydro-lH-inden-5- yl)oxy]-2-furamide
  • Example B90 N-(2- ⁇ [2-(dimethylamino)ethyl]amino ⁇ -4,6-dimethoxypyrimidin-5- yl)-5-[(3,3,6-trimethyl-2,3-dihydro-lH-inden-5-yl)oxy]-2-furamide
  • Example B91 5-[(3,5,5,7,8,8-hexamethyl-5,6,7,8- tetrahydro-2- naphthalenyl]oxy ⁇ -N-(2,4,6-triethyl-5-pyrimidinyl)-2-furamide
  • Example B103 N- ⁇ 4,6-dimethoxy-2-[methyl(pyridin-2- ylmethyl)amino]pyrimidin-5-yl ⁇ -5-[(3,3,6-trimethyl-2,3-dihydro-lH-inden-5- yl)oxy]-2-furamide
  • Example B104 5-[(6-methoxy-3,3-dimethyI-2,3-dihydro-lH-inden-5-yl)oxy]-N- (2,4,6-trimethoxy-5-pyrimidinyl)-2-furamide
  • Example B106 5-[(4,4,7,8-tetra-mehtyl-l,2,3,4-tetrahydroquinolin-6yl)oxy]-N- (2,4,6-trimethoxyphenyl)-2-furamide
  • Example BllO 4-[(7-chloro-4,4-dimethyl-l,2,3,4-tetrahydroquinoIin-6-yI)oxy]-N- (2,4,6-trimethoxypyrimidin-5-yI)-2-furamide
  • Example B112 5- ⁇ 5-(diethyIamino)-2-methyIphenoxy]-N-(4,6-dimethoxy-2- ⁇ [3- (4-methylpiperazin-l-yl)-propyl]amino ⁇ pyrimidin-5-yl)-2-furamide
  • Example B115 N-(4,6-dimethoxy-2- ⁇ [3-(4-methylpiperazin-l- yl)propyl]amino ⁇ pyrimidin-5-yl)-5-[(3,3,6-trimethyl-2,3-dihydro-lH-inden-5- yl)oxy]-2-furamide acetic acid salt
  • Example B117 N-(4,6-dimethoxy-2- ⁇ [3-(4-morpholinyl)propyl]amino ⁇ -5- pyrimidinyl)-5-[(3,3,6-trimethyl-l,3-dihydro-2-benzofuran-5-yl)oxy]-2-furamide
  • Example B118 N-(4,6-dimethoxy-2- ⁇ [3-(4-morpholinyl)propyl]amino ⁇ -5- pyrimidinyl)-5-[(l-methoxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2- > naphthaIenyl)oxy]-2-furamide
  • Example B120 5-[(7-chloro-4,4-dimethyl-l,2,3,4-tetrahydro-6-quinolinyl)oxy]-N- ⁇ 2,6-dimethoxy-4-[3-(4-morpholinyl)propoxy]pyrimidinyI ⁇ -2-furamide
  • Example B121 5-(2-bromo-5-tert-butylphenoxy)-N- ⁇ 4,6-dimethoxy-2-[(3- morpholin-4-ylpropyl)amino]pyrimidin-5-yl ⁇ 2-furamide
  • Example B122 N- ⁇ 4,6-dimethoxy-2-[(3-morpholin-4-ylpropyl)amino]pyrimidin- 5-yl ⁇ -5-[(4,4,7-trimethyl-3,4-dihydro-2H-chromen-6-yl)oxy]-2-furamide
  • Example B123 ethyl 4-[(5- ⁇ [5-(5-tert-butyl-2-methoxyphenoxy)-2-furoyl]amino ⁇ - 4,6-dimethoxy-2-pyrimidinyl)amino]butanoate
  • Example B125 [5-(tert-butyl)-2-methoxyphenoxy]-N-(4,6-dimethoxy]-2- ⁇ [3-(4- 0 morpholinyl)propyl]amino ⁇ -5-pyrimidinyl)-2-furamide
  • Example B126 N-(4,6-dimethoxy-2- ⁇ [3-(4-methyl-l-piperazinyI)propyl]amino ⁇ - 5-pyrimidinyl)-5-[(6-methoxy-3,3-dimethyl-2,3-dihydro-lH-inden-5-yl)oxy-2- furamide
  • Example B127 N-(4,6-dimethoxy-2- ⁇ [3-(4-methyI-l-piperazinyl)propyl]amino ⁇ - 5-pyrimidinyl-5-[(5-methoxy-l,l-dimethyl-lH-inden-6-yl)oxy]-2-furamide
  • Example B128 N-(4,6-dimethoxy-2- ⁇ [3-(4-morpholinyI)propyl]amino ⁇ -5- pyrimidinyl)-5-[(6-methoxy-3,3-dimethyl-2,3-dihydro-lH-inden-5-yl)oxy]-2- furamide
