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EP1307193A1 - Agoniste d'activite hormonale stimulant un follicule - Google Patents

Agoniste d'activite hormonale stimulant un follicule

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Publication number
EP1307193A1
EP1307193A1 EP01955958A EP01955958A EP1307193A1 EP 1307193 A1 EP1307193 A1 EP 1307193A1 EP 01955958 A EP01955958 A EP 01955958A EP 01955958 A EP01955958 A EP 01955958A EP 1307193 A1 EP1307193 A1 EP 1307193A1
Authority
EP
European Patent Office
Prior art keywords
substituted
group
alkyl
mmol
member selected
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01955958A
Other languages
German (de)
English (en)
Inventor
Randall A. Scheuerman
Stephen D. Yanofsky
Christopher P. Holmes
Derek Maclean
Beatrice Ruhland
Ronald W. Barrett
Jay E. Wrobel
Wenling Kao
Ariamala Gopalsamy
Fuk-Wah Sum
Baihua Hu
John F. Rogers
James W. Jetter
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
Affymax Researh Institute Inc
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Filing date
Publication date
Application filed by Affymax Researh Institute Inc filed Critical Affymax Researh Institute Inc
Publication of EP1307193A1 publication Critical patent/EP1307193A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • 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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • 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
    • A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D277/14—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This invention relates broadly to novel thiazolidinones. More specifically, the invention relates to thiazolidinones which modulate Follicle Stimulating Hormone (FSH) activity.
  • FSH Follicle Stimulating Hormone
  • germ cells are stored in the ovaries of the human female at the time of puberty. No further germ cells are made. Beginning at the time of puberty and ending at menopause, there are approximately 400 ovulatory rnenstrual cycles which consume essentially all of the germ cells in the human ovary. About 1,000 germ cells are consumed in each menstrual period. However, in any one menstrual cycle, only one germ cell, developed in what becomes the dominant follicle, is ovulated and available for pregnancy.
  • LH luteinizing hormone
  • FSH follicle stimulating hormone
  • hCG chorionic gonadotropin
  • GRF somatotrophin releasing factor
  • Thiazolidinones are a class of small molecule organic compounds which have found limited pharmaceutical use. For example, thiazolidinones have been found to have central nervous system activity. See, for example, Tripathi, et al, "Thiazolidinone congeners as central nervous system active agents.” Arzneistoffforschung 43:632-5 (1993). CNS activities which have been identified include, for example, antipsychotic properties.
  • Thiazolidinones have also been used as antimicrobial agents. See, for example, Ley, et al, "Inhibition of multiplication of Mycobacterium leprae by several antithyroid drugs.” Am. Rev. Respir. Dis. 111:651-5 (1975).
  • novel thiazolidinones offer the promise for discovering new pharmaceutical agents with applications in areas as diverse as, for example, antimicrobial therapy and the treatment of strokes with CNS antuschemic agents.
  • novel thiazolidinones are regulators of mammalian fertility.
  • the present invention provides a class of novel thiazolidinones possessing a range of pharmaceutical applications and activities.
  • the present invention provides novel thiazolidinones having the formula:
  • R 1 is a member selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocychc and substituted heterocylic groups;
  • R 2 is a member selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocychc and substituted heterocylic groups;
  • R 5 and R 6 are independently members selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, arylalkyl, substituted arylalkyl, heterocyclicalkyl and substituted heterocyclicalkyl groups;
  • Y is a member selected from the group consisting of O, S, and NH;
  • Y is a member selected from the group consisting of CH 2 , O, S, and NR ;
  • Y is a member selected from the group consisting of O and NR ;
  • R 7 is a member selected from the group consisting of hydrogen and lower alkyl
  • X 2 is a member selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, heterocychc, substituted heterocychc, arylalkyl, substituted arylalkyl, heterocyclicalkyl and substituted heterocyclicalkyl groups; m is an integer from 0 to 3; n is 0 or 1 ; and s is 1 or 2.
  • the present invention provides novel thiazolidinones having the structure:
  • R 1 is a member selected from the group consisting of aryl, substituted aryl, arylalkyl and substituted arylalkyl groups;
  • R 2 is a member selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocychc and substituted heterocychc groups;
  • R 3 and R 4 are independently members selected from the group consisting of hydrogen, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, heterocychc and substituted heterocychc groups;
  • the invention provides a class of FSH receptor agonists, wherein the receptor agonists are noncompetitive with FSH for the receptor FSH binding site.
  • the invention provides a class of compounds that modulate FSH hormone activity, the compounds having: (a) a molecular weight of from about 50 daltons to about 1000 daltons; and (b) an FSH agonist activity corresponding to an EC 50 standard of no more than 50 ⁇ M, preferably no more than 2 ⁇ M; wherein the agonist activity of this class of compounds to the FSH receptor is competitively inhibited by a compound having the formula: wherein,
  • R 1 is a member selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocychc and substituted heterocylic groups;
  • R 2 is a member selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocychc and substituted heterocylic groups;
  • R 5 and R 6 are independently members selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, arylalkyl, substituted arylalkyl, heterocyclicalkyl and substituted heterocyclicalkyl groups;
  • Y is a member selected from the group consisting of O, S, and NH;
  • Y 2 is a member selected from the group consisting of CH 2 , O, S, and NR 5 ;
  • Y 3 is a member selected from the group consisting of O and NR 6 R 7 ;
  • R is a member selected from the group consisting of hydrogen and lower alkyl
  • X 2 is a member selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, heterocychc, substituted heterocychc, arylalkyl, substituted arylalkyl, heterocyclicalkyl and substituted heterocyclicalkyl groups; m is an integer from 0 to 3; n is O or 1; and s is 1 or 2.
  • the invention provides a class of compounds that modulate FSH hormone activity, the compounds having: (a) a molecular weight of from about 200 daltons to about 1000 daltons; and (b) an FSH agonist activity corresponding to an EC50 standard of no more than 50 ⁇ M, preferably no more than 2 ⁇ M; wherein the agonist activity of this class of compoimds to the FSH receptor is competitively inhibited by a compound having the formula:
  • R 1 is a member selected from the group consisting of aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocychc and substituted heterocychc groups
  • R 2 is a member selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocychc and substituted heterocychc groups
  • R 3 and R 4 are independently members selected from the group consisting of hydrogen, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, heterocychc and substituted heterocychc groups
  • this class of compounds has a molecular weight of about 300 daltons to about 800 daltons. In another preferred embodiment, this class of compounds has an FSH receptor agonist activity, as expressed by an EC 5 o standard, of no more than 1 ⁇ M and, more preferably, of no more than 500 nM.
