WO2003082278A1 - Thiazolidine carboxamide derivatives as modulators of the prostaglandin f receptor - Google Patents

Thiazolidine carboxamide derivatives as modulators of the prostaglandin f receptor Download PDF

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Publication number
WO2003082278A1
WO2003082278A1 PCT/EP2003/050083 EP0350083W WO03082278A1 WO 2003082278 A1 WO2003082278 A1 WO 2003082278A1 EP 0350083 W EP0350083 W EP 0350083W WO 03082278 A1 WO03082278 A1 WO 03082278A1
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WIPO (PCT)
Prior art keywords
thiazolidine
carboxamide
biphenyl
ylsulfonyl
amino
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PCT/EP2003/050083
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French (fr)
Inventor
Patrick Page
Catherine Jorand-Lebrun
Anna Quattropani
Vincent Pomel
Matthias Schwarz
Estelle Hamelin
Russell J. Thomas
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Applied Research Systems Ars Holding N.V.
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Priority to CA002477265A priority Critical patent/CA2477265A1/en
Priority to EP03730168A priority patent/EP1487442B1/en
Application filed by Applied Research Systems Ars Holding N.V. filed Critical Applied Research Systems Ars Holding N.V.
Priority to IL16421203A priority patent/IL164212A0/en
Priority to BR0308748-4A priority patent/BR0308748A/en
Priority to US10/508,014 priority patent/US20050215605A1/en
Priority to MXPA04009374A priority patent/MXPA04009374A/en
Priority to JP2003579816A priority patent/JP4602672B2/en
Priority to YU81604A priority patent/RS81604A/en
Priority to DE60335175T priority patent/DE60335175D1/en
Priority to KR10-2004-7015040A priority patent/KR20040095311A/en
Priority to AU2003240757A priority patent/AU2003240757B2/en
Priority to AT03730168T priority patent/ATE489951T1/en
Priority to EA200401270A priority patent/EA007328B1/en
Priority to UA20040907830A priority patent/UA78021C2/en
Publication of WO2003082278A1 publication Critical patent/WO2003082278A1/en
Priority to HRP20040759 priority patent/HRP20040759A2/en
Priority to NO20044262A priority patent/NO20044262L/en
Priority to HK05109463.4A priority patent/HK1075215A1/en
Priority to US12/140,682 priority patent/US8415480B2/en
Priority to AU2008207407A priority patent/AU2008207407A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic 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
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic 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
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/04—Drugs for genital or sexual disorders; Contraceptives for inducing labour or abortion; Uterotonics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/06—Antiabortive agents; Labour repressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/582—Recycling of unreacted starting or intermediate materials

Definitions

  • This present invention is related to thiazolidine carboxamide derivatives of formula (II) for the treatment and/or prophylaxis of preterm labor, premature birth, dysmenorrhea and for stopping labor prior to cesarean delivery.
  • the present invention is related to substituted thiazolidine carboxamide derivatives for the modulation, notably the inhibition of the activity or function ofthe prostaglandin receptors, particularly ofthe prostaglandin F? receptor.
  • the present invention is related to novel thiazolidine carboxamide derivatives of formulae (I) and (la).
  • oxytocin plays a major role in initiating labor in mammals, notably in humans.
  • oxytocin exerts said effect in a direct as well as an indirect way, by contracting the uterine myometrium and by enhancing the synthesis and release of contractile prostaglandins from the uterine endometrium/decidua.
  • These prostaglandins may furthermore play a role in the cervical ripening process.
  • the high circulating concentrations of progesterone induce uterine quiescence while the uterus acquires contractile ability.
  • plasma progesterone concentrations fall, oxytocin receptor expression in the uterus increases markedly, and uterine contractile activity increases.
  • the contractions rise to a crescendo, resulting in delivery as a result of two interacting positive feedback loop. The first is a local uterine loop: within the uterus itself, prostaglandins and other uterotonic factors are produced and released in response to uterine contractions.
  • the second loop involves the hypothalamus: in response to uterine contractions and vaginal and cervical distension, magnocellular oxytocin neurons in the hypothalamus increase their activity resulting in the release of oxytocin from their axon terminals in the posterior pituitary; the released oxytocin acts upon the uterus both to stimulate the further production of prostaglandins and to contribute further to the contractions of the uterus.
  • magnocellular oxytocin neurons in the hypothalamus increase their activity resulting in the release of oxytocin from their axon terminals in the posterior pituitary; the released oxytocin acts upon the uterus both to stimulate the further production of prostaglandins and to contribute further to the contractions of the uterus.
  • magnesium sulfate for the treatment of preterm labor, several approaches have been considered such as the use of magnesium sulfate, ethanol or therapeutic agents acting as ⁇ 2 adrenergic agonists or oxytocin antagonists:
  • Ethanol is effective in preventing premature labor, but it does not produce a corresponding reduction in the incidence of fetal respiratory distress. Also, ethanol is assumed to have a negative impact on the fetus.
  • the ⁇ 2 -adrenergic receptor generally causes an inhibitory action within the cells wherein it is expressed (muscles, heart, uterus etc).
  • ⁇ 2 -adrenergic agonists are used to activate said inhibitory action of the receptor.
  • ⁇ 2 -adrenergic agonists are sympathomimetics which - among others - inhibit uterine contractility.
  • Known ⁇ 2 - adrenergic agonists for the treatment of preterm labor are Ritodrine, Terbutaline and Albuterol.
  • Oxytocin antagonists Oxytocin (OT) is a peptide hormone causing the contraction of the uterus of mammals during labor.
  • Oxytocin (OT) receptors increase dramatically during the course of pregnancy.
  • the concentration of OT receptors has been shown to correlate with spontaneous uterine activity.
  • oxytocin may be a physiological initiator of labor in several mammalian species including humans.
  • oxytocin is believed to exert this effect in two different parts, either by directly contracting the uterine myometrium and by enhancing the synthesis and release of contractile prostaglandins from the uterine endometrium/decidua. Therefore, by blocking oxytocin, the direct (contractile) and indirect (enhanced prostaglandin synthesis) effects of oxytocin on the uterus may be achieved.
  • Prostaglandins PGs
  • PEF 2 ⁇ prostaglandin F 2 ⁇
  • PGs Prostaglandin F 2 ⁇
  • FP Prostaglandin F receptor
  • PGF 2 ⁇ Actions of PGF 2 ⁇ are mediated by the PGF receptor (FP), which is a heterotrimeric guanosine triphosphate - binding protein (G protein) - coupled rhodopsin type receptor specific to this PG (Science vol.277, p.681-83 (1998) by Yuhihiko Sugimoto et al.).
  • FP PGF receptor
  • G protein guanosine triphosphate - binding protein
  • rhodopsin type receptor specific to this PG Science vol.277, p.681-83 (1998) by Yuhihiko Sugimoto et al.
  • These prostaglandins belong to a group of eicosanoids that are produced by the enzymatic activity of cyclooxygenase. Together with the thromboxanes, prostaglandins constitute the prostanoid subgroup ofthe eicosanoids.
  • Prostaglandins (PGs) mediate various physiological processes such as fever
  • PGF 2 ⁇ is synthesized, to varying degrees, by almost every tissue in the body and is a stimulant of several different types of physiological functions including granulose lutein cell death, myometrial smooth muscle contraction, Leydig cell testosterone synthesis regulation, regulation of oviductal cilia beating, bronchoconstriction, and bone metabolism. They are synthesized in fetal and maternal membranes and act to ripen the cervix and contract the myometrium. PGF 2 ⁇ is a major prostaglandin for enhancing uterine contractility.
  • EPj Specific prostaglandin receptors
  • EP 2 and EP 4 receptors are expressed in the human myometrium.
  • Activation of EP 2 and EP 4 receptors results in smooth muscle relaxation whereas activation ofthe PGF2 « -selective receptor (FP receptor) results in contraction.
  • the prostaglandin F 2 ⁇ receptor acts via a G protein-coupled receptor, coupled to
  • p38 inhibitor 4-[5-(4-fluorophenyl)-4-(4-pyridyl)- imidazol-2-yl]phenol
  • p38 inhibitor 4-[5-(4-fluorophenyl)-4-(4-pyridyl)- imidazol-2-yl]phenol
  • a phtalide derivative as an active component
  • US-6,271 ,201 Board of Regents, the University of Texas System discloses a method for regulating placental cell production of thromboxane and PGF ⁇ comprising treating placenta cells with a pharmacologically effective amount of insulin-like growth factor I sufficient to inhibit thromboxane and prostaglandin F 2 ⁇ production without affecting prostacyclin or prostaglandin E 2 production. Summary ofthe invention
  • the present invention relates to the use of thiazolidine carboxamide derivatives of formula (II),
  • compositions for the treatment and/or prevention of preterm labor, premature birth, dysmenorrhea, and for stopping labor prior to cesarean delivery are inhibitors of prostaglandin receptors, particularly ofthe prostaglandin F2 receptor (FP).
  • the present invention relates to novel thiazolidine carboxamide derivatives of formula (I), wherein G' is an aryl, heteroaryl or cycloalkyl or a heterocycloalkyl moiety.
  • compounds ofthe present invention are modulators of the Prostaglandin receptor, in particular of the Prostaglandin F 2 ⁇ receptor (FP) function.
  • the Prostaglandin F 2 ⁇ receptor (FP) is bound by the compounds of the present invention, PGF 2 ⁇ is antagonized by being blocked from its receptor and thus being unable to exert its biological or pharmacological effects.
  • the compounds ofthe present invention are therefore useful in the treatment and prevention of preterm labor, premature birth and for stopping labor prior to cesarean delivery.
  • the compounds of the present invention are also useful in the treatment of dysmenorrhea which may be defined as a cyclic pain associated with menses during ovulatory cycles.
  • the pain is thought to result from uterine contractions and ischemia, probably mediated by the effect of prostaglandins produced in the secretory endometrium.
  • a FP antagonist is more efficacious for treating dysmenorrhea than current regimens.
  • compounds of the present invention are useful in the treatment and prevention of prostaglandin related disorders of mammals and especially humans. It is a purpose of this invention to provide a method of antagonizing the functions of prostaglandins, particularly prostaglandin F 2 ⁇ , in disease states in mammals. It is another purpose of this invention to develop a method of preventing or treating prostaglandin F 2 ⁇ related disorders by antagonizing the binding of said prostaglandin to its receptor.
  • the following paragraphs provide definitions ofthe various chemical moieties that make up the compounds according to the invention and are intended to apply uniformly throughout the specification and claims unless an otherwise expressly set out definition provides a broader definition.
  • Ci-C ⁇ -alkyl refers to monovalent alkyl groups having 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert- butyl, n-hexyl and the like.
  • Aryl refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl).
  • Preferred aryl include phenyl, naphthyl, phenantrenyl and the like.
  • Ci-C ⁇ -alkyl aryl refers to Ci-C ⁇ -alkyl groups having an aryl substituent, including benzyl, phenethyl and the like.
  • Heteroaryl refers to a monocyclic heteroaromatic, or a bicyclic or a tricyclic fused-ring heteroaromatic group.
  • Particular examples of heteroaromatic groups include optionally substituted pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1 ,2,3 -triazolyl, 1 ,2,4-triazolyl, 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadia- zolyl, 1,2,5-oxadiazolyl, l ,3,4-oxadiazolyl,l,3,4-triazinyl, 1 ,2,3-triazinyl, benzofuryl, [2,3- dihydrojbenzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl
  • Ci-C ⁇ -alkyl heteroaryl refers to C ⁇ -C 6 -alkyl groups having a heteroaryl substituent, including 2-furylmethyl, 2-thienylmethyl, 2-(l H-indol-3-yl)ethyl and the like.
  • C 2 -C6-alkenyl aryl refers to C 2 -C6-alkenyl groups having an aryl substituent, including 2- phenylvinyl and the like.
  • C 2 -C6-alkenyl heteroaryl refers to C2-C 6 -alkenyl groups having a heteroaryl substituent, including 2-(3-pyridinyl)vinyl and the like.
  • C 2 -C6-alkynyl refers to alkynyl groups preferably having from 2 to 6 carbon atoms and having at least 1 -2 sites of alkynyl unsaturation, preferred alkynyl groups include ethynyl (-C ⁇ CH), propargy 1 (-CH 2 C ⁇ CH), and the like.
  • C 2 -C 6 -alkynyl aryl refers to C 2 -C 6 -alkynyl groups having an aryl substituent, including phenylethynyl and the like.
  • C 2 -C6-alkynyl heteroaryl refers to C2-C 6 -aIkynyl groups having a heteroaryl substituent, including 2-thienylethynyl and the like.
  • Cs-Cg-cycloalkyl refers to a saturated carbocyclic group of from 3 to 8 carbon atoms having a single ring (e.g., cyclohexyl) or multiple condensed rings (e.g., norbornyl).
  • Preferred cycloalkyl include cyclopentyl, cyclohexyl, norbornyl and the like.
  • Heterocycloalkyl refers to a C ⁇ -Cg-cycloalkyl group according to the definition above, in which up to 3 carbon atoms are replaced by heteroatoms chosen from the group consisting of O, S, NR, R being defined as hydrogen or methyl.
  • Preferred heterocycloalkyl include pyrrolidine, piperidine, piperazine, 1-methylpiperazine, morpholine, and the like.
  • -C 6 -alkyl cycloalkyl refers to Ci-C ⁇ -alkyl groups having a cycloalkyl substituent, including cyclohexylmethyl, cyclopentylpropyl, and the like.
  • Ci-C ⁇ -alkyl heterocycloalkyl refers to Ci-C ⁇ -alkyl groups having a heterocycloalkyl substituent, including 2-(l -pyrrolidinyl)ethyl, 4-morpholinylmethyI, (l-methyl-4- piperidinyl)methyl and the like.
  • Carboxy refers to the group -C(0)OH.
  • Ci-Cs-alkyl carboxy refers to Ci-Cs-alkyl groups having an carboxy substituent, including 2-carboxyethyl and the like.