  • Example B129 N-(4,6-dimethoxy-2- ⁇ [3-(4-morpholinyl)propyl]amino ⁇ -5- pyrimidinyl)-5-[(5-methoxy-l,l-dimethyl-lH-inden-6-yl)oxy]-2-furamide
  • Example B130 N-(2,6-dimethoxy-4- ⁇ [3-(4-methyl-l- piperazinyl)propyl]amino ⁇ phenyl)-5-[(6-methoxy-3,3-dimethyl-2,3-dihydro-lH- inden-5-yl)oxy] -2-f uramide
  • Example B131 N-(2- ⁇ [3-dimethylamino)propyl]amino ⁇ -4,6-dimethoxy-5- pyrimidinyl)-5-[(5-methoxy-l,l-dimethyl-lH-inden-6-yl)oxy]-2-furamide
  • Example B132 N-(2- ⁇ [3-(dimethylamino)propyl]amino ⁇ -4,6-dimethoxy-5- pyrimidinyl)-5-[(6-methoxy-3,3-dimethyl-2,3-dihydro-lH-inden-5-yI)oxy]-2- furamide
  • Example B133 5-(2-bromo-5-tert-butylphenoxy)-N-(2- ⁇ [3-(lH-imidazol-l- yl)propyl]amino ⁇ -4.6-dimethoxypyrimidin-5-yl)-2-furamide
  • Example B134 5-(2-bromo-5-tertbutylphenoxy)-N- ⁇ 4,6-dimethoxy-2-[(2- pyrrolidin-l-ylethyl)amino]pyrimidin-5-yl ⁇ -2-furamide
  • Example B135 5-(2-bromo-5-tert-butylphenoxy)-N-(2- ⁇ [3- (dimethylamino)propyl]amino ⁇ -4,6-dimethoxypyrimidin-5-yl)-2-furamide
  • Example B137 5-[(6-chloro-3,3-dimethyl-2,3-dihydro-lH-inden-5-yl)oxy]-N-(4,6- dimethoxy-2- ⁇ [3-(4-methyI-l-piperazinyl)propyl]amino ⁇ -5-pyrimidinyl)-2- furamide
  • Example B138 N- ⁇ 2-[(2-aminoethyl)(propyl)amino]-4,6-dimethoxypyrimidin-5- yl ⁇ -5-(2-bromo-5-tert-butylphenoxy)-2-furamide
  • Example B140 N-(2-chloro-4,6-dimethoxypyrimidin-5-yl)-5-[(3,3,6-trimethyl- l,3-dihydro-2-benzofuran-5-yl)oxy]-2-furamide
  • Example B141 N- ⁇ 4,6-dimethoxy-2-[(3-piperidin-l-ylpropyl)amino] pyrimdine- 5-yl ⁇ -5-[(3,3,6-trimethyl-2,3-dihydro-lH-inden-5-yl)oxy]-2-furamide
  • Example B145 l-te/ , i'-butyl-3,4-dimethyI-lH-pyrazolo[3,4-6]pyridin-6-yl 5- [(3,3,6-trimethyl-l,3-dihydro-2-benzofuran-5-yl)oxy]-2-furoate
  • Example B147 N-(2-anilino-4,6-dimethoxypyrimidin-5-yl)-5-[(3,3,6-trimethyI- l,3-dihydro-2-benzofuran-5-yl)oxy]-2-furamide
  • Example B148 N-(4,6>dimethoxy-2- ⁇ [2-(methyl ⁇ 5-[(3,3,6-trimethyl-l,3-dihydro- 2-benzofuran-5-yl)oxy]-2-furoyl ⁇ amino)ethyl]amino ⁇ pyrimidin-5-yl)-5-[(3,3,6- trimethyl-1 ,3-dihy dro-2-benzofuran-5-yl)oxy] -2-f uramide
  • Example B149 l,3,4-trimethyl-lH-pyrazolo[3,4-6]pyridin-6-yl 5-[(3,3,6- trimethyl-l,3-dihydro-2-benzofuran-5-yl)oxy]-2-furoate
  • Example B150 N-(2,4,6-trimethoxypyrimidin-5-yl)-5-[(3,3,6-trimethyl-l,3- dihydro-2-benzofuran-5-yl)oxy]-2-furamide
  • Example B151 5-(2-bromo-5-tert-butyIphenoxy)-N-(4,6-dimethoxy-2- ⁇ [3-(4- methylpiperazin-l-yl)propyl]amino ⁇ pyrimidin-5-yl)-2-furamide acetate salt
  • Compound B152 was synthesized according to scheme B wherein the phenol was synthesized according to the following scheme.