  • the invention provides methods of using the compounds, i.e., thiazolidinones, for diverse pharmaceutical applications including, for example, CNS antuschemic agents, agents with antipsychotic or other psychoactive properties, antimicrobial agents and mammalian fertility regulating agents.
  • the thiazolidinones are preferably agonists of the FSH receptor.
  • the present invention provides pharmaceutical compositions which contain one or more of the compounds of the invention in conjunction with pharmaceutically acceptable excipients, carriers, diluents, etc.
  • the pharmaceutical compositions can also contain agents which are themselves pharmacologically active and which serve to enhance, supplement, decrease or otherwise regulate the pharmacological effect of the pharmaceutical compositions.
  • HATU [O-(7-Azabenzotriazol-l-yl)-l, 1,3,3- tetramethyluromumhexafluorophosphate]
  • DIEA diisopropylethylamine
  • FMOC fluorenylmethoxycarbonyl
  • DECP diethyl cyanophosphonate
  • DCM dichloromethane
  • DBU l,8-diazabicyclo[5.4.0]undec-7-ene
  • CHO Chinese hamster ovary
  • RBF round- bottomed flask.
  • R groups e.g., R 1 , R 2 , R 4 and R 5
  • R 1 , R 2 and R 3 may all be substituted alkyls or R 1 and R 2 may be a substituted alkyl and R 3 may be an aryl, etc.
  • R group will generally have the structure which is recognized in the art as corresponding to R groups having that name.
  • representative R groups as enumerated above are defined herein. These definitions are intended to supplement and illustrate, not preclude, the definitions known to those of skill in the art.
  • alkyl is used herein to refer to a branched or unbranched, saturated or unsaturated, monovalent hydrocarbon radical having from 1-12 carbons and preferably, from 1-6 carbons. When the alkyl group has from 1-6 carbons, it is referred to as a "lower alkyl.”
  • Suitable alkyl radicals include, for example, methyl, ethyl, n-propyl, i-propyl, 2-propenyl (or allyl), n-butyl, t-butyl (or 2-methylpropyl), etc.
  • Substituted alkyl refers to alkyl as just described including one or more functional groups such as lower alkyl, aryl, acyl, halogen, (i.e., alkylhalos, e.g., CF 3 ), hydroxy, nitro, cyano, amino, alkoxy, alkylamino, acylamino, acyloxy, aryloxy, arloxyalkyl, mercapto, carboxylic acid, carboxylic acid derivatives, sulfonic acids, sulfonic acid derivatives, both saturated and unsaturated cyclic hydrocarbons, heterocycles and the like. These groups may be attached to any which are fused to the arom heterocycles and the like. These groups may be attached to any carbon of the alkyl moiety.
  • aryl is used herein to refer to an aromatic substituent having a single aromatic ring or multiple aromatic rings which are fused together, linked covalently, or linked to a common group such as a methylene or ethylene moiety.
  • the common linking group may also be a carbonyl as in benzophenone.
  • the aromatic ring(s) may include phenyl, naphthyl, biphenyl, diphenylmethyl and benzophenone among others.
  • Substituted aryl refers to aryl as just described including one or more functional groups such as lower alkyl, acyl, halogen, alkylhalos (e.g., CF 3 ), hydroxy, nitro, cyano, amino, alkoxy, alkylamino, acylamino, acyloxy, mercapto, carboxylic acid amide, sulfonic acid amide and both saturated and unsaturated cyclic hydrocarbons which are fused to the aromatic ring(s), linked covalently or linked to a common group such as a methylene or ethylene moiety.
  • the linking group may also be a carbonyl such as in cyclohexyl phenyl ketone.
  • arylalkyl is used herein to refer to a subset of “aryl” in which the aryl group is attached through an alkyl group as defined herein. Examples include, but are not limited to, benzyl, phenylethyl and phenylpropyl groups.
  • Substituted arylalkyl defines a subset of “arylalkyl” wherein the aryl moiety of the arylalkyl group is substituted as defined herein for aryl groups.
  • halogen is used herein to refer to fluorine, bromine, chlorine and iodine atoms.
  • hydroxy is used herein to refer to the group -OH.
  • amino is used herein to refer to the group-NRR', where R and R' may independently be hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl or acyl.
  • alkoxy is used herein to refer to the -OR group, where R is a lower alkyl or substituted lower alkyl, wherein the alkyl and substituted lower alkyl groups are as described herein.
  • Suitable alkoxy radicals include, for example, methoxy, ethoxy, t-butoxy, etc.
  • aryloxy is used herein to refer to the -OR group, wherein R is an aryl, substituted aryl, arylalkyl or substituted arylalkyl as described above. Examples include phenoxy, benzyloxy, phenethyloxy and substituted derivatives thereof.
  • alkylamino denotes secondary and tertiary amines wherein the alkyl groups may be either the same or different and may consist of straight or branches, saturated or unsaturated hydrocarbons.
  • heterocyclychc is used herein to describe a monovalent group having a single ring or multiple condensed rings from 1-12 carbon atoms and from 1-4 heteroatoms selected from nitrogen, sulfur or oxygen within the ring.
  • heterocycles include, for example, tetrahydrofuran, morpholine, piperidine, pyrrolidine, thiophene, pyridine, isoxazole, phthalimide, pyrazole, indole, furan, benzo-fused analogs of these rings, etc.
  • substituted heterocychc as used herein describes a subset of “heterocychc” wherein the heterocycle nucleus is substituted with one or more functional groups such as lower alkyl, acyl, halogen, alkylhalos (e.g., CF 3 ), hydroxy, amino, alkoxy, alkylmino, acylamino, acyloxy, mercapto, etc.
  • functional groups such as lower alkyl, acyl, halogen, alkylhalos (e.g., CF 3 ), hydroxy, amino, alkoxy, alkylmino, acylamino, acyloxy, mercapto, etc.
  • heterocyclicalkyl is used herein to refer to a subset of “heterocylic” in which the heterocylcic group is attached through an alkyl group as defined herein.
  • Substituted heterocyclicalkyl defines a subset of “heterocyclicalkyl” wherein the heterocychc moiety of the heterocyclicalkyl group is substituted as defined herein for heterocychc groups.
  • pharmaceutically acceptable salt refers to those salts of compounds which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and organic acids such as, for example, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • Pharmaceutically acceptable salts include, for example, alkali metal salts, such as sodium and potassium, alkaline earth salts and ammonium salts.
  • contacting is used herein interchangeably with the following: combined with, added to, mixed with, passed over, incubated with, flowed over, etc.