  • Acyl refers to the group -C(0)R where R includes "C ⁇ -C 6 -alkyl”, “aryl”, “heteroaryl”, “Ci-C ⁇ -alkyl aryl” or "C
  • C ⁇ -C 5 -alkyl acyl refers to Ci-Cs-alkyl groups having an acyl substituent, including 2- acetylethyl and the like.
  • Acyloxy refers to the group -OC(0)R where R includes “C,-C 6 -alkyl”, “aryl”, “heteroaryl”, “C,-C 6 -alkyl aryl” or “C,-C 6 -alkyl heteroaryl”.
  • C ⁇ -C 5 -alkyl acyloxy refers to C ⁇ -C 5 -alkyl groups having an acyloxy substituent, including 2-(acetyloxy)ethyl and the like.
  • Alkoxy refers to the group -O-R where R includes "Ci-C ⁇ -alkyl” or “aryl” or “heteroaryl” or "Ci-C ⁇ -alkyl aryl” or “Ci-C ⁇ -alkyl heteroaryl”.
  • Preferred alkoxy groups include by way of example, methoxy, ethoxy, phenoxy and the like.
  • Ci-Cs-alkyl alkoxy refers to Ci-Cs-alkyl groups having an alkoxy substituent, including 2-ethoxyethyl and the like.
  • Alkoxycarbonyl refers to the group -C(0)OR where R includes H, "C ⁇ -C 6 -alkyl” or “aryl” or “heteroaryl” or "C,-C 6 -alkyl aryl” or "C ⁇ -C 6 -alkyl heteroaryl”.
  • Ci-Cs-alkyl alkoxycarbonyl refers to Ci-Cs-alkyl groups having an alkoxycarbonyl substituent, including 2-(benzyloxycarbonyl)ethyl and the like.
  • Aminocarbonyl refers to the group -C(0)NRR' where each R, R' includes independently hydrogen or Cj-C ⁇ -alkyl or aryl or heteroaryl or "Ci-C ⁇ -alkyl aryl” or "C ⁇ -C 6 -alkyl heteroaryl".
  • Ci-Cs-alkyl aminocarbonyl refers to Ci-Cs-alkyl groups having an aminocarbonyl substituent, including 2-(dimethylaminocarbonyl)ethyl and the like.
  • Acylamino refers to the group -NRC(0)R' where each R, R' is independently hydrogen or "C-C ⁇ -alkyl” or “aryl” or “heteroaryl” or "C,-C 6 -alkyl aryl” or "C ⁇ -C 6 -alkyl heteroaryl”.
  • Ci-Cs-alkyl acylamino refers to Ci-Cs-alkyl groups having an acylamino substituent, including 2-(propionylamino)ethyl and the like.
  • “Ureido” refers to the group -NRC(0)NR'R" where each R, R ⁇ R" is independently hydrogen or "C,-C 6 -alkyl” or “aryl” or “heteroaryl” or “C ⁇ -C 6 -alkyl aryl” or “C,-C 6 -alkyl heteroaryl” "cycloalkyl” or “heterocycloalkyl”, and where R' and R", together with the nitrogen atom to which they are attached, can optionally form a 3-8-membered heterocycloalkyl ring.
  • Ci-Cs-alkyl ureido refers to Ci-Cs-alkyl groups having an ureido substituent, including 2- (N'-methylureido)ethyl and the like.
  • Amino refers to the group -NRR' where each R,R' is independently hydrogen or "C ⁇ -C 6 - alkyl” or “aryl” or “heteroaryl” or “C ⁇ -C 6 -alkyl aryl” or “C ⁇ -C 6 -alkyl heteroaryl", or "cycloalkyl", or “heterocycloalkyl”, and where R and R', together with the nitrogen atom to which they are attached, can optionally form a 3-8-membered heterocycloalkyl ring.
  • Ci-Cs-alkyl amino refers to Ci-Cs-alkyl groups having an amino substituent, including 2- (l -pyrrolidinyl)ethyl and the like.
  • Ammonium refers to a positively charged group -N + RR'R", where each R,R',R" is independently "C,-C 6 -alkyl” or “C,-C 6 -alkyl aryl” or “C,-C 6 -alkyl heteroaryl", or "cycloalkyl", or “heterocycloalkyl”, and where R and R', together with the nitrogen atom to which they are attached, can optionally form a 3-8-membered heterocycloalkyl ring.
  • Halogen refers to fluoro, chloro, bromo and iodo atoms.
  • “Sulfonyloxy” refers to a group -OSO2-R wherein R is selected from H, "Ci-C ⁇ -alkyl", “C ⁇ -C 6 -alkyl” substituted with halogens, e.g., an -OSO2-CF3 group, "aryl", “heteroaryl” , “Ci-C ⁇ -alkyl aryl” or “C ⁇ -C 6 -alkyl heteroaryl".
  • Ci-Cs-alkyl sulfonyloxy refers to Ci-Cs-alkyl groups having a sulfonyloxy substituent, including 2-(methylsulfonyloxy)ethyl and the like.
  • “Sulfonyl” refers to group “-SO2-R” wherein R is selected from H, “aryl”, “heteroaryl”, “C,-C 6 -alkyl”, “C
  • C ⁇ -C 5 -alkyl sulfonyl refers to Ci-Cs-alkyl groups having a sulfonyl substituent, including 2-(methylsulfonyl)ethyl and the like.
  • “Sulfinyl” refers to a group “-S(0)-R” wherein R is selected from H, “C,-C 6 -alkyl", “C,- C 6 -alkyl” substituted with halogens, e.g, an -SO-CF3 group, "aryl", “heteroaryl” , “C C 6 - alkyl aryl” or “C ⁇ -C 6 -alkyl heteroaryl”.
  • Ci-Cs-alkyl sulfinyl refers to Ci-Cs-alkyl groups having a sulfinyl substituent, including 2-(methylsulfinyl)ethyl and the like.
  • Sulfanyl refers to groups -S-R where R includes "C ⁇ -C 6 -alkyl” or “aryl” or “hetero-aryl” or "C ⁇ -C 6 -alkyl aryl” or “C]-C 6 -alkyl heteroaryl".
  • Preferred sulfanyl groups include methylsulfanyl, ethylsulfanyl, and the like.
  • Ci-Cs-alkyl sulfanyl refers to Ci-Cs-alkyl groups having a sulfanyl substituent, including 2-(ethylsulfanyl)ethyl and the like.
  • Sulfonylamino refers to a group -NRS0 2 -R' where each R, R' is independently hydrogen or "Ci-C ⁇ -alkyl” or “aryl” or “heteroaryl” or "C C 6 -alkyl aryl” or "C r C 6 -alkyl heteroaryl".
  • Ci-Cs-alkyl sulfonylamino refers to Ci-Cs-alkyl groups having a sulfonylamino substituent, including 2-(ethylsulfonylamino)ethyl and the like.
  • substitution could also comprise situations where neighbouring substituents have undergone ring closure, notably when vicinal functional substituents are involved, thus forming, e.g., lactams, lactons, cyclic anhydrides, but also acetals, thioacetals, aminals formed by ring closure for instance in an effort to obtain a protective group.
  • “Pharmaceutically acceptable salts or complexes” refers to salts or complexes ofthe below- identified compounds of formulae (I) and (II) that retain the desired biological activity.
  • examples of such salts include, but are not restricted to acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts fonned with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, and poly-galacturonic acid.
  • inorganic acids e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,
  • Said compounds can also be administered as pharmaceutically acceptable quaternary salts known by a person skilled in the art, which specifically include the quarternary ammonium salt of the formula -NR,R',R" + Z " , wherein R, R', R" is independently hydrogen, alkyl, or benzyl, C ⁇ -C 6 - alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C ⁇ -C 6 -alkyl aryl, d-C 6 -alkyl heteroaryl, cycloalkyl, heterocycloalkyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methyl sulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate,
  • “Pharmaceutically active derivative” refers to any compound that upon administration to the recipient, is capable of providing directly or indirectly, the activity disclosed herein.
  • Enantiomeric excess refers to the products that are obtained by an asymmetric syn- thesis, i.e. a synthesis involving non-racemic starting materials and/or reagents or a synthesis comprising at least one enantioselective step, whereby a surplus of one enantiomer in the order of at least about 52% ee is yielded.
  • Said formula also comprises its tautomers, its geometrical isomers, its optically active forms as enantiomers, diastereomers and its racemate forms, as well as pharmaceutically acceptable salts thereof.
  • Preferred pharmaceutically acceptable salts ofthe formula (I) are acid addition salts formed with pharmaceutically acceptable acids like hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulfonate, benzenesulfonate, and para- toluenesulfonate salts.
  • a first aspect of the present invention consists in the use of compounds of formula (II)
  • G is selected from the group consisting of substituted or unsubstituted Ci-C ⁇ -alkyl aryl, substituted or unsubstituted C ⁇ -C 6 -alkyl heteroaryl, substituted or unsubstituted C ⁇ -C 6 -alkyl cycloalkyl, substituted or unsubstituted C
  • R 1 is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Cs-Cs-cycloalkyl or -heterocyclo- alkyl, said (hetero)cycloalkyl or aryl or heteroaryl groups may be fused with (hetero)- cycloalkyl or aryl or heteroaryl groups.
  • R is H, carboxy, acyl, alkoxycarbonyl, aminocarbonyl, substituted or unsubstituted C 1 -C 5 - alkyl carboxy, substituted or unsubstituted Ci-Cs-alkyl acyl, substituted or unsubstituted Ci-Cs-alkyl alkoxycarbonyl, substituted or unsubstituted Ci-Cs-alkyl aminocarbonyl, substituted or unsubstituted Ci-Cs-alkyl acyloxy, substituted or unsubstituted Ci-Cs-alkyl acylamino, substituted or unsubstituted Ci-Cs-alkyl ureido, substituted or unsubstituted Ci- Cs-alkyl amino, substituted or unsubstituted Ci-Cs-alkyl alkoxy, substituted or unsubstituted Ci-Cs-alkyl sulfanyl, substituted or unsubstituted
  • R and G may form a C 3 -Cs-cycloalkyl ring.
  • R 4 is selected from the group consisting of substituted or unsubstituted C ⁇ -C6-alkyl, substituted or unsubstituted C 2 -C 6 -alkenyl, substituted or unsubstituted C 2 -C 6 -alkynyl.
  • n is an integer from 0 to 2.
  • G is an aryl group, e.g., a substituted or unsubstituted phenyl, like a biphenyl.
  • Compounds according to formula (II) are particularly useful for the treatment, including the acute management and the prophylaxis, of preterm labor.
  • the compounds according to formula (II) are suitable for the modulation, notably the inhibition ofthe activity of prostaglandins and particularly prostaglandin F20. It is therefore believed that the compounds of the present invention are also particularly useful for the treatment and/or prevention of disorders which are mediated by prostaglandin F2 ⁇ - Said treatment involves the modulation - notably the inhibition or the down regulation - ofthe prostaglandin function.
  • a further aspect ofthe invention consists in novel thiazolidine carboxamide derivatives of formula (I), wherein G' is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Cs-Cs-cycloalkyl or -heterocycloalkyl, said cycloalkyl or aryl or heteroaryl groups may be fused with cycloalkyl or aryl or heteroaryl groups.
  • More preferred compounds have the formula (la):
  • Formulae (I), (la) and (II) comprise also the geometrical isomers, the optically active forms, including enantiomers, diastereoisomers and its racemate forms, as well as pharmaceutically acceptable salts and pharmaceutically active derivatives thereof.
  • R 1 is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 3 -Cs-cycloalkyl or -heterocycloalkyl, said (hetero)cycloalkyl or aryl or heteroaryl groups may be fused with (heterocycloalkyl or aryl or heteroaryl groups.
  • R 1 is selected from the group consisting of an aryl or heteroaryl group optionally substituted with one or several substituents selected from the group consisting of aryl, heteroaryl, halogen, alkoxy, sulfanyl, straight or branched C ⁇ -C 6 -alkyl.
  • R is selected from the group consisting of H, carboxy, acyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted Ci-Cs-alkyl carboxy, substituted or unsubstituted Ci-Cs-alkyl acyl, substituted or unsubstituted Ci-Cs-alkyl alkoxycarbonyl, substituted or unsubstituted Ci-Cs-alkyl aminocarbonyl, substituted or unsubstituted Ci-Cs-alkyl acyloxy, substituted or unsubstituted Ci- Cs-alkyl acylamino, substituted or unsubstituted Ci-Cs-alkyl ureido, substituted or unsubstituted Cj-Cs-alkyl amino, substituted or unsubstituted Ci-Cs-alkyl alkoxy, substituted or unsubstituted Ci
  • R 2 is selected from the group consisting of carboxy, acyl, substituted or unsubstituted alkoxycarbonyl, aminocarbonyl, substituted or unsubstituted Ci-Cs-alkyl carboxy, substituted or unsubstituted Ci-Cs-alkyl acyl, substituted or unsubstituted Ci-Cs-alkyl alkoxycarbonyl, substituted or unsubstituted Ci-Cs-alkyl aminocarbonyl, substituted or unsubstituted Ci-Cs-alkyl acyloxy, substituted or unsubstituted Ci-Cs-alkyl acylamino, substituted or unsubstituted Ci-Cs-alkyl ureido, substituted or unsubstituted C ⁇ -C 5 -alkyl amino, substituted or unsubstituted Ci-Cs-alkyl alkoxy, substituted or unsubstituted Ci-Cs---alkyl
  • R may be a group Cj-C 3 -alkyl-A-R , wherein :
  • A is O or N-B-R 6 .
  • an amino acid residue e.g. alanine, phenylalanine, valine, leucine, isoleucine, proline, glycine, methionine, tryptophane, threonine, serine, etc.
