WO2013117299A1 - Deuterated thiazolidinone analogues as agonists for follicle stimulating hormone receptor - Google Patents

Deuterated thiazolidinone analogues as agonists for follicle stimulating hormone receptor Download PDF

Info

Publication number
WO2013117299A1
WO2013117299A1 PCT/EP2013/000215 EP2013000215W WO2013117299A1 WO 2013117299 A1 WO2013117299 A1 WO 2013117299A1 EP 2013000215 W EP2013000215 W EP 2013000215W WO 2013117299 A1 WO2013117299 A1 WO 2013117299A1
Authority
WO
WIPO (PCT)
Prior art keywords
deuterium
acid
hydrogen
compounds
phenyl
Prior art date
Application number
PCT/EP2013/000215
Other languages
French (fr)
Inventor
Henry Yu
Marianne DONNELLY
Original Assignee
Merck Patent Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US14/372,102 priority Critical patent/US20150111933A1/en
Priority to RU2014136334A priority patent/RU2014136334A/en
Priority to CA2860489A priority patent/CA2860489C/en
Priority to EP13702741.3A priority patent/EP2812320B1/en
Application filed by Merck Patent Gmbh filed Critical Merck Patent Gmbh
Priority to ES13702741.3T priority patent/ES2672326T3/en
Priority to BR112014019351A priority patent/BR112014019351A8/en
Priority to SG11201403540RA priority patent/SG11201403540RA/en
Priority to AU2013218368A priority patent/AU2013218368B2/en
Priority to MX2014009416A priority patent/MX2014009416A/en
Priority to CN201380008413.8A priority patent/CN104114544A/en
Priority to KR20147021930A priority patent/KR20140120903A/en
Priority to JP2014555967A priority patent/JP6386382B2/en
Publication of WO2013117299A1 publication Critical patent/WO2013117299A1/en
Priority to IL233983A priority patent/IL233983B/en
Priority to HK15102455.7A priority patent/HK1201837A1/en