  • the thiazolidinone compounds of present invention can be "administered" to a subject by any conventional method such as, for example, parenteral, oral, topical and inhalation routes as described herein.
  • An amount sufficient” or “an effective amount” is that amount of a given thiazolidinone analog which exhibits the binding/activity of interest or, which provides an improvement in gamete recruitment.
  • EC50 is the effective concentration, i.e., the concentration of a compound at which 50% of the maximal response of that obtained with FSH would be achieved.
  • Non-competitive refers to the nature of the agonist activity exhibited by the compounds of the invention, wherein the compounds act as agonists of and activate the FSH receptor without substantially reducing the magnitude of binding of FSH to the receptor.
  • Magnitude of binding refers to the amount of FSH bound by a receptor population and/or the strength of the binding interaction between FSH and the FSH receptor.
  • the present invention is directed to novel thiazolidinone compounds which exhibit a range of pharmaceutical activities.
  • the novel compounds are small molecule FSH receptor agonists. These compounds offer numerous advantages over the current state of the art (i.e., gonadotrophins of urinary origin and recombinant FSH).
  • the compounds of the instant invention are inexpensive and both easily prepared and purified.
  • the compounds exhibit a range of activity regarding the FSH receptor. Such a manifold of compounds of differing activity provides an opportunity to the clinician to modulate the desired level of fertility induction by judicious choice of the fertility-inducing agent.
  • novel thiazolidinones exhibit a pharmacokinetic profile which is distinct from that of conventional peptidic hormone preparations.
  • the pharmacokinetic profile can be further modified by judicious choice of the route of administration and manipulating the nature of the substituents on the thiazolidinone nucleus.
  • the present invention provides a compound having a formula:
  • R 1 is a member selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocychc and substituted heterocylic groups;
  • R 2 is a member selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocychc and substituted heterocylic groups;
  • R 5 and R 6 are independently members selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, arylalkyl, substituted arylalkyl, heterocyclicalkyl and substituted heterocyclicalkyl groups;
  • Y is a member selected from the group consisting of O, S, and NH;
  • Y 2 is a member selected from the group consisting of CH 2 , O, S, and NR 5 ;
  • Y is a member selected from the group consisting of O and NR R ;
  • R 7 is a member selected from the group consisting of hydrogen and lower alkyl
  • X 2 is a member selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, heterocychc, substituted heterocychc, arylalkyl, substituted arylalkyl, heterocyclicalkyl and substituted heterocyclicalkyl groups; m is an integer from 0 to 3; n is O or 1; and s is 1 or 2.
  • the present invention provides a compound wherein,
  • R 5 and R 6 are independently members selected from the group consisting of hydrogen, -(CH 2 ) q X 2 , and wherein p is an integer from 1 to 2; q is an integer from 0 to 5;
  • X is a member selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, heterocychc, substituted heterocychc, arylalkyl, substituted arylalkyl, heterocyclicalkyl and substituted heterocyclicalkyl groups; and
  • R 1 is a member selected from the group consisting of
  • R > 8 and ⁇ R9 are independently members selected form the group consisting of H, halogen, ketone, alkyl, substituted alkyl, phenyl, substituted phenyl, lower alkoxy, aryloxy, substituted aryloxy, carboxylic acid, carboxylic acid amide, sulfonic acid, sulfonic acid amide, alkynyl, substituted alkynyl and -CONR ⁇ CH ⁇ t Z wherein t is an integer from one to four;
  • R 10 is a member selected from the group consisting of H and lower alkyl
  • A is a member selected from the group consisting of -C alkyl and substituted -C 4 alkyl, wherein each carbon atom is independently substituted with members selected from the group consisting of H, amino, alkyl, substituted alkyl, spirocyclic alkyl, substituted spirocyclic alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocychc, and substituted heterocychc groups;
  • X 3 is a member selected from the group consisting of O, S, SO, SO 2 and NR 10 ;
  • Z is a member selected from the group consisting of alkylamino, dialkylamino,
  • w is an integer from 1 to 3;
  • Y is a member selected from the group consisting of O, S and NR 10 ;.
  • R 2 is a member selected from the group consisting of
  • R » ⁇ and R , 12 are independently members selected from the group consisting of H, halogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, phenyl, substituted phenyl, aryloxy, substituted aryloxy, alkynyl, substituted alkynyl, nitro, cyano, aminoarylalkyl and substituted aminoarylalkyl; u is an integer from 1 and 4;
  • X 4 is a member selected from the group consisting of O, S, NR 13 , and CR 13 ;
  • X 5 is a member selected from the group consisting of O, S, NH, and CH;
  • R is a member selected from the group consisting of H, and lower alkyl.
  • R and R are independently members selected form the group consisting of H, halogen, ketone, alkyl, substituted alkyl, carboxylic acid amide, sulfonic acid amide and alkynyl and -CONR 1 (CH 2 ) t Z wherein t is an integer from one and four; wherein
  • Z is a member selected from the group consisting of alkylamino, dialkylamino,
  • w is an integer from 1 to 5;
  • Y is a member selected from the group consisting of O, S, and NR 10 ;
  • R 1 is a member selected from the group consisting of H, and lower alkyl.
  • the present invention provides a compound wherein,
  • R and R are independently members selected from the group consisting of hydrogen, halogen, alkoxy, substituted alkoxy, aryloxy, -----R 14 , and -X 6 -( CH 2 ) V R 14 wherein
  • R 14 is a member selected from the group consisting of phenyl, substituted phenyl, alkyl, alkenyl, cyloalkyl, cycloalkenyl, CH 2 (X 7 ) Z R 15 , CONHR 15 , COR 15 , pyridine, thiophene, furan, pyrrole and phenylsulfonyl;
  • X 6 is a member selected from the group consisting of O, S, NH, and CH 2 O;
  • X 7 is.a member selected from the group consisting of O, S, and R 14 ;
  • R 15 is a member selected from the group consisting of H, alkyl and phenyl; v is an integer from 0 to 3; and z is O or 1.
  • the present invention provides a compound wherein, when substituent R 4 , on C-5, is H, and a second substituent at C-5 (R ) is not H, said substituent R on C-5 and substituent R on C-2 are oriented in a cis manner.
  • the present invention provides novel thiazolidinones having the formula:
  • R 1 is a member selected from the group consisting of aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocychc and substituted heterocychc groups;
  • R 2 is a member selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocychc and substituted heterocychc groups;
  • R 3 and R 4 are independently members selected from the group consisting of hydrogen, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, heterocychc and substituted heterocychc groups; and
  • R 1 is aryl or substituted aryl. In another preferred embodiment, R 1 is phenyl or substituted phenyl. In a further preferred embodiment, R 1 is substituted phenyl as in Formula (IN)
  • R 11 , R 12 , R 13 , R 14 and R 15 are independently members selected from the group consisting of H, halogen, lower alkyl, substituted lower alkyl, phenyl, lower alkoxy, aryloxy, substituted aryloxy, carboxyl, ester and amide groups.