  • R 5 , R 6 and R 7 are independently from each other selected from the group consisting of H, substituted or unsubstituted C ⁇ -C 6 -alkyl, substituted or unsubstituted C2-C6-alkenyl, substituted or unsubstituted C2-C 6 -alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 3 -Cs-cycloalkyl or heterocycloalkyl, substituted or unsubstituted C
  • R 5 and B-R 6 in particular if B is a bond
  • R 6 and R 7 together with the respective nitrogen atoms to which they are attached, can optionally form substituted or unsubstituted heterocycloalkyl rings.
  • R is C
  • R " is a substituted or unsubstituted phenyl, pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl.
  • Said phenyl, pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl moieties may optionally be substituted by at least one substituent selected from the group consisting of H, hydroxy, halogen, carboxy, acyl, aminocarbonyl, acylamino, Ci-Cs-alkyl amino, Ci-Cs-alkyl alkoxy, Ci-Cs-alkyl carboxy, Ci-Cs-alkyl acyl, Ci-Cs-alkyl aminocarbonyl, Ci-Cs-alkyl acylamino, Ci-Cs-alkyl ureido, Ci-Cs-alkyl sulfanyl, C
  • substituents are methoxy, carboxy-methoxy, hydroxy- methyl, carboxymethyl, sulfonyloxymethyl, dimethylaminomethyl, 4-morpholinylmethyl, 1-piperidinylmethyl, 1 -pyrrolidinylmethyl, (4-methyl-l-piperazinyl)-methyl, ethoxy, 2- methoxyethoxy, 2-hydroxyethoxy, 2-carboxyethoxy, 2-sulfonyloxy-ethoxy, 2-(dimethyl- amino)ethoxy, 2-(4-morpholinyl)ethoxy, 2-(l-pyrrolidinyl)ethoxy, 2-(l -piperidinyI)ethoxy, 2-(4-methyl-l -piperazinyl)ethoxy, 2-hydroxyethyl, 2-methoxyethyl, 2-carboxyethyl, 2- sulfonyloxyethyl, 2-(dimethylamino)ethyl, 2-(4-
  • R J is selected from the group consisting of substituted or unsubstituted C
  • n is an integer from 0 to 2.
  • R 4 is selected from the group consisting of substituted or unsubstituted C ⁇ -C 6 -alkyl, substituted or unsubstituted C 2 -C6-alkenyl, substituted or unsubstituted C 2 -C6-alkynyl.
  • R 1 is a phenyl substituted with a group selected from straight or branched C i-Cs-alkyl or aryl
  • R is selected from the group consisting of d-Cs-alkyl-A-R 5 wherein A is O and R 5 is H, or A is N-B-R 6 with B being a bond and R 5 and R 6 being each independently selected from the group consisting of Ci-Cs-alkyl, C 1 -C3- alkyl aryl, C i-Cs-alkyl heteroaryl, C ⁇ -C3-alkyl-hydroxy.
  • R is a biphenyl or a tert-buty ⁇ phenyl group
  • R 2 is d-Cs-alkyl-A-R 5 , wherein A is O and R 5 is H, or A is N-B-R 6
  • R 5 and R 6 are each independently from each other C ⁇ -C3-alkyl, C ⁇ -C3-alkyl aryl, C i-Cs-alkyl heteroaryl, or Ci- Cs-alkyl hydroxy
  • B is a bond
  • R J is fluorine
  • m is either 0, 1 , or 2
  • n is 0.
  • R 1 is a biphenyl or a tert-b y ⁇ phenyl group
  • R is pyrid-2-yl, carrying one or several substituents selected from the group consisting of H, OH, alkoxy, Ci-Cs-alkyl amino, Ci-Cs-alkyl hydroxy, Ci-Cs-alkyl carboxy, Ci- -alkyl sulfonyloxy
  • R J is fluorine
  • m is either 0, 1 , or 2
  • n is 0.
  • Compounds ofthe present invention are in particular those ofthe group consisting of:
  • Still a further aspect ofthe present invention is the use of the novel compounds of formula (I) as medicament.
  • Still a further object of the present invention is a process for preparing l,3-thiazolidine-2- carboxamide derivatives according to formula (I).
  • the l ,3-thiazolidine-2-carboxamide derivatives exemplified in this invention may be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimisation procedures.
  • the l ,3-thiazolidine-2-carboxamide derivatives ofthe present invention may be obtained by several synthetic approaches, using both solution-phase and solid-phase chemistry protocols.
  • l ,3-thiazolidine-2-carboxamide derivatives according to the general formula (I), whereby R 1 , R 2 , R 4 , G' and n are as above defined, may be prepared from the corresponding carboxylic acid compounds (III), amines (IV), and sulfonyl chlorides (VI), using standard solution- phase chemistry protocols well known to the practitioner skilled in the art.
  • Intermediates of formula V, wherein PG is a suitable N-protecting group (such as Boc, Fmoc, Cbz, and others) can be obtained from the corresponding carboxylic acid compounds (III) and amines (IV) using standard amide coupling conditions well known to the practitioner skilled in the art. Removal of the 7V- protecting group (e.g., in cases where PG is Boc, using dilute TFA in DCM, or HCl in
  • l,3-thiazolidine-2-carboxylic acid derivatives may be reacted with sulfonyl chlorides (VI), using well known standard solution-phase chemistry protocols, such as e.g. the Schotten-Baumann conditions, affording intermediates of general formula (VIII).
  • the latter can subsequently be reacted with amines (IV) using standard peptide coupling conditions well known to the practitioner skilled in the art, to yield products of general formula (I).
  • l ,3-thiazolidine-2-carboxylic acid ester derivatives (IX) may be reacted with sulfonyl chlorides (VI), followed by saponification of the ester moiety using standard reagents like NaOH, HCl, Boron tribromide, KOSi(CH 3 ) 3 , or others, to allow isolation ofthe corresponding carboxylic acid intermediates (VIII).
  • the latter are then reacted with amines (IV) using standard amide coupling conditions well known to the practitioner skilled in the art to yield products of general formula (I).
  • sulfonic acids (X) and precursors (XI) are either obtained from commercial sources or synthesized from commercial starting materials, using standard methods well known to those skilled in the art, of which some are exemplified in Scheme 5 and described hereinafter in the Examples.
  • bromobenzenesulfonates (XII) may be reacted with boronic acids (XIII) in presence of a palladium catalyst to yield the sulfonic acids (X).
  • bromobenzenesulfonates (XII) may be converted into the corresponding sulfonic esters (XIV) by treatment with, e.g., thionyl chloride followed by 2-methyl-l - propanol.
  • Sulfonic esters (XIV) can then be transformed in to the corresponding boronic acid derivatives (XV) using, e.g., triisopropylborate in the presence of n-butyllithium.
  • Palladium(O) catalysed cross-coupling between the boronic acid derivatives (XV) and suitable substituted or unsubstituted aryl or heteroaryl halides affords the desired sulfonic acids (X).
  • the amine compounds (IV) may be obtained using, e.g., the process shown in Scheme 6.
  • substituted or unsubstituted aromatic or heteroaromatic aldehydes (XVI) are reacted with commercially available aminoalcohols (XVII) to form the corresponding imines (XV111), followed by addition of a carbanion species (XIX), such as, e.g., a Grignard reagent, organocuprate or organolithium reagents, or others, using standard conditions well known to the person skilled in the art.
  • a carbanion species such as, e.g., a Grignard reagent, organocuprate or organolithium reagents, or others, using standard conditions well known to the person skilled in the art.
  • the resulting secondary amines (XX) can subsequently be converted into the corresponding primary amine analogues (IV) by oxidative cleavage using, e.g., periodic acid, as described hereinafter in the Examples.
  • This process also allows for the obtention of optically pure amines (IV*), by means of using optically active aminoalcohols (XVII*), as described hereinafter in Scheme z.
  • XVI or XVI* substituted or unsubstituted aryl and heteroaryl aldehydes
  • the amine compounds (IV) may be obtained using, e.g., the process shown in Scheme 9.
  • substituted or unsubstituted aromatic (XVII*) are reacted with acyl chlorides (XVIII*) to form the corresponding ketones (XIX*), or by reaction of substituted or unsubstituted lithiated aromatic (XXXXI*) with nitriles derivatives (XXXXII*).
  • the ketones (XIX*) were then treated with hydroxylamine to give the corresponding oxime (XXXXIIF).
  • Subsequent reduction of the oxime (XXXXIir) with an appropriated reductive agent using standard conditions well known to the person skilled in the art, allow to access to the amine compounds (IV) as described hereinafter in the Examples.
  • these functional group interconversions can be effected on the level of either the free amines (IV, IV), or the suitably protected amines (XXIV, XXIV), or the l ,3-thiazolidine-2-carboxamide compounds (V, V) or (I, F).
  • the choice of the best synthetic strategy will be governed by the nature of the functional groups to be interconverted, and the compatibility of the required reaction conditions with other functional groups present in the corresponding compounds, as will be well appreciated by the person skilled in the art.
  • less complex mixtures of stereoisomers up to pure stereoisomers can be obtained by using the corresponding optically pure starting materials (HI*), (IV*), (VII*), and/or (IX*) for the syntheses outlined in the above Schemes, in particular Schemes 1-3.
  • Optically pure amines (IV*) are either obtained from commercial sources or made by current methods known to the person skilled in the art, including stereoselective chemical synthesis, chemical resolution, enzymatic resolution, or combinations thereof, as exemplified in Scheme 12 and in the Examples hereinafter.
  • optically pure amines (IV*) can be obtained, e.g., by adapting the process outlined in Scheme 6 above, by means of using a chiral auxiliary (XVII*), such as, e.g., valinol or others, which are obtained in optically pure form either from commercial sources or by standard methods described in the literature (Scheme 7-9, Example A).
  • a chiral auxiliary (XVII*) such as, e.g., valinol or others, which are obtained in optically pure form either from commercial sources or by standard methods described in the literature (Scheme 7-9, Example A).
  • chiral amines (IV*) may be obtained by enzymatic resolution of appropriate racemic precursors (IV), and subsequently transformed into other chiral amines (IV*) by standard functional group interconversion methods, such as those outlined in Scheme 1 1 above.
  • Example A stereoselective synthesis with chiral auxiliary
  • Example B enzymatic resolution of racemic starting materials
  • Enzyme e.g. Reduction, (e.g. lipase) (see Scheme 8)
  • the carboxylic acid intermediates (VIII) may be reacted with amines (IV) to lead to the corresponding carboxylic acid intermediate (Ta).
  • the primary amide compound (Tb) was isolated after formation of the anydride mixte ofthe carboxylic acid compound (la) and treatment with an excess of ammonia. Dehydratation of the primary amide (lb) with cyanuric chloride allow to accesse to the nitrile derivative (lc), which was subsequently treated with hydroxylamine to give the amidoxime (Id).
  • amidoxime intermediate (Id) was then reacted with an appropriated carboxylic acid using standard amide coupling conditions and heated up to allow cylisation and formation ofthe final compound oxadiazole using conditions well known to the practitioner skilled in the art to yield products of general formula (I).
  • l,3-thiazolidine-2-carboxamide derivatives of general formula (I) by solution-phase methods.
  • l,3-thiazolidine-2-carboxamide derivatives of formula (I) wherein the substituents R , R " , R , G' and n are as above defined, are prepared by solid-phase protocols, such as, e.g., that outlined in Schemes 1 -12 and described hereinafter in the Examples. Therein, the filled circles symbolize the resin beads to which the corresponding compounds are linked during the solid phase synthesis.
  • N-protected 1,3- thiazolidine-2-carboxylic acids (III) are reacted, e.g., with Kaiser oxime resin using, e.g., standard carbodiimide-mediated coupling conditions well known to the practitioner skilled in the art, followed by removal of the protecting group.
  • the resulting intermediates are treated with sulfonyl chlorides (VI) in the presence of a base, affording resin-bound intermediates of general formula (XXXIX).
  • the linkage to the resin is cleaved by prolonged treatment with amines (IV) and, in certain cases, low percentages of a weak acid, such as HO Ac.
  • compositions of this invention can be isolated in association with solvent molecules by crystallization from evaporation of an appropriate solvent.
  • the pharmaceutically acceptable acid addition salts ofthe compounds of formula II which contain a basic center, may be prepared in a conventional manner.
  • a solution ofthe free base may be treated with a suitable acid, either neat or in a suitable solution, and the resulting salt isolated either by filtration or by evaporation under vacuum ofthe reaction solvent.
  • Pharmaceutically acceptable base addition salts may be obtained in an analogous manner by treating a solution of compound of formula I with a suitable base. Both types of salts may be formed or intercon verted using ion-exchange resin techniques.
  • a final aspect ofthe present invention are intermediate compounds of the formula (Va)- wherein G' is a phenyl - as used in the method illustrated in Scheme 1 , in particular for preparing compounds of formula (la).
  • PG is H
  • R 2 , R 3 , R 4 , m and n are as defined above, with the proviso, though, that R 2 may not be a hydrogen.
  • R 1 is a 1,1 ' -biphenyl or a tert-bu y ⁇ phenyl moiety and R 4 and n are as above defined.
  • thiazolidine carboxamide derivatives ofthe present invention are typically administered in the form of a pharmaceutical composition.
  • pharmaceutical compositions comprising a compound of formula (II) and a pharmaceutically acceptable carrier, diluent or excipient therefore are also within the scope ofthe present invention.
  • a person skilled in the art is aware of a whole variety of such carrier, diluent or excipient compounds suitable to formulate a pharmaceutical composition.
  • compositions and unit dosages thereof may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, or in the form of sterile injectable solutions for parenteral (including subcutaneous use).
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount ofthe active ingredient commensurate with the intended daily dosage range to be employed.
  • compositions containing thiazolidine carboxamide derivatives of this invention can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • the compounds of this invention are administered in a pharmaceutically effective amount.
  • the amount of the compound actually administered will typically be determined by a physician, in the light ofthe relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response ofthe individual patient, the severity of the patient's symptoms, and the like.
  • compositions ofthe present invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
  • the compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, premeasured ampoules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • the thiazolidine carboxamide derivative is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40%) by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
  • Solid forms may include, for example, any ofthe following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatine; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatine
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art.