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D277/00Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08Heterocyclic 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
    • C07D277/12Heterocyclic 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
    • C07D277/14Oxygen atoms
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/42Gynaecological or obstetrical instruments or methods
    • A61B17/425Gynaecological or obstetrical instruments or methods for reproduction or fertilisation
    • A61B17/435Gynaecological or obstetrical instruments or methods for reproduction or fertilisation for embryo or ova transplantation
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425Thiazoles
    • A61K31/4261,3-Thiazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00Drugs for genital or sexual disorders; Contraceptives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002Heterocyclic compounds
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention relates to deuterated thiazolidinone analogues as agonists for follicle stimulating hormone receptor and their use for treating fertility disorders.
  • Gonadotropins serve important functions in a variety of bodily functions including metabolism, temperature regulation and the reproductive process. Gonadotropins act on specific gonadal cell types to initiate ovarian and testicular differentiation and steroidogenesis.
  • the gonadotropin FSH follicle stimulating hormone
  • FSH is a heterodimeric glycoprotein hormone that shares structural similarities with luteinizing hormone (LH) and thyroid stimulating hormone (TSH), both of which are also produced in the pituitary gland, and chorionic gonadotropin (CG), which is produced in the placenta.
  • LH luteinizing hormone
  • TSH thyroid stimulating hormone
  • CG chorionic gonadotropin
  • FSH plays a pivotal role in the stimulation of follicle development and maturation and in addition, it is the major hormone regulating secretion of estrogens, whereas LH induces ovulation.
  • FSH is responsible for the integrity of the seminiferous tubules and acts on Sertoli cells to support gametogenesis.
  • the hormones are relatively large (28-38 kDa) and are composed of a common a-subunit non-covalently bound to a distinct ⁇ -subunit that confers receptor binding specificity.
  • the cellular receptor for these hormones is expressed on testicular Sertoli cells and ovarian granulosa cells.
  • the FSH receptor is known to be members of the G protein-coupled class of membrane-bound receptors, which when activated stimulate an increase in the activity of adenylyl cyclase. This results in an increase in the level of the intracellular second messenger adenosine 3", ⁇ -monophosphate (cAMP), which in turn causes increased steroid synthesis and secretion.
  • cAMP ⁇ -monophosphate
  • Hydropathicity plots of the amino acid sequences of these receptors reveal three general domains: a hydrophilic amino-terminal region, considered to be the amino- terminal extracellular domain; seven hydrophobic segments of membrane-spanning length, considered to be the transmembrane domain; and a carboxy-terminal region that contains potential phosphorylation sites (serine, threonine, and tyrosine residues), considered to be the carboxy-terminal intracellular or cytoplasmic domain.
  • the glycoprotein hormone receptor family is distinguished from other G protein- coupled receptors, such as the ⁇ -2-adrenergic, rhodopsin, and substance K receptors, by the large size of the hydrophilic amino-terminal domain, which is involved in hormone binding.
  • FSH is a parenterally-administered protein product used by specialists for ovulation induction and for controlled ovarial hyperstimulation. Whereas ovulation induction is directed at achieving a single follicle to ovulate, controlled ovarial hyperstimulation is directed at harvesting multiple oocytes for use in various in-vitro assisted reproductive technologies, e.g. in-vitro fertilization (IVF). FSH is also used clinically to treat male hypogonadism and male infertility, e.g.
  • Follicle stimulating hormone receptor is a highly specific target in the ovarian follicle growth process and is exclusively expressed in the ovary.
  • FSH Follicle stimulating hormone receptor
  • Pelletier JC et al. disclose the preparation of highly substituted gamma-lactam follicle stimulating hormone receptor agonists (Bioorg. Med. Chem. 2005, 13: 5986- 5995).
  • WO 02/09705 is directed to thiazolidinones as agonists of follicle stimulating hormone activity.
  • WO 02/09706 relates to novel thiazolidinones as agonists of follicle stimulating hormone activity and discloses compound
  • reference compound (hereinafter referred to as reference compound)
  • the present invention has the object to provide deuterated thiazolidinone analogues as agonists for FSHR.
  • each Y is independently from each other selected from the group consisting of: "hydrogen (H), deuterium (D)";
  • X is selected from the group consisting of: "S, sulfoxide”
  • R1 , R2 are independently from each other selected from the group consisting of: "hydrogen (H), deuterium (D), methyl, CH 2 D, CHD 2 , CD 3 , ethyl, CHDCH 3 , CHDCH 2 D, CHDCHDz, CHDCD 3l CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 , CD 2 CD 3 "; with the proviso that at least one Y is deuterium (D) or at least one of R1 , R2 comprises at least one deuterium (D); optionally, at least one carbon atom is independently from each other replaced by 13 C; and the physiologically acceptable salts, solvates, tautomers and
  • a deuterated thiazolidinone derivative according to formula (I) supra wherein at least one carbon atom is replaced by 13 C; and the physiologically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.
  • a compound according to formula (I) supra and above embodiments wherein: Yi5, Yi6, Yi7, Yi8 are deuterium (D); and the physiologically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.
  • a compound according to formula (I) supra and above embodiments is provided, wherein:
  • Ye. Y?. Ye. Y9 are deuterium (D); and the physiologically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.
  • R n and/or R 2 are CD 3 ; and the physiologically acceptable salts, solvates, tautomers and
  • Y ⁇ , Y 2 , Y 3 , Y , Y5 are deuterium (D) and the other Y are hydrogen (H) and none of R ⁇ R 2 comprises one or more deuterium (D); or (e) all Y are hydrogen (H) and both of R ⁇ R 2 are CD 3 ; or
  • Y 6 , Y7, Ys, Y9, Y15, Y16, Yi7, Y18 are deuterium (D) and the other Y are hydrogen (H) and one of R, , R 2 is CD 3 and the other one of R ⁇ R 2 does not comprise one or more deuterium (D); or
  • Y 2 , ⁇ 3 , ⁇ 4 , ⁇ 5 , ⁇ 6 , ⁇ , ⁇ 8 , ⁇ 9 , ⁇ 5, ⁇ 6, ⁇ 17 , ⁇ 8 are deuterium (D) and the other Y are hydrogen (H) and one of R 2 is CD 3 and the other one of R 1t R 2 does not comprise one or more deuterium (D); and the physiologically acceptable salts, solvates, tautomers and
  • the object of the present invention has surprisingly been solved by providing a compound selected from the group consisting of:
  • substituted means that the corresponding radical, group or moiety has one or more substituents. Where a radical has a plurality of substituents, and a selection of various substituents is specified, the substituents are selected independently of one another and do not need to be identical.
  • composition as in pharmaceutical composition, for the purposes of this invention is intended to encompass a product comprising the active
  • compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • administering a should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individualist need.
  • effective amount refers to any amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.
  • All stereoisomers of the compounds of the invention are contemplated, either in a mixture or in pure or substantially pure form.
  • the compounds of the invention can have asymmetric centers at any of the carbon atoms. Consequently, they can exist in the form of their racemates, in the form of the pure enantiomers and/or diastereomers or in the form of mixtures of these enantiomers and/or diastereomers.
  • the mixtures may have any desired mixing ratio of the stereoisomers.
  • the compounds of the invention which have one or more centers of chirality and which occur as racemates or as diastereomer mixtures can be fractionated by methods known per se into their optical pure isomers, i.e.
  • the separation of the compounds of the invention can take place by column separation on chiral or nonchiral phases or by
  • the compounds of the invention may be present in the form of their double bond isomers as "pure" E or Z isomers, or in the form of mixtures of these double bond isomers.
  • the compounds of the invention may be in the form of the tautomers, such as keto-enol tautomers.
  • the compounds of the invention can be in the form of any desired prodrugs such as, for example, esters, carbonates, carbamates, ureas, amides or phosphates, in which cases the actually biologically active form is released only through metabolism.
  • Any compound that can be converted in vivo to provide the bioactive agent i.e. compounds of the invention
  • Various forms of prodrugs are well known in the art and are described for instance in:
  • Any biologically active compound that was converted in vivo by metabolism from any of the compounds of the invention is a metabolite within the scope and spirit of the invention.
  • the compounds of the invention can, if they have a sufficiently basic group such as, for example, a secondary or tertiary amine, be converted with inorganic and organic acids into salts.
  • the pharmaceutically acceptable salts of the compounds of the invention are preferably formed with hydrochloric acid, hydrobromic acid, iodic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, sulfoacetic acid, trifluoroacetic acid, oxalic acid, malonic acid, maleic acid, succinic acid, tartaric acid, racemic acid, malic acid, embonic acid, mandelic acid, fumaric acid, lactic acid, citric acid, taurocholic acid, glutaric acid, stearic acid, glutamic acid or aspartic acid.
  • the salts which are formed are, inter alia, hydrochlorides, chlorides, hydrobromides, bromides, iodides, sulfates, phosphates, methanesulfonates, tosylates, carbonates, bicarbonates, formates, acetates, sulfoacetates, triflates, oxalates, malonates, maleates, succinates, tartrates, malates, embonates, mandelates, fumarates, lactates, citrates, glutarates, stearates, aspartates and glutamates.
  • the stoichiometry of the salts formed from the compounds of the invention may moreover be an integral or non-integral multiple of one.
  • the compounds of the invention can, if they contain a sufficiently acidic group such as, for example, the carboxy, sulfonic acid, phosphoric acid or a phenolic group, be converted with inorganic and organic bases into their physiologically tolerated salts.
  • suitable inorganic bases are ammonium, sodium hydroxide, potassium hydroxide, calcium hydroxide
  • organic bases are ethanolamine, diethanolamine, triethanolamine, ethylenediamine, t-butylamine, t- octylamine, dehydroabietylamine, cyclohexylamine, dibenzylethylene-diamine and lysine.
  • the stoichiometry of the salts formed from the compounds of the invention can moreover be an integral or non-integral multiple of one.
  • the compounds of the invention are in the form of their solvates and, in particular, hydrates which can be obtained for example by crystallization from a solvent or from aqueous solution. It is moreover possible for one, two, three or any number of solvate or water molecules to combine with the compounds of the invention to give solvates and hydrates.
  • solvate is meant a hydrate, an alcoholate, or other solvate of crystallization.
  • the compounds of the invention preferably exhibit an advantageous biological activity, which is easily demonstrated in cell culture-based assays, for example assays as described herein or in prior art (cf. e.g. WO 2002/009706, which is incorporated herein by reference).
  • the compounds of the invention preferably exhibit and cause an agonistic effect.
  • the compounds of the invention have an FSHR agonist activity, as expressed by an EC 50 standard, of less than 1000 nM, more preferably less than 500 nM.
  • "ECso" is the effective concentration of a compound at which 50 % of the maximal response of that obtained with FSH would be obtained.
  • the compounds of the invention are useful in the prophylaxis and/or treatment of diseases that are dependent on the said signaling pathways by interaction with one or more of the said signaling pathways.
  • the present invention therefore relates to compounds of the invention as modulators, preferably agonists, more preferably positive allosteric modulators, of the signaling pathways described herein, preferably of the FSHR-mediated signaling pathway.
  • the compounds of the invention are supposed to bind to the intracellular receptor domain without a competitive interaction with FSH, but they act as an allosteric enhancer of FSH on its receptor.
  • the non-competitive interaction refers to the nature of the agonist activity exhibited by the compounds of the invention, wherein the compounds activate FSHR without substantially reducing the magnitude of binding of FSH to FSHR.
  • the method of the invention can be performed either in-vitro or in-vivo.
  • the susceptibility of a particular cell to treatment with the compounds according to the invention can be particularly determined by in-vitro tests, whether in the course of research or clinical application.
  • a culture of the cell is combined with a compound according to the invention at various concentrations for a period of time which is sufficient to allow the active agents to modulate FSHR activity, usually between about one hour and one week.
  • In-vitro treatment can be carried out using cultivated cells from a biopsy sample or cell line.
  • a follicle cell is stimulated for maturation. The viable cells remaining after the treatment are counted and further processed.
  • a physiologically acceptable salt of a compound of the invention can also be obtained by isolating and/or treating the compound of the invention obtained by the described reaction with an acid or a base.
  • the compounds of the invention and also the starting materials for their preparation are, are prepared by methods as described in the examples or by methods known per se, as described in the literature (for example in standard works, such as Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York), to be precise under reaction conditions which are known and suitable for the said reactions. Use can also be made here of variants which are known per se, but are not mentioned here in greater detail.
  • the starting materials for the claimed process may, if desired, also be formed in situ by not isolating them from the reaction mixture, but instead immediately converting them further into the compounds of the invention. On the other hand, it is possible to carry out the reaction stepwise.
  • the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions.
  • suitable solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1 ,2- dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides
  • Polar solvents are in general preferred.
  • suitable polar solvents are chlorinated hydrocarbons, alcohols, glycol ethers, nitriles, amides and sulfoxides or mixtures thereof. More preferred are amides, especially dimethylformamide (DMF).
  • the reaction temperature is between about -100° C and 300° C, depending on the reaction step and the conditions used.
  • Reaction times are generally in the range between some minutes and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily determinable by methods known in the art, for example reaction monitoring. Based on the reaction
  • reaction times generally lie in the range between 10 min and 48 hrs.
  • a base of a compound of the invention can be converted into the associated acid-addition salt using an acid, for example by reaction of equivalent amounts of the base and the acid in a preferably inert solvent, such as ethanol, followed by evaporation.
  • Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts.
  • inorganic acids for example sulfuric acid, sulfurous acid, dithionic acid, nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as, for example, orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, hexanoic acid, octanoic acid, decanoic acid, hexadecanoic acid, octadecanoic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid,
  • inorganic acids for
  • parachlorophenoxyisobutyric acid parachlorophenoxyisobutyric acid, cyclohexanecarboxylic acid, glucose 1- phosphate, naphthalenemono- and -disulfonic acids or laurylsulfuric acid.
  • Salts with physiologically unacceptable acids for example picrates, can be used to isolate and/or purify the compounds of the invention.
  • compounds of the invention can be converted into the corresponding metal salts, in particular alkali metal salts or alkaline earth metal salts, or into the corresponding ammonium salts, using bases (for example sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate).
  • bases for example sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
  • Suitable salts are furthermore substituted ammonium salts, for example the dimethyl-, diethyl- and diisopropylammonium salts, monoethanol-, diethanol- and diisopropanolammonium salts, cyclohexyl- and dicyclohexylammonium salts, dibenzylethylenediammonium salts, furthermore, for example, salts with arginine or lysine.
  • the free bases of the compounds of the invention can be liberated from their salts by treatment with strong bases, such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, so long as no further acidic groups are present in the molecule.
  • strong bases such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate
  • bases are alkali metal hydroxides, alkaline earth metal hydroxides or organic bases in the form of primary, secondary or tertiary amines.
  • Every reaction step described herein can optionally be followed by one or more working up procedures and/or isolating procedures. Suitable such procedures are known in the art, for example from standard works, such as Houben-Weyl,
  • the object of the present invention has surprisingly been solved in another aspect by providing a medicament comprising at least one compound of the invention.
  • the object of the present invention has surprisingly been solved in another aspect by providing a medicament comprising at least one compound of the invention for use in the prophylactic or therapeutic treatment and/or monitoring of fertility disorders.
  • Object of the present invention is also the use of compounds according to formula (I) and/or physiologically acceptable salts thereof for modulating a FSH receptor, particularly in the presence of FSH.
  • modulation denotes any change in FSHR-mediated signal transduction, which is based on the action of the specific inventive compounds capable to interact with the FSHR target in such a manner that makes recognition, binding and activating possible.
  • the compounds are characterized by such a high affinity to FSHR, which ensures a reliable binding and preferably a positive allosteric modulation of FSHR. More preferably, the substances are mono-specific in order to guarantee an exclusive and directed recognition with the single FSHR target.
  • the term “modulation” denotes any change in FSHR-mediated signal transduction, which is based on the action of the specific inventive compounds capable to interact
  • "recognition” - without being limited thereto - relates to any type of interaction between the specific compounds and the target, particularly covalent or non- covalent binding or association, such as a covalent bond, hydrophobic/ hydrophilic interactions, van der Waals forces, ion pairs, hydrogen bonds, ligand-receptor interactions, and the like. Such association may also encompass the presence of other molecules such as peptides, proteins or nucleotide sequences.
  • the present receptor/ligand-interaction is characterized by high affinity, high selectivity and minimal or even lacking cross-reactivity to other target molecules to exclude unhealthy and harmful impacts to the treated subject.
  • Compounds of the invention may be used in combination with one or more other active substances (ingredients, drugs) in the treatment, prevention, suppression or amelioration of diseases or conditions for which compounds of the invention or the other substances have utility.
  • the combination of the drugs is safer or more effective than either drug alone, or the combination is safer or more effective than would it be expected based on the additive properties of the individual drugs.
  • Such other drug(s) may be administered, by a route and in an amount commonly used contemporaneously or sequentially with a compound of the invention.
  • a combination product containing such other drug(s) and the compound of the invention is preferred.
  • combination therapy also includes therapies in which the compound of the invention and one or more other drugs are administered on different overlapping schedules. It is contemplated that when used in
  • the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the invention.
  • the present compounds are suitable for combination with known fertility- inducing agents.
  • the other active (pharmaceutical) ingredient is selected from the group of FSH, a-FSH (Gonal F), ⁇ -FSH, LH, hMG and 2-(4-(2-chloro-1 ,2- diphenylethenyl)-phenoxy)-N,N-diethyl-ethanamine citrate (Chlomifene citrate).
  • Further ovulation adjuncts are known to those of skill in the art (cf. e.g.
  • a medicament according to above aspects and embodiments is provided, wherein in such medicament comprises at least one additional pharmacologically active substance (drug, ingredient).
  • the at least one pharmacologically active substance is a substance as described herein.
  • a medicament according to above aspects and embodiments is provided, wherein the medicament is applied before and/or during and/or after treatment with at least one additional pharmacologically active substance.
  • the at least one pharmacologically active substance is a substance as described herein.
  • composition comprising a therapeutically effective amount of at least one compound of the invention.
  • the pharmaceutical composition contains at least one additional compound selected from the group consisting of physiologically acceptable excipients, auxiliaries, adjuvants, diluents, carriers and/or additional pharmaceutically active substance other than the compounds of the invention.
  • a pharmaceutical composition which comprises at least one compound of the invention, at least one pharmacologically active substance other than the compounds of the invention as described herein; and a pharmaceutically acceptable carrier.