  • R 1 is a substituted phenyl according to Formula (IN) and R 11 , R 12 , R 13 , R 14 and R 15 are independently members selected from the group consisting of H, halogen, substituted alkyl, ketone, ester, amide and nitro groups.
  • R 1 is substituted phenyl according to Formula (IN) and R 11 , R 12 , R 13 , R 14 and R 15 are independently members selected from the group consisting of H, halogen and amide groups.
  • R is a member selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocychc and substituted heterocychc groups.
  • R 2 is an aryl group.
  • a preferred aryl group is the phenyl group and a preferred substituted aryl group is a substituted phenyl group.
  • R 2 is a substituted phenyl according to Formula (N) or a five-membered ring according to Formula (VI)
  • R 21 , R 22 , R 23 , R 24 , R 25 are members independently selected from the group consisting of H, halogen, lower alkyl, substituted lower alkyl, lower alkoxy, substituted lower alkoxy, phenyl, substituted phenyl, aryloxy, substituted aryloxy, alkynyl, substituted alkynyl and nitro groups.
  • Preferred aryloxy groups are phenoxy and benzyloxy and preferred substituted aryloxy groups are substituted phenoxy and substituted benzyloxy.
  • Y is a member selected from the group consisting of-CH 2 -, -O-, -S- and NR 26 wherein R 26 is H or lower alkyl.
  • R 21 , R 22 , R 23 , R 24 and R 25 are independently members selected from the group consisting of H, halogen, lower alkoxy and substituted aryl groups according to Formula (Nil)
  • R 31 , R 32 , R 33 , R 34 and R 35 are members independently selected from the group consisting of hydrogen, halogen, nitro and trifluoromethyl, alkyl, substituted alkyl, alkoxy and hydroxy.
  • X 1 is a member selected from the group consisting of O, ⁇ R 36 , S, C, CH and CH 2 ; R is H or lower alkyl; m is an integer from 0 to 5; n is an integer from 0 to 3, p is an integer from 0 to 3 and q is an integer from 0 to 2. When q ⁇ 2, a multiple bond exists between CH q and X 1 .
  • R 21 , R 22 , R 23 , R 24 and.R 25 are independently chosen from hydrogen and the groups according to Formulae (NIII) and (IX):
  • R 41 , R 42 , R 43 , R 44 and R 45 are members independently selected from the group consisting of hydrogen, halogen, nitro and trifluoromethyl.
  • n is an integer from 0 to 3 and X 1 is O or ⁇ H.
  • R 3 and R 4 are the same or different and are members independently selected from the group consisting of H and structures according to Formula (X):
  • X is an integer from 0 to 5, preferably from 1 to 5.
  • X 2 is a member selected from the group consisting of aryl, substituted aryl, heterocychc and substituted heterocychc. In a further preferred embodiment, X is heterocychc or substituted aryl. In still further preferred embodiments, X 2 is phenyl, substituted phenyl, indole or substituted indole.
  • the compounds of the invention can exist in a number of different isomeric and stereoisomeric forms.
  • the configuration of C-2 and C-5 can be such that their substituents are in either a cis or trans configuration. In preferred embodiments, the compounds exist in the cis configuration. Additionally, the combination of absolute configurations available to C-2 and C-5 can take any one of four permutations.
  • the thiazolidinone nucleus can be 2S, 5S; 2R, 5R; 2S, 5R; or 2R, 5S. Presently preferred embodiments are those in which the configuration at C- 2 and C-5 are 2S, 5R.
  • the compounds of the present invention can be used for diverse pharmaceutical applications including, for example, CNS antuschemic agents, agents with antipsychotic or other psychoactive properties, antimicrobial agents and mammalian fertility regulating agents.
  • the thiazolidinones are preferably agonists of the FSH receptor.
  • Tables I-NI Examples of presently preferred thiazolidinones having FSH agonist activity are displayed in Tables I-NI.
  • the EC 5 o values of the compounds displayed in Tables I-NI are less than about 500 riM. Table I.
  • the invention provides a class of FSH receptor agonists, wherein the receptor agonist activity is noncompetitve with FSH.
  • the non-competitive FSH agonists are organic molecules with a molecular weight of from about 50 daltons to about 1000 daltons, more preferably from about 200 daltons to about 1000 daltons.
  • the inventiorf provides for pharmaceutical formulations containing a FSH receptor agonist which is non- competitive with FSH.
  • the invention provides regulators of mammalian fertility which are useful in the diverse applications described herein for the thiazolidinones of the invention.
  • the present invention provides pharmaceutical compositions which contain one or more of the compounds of the invention in conjunction with pharmaceutically acceptable excipients, carriers, diluents, etc.
  • the pharmaceutical compositions can also contain other agents which are themselves pharmacologically active and which serve to enhance, supplement, decrease or otherwise regulate the pharmacological effect of the pharmaceutical compositions.
  • the compounds, i.e., thiazolidinones, of the present invention can be administered to a mammal, e.g., a human patient, alone, in the form of a pharmaceutically acceptable salt, or in the form of a pharmaceutical composition where the compound is mixed with suitable carriers or excipient(s) in a therapeutically effective amount.
  • the compounds and compositions of the invention can be admimstered to induce greater fertility in the patient or they can be administered to stimulate the production of ova which will be removed, fertilized in vitro and implanted in the patient or a surrogate.
  • the compounds and compositions of the present invention can be used for the treatment of male, as well as female, infertility. See, for example, Reichert, et al., "The follicle stimulating hormone (FSH) receptor in testis: interaction with FSH, mechanism of signal transduction, and properties of the purified receptor," Biol. Reprod. 40:13-26 (1989), the disclosure of which is incorporated herein by reference.
  • FSH follicle stimulating hormone
  • the compounds of this invention can be incorporated into a variety of formulations for therapeutic administration. More particularly, the compounds of the present invention can be formulated into pharmaceutical compositions by combination with appropriate, pharmaceutically acceptable carriers or diluents, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, pills, powders, granules, dragees, gels, slurries, ointments, solutions, suppositories, injections, inhalants and aerosols. As such, administration of the compounds can be achieved in various ways, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, intracheal, etc., administration.
  • the compound can be administered in a local rather than systemic manner, for example, via injection of the compound directly into an ovary, often in a depot or sustained release formulation.