  • the thiazolidine carboxamide derivatives of formula (I) in such compositions is typically a minor component, frequently ranging between 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
  • the compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems.
  • sustained release materials can also be found in the inco ⁇ orated materials in Remington 's Pharmaceutical Sciences.
  • the imine (XVIII*) resulting from the precedent step e.g. (27?)-3-methyl-2- ⁇ [(£')-2- pyridinylmethylidene]amino ⁇ -l -butanol (100 mmol) was dissolved in dry DCM (100 ml).
  • TEA (15.3 ml, 110 mmol, 1.1 eq)
  • chlorotrimethylsilane (13.9 ml, 110 mmol, l.leq) was added to the stirred solution.
  • the reaction was followed by LC/MS. After 2h30, the reaction was complete.
  • silylated imine from the previous step e.g. (2R)-3-methyl-N-[(-£ ' )-2- pyridinylmethylidene]-l-[(trimethylsilyl)oxy]-2-butanamine was dissolved in dry THF (500 ml) and the solution was cooled down to -78° C.
  • a 1 M solution of phenylmagnesiumbromide in THF 200 ml, 200 mmol, 2eq ) was added dropwise while the mixture was stirred by a magnetic bar. The mixture was further stirred 2 hours at -78° C. The temperature was then slowly increased up to room temperature overnight.
  • reaction mixture was quenched with aqueous NaHCOs and analysed by LC-MS to detect the O-silylated products. After one night, the mixture was quenched with HCl IM (250 ml) and the mixture was stirred at room temperature until the desilylation was complete (after lh, LC/MS analysis). The aqueous phase was further acidified with the addition of 5M HCl solution (20 ml).
  • Steps a) to d) described in method A were applied to the aldehyde (XVI*) from the previous step, e.g., 5-[2-(dimethylamino) ethoxy] pyridine-2-carboxaldehyde, affording the desired amine (IV, IV*), e.g., [2-( ⁇ 6-[(R)-amino(phenyl)methyl]pyridin-3- yl ⁇ oxy)ethyl]dimethylamine (165 mg, 96% yield). This crude primary amine was used without further purification.
  • Method A a) Protocol for the formation ofthe ketone intermediates (XIX*); e.g., (6-chloropyridin-3- yl)(phenyl)methanone.
  • a carboxylic acid e.g., 6-Chloronicotinic acid (3.151 g, 20 mmol) was dissolved in dry DCM. The mixture was cooled down to 0°C. Oxalyl chloride (2.58 mL, 30 mmol) followed by DMF (77 ⁇ L) were added. The mixture was stirred at 0°C for lh30, then at RT overnight. The solvents were evaporated. The crude product was dissolved in toluene and the solvents were evaporated again to give the corresponding acid chloride (XVIII*), e.g., 6-chloronicotinoyl chloride (2.886 g, 82% yield).
  • XVIII* e.g., 6-chloronicotinoyl chloride
  • Protocol for the formation of the oxime intermediates (XXXXIII*); e.g., (6- chloropyridin-3-yl)(phenyl)methanone oxime.
  • ethyl acetate 40 mL
  • the oxime obtained from the precedent step (XIX*), e.g., (6-chloropyridin-3- yl)(phenyl)methanone oxime (368 mg, 1.58 mmol) was dissolved in glacial acetic acid (20 mL).
  • Metallic Zn (1.034 g, 15.8 mmol) was added in portions at RT.
  • the reaction was followed by LC-MS. After a complete reduction ofthe oxime functionality, the reaction mixture was filtered and the solvents were evaporated. The crude residue was dissolved in DCM and was washed with three portions of NaHC ⁇ 3 sat. It was then dried over MgS0 4 , filtrated and evaporated.
  • intermediates (XIX*); e.g., (6-chloropyridin-3- yl)(phenyl)methanone (217 mg, 1 mmol) was added together with dry THF (1.5mL) and 2M solution of dimethylamine in THF (3 mL, 6 eq). This mixture was heated 120 min under microwave at 180°C. As the reaction was complete, water was added. The aqueous solution was basified with NaOH 5M to pH 8. It was then extracted with three portions of ethyl acetate.
  • Protocol for the reduction of boc group into tertiary amine e.g., 1-(1- methylpiperidin-4-yl)-l -pheny lmethanamine.
  • Method C Preparation of amines of general formula (IV*VIV* by enzymatic resolution ;e.g. (SV3- amino-3-(2,4-difluorophenyP-l -propanol and (RV3-amino-3-(2.4-difluorophenyl -l- propanol
  • the amino acid (XXV), e.g., 3-(4-fluorophenyl)- ⁇ -alanine (1 eq.) was dissolved in dry THF (30 vol.) and BH .DMS (2.5eq) was added. The mixtures were then refluxed between 2h00 and 24h00 until total disappearance of the starting material by LC-MS analysis. The reaction was then quenched by adding MeOH slowly and the mixture was stirred for lh at room temperature. The solvents were then removed by evaporation and 15 ml of aq.KOH solution (20%) was added. The compounds were then extracted with DCM and dried with Na 2 S0 , filtered and the DCM removed. The yields of desired compounds (XXVI), e.g., 3- (4-fluorophenyl)- ⁇ -aIanine, varied between 70 and 90%.
  • Methyl acrylate (3.1g, l eq, 36mmol) was dissolved in CHCI 3 (50ml) and methyl amine (1.68g, 1.5eq, 56mmol) was added in one portion. The reaction mixture was stirred and heated to 40°C for 12h. The solvents evaporated at the pump to give a yellowish oil, methyl 3-(methylamino)propanoate (3.6g, 85.3% yield).
  • 4-bromobenzenesulfonyl chloride 850g, 0.19mol was suspended in 2-propanol (45ml, 3eq) and the slurry was cooled to less then 10°C. Pyridine (32ml, 2eq) was added in portions while maintaining the reaction temperature below 10 C. After reaction completion (ca. 3 hours), 11ml of glacial acetic acid followed by 250ml of methyl tert-butyl ether (MTBE) were added. The layers were separated and the rich organic layer was successively washed with 125ml of IN aqueous hydrochloric acid and 150ml of saturated sodium bicarbonate solutions.
  • 2-propanol 45ml, 3eq
  • Pyridine 32ml, 2eq
  • MTBE methyl tert-butyl ether
  • the rich MTBE solution was solvent exchanged into hexane (i.e., the addition of hexane with concurrent distillation of MTBE) to induce crystallisation.
  • the crystal slurry was filtered, washed and dried in vacuo at no more than 25°C, to give 48g (87% yield) of isobutyl 4-bromobenzenesulfonate.
  • the THF-Hexane-MTBE solution containing 23g (93.3mmol) of 4-(isobutoxysulfonyl) phenylboronic acid was concentrated to a concentration of ca. 7ml/g.
  • a portion of this solution containing ca. 4.7g (19mmol, 0.26eq) was added to a solution of 15.4g (75mmol) of 3-iodopyridine dissolved in 100ml of degassed tetrahydrofuran.
  • tris(dibenzylidene acetone) dipalladium (0) (0.5g, 0.6mol%) and degassed aqueous sodium carbonate solution 300ml, 3eq
  • the reaction mixture was stirred at -25°C for 30min after which time an amine (IV)/(IV*), e.g., (3-S -3-amino-3-phenyl-l -propanol (0.778g, 5.14mmol) was added drop-wise over a period of lOmin.
  • the reaction mixture was allowed to gradually warm to room temperature and stirred overnight.
  • the solvent was removed and the residue re-dissolved in ethyl acetate (150ml).
  • the organic layer was washed subsequently with a saturated solution of ammonium chloride (100ml), saturated bicarbonate (100ml) and brine (100ml).
  • the antipodal intermediate, tert-bx ⁇ Xy ⁇ 2-( ⁇ [(l ⁇ S)-3-hydroxy-l -pheny 1- propyl]amino ⁇ carbonyl)- l ,3-thiazolidine-3-carboxylate, as well as the racemic intermediate, rt-butyl 2-( ⁇ [3-hydroxy-l-phenylpropyl]amino ⁇ carbonyl)-l ,3-thiazolidine-3- carboxylate were made according to the same protocol, starting from commercial (37?)-3- amino-3-phenylpropan-l-ol or 3-amino-3-phenylpropan-l-ol, respectively.
  • VI sulfonyl chloride
  • reaction mixture was diluted with DCM (50ml) and washed with a IM HCl solution (2x50ml) and with brine (50ml) before drying over magnesium sulfate, filtering and removal of solvent in vacuo.
  • the desired product of general structure (VIII) e.g., 3-([l,l'-biphenyl]-4-ylsulfonyl)-l,3-thiazolidine-2-carboxylic acid, was isolated as a white powder (1.8g, 94%).
  • Phthalamide (395mg, 1.5eq, 2.69mmol), diethylazodicarboxylate (470mg, 1.5eq, 2.69mmol) and polymer bound triphenyl phosphine (l .Og, 1.5eq, 2.70mmol) were then added and the reaction mixture was shaken for 12 hours at RT.
  • the triphenyl phosphine resin was filtered off and the THF solution evaporated in vacuo. The residue was taken up in DCM and washed twice with a saturated sodium carbonate solution and then water.
  • Example 1 General protocols for the solution- phase synthesis of l ,3-thiazolidine-2- carboxamide derivatives of general formula (I); e.g., 3-([ l , r-biphenyl]-4-y Isulfony D-N- [( 1 -S r )-3-hydroxy- 1 -phenylpropyl]- l ,3-thiazolidine-2-carboxamide; (2 r )-3-([l .l '-biphenyl]- 4-y Isulfony ⁇ )-N-[( 1 f )-3-hydroxy- 1 -pheny Ipropyll- 1 ,3-thiazolidine-2-carboxamide: (27?)-3- r ⁇ ,l '-biphenyl]-4-v Isulfony0-N-[(1 y)-3-hydroxy- 1 -phenylpropyl]- 1 ,3-thiazolidine-2- carboxamide.
  • NMM N-methyl mo ⁇ holine
  • VIII general formula (Intermediate 8, 4.50g, leq, 12.86mmol), e.g., 3-([l,l '- biphenyl]-4-ylsulfonyl)-l ,3-thiazolidine-2-carboxylic acid, in dry THF (100ml) and the reaction mixture was cooled down to -25°C. To the reaction mixture was then added drop wise, over a period of 5 minutes, isobutyl chloroformate (1.84g, 1.05eq, 13.50mmol) in solution in dry THF (20ml).
  • Method A A solution was made containing a compound of general structure (V) (Intermediate 6, 0.788 g, 2.15 mmol), e.g., tert-butyl 2-( ⁇ [(l_ )-3-hydroxy-l-phenylpropyl]amino ⁇ carbonyl)- 1 , 3 -thiazolidine-3 -carboxy late, in anhydrous DCM (50 ml).
  • V general structure
  • the desired product e.g., N-[(l»S)-3-hydroxy-l-phenylpropyl]- l ,3-thiazolidine-2-carboxamide hydrochloride, was isolated as a white solid and used for the next step without further purification and characterization.
  • the last 50 mL of 5M ⁇ aOH solution were added at -10°C due to formation if ice in the flask..
  • the slurry was extracted with DCM (5x 500mL) and dried over MgS04 and evaporated to almost dryness.
  • the desired product e.g. , (2S)- ⁇ -[(R)-phenyl(pyridin-2-yl)methyl]- 1 ,3-thiazolidine-2-carboxamide hydrochloride, was isolated and used for the next step without further purification and shows no trace of racemisation.
  • Aminomethyl polystyrene resin 250mg was added to the reaction mixture and stirred for one hour before filtering at the pump. The solution was washed with citric acid (aq) (2 x 50ml), then dried over MgS0 4 , and evaporated in vacuo.
  • Method B To a solution of a compound of general structure (X) (commercial or Intermediate 4, 504mg, l eq, 2.1 mmol), e.g., [l ,l'-biphenyl]-4-sulfonic acid, in dry THF (20ml), at 0°C, was drop wise added thionyl chloride (580mg, 2eq, 4.3mmol) in dry THF solution (10ml). The reaction mixture was stirred at room temperature over a 2h period.
  • thionyl chloride 580mg, 2eq, 4.3mmol
  • Aminomethyl polystyrene resin 25 Omg was added to the reaction mixture and stirred for one hour before filtering at the pump. The solution was washed with citric acid (aq) (2 x 50ml) and then dried over MgS0 4 , and evaporated in vacuo.
  • Example 2 3-([ 1 , 1 '-biphenyll-4-ylsulfonvn-N- ( lR)-2-hvdroxy- 1 -phenylethyll- 1.3- thiazolidine-2-carboxamide.
  • Example 3 3-([ 1 , 1 '-biphenyl]-4-ylsulfonyl)-N-[(7?)-phenyl(2-pyridinyl)methyl]- 1 ,3- thiazolidine-2-carboxamide.
  • Example 4 3-([l .1 '-bipheny ⁇ -4-ylsulfonvD-N-[ 1 -(4-fluorophenyl)-3-hydro ⁇ ypropyll- 1 ,3- thiazolidine-2-carboxamide.
  • 3- ([l ,l '-biphenyl]-4-y Isulfony I)- l ,3-thiazolidine-2-carboxy lie acid (Intermediate 8) and 3- amino-3-(4-fluorophenyl)-l -propanol (Intermediate 2) the title compound was obtained in 92% purity by HPLC.
  • Example 5 3-([ 1 , 1 '-biphenyl] -4- ylsulfonyU-N- [ 1 -(3-furyl)-3-hydroxypropyl]- 1 ,3- thiazolidine-2-carboxamide.
  • Example 6 3-(ri, r-biphenyl]-4-ylsulfonylVN-ri -(2-chloropheny ⁇ -3-hydroxypropyl]- 1.3- thiazolidine-2-carboxamide.
  • Example 7 3-([ 1 , 1 '-biphenyl] -4-ylsulfonyl -N-[ 1 -(3-chlorophenyl)-3-hydroxypiOpyl]- 1 ,3- thiazolidine-2-carboxamide.