  • a further embodiment of the present invention is a process for the manufacture of said pharmaceutical compositions, characterized in that one or more compounds according to the invention and one or more compounds selected from the group consisting of solid, liquid or semiliquid excipients, auxiliaries, adjuvants, diluents, carriers and pharmaceutically active agents other than the compounds according to the invention, are converted in a suitable dosage form.
  • a kit is provided comprising a therapeutically effective amount of at least one compound of the invention and/or at least one pharmaceutical composition as described herein and a therapeutically effective amount of at least one further pharmacologically active substance other than the compounds of the invention.
  • a method for modulating a FSH receptor in a positive allosteric manner wherein a cell capable of expressing the FSH receptor is contacted in the presence of FSH with at least one compound of the invention or at least one pharmaceutical composition as described supra.
  • a method for treating fertility disorders wherein a therapeutically effective amount of at least one compound of the invention or at least one pharmaceutical composition as described supra is administered to a mammal in need of such treatment.
  • a method for in-vitro fertilization comprising the steps of:
  • compositions of the present invention may be administered by any means that achieve their intended purpose.
  • administration may be by oral, parenteral, topical, enteral, intravenous, intramuscular, inhalant, nasal, intraarticular, intraspinal, transtracheal, transocular, subcutaneous, intraperitoneal, transdermal, or buccal routes.
  • administration may be by the oral route.
  • the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired. Parenteral administration is preferred. Oral administration is especially preferred.
  • Suitable dosage forms include, but are not limited to capsules, tablets, pellets, dragees, semi-solids, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, cataplasms, gels, tapes, eye drops, solution, syrups, aerosols, suspension, emulsion, which can be produced according to methods known in the art, for example as described below:
  • tablets mixing of active ingredient/s and auxiliaries, compression of said mixture into tablets (direct compression), optionally granulation of part of mixture before compression.
  • capsules mixing of active ingredient/s and auxiliaries to obtain a flowable powder, optionally granulating powder, filling powders/granulate into opened capsules, capping of capsules.
  • suppositories rectal and vaginal: dissolving/dispersing active ingredient/s in carrier material liquified by heat (rectal: carrier material normally a wax; vaginal: carrier normally a heated solution of a gelling agent), casting said mixture into suppository forms, annealing and withdrawal suppositories from the forms.
  • aerosols dispersing/dissolving active agent s in a propellant, bottling said mixture into an atomizer.
  • non-chemical routes for the production of pharmaceutical compositions and/or pharmaceutical preparations comprise processing steps on suitable mechanical means known in the art that transfer one or more compounds ofthe invenion into a dosage form suitable for administration to a patient in need of such a treatment.
  • the transfer of one or more compounds of the invention into such a dosage form comprises the addition of one or more compounds, selected from the group consisting of carriers, excipients, auxiliaries and pharmaceutical active ingredients other than the compounds of the invention.
  • Suitable processing steps include, but are not limited to combining, milling, mixing, granulating, dissolving, dispersing, homogenizing, casting and/or compressing the respective active and non-active ingredients.
  • Mechanical means for performing said processing steps are known in the art, for example from Ullmann's Encyclopedia of Industrial Chemistry, 5th Edition.
  • active ingredients are preferably at least one compound of the invention and one or more additional compounds other than the compounds of the invention, which show valuable pharmaceutical properties, preferably those pharmaceutical active agents other than the compounds of the invention, which are disclosed herein.
  • Particularly suitable for oral use are tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops, suitable for rectal use are suppositories, suitable for parenteral use are solutions, preferably oil-based or aqueous solutions, furthermore suspensions, emulsions or implants, and suitable for topical use are ointments, creams or powders.
  • the compounds of the invention may also be lyophilised and the resultant lyophilisates used, for example, for the preparation of injection preparations.
  • the preparations indicated may be sterilised and/or comprise assistants, such as lubricants, preservatives, stabilisers and/or wetting agents, emulsifiers, salts for modifying the osmotic pressure, buffer substances, dyes, flavours and/or a plurality of further active ingredients, for example one or more vitamins.
  • assistants such as lubricants, preservatives, stabilisers and/or wetting agents, emulsifiers, salts for modifying the osmotic pressure, buffer substances, dyes, flavours and/or a plurality of further active ingredients, for example one or more vitamins.
  • Suitable excipients are organic or inorganic substances, which are suitable for enteral (for example oral), parenteral or topical administration and do not react with the compounds of the invention, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatine, carbohydrates, such as lactose, sucrose, mannitol, sorbitol or starch (maize starch, wheat starch, rice starch, potato starch), cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, magnesium stearate, talc, gelatine, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyvinyl pyrrolidone and/or vaseline.
  • enteral for example oral
  • parenteral or topical administration do not react with the compounds of the invention
  • carbohydrates such as lactose, sucrose, mannitol
  • disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • Auxiliaries include, without limitation, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with suitable coatings, which, if desired, are resistant to gastric juices.
  • concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • the tablet, dragee or pill can comprise an inner dosage and an outer dosage component me latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, acetyl alcohol, solutions of suitable cellulose preparations such as acetyl-cellulose phthalate, cellulose acetate or hydroxypropylmethyl-cellulose phthalate, are used.
  • Dye stuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
  • Suitable carrier substances are organic or inorganic substances which are suitable for enteral (e.g. oral) or parenteral administration or topical application and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petroleum jelly.
  • tablets, coated tablets, capsules, syrups, suspensions, drops or suppositories are used for enteral administration, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, are used for parenteral administration, and ointments, creams or powders are used for topical application.
  • the compounds of the invention can also be lyophilized and the lyophilizates obtained can be used, for example, for the production of injection preparations.
  • the preparations indicated can be sterilized and/or can contain excipients such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffer substances, colorants, flavourings and/or aromatizers. They can, if desired, also contain one or more further active
  • Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatine, as well as soft, sealed capsules made of gelatine and a plasticizer such as glycerol or sorbitol.
  • the push-fit capsules can contain the active compounds in the form of granules, which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin.
  • suitable liquids such as fatty oils, or liquid paraffin.
  • stabilizers may be added.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatine.
  • Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts and alkaline solutions.
  • suspensions of the active compounds as appropriate oily injection suspensions may be administered.
  • Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400).
  • Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, including, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran, optionally, the suspension may also contain stabilizers.
  • inhalation spray for administration as an inhalation spray, it is possible to use sprays in which the active ingredient is either dissolved or suspended in a propellant gas or propellant gas mixture (for example C0 2 or chlorofluorocarbons).
  • a propellant gas or propellant gas mixture for example C0 2 or chlorofluorocarbons.
  • the active ingredient is advantageously used here in micronized form, in which case one or more additional physiologically acceptable solvents may be present, for example ethanol.
  • Inhalation solutions can be administered with the aid of conventional inhalers.
  • Possible pharmaceutical preparations which can be used rectally include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons.
  • gelatine rectal capsules which consist of a combination of the active compounds with a base.
  • Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.
  • the compounds of the present invention will be in the form of pharmaceutically acceptable salts.
  • Other salts may, however, be useful in the preparation of the compounds of the invention or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic bases, e.g. quaternary ammonium salts.
  • the pharmaceutical preparations can be employed as medicaments in human and veterinary medicine.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function. Said therapeutic effective amount of one or more of the compounds of the invention is known to the skilled artisan or can be easily determined by standard methods known in the art.
  • the compounds of the invention and the additional active substances are generally administered analogously to commercial preparations.
  • suitable doses that are therapeutically effective lie in the range between 0.0005 mg and 1000 mg, preferably between 0.005 mg and 500 mg and especially between 0.5 mg and 100 mg per dose unit.
  • the daily dose is preferably between about 0.001 mg/kg and 10 mg/kg of body weight.
  • dose levels can vary as a function of the specific compound, the severity of the symptoms and the susceptibility of the subject to side effects. Some of the specific compounds are more potent than others.
  • Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound.
  • mammalian species are regarded as being comprised.
  • such mammals are selected from the group consisting of "primate, human, rodent, equine, bovine, canine, feline, domestic animals, cattle, livestock, pets, cow, sheep, pig, goat, horse, pony, donkey, hinny, mule, hare, rabbit, cat, dog, guinea pig, hamster, rat, mouse". More preferably, such mammals are humans.
  • Animal models are of interest for
  • the specific dose for the individual patient depends, however, on the multitude of factors, for example on the efficacy of the specific compounds employed, on the age, body weight, general state of health, the sex, the kind of diet, on the time and route of administration, on the excretion rate, the kind of administration and the dosage form to be administered, the pharmaceutical combination and severity of the particular disorder to which the therapy relates.
  • the specific therapeutic effective dose for the individual patient can readily be determined by routine experimentation, for example by the doctor or physician, which advises or attends the therapeutic treatment.
  • the susceptibility of a particular cell to treatment with the subject compounds may be determined by in vitro testing.
  • a culture of the cell is combined with a subject compound at varying concentrations for a period of time sufficient to allow the active agents to show a relevant reaction, usually between about one hour and one week.
  • cultured cells from a biopsy sample may be used.
  • Step 1
  • Step 3 To [(2S,5R)-3-(3-Carbamoyl-phenyl)-4-oxo-2-(4-phenylethynyl-phenyl)- thiazolidin-5-yl]-acetic acid (50.00 mg; 0.11 mmol; 1.00 eq.) in dichloromethane(2.00 ml; 31.20 mmol; 284.87 eq.) was added ⁇ , ⁇ -Diisopropylethylamine (0.02 ml; 0.13 mmol; 1.20 eq.), 2-(4-hydroxy-3-methoxyphenyl)ethyl-1 , 1 ,2,2- oVamine HCI (25.02mg, 0.12mmol, 1.1 eq.) and 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.05 ml; 0.16 mmol; 1.50 eq.).
  • Example 3 3-((2S,5R)-4-oxo-5-(2-oxo-2-((1 ,1 ⁇ - ⁇ -(S-methoxy ⁇ -imethoxy- , 3 )phenyl)ethyl)amino)ethyl)-2-(4-(phenylethynyl)phenyl)thiazolidin-3-yl)benzamide
  • product was obtained from 3-((2S,5R)-4-oxo-5-(2- oxo-2-((1 ,1 ,2,2- ⁇ 3 ⁇ 4-2-(4-hydroxy-3-methoxyphenyl)ethyl)amino)ethyl)-2-(4- (phenylethynyl)phenyl)thiazolidin-3-yl)benzamide (35.00 mg; 0.06 mmol; 1.00 eq.) and dimethyl sulfate- ⁇ (2.92 ⁇ ; 0.03 mmol; 0.50 eq.). The reaction was stirred at RT overnight. The desired product was isolated by flash chromatography (10g, KPNH, 0 to 20% MeOH/DCM) to afford product as white solid (22.3mg, 63%).
  • Example 5 3-((2S,5R)-4-oxo-5-(2-oxo-2-((1 , 1 ,2,2-£ 4 -2-(3-ethoxy-4-(methoxy- d 3 )phenyl)ethyl)amino)ethyl)-2-(4-(phenylethynyl)phenyl)thiazolidin-3-yl)benzamide
  • product was obtain from 3-[(2S,5R)-5- ⁇ [2-(3- Ethoxy-4-hydroxy-phenyl)-ethylcarbamoyl]-methyl ⁇ -4-oxo-2-(4-phenylethynyl- phenyl)-thiazolidin-3-yl]-benzamide (50.00 mg; 0.08 mmol; 1.00 eq.) and dimethyl sulfate-cfe (4.10 ⁇ ; 0.04 mmol; 0.50 eq.). 28.9mg (56%) of the title compound was obtained as white solid.
  • Example 8 3-((2S,5R)-5-(2-((3-ethoxy-4-methoxyphenethyl)amino)-2-oxoethyl)-4- oxo-2-(4-((phenyl-cfe)ethynyl)phenyl)thiazolidin-3-yl)benzamide
  • Step 1 To 4-bromobenzaldehyde (750.00 mg; 4.05 mmol; 1.00 eq.), was added zinc chloride (55.25 mg; 0.41 mmol; 0.10 eq.), bis(tri-tert-butylphosphine)palladium(0) (41.43 mg; 0.08 mmol; 0.02 eq.), THF (1.00 ml; 12.34 mmol; 3.04 eq.),
  • Step 2 In a similar manner to example 1 step 1 & 2, 2-((2S,5R)-3-(3- carbamoylphenyl)-4-oxo-2-(4-(phenyl-i/5-ethynyl)phenyl)thiazolidin-5-yl)acetic acid was obtained from 4-(phenyl-d 5 -ethynyl)benzaldehyde (206mg, 0.98mmol), (S)-2- Mercapto-succinic acid (439.23 mg; 2.93 mmol; 3.00 eq.) and 3-aminobenzamide (132.76 mg; 0.98 mmol; 1.00 eq.). Final product was isolated by prep HPLC.
  • Example 9 3-((2S,5R)-4-oxo-5-(2-oxo-2-((1 , 1 ,2,2-d,-2-(3-ethoxy-4- methoxyphenyl)ethyl)amino)ethyl)-2-(4-((phenyl-c 5 )ethynyl)phenyl)thiazolidin-3- yl)benzamide
  • Example 11 3-((2S,5R)-4-oxo-5-(2-oxo-2-((1 ,1 ,2,2-d 4 -2-(3-ethoxy-4- hydroxyphenyl)ethyl)amino)ethyl)-2-(4-((phenyl-i 5)ethynyl)phenyl)thiazolidin-3- yl)benzamide
  • product was obtained from 2-((2S,5R)-3-(3- carbamoylphenyl)-4-oxo-2-(4-(phenyl-d 5 -ethynyl)phenyl)thiazolidin-5-yl)acetic acid (16.6 mg; 0.04 mmol; 1.00 eq.), and 2-(3-ethoxy-4-hydroxyphenyl)ethyl-1 , 1 ,2,2- examine HCI (8.22mg, 0.06mmol, 1.1 eq.). 2.5 mg (10%) of the title product was obtained as white solid.
  • product was obtained from 32-((2S,5R)-3-(3- carbamoylphenyl)-4-oxo-2-(4-(phenyl-c/ 5 -ethynyl)phenyl)thiazolidin-5-yl)acetic acid (16.6 mg; 0.04 mmol; 1.00 eq.), and 4-(2-Amino-ethyl)-benzene-1 ,2-diol (6.06mg, 0.04 mmol, 1.1 eq.). The title compound was obtained (2.7 mg, 10%) of as white solid.
  • Example 13 3-((2S,5R)-4-oxo-5-(2-oxo-2-((1 ,1 ,2,2-d4-2-(3-ethoxy-4-methox-d3- ypheny ethyl)amino)ethyl)-2-(4-((phenyl-tf 5 )ethynyl)phenyl)thiazoh ' din-3- yl)benzamide
  • product was obtained from product from example 11 (55mg, 0.09 mmol, 1 eq.) and dimethyl sulfate- d 5 (4.55 ⁇ ; 0.04 mmol; 0.50 eq.). A 26 mg (39%) of the title product was obtained as white solid.
  • Example 14 3-((2S,5RH-oxo-5-(2-oxo-2-((1 ,1 ,2,2-d 4 -2-(3-ethoxy-4- methoxyphenyl)ethyl)amino)ethyl)-2-(2 J 3,5,6-o'4-4-(phenylethynyl)phenyl)thiazolidin-
  • Step 1 To 4-chlorobenzaldehyde-2,3,5,6-tf 4 (1 00 g; 6.92 mmol; 1.00 eq.) was added caesium carbonate (4506.86 mg; 13.83 mmol; 2.00 eq.), 2- dicyclohexylphosphino- ⁇ '.e'-triisopropylbiphenyl (659.40 mg; 1.38 mmol; 0.20 eq.) and MeCN (60.00 ml; 1148.76 mmol; 166.10 eq.). Then phenylacetylene (1.12 ml; 10.24 mmol; 1.48 eq.) was added and reaction mixture was vacuum/nitrogen flush 3 times.
  • caesium carbonate 4506.86 mg; 13.83 mmol; 2.00 eq.
  • 2- dicyclohexylphosphino- ⁇ '.e'-triisopropylbiphenyl 659.40 mg; 1.38
  • Step 2 In a similar manner to example 1 step 1&2, 2, 2-((2S,5R)-3-(3- carbamoylphenyl)-4-oxo-2-(4-(phenyl-ethynyl)phenyl- / )thiazolidin-5-yl)acetic acid was obtained from 4-(phenyl-ethynyl)benzaldehyde-2,3 relieve5,6-d4 (386 mg, 1.84 mmol), S)-2-Mercapto-succinic acid (826.95 mg; 5.51 mmol; 3.00 eq.) and 3- aminobenzamide (249.95 mg; 1.84 mmol; 1.00 eq.). Final product was isolated by prep HPLC. (27 mg, 5% yield over 2 steps).
  • Step 3 In a similar manner to example 1 , product was obtained from 2, 2-((2S,5R)- 3-(3-carbamoylphenyl)-4-oxo-2-(4-(phenyl-ethynyl)phenyl-d 4 )thiazolidin-5-yl)acetic acid (13 mg, 0.02mmol), and 2-(3-ethoxy-4-methoxyphenyl)ethyl-1 , 1 ,2,2- diamine HCI (5.87mg, 0.02mmol, 1.1 eq.). A 6.3 mg (43%) of the title compound was obtained as white solid.
  • Example 15 3-((2S,5R)-4-oxo-5-(2-oxo-2-((1 ,1 ,2,2-i/4-2-(3-ethoxy-4-methoxy-d 3 - phenyl)ethyl)amino)ethyl)-2-(2,3,5,6-o , 4-4-(phenylethynyl)phenyl)thiazolidin-3- yl)benzamide
  • Example 16 3-((2S,5R)-4-oxo-5-(2-oxo-2-((1 ,1 ,2,2-i 4-2-(3-ethoxy-4-methoxy-d3- phenyl)ethyl)amino)ethyl)-2-(2,3,5,6-d 4 -4-(phenylethynyl)phenyl-c/ 5 )thiazolidin-3- yl)benzamide
  • Step 1 In a similar manner to example 14 step 1 , 4-(phenyl-cf 5 - ethynyl)benzaldehyde-2,3,4,6-Q4 was obtained from 4-chlorobenzaldehyde-2, 3,5,6- d 4 (2.79 g; 19.30 mmol; 1.00 eq.), and Ethynyl-benzene-cfe (3.10 g; 28.93 mmol; 1.50 eq.). Isolated 3.16 g (76%) of 4-(phenyl-o , 5 -ethynyl)benzaldehyde-2,3,5,6-d 4 as an off white solid.
  • Step 2 In a similar manner to example 1 step 1&2, 2-((2S,5R)-3-(3- carbamoylphenyl)-4-oxo-2-(4-(phenyl-o , 5-ethynyl)phenyl- d ⁇ thiazolidin-S-y acetic acid was obtained from 4-(phenyl-c/ 5 -ethynyl)benzaldehyde-2,3,5,6-o' (2.00 g; 9.29 mmol; 1.00 eq.), (S)-2-Mercapto-succinic acid (4.18 g; 27.87 mmol; 3.00 eq.) and 3- aminobenzamide (1.26 g; 9.29 mmol; 1.00 eq.) Final product was isolated by prep HPLC. (276 mg, 10% yield over 2 steps).
  • Step 3 In a similar manner to example 1, product was obtained from 2-((2S,5R)-3- (3-carbamoylphenyl)-4-oxo-2-(4-(phenyl-d 5 -ethynyl)phenyl- o* 4 )thiazolidin-5-yl)acetic acid (60 mg, 0.13 mmol), and 2-(3-ethoxy-4-methoxy-c/3-phenyl)ethyl-1 ,1 ,2,2-o 4 - amine HCI (33.85 mg, 0.14 mmol, 1.1 eq.). A 60 mg (72%) of the title compound was obtained as white solid.
  • Step 1 In a similar manner to example 1 , product was obtained from 2-((2S,5R)-3- (3-carbamoylphenyl)-4-oxo-2-(4-(phenyl-ii5-ethynyl)phenyl-d4)thiazolidin-5-yl)acetic acid (50 mg, 0.1 1 mmol) and 2-(3,4-dihydroxy)ethyl-1 ,1 ,2,2-oVamine HCI (22.8 mg, 0.12 mmol, 1.1 eq.). Isolated 6 mg (9%) of product as white solid.
  • Step 2 In a similar manner to example 3, product was obtained from product example 17 step 1 (6 mg, 0.01 mmol) and dimethyl sulfate-cf 6 (0.5 ⁇ ; 0.005 mmol; 0.50 eq.). Isolated 3.2 mg (52%) of the title product as white solid.
  • Example 22 3-((2S,5R) ⁇ -oxo-5-(2-oxo-2-((1 ,1,2,2-d4-2-(3-ethoxy-4- methoxyphenyl)ethyl)amino)ethyl)-2-(4-((phenyl)ethynyl)phenyl)thiazolidin-3- yl)benzamide
  • Step 1 To [(2S,5R)-3-(3-Carbamoyl-phenyl)-4-oxo-2-(4-phenylethynyl-phenyl)- thiazolidin-5-yl]-acetic acid (150.00 mg; 0.33 mmol; 1.00 eq.) , in toluene (1.00 ml) , was added N-ethyl-N-isopropylpropan-2-amine (0.06 ml; 0.33 mmol; 1.00 eq.) , diphenyl azidophosphate (0.08 ml; 0.38 mmol; 1.15 eq.) and 2-methylpropan-2-ol (1.00 ml). Mixture was heated to 100C for 5h. Reaction was cooled, concentrated and purified by flash chromatography (silica gel 10g, 0 to 5% MeOH/EtOAc).
  • Step 2 To [(2S,5R)-3-(3-Carbamoyl-phenyl)-4-oxo-2-(4-phenylethynyl-phenyl)- thiazolidin-5-ylmethyl]-carbamic acid tert-butyl ester (90.00 mg; 0.17 mmol; 1.00 eq.) in dichloromethane (1.00 ml) was added trifluoroacetic acid (50.00 ⁇ ; 0.67 mmol; 3.93 eq.). The reaction was stirred at room temperature overnight. Product was purified by flash chromatography (KPNH, 10g, 0 to 20% MeOH/DCM).
  • Step 3 To 3-[(2S,5R)-5-Aminomethyl-4-oxo-2-(4-phenylethynyl-phenyl)-thiazolidin- 3-yl]-benzamide (30.00 mg; 0.07 mmol; 1.00 eq.) in DCM (2.00 ml; 31.20 mmol; 444.63 eq.) was added 3-(3-ethoxy-4-methoxyphenyl)propanoic-2,2, 3,3-0*4 acid (19.22 mg, 0.08 mmol, 1.1 eq.), N,N-Diisopropylethylamine (0.01 ml; 0.08 mmol;
  • the compound plate map was as follows: Column 1 : 2 pL of DMSO; Column 2: 2 pL of DMSO; Columns 3-12 and 13-24: 2 ⁇ _ of test compound, diluted 1 :4 in 100% DMSO, or 2 pL of FSH, diluted 1 :4 in DMEM/F12+0.1% BSA.
  • the starting concentration for FSH was 50 nM (final concentration was 0.5 nM).
  • Column 23 contained 2 pLof ECi 00 FSH reference (100X) (diluted in DMEM/F12 + 0.1 % BSA) at a final concentration of 0.5 nM, and Column 24 contained 2 ⁇ _ of 1 mM AS707664/2 reference compound 2.
  • 5 ⁇ _ of compound + EC 2 o FSH mixture were transferred to cell plates (1 :2 dilution into 5 ⁇ _ of cell media) The plates were incubated at 37 °C for 1 h.
  • 10 ⁇ _ of mixed HTRF (CisBio # 62AM4PEC) reagents were added per well and incubated at room temperature for 1 h. The plates were read on Envision using the cAMP HTRF - low volume 384 well protocol. The readout was the calculated fluorescence ratio (665 nm / 620 nm). The results are depicted in table 1.
  • a Tecan Genesis workstation (RSP 150/8) was used for to perform the microsomal incubations. Analysis was carried out using a Waters ACQUITY UPLC system coupled to an ABSciex API3000 mass spectrometer. Data analysis was performed using Assay Explorer (Symyx).
  • Each experiment consists of 12 test and 2 reference compounds.
  • the reference compounds are incubated as a cocktail.
  • Dilution of test compounds was done in 2 steps from a 10 mM DMSO stock solution. First 4 ⁇ stock solution was added to 196 ⁇ . of 20% DMSO in potassium phosphate buffer pH 7.4. In a second step 10 ⁇ _ of the first dilution were added to 1890 ⁇ _ potassium phosphate buffer and 100 ⁇ _ internal standard solution to a final concentration of 0.8 ⁇ .
  • the incubations were stopped after 5, 10, 20 and 30 min by adding 250 ⁇ _ cold acetonitrile to the individual wells.
  • the quenched samples were then centrifuged at 4000g for 1 h at 4 °C. 100 ⁇ _ of the supernatant were transferred into 96 well plates for analysis.
  • Clint ( ⁇ -Jmin/mg protein) k 1000 /protein concentration.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Reproductive Health (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Surgery (AREA)
  • Pregnancy & Childbirth (AREA)
  • Epidemiology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Endocrinology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biomedical Technology (AREA)
  • Transplantation (AREA)
  • Medical Informatics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