  • the compounds can be administered in a targeted drug delivery system, for example, in a liposome coated with an organ surface receptor-specific antibody. Such liposomes will be targeted to and taken up selectively by the organ.
  • the compounds may be administered in the form of their pharmaceutically acceptable salts, or they may also be used alone or in appropriate association, as well as in combination with other pharmaceutically active compounds.
  • the discussion which follows is based on the use of the compounds of the invention as fertility-inducing agents. That pharmaceutical compositions containing the novel thiazolidinones are useful in other applications, and are not limited to use as fertility-inducing agents will be apparent to those of skill in the art.
  • adjuncts which serve a purpose analogous to those discussed below (i.e., enhance or supplement the thiazolidinone therapeutic activity) can be included within the formulation.
  • the thiazolidinone analogs of the present invention can be administered alone, in combination with each other, or they can be used in combination with other known compounds (e.g., fertility-inducing agent, such as FSH, LH and hMG).
  • Other agents which can be included in the pharmaceutical compositions include ovulation adjuncts such as, for example, cytokines (e.g., IGF-1 and TGF- ⁇ ) and narrow action oligopeptides (e.g., activins, irihibins and follistatins). See, for example, Gast, "Evolution of clinical agents for ovulation induction.” Am. J.
  • compositions described herein can be manufactured in a manner that is known to those of skill in the art, i.e., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • the following methods and excipients are merely exemplary and are in no way limiting.
  • the compounds can be formulated into preparations by dissolving, suspending or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.
  • the compounds of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's 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 with pharmaceutically acceptable carriers that are well known in the art.
  • Such carriers enable the compounds to be formulated as tablets, pills, dragees, capsules, emulsions, lipophilic and hydrophilic suspensions, 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 by mixing the compounds with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked 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, talc, 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 compound doses.
  • 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 filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds 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.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present invention are conveniently delivered in the form ofan aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, or from propellant-free, dry-powder inhalers.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, or from propellant-free, dry-powder inhalers.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas
  • propellant-free, dry-powder inhalers e.g.
  • 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 ampules or in multidose 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.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form.
  • suspensions of the active compounds 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.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • 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, carbowaxes, polyethylene glycols or other glycerides, all of which melt at body temperature, yet are solidified at room temperature.
  • rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, carbowaxes, polyethylene glycols or other glycerides, all of which melt at body temperature, yet are solidified at room temperature.
  • 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.
  • hydrophobic pharmaceutical compounds may be employed.
  • Liposomes and emulsions are well 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 well 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.
  • compositions also may comprise suitable solid or gel phase carriers or excipients.
  • suitable solid or gel phase carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in a therapeutically effective amount.
  • the amount of composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician. Determination of an effective amounUs well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • a therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose can be formulated in animal models to achieve a circulating concentration range that includes the EC 5 o as determined in cell culture. Such information can be used to more accurately determine useful doses in humans.
  • Initial dosages can also be estimated from in vitro or in vivo data.
  • Initial dosages can also be formulated by comparing the effectiveness of the compounds described herein in cell culture assays with the effectiveness of known drugs. For instance, when used as fertility agents, initial dosages can be formulated by comparing the effectiveness of the compounds described herein in cell culture assays with the effectiveness of known fertility agents such as hMG or FSH. In this method, an initial dosage can be obtained by multiplying the ratio of effective concentrations obtained in cell culture assay for the compound of the present invention and a known fertility drug by the effective dosage of the known fertility drug.
  • a compound of the present invention is twice as effective in cell culture assay as hMG (i.e., the EC 5 o of that compound is equal to one-half the EC 50 of hMG in the same assay)
  • an initial effective dosage of the compound of the present invention would be one-half the known dosage for hMG.
  • toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD 5 o (the dose required to cause death in 50% of the subjects tested) and the ED 5 o (the dose that produces a defined effect in 50% of the subjects tested).
  • the dose ratio between toxic and therapeutic effect is the therapeutic index and can be expressed as the ratio between LD 5 o and ED 50 .
  • Compounds which exhibit high therapeutic indices are preferred.
  • the data obtained from these cell culture assays and animal studies can be used in formulating a dosage range that is appropriate for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 5 o with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. See, for example, Fingl, et al, In: The Pharmacological Basis of Therapeutics, Ch. 1, p. 1 (1975).
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active compound which are sufficient to maintain therapeutic effect.
  • Usual patient dosages for oral administration range from about 50-2000 mg/kg/day, commonly from about 100-1000 mg/kg/day, preferably from about 150-700 mg/kg/day and most preferably from about 250-500 mg/kg/day.
  • therapeutically effective serum levels will be achieved by administering multiple doses each day.
  • the effective local concentration of the drug may not be related to plasma concentration.
  • One having skill in the art will be able to optimize therapeutically effective local dosages without undue experimentation.
  • compositions of the invention When used as fertility-inducing agents in the female, the compositions of the invention can be evaluated for their effectiveness by any of a number of art accepted parameters including number of follicles, number of oocytes, number of transferrable embryos, number of pregnancies, the total dose administered and the treatment length. Similarly accepted criteria are available for evaluating the safety of a fertility-inducing agent including incidence of ovarian hyperstimulation and incidence of multiple gestation. When used to enhance fertility in the male, effectiveness can be adduced by increased sperm count, sperm motility and the like. Additional criteria and methods for assessing the efficacy of a thiazolidinone-containing pharmaceutical composition, when used as a fertility-inducing agent or for another purpose, will be apparent to those of skill in the art.
  • the thiazolidinones can be incorporated into the pharmaceutical formulation as mixtures of diastereomers, mixtures of enantiomers or as stereochemically distinct compounds.
  • the origin of the isomerism is the chirality of the carbons at positions 2 and 5 of the thiazolidinone ring structure (Formula I).
  • the thiazolidinone component of the pharmaceutical composition is a mixture of cis and trans isomers.
  • the mixture of cis and trans isomers is enriched in the cis isomer relative to the trans isomer.
  • the thiazolidinone is present as the substantially pure cis isomer.
  • the stereochemistry of the carbon atoms at positions 2 and 5 of the ring is yet another feature of the thiazolidinone constituent which can be varied.
  • the thiazolidinone constituent is a mixture of the 2S, 5R and 5S, 2R isomers.
  • the thiazolidinone constituent is enriched in the 2S, 5R isomer.
  • the thiazolidinone constituent is substantially pure 2S, 5R.
  • the compounds of the invention are useful in vitro as unique tools for understanding the biological role of FSH, including the evaluation of the many factors thought to influence, and be influenced by, the production of FSH and the interaction of FSH with the FSH-R (e.g., the mechanism of FSH signal transduction/receptor activation).