  • Example B153 5-[(5-chloro-l,l,7-trimethyI-2,3-dihydro-lH-inden-4-yl)oxy]-N- ⁇ 4,6-dimethoxy-2-[(3-morpholin-4-ylpropyl)amino]pyrimidin-5-yl ⁇ -2-furamide acetate
  • Example B154 5-(2-bromo-5-tert-butyIphenoxy)-N-(4,6-dimethoxy-2- ⁇ [2- (propylamino)ethyl]amino ⁇ pyrimidin-5-yl)-2-furamide acetate salt
  • 5-bromo-2-furoyl chloride 32 A suspension of 5-bromo-2-furoic acid (31, 57.3 g, 300 mmol) in anhydrous benzene (100 mL) containing few drops of anhydrous DMF was heated to reflux under nitrogen as thionyl chloride (1.1 equiv., 24.6 mL) in benzene (35 mL) was added dropwise. The resulting pale brown solution was further reflux for an additional 10 hours. The solution was cooled to room temperature and concentrated under vacuum to give 61.5 g (98%) of crude acid chloride. The 1 HNMR ofthe crude showed >95%> purity. The crude acid chloride 32 thus obtained was used in the next step without further purification. NMR data consistent with the title product were as follows: 1 HNMR (CDC1 3 ): ⁇ 6.74 (d, IH), 7.38 (d, IH).
  • 5-bromo-N-(2,4,6-trimethoxyphenyl)-2-furamide 34 A mixture of frimethoxyaniline hydrochloride (33, 1.2 equiv., 21.1 g, 96 mmol) and triethyl amine (2.5 equiv., 27.9 mL, 200 mmol) in dichloromethane (200 mL) was stirred at 0°C under nitrogen as a solution of 5-bromo-2-furoyl chloride (16.8 g, 80 mmol) in dichloromethane (120 mL) was added dropwise. The solution was allowed to warm to room temperature and further stirred for 12 hours.
  • NMR data consistent with the titie product were as follows: 1H NMR (CDC1 3 ): ⁇ 3.82 (s, 9H), 6.18 (s, 2H), 6.47 (d, IH), 7.19 (d, IH), 7.29 (br s, IH).
  • 5-aryIoxy-2-furamide 36 A suspension of a phenol (35, 2.85 g, 13 mmol) and cesium carbonate (1.3 equiv., 4.24 g, 13 mmol) in anhydrous DMF (20 mL) was stirred at room temperature under nitrogen for 15 minutes before adding 5-bromo-N- (2,4,6-trimethoxyphenyl)-2-furamide (34, 3.57 g, 10 mmol) at once.
  • 5-hydroxy-6-methoxy-3,3-dimethyl-l-indanone (iii) A mixture of 3,3- dimethylacrylic acid, 2-methoxyphenol (1.25 equiv.), and polyphosphoric acid (3 g/mmol) was heated to 45 °C for 0.5 hours. The reaction temperature was gradually increased to 110 °C and kept at that temperature for 2 hours. The viscous oil was cooled to 55-60 °C and extracted extensively with ethyl acetate. The organic layer was washed with saturated NaHCO 3 , dried over Na 2 SO 4 and concentrated. The crude residue was recrystallized from ether to afford 5-hydroxy-6-methoxy-3,3-dimethyl-l- indanone in 30-35% isolated yield.
  • 1-indanone was hydrogenated with 10%) Pd on carbon (25 mg mmol), in the presence of catalytic amount of concentrated H SO ( 25 mg/mmol) in methanol (2 mL/mmol) for 15 hours. The resulting suspension was filtered through Celite and washed the precipitate with ethyl acetate. The filfrate was dried over Na 2 SO and concentrated to give 6-methoxy-3,3-dimethyl-5-indanol in 90%> yield.
  • Example C13 5-[(3-formyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2- naphthalenyl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide
  • Example C18 5-[(3-ChIoro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2- naphthalenyl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide
  • Example C22 [3,5-dimethoxy-2-( ⁇ 5-[(3,5,5,8,8-pentamethyl-5,6,7,8- tetrahydronaphthalen-2-yl)oxy]-2-furoyl ⁇ amino)phenoxy]acetic acid

Abstract

La présente invention concerne des agents GnRH non peptidiques qui sont capables d'inhiber l'effet de la gonadolibérine. Ces composés et leurs sels pharmaceutiquement acceptables, les promédicaments et les métabolites actifs de ces derniers sont adaptés pour traiter les troubles de la reproduction chez les mammifères et les tumeurs dépendant des hormones stéroïdes ainsi que pour réguler la fertilité, cas pour lequel la suppression de la libération de gonadotrophine est indiquée. Des méthodes de synthèse de ces composés et des intermédiaires utiles pour les préparer sont également présentées.
EP02739712A 2001-06-06 2002-06-05 Agents gnrh non peptidiques, compositions pharmaceutiques et methodes d'utilisation de ces dernieres, procedes de preparation de ces composes Withdrawn EP1401427A4 (fr)

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MXPA03011002A (es) 2004-10-28
AU2002312348A1 (en) 2002-12-16
BR0210191A (pt) 2004-04-06
JP2005501006A (ja) 2005-01-13
CA2449843A1 (fr) 2002-12-12
WO2002098363A2 (fr) 2002-12-12
EP1401427A4 (fr) 2004-12-01
WO2002098363A3 (fr) 2003-03-20

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