The present invention relates to deuterated thiazolidinone analogues as agonists for follicle stimulating hormone receptor and their use for treating fertility disorders.

Description

Deuterated Thiazolidinone Analogues as Agonists
for Follicle Stimulating Hormone Receptor
Description Technical field
The present invention relates to deuterated thiazolidinone analogues as agonists for follicle stimulating hormone receptor and their use for treating fertility disorders. Prior art
Gonadotropins serve important functions in a variety of bodily functions including metabolism, temperature regulation and the reproductive process. Gonadotropins act on specific gonadal cell types to initiate ovarian and testicular differentiation and steroidogenesis. The gonadotropin FSH (follicle stimulating hormone) is released from the anterior pituitary under the influence of gonadotropin-releasing hormone and estrogens, and from the placenta during pregnancy. FSH is a heterodimeric glycoprotein hormone that shares structural similarities with luteinizing hormone (LH) and thyroid stimulating hormone (TSH), both of which are also produced in the pituitary gland, and chorionic gonadotropin (CG), which is produced in the placenta. In the female, FSH plays a pivotal role in the stimulation of follicle development and maturation and in addition, it is the major hormone regulating secretion of estrogens, whereas LH induces ovulation. In the male, FSH is responsible for the integrity of the seminiferous tubules and acts on Sertoli cells to support gametogenesis.
The hormones are relatively large (28-38 kDa) and are composed of a common a-subunit non-covalently bound to a distinct β-subunit that confers receptor binding specificity. The cellular receptor for these hormones is expressed on testicular Sertoli cells and ovarian granulosa cells. The FSH receptor is known to be members of the G protein-coupled class of membrane-bound receptors, which when activated stimulate an increase in the activity of adenylyl cyclase. This results in an increase in the level of the intracellular second messenger adenosine 3", ^-monophosphate (cAMP), which in turn causes increased steroid synthesis and secretion.
Hydropathicity plots of the amino acid sequences of these receptors reveal three general domains: a hydrophilic amino-terminal region, considered to be the amino- terminal extracellular domain; seven hydrophobic segments of membrane-spanning length, considered to be the transmembrane domain; and a carboxy-terminal region that contains potential phosphorylation sites (serine, threonine, and tyrosine residues), considered to be the carboxy-terminal intracellular or cytoplasmic domain. The glycoprotein hormone receptor family is distinguished from other G protein- coupled receptors, such as the β-2-adrenergic, rhodopsin, and substance K receptors, by the large size of the hydrophilic amino-terminal domain, which is involved in hormone binding.
Annually in the U.S. there are 2.4 million couples experiencing infertility that are potential candidates for treatment. FSH, either extracted from urine or produced by recombinant DNA technology, is a parenterally-administered protein product used by specialists for ovulation induction and for controlled ovarial hyperstimulation. Whereas ovulation induction is directed at achieving a single follicle to ovulate, controlled ovarial hyperstimulation is directed at harvesting multiple oocytes for use in various in-vitro assisted reproductive technologies, e.g. in-vitro fertilization (IVF). FSH is also used clinically to treat male hypogonadism and male infertility, e.g.
some types of failure of spermatogenesis.
Follicle stimulating hormone receptor (FSHR) is a highly specific target in the ovarian follicle growth process and is exclusively expressed in the ovary. However, the use of FSH is limited by its high cost, lack of oral dosing, and need of extensive monitoring by specialist physicians. Hence, identification of a non-peptidic small molecule substitute for FSH that could potentially be developed for oral
administration is desirable. Low molecular weight FSH mimetics with agonistic properties are disclosed in the international applications WO 2002/09706 and
WO 2010/136438 as well as the patent US 6,653,338. There is still a need for low molecular weight hormone mimetics that selectively activate FSHR.
Further prior art is as follows:
Pelletier JC et al. disclose the preparation of highly substituted gamma-lactam follicle stimulating hormone receptor agonists (Bioorg. Med. Chem. 2005, 13: 5986- 5995).
Wrobel J et al. describe 5-alkylated thiazolidinones as follicle-stimulating hormone receptor agonists (Bioorg. Med. Chem. 2006, 14: 5729-5741 ). WO 02/09705 is directed to thiazolidinones as agonists of follicle stimulating hormone activity.
WO 02/09706 relates to novel thiazolidinones as agonists of follicle stimulating hormone activity and discloses compound
Figure imgf000004_0001
(hereinafter referred to as reference compound)
in table 1 on page 20.
However, the prior art is silent about the substitution of one or more hydrogen (H) atoms of above reference compound by deuterium (D).
The citation of any reference in this application is not an admission that the reference is relevant prior art to this application.
Description of the invention
The present invention has the object to provide deuterated thiazolidinone analogues as agonists for FSHR.
The object of the present invention has surprisingly been solved in one aspect by providing a deuterated thiazolidinone derivative according to formula (I)
Figure imgf000005_0001
wherein: each Y is independently from each other selected from the group consisting of: "hydrogen (H), deuterium (D)";
X is selected from the group consisting of: "S, sulfoxide";
R1 , R2 are independently from each other selected from the group consisting of: "hydrogen (H), deuterium (D), methyl, CH2D, CHD2, CD3, ethyl, CHDCH3, CHDCH2D, CHDCHDz, CHDCD3l CD2CH3, CD2CH2D, CD2CHD2, CD2CD3"; with the proviso that at least one Y is deuterium (D) or at least one of R1 , R2 comprises at least one deuterium (D); optionally, at least one carbon atom is independently from each other replaced by 13C; and the physiologically acceptable salts, solvates, tautomers and
stereoisomers thereof, including mixtures thereof in all ratios.
In a preferred embodiment, a deuterated thiazolidinone derivative according to formula (I) supra is provided, wherein at least one carbon atom is replaced by 13C; and the physiologically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.
In a preferred embodiment, a compound according to formula (I) supra and above embodiments is provided, wherein: Yi5, Yi6, Yi7, Yi8 are deuterium (D); and the physiologically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios. In a preferred embodiment, a compound according to formula (I) supra and above embodiments is provided, wherein:
Yi , Y2, Ys. Yo, Ys are deuterium (D); and the physiologically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.
In a preferred embodiment, a compound according to formula (I) supra and above embodiments is provided, wherein:
Ye. Y?. Ye. Y9 are deuterium (D); and the physiologically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.
In a preferred embodiment, a compound according to formula (I) supra and above embodiments is provided, wherein:
Rn and/or R2 are CD3; and the physiologically acceptable salts, solvates, tautomers and
stereoisomers thereof, including mixtures thereof in all ratios.
In a preferred embodiment, a compound according to formula (I) supra and above embodiments is provided, wherein:
(a) Y15, Yi6, Yi7, Yi8 are deuterium (D) and the other Y are hydrogen (H) and none of R^ R2 comprises one or more deuterium (D); or (b) Yi5, Yi6, Yi7, Yi8 are deuterium (D) and the other Y are hydrogen (H) and one of RL R2 is CD3 and the other one of R^ R2 does not comprise one or more deuterium (D); or
(c) all Y are hydrogen (H) and one of R^ R2 is CD3 and the other one of R^ R2 does not comprise one or more deuterium (D); or
(d) Y^, Y2, Y3, Y , Y5 are deuterium (D) and the other Y are hydrogen (H) and none of R^ R2 comprises one or more deuterium (D); or (e) all Y are hydrogen (H) and both of R^ R2 are CD3; or
(f) Yi , Yz, Y3, Y4, Ys, Yi5, Y16, Yi7. Y18 are deuterium (D) and the other Y are hydrogen (H) and none of Ri , R2 comprises one or more deuterium (D); or (g) Yi , Y2, Y3, Y4, Ys, Yi5, Y16, Yi?, Y18 are deuterium (D) and the other Y are hydrogen (H) and one of R1 ( R2 is CD3 and the other one of R^ R2 does not comprise one or more deuterium (D); or
(h) Y6, Y7, Ys, Y9, Y15, Y16, Yi7, Y18 are deuterium (D) and the other Y are hydrogen (H) and one of R, , R2 is CD3 and the other one of R^ R2 does not comprise one or more deuterium (D); or
(i) Yi, Y2, Y3, Y4, Ys, Ye. Y7, Y8, Y9, Yi5, Y16, Y17, Y18 are deuterium (D) and the other Y are hydrogen (H) and both of Rn , R2 are CD3; or 0) Υι. Y2, Υ3, Υ4, Υ5, Υ6, Υτ, Υ8, Υ9, Υΐ5, Υΐ6, Υ17, Υΐ8 are deuterium (D) and the other Y are hydrogen (H) and one of R2 is CD3 and the other one of R1t R2 does not comprise one or more deuterium (D); and the physiologically acceptable salts, solvates, tautomers and
stereoisomers thereof, including mixtures thereof in all ratios.
In another aspect, the object of the present invention has surprisingly been solved by providing a compound selected from the group consisting of:
Compound Structure
Figure imgf000009_0001