  • Example 2 Following the general strategies and protocols outlined in Example 1, starting from 3- ([l,r-biphenyl]-4-ylsulfonyl)-l,3-thiazolidine-2-carboxylic acid (Inte ⁇ nediate 8) and 3- amino-3-(2-chlorophenyl)-l -propanol (Intermediate 2), the title compound was obtained in 99% purity by HPLC.
  • Example 8 N-ri- ⁇ .3-benzodioxol-5-ylV3-hvdroxypropyl]-3-([l .r-biphenyl]-4- ylsulfonyO- 1 ,3-thiazolidine-2-carboxamide.
  • Example 2 Following the general strategies and protocols outlined in Example 1 , starting from 3- ([l,l '-biphenyl]-4-y Isulfony I)- l ,3-thiazolidine-2-carboxylic acid (Intermediate 8) and 3- amino-3-(l ,3-benzodioxol-5-yl)-l-propanol (Intermediate 2), the title compound was obtained in 92% purity by HPLC.
  • Example 9 2,S -3-[(4-fert-butylphenynsulfonyl1-N- (l t y)-3-hydroxy-l-phenylpropyl]-1.3- thiazolidine-2 -carboxamide.
  • Example 10 (25 f )-N-[(1 f )-3-hydroxy-l-phenylpropyl]-3-[(4-fert-pentylphenyl)sulfonyl]- 1 ,3-thiazolidine-2-carboxamide.
  • Example 11 3-([l,r-biphenyl]-4-ylsulfonyl)-N-[l-(2-fluorophenyl)-3-hydroxypropyl]-l,3- thiazolidine-2-carboxamide.
  • the title compound was obtained in 96% purity by HPLC.
  • Example 12 3-([l , 1 '-biphenyl] -4-y Isulfony l)-N-[ 1 -(2-methylphenyl)-3-hydroxypropyl]- 1 ,3-thiazolidine-2-carboxamide.
  • Example 14 3-([l,r-biphenyl]-4-ylsulfonyf)-N-[l -(2,6-difluorophenyl)-3-hydroxypropyl]- 1 ,3-thiazolidine-2-carboxamide.
  • Example 15 3-([l , 1 '-biphenyl]-4-ylsulfonyO-N-[l -(2,4-dimethylpheny0-3-hydroxypropyl]- 1 ,3-thiazolidine-2-carboxamide.
  • Example 16 General protocols for the solution-phase synthesis of l ,3-thiazolidine-2- carboxamide derivatives of general formula (I) from intermediates of general formula (XXVIII) (Intermediates 8)
  • the mesylate derivative of general formula (XX VIII) (Intermediate 8, leq.) was dissolved in dry THF (e.g., dilution 760mg in 76ml of THF).
  • Sodium iodide (10 eq.), anhydrous potassium carbonate (2eq.) and the amine of general structure HNR 5 R 6 (3.5eq.) were added and the reaction mixtures were shaken at room temperature for 6 days. Potassium carbonate and sodium iodide were filtered and the THF evaporated.
  • the residue was dissolved in DCM and Ameba (aminomethylbenzylaldehyde) resin (2 eq.) was added to the flask. The reaction was shaken at room temperature over night.
  • the resin was filtered and the solvent removed.
  • the compounds were analyzed by LC-MS. When the purity was ⁇ 60%, the compound was further purified using amberlyst 15 resin in MeOH.
  • the reaction mixture was shaken at room temperature for 2 days.
  • the resin was filtered and washed with methanol.
  • the final product of general structure (I) was then released using concentrated HCl/MeOH (1/1 ) over night.
  • Example 17 (2S)-3-( ⁇ 1.1 '-bipheny l]-4-v Isulfony ⁇ )-N- U 1 -SV3-[(2-fury lmethy l ⁇ methy IV amino]-! -phenylpropyl ⁇ - l,3-thiazolidine-2-carboxamide.
  • Example 18 (2 t S f )-3-(ri.l , -biphenyl]-4-ylsulfonyl)-N-r(l-y)-3-(diethylamino)-l -phenylpropyl]-!, 3-thiazolidine-2-carboxamide.
  • Example 19 (2-y -N-((l-S , )-3-rbenzyl(methvnaminol-l-phenylpropyl ⁇ -3-(ri.l'-biphenyl]-4- ylsulfonvD- 1 ,3-thiazolidine-2-carboxamide.
  • Example 20 (2S)-3-( ⁇ ,l'-biphenyl]-4-ylsulfonyl)-N-(( 1- ⁇ -3--! methyl[2-(2-pyridinyl)ethyl]- aminol - 1 -phenylpropyl)- 1 ,3 -thiazolidine-2-carboxamide.
  • Example 21 (2S)-3-( ⁇ .1 '-biphenyll-4-ylsulfonyn-N- ⁇ ( 1 -SV3-[(2-hydroxyethvn(methviy amino]-l-phenylpropyl ⁇ -1 ,3-thiazolidine-2-carboxamide.
  • Example 22 methyl [[(3S)-3-( ⁇ [(2-S f )-3-([l .1 '-biphenyl]-4-ylsulfonyn-l .3-thiazolidin-2- yl] carbony 1 ⁇ amino)-3 -pheny lpropy 1] (methy Damino] acetate .
  • Example 23 3 -([1,1 '-biphenyl] -4-ylsulfonyl)-N-[ 1 -phenyl-3 -( 1 -pyrrolidinyDpropyl]- 1 ,3- thiazolidine-2-carboxamide.
  • Example 24 3-([ 1 , 1 '-biphenyl] -4- ylsulfonylVN- [3 -(dimethylaminoV 1 -phenylpropyl] -1,3- thiazolidine-2-carboxamide.
  • the title compound was obtained in 99.6%o purity by HPLC.
  • Example 25 -V-[3-(l-azepanyl)-l-phenylpropyl]-3-([l,r-biphenyl]-4-ylsulfonyl)-l,3- thiazolidine-2-carboxamide.
  • Example 26 3-( ⁇ 1.1 '-biphenyll-4-ylsulfonylVN-l 1 -phenyl-3-( 1 -piperidinvDpropyl]- 1.3- thiazolidine-2-carboxamide.
  • Example 27 3-([l ,l'-biphenyl]-4-ylsulfonyl)-N-[3-(4-mo ⁇ holiny ⁇ -l-phenylpropyl]-l,3- thi azolidine-2 -carboxamide .
  • Example 29 3-([l,r-biphenyl]-4-ylsulfonyl)-N- ⁇ 3-[(3-hydroxy-3-phenylpropyl (methyl)- amino]- 1 -phenylpropyl ⁇ - 1 ,3-thiazolidine-2-carboxamide.
  • Example 30 3-( ⁇ ,r-biphenyl1-4-ylsulfony ⁇ -N-(3-[(2-hydroxycvclohexy ⁇ amino]-l- phenylpropy - 1 ,3-thiazolidine-2-carboxamide.
  • Example 31 iV-[3-(benzylamino)- 1 -phenylpropyl] -3 -([ 1 , 1 '-biphenyl] -4-ylsulfonyl)- 1 ,3- thiazolidine-2 -carboxamide .
  • Example 32 3-([l.1 '-bipheny ll-4-ylsulfonyn-N-(l -phenyl-3- ⁇ [2-(2-pyridinvnethyl]- amino ⁇ propyl)- 1 , 3 -thiazolidine-2-carboxamide.
  • Diisopropylcarbodiimide (4.5g, 35.7mmol) was then added to the suspension and shaken overnight at ambient temperature. The resin was then filtered at the pump and washed sequentially with NMP, DCM, MeOH and finally diethyl ether before being dried at 40°C in vacuo.
  • the resin from the previous deprotection step was transferred into a 96-well filter-plate (approx. 50mg of dry resin/well; Loading 0.93mmol/g; 0.047mmol) and each well treated with a sulfonyl chloride (VI) (0.140mmol, 3eq) and diisopropylethylamine (0.140mmol, 3eq) in NMP (1 ml), overnight. The plate was then sealed and shaken overnight at ambient temperature. After this time, the resin aliquots were filtered, washed sequentially with aliquots of NMP, DCM and finally diethyl ether before being dried at room temperature in vacuo.
  • VI sulfonyl chloride
  • NMP diisopropylethylamine
  • Example 34 N-benzyl-3-([l , l '-biphenyl]-4-y Isulfony 1)-1 , 3-th iazolidine-2-carboxamide.
  • Example 33 Following the general solid phase method as outlined Example 33, starting from 3-(tert- butoxycarbonyl)- l ,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, [l , l '-biphenyl]-4- sulfonyl chloride and benzylamine, the title compound was obtained in 97% purity by HPLC.
  • Example 35 N-benzyl-3-[(4-tert-butylphenyl)sulfonyl]-l,3-thiazolidine-2-carboxamide.
  • Example 33 Following the general solid phase method as outlined Example 33, starting from 3-(tert- butoxycarbonyl)-l,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, 4-tert- butylbenzenesulfonyl chloride and benzylamine, the title compound was obtained in 97.1% purity by HPLC.
  • Example 36 3-([l,r-biphenyl]-4-ylsulfonyl)-N-(4-methoxybenzyl)-l,3-thiazolidine-2- carboxamide.
  • Example 33 Following the general solid phase method as outlined Example 33, starting from 3-(tert- butoxycarbonyl)-l,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, 1,1 '-bipheny 1-4- sulfonyl chloride and 4-methoxyphenyl)methanamine, the title compound was obtained in 98% purity by HPLC.
  • Example 37 3-([l ,l'-biphenyl]-4-ylsulfonyl)-N-(2-thienylmethyl)-l ,3-thiazolidine-2- carboxamide.
  • Example 33 Following the general solid phase method as outlined Example 33, starting from 3-(tert- butoxycarbonyl)- 1,3 -thiazolidine-2 -carboxy lie acid, Kaiser oxime resin, l,l'-biphenyl-4- sulfonyl chloride and 2-thienylmethanamine, the title compound was obtained in 94% purity by HPLC.
  • Example 38 3-([l.r-biphenyl]-4-ylsulfonyl)-N-(2-furylmethyl - 3-thiazolidine-2- carboxamide.
  • the title compound was obtained in 92.2%> purity by HPLC.
  • Example 39 3-([l,r-biphenyl]-4-ylsulfonyl)-N-(4-fluorobenzyl)-l,3-thiazolidine-2- carboxamide.
  • Example 33 Following the general solid phase method as outlined Example 33, starting from 3-(tert- butoxycarbonyl)-l ,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, l,l'-biphenyl-4- sulfonyl chloride and (4-fluorophenyl)methanamine, the title compound was obtained in 92% purity by HPLC.
  • Example 33 Following the general solid phase method as outlined Example 33, starting from 3-(tert- butoxy-carbonyl)-l ,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, l ,l'-biphenyl-4- sulfonyl chloride and benzhydrylamine, the title compound was obtained in 98.5%> purity by HPLC.
  • Example 41 3-([l,r-biphenyl1-4-ylsulfonyl -N-[l-(4-fluoro ⁇ henyl)ethyl]-l,3-thiazolidine- 2-carboxamide.
  • Example 33 Following the general solid phase method as outlined Example 33, starting from 3-(tert- butoxycarbonyl)-l,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, l,l'-biphenyl-4- sulfonyl chloride and 1 -(4-fluorophenyl)ethanamine, the title compound was obtained in 85% purity by HPLC.
  • Example 33 Following the general solid phase method as outlined Example 33, starting from 3-(tert- butoxycarbonyl)-l,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, l,l'-biphenyI-4- sulfonyl chloride and (2-methylphenyl)methanamine, the title compound was obtained in 99% purity by HPLC.
  • Example 43 3-([ 1 , 1 '-biphenyl] -4-ylsulfonyl -N-(2,6-difluorobenzyl)- 1 ,3-thiazolidine-2- carboxamide.
  • Example 33 Following the general solid phase method as outlined Example 33, starting from 3-(tert- butoxycarbonyl)-l ,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, l,l'-biphenyl-4- sulfonyl chloride and 2,6-difluorophenyl)methanamine, the title compound was obtained in 85% purity by HPLC.
  • Example 44 3-(ri,r-biphenyll-4-ylsulfonylVN-(2,3-difluorobenzyl)-1.3-thiazolidine-2- carboxamide.
  • the title compound was obtained in 93.4% purity by HPLC.
  • Example 45 3-([ 1 , 1 '-biphenyl] -4-ylsulfonyl)-N-(2-methoxybenzyl)- 1 ,3-thiazolidine-2- carboxamide.
  • Example 33 Following the general solid phase method as outlined Example 33, starting from 3-(tert- butoxycarbonyl)-l ,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, l, l'-biphenyl-4- sulfonyl chloride and (2-methoxyphenyl)methanamine, the title compound was obtained in 98.5% purity by HPLC.
  • Example 46 3-([l.r-biphenyll-4-ylsulfonv ⁇ -N-(2-chlorobenzyl -1.3-thiazolidine-2- carboxamide.
  • the title compound was obtained in 85% purity by HPLC.
  • Example 47 3-([l.r-biphenyl]-4-ylsulfony ⁇ -N-(2-fluorobenzyl)-l,3-thiazolidine-2- carboxamide.
  • Example 33 Following the general solid phase method as outlined Example 33, starting from 3-(tert- butoxycarbonyl)- l,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, 1 , l'-biphenyl-4- sulfonyl chloride and (2-fluorophenyl)methanamine, the title compound was obtained in 88.6% purity by HPLC.
  • Example 48 General protocols for the solution-phase synthesis of 1.3-thiazolidine-2- carboxamide derivatives of general formula (XXX111); e.g., N-[3-(acetylamino)-l- phenylpropyl]-3-([l,r-biphenyl]-4-ylsulfonyl -1.3-thiazolidine-2-carboxamide: 3-flT,l'- biphenyl1-4-ylsulfony ⁇ -N- ⁇ 3-r(methylsulfony ⁇ amino]-l- ⁇ henylpropy -l,3-thiazolidine-2- carboxamide.