  • the present compounds are also useful in the development of other compounds that interact with the FSH-R, because the present compounds provide important structure-activity relationship (SAR) information that facilitate that development.
  • SAR structure-activity relationship
  • Compounds of the present invention that bind to the FSH receptor can be used as reagents for detecting FSH receptors on living cells, fixed cells, in biological fluids, in tissue homogenates, in purified, natural biological materials, etc. For example, by labelling such compounds, one can identify cells having FSH-R on their surfaces.
  • compounds of the present invention can be used in in situ staining, FACS (fluorescence-activated cell sorting), western blotting, ELISA (enzyme-linked immunoadsorptive assay), etc.
  • compounds of the present invention can be used in receptor purification, or in purifying cells expressing FSH receptors on the cell surface (or inside permeabilized cells).
  • the compounds of the invention can also be utilized as commercial research reagents for various medical research and diagnostic uses. Such uses can include but are not limited to: (1) use as a calibration standard for quantitating the activities of candidate FSH agonists in a variety of functional assays; (2) use as blocking reagents in random compound screening, i.e., in looking for new families of FSH receptor ligands, the compounds can be used to block recovery of the presently claimed FSH compounds; (3) use in the co-crystallization with FSH receptor, i.e., the compounds of the present invention will allow formation of crystals of the compound bound to the FSH receptor, enabling the determination of receptor/compound structure by x-ray crystallography; (4) other research and diagnostic applications wherein the FSH-receptor is preferably activated or such activation is conveniently calibrated against a known quantity of an FSH agonist, and the like; (5) use in assays as probes for determining the expression of FSH receptors on the surface of cells; and (6) developing assays
  • Example 1 details the assembly of a library in which the amino acid component is varied.
  • Example 2 the synthesis of a library in which the aldehyde component is varied is set forth.
  • Example 3 illustrates a library, wherein the amine component is varied.
  • Example 4 illustrates a scaled-up synthesis of one exemplary novel thiazolidinone.
  • Example 5 sets forth the synthetic route to enantiomerically pure thiazolidinones from an enantiomerically pure mercaptosuccinic acid precursor.
  • Example 6 details the synthesis of thiophene compounds of the invention.
  • Example 7 sets forth the synthesis of phenethylamine compounds of the invention.
  • Example 8 details the synthesis of a benzyl ether derivative of the invention.
  • Example 9 details the preparation of iodobenzyl derivatives of compounds of the invention.
  • Example 10 illustrates the exchange of acetylene for iodine in the compound of Example 9.
  • Example 11 illustrates the coupling of pyridine to the acetyline moiety of the compound of Example 10.
  • Example 12 illustrates the derivatization of the carboxylic acid moiety of the compound of Example 11 with an amine.
  • Example 13 illustrates the oxidation of the ring sulfur of a thiazolidinone compound of the invention.
  • Example 14 details the experimental protocol for assaying the compounds of the invention for their ability to act as FSH antagonists.
  • Example 15 illustrates an assay for determining whether the compounds of the invention compete with FSH for the FSH binding site.
  • Example 1
  • This example details the synthesis of a library of thiazolidinones in which the amino acid component is varied.
  • a 96 well parallel synthesis apparatus was added 50 mg of Argogel-Rink Amide-FMOC (0.33 mmol/g loading) to 30 of the wells.
  • the resin was washed with dichloromethane (100 mL) and N,N-dimethylformamide (100 mL).
  • the resin was then deprotected with 20% piperidine in N,N-dimethylformamide (1 mL) for 30 minutes.
  • the resin was then washed exhaustively with dichloromethane and N,N-dimethylformamide. To each well was added 5 eq.
  • the resin was then treated with 20 eq. of 4-(phenethynyl)benzaldehyde and 40 eq. of mercaptosuccinic acid in THF (1 mL) and heated at 60°C for 16 hours. The apparatus was cooled and washed with hot THF. The resin was then washed exhaustively with dichloromethane and N,N-dimethylformamide.
  • This example illustrates the assembly of a library of the compounds of the novel thiazolidinones of the invention in which the structure of the aldehyde component is varied.
  • the resin was distributed into 96 wells on a parallel synthesis apparatus (-50 mg/well). To each well was added 20 eq. one of 96 different aldehydes (see below) and 40 eq mercaptosuccinic acid. THF (1 mL) was added to each well and heated at 70°C for 24 hours. The apparatus was cooled and each well was washed exhaustively with THF, DCM, DMF, DCM, MeOH, DCM, DMF in sequence.
  • This example illustrates the assembly of a thiazolidinone library, wherein the amine component of the thiazolidinone is varied over the library.
  • the resin was transferred to a 250 mL RBF and treated with 20 eq of 4- (phenethynyl)benzaldehyde and 40 eq of mercaptosuccinic acid in THF and heated at 60°C for 16 hours.
  • the vessels were cooled and transferred with THF to a 250 mL peptide vessel and washed with hot THF (250 mL).
  • the resin was then washed exhaustively with dichloromethane and N,N-dimethylformamide.
  • the resin was distributed into 96 wells on a parallel, synthesis apparatus (-50 mg/well). To each well was added and reacted with 20 eq. of one of 96 different amines, 20 eq.
  • Example 4 sets forth a preparative synthetic route to a representative thiazolidinone of the invention, 3-[5- ⁇ [-(3,4-dichlorophenyl)ethylcarbamoyl]methyl ⁇ -4- oxo-2-(4-phenylethynylphenyl)-thiazolidin-3-yl]benz--mide.
  • the material was purified by preparative HPLC (1.25 mL injection, 8 column, isocratic 60% AcCN H 2 0, 30 mL/min), collected in 50 mL centrifuge tubes, and lyophilized to give the cis enantiomers of 3-[5- ⁇ [2-(3 ,4-dichlorophenyl)ethylcarbamoyl]methyl ⁇ -4-oxo-2-(4-phenylethynylphenyl)- thiazolidin-3-yl]benzamide as a white powder (35.0 mg, 0.056 mmol, 56%).
  • the enantiomers can be resolved by chiral chromatography to obtain optically pure compounds. Conditions for separation varies with each compound. A preparative Chiracel OD column was used to resolve the enantiomers of AF17102 and AF17439.
  • the individual enantiomers can be prepared synthetically by employing optically pure mercaptosuccinic acid in the thiazolidinone synthesis.
  • Example 5
  • L-aspartic acid ((S)-aspartic acid, 25 g, 188 mmol) and 245 mL of 5 N HBr.