Figure imgf000010_0001

Figure imgf000011_0001

Figure imgf000012_0001
Figure imgf000013_0001
 and the physiologically acceptable salts, solvates, tautomers and
stereoisomers thereof, including mixtures thereof in all ratios.
For the avoidance of doubt, if chemical name and chemical structure of the above illustrated compounds do not correspond by mistake, the chemical structure is regarded to unambigously define the compound.
All the above generically or explicitly disclosed compounds, including preferred embodiments of the herein disclosed formula (I) and Compounds 1 to 22, are hereinafter referred to as compounds of the (present) invention.
The nomenclature as used herein for defining compounds, especially the compounds according to the invention, is in general based on the rules of the lUPAC organisation for chemical compounds and especially organic compounds.
The terms indicated for explanation of the above compounds of the invention always, unless indicated otherwise in the description or in the claims, have the following meanings:
The term "unsubstituted" means that the corresponding radical, group or moiety has no substituents.
The term "substituted" means that the corresponding radical, group or moiety has one or more substituents. Where a radical has a plurality of substituents, and a selection of various substituents is specified, the substituents are selected independently of one another and do not need to be identical.
The term "composition", as in pharmaceutical composition, for the purposes of this invention is intended to encompass a product comprising the active
ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
The terms "administration of and "administering a" compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individualist need. As used herein, the term "effective amount" refers to any amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.
All stereoisomers of the compounds of the invention are contemplated, either in a mixture or in pure or substantially pure form. The compounds of the invention can have asymmetric centers at any of the carbon atoms. Consequently, they can exist in the form of their racemates, in the form of the pure enantiomers and/or diastereomers or in the form of mixtures of these enantiomers and/or diastereomers. The mixtures may have any desired mixing ratio of the stereoisomers.
Thus, for example, the compounds of the invention which have one or more centers of chirality and which occur as racemates or as diastereomer mixtures can be fractionated by methods known per se into their optical pure isomers, i.e.
enantiomers or diastereomers. The separation of the compounds of the invention can take place by column separation on chiral or nonchiral phases or by
recrystallization from an optionally optically active solvent or with use of an optically active acid or base or by derivatization with an optically active reagent such as, for example, an optically active alcohol, and subsequent elimination of the radical.
The compounds of the invention may be present in the form of their double bond isomers as "pure" E or Z isomers, or in the form of mixtures of these double bond isomers.
Where possible, the compounds of the invention may be in the form of the tautomers, such as keto-enol tautomers.
It is likewise possible for the compounds of the invention to be in the form of any desired prodrugs such as, for example, esters, carbonates, carbamates, ureas, amides or phosphates, in which cases the actually biologically active form is released only through metabolism. Any compound that can be converted in vivo to provide the bioactive agent (i.e. compounds of the invention) is a prodrug within the scope and spirit of the invention. Various forms of prodrugs are well known in the art and are described for instance in:
(i) Wermuth CG et al., Chapter 31 : 671-696, The Practice of Medicinal Chemistry,
Academic Press 1996;
(ii) Bundgaard H, Design of Prodrugs, Elsevier 1985; and
(iii) Bundgaard H, Chapter 5: 131-191 , A Textbook of Drug Design and
Development, Harwood Academic Publishers 1991.
Said references are incorporated herein by reference.
It is further known that chemical substances are converted in the body into metabolites which may where appropriate likewise elicit the desired biological effect - in some circumstances even in more pronounced form.
Any biologically active compound that was converted in vivo by metabolism from any of the compounds of the invention is a metabolite within the scope and spirit of the invention.
The compounds of the invention can, if they have a sufficiently basic group such as, for example, a secondary or tertiary amine, be converted with inorganic and organic acids into salts. The pharmaceutically acceptable salts of the compounds of the invention are preferably formed with hydrochloric acid, hydrobromic acid, iodic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, sulfoacetic acid, trifluoroacetic acid, oxalic acid, malonic acid, maleic acid, succinic acid, tartaric acid, racemic acid, malic acid, embonic acid, mandelic acid, fumaric acid, lactic acid, citric acid, taurocholic acid, glutaric acid, stearic acid, glutamic acid or aspartic acid. The salts which are formed are, inter alia, hydrochlorides, chlorides, hydrobromides, bromides, iodides, sulfates, phosphates, methanesulfonates, tosylates, carbonates, bicarbonates, formates, acetates, sulfoacetates, triflates, oxalates, malonates, maleates, succinates, tartrates, malates, embonates, mandelates, fumarates, lactates, citrates, glutarates, stearates, aspartates and glutamates. The stoichiometry of the salts formed from the compounds of the invention may moreover be an integral or non-integral multiple of one.
The compounds of the invention can, if they contain a sufficiently acidic group such as, for example, the carboxy, sulfonic acid, phosphoric acid or a phenolic group, be converted with inorganic and organic bases into their physiologically tolerated salts. Examples of suitable inorganic bases are ammonium, sodium hydroxide, potassium hydroxide, calcium hydroxide, and of organic bases are ethanolamine, diethanolamine, triethanolamine, ethylenediamine, t-butylamine, t- octylamine, dehydroabietylamine, cyclohexylamine, dibenzylethylene-diamine and lysine. The stoichiometry of the salts formed from the compounds of the invention can moreover be an integral or non-integral multiple of one.
It is likewise possible for the compounds of the invention to be in the form of their solvates and, in particular, hydrates which can be obtained for example by crystallization from a solvent or from aqueous solution. It is moreover possible for one, two, three or any number of solvate or water molecules to combine with the compounds of the invention to give solvates and hydrates.
By the term "solvate" is meant a hydrate, an alcoholate, or other solvate of crystallization.
It is known that chemical substances form solids which exist in different order states which are referred to as polymorphic forms or modifications. The various modifications of a polymorphic substance may differ greatly in their physical properties. The compounds of the invention can exist in various polymorphic forms and certain modifications may moreover be metastable. All these polymorphic forms of the compounds are to be regarded as belonging to the invention. Following the incubation of compounds of the invention in human and rat hepatic microsomes intrinsic clearance (Clint) was reduced. As shown in Table 1 , specifically compound 1 to 20 and 22 demonstrated a decreased Clint in rat hepatic microsome compared to reference compound. Compound 1 to 3, 4, 10, 19 and 22 demonstrated a decreased Clint in human hepatic microsome compared to reference compound. This is accompanied by a corresponding reduction in pharmacokinetic clearance and decrease in volume distribution. Such changes might reduce dosage and dosing frequency, which results in a better safety profile. Moreover, the further reduced pharmacokinetic interactions between the compounds of the invention and other drugs metabolized by the same metabolic enzymes (e.g. CYP) provide an increased safety as compared to reference compound.
The compounds of the invention preferably exhibit an advantageous biological activity, which is easily demonstrated in cell culture-based assays, for example assays as described herein or in prior art (cf. e.g. WO 2002/009706, which is incorporated herein by reference). In such assays, the compounds of the invention preferably exhibit and cause an agonistic effect. It is preferred that the compounds of the invention have an FSHR agonist activity, as expressed by an EC50 standard, of less than 1000 nM, more preferably less than 500 nM. "ECso" is the effective concentration of a compound at which 50 % of the maximal response of that obtained with FSH would be obtained.
As discussed herein, these signaling pathways are relevant for various diseases, preferably fertility disorders. Accordingly, the compounds of the invention are useful in the prophylaxis and/or treatment of diseases that are dependent on the said signaling pathways by interaction with one or more of the said signaling pathways. The present invention therefore relates to compounds of the invention as modulators, preferably agonists, more preferably positive allosteric modulators, of the signaling pathways described herein, preferably of the FSHR-mediated signaling pathway. The compounds of the invention are supposed to bind to the intracellular receptor domain without a competitive interaction with FSH, but they act as an allosteric enhancer of FSH on its receptor. The non-competitive interaction refers to the nature of the agonist activity exhibited by the compounds of the invention, wherein the compounds activate FSHR without substantially reducing the magnitude of binding of FSH to FSHR. The method of the invention can be performed either in-vitro or in-vivo. The susceptibility of a particular cell to treatment with the compounds according to the invention can be particularly determined by in-vitro tests, whether in the course of research or clinical application. Typically, a culture of the cell is combined with a compound according to the invention at various concentrations for a period of time which is sufficient to allow the active agents to modulate FSHR activity, usually between about one hour and one week. In-vitro treatment can be carried out using cultivated cells from a biopsy sample or cell line. In a preferred aspect of the invention, a follicle cell is stimulated for maturation. The viable cells remaining after the treatment are counted and further processed.
Some crude products were subjected to standard chromatography using solvent mixtures containing methanol, ethanol, isopropanol, n-hexane, cyclohexane, dichloromethane, n-heptane or petrol ether, respectively. For a further detailed description of the manufacturing processes, please refer also to the examples and the following general description of the preferred conditions. A physiologically acceptable salt of a compound of the invention can also be obtained by isolating and/or treating the compound of the invention obtained by the described reaction with an acid or a base.
The compounds of the invention and also the starting materials for their preparation are, are prepared by methods as described in the examples or by methods known per se, as described in the literature (for example in standard works, such as Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York), to be precise under reaction conditions which are known and suitable for the said reactions. Use can also be made here of variants which are known per se, but are not mentioned here in greater detail.
The starting materials for the claimed process may, if desired, also be formed in situ by not isolating them from the reaction mixture, but instead immediately converting them further into the compounds of the invention. On the other hand, it is possible to carry out the reaction stepwise.
Preferably, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1 ,2- dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methyl pyrrolidinone (NMP); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of the said solvents or mixtures with water. Polar solvents are in general preferred. Examples for suitable polar solvents are chlorinated hydrocarbons, alcohols, glycol ethers, nitriles, amides and sulfoxides or mixtures thereof. More preferred are amides, especially dimethylformamide (DMF).
As stated above, the reaction temperature is between about -100° C and 300° C, depending on the reaction step and the conditions used.
Reaction times are generally in the range between some minutes and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily determinable by methods known in the art, for example reaction monitoring. Based on the reaction
temperatures given above, suitable reaction times generally lie in the range between 10 min and 48 hrs.
A base of a compound of the invention can be converted into the associated acid-addition salt using an acid, for example by reaction of equivalent amounts of the base and the acid in a preferably inert solvent, such as ethanol, followed by evaporation. Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, sulfurous acid, dithionic acid, nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as, for example, orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, hexanoic acid, octanoic acid, decanoic acid, hexadecanoic acid, octadecanoic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, trimethoxybenzoic acid, adamantanecarboxylic acid, p- toluenesulfonic acid, glycolic acid, embonic acid, chlorophenoxyacetic acid, aspartic acid, glutamic acid, proline, glyoxylic acid, palmitic acid,
parachlorophenoxyisobutyric acid, cyclohexanecarboxylic acid, glucose 1- phosphate, naphthalenemono- and -disulfonic acids or laurylsulfuric acid.
Salts with physiologically unacceptable acids, for example picrates, can be used to isolate and/or purify the compounds of the invention.
On the other hand, compounds of the invention can be converted into the corresponding metal salts, in particular alkali metal salts or alkaline earth metal salts, or into the corresponding ammonium salts, using bases (for example sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate).
Suitable salts are furthermore substituted ammonium salts, for example the dimethyl-, diethyl- and diisopropylammonium salts, monoethanol-, diethanol- and diisopropanolammonium salts, cyclohexyl- and dicyclohexylammonium salts, dibenzylethylenediammonium salts, furthermore, for example, salts with arginine or lysine.
If desired, the free bases of the compounds of the invention can be liberated from their salts by treatment with strong bases, such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, so long as no further acidic groups are present in the molecule. In the cases where the
compounds of the invention have free acid groups, salt formation can likewise be achieved by treatment with bases. Suitable bases are alkali metal hydroxides, alkaline earth metal hydroxides or organic bases in the form of primary, secondary or tertiary amines.
Every reaction step described herein can optionally be followed by one or more working up procedures and/or isolating procedures. Suitable such procedures are known in the art, for example from standard works, such as Houben-Weyl,
Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme- Verlag, Stuttgart). Examples for such procedures include, but are not limited to evaporating a solvent, distilling, crystallization, fractionised crystallization, extraction procedures, washing procedures, digesting procedures, filtration procedures, chromatography, chromatography by HPLC and drying procedures, especially drying procedures in vacuo and/or elevated temperature.
The object of the present invention has surprisingly been solved in another aspect by providing a medicament comprising at least one compound of the invention.
The object of the present invention has surprisingly been solved in another aspect by providing a medicament comprising at least one compound of the invention for use in the prophylactic or therapeutic treatment and/or monitoring of fertility disorders. Object of the present invention is also the use of compounds according to formula (I) and/or physiologically acceptable salts thereof for modulating a FSH receptor, particularly in the presence of FSH. The term "modulation" denotes any change in FSHR-mediated signal transduction, which is based on the action of the specific inventive compounds capable to interact with the FSHR target in such a manner that makes recognition, binding and activating possible. The compounds are characterized by such a high affinity to FSHR, which ensures a reliable binding and preferably a positive allosteric modulation of FSHR. More preferably, the substances are mono-specific in order to guarantee an exclusive and directed recognition with the single FSHR target. In the context of the present invention, the term
"recognition" - without being limited thereto - relates to any type of interaction between the specific compounds and the target, particularly covalent or non- covalent binding or association, such as a covalent bond, hydrophobic/ hydrophilic interactions, van der Waals forces, ion pairs, hydrogen bonds, ligand-receptor interactions, and the like. Such association may also encompass the presence of other molecules such as peptides, proteins or nucleotide sequences. The present receptor/ligand-interaction is characterized by high affinity, high selectivity and minimal or even lacking cross-reactivity to other target molecules to exclude unhealthy and harmful impacts to the treated subject.
Compounds of the invention may be used in combination with one or more other active substances (ingredients, drugs) in the treatment, prevention, suppression or amelioration of diseases or conditions for which compounds of the invention or the other substances have utility. Typically the combination of the drugs is safer or more effective than either drug alone, or the combination is safer or more effective than would it be expected based on the additive properties of the individual drugs. Such other drug(s) may be administered, by a route and in an amount commonly used contemporaneously or sequentially with a compound of the invention. When a compound of the invention is used contemporaneously with one or more other drugs, a combination product containing such other drug(s) and the compound of the invention is preferred. However, combination therapy also includes therapies in which the compound of the invention and one or more other drugs are administered on different overlapping schedules. It is contemplated that when used in
combination with other active ingredients, the compound of the present invention or the other active ingredient or both may be used effectively in lower doses than when each is used alone. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the invention. The present compounds are suitable for combination with known fertility- inducing agents. Preferably, the other active (pharmaceutical) ingredient is selected from the group of FSH, a-FSH (Gonal F), β-FSH, LH, hMG and 2-(4-(2-chloro-1 ,2- diphenylethenyl)-phenoxy)-N,N-diethyl-ethanamine citrate (Chlomifene citrate). Further ovulation adjuncts are known to those of skill in the art (cf. e.g.
WO 2002/09706, which is incorporated herein by reference) and are useful with the compounds of the present invention.
In another aspect of the invention, a medicament according to above aspects and embodiments is provided, wherein in such medicament comprises at least one additional pharmacologically active substance (drug, ingredient).
In a preferred embodiment the at least one pharmacologically active substance is a substance as described herein.
In another aspect of the invention, a medicament according to above aspects and embodiments is provided, wherein the medicament is applied before and/or during and/or after treatment with at least one additional pharmacologically active substance.
In a preferred embodiment the at least one pharmacologically active substance is a substance as described herein.
In another aspect of the invention, a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of the invention is provided.
In a preferred embodiment, the pharmaceutical composition contains at least one additional compound selected from the group consisting of physiologically acceptable excipients, auxiliaries, adjuvants, diluents, carriers and/or additional pharmaceutically active substance other than the compounds of the invention.
In another aspect of the invention, a pharmaceutical composition is disclosed which comprises at least one compound of the invention, at least one pharmacologically active substance other than the compounds of the invention as described herein; and a pharmaceutically acceptable carrier.