  • N-[3-amino-l-phenylpropyl]-3-([l ,r-biphenyl]-4-ylsulfonyl)-l ,3-thiazolidine-2- carboxamide (Intermediate 9, 50mgs, 1.Oeq, O.l Ommol) was dissolved in 5 ml DCM in presence of 30 ⁇ l triethylamine.
  • Acetyl chloride (l O ⁇ l, 1. l eq, 0.1 l mol) was introduced slowly at 0°C and the reaction mixture stirred for 30 minutes. It was then hydrolyzed by addition of aqueous sodium carbonate (10%) (5ml), and the compound extracted with
  • thiazolidine intermediates of general structure (XXXI) or (XXXII), e.g., N- [3-amino-l -phenylpropyI]-3-([l ,r-biphenyl]-4-ylsulfonyl)-l ,3-thiazolidine-2-carboxamide (Intermediate 9, 50mgs, 1.Oeq, O.l Ommol), were dissolved in 10ml DCM in presence of 30 ⁇ l of triethylamine at 0°C. Methane sulfonylchloride (l O ⁇ l, 1.leq, 0.1 lmol) was introduced slowly and reaction mixture was stirred at 0°C for 30 minutes.
  • Example 49 General protocols for the solution-phase synthesis of 1 ,3-thiazolidine-2- carboxamide derivatives of general formula (XXVIO; e.g.. 3-( ⁇ ,r-biphenyl]-4-ylsulfonylV N-[3-phenoxy-l-phenylpropyl]-l ,3-thiazolidine-2-carboxamide.
  • Phenol (252 mg, 1.5 eq, 2.69 mmol), diethylazodicarboxylate (470mg, 1.5 eq, 2.69 mmol) and triphenyl phosphine polymer bound (1.0 g, 1.5 eq, 2.70 mmol) were then added and the reaction mixture was shaken for 12 hours at RT.
  • Triphenyl phosphine resin was filtered off and the THF solution evaporated in vacuo. The residue was taken up in DCM and washed twice with saturated sodium carbonate solution and then water.
  • Example 50 3-(biphenyl-4-ylsulfonyl)-N-r(2-chloropyridin-4-yl)(phenv ⁇ methyl]-l .3- thiazolidine-2-carboxamide.
  • Example 1 3-([l , -biphenyl]-4-ylsulfonyl)-l ,3-thiazolidine-2-carboxylic acid (Intermediate 8) and l-(2- chloropyridin-4-yl)-l-phenylmethanamine (Intermediate 2), the title compound was obtained in 98%o purity by HPLC.
  • Example 51 3-(biphenyl-4-ylsulfonylVN-[(6-chloropyridin-3-yl)(phenyl)methyl]- 1 ,3- thiazolidine-2-carboxamide.
  • Example 53 3-(biphenyl-4-ylsulfonyl)-N-[[6-(dimethylamino)pyridin-3- yl](phenyl)methyl]-l,3-thiazolidine-2-carboxamide.
  • Example 54 3-(biphenyl-4-ylsulfonyl -N-[(R)- ⁇ 5-[2-(dimethylamino ethoxy]pyridin-2- yl
  • Example 55 4-r(-S -r( ⁇ r2 ⁇ -3-[(2'-fluorobiphenyl-4-vnsulfonyll-l,3-thiazolidin-2- yU carbonyDamino] (pheny Dmethyl]- 1 -methylpiperidinium methanesulfonate.
  • Example 2 Following the strategies and protocols outlined in Example 1 , the title compound was obtained in 99% purity by HPLC.
  • Example 56 benzeneacetic acid, alpha,alpha-dimethyl-4-[[2-[[[(R)-phenyl-2- pyridinylmethyl]amino]carbonyl]-3-thiazolidinyl]sulfonyl]-, methyl ester
  • Example 58 Preparation of product lb. e.g. N-(2-amino-2-oxo-l -pheny lethyl)-3-(biphenyl- 4-ylsulfonyl)- 1 ,3-thiazolidine-2-carboxamide.
  • Example 60 Preparation of product I, e.g. 3-(biphenyl-4-ylsulfonyl)-7V-[[5-(2- hydroxyethyl)-l ,2,4-oxadiazol-3-yl](phenyl)methyl]-l ,3-thiazolidine-2-carboxamide.
  • Triethylamine (92 ⁇ l, 0.66 mmol) was slowly added to a suspension of product lc, e.g., 3- (biphenyl-4-ylsulfonyl)-N-[cyano(phenyl)methyl]-l,3-thiazolidine-2-carboxamide, and hydroxylamine.hydrochloride (46 mg, 0.66 mmol) in ethanol (5 mL), under stirring. The reaction mixture was heated under reflux for 16h, and then cooled to RT. The solvents were removed and the resulting solid was suspended in water and extracted with three protions of EtOAc.
  • product lc e.g., 3- (biphenyl-4-ylsulfonyl)-N-[cyano(phenyl)methyl]-l,3-thiazolidine-2-carboxamide, and hydroxylamine.hydrochloride (46 mg, 0.66 mmol) in ethanol (5 mL), under stirring.
  • the reaction mixture was heated
  • intermediate Id e.g., N-[(17?,2Z)-2-amino-2-(hydroxyimino)-l-phenylethyl]-3- (biphenyl-4-ylsulfonyl)-l,3-thiazolidine-2-carboxamide (272 mg, quantitative yield) which was directly used in the next step.
  • Carboxylic acid e.g., 3-tert-butoxypropionic acid (35 mg, 0.24 mmol), was dissolved in THF (2 mL). The resulting solution was cooled down to -15°C. NMM (84 ⁇ L, 0.76 mmol), followed by isobutyl chloroformate (33 ⁇ L, 0.25 mmol), were added. The mixture was stirred at -15°C for 30 min.
  • Intermediate Id e.g.
  • Example 61 Preparation of product XXX, e.g. 2-thiazolidinecarboxamide, 3-[[4-(2-fluoro- l,l -dimethylethy ⁇ phenyl]sulfonyl]- ⁇ -[(RVphenyl-2-pyridinylmethyl]-
  • product XXX e.g. 2-thiazolidinecarboxamide, 3-[[4-(2-fluoro- l,l -dimethylethy ⁇ phenyl]sulfonyl]- ⁇ -[(RVphenyl-2-pyridinylmethyl]-
  • Example X The compound benzeneacetic acid, alpha,alpha-dimethyl-4-[[2-[[[(R)-phenyl-2-pyridinyl- methyl]amino]carbonyl]-3-thiazolidinyl]sulfonyl]-, methyl ester (Example X) (54 mg, O.lmmol) was dissolved in 3mL of anhydrous THF. The solution was cooled down to zero degree and LiBH4 was added (3mg, 0.15mmol, 1.5eq). The reaction mixture was agitated for 2h. The reaction mixture was quenched by addition of H 2 O. The organic solvent was evaporated under reduced pressure, and the residue redissolved in EtOAc.
  • the compound 2-thiazolidinecarboxamide, 3-[[4-(2-hydroxy-l ,l-dimethylethyl)phenyl] sulfonyl]-N-[(R)-phenyl-2-pyridinylmethyl]- (43mg, 0.08mmol) was dissolved in 2mL anhydrous DCM. The solution was cooled down to -78°C, and DAST (0.02mL, 0.17mmol, 2eq) was added. The reaction mixture was stirred for 24h at -78°C and warmed to room temperature. The reaction was quenched by addition of NaHCC. 3 sat. and agitated for lh. The product was extracted with DCM (50mL).
  • Example 63 (2S -3-r(2'-fluorobiphenyl-4-yl sulfonvn-N-r(R -phenyl(pyridin-2-yl)methyl]- 1 ,3-thiazolidinc-2-carboxamide.
  • 2S tert-butyl (2S)-2-( ⁇ [(R)-phenyl(pyridin-2-yl)methyl]amino ⁇ - carbonyl)-l, 3 -thiazolidine-3 -carboxylate (Intermediate 6) and 2'-fluorobiphenyl-4- yl)sulfonyl chloride, the title compound was obtained in 99% purity by HPLC.
  • Example 64 (2 S)-3 -(bipheny 1-4-y Isulfony 1 -N-[(1 S)-l-(4-fluorophenyl)-3-hydroxypropyl]- 1 ,3-thiazolidine-2-carboxamide.
  • Example 65 3-( 1 , 1 '-biphenyl-4-ylsulfonyl -N-[ 1 -(2,6-difluorophenyl)-3-hydroxypropyl]- 1 ,3-thiazolidine-2-carboxamide.
  • Example 66 (2S)-N-[(1 S)-l-(4-fluorophenyl -3-hvdroxypropyl]-3-[(2'-fluorobiphenyl-4- vDsulfonyl]- 1 ,3-thiazolidine-2-carboxamide.
  • Example 68 General protocols for the solution-phase synthesis of l,3-thiazolidine-2- carboxamide derivatives of general formula (I); e.g.. (3S -3-( ⁇ [(2S)-3-(biphenyl-4- ylsulfonyl -l,3-thiazolidin-2-yl]carbonyl ⁇ amino)-3-(2,6-difluorophenyl)propyl L-valinate, (3S -3-(2.6-difluorophenylV3-r( ⁇ (2S)-3-[(2'-fluorobiphenyl-4-yl sulfonyl]-1.3-thiazolidin- 2-yl ⁇ carbonyl)amino]propyl L-valinate, (3S)-3-( ⁇ [(2S -3-(biphenyl-4-ylsulfonyl -l,3- thiazolidin-2-yl]carbonyl ⁇ amino)-3-phen
  • Example 69 (3SV3-(([(2S)-3-(biphenyl-4-ylsulfonyl -l,3-thiazolidin-2-yl]carbonyl ⁇ - amino)-3-(2,6-difluorophenyl)propyl L-valinate.
  • Example 65 Following the general strategies and protocols outlined in Example 68, starting from 3- (l,r-biphenyl-4-ylsulfonyl)-N-[l-(2,6-difluorophenyl)-3-hydroxypropyl]-l,3-thiazolidine- 2-carboxamide (Example 65), the title compound was obtained in 99% purity by HPLC.
  • Example 70 (3SV3-(U(2S -3-(biphenyl-4-ylsulfonvn-l ,3-thiazolidin-2-yllcarbonyU- amino)-3-phenylpropyl L-valinate.
  • Example 1 Following the general strategies and protocols outlined in Example 68, starting from (25)- 3-([l ,l'-biphenyl]-4-ylsulfonyl)-N-[(l S)-3-hydroxy- 1 -phenylpropyl]- l,3-thiazolidine-2- carboxamide (Example 1), the title compound was obtained in 99% purity by HPLC.
  • Example 71 (3S -3-[( ⁇ (2S -3-r(2'-fluorobiphenyl-4-yl sulfonyll-1.3-thiazolidin-2- yl ⁇ carbonyDamino]- 3 -phenylpropyl L-valinate.
  • Example 67 Following the general strategies and protocols outlined in Example 68, starting from (2S)- 3-[(2'-fluoro-l , l'-biphenyl-4-yl)sulfonyl]-N-[(l S)-3-hydroxy- 1 -phenylpropyl]- 1 ,3- thiazolidine-2-carboxamide (Example 67), the title compound was obtained in 99% purity by HPLC.
  • Example 72 (2SV3-(l .l'-biphenyl-4-ylsulfonyn-N-r(lS -3-hydro ⁇ y-l-(2.4-difluoro- phenyPpropyl]- 1 ,3-thiazolidine-2-carboxamide.

Abstract

The present invention is related to thiazolidine carboxamide derivatives of formula (II) for the treatment and/or prophylaxis of preterm labor, premature birth, dysmenorrhea and for stopping labor prior to cesarean delivery. G is selected from the group consisting of C1-C6-alkyl aryl, C1-C6-alkyl heteroaryl, C1-C6 Alkyl cycloalkyl, C1-C6-alkyl heteroaryl, aryl, heteroaryl, C3-C8-cycloalkyl or -heterocyclo­alkyl, said cycloalkyl or aryl or heteroaryl groups may be fused with cycloalkyl or aryl or heteroaryl groups. R1 is selected from the group consisting of aryl, heteroaryl, C3-C8-cycloalkyl or - heterocyclo-alkyl, said (hetero)cycloalkyl or aryl or heteroaryl groups may be fused with (hetero)cycloalkyl or aryl or heteroaryl groups. R2 is selected from the group consisting of H, carboxy, acyl, alkoxycarbonyl, amino­carbonyl, C1-C5-alkyl carboxy, C1-C5-alkyl acyl, C1-C5-alkyl alkoxycarbonyl, C1-C5-alkyl aminocarbonyl, C1-C5-alkyl acyloxy, C1-C5-alkyl acylamino, C1 -C5-alkyl ureido, C1-C5alkyl amino, C1-C5-alkyl alkoxy, C1-C5-alkyl sulfanyl, C1-C5-alkyl sulfinyl, C1-C5-alkyl sulfonyl, C1-C5-alkyl sulfonylamino, C1-C5-alkyl sulfonyloxy, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, aryl, heteroaryl, C3-C8-cycloalkyl, heterocycloalkyl, C1-C6-alkyl aryl, C2-C6-alkyl heteroaryl, C1-C6-alkyl cycloalkyl, C1-C6-alkyl heterocycloalkyl, C2-C6-alkenyl aryl, C2-C6-alkenyl heteroaryl, C2-C6-alkynyl aryl, or C2-C6-alkynyl heteroaryl.

Description

THIAZOLIDINE CARBOXAMIDE DERIVATIVES AS MODULATORS OF THE PROSTAGLANDIN F RECEPTOR
Field ofthe invention
This present invention is related to thiazolidine carboxamide derivatives of formula (II) for the treatment and/or prophylaxis of preterm labor, premature birth, dysmenorrhea and for stopping labor prior to cesarean delivery. Specifically, the present invention is related to substituted thiazolidine carboxamide derivatives for the modulation, notably the inhibition of the activity or function ofthe prostaglandin receptors, particularly ofthe prostaglandin F? receptor. Also, the present invention is related to novel thiazolidine carboxamide derivatives of formulae (I) and (la).