  • the reaction was cooled in an ice bath to 0-50°C, followed by the dropwise addition of sodium nitrite (20.7 g, 301 mmol) in 75 mL of water over five hours. The temperature was maintained below 50°C during the addition. After the addition was complete, the reaction was allowed to stir for 12 hours at 23-25°C.
  • the reaction was diluted with diethyl ether (120 mL). The aqueous layer was removed and the organic phase was washed with 1 N HCI (100 mL).
  • the resin was split into 2 equal portions and each portion was treated with 10 eq of 4-benzyloxybenzaldehyde and 20 eq. of either R (70% EE) or S (75% EE) mercaptosuccinic.
  • Acetonitrile (5 mL) was added and the reaction was left at RT for 48 hours, then 55 °C for 48 hours.
  • the vessels were cooled and their contents were transferred with THF to a peptide vessel, and washed with hot THF.
  • the resin was then washed exhaustively with dichloromethane and N,N-dimethylformamide.
  • the trans isomer was transferred to a 500 mL RBF, with 200 mL THF, and 10 equivalents of DBU.
  • the reaction was heated under reflux, followed by the addition of -20 mL of methanol.
  • the reaction was reflux for 24 hours, cooled, and the solvent removed under reduced pressure.
  • the residue was dissolved in EtOAc (250 mL) and washed with 1 N HCI (2 x 300 mL).
  • the organic layer was filtered to remove the trans isomer, and then concentrated under reduced pressure.
  • the remaining material was triturated with acetonitrile, filtered, and process repeated to achieve material with 95:5 cistrans ratio. This material was then recrystallized from acetonitrile to afford the cis isomer (>97:3).
  • This example illustrates the synthesis of a benzyl ether derivative of the invention.
  • This example illustrates the preparation of iodobenzyl derivatives of compounds of the invention.
  • This example illustrates the exchange of acetylene for iodine in the compound of Example 9.
  • This example illustrates the coupling of pyridine to the acetyline moiety of the compound of example 10.
  • This example illustrates the derivatization of the carboxylic acid moiety of the compound of Example 11 with an amine.
  • This example details the protocols utilized to assay the thiazolidinone library compounds for FSH agonist activity. a. Testing compounds for agonist activity using a cell-based reporter assay
  • Binding of FSH to the FSH receptor results in an increase in intracellular cAMP.
  • Increases in cAMP can be monitored by the use of reporter constructs (George, SE, Bungay, PJ and Naylor, LH, "Functional coupling of endogenous serotonin and calcitonin receptor in CHO cells to a cAMP responsive lucif erase reporter gene," J. Neurochem. 69 1278-1285 (1997), the teachings of which are incorporated herein by reference), in which the firefly luciferase gene is placed under CRE control.
  • the human FSH receptor gene was cotransfected into CHO cells with a CRE-luciferase vector and cells expressing the FSH receptor were sorted by FACS as described above for the binding assay. Individual clones were examined for their ability to produce luciferase in response to stimulation with 1 ⁇ M FSH. Clone 1D7, which produces a response of 20-40,000 cps against a basal level of about 1,000 cps, was chosen for testing of compounds. This clone responded to FSH with an EC50 of about 80 pM.
  • the human FSH receptor was cloned into the ⁇ -T8-12CA5-KH expression vector (Koller, et alJ, "A generic method for the production of cell lines expressing high levels of transmembrane receptors," Analytical Biochem. 250:51-60 (1997), which is incorporated herein by reference), and transfected into CHO cells. After G418 selection, cells were stained with FITC-labeled 12CA5 antibody and those expressing the FSH receptor were collected by FACS. Individual clones were expanded and examined for binding of 125 I labeled FSH. CHO FSH-R clone 1H6 was expanded in a 15 liter spinner and membranes were prepared as described (Koller, et al, Analytical Biochem. 250 51-60 (1997)).
  • Membranes were prepared from Chinese hamster ovary (CHO) cells which expressed FSH-R as described above. These cells specifically bind 125 I-labeled FSH. When a binding assay was performed in the presence of 100 ⁇ M thiazolidinone, no inhibition of the radiolabeled FSH was observed. Thus, although the thiazolidinones are able to bind to the FSH receptor and to elicit a response, they do not block the interaction between FSH and its receptor.
  • the resin prepared above was distributed into a number of scintillation vials according to the number of different aldehydes to be used.
  • To each amino acid on Rink Amide Resin (0.424 mmol) was added a solution of lOeq. of aldehyde (4.24mmol) and 20eq. of mercaptosuccinic acid (1.27g, 8.48mmol) in anhydrous THF (10 ml).
  • the resulting reaction mixture was heated at 60°C on the J-KEM block for 48 hr, the mixture was filtered, washed with THF (3 x 10ml), MeOH (3 x 10ml), and CH 2 C1 2 (3 x 10ml).
  • the products were cleaved from the solid support for characterization according to the following procedure. To each well was added 95% TFA DCM (2 ml). The resin was left standing for 1 h, and the solution were filtered into a 48 or 96 wells Robbins microtiter plate. The resin in each well was washed with dichloromethane (2 ml). The solutions were concentrated under a nitrogen stream and dried in Savant under vacuum. The compounds were purified by Gilson prep HPLC and the required fractions were concentrated in Savant. The final product was characterized by LC/MS. The structure for the libraries generated are shown in the following Table.
  • the ethyl acetate fraction was washed two additional times with acid.
  • the organic layer was separated, washed with brine and dried using MgSO 4 .
  • the solvent was removed under reduced pressure, yielding a mixture of cis and trans epimers as a white solid.
  • This material was dissolved in DMF (10 ml) and K 2 CO 3 (280 mg, 2 mmol) and benzyl bromide (340 mg, 2 mmol) were added. After 3h, the reaction was complete.
  • the DMF was partitioned between ethyl acetate and brine twice.
  • the organic layer was washed with 3N HCI twice.
  • the organic layer was washed with brine, dried over MgSO4 and concentrated under vacuum to yield an oil.
  • the DMF solution was partitioned between ethyl acetate and brine twice, and the organic layer dried using magnesium sulfate. The solvent was removed under vacuum. The crude material was purified using silica gel flash chromotography (3% methanol:DCM), yielding the title compound (32 mg, 60%) as a yellow oil.
  • HATU (380 mg, 1.0 mmol) was added and the solution was allowed to stir at room temperature for 15 hours.
  • the DMF solution was partitioned between ethyl acetate and brine twice, and the organic layer was washed twice with 3N HCI. The organic layer was washed again with brine and dried using MgSO 4 . The solvent was removed under vacuum, yielding the crude products as a yellow oil.