A further embodiment of the present invention is a process for the manufacture of said pharmaceutical compositions, characterized in that one or more compounds according to the invention and one or more compounds selected from the group consisting of solid, liquid or semiliquid excipients, auxiliaries, adjuvants, diluents, carriers and pharmaceutically active agents other than the compounds according to the invention, are converted in a suitable dosage form. In another aspect of the invention, a kit is provided comprising a therapeutically effective amount of at least one compound of the invention and/or at least one pharmaceutical composition as described herein and a therapeutically effective amount of at least one further pharmacologically active substance other than the compounds of the invention.
In another aspect of the invention, a method for modulating a FSH receptor in a positive allosteric manner is provided, wherein a cell capable of expressing the FSH receptor is contacted in the presence of FSH with at least one compound of the invention or at least one pharmaceutical composition as described supra.
In another aspect of the invention, a method for treating fertility disorders is provided, wherein a therapeutically effective amount of at least one compound of the invention or at least one pharmaceutical composition as described supra is administered to a mammal in need of such treatment.
In another aspect of the invention, a method for in-vitro fertilization is provided comprising the steps of:
(a) treating a mammal according to above method for treating fertility
disorders,
(b) collecting ova from said mammal,
(c) fertilizing said ova, and
(d) implanting said fertilized ova into a host mammal.
The pharmaceutical compositions of the present invention may be administered by any means that achieve their intended purpose. For example, administration may be by oral, parenteral, topical, enteral, intravenous, intramuscular, inhalant, nasal, intraarticular, intraspinal, transtracheal, transocular, subcutaneous, intraperitoneal, transdermal, or buccal routes. Alternatively, or concurrently, administration may be by the oral route. The dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired. Parenteral administration is preferred. Oral administration is especially preferred.
Suitable dosage forms include, but are not limited to capsules, tablets, pellets, dragees, semi-solids, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, cataplasms, gels, tapes, eye drops, solution, syrups, aerosols, suspension, emulsion, which can be produced according to methods known in the art, for example as described below:
tablets: mixing of active ingredient/s and auxiliaries, compression of said mixture into tablets (direct compression), optionally granulation of part of mixture before compression.
capsules: mixing of active ingredient/s and auxiliaries to obtain a flowable powder, optionally granulating powder, filling powders/granulate into opened capsules, capping of capsules.
semi-solids (ointments, gels, creams): dissolving/dispersing active ingredient/s in an aqueous or fatty carrier; subsequent mixing of aqueous/fatty phase with complementary fatty/ aqueous phase, homogenization (creams only).
suppositories (rectal and vaginal): dissolving/dispersing active ingredient/s in carrier material liquified by heat (rectal: carrier material normally a wax; vaginal: carrier normally a heated solution of a gelling agent), casting said mixture into suppository forms, annealing and withdrawal suppositories from the forms.
aerosols: dispersing/dissolving active agent s in a propellant, bottling said mixture into an atomizer.
In general, non-chemical routes for the production of pharmaceutical compositions and/or pharmaceutical preparations comprise processing steps on suitable mechanical means known in the art that transfer one or more compounds ofthe invenion into a dosage form suitable for administration to a patient in need of such a treatment. Usually, the transfer of one or more compounds of the invention into such a dosage form comprises the addition of one or more compounds, selected from the group consisting of carriers, excipients, auxiliaries and pharmaceutical active ingredients other than the compounds of the invention.
Suitable processing steps include, but are not limited to combining, milling, mixing, granulating, dissolving, dispersing, homogenizing, casting and/or compressing the respective active and non-active ingredients. Mechanical means for performing said processing steps are known in the art, for example from Ullmann's Encyclopedia of Industrial Chemistry, 5th Edition. In this respect, active ingredients are preferably at least one compound of the invention and one or more additional compounds other than the compounds of the invention, which show valuable pharmaceutical properties, preferably those pharmaceutical active agents other than the compounds of the invention, which are disclosed herein.
Particularly suitable for oral use are tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops, suitable for rectal use are suppositories, suitable for parenteral use are solutions, preferably oil-based or aqueous solutions, furthermore suspensions, emulsions or implants, and suitable for topical use are ointments, creams or powders. The compounds of the invention may also be lyophilised and the resultant lyophilisates used, for example, for the preparation of injection preparations. The preparations indicated may be sterilised and/or comprise assistants, such as lubricants, preservatives, stabilisers and/or wetting agents, emulsifiers, salts for modifying the osmotic pressure, buffer substances, dyes, flavours and/or a plurality of further active ingredients, for example one or more vitamins.
Suitable excipients are organic or inorganic substances, which are suitable for enteral (for example oral), parenteral or topical administration and do not react with the compounds of the invention, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatine, carbohydrates, such as lactose, sucrose, mannitol, sorbitol or starch (maize starch, wheat starch, rice starch, potato starch), cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, magnesium stearate, talc, gelatine, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyvinyl pyrrolidone and/or vaseline.
If desired, disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries include, without limitation, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings, which, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices or to provide a dosage form affording the advantage of prolonged action, the tablet, dragee or pill can comprise an inner dosage and an outer dosage component me latter being in the form of an envelope over the former. The two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, acetyl alcohol, solutions of suitable cellulose preparations such as acetyl-cellulose phthalate, cellulose acetate or hydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
Suitable carrier substances are organic or inorganic substances which are suitable for enteral (e.g. oral) or parenteral administration or topical application and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petroleum jelly. In particular, tablets, coated tablets, capsules, syrups, suspensions, drops or suppositories are used for enteral administration, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, are used for parenteral administration, and ointments, creams or powders are used for topical application. The compounds of the invention can also be lyophilized and the lyophilizates obtained can be used, for example, for the production of injection preparations.
The preparations indicated can be sterilized and/or can contain excipients such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffer substances, colorants, flavourings and/or aromatizers. They can, if desired, also contain one or more further active
compounds, e.g. one or more vitamins.
Other pharmaceutical preparations, which can be used orally include push-fit capsules made of gelatine, as well as soft, sealed capsules made of gelatine and a plasticizer such as glycerol or sorbitol. The push-fit capsules can contain the active compounds in the form of granules, which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin. In addition, stabilizers may be added.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatine.
Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts and alkaline solutions. In addition, suspensions of the active compounds as appropriate oily injection suspensions may be administered. Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400).
Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, including, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran, optionally, the suspension may also contain stabilizers.
For administration as an inhalation spray, it is possible to use sprays in which the active ingredient is either dissolved or suspended in a propellant gas or propellant gas mixture (for example C02 or chlorofluorocarbons). The active ingredient is advantageously used here in micronized form, in which case one or more additional physiologically acceptable solvents may be present, for example ethanol. Inhalation solutions can be administered with the aid of conventional inhalers.
Possible pharmaceutical preparations, which can be used rectally include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons. In addition, it is also possible to use gelatine rectal capsules, which consist of a combination of the active compounds with a base. Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.
For use in medicine, the compounds of the present invention will be in the form of pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic bases, e.g. quaternary ammonium salts.
The pharmaceutical preparations can be employed as medicaments in human and veterinary medicine. As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function. Said therapeutic effective amount of one or more of the compounds of the invention is known to the skilled artisan or can be easily determined by standard methods known in the art.
The compounds of the invention and the additional active substances are generally administered analogously to commercial preparations. Usually, suitable doses that are therapeutically effective lie in the range between 0.0005 mg and 1000 mg, preferably between 0.005 mg and 500 mg and especially between 0.5 mg and 100 mg per dose unit. The daily dose is preferably between about 0.001 mg/kg and 10 mg/kg of body weight. Those of skill will readily appreciate that dose levels can vary as a function of the specific compound, the severity of the symptoms and the susceptibility of the subject to side effects. Some of the specific compounds are more potent than others. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound.
For the purpose of the present invention, all mammalian species are regarded as being comprised. In a preferred embodiment, such mammals are selected from the group consisting of "primate, human, rodent, equine, bovine, canine, feline, domestic animals, cattle, livestock, pets, cow, sheep, pig, goat, horse, pony, donkey, hinny, mule, hare, rabbit, cat, dog, guinea pig, hamster, rat, mouse". More preferably, such mammals are humans. Animal models are of interest for
experimental investigations, providing a model for treatment of human diseases.
The specific dose for the individual patient depends, however, on the multitude of factors, for example on the efficacy of the specific compounds employed, on the age, body weight, general state of health, the sex, the kind of diet, on the time and route of administration, on the excretion rate, the kind of administration and the dosage form to be administered, the pharmaceutical combination and severity of the particular disorder to which the therapy relates. The specific therapeutic effective dose for the individual patient can readily be determined by routine experimentation, for example by the doctor or physician, which advises or attends the therapeutic treatment.
In the case of many disorders, the susceptibility of a particular cell to treatment with the subject compounds may be determined by in vitro testing. Typically a culture of the cell is combined with a subject compound at varying concentrations for a period of time sufficient to allow the active agents to show a relevant reaction, usually between about one hour and one week. For in vitro testing, cultured cells from a biopsy sample may be used.
Even without further details, it is assumed that a person skilled in the art will be able to utilise the above description in the broadest scope. The preferred
embodiments should therefore merely be regarded as descriptive disclosure, which is absolutely not limiting in any way. Above and below, all temperatures are indicated in °C. In the following examples, "conventional work-up" means that, if necessary, the solvent is removed, water is added if necessary, the pH is adjusted, if necessary, to between 2 and 10, depending on the constitution of the end product, the mixture is extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is washed with saturated NaHC03 solution, if desired with water and saturated NaCI solution, is dried over sodium sulfate, filtered and evaporated, and the product is purified by chromatography on silica gel, by preparative HPLC and/or by crystallisation. The purified compounds are, if desired, freeze-dried.
The contents of all cited references are hereby incorporated by reference in their entirety. The invention is explained in more detail by means of the following examples without, however, being restricted thereto.
Examples
Standard description of analytical equipment
1H NMR was recorded on a Joel 400 MHz spectrometer, using residual signal of deuterated solvent as internal reference. Chemical shifts (δ) are reported in ppm relative to the residual solvent signal (δ = 2.49 ppm for 1H NMR in DMSO-cfe). 1H NMR data are reported as follows: chemical shift (multiplicity, coupling constants, and number of hydrogens). Multiplicity is abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).
LCMS method:
Column: Xbridge C8, 4.6x50mm 5um
Mobile Phase A: Water +0.1 %TFA
Mobile Phase B: ACN +0.1%TFA
Gradient: 5-95%B in 3.5 minutes
Flow: 0.8 mL/min
Wavelength 254nm
Mass Scan: 100-900 Da Example 1 : 3-((2S,5R)-4-oxo-5-(2-oxo-2-((1 , 1 ,2,2- c/4-2-(4-hydroxy-3- methoxyphenyl)ethyl)amino)ethyl)-2-(4-(phenylethynyl)phenyl)thiazolidin-3- yl)benzamide
Figure imgf000032_0001
Step 1 :
Figure imgf000033_0001
Similar procedures described in WO 02/09705 & WO 02/09706
To a solution of 4-(phenylethynyl)benzaldehyde (2.8 g, 13.6 mmol, 1 eq) in MeCN (240 ml) was added (S)-2-mercaptosuccinic acid (6. 2 g, 40.8 mmol, 3 eq) and 3- aminobenzamide (1.85 g, 13.6 mmol, 1 eq). The reaction was stirred at 83°C for 3 days. The reaction was cooled and filtered to give solid. The solid was adjusted PH= 8~9 with saturated Na2C03 and extracted with ethyl acetate (50 ml* 3). The water phase was adjusted PH=3~4 with 4N HCI and filtered to give solid. The solid was washed with EtOH (10 ml) and MeCN (10 ml) to afford title compound as a light yellow solid (3 g, 51.7%).
Step 2:
Figure imgf000033_0002
Similar procedures described in WO 02/09705 & WO 02/09706
To a solution of 2-((2S,5S)-3-(3-carbamoylphenyl)-4-oxo-2-(4- (phenylethynyl)phenyl)thiazolidin-5-yl)acetic acid (2.5 g, 5.58 mmol, 1 eq) in THF (127.5 ml) was added DBU (8.5 g, 55.8 mmol, 10eq) and MeOH (12.75 ml). The reaction was stirred at 70°C overnight. The reaction was cooled and evaporated. The residue was taken in ethyl acetate and 1 HCI and filtered. The filtrate was washed with 1 N HCI, brine, dried over Na2S04, filtrated and evaporated to give a solid (1.7 g). The solid was re-crystallized from MeCN to obtain 2-((2S,5R)-3-(3- carbamoylphenyl)-4-oxo-2-(4-(phenylethynyl)phenyl)thiazolidin-5-yl)acetic acid (0.6 g, 24 %). Step 3: To [(2S,5R)-3-(3-Carbamoyl-phenyl)-4-oxo-2-(4-phenylethynyl-phenyl)- thiazolidin-5-yl]-acetic acid (50.00 mg; 0.11 mmol; 1.00 eq.) in dichloromethane(2.00 ml; 31.20 mmol; 284.87 eq.) was added Ν,Ν-Diisopropylethylamine (0.02 ml; 0.13 mmol; 1.20 eq.), 2-(4-hydroxy-3-methoxyphenyl)ethyl-1 , 1 ,2,2- oVamine HCI (25.02mg, 0.12mmol, 1.1 eq.) and 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.05 ml; 0.16 mmol; 1.50 eq.). The reaction was stirred at RT for 5h.
The desired product was isolated by flash chromatography (10g, silica gel, 0 to 20% MeOH/DCM over 7CV) to afford product as white solid (35.2mg, 53%).
1H NMR (500 MHz, cd3od) δ 7.81 (s, 1 H), 7.67 (d, J = 7.5, 1H), 7.51 - 7.25 (m, 11 H), 6.77 (s, 1 H), 6.73 - 6.57 (m, 2H), 6.42 (s, 1H), 4.50 (dd, J = 8.4, 3.9, 1 H), 3.77 (s, 3H), 3.10 (dd, J = 15.2, 4.0, 1 H), 2.89 (dd, J = 15.2, 8.5, 1 H). m/z: 609 ; 610 [M+H]+
Example 2: 3-((2S,5R)-4-oxo-5-(2-oxo-2-((1 ,1 ,2,2-d4-2-(3,4- dimethoxyphenyl)ethyl)amino)ethyl)-2-(4-(phenylethynyl)phenyl)thiazolidin-3- yl)benzamide
Figure imgf000034_0001
To 3-((2S,5R)-4-oxo-5-(2-oxo-2-((1 , 1 ,2,2- d4-2-(4-hydroxy-3- methoxyphenyl)ethyl)amino)ethyl)-2-(4-(phenylethynyl)phenyl)thiazolidin-3- yl)benzamide (example 1) (25.00 mg; 0.04 mmol; 1.00 eq.) in acetone (1.00 mi; 13.62 mmol; 332.16 eq.) was added potassium carbonate (0.04 g; 0.27 mmol; 6.50 eq.), and dimethyl sulfate (0.18 μΙ; 0.008 mmol; 0.04 eq.). The reaction was stirred at RT overnight. The desired product was isolated by flash chromatography (10g, KPNH, 0 to 20% MeOH/DCM) to afford product as white solid (8.9mg, 35%).
1H NMR (500 MHz, cd3od) δ 7.83 - 7.78 (m, 1 H), 7.69 - 7.64 (m, 1 H), 7.50 - 7.30 (m, 11 H), 6.81 (dd, J = 5.0, 3.1 , 2H), 6.74 (dd, J = 8.2, 2.0, 1 H), 6.42 (s, 1 H), 4.53 - 4.47 (m, 1 H), 3.76 (t, J = 4.6, 6H), 3.10 (dd, J = 15.3, 4.1 , 1 H), 2.89 (dd, J = 15.3, 8.5, 1 H).
m/z: 624 ; 625 [M+H]+
Example 3: 3-((2S,5R)-4-oxo-5-(2-oxo-2-((1 ,1 ^^-^-(S-methoxy^-imethoxy- ,3)phenyl)ethyl)amino)ethyl)-2-(4-(phenylethynyl)phenyl)thiazolidin-3-yl)benzamide
Figure imgf000035_0001
In a similar manner to example 2, product was obtained from 3-((2S,5R)-4-oxo-5-(2- oxo-2-((1 ,1 ,2,2- <¾-2-(4-hydroxy-3-methoxyphenyl)ethyl)amino)ethyl)-2-(4- (phenylethynyl)phenyl)thiazolidin-3-yl)benzamide (35.00 mg; 0.06 mmol; 1.00 eq.) and dimethyl sulfate-^ (2.92 μΙ; 0.03 mmol; 0.50 eq.). The reaction was stirred at RT overnight. The desired product was isolated by flash chromatography (10g, KPNH, 0 to 20% MeOH/DCM) to afford product as white solid (22.3mg, 63%).
1H NMR (500 MHz, cd3od) δ 7.83 - 7.79 (m, 1 H), 7.70 - 7.65 (m, 1 H), 7.48 - 7.30 (m, 11 H), 6.83 - 6.77 (m, 2H), 6.74 (dd, J = 8.2, 2.0, 1 H), 6.42 (s, 1 H), 4.53 - 4.47 (m, 1 H), 3.75 (s, 3H), 3.10 (dd, J = 15.2, 4.1 , 1H), 2.89 (dd, J = 15.3, 8.5, 1 H).
m/z: 626 ; 627 [M+H]+
Example 4: 3-((2S,5R)-4-oxo-5-(2-oxo-2-((1 ,1 ,2,2-d4-2-(3-ethoxy-4- methoxyphenyl)ethyl)amino)ethyl)-2-(4-(phenylethynyl)phenyl)thiazolidin-3- yl)benzamide
Figure imgf000036_0001
In a similar manner to example 1 , product was obtained from [(2S,5R)-3-(3- Carbamoyl-phenyl)-4-oxo-2-(4-phenylethynyl-phenyl)-thiazolidin-5-yl]-acetic acid (50.00 mg; 0.11 mmol; 1.00 eq.) and 2-(3-ethoxy-4-methoxyphenyl)ethyl-1 ,1 ,2,2-G4- amine HCI (28.40 mg; 0.12 mmol; 1.10 eq.). Isolated 44.2mg (63%) of the title compound as white solid.
H NMR (500 MHz, cd3od) δ 7.81 (s, 1 H), 7.67 (d, J = 7.6, 1 H), 7.50 - 7.29 (m, 11 H), 6.87 - 6.69 (m, 3H), 6.42 (s, 1 H), 4.50 (dd, J = 8.4, 3.9, 1 H), 3.99 (dt, J = 12.3, 6.2, 2H), 3.80 - 3.71 (m, 3H), 3.09 (dd, = 15.2, 3.8, 1 H), 2.90 (dd, J = 15.3, 8.4, 1 H), 1.38 - 1.25 (m, 3H).
m/z: 637 ; 638 [M+H]+
Example 5: 3-((2S,5R)-4-oxo-5-(2-oxo-2-((1 , 1 ,2,2-£ 4-2-(3-ethoxy-4-(methoxy- d3)phenyl)ethyl)amino)ethyl)-2-(4-(phenylethynyl)phenyl)thiazolidin-3-yl)benzamide
Figure imgf000036_0002
In a similar manner to example 1 , product was obtained from [(2S,5R)-3-(3- Carbamoyl-phenyl)-4-oxo-2-(4-phenylethynyl-phenyl)-thiazolidin-5-yl]-acetic acid (50.00 mg; 0.11 mmol; 1.00 eq.) and 2-(3-ethoxy-4-methoxy-d3-phenyl)ethyl-1 , 1 ,2,2- d -amine HCI ((28.77 mg; 0.12 mmol; 1.10 eq.). 54.2 mg (77%) of the title compound was obtained as white solid. H NMR (500 MHz, cd3od) δ 7.83 - 7.79 (m, 1H), 7.69 - 7.65 (m, 1H), 7.50 - 7.26 (m, 11 H), 6.80 (dd, J = 8.4, 5.0, 2H), 6.74 (dd, J = 8.1 , 2.0, 1H), 6.41 (s, 1H), 4.52 - 4.46 (m, 1 H), 4.02 - 3.94 (m, 2H), 3.09 (dd, J = 15.3, 4.0, 1 H), 2.90 (dd, J = 15.3, 8.4, 1H), 1.33 (t, J = 7.0, 3H).
m/z: 640 ; 641 [M+H]+
Example 6: 3-((2S,5R)-4-oxo-5-(2-oxo-2-((2-(3-ethoxy-4-(methoxy- d3)phenyl)ethyl)amino)ethyl)-2-(4-(phenylethynyl)phenyl)thiazolidin-3-yl)benzamide
Figure imgf000037_0001
In a similar manner to example 3, product was obtain from 3-[(2S,5R)-5-{[2-(3- Ethoxy-4-hydroxy-phenyl)-ethylcarbamoyl]-methyl}-4-oxo-2-(4-phenylethynyl- phenyl)-thiazolidin-3-yl]-benzamide (50.00 mg; 0.08 mmol; 1.00 eq.) and dimethyl sulfate-cfe (4.10 μΙ; 0.04 mmol; 0.50 eq.). 28.9mg (56%) of the title compound was obtained as white solid.
Ή NMR (500 MHz, cd3od) δ 7.84 - 7.79 (m, 1H), 7.69 - 7.64 (m, 1 H), 7.49 - 7.29 (m, 11 H), 6.79 (dd, J = 7.5, 5.0, 2H), 6.74 (dd, J = 8.1 , 2.0, 1H), 6.41 (s, 1H), 4.51 - 4.47 (m, 1H), 4.01 - 3.93 (m, 2H), 3.46 - 3.39 (m, 2H), 3.09 (dd, J = 15.3, 4.0, 1H), 2.90 (dd, J = 15.3, 8.4, 1 H), 2.76 - 2.69 (m, 2H), .35 - 1.30 (m, 3H).
m/z: 636 ; 637 [M+H]+
Example 7: 3-((2S,5R)-4-oxo-5-(2-oxo-2-((2-(3,4-dimethoxypheny- ¾l)ethyl)amino)ethyl)-2-(4-(phenylethynyl)phenyl)thiazolidin-3-yl)benzamide
Figure imgf000038_0001