Background ofthe invention
In the field of obstetrics, one of the most important problems is the management of preterm labor and premature birth as they represent a major cause of perinatal morbidity and mortality.
In recent years, strong evidence has accumulated indicating that the hormone oxytocin plays a major role in initiating labor in mammals, notably in humans. Thereby, it is assumed that oxytocin exerts said effect in a direct as well as an indirect way, by contracting the uterine myometrium and by enhancing the synthesis and release of contractile prostaglandins from the uterine endometrium/decidua. These prostaglandins may furthermore play a role in the cervical ripening process.
In parturition, the high circulating concentrations of progesterone induce uterine quiescence while the uterus acquires contractile ability. Shortly before term, plasma progesterone concentrations fall, oxytocin receptor expression in the uterus increases markedly, and uterine contractile activity increases. At term, the contractions rise to a crescendo, resulting in delivery as a result of two interacting positive feedback loop. The first is a local uterine loop: within the uterus itself, prostaglandins and other uterotonic factors are produced and released in response to uterine contractions. The second loop involves the hypothalamus: in response to uterine contractions and vaginal and cervical distension, magnocellular oxytocin neurons in the hypothalamus increase their activity resulting in the release of oxytocin from their axon terminals in the posterior pituitary; the released oxytocin acts upon the uterus both to stimulate the further production of prostaglandins and to contribute further to the contractions of the uterus. (Journal of Endocrinology 157, p.343-359 (1998) by J. A Russell and al.).
For the treatment of preterm labor, several approaches have been considered such as the use of magnesium sulfate, ethanol or therapeutic agents acting as β2 adrenergic agonists or oxytocin antagonists:
• With the use of magnesium sulfate, it has been observed that plasma concentrations above the therapeutic range of 4 to 8 mg/dL can cause inhibition of cardiac conduction and neuromuscular transmission, respiratory depression and cardiac arrest, thus making this agent unsuitable notably when the renal function is impaired.
• Ethanol is effective in preventing premature labor, but it does not produce a corresponding reduction in the incidence of fetal respiratory distress. Also, ethanol is assumed to have a negative impact on the fetus.
• The β2-adrenergic receptor generally causes an inhibitory action within the cells wherein it is expressed (muscles, heart, uterus etc). β2-adrenergic agonists are used to activate said inhibitory action of the receptor. Hence, β2-adrenergic agonists are sympathomimetics which - among others - inhibit uterine contractility. Known β2- adrenergic agonists for the treatment of preterm labor are Ritodrine, Terbutaline and Albuterol. • Oxytocin antagonists: Oxytocin (OT) is a peptide hormone causing the contraction of the uterus of mammals during labor. Oxytocin (OT) receptors increase dramatically during the course of pregnancy. The concentration of OT receptors has been shown to correlate with spontaneous uterine activity. In the last few years, a number of papers have suggested that the hormone oxytocin may be a physiological initiator of labor in several mammalian species including humans. Furthermore, oxytocin is believed to exert this effect in two different parts, either by directly contracting the uterine myometrium and by enhancing the synthesis and release of contractile prostaglandins from the uterine endometrium/decidua. Therefore, by blocking oxytocin, the direct (contractile) and indirect (enhanced prostaglandin synthesis) effects of oxytocin on the uterus may be achieved.
Prostaglandins (PGs), more particularly prostaglandin F2α (PGF2α), play a key role in the normal physiology of several tissues including ovary, oviduct, uterus, testis, lung and possibly eye and heart and is implicated in reproductive functions such as ovulation, luteolysis and parturition. It is well known that parturition is initiated when prostaglandin F2α interacts with FP (Prostaglandin F receptor) in ovarian luteal cells of the pregnant mice to induce luteolysis. (Science vol. 277 p.681-687 (1997) by Yuhihiko Sugimoto et al). Actions of PGF2α are mediated by the PGF receptor (FP), which is a heterotrimeric guanosine triphosphate - binding protein (G protein) - coupled rhodopsin type receptor specific to this PG (Science vol.277, p.681-83 (1998) by Yuhihiko Sugimoto et al.). These prostaglandins belong to a group of eicosanoids that are produced by the enzymatic activity of cyclooxygenase. Together with the thromboxanes, prostaglandins constitute the prostanoid subgroup ofthe eicosanoids. Prostaglandins (PGs) mediate various physiological processes such as fever generation and inflammation. Aspirin and related drugs act through inhibition of PG biosynthesis.
PGF2α is synthesized, to varying degrees, by almost every tissue in the body and is a stimulant of several different types of physiological functions including granulose lutein cell death, myometrial smooth muscle contraction, Leydig cell testosterone synthesis regulation, regulation of oviductal cilia beating, bronchoconstriction, and bone metabolism. They are synthesized in fetal and maternal membranes and act to ripen the cervix and contract the myometrium. PGF2α is a major prostaglandin for enhancing uterine contractility.
Specific prostaglandin receptors (EPj, EP2, EP4 and FP) are expressed in the human myometrium. Activation of EP2 and EP4 receptors results in smooth muscle relaxation whereas activation ofthe PGF2«-selective receptor (FP receptor) results in contraction. Indeed, the prostaglandin F2α receptor acts via a G protein-coupled receptor, coupled to
9-1- activation of phospholipase C and increases in IP3 that release Ca" from intracellular stores. The increases in intracellular calcium that ensue lead to increased contraction of smooth muscle via activation of myosin light chain kinase. Also, it is known that mice lacking the FP receptor have normal fertility but no labor at term. However healthy pups were delivered by cesarean cut. One ofthe most important roles of PGF2 is in reproductive biology as a luteolytic agent. In the non-pregnant state, at the end ofthe luteal phase, increased pulsatile serum levels of PGF? (of uterine origin) cause apoptotic cell death of the granulosam lutein cells (Res.Reprod. 16: 1 -2 (1984) by McCracken).
There is recent evidence for up-regulation of the contractile FP receptor with the onset and during progression of labor. Also, recent reports indidcate that oxytocin induces production of PGs in human myometrial cells via upregulation of COX-2. Such a mechanism may explain the sustained release of PGs in uterine tissue, promoting labor. Therefore, there is strong evidence that interfering with the prostaglandin pathway by blocking selectively the contractile FP receptor will delay the progression of labor. A compound able to block the interaction between PGF2α and its receptor, i.e. a PGF2α-receptor antagonist, is therefore assumed to be more efficacious for treating preterm labor than current regimens. Because of the involvement of PGF2« in birth initiation, several approaches have already been performed to test new PGF2α inhibitors. Indomethacin is a well known prostaglandin inhibitor and has already been tested to study the possible mode of action of prostaglandins (Prostaglandins, 12(6) p.1053-9 (1976) by Chatterjee A.). In J. Reprod. Fertil, 116(1), p.103-11 1 (1999) Williams B. J. et al observed that flunixin meglumin disrupted the normal 13,14-dihydro-15-keto prostaglandin F20. profile but did not abolish prostaglandin synthesis completely or delay the onset of labor in treated animals. Mattos R. et al (Rev. Reprod., 5(1), p.38-45 (2000) use polyun saturated fatty acids such as linoleic, linolenic, eicosapentaenoic and docosahexaenoic acids which may inhibit prostaglandin F2α.
Recently, a phenol derivative known as p38 inhibitor (4-[5-(4-fluorophenyl)-4-(4-pyridyl)- imidazol-2-yl]phenol) has been tested and it has been observed that said compound inhibited both prostaglandin F production and COX-2 expression induced by stimulation with IL-l β (Biochem. Biophys. Res. Commun., 288(5), p. i 155-1 161 (2001 ) by Chuo-ku Chiba).
Tsumura & Co proposed prostaglandin F2α inhibitor active to relax the smooth muscle of uterine and effective for the remedy of abdominal pain caused by abortion, premature labor and dysfunction, by using a phtalide derivative as an active component (JP-01050818). In their patent (US-6,271 ,201 ), Board of Regents, the University of Texas System discloses a method for regulating placental cell production of thromboxane and PGF α comprising treating placenta cells with a pharmacologically effective amount of insulin-like growth factor I sufficient to inhibit thromboxane and prostaglandin F2α production without affecting prostacyclin or prostaglandin E2 production. Summary ofthe invention
The present invention relates to the use of thiazolidine carboxamide derivatives of formula (II),
Figure imgf000007_0001
as well as pharmaceutically acceptable salts thereof, for the preparation of pharmaceutical compositions for the treatment and/or prevention of preterm labor, premature birth, dysmenorrhea, and for stopping labor prior to cesarean delivery. Compounds of this invention are inhibitors of prostaglandin receptors, particularly ofthe prostaglandin F2 receptor (FP).
Also, the present invention relates to novel thiazolidine carboxamide derivatives of formula (I), wherein G' is an aryl, heteroaryl or cycloalkyl or a heterocycloalkyl moiety.
Figure imgf000007_0002
In particular the present invention relates to novel thiazolidine carboxamide derivatives of formula (la):
Figure imgf000008_0001
Detailled description of the invention:
It has now been found that compounds ofthe present invention are modulators of the Prostaglandin receptor, in particular of the Prostaglandin F2α receptor (FP) function. When the Prostaglandin F2α receptor (FP) is bound by the compounds of the present invention, PGF2α is antagonized by being blocked from its receptor and thus being unable to exert its biological or pharmacological effects. The compounds ofthe present invention are therefore useful in the treatment and prevention of preterm labor, premature birth and for stopping labor prior to cesarean delivery.
The compounds of the present invention are also useful in the treatment of dysmenorrhea which may be defined as a cyclic pain associated with menses during ovulatory cycles. The pain is thought to result from uterine contractions and ischemia, probably mediated by the effect of prostaglandins produced in the secretory endometrium. By blocking both the effects of prostaglandin F2« on the uterus, a FP antagonist is more efficacious for treating dysmenorrhea than current regimens.
In particular, compounds of the present invention are useful in the treatment and prevention of prostaglandin related disorders of mammals and especially humans. It is a purpose of this invention to provide a method of antagonizing the functions of prostaglandins, particularly prostaglandin F2α, in disease states in mammals. It is another purpose of this invention to develop a method of preventing or treating prostaglandin F2α related disorders by antagonizing the binding of said prostaglandin to its receptor. The following paragraphs provide definitions ofthe various chemical moieties that make up the compounds according to the invention and are intended to apply uniformly throughout the specification and claims unless an otherwise expressly set out definition provides a broader definition.
"Ci-Cό -alkyl" refers to monovalent alkyl groups having 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert- butyl, n-hexyl and the like.
"Aryl" refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl). Preferred aryl include phenyl, naphthyl, phenantrenyl and the like.
"Ci-Cό-alkyl aryl" refers to Ci-Cό-alkyl groups having an aryl substituent, including benzyl, phenethyl and the like.
"Heteroaryl" refers to a monocyclic heteroaromatic, or a bicyclic or a tricyclic fused-ring heteroaromatic group. Particular examples of heteroaromatic groups include optionally substituted pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1 ,2,3 -triazolyl, 1 ,2,4-triazolyl, 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadia- zolyl, 1,2,5-oxadiazolyl, l ,3,4-oxadiazolyl,l,3,4-triazinyl, 1 ,2,3-triazinyl, benzofuryl, [2,3- dihydrojbenzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo[l ,2-a]pyridyl, benzothiazolyl, benzoxa- zolyl, quinolizinyl, quinazolinyl, pthalazinyl, quinoxalinyl, cinnolinyl, napthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthenyl or benzoquinolyl.
"Ci-Cό-alkyl heteroaryl" refers to Cι-C6-alkyl groups having a heteroaryl substituent, including 2-furylmethyl, 2-thienylmethyl, 2-(l H-indol-3-yl)ethyl and the like. "C2-C6-alkenyl" refers to alkenyl groups preferably having from 2 to 6 carbon atoms and having at least 1 or 2 sites of alkenyl unsaturation. Preferable alkenyl groups include ethenyl (-CH=CH2), n-2-propenyl (allyl, -CH2CH=CH2) and the like.
"C2-C6-alkenyl aryl" refers to C2-C6-alkenyl groups having an aryl substituent, including 2- phenylvinyl and the like.
"C2-C6-alkenyl heteroaryl" refers to C2-C6-alkenyl groups having a heteroaryl substituent, including 2-(3-pyridinyl)vinyl and the like.
"C2-C6-alkynyl" refers to alkynyl groups preferably having from 2 to 6 carbon atoms and having at least 1 -2 sites of alkynyl unsaturation, preferred alkynyl groups include ethynyl (-C≡CH), propargy 1 (-CH2C≡CH), and the like.
"C2-C6-alkynyl aryl" refers to C2-C6-alkynyl groups having an aryl substituent, including phenylethynyl and the like.
"C2-C6-alkynyl heteroaryl" refers to C2-C6-aIkynyl groups having a heteroaryl substituent, including 2-thienylethynyl and the like.
"Cs-Cg-cycloalkyl" refers to a saturated carbocyclic group of from 3 to 8 carbon atoms having a single ring (e.g., cyclohexyl) or multiple condensed rings (e.g., norbornyl). Preferred cycloalkyl include cyclopentyl, cyclohexyl, norbornyl and the like.
"Heterocycloalkyl" refers to a Cβ-Cg-cycloalkyl group according to the definition above, in which up to 3 carbon atoms are replaced by heteroatoms chosen from the group consisting of O, S, NR, R being defined as hydrogen or methyl. Preferred heterocycloalkyl include pyrrolidine, piperidine, piperazine, 1-methylpiperazine, morpholine, and the like.
"C|-C6-alkyl cycloalkyl" refers to Ci-Cό-alkyl groups having a cycloalkyl substituent, including cyclohexylmethyl, cyclopentylpropyl, and the like. "Ci-Cό-alkyl heterocycloalkyl" refers to Ci-Cό-alkyl groups having a heterocycloalkyl substituent, including 2-(l -pyrrolidinyl)ethyl, 4-morpholinylmethyI, (l-methyl-4- piperidinyl)methyl and the like.