  • HATU (380 mg, 1.0 mmol) was added and the solution was allowed to stir at room temperature for 15 hours.
  • the DMF solution was partitioned between ethyl acetate and brine twice, and the organic layer was washed twice with 3N HCI. The organic layer was washed again with brine and dried using MgSO 4 . The solvent was removed under vacuum, yielding the crude products as a yellow oil.
  • N-[2-(3-ethoxy-4-methoxyphenyl)ethyl]-2,2,2,-trifluoroacetamide 500 mg, 1.7 mmol was dissolved in MeOH (16 mL). Iodine (765 mg, 3.0 mmol) was added. This solution was treated with HIO 3 (264 mg, 1.5 mmol, dissolved inl7 mL of water). The reaction mixture was protected from light, and it was allowed to stir under nitrogen for 20 hours. The reaction mixture was partitioned between ethyl acetate and a weak sodium bisulfite solution. The ethyl acetate layer was washed one additional time with bisulfite, and then it was washed with bicarbonate.
  • N-[2-(5-Ethoxy-2-iodo-4-methoxyphenyl)ethyl]-2,2,2,-trifluroacetamide (2.0 g, 4.8 mmol) was stirred in MeOH (60 mL) and water (20 mL). Lithium hydroxide monohydrate (1.05 g, 25 mmol) was added and the mixture was heated to 60°C and allowed to stir for 1 hour. The reaction mixture was diluted with ethyl acetate, and washed three times with water. It was dried using brine and magnesium sulfate, and concentrated under vacuum to yield the title compound (1.4 g, 89%).
  • the DMF solution was diluted with ethyl acetate, washed twice with brine, and twice with 3N HCI.
  • the ethyl acetate was dried over MgSO4, and concentrated by rotary evaporation.
  • This crude was purified using silica gel column chromatography (6% MeOH/DCM) to yield the product (1 lOmg, 25%) as yellow solid.
  • the DMF solution was partitioned between ethyl acetate and brine twice, and the organic layer dried using magnesium sulfate. The solvent was removed under vacuum. The crude material was purified using silica gel flash chromotography (4 % methanol:DCM), yielding the title compound (20 mg, 28%) as a yellow oil.
  • a CH 2 Ph 0 a) CH 3 CN, mole, sieves 4A, 80°C; b) BOP, DIEA, THF for 6 hrs then reduced with 1.15 eq NaBH 4 ; c) LiCl, LiTMS 2 , RX, -78°C to -40°C; d) NH4OH, CH 3 OH; e) Jones oxidation, 0°C; f) RNH 2 , HATU, DIAE, DMF, g) MCPBA, NMP, 60°C.
  • this compound (2.51 g) was dissolved in THF (15 ml) and treated with 1M diborane in THF (36 ml, 36 mmol). The solution was heated under reflux for 2 hours, then cooled to 0°, treated with water (10 ml) and 20% KOH aqueous solution (10 ml).
  • Example 85 Example 85
  • Example 86 Using the procedure of Example 83 and substituting 3- chlorophenethylamine, the title compound was obtained as a white solid; 1 HNMR (DMSO-d 6 ) ⁇ 6.80-8.00 (m, 17 H), 6.55 (s, IH), 4.99 (s, 2H), 4.17 (m, 2H), 3.23 (m, 2H), 2.71 (t, 2H), 2.17 (m, 2H); MS (ES-positive): [M+ H] + 644. HPLC determined that this compound 90.8 % purity.
  • Example 86 Example 86
  • Example 87 Using the procedure of Example 83 and substituting 3- triflouromethoxyphenethylamine, the title compound was obtained as a white solid; 1 HNMR (DMSO-d 6 ) ⁇ 6.80-8.00 (m, 17 H), 6.55 (s, IH), 5.00 (s, 2H), 4.25 (m, 4H), 2.20 (m, 2H), 1.65 (s, 3H); MS (ES-positive): [M+ H] + 680. HPLC determined that this compound 93.9 % purity.
  • Example 87
  • Example 89 Using the procedure of Example 83 and substituting 3-iodophenethylamine, the title compound was obtained as a white solid; 1 HNMR (DMSO-d 6 ) ⁇ 6.70-8.15 (m, 17 H), 6.55 (s, IH), 4.98 (s, 2H), 4.17 (m, 4H), 2.25 (m, 2H), 1.65 (s, 3H); MS (ES-positive): [M+ H] + 722; HPLC determined that this compound 91.3 % purity.
  • Example 89 Example 89

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Abstract

Selon un premier mode de réalisation, l'invention concerne de nouveaux composés. L'invention concerne également un agoniste de récepteur d'hormone de stimulation de follicule (FSH), dans lequel l'agoniste se lie à un récepteur de FSH possédant un site de liaison de FSH, et dans lequel ledit agoniste n'entre pas en concurrence avec FSH pour le site de liaison de FSH. Selon un second mode de réalisation, l'invention concerne des méthodes d'utilisation desdits composés dans diverses applications pharmaceutiques, par exemple, des thérapies utilisant des agents anti-ischémiques CNS, des agents possédant des propriétés antipsychotiques ou psychoactives, des agents antimicrobiens, et un agent de régulation de la fertilité d'un mammifère.
EP01955958A 2000-07-27 2001-07-24 Agoniste d'activite hormonale stimulant un follicule Withdrawn EP1307193A1 (fr)

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US629248 2000-07-27
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US20080004263A1 (en) * 2004-03-04 2008-01-03 Santora Vincent J Ligands of Follicle Stimulating Hormone Receptor and Methods of Use Thereof
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UA92009C2 (ru) 2005-05-04 2010-09-27 Н.В. Органон Производные 4-фенил-5-оксо-1,4,5,6,7,8-гексагидрохинолина для лечения бесплодия
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JP6386382B2 (ja) 2012-02-08 2018-09-05 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ 卵胞刺激ホルモン受容体のアゴニストとしての重水素化されたチアゾリジノン類似体
RU2663898C2 (ru) 2013-06-24 2018-08-13 Мерк Патент Гмбх Пиразольные соединения в качестве модуляторов fshr и их применение
CN105658650B (zh) 2013-06-24 2019-01-08 默克专利有限公司 用作卵泡刺激素受体调节剂的咪唑化合物及其用途
US9399623B2 (en) 2014-06-05 2016-07-26 Merck Patent Gmbh Quinoline derivatives and their use in neurodegenerative diseases
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RU2017111200A (ru) 2014-09-05 2018-10-05 Мерк Патент Гмбх Циклогексилэтилзамещенные диаза- и триаза-трициклические соединения в качестве антагонистов индоламин-2,3-диоксигеназы для лечения рака
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