In a similar manner to example 3, product was obtained from 3-[(2S,5R)-5-{[2-(3,4- Dihydroxy-phenyl)-ethylcarbamoyl]-methyl}-4-oxo-2-(4-phenylethynyl-phenyl)- thiazolidin-3-yl]-benzamide (10.00 mg; 0.02 mmol; 1.00 eq.), and dimethyl sulfate-£ { (3.44 μΙ; 0.03 mmol; 2.00 eq.). 4.3 mg (41%) of the title compound was obtained as white solid.
1H NMR (400 MHz, MeOD) δ 7.83 (s, 1 H), 7.70 (d, J = 7.5, 1 H), 7.53 - 7.32 (m, 11 H), 6.82 (d, J = 4.4, 2H), 6.77 (d, J = 8.2, 1 H), 6.44 (s, 1 H), 4.52 (dd, J = 8.4, 4.0, 1 H), 3.46 (t, J = 7.1 , 2H), 3.13 (dd, J = 15.3, 4.1 , 1 H), 2.92 (dd, J = 15.3, 8.5, 1 H), 2.77 (t, J = 7.1 , 2H).
m/z: 625 ; 626 [M+Hf
Example 8: 3-((2S,5R)-5-(2-((3-ethoxy-4-methoxyphenethyl)amino)-2-oxoethyl)-4- oxo-2-(4-((phenyl-cfe)ethynyl)phenyl)thiazolidin-3-yl)benzamide
Figure imgf000038_0002
Step 1 : To 4-bromobenzaldehyde (750.00 mg; 4.05 mmol; 1.00 eq.), was added zinc chloride (55.25 mg; 0.41 mmol; 0.10 eq.), bis(tri-tert-butylphosphine)palladium(0) (41.43 mg; 0.08 mmol; 0.02 eq.), THF (1.00 ml; 12.34 mmol; 3.04 eq.),
diisopropylamine (0.13 ml; 0.92 mmol; 0.23 eq.). Then phenyl- cfe-acetylene (477.85 mg; 4.46 mmol; 1.10 eq.) was added. The reaction was stirred at RT overnight. The desired product was isolated by flash chromatography (0 to 20% EtOAC/Hex, over 10 CV). 206 mg (24%) of the title product was obtained as light yellow solid. Step 2: In a similar manner to example 1 step 1 & 2, 2-((2S,5R)-3-(3- carbamoylphenyl)-4-oxo-2-(4-(phenyl-i/5-ethynyl)phenyl)thiazolidin-5-yl)acetic acid was obtained from 4-(phenyl-d5-ethynyl)benzaldehyde (206mg, 0.98mmol), (S)-2- Mercapto-succinic acid (439.23 mg; 2.93 mmol; 3.00 eq.) and 3-aminobenzamide (132.76 mg; 0.98 mmol; 1.00 eq.). Final product was isolated by prep HPLC.
(131 mg, 10% yield over 2 steps).
1H NMR (400 MHz, MeOD) δ 7.83 (s, 1 H), 7.70 (d, J = 7.3, 1 H), 7.43 (dt, J = 14.3, 7.8, 6H), 6.90 - 6.70 (m, 3H), 6.44 (s, 1 H), 4.52 (dd, J = 8.2, 3.8, 1 H), 4.02 (dd, J = 14.0, 6.9, 2H), 3.78 (s, 3H), 3.46 (t, J = 7.1 , 2H), 3.12 (dd, J = 15.5, 4.4, 1 H), 2.92 (dd, J = 15.5, 8.3, 1 H), 2.76 (t, J = 7.1 , 2H), 1.35 (dd, J = 16.1 , 9.1 , 3H).
m/z: 638 ; 639 [M+Hf
Example 9: 3-((2S,5R)-4-oxo-5-(2-oxo-2-((1 , 1 ,2,2-d,-2-(3-ethoxy-4- methoxyphenyl)ethyl)amino)ethyl)-2-(4-((phenyl-c 5)ethynyl)phenyl)thiazolidin-3- yl)benzamide
Figure imgf000039_0001
In a similar manner to example 1 , product was obtained from 3-[(2S,5R)-5-{[2-(3,4- Dihydroxy-phenyl)-ethylcarbamoyl]-methyl}-4-oxo-2-(4-phenyl- cfe-ethynyl-phenyl)- thiazolidin-3-yl]-benzamide (25.00 mg; 0.05 mmol; 1.00 eq.) and 2-(3-ethoxy-4- methoxy-phenyl)ethyl-1 , 1 ,2,2- examine HCI (11.87mg, 0.06mmol, 1.1 eq.). The title product (24.5 mg, 70%) was obtained as white solid.
1H NMR (400 MHz, CDCI3) δ 7.72 (s, 1 H), 7.59 (d, J = 7.3, 1H), 7.38 (ddd, J = 15.1 , 14.3, 8.4, 5H), 6.91 - 6.60 (m, 3H), 6.21 (s, 1 H), 5.83 (s, 1 H), 4.48 (dd, J = 7.7, 4.6, 1H), 4.08 (dd, J = 13.7, 6.7, 2H), 3.87 (s, 3H), 3.17 (dd, J = 15.4, 4.5, 1 H), 2.81 (dd, J = 15.4, 8.3, 1 H), 1.45 (t, J = 7.0, 3H).
m/z: 642 ; 643 [M+H]+ Example 10: 3-((2Sl5R)-4-oxo-5-(2-oxo-2-((1 l1 ,2,2-d4-2-(3-ethoxy-4-methoxy-o, 3- phenyl)ethyl)amino)ethyl)-2-(4-((phenyl-c^
Figure imgf000040_0001
In a similar manner to example 1 , product was obtained from 2-((2S,5R)-3-(3- carbamoylphenyl)-4-oxo-2-(4-(phenyl-o'5-ethynyl)phenyl)thiazolidin-5-yl)acetic acid (25.00 mg; 0.05 mmol; 1.00 eq.) and 2-(3-ethoxy-4-methoxy- d3-phenyl)ethyl- 1,1 ,2,2- oVamine HCI (12.05mg, 0.06mmol, 1.1 eq.). A 29.10 mg of the title product (83.2%) was obtained as white solid.
1H NMR (400 MHz, CDCI3) δ 7.72 (s, 1H), 7.59 (d, J = 7.3, 1H), 7.45 - 7.30 (m, 5H), 6.81 (d, J = 8.6, 1H), 6.74 (dd, J = 5.7, 2.0, 2H), 6.21 (s, 1H), 5.83 (s, 1H), 4.48 (dd, J = 8.2, 4.4, 1 H), 4.08 (dd, J = 14.4, 7.3, 2H), 3.17 (dd, J = 15.4, 4.5, 1H), 2.81 (dd, J = 15.4, 8.3, 1 H), 1.45 (t, J = 7.0, 3H).
m/z: 645 ; 646 [M+H]+
Example 11 : 3-((2S,5R)-4-oxo-5-(2-oxo-2-((1 ,1 ,2,2-d4-2-(3-ethoxy-4- hydroxyphenyl)ethyl)amino)ethyl)-2-(4-((phenyl-i 5)ethynyl)phenyl)thiazolidin-3- yl)benzamide
Figure imgf000041_0001
In a similar manner to example 1 , product was obtained from 2-((2S,5R)-3-(3- carbamoylphenyl)-4-oxo-2-(4-(phenyl-d5-ethynyl)phenyl)thiazolidin-5-yl)acetic acid (16.6 mg; 0.04 mmol; 1.00 eq.), and 2-(3-ethoxy-4-hydroxyphenyl)ethyl-1 , 1 ,2,2- examine HCI (8.22mg, 0.06mmol, 1.1 eq.). 2.5 mg (10%) of the title product was obtained as white solid.
H N R (400 MHz, MeOD) δ 7.83 (s, 1 H), 7.70 (d, J = 7.4, 1H), 7.49 - 7.38 (m, 6H), 7.11 (dd, J = 8.1 , 1.6, 1 H), 6.93 (s, 1 H), 6.78 (dd, J = 8.2, 2.0, 1 H), 6.45 (s, 1 H), 4.53 (dd, J = 7.9, 4.5, 1 H), 3.80 (s, 3H), 3.11 (d, J = 4.0, 1 H), 2.92 (dd, J = 15.3, 8.4, 1 H). m/z: 614 ; 615 [M+H]+
Example 12: 3-((2S,5R)-5-(2-((3,4-dihydroxyphenethyl)amino)-2-oxoethyl)-4-oxo-2- -phenyl-cf5)ethynyl)phenyl)thiazolidin-3-yl)benzamide
Figure imgf000041_0002
In a similar manner to example 1 , product was obtained from 32-((2S,5R)-3-(3- carbamoylphenyl)-4-oxo-2-(4-(phenyl-c/5-ethynyl)phenyl)thiazolidin-5-yl)acetic acid (16.6 mg; 0.04 mmol; 1.00 eq.), and 4-(2-Amino-ethyl)-benzene-1 ,2-diol (6.06mg, 0.04 mmol, 1.1 eq.). The title compound was obtained (2.7 mg, 10%) of as white solid. H NMR (400 MHz, MeOD) δ 7.82 (s, 1H), 7.70 (d, J = 7.3, 1H), 7.55 - 7.29 (m, 6H), 7.08 (d, J = 8.0, 1 H), 6.86 (dd, J = 25.6, 8.1, 1H), 6.68 (dd, J = 8.2, 1.9, 1H), 6.44 (s, 1 H), 4.53 (dd, J = 8.3, 4.0, 1H), 3.44 (qd, J = 13.6, 7.5, 2H), 3.14 (dd, J = 15.2, 4.2, 1H), 2.91 (dd, J = 15.3, 8.5, 1H), 2.81 - 2.70 (m, 2H).
m/z: 596 ; 597 [M+H]+
Example 13: 3-((2S,5R)-4-oxo-5-(2-oxo-2-((1 ,1 ,2,2-d4-2-(3-ethoxy-4-methox-d3- ypheny ethyl)amino)ethyl)-2-(4-((phenyl-tf5)ethynyl)phenyl)thiazoh'din-3- yl)benzamide
Figure imgf000042_0001
In a similar manner to example 3, product was obtained from product from example 11 (55mg, 0.09 mmol, 1 eq.) and dimethyl sulfate- d5 (4.55 μΙ; 0.04 mmol; 0.50 eq.). A 26 mg (39%) of the title product was obtained as white solid.
1H NMR (400 MHz, MeOD) δ 7.83 (d, J = 1.8, 1H), 7.70 (dt, J = 7.4, 1.5, 1H), 7.44 (ddd, J = 19.0, 11.4, 6.5, 6H), 6.83 (dd, J = 5.0, 3.1 , 2H), 6.77 (dd, J = 8.2, 1.9, 1H), 6.45 (s, 1H), 4.53 (dd, J = 8.2, 3.8, 1H), 3.79 (s, 3H), 3.13 (dd, J = 15.3, 4.1 , 1H), 2.92 (dd, J = 15.3, 8.5, 1H).
m/z: 631 ; 632 [M+Hf
Example 14: 3-((2S,5RH-oxo-5-(2-oxo-2-((1 ,1 ,2,2-d4-2-(3-ethoxy-4- methoxyphenyl)ethyl)amino)ethyl)-2-(2J3,5,6-o'4-4-(phenylethynyl)phenyl)thiazolidin-
3-yl)benzamide
Figure imgf000043_0001
Step 1 : To 4-chlorobenzaldehyde-2,3,5,6-tf4 (1 00 g; 6.92 mmol; 1.00 eq.) was added caesium carbonate (4506.86 mg; 13.83 mmol; 2.00 eq.), 2- dicyclohexylphosphino- ^'.e'-triisopropylbiphenyl (659.40 mg; 1.38 mmol; 0.20 eq.) and MeCN (60.00 ml; 1148.76 mmol; 166.10 eq.). Then phenylacetylene (1.12 ml; 10.24 mmol; 1.48 eq.) was added and reaction mixture was vacuum/nitrogen flush 3 times. Then dichlorobis(acetonitrile)palladium (II) (179.42 mg; 0.69 mmol; 0.10 eq.) was added and another vacuum/nitrogen flush was done. Reaction was put in a preheated oil bath (83°C) and heated for 5h. Product was isolated by flash chromatography (silica gel, 100g column, DCM/hexanes)
Step 2: In a similar manner to example 1 step 1&2, 2, 2-((2S,5R)-3-(3- carbamoylphenyl)-4-oxo-2-(4-(phenyl-ethynyl)phenyl- / )thiazolidin-5-yl)acetic acid was obtained from 4-(phenyl-ethynyl)benzaldehyde-2,3„5,6-d4 (386 mg, 1.84 mmol), S)-2-Mercapto-succinic acid (826.95 mg; 5.51 mmol; 3.00 eq.) and 3- aminobenzamide (249.95 mg; 1.84 mmol; 1.00 eq.). Final product was isolated by prep HPLC. (27 mg, 5% yield over 2 steps).
Step 3: In a similar manner to example 1 , product was obtained from 2, 2-((2S,5R)- 3-(3-carbamoylphenyl)-4-oxo-2-(4-(phenyl-ethynyl)phenyl-d4)thiazolidin-5-yl)acetic acid (13 mg, 0.02mmol), and 2-(3-ethoxy-4-methoxyphenyl)ethyl-1 , 1 ,2,2- diamine HCI (5.87mg, 0.02mmol, 1.1 eq.). A 6.3 mg (43%) of the title compound was obtained as white solid.
1H NMR (400 MHz, eOD) δ 7.83 (d, J = 1.7, 1H), 7.73 - 7.63 (m, 1 H), 7.54 - 7.27 (m, 7H), 6.88 - 6.72 (m, 3H), 6.44 (d, J = 0.8, 1 H), 4.52 (dd, J = 8.2, 3.9, 1 H), 4.07 - 3.95 (m, 2H), 3.78 (s, 3H), 3.12 (dd, J = 15.3, 4.1 , 1 H), 2.92 (dd, J = 15.3, 8.4, 1 H), 1.35 (t, J = 7.0, 3H). m/z: 641 ; 642 [M+H]+
Example 15: 3-((2S,5R)-4-oxo-5-(2-oxo-2-((1 ,1 ,2,2-i/4-2-(3-ethoxy-4-methoxy-d3- phenyl)ethyl)amino)ethyl)-2-(2,3,5,6-o,4-4-(phenylethynyl)phenyl)thiazolidin-3- yl)benzamide
Figure imgf000044_0001
In a similar manner to example 1 , product was obtained from 2, 2-((2S,5R)-3-(3- car amoylphenyl)-4-oxo-2-(4-(phenyl-ethynyl)phenyl-iy4)thiazolidin-5-yl)acetic acid (13 mg, 0.02mmol), and 2-(3-ethoxy-4-methoxy-d3-phenyl)ethyl-1 ,1 ,2,2-d4-amine HCI (5.87mg, 0.02mmol, 1.1 eq.). The title compound was obtained as white solid (8.5 mg 58%).
1H NMR (400 MHz, MeOD) δ 7.83 (t, J = 1.7, 1 H), 7.70 (dt, J = 7.4, 1.5, 1 H), 7.51 - 7.33 (m, 7H), 6.82 (dd, J = 7.0, 5.1 , 2H), 6.77 (dd, J = 8.1 , 2.0, 1 H), 6.44 (d, J = 0.9, 1 H), 4.55 - 4.47 (m, 1 H), 4.06 - 3.97 (m, 2H), 3.12 (dd, J = 15.3, 4.1 , 1 H), 2.92 (dd, J = 15.3, 8.4, 1 H), 1.36 (t, J = 7.0, 3H).
m/z: 644 ; 645 [M+H]+
Example 16: 3-((2S,5R)-4-oxo-5-(2-oxo-2-((1 ,1 ,2,2-i 4-2-(3-ethoxy-4-methoxy-d3- phenyl)ethyl)amino)ethyl)-2-(2,3,5,6-d4-4-(phenylethynyl)phenyl-c/5)thiazolidin-3- yl)benzamide
Figure imgf000045_0001
Step 1 : In a similar manner to example 14 step 1 , 4-(phenyl-cf5- ethynyl)benzaldehyde-2,3,4,6-Q4 was obtained from 4-chlorobenzaldehyde-2, 3,5,6- d4 (2.79 g; 19.30 mmol; 1.00 eq.), and Ethynyl-benzene-cfe (3.10 g; 28.93 mmol; 1.50 eq.). Isolated 3.16 g (76%) of 4-(phenyl-o, 5-ethynyl)benzaldehyde-2,3,5,6-d4 as an off white solid.
Step 2: In a similar manner to example 1 step 1&2, 2-((2S,5R)-3-(3- carbamoylphenyl)-4-oxo-2-(4-(phenyl-o,5-ethynyl)phenyl- d^thiazolidin-S-y acetic acid was obtained from 4-(phenyl-c/5-ethynyl)benzaldehyde-2,3,5,6-o' (2.00 g; 9.29 mmol; 1.00 eq.), (S)-2-Mercapto-succinic acid (4.18 g; 27.87 mmol; 3.00 eq.) and 3- aminobenzamide (1.26 g; 9.29 mmol; 1.00 eq.) Final product was isolated by prep HPLC. (276 mg, 10% yield over 2 steps).
Step 3: In a similar manner to example 1, product was obtained from 2-((2S,5R)-3- (3-carbamoylphenyl)-4-oxo-2-(4-(phenyl-d5-ethynyl)phenyl- o*4)thiazolidin-5-yl)acetic acid (60 mg, 0.13 mmol), and 2-(3-ethoxy-4-methoxy-c/3-phenyl)ethyl-1 ,1 ,2,2-o4- amine HCI (33.85 mg, 0.14 mmol, 1.1 eq.). A 60 mg (72%) of the title compound was obtained as white solid.
H NMR (400 MHz, MeOD) δ 7.83 (s, 1 H), 7.70 (d, J = 7.5, 1 H), 7.50 - 7.35 (m, 2H), 6.79 (ddd, J = 10.1 , 9.0, 5.1 , 3H), 6.44 (s, 1 H), 4.52 (dd, J = 8.3, 4.0, 1 H), 4.01 (q, J = 7.0, 2H), 3.12 (dd, J = 15.3, 4.1 , 1 H), 2.92 (dd, J = 15.3, 8.4, 1 H), 1.35 (t, J = 7.0, 3H).
m/z: 649 ; 650 [M+H]+ Example 17:
Figure imgf000046_0001
phenyl)ethyl)amino)ethyl)-2-(2,3,5,6-d4-4-(phenylethynyl)phenyl-ci5)thiazolidm yl)benzamide
Figure imgf000046_0002
Step 1 : In a similar manner to example 1 , product was obtained from 2-((2S,5R)-3- (3-carbamoylphenyl)-4-oxo-2-(4-(phenyl-ii5-ethynyl)phenyl-d4)thiazolidin-5-yl)acetic acid (50 mg, 0.1 1 mmol) and 2-(3,4-dihydroxy)ethyl-1 ,1 ,2,2-oVamine HCI (22.8 mg, 0.12 mmol, 1.1 eq.). Isolated 6 mg (9%) of product as white solid.
Step 2: In a similar manner to example 3, product was obtained from product example 17 step 1 (6 mg, 0.01 mmol) and dimethyl sulfate-cf6 (0.5 μΙ; 0.005 mmol; 0.50 eq.). Isolated 3.2 mg (52%) of the title product as white solid.
1H NMR (400 MHz, MeOD) δ 7.83 (d, J = 1.7, 1H), 7.70 (d, J = 7.5, 1 H), 7.43 (dt, J = 15.4, 4.8, 2H), 6.83 (dd, J = 5.0, 3.1 , 2H), 6.77 (dd, J = 8.2, 1.9, 1 H), 6.45 (s, 1 H), 4.53 (dd, J = 8.4, 4.0, 1 H), 3.12 (dd, J = 15.3, 4.1 , 1 H), 2.92 (dd, J = 15.3, 8.5, 1 H). m/z: 638 ; 639 [M+H]+
Example 18:
Figure imgf000047_0001
To product from example 17 (100.00 mg; 0.16 mmol; 1.00 eq.) in MeCN (3.80 ml; 72.75 mmol; 464.79 eq.) and water (0.20 ml; 11.10 mmol; 70.92 eq.) (10:1) was added a 1 mL solution of 1-chloromethyl-4-fluoro-1 ,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (66.54 mg; 0.19 mmol; 1.20 eq.) in MeCN (2ml_) and water (0.2mL). The reaction was stirred at RT for 30 min. Product was isolated by prep HPLC (40% ACN/60% water for 5min, then up to 60% ACN/40% water for 20min, 254nm, 0.1%TFA). A 36 mg (30%) of the title product was obtained as white solid. Stereochemistry at sulfoxide was arbitrary assigned.
1H NMR (400 MHz, MeOD) δ 7.85 (s, 1 H), 7.68 (d, J = 7.5, 1 H), 7.48 - 7.35 (m, 2H), 6.93 - 6.84 (m, 2H), 6.79 (dd, J = 8.1 , 1.9, 1 H), 6.55 (s, 1 H), 4.55 (dd, J = 10.6, 3.8, 1 H), 3.23 (dd, J = 16.8, 3.8, 1 H), 3.02 (dd, J = 16.7, 10.7, 1 H).
m/z. 654 ; 655 [M+Hf
Figure imgf000047_0002
To product from example 17 (80.00 mg; 0.13 mmol; 1.00 eq.) in dichloromethane (2mL) was added 3-chloroperbenzoic acid (28.06 mg; 0.13 mmol; 1.00 eq.). The reaction was stirred at RT for 1 h. Product was isolated by prep HPLC (40 to 65% ACN/water over 20 min, 0.1% TFA). A 46.2 mg (48%) of the title product was obtained as white solid. Stereochemistry at sulfoxide was arbitrary assigned.
1H NMR (400 MHz, MeOD) δ 8.07 (s, 1H), 7.79 (d, J = 7.9, 1 H), 7.71 (d, J = 9.4, 1 H), 7.53 (t, J = 8.0, 1 H), 6.86 (dd, J = 7.0, 5.1 , 2H), 6.77 (dd, J = 8.1 , 2.0, 1 H), 6.40 (s, 1H), 4.41 (dd, J = 10.5, 4.0, 1 H), 3.17 - 3.10 (m, 1H), 2.90 (dd, J = 16.8, 10.5, 1 H).
m/z: 654 ; 655 [M+Hf
Examples 20 and 21 :
Figure imgf000048_0001
Example 20 Example 21
To product from example 16 (45.00 mg; 0.07 mmol; 1.00 eq.) in dichloromethane was added 3chloroperbenzoic acid (15.52 mg; 0.07 mmol; 1.00 eq.). The reaction was stirred at RT for 4h. Product was purified by prep HPLC (40 to 65% ACN/water over 20 min, 0.1 % TFA). Product example 20 eluted at 53%. Isolated 3.7 mg of example 20 (7%) as white solid. Product example 21 , eluted at 55%. A 10.6 mg (20%) of example 21 as white solid was obtained. Stereochemistry at sulfoxide arbitrary assigned.
Example 20: 1H NMR (500 MHz, cd3od) δ 7.86 (d, J = 14.5, 1 H), 7.67 (d, J = 8.0, 1 H), 7.58 - 7.23 (m, 2H), 7.07 - 6.68 (m, 3H), 6.54 (s, 1 H), 4.54 (d, J = 7.0, 1 H), 4.06 (q, J = 6.8, 2H), 3.24 - 3.08 (m, 1 H), 3.00 (dd, J = 16.8, 10.9, 1 H), 1.38 (t, J = 7.0, 3H).
m/z: 654 ; 655 [M+H]+ Example 21 :
1H N R (500 MHz, cd3od) δ 8.06 (s, 1 H), 7.74 (dd, J = 34.9, 8.1 , 2H), 7.51 (t, J = 7.9, 1 H), 6.97 - 6.68 (m, 3H), 6.40 (s, 1 H), 4.39 (dd, J = 10.5, 3.9, 1 H), 4.05 (q, J = 7.0, 2H), 3.18 - 3.02 (m, 1 H), 2.89 (dd, J = 16.8, 10.6, 1 H), 1.43 - 1.23 (m, 3H). m/z: 654 ; 655 [M+H]+
Example 22: 3-((2S,5R)^-oxo-5-(2-oxo-2-((1 ,1,2,2-d4-2-(3-ethoxy-4- methoxyphenyl)ethyl)amino)ethyl)-2-(4-((phenyl)ethynyl)phenyl)thiazolidin-3- yl)benzamide
Figure imgf000049_0001
Step 1 : To [(2S,5R)-3-(3-Carbamoyl-phenyl)-4-oxo-2-(4-phenylethynyl-phenyl)- thiazolidin-5-yl]-acetic acid (150.00 mg; 0.33 mmol; 1.00 eq.) , in toluene (1.00 ml) , was added N-ethyl-N-isopropylpropan-2-amine (0.06 ml; 0.33 mmol; 1.00 eq.) , diphenyl azidophosphate (0.08 ml; 0.38 mmol; 1.15 eq.) and 2-methylpropan-2-ol (1.00 ml). Mixture was heated to 100C for 5h. Reaction was cooled, concentrated and purified by flash chromatography (silica gel 10g, 0 to 5% MeOH/EtOAc).
Isolated 91 mg of [(2S,5R)-3-(3-Carbamoyl-phenyl)-4-oxo-2-(4-phenylethynyl- phenyl)-thiazolidin-5-ylmethyl]-carbamic acid tert-butyl ester (53%) as an off white solid.
Step 2: To [(2S,5R)-3-(3-Carbamoyl-phenyl)-4-oxo-2-(4-phenylethynyl-phenyl)- thiazolidin-5-ylmethyl]-carbamic acid tert-butyl ester (90.00 mg; 0.17 mmol; 1.00 eq.) in dichloromethane (1.00 ml) was added trifluoroacetic acid (50.00 μΙ; 0.67 mmol; 3.93 eq.). The reaction was stirred at room temperature overnight. Product was purified by flash chromatography (KPNH, 10g, 0 to 20% MeOH/DCM). Isolated 53 mg of 3-[(2S,5R)-5-aminomethyl-4-oxo-2-(4-phenylethynyl-phenyl)-thiazolidin-3-yl]- benzamide (77%) as white solid. Step 3: To 3-[(2S,5R)-5-Aminomethyl-4-oxo-2-(4-phenylethynyl-phenyl)-thiazolidin- 3-yl]-benzamide (30.00 mg; 0.07 mmol; 1.00 eq.) in DCM (2.00 ml; 31.20 mmol; 444.63 eq.) was added 3-(3-ethoxy-4-methoxyphenyl)propanoic-2,2, 3,3-0*4 acid (19.22 mg, 0.08 mmol, 1.1 eq.), N,N-Diisopropylethylamine (0.01 ml; 0.08 mmol;
1.20 eq.) and 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.03 ml; 0.11 mmol; 1.50 eq.). The reaction was stirred at RT 1h. Product was purified by flash chromatography (KPNH, 0 to 20% MeOH/DCM). The title product was obtained as white solid (30.1 mg 68%).
'H NMR (400 MHz, CDCI3) δ 7.73 (s, 1 H), 7.66 (d, J = 7.9, 1 H), 7.52 (dd, J = 12.3, 5.4, 2H), 7.44 (d, J = 8.3, 2H), 7.36 (dd, J = 5.8, 2.6, 3H), 7.27 - 7.19 (m, 3H), 6.83 (d, J = 8.8, 1 H), 6.80 - 6.74 (m, 2H), 6.45 (s, 1 H), 6.11 (s, 1 H), 4.14 - 4.03 (m, 3H), 4.02 - 3.95 (m, 1 H), 3.85 (s, 3H), 3.53 (d, J = 12.7, 1 H), 1.42 (t, J = 7.0, 3H).
m/z: 637 ; 638 [M+H]+
EC of cyclic AMP production in CHO FSHR cells + EC FSH
2500 Cho-FSHR-LUC-1-1-43 cells were plated per well in 5 μΙ_ of phenol red free DMEM/F12 + 1% FBS. Cells were plated in 384 well, solid white low volume plates (Greiner 784075) by Multidrop. Cells were assayed by adding 100 μΙ_ of 2X EC20 FSH/IBMX in DMEM/F12 + 0.1 % BSA) by Multidrop to 2 μΙ_ of test compound stamped in 384 well plates (compounds are diluted 1 :50). The final FSH
concentration was 0.265 pM, and the final IBMX concentration was 200 μΜ. The compound plate map was as follows: Column 1 : 2 pL of DMSO; Column 2: 2 pL of DMSO; Columns 3-12 and 13-24: 2 μΙ_ of test compound, diluted 1 :4 in 100% DMSO, or 2 pL of FSH, diluted 1 :4 in DMEM/F12+0.1% BSA. The starting concentration for FSH was 50 nM (final concentration was 0.5 nM). Furthermore, Column 23 contained 2 pLof ECi00 FSH reference (100X) (diluted in DMEM/F12 + 0.1 % BSA) at a final concentration of 0.5 nM, and Column 24 contained 2 μΙ_ of 1 mM AS707664/2 reference compound 2. 5 μΙ_ of compound + EC2o FSH mixture were transferred to cell plates (1 :2 dilution into 5 μΙ_ of cell media) The plates were incubated at 37 °C for 1 h. 10 μΙ_ of mixed HTRF (CisBio # 62AM4PEC) reagents were added per well and incubated at room temperature for 1 h. The plates were read on Envision using the cAMP HTRF - low volume 384 well protocol. The readout was the calculated fluorescence ratio (665 nm / 620 nm). The results are depicted in table 1.
Intrinsic clearance (Clint) assay protocol:
Instrumentation
A Tecan Genesis workstation (RSP 150/8) was used for to perform the microsomal incubations. Analysis was carried out using a Waters ACQUITY UPLC system coupled to an ABSciex API3000 mass spectrometer. Data analysis was performed using Assay Explorer (Symyx).
UPLC conditions
Column : Acquity UPLC BEH C18, 2.1 x 50mm, 1.7 urn (Waters)
Mobile phases : A = 0.1 % formic acid in water
B = acetonitrile
Gradient Time %A %B
initial 90 10
0.47 5 95
0.65 5 95
0.66 90 10
Flow rate : 0.750 mL/min
Detection : ESI, MRM
Injection : 10 uL
Column temperature: 50°C
Chemicals
0.1 M potassium phosphate buffer pH 7.4 containing 1 mM MgCI2
15 mM NADPH in phosphate buffer
4.4 mg protein/mL liver microsomes in phosphate buffer
acetonitrile
20% DMSO in water
Microsomal Incubation
Each experiment consists of 12 test and 2 reference compounds. The reference compounds are incubated as a cocktail.
Dilution of test compounds was done in 2 steps from a 10 mM DMSO stock solution. First 4 ί stock solution was added to 196 μΐ. of 20% DMSO in potassium phosphate buffer pH 7.4. In a second step 10 μΙ_ of the first dilution were added to 1890 μΙ_ potassium phosphate buffer and 100 μΙ_ internal standard solution to a final concentration of 0.8 μΜ.
100 μί of the final compound dilution were aliquoted into a 96 deep well plate. 12.5 μΙ_ liver microsomes were added to each well (0.5 mg/mL final protein
concentration) and the samples preincubated for 5 min at 37 °C and 800 rpm agitation.
After the preincubation, 250 μΙ_ cold acetonitrile were added to the 0 min samples to prevent a reaction. Following this, 12.5 μΙ_ NADPH solution were added to all wells to start the incubation, with the exception of the 0 min and 30 min controls without cofactor, where the NADPH was substituted for phosphate buffer.
The incubations were stopped after 5, 10, 20 and 30 min by adding 250 μΙ_ cold acetonitrile to the individual wells.
The quenched samples were then centrifuged at 4000g for 1 h at 4 °C. 100 μΙ_ of the supernatant were transferred into 96 well plates for analysis.
Data Analysis
The metabolic stability of each compound was determined by measurement of the change in LC- S/MS peak area over time. Assay Explorer software was used to automatically calculate the slope k of the decline. The intrinsic clearance (Clint) of each compound was then calculated according to the formula:
Clint (μ-Jmin/mg protein) = k 1000 /protein concentration.
Classification of results
Figure imgf000052_0001
The results are depicted in table 1. Table 1
EC50 of CAMP
Clint (human/rat)
Compound production
^L/min/mg protein] [nWI (% effect)]
Reference compound 0.3 (98) 182/120
1 0.87 (99) 67/31
2 1.9 (97) 106/24
3 1.7 (97) 111/29
4 0.7 (99) 191/51
5 0.8 (99) 168/45
6 0.7 (96) 208/56
7 0.5 (99) 184/44
8 1.7 (99) 188/54
9 0.3 (97) 181/31
10 0.3 (98) 161/23
11 335 (99)
12 220 (99)
13 1.3 (97)
14 2 (99) 492/95
15 0.6 (99)
16 0.7 (100)
17 0.9 (100)
18 0.7 (101)
19 101 (100) 127/61 20 25(103) 35/18
21 113(103) 351/241
22 349 (101) 46/11
10
15
20
25
35