"Carboxy" refers to the group -C(0)OH.
"Ci-Cs-alkyl carboxy" refers to Ci-Cs-alkyl groups having an carboxy substituent, including 2-carboxyethyl and the like.
"Acyl" refers to the group -C(0)R where R includes "Cι-C6-alkyl", "aryl", "heteroaryl", "Ci-Cβ-alkyl aryl" or "C|-C6-alkyl heteroaryl".
"Cι-C5-alkyl acyl" refers to Ci-Cs-alkyl groups having an acyl substituent, including 2- acetylethyl and the like.
"Acyloxy" refers to the group -OC(0)R where R includes "C,-C6-alkyl", "aryl", "heteroaryl", "C,-C6-alkyl aryl" or "C,-C6-alkyl heteroaryl".
"Cι-C5-alkyl acyloxy" refers to Cι-C5-alkyl groups having an acyloxy substituent, including 2-(acetyloxy)ethyl and the like.
"Alkoxy" refers to the group -O-R where R includes "Ci-Cό-alkyl" or "aryl" or "heteroaryl" or "Ci-Cό-alkyl aryl" or "Ci-Cό-alkyl heteroaryl". Preferred alkoxy groups include by way of example, methoxy, ethoxy, phenoxy and the like.
"C|-C5-alkyl alkoxy" refers to Ci-Cs-alkyl groups having an alkoxy substituent, including 2-ethoxyethyl and the like.
"Alkoxycarbonyl" refers to the group -C(0)OR where R includes H, "Cι-C6-alkyl" or "aryl" or "heteroaryl" or "C,-C6-alkyl aryl" or "Cι-C6-alkyl heteroaryl".
"Ci-Cs-alkyl alkoxycarbonyl" refers to Ci-Cs-alkyl groups having an alkoxycarbonyl substituent, including 2-(benzyloxycarbonyl)ethyl and the like. "Aminocarbonyl" refers to the group -C(0)NRR' where each R, R' includes independently hydrogen or Cj-Cό-alkyl or aryl or heteroaryl or "Ci-Cδ-alkyl aryl" or "Cι-C6-alkyl heteroaryl".
"Ci-Cs-alkyl aminocarbonyl" refers to Ci-Cs-alkyl groups having an aminocarbonyl substituent, including 2-(dimethylaminocarbonyl)ethyl and the like.
"Acylamino" refers to the group -NRC(0)R' where each R, R' is independently hydrogen or "C-Cβ-alkyl" or "aryl" or "heteroaryl" or "C,-C6-alkyl aryl" or "Cι-C6-alkyl heteroaryl".
"Ci-Cs-alkyl acylamino" refers to Ci-Cs-alkyl groups having an acylamino substituent, including 2-(propionylamino)ethyl and the like.
"Ureido" refers to the group -NRC(0)NR'R" where each R, R\ R" is independently hydrogen or "C,-C6-alkyl" or "aryl" or "heteroaryl" or "Cι-C6-alkyl aryl" or "C,-C6-alkyl heteroaryl" "cycloalkyl" or "heterocycloalkyl", and where R' and R", together with the nitrogen atom to which they are attached, can optionally form a 3-8-membered heterocycloalkyl ring.
"Ci-Cs-alkyl ureido" refers to Ci-Cs-alkyl groups having an ureido substituent, including 2- (N'-methylureido)ethyl and the like.
"Amino" refers to the group -NRR' where each R,R' is independently hydrogen or "C ι-C6- alkyl" or "aryl" or "heteroaryl" or "Cι-C6-alkyl aryl" or "Cι-C6-alkyl heteroaryl", or "cycloalkyl", or "heterocycloalkyl", and where R and R', together with the nitrogen atom to which they are attached, can optionally form a 3-8-membered heterocycloalkyl ring.
"Ci-Cs-alkyl amino" refers to Ci-Cs-alkyl groups having an amino substituent, including 2- (l -pyrrolidinyl)ethyl and the like.
"Ammonium" refers to a positively charged group -N+RR'R", where each R,R',R" is independently "C,-C6-alkyl" or "C,-C6-alkyl aryl" or "C,-C6-alkyl heteroaryl", or "cycloalkyl", or "heterocycloalkyl", and where R and R', together with the nitrogen atom to which they are attached, can optionally form a 3-8-membered heterocycloalkyl ring.
"Halogen" refers to fluoro, chloro, bromo and iodo atoms.
"Sulfonyloxy" refers to a group -OSO2-R wherein R is selected from H, "Ci-Cό-alkyl", "Cι-C6-alkyl" substituted with halogens, e.g., an -OSO2-CF3 group, "aryl", "heteroaryl" , "Ci-Cβ-alkyl aryl" or "Cι-C6-alkyl heteroaryl".
"Ci-Cs-alkyl sulfonyloxy" refers to Ci-Cs-alkyl groups having a sulfonyloxy substituent, including 2-(methylsulfonyloxy)ethyl and the like.
"Sulfonyl" refers to group "-SO2-R" wherein R is selected from H, "aryl", "heteroaryl", "C,-C6-alkyl", "C|-C6-alkyl" substituted with halogens, e.g., an -S02-CF3 group, "Cι-C6- alkyl aryl" or "Cι-C6-alkyl heteroaryl".
"Cι-C5-alkyl sulfonyl" refers to Ci-Cs-alkyl groups having a sulfonyl substituent, including 2-(methylsulfonyl)ethyl and the like.
"Sulfinyl" refers to a group "-S(0)-R" wherein R is selected from H, "C,-C6-alkyl", "C,- C6-alkyl" substituted with halogens, e.g, an -SO-CF3 group, "aryl", "heteroaryl" , "C C6- alkyl aryl" or "Cι-C6-alkyl heteroaryl".
"Ci-Cs-alkyl sulfinyl" refers to Ci-Cs-alkyl groups having a sulfinyl substituent, including 2-(methylsulfinyl)ethyl and the like.
"Sulfanyl" refers to groups -S-R where R includes "Cι-C6-alkyl" or "aryl" or "hetero-aryl" or "Cι-C6-alkyl aryl" or "C]-C6-alkyl heteroaryl". Preferred sulfanyl groups include methylsulfanyl, ethylsulfanyl, and the like.
"Ci-Cs-alkyl sulfanyl" refers to Ci-Cs-alkyl groups having a sulfanyl substituent, including 2-(ethylsulfanyl)ethyl and the like. "Sulfonylamino" refers to a group -NRS02-R' where each R, R' is independently hydrogen or "Ci-Cβ-alkyl" or "aryl" or "heteroaryl" or "C C6-alkyl aryl" or "CrC6-alkyl heteroaryl".
"Ci-Cs-alkyl sulfonylamino" refers to Ci-Cs-alkyl groups having a sulfonylamino substituent, including 2-(ethylsulfonylamino)ethyl and the like.
"Substituted or unsubstituted" : Unless otherwise constrained by the definition of the individual substituent, the above set out groups, like "alkyl", "alkenyl", "alkynyl", "aryl" and "heteroaryl" etc. groups can optionally be substituted with from 1 to 5 substituents selected from the group consisting of "Cι-C6-alkyl", "C2-C6-alkenyl", "C2-C6-alkynyl", "cycloalkyl", "heterocycloalkyl", "C|-C6-alkyl aryl", "C,-C6-alkyl heteroaryl", "C,-C6-alkyl cycloalkyl", "C|-C6-alkyl heterocycloalkyl", "amino", "ammonium", "acyl", "acyloxy", "acylamino", "aminocarbonyl", "alkoxycarbonyl", "ureido", "aryl", "heteroaryl", "sulfinyl", "sulfonyl", "alkoxy", "sulfanyl", "halogen", "carboxy", trihalomethyl, cyano, hydroxy, mercapto, nitro, and the like. Alternatively said substitution could also comprise situations where neighbouring substituents have undergone ring closure, notably when vicinal functional substituents are involved, thus forming, e.g., lactams, lactons, cyclic anhydrides, but also acetals, thioacetals, aminals formed by ring closure for instance in an effort to obtain a protective group.
"Pharmaceutically acceptable salts or complexes" refers to salts or complexes ofthe below- identified compounds of formulae (I) and (II) that retain the desired biological activity. Examples of such salts include, but are not restricted to acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts fonned with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, and poly-galacturonic acid. Said compounds can also be administered as pharmaceutically acceptable quaternary salts known by a person skilled in the art, which specifically include the quarternary ammonium salt of the formula -NR,R',R" + Z", wherein R, R', R" is independently hydrogen, alkyl, or benzyl, Cι-C6- alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Cι-C6-alkyl aryl, d-C6-alkyl heteroaryl, cycloalkyl, heterocycloalkyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methyl sulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate, and diphenylacetate).
"Pharmaceutically active derivative" refers to any compound that upon administration to the recipient, is capable of providing directly or indirectly, the activity disclosed herein.
"Enantiomeric excess" (ee) refers to the products that are obtained by an asymmetric syn- thesis, i.e. a synthesis involving non-racemic starting materials and/or reagents or a synthesis comprising at least one enantioselective step, whereby a surplus of one enantiomer in the order of at least about 52% ee is yielded.
Said formula also comprises its tautomers, its geometrical isomers, its optically active forms as enantiomers, diastereomers and its racemate forms, as well as pharmaceutically acceptable salts thereof. Preferred pharmaceutically acceptable salts ofthe formula (I) are acid addition salts formed with pharmaceutically acceptable acids like hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulfonate, benzenesulfonate, and para- toluenesulfonate salts.
A first aspect of the present invention consists in the use of compounds of formula (II)
Figure imgf000015_0001
as well as its geometrical isomers, its optically active forms as enantiomers, diastereomers and its racemate forms, as well as pharmaceutically acceptable salts and pharmaceutically active derivatives thereof, for the preparation of a medicament for the treatment and/or prevention of preterm labor, premature birth, dysmenorrhea, and for stopping labor prior to cesarean delivery.
The substituents within formula (II) are defined as follows :
G is selected from the group consisting of substituted or unsubstituted Ci-Cό-alkyl aryl, substituted or unsubstituted Cι-C6-alkyl heteroaryl, substituted or unsubstituted Cι-C6-alkyl cycloalkyl, substituted or unsubstituted C|-C6-alkyl heteroaryl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Cs-Cg-cycloalkyl or -heterocycloalkyl, said cycloalkyl or aryl or heteroaryl groups may be fused with cycloalkyl or aryl or heteroaryl groups.
R1 is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Cs-Cs-cycloalkyl or -heterocyclo- alkyl, said (hetero)cycloalkyl or aryl or heteroaryl groups may be fused with (hetero)- cycloalkyl or aryl or heteroaryl groups.
R is H, carboxy, acyl, alkoxycarbonyl, aminocarbonyl, substituted or unsubstituted C1-C5- alkyl carboxy, substituted or unsubstituted Ci-Cs-alkyl acyl, substituted or unsubstituted Ci-Cs-alkyl alkoxycarbonyl, substituted or unsubstituted Ci-Cs-alkyl aminocarbonyl, substituted or unsubstituted Ci-Cs-alkyl acyloxy, substituted or unsubstituted Ci-Cs-alkyl acylamino, substituted or unsubstituted Ci-Cs-alkyl ureido, substituted or unsubstituted Ci- Cs-alkyl amino, substituted or unsubstituted Ci-Cs-alkyl alkoxy, substituted or unsubstituted Ci-Cs-alkyl sulfanyl, substituted or unsubstituted Ci-Cs-alkyl sulfinyl, substituted or unsubstituted Ci-Cs-alkyl sulfonyl, substituted or unsubstituted Ci-Cs-alkyl sulfonylamino, substituted or unsubstituted Ci-Cs-alkyl sulfonyloxy, substituted or unsubstituted Cι-C6- alkyl, substituted or unsubstituted C2-C6-alkenyl, substituted or unsubstituted C2-C6- alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Cs-Cs-cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted Cι-C6-alkyl aryl, substituted or unsubstituted C2-C6-alkyl heteroaryl, substituted or unsubstituted Cι-C6-alkyl cycloalkyl, substituted or unsubstituted C|-C6-aIkyl heterocycloalkyl, substituted or unsubstituted C2-C6-alkenyl aryl, substituted or unsubstituted C2-C6-alkenyl heteroaryl, substituted or unsubstituted C2-C6-alkynyl aryl, or substituted or unsubstituted C2-C6-alkynyl heteroaryl.
Alternatively, R and G may form a C3-Cs-cycloalkyl ring.
R4 is selected from the group consisting of substituted or unsubstituted Cι-C6-alkyl, substituted or unsubstituted C2-C6-alkenyl, substituted or unsubstituted C2-C6-alkynyl.
n is an integer from 0 to 2.
According to one embodiment, G is an aryl group, e.g., a substituted or unsubstituted phenyl, like a biphenyl.
Compounds according to formula (II) are particularly useful for the treatment, including the acute management and the prophylaxis, of preterm labor.
In one embodiment ofthe present invention, the compounds according to formula (II) are suitable for the modulation, notably the inhibition ofthe activity of prostaglandins and particularly prostaglandin F20.. It is therefore believed that the compounds of the present invention are also particularly useful for the treatment and/or prevention of disorders which are mediated by prostaglandin F2α- Said treatment involves the modulation - notably the inhibition or the down regulation - ofthe prostaglandin function.
A further aspect ofthe invention consists in novel thiazolidine carboxamide derivatives of formula (I), wherein G' is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Cs-Cs-cycloalkyl or -heterocycloalkyl, said cycloalkyl or aryl or heteroaryl groups may be fused with cycloalkyl or aryl or heteroaryl groups.
Figure imgf000018_0001
More preferred compounds have the formula (la):
Figure imgf000018_0002
Formulae (I), (la) and (II) comprise also the geometrical isomers, the optically active forms, including enantiomers, diastereoisomers and its racemate forms, as well as pharmaceutically acceptable salts and pharmaceutically active derivatives thereof.
Substituents in formulae (I) and/or (la) are defined as follows:
R1 is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-Cs-cycloalkyl