Claims

Claims
Figure imgf000055_0001
each Y is independently from each other selected from the group consisting of: "hydrogen (H), deuterium (D)n;
X is selected from the group consisting of: "S, sulfoxide";
R1 , R2 are independently from each other selected from the group consisting of: "hydrogen (H), deuterium (D), methyl, CH2D, CHD2, CD3, ethyl, CHDCH3, CHDCH2D, CHDCHD2, CHDCD3, CD2CH3, CD2CH2D, CD2CHD2, CD2CD3"; with the proviso that at least one Y is deuterium (D) or at least one of R1 , R2 comprises at least one deuterium (D); optionally, at least one carbon atom is independently from each other replaced by 13C; and the physiologically acceptable salts, solvates, tautomers and
stereoisomers thereof, including mixtures thereof in all ratios.
2. Deuterated thiazolidinone derivative as claimed in claim 1 , wherein at least one carbon atom is replaced by 13C; and the physiologically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.
Deuterated thiazolidinone derivative as claimed in any of claims 1 to 2, wherein
Yi5, Yi6, Yi7, Yi8 are deuterium (D); and the physiologically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.
Deuterated thiazolidinone derivative as claimed in any of claims 1 to 3, wherein
Yi, Y2, Y3> Y4, Ys are deuterium (D); and the physiologically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.
Deuterated thiazolidinone derivative as claimed in any of claims 1 to 4, wherein
Y6, ?, Υβ, Y9 are deuterium (D); and the physiologically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.
6. Deuterated thiazolidinone derivative as claimed in any of claims 1 to 5, wherein and/or R2 are CD3; and the physiologically acceptable salts, solvates, tautomers and
stereoisomers thereof, including mixtures thereof in all ratios.
Deuterated thiazolidinone derivative as claimed in any of claims 1 to 6, wherein
(a) Yi5, Yi6, Yi7> Yi8 are deuterium (D) and the other Y are hydrogen (H) and none of Ri, R2 comprises one or more deuterium (D); or
(b) Yi5, Yi6, Yi7. Yia are deuterium (D) and the other Y are hydrogen (H) and one of Rn, R2 is CD3 and the other one of Ri, R2 does not comprise one or more deuterium (D); or
(c) all Y are hydrogen (H) and one of R^ R2 is CD3 and the other one of R1 t R2 does not comprise one or more deuterium (D); or
(d) Y1 f Y2l Y3, Y4, Ys are deuterium (D) and the other Y are hydrogen (H) and none of R2 comprises one or more deuterium (D); or
(e) all Y are hydrogen (H) and both of R^ R2 are CD3; or
(f) Yi, Y2, Y3, Y4, Ys, Yi5, Yi6, Yi7, Y18 are deuterium (D) and the other Y are hydrogen (H) and none of Ri, R2 comprises one or more deuterium (D); or
(g) Yi, Y2, Y3, Y4, Ys, Yi5, Y16, Yi?, Y18 are deuterium (D) and the other Y are hydrogen (H) and one of R1 t R2 is CD3 and the other one of R^ R2 does not comprise one or more deuterium (D); or
(h) Y6, Y7, Y8, Y9, Yi5, Y16. Yi7, Y18 are deuterium (D) and the other Y are hydrogen (H) and one of Ri, R2 is CD3 and the other one of R1 t R2 does not comprise one or more deuterium (D); or Yi. Y2, Υ3, Υ4, Ys, Ye, Υ7, Υβ, Υ9. Υΐ5, Υιβ, Υΐ7, Υΐ8 are deuterium (D) and the other Y are hydrogen (H) and both of R2 are CD3; or
Yi. Y2, Y3. Y4, Y5, Y6, Y7. Ye, Ye. Yi5, Yi6, Yi7, Yi8 are deuterium (D) and the other Y are hydrogen (H) and one of R2 is CD3 and the other one of RL R2 does not comprise one or more deuterium (D); and the physiologically acceptable salts, solvates, tautomers and
stereoisomers thereof, including mixtures thereof in all ratios.
Deuterated thiazolidinone derivative selected from the group consisting of:
Figure imgf000058_0001
Figure imgf000059_0001

Figure imgf000060_0001

Figure imgf000061_0001
35
Figure imgf000062_0001
Figure imgf000063_0001
 and the physiologically acceptable salts, solvates, tautomers and
stereoisomers thereof, including mixtures thereof in all ratios.
Medicament comprising at least one compound according to any of claims 1 to 8.
Medicament comprising at least one compound according to any of claims 1 to 8 for use in the prophylactic or therapeutic treatment and/or monitoring of fertility disorders.
Pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to any of claims 1 to 8, optionally further comprising at least one additional compound selected from the group consisting of physiologically acceptable excipients, auxiliaries, adjuvants, diluents, carriers and/or additional pharmaceutically active substance other than the compound according to any of claims 1 to 8.
Kit comprising a therapeutically effective amount of at least one compound according to any of claims 1 to 8 and/or at least one pharmaceutical composition according to claim 11 and a therapeutically effective amount of at least one further pharmacologically active substance other than the compound according to any of claims 1 to 8.
A method for modulating a FSH receptor in a positive allosteric manner, wherein a cell capable of expressing the FSH receptor is contacted in the presence of FSH with at least one compound according to any of claims 1 to 8 or at least one pharmaceutical composition according to claim 1 1.
A method for treating fertility disorders, wherein a therapeutically effective amount of at least one compound according to any of claims 1 to 8 or at least one pharmaceutical composition according to claim 1 1 is administered to a mammal in need of such treatment.
15. A method for in-vitro fertilization comprising the steps of:
(a) treating a mammal according to the method of claim 14, (b) collecting ova from said mammal,
(c) fertilizing said ova, and
(d) implanting said fertilized ova into a host mammal.
PCT/EP2013/000215 2012-02-08 2013-01-24 Deuterated thiazolidinone analogues as agonists for follicle stimulating hormone receptor WO2013117299A1 (en)

Priority Applications (14)

Application Number Priority Date Filing Date Title
BR112014019351A BR112014019351A8 (en) 2012-02-08 2013-01-24 DEUTERATED THIAZOLIDINONE ANALOGS AS AGONISTS FOR FOLLICLE STIMULATING HORMONE RECEPTOR
CA2860489A CA2860489C (en) 2012-02-08 2013-01-24 Deuterated thiazolidinone analogues as agonists for follicle stimulating hormone receptor
EP13702741.3A EP2812320B1 (en) 2012-02-08 2013-01-24 Deuterated thiazolidinone analogues as agonists for follicle stimulating hormone receptor
AU2013218368A AU2013218368B2 (en) 2012-02-08 2013-01-24 Deuterated thiazolidinone analogues as agonists for follicle stimulating hormone receptor
ES13702741.3T ES2672326T3 (en) 2012-02-08 2013-01-24 Deuterated thiazolidinone analogues as agonists for the follicle stimulating hormone receptor
RU2014136334A RU2014136334A (en) 2012-02-08 2013-01-24 DEUTERED THIAZOLIDININE ANALOGUES AS FOLICULOSTIMULATING HORMONE RECEPTOR AGONISTS
SG11201403540RA SG11201403540RA (en) 2012-02-08 2013-01-24 Deuterated thiazolidinone analogues as agonists for follicle stimulating hormone receptor
US14/372,102 US20150111933A1 (en) 2012-02-08 2013-01-24 Deuterated Thiazolidinone Analogues as Agonists for Follicle Stimulating Hormone Receptor
MX2014009416A MX2014009416A (en) 2012-02-08 2013-01-24 Deuterated thiazolidinone analogues as agonists for follicle stimulating hormone receptor.
CN201380008413.8A CN104114544A (en) 2012-02-08 2013-01-24 Deuterated thiazolidinone analogues as agonists for follicle stimulating hormone receptor
KR20147021930A KR20140120903A (en) 2012-02-08 2013-01-24 Deuterated thiazolidinone analogues as agonists for follicle stimulating hormone recetor
JP2014555967A JP6386382B2 (en) 2012-02-08 2013-01-24 Deuterated thiazolidinone analogues as agonists of follicle stimulating hormone receptors
IL233983A IL233983B (en) 2012-02-08 2014-08-06 Thiazolidinone derivatives and pharmaceutical compositions containing them
HK15102455.7A HK1201837A1 (en) 2012-02-08 2015-03-10 Deuterated thiazolidinone analogues as agonists for follicle stimulating hormone receptor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201261596417P 2012-02-08 2012-02-08
US61/596,417 2012-02-08

Publications (1)

Publication Number Publication Date
WO2013117299A1 true WO2013117299A1 (en) 2013-08-15

Family

ID=47666083

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2013/000215 WO2013117299A1 (en) 2012-02-08 2013-01-24 Deuterated thiazolidinone analogues as agonists for follicle stimulating hormone receptor

Country Status (15)

Country Link
US (1) US20150111933A1 (en)
EP (1) EP2812320B1 (en)
JP (1) JP6386382B2 (en)
KR (1) KR20140120903A (en)
CN (1) CN104114544A (en)
AU (1) AU2013218368B2 (en)
BR (1) BR112014019351A8 (en)
CA (1) CA2860489C (en)
ES (1) ES2672326T3 (en)
HK (1) HK1201837A1 (en)
IL (1) IL233983B (en)
MX (1) MX2014009416A (en)
RU (1) RU2014136334A (en)
SG (1) SG11201403540RA (en)
WO (1) WO2013117299A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10208055B2 (en) 2014-06-23 2019-02-19 Tocopherx, Inc. Pyrazole compounds as modulators of FSHR and uses thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002009706A1 (en) 2000-07-27 2002-02-07 Smithkline Beecham Corporation Agonists of follicle stimulating hormone activity
WO2002009705A2 (en) 2000-07-31 2002-02-07 Smithkline Beecham Corporation Agonist of follicle stimulating hormone activity
US6653338B2 (en) 1998-08-07 2003-11-25 Applied Research Systems Ars Holding N.A. FSH mimetics for the treatment of infertility
WO2009045476A1 (en) * 2007-10-02 2009-04-09 Concert Pharmaceuticals, Inc. Pyrimidinedione derivatives
WO2010136438A1 (en) 2009-05-27 2010-12-02 N.V. Organon (dihydro) imidazoiso (5, 1-a) quinolines as fsh receptor agonists for the treatment of fertility disorders

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6221335B1 (en) * 1994-03-25 2001-04-24 Isotechnika, Inc. Method of using deuterated calcium channel blockers
US6440710B1 (en) * 1998-12-10 2002-08-27 The Scripps Research Institute Antibody-catalyzed deuteration, tritiation, dedeuteration or detritiation of carbonyl compounds
ES2193921T3 (en) * 1999-12-03 2003-11-16 Pfizer Prod Inc SULFAMOILHETEROARIL-PIRAZOL COMPOUNDS AS ANTINFLAMATORY / ANALGESIC AGENTS.
TW200413273A (en) * 2002-11-15 2004-08-01 Wako Pure Chem Ind Ltd Heavy hydrogenation method of heterocyclic rings
US7598273B2 (en) * 2005-10-06 2009-10-06 Auspex Pharmaceuticals, Inc Inhibitors of the gastric H+, K+-ATPase with enhanced therapeutic properties
US7750168B2 (en) * 2006-02-10 2010-07-06 Sigma-Aldrich Co. Stabilized deuteroborane-tetrahydrofuran complex
CN102143949A (en) * 2008-09-03 2011-08-03 泰华制药工业有限公司 2-oxo-1,2-dihydro-quinoline modulators of immune function

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6653338B2 (en) 1998-08-07 2003-11-25 Applied Research Systems Ars Holding N.A. FSH mimetics for the treatment of infertility
WO2002009706A1 (en) 2000-07-27 2002-02-07 Smithkline Beecham Corporation Agonists of follicle stimulating hormone activity
WO2002009705A2 (en) 2000-07-31 2002-02-07 Smithkline Beecham Corporation Agonist of follicle stimulating hormone activity
WO2009045476A1 (en) * 2007-10-02 2009-04-09 Concert Pharmaceuticals, Inc. Pyrimidinedione derivatives
WO2010136438A1 (en) 2009-05-27 2010-12-02 N.V. Organon (dihydro) imidazoiso (5, 1-a) quinolines as fsh receptor agonists for the treatment of fertility disorders

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
"Organic Reactions", JOHN WILEY & SONS
BUNDGAARD H: "A Textbook of Drug Design and Development", 1991, HARWOOD ACADEMIC PUBLISHERS, pages: 131 - 191
BUNDGAARD H: "Design of Prodrugs", 1985, ELSEVIER
FOSTER A B: "Deuterium isotope effects in the metabolism of drugs and xenobiotics: implications for drug design", ADVANCES IN DRUG RESEARCH, ACADEMIC PRESS, LONDON, GB, vol. 14, 1985, pages 1 - 40, XP009086953, ISSN: 0065-2490 *
HOUBEN-WEYL: "Methoden der Organischen Chemie [Methods of Organic Chemistry", GEORG THIEME VERLAG
KUSHNER DJ ET AL: "Pharmacological uses and perspectives of heavy water and deuterated compounds", CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY, OTTAWA, ONT, CA, vol. 77, no. 2, February 1999 (1999-02-01), pages 79 - 88, XP009086918 *
PELLETIER JC ET AL.: "disclose the preparation of highly substituted gamma-lactam follicle stimulating hormone receptor agonists", BIOORG. MED. CHEM., vol. 13, 2005, pages 5986 - 5995, XP002415222, DOI: doi:10.1016/j.bmc.2005.07.025
WERMUTH CG ET AL.: "The Practice of Medicinal Chemistry", 1996, ACADEMIC PRESS, pages: 671 - 696
WROBEL J ET AL.: "5-alkylated thiazolidinones as follicle-stimulating hormone receptor agonists", BIOORG. MED. CHEM., vol. 14, 2006, pages 5729 - 5741, XP025133476, DOI: doi:10.1016/j.bmc.2006.04.012

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10208055B2 (en) 2014-06-23 2019-02-19 Tocopherx, Inc. Pyrazole compounds as modulators of FSHR and uses thereof
US10941152B2 (en) 2014-06-23 2021-03-09 Ares Trading S.A. Pyrazole compounds as modulators of FSHR and uses thereof

Also Published As

Publication number Publication date
IL233983A0 (en) 2014-09-30
EP2812320B1 (en) 2018-03-07
MX2014009416A (en) 2014-11-10
IL233983B (en) 2019-12-31
JP6386382B2 (en) 2018-09-05
KR20140120903A (en) 2014-10-14
BR112014019351A2 (en) 2017-06-20
RU2014136334A (en) 2016-04-10
JP2015511943A (en) 2015-04-23
SG11201403540RA (en) 2014-07-30
US20150111933A1 (en) 2015-04-23
EP2812320A1 (en) 2014-12-17
HK1201837A1 (en) 2015-09-11
AU2013218368B2 (en) 2017-09-07
CN104114544A (en) 2014-10-22
ES2672326T3 (en) 2018-06-13
CA2860489C (en) 2019-11-12
CA2860489A1 (en) 2013-08-15
AU2013218368A1 (en) 2014-07-17
BR112014019351A8 (en) 2017-07-11

Similar Documents

Publication Publication Date Title
AU2014214326B2 (en) Substituted quinoxaline derivatives and their use as positive allosteric modulators of mGluR4
JP5897566B2 (en) Cyclic N, N&#39;-diarylthiourea and N, N&#39;-diarylurea-androgen receptor antagonists, anticancer agents, methods for their preparation and uses
KR20110111472A (en) Novel polymorphic forms of 3-(1-{3-[5-(1-methyl-piperidin-4ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride salt and processes of manufacturing thereof
JP2017538676A (en) Small molecule inhibitors of mitochondrial permeability transition pore (mtPTP)
JP6340103B2 (en) Benzothiazolone compounds
AU2014211728B2 (en) Spiro-quinazolinone derivatives useful for the treatment of neurological diseases and conditions
EP2314569A1 (en) Novel polymorphic forms of (S)-2-[4-(3-Fluoro-benzyloxy)-benzylamino]-propionamide mesylate salt and processes of manufacturing thereof
TW200922584A (en) Organic compounds
US10059671B2 (en) Positive allosteric modulators of mGluR3
AU2014214324B2 (en) Substituted acetylene derivatives and their use as positive allosteric modulators of mGluR4
AU2013218368B2 (en) Deuterated thiazolidinone analogues as agonists for follicle stimulating hormone receptor
AU2009287118B2 (en) Fused pyrrolidino-cyclopropane derivatives as selective 11-beta-hydroxysteroid dehydrogenase type 1 inhibitors
US11773076B2 (en) Crystalline forms of a somatostatin modulator
JP7498504B2 (en) Use of aminothiol compounds as neuroprotective agents for the brain or heart
KR20110089462A (en) Novel polymorphic forms of 6-(1-methyl-1h-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4-yl-ethoxy)-pyrimidin-2-yl]-benzyl}-2h-pyridazin-3-one dihydrogenphosphate and processes of manufacturing thereof

Legal Events

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

Ref document number: 13702741

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2860489

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2013702741

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 14372102

Country of ref document: US

ENP Entry into the national phase

Ref document number: 2013218368

Country of ref document: AU

Date of ref document: 20130124

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: MX/A/2014/009416

Country of ref document: MX

ENP Entry into the national phase

Ref document number: 20147021930

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 233983

Country of ref document: IL

ENP Entry into the national phase

Ref document number: 2014555967

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2014136334

Country of ref document: RU

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112014019351

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 112014019351

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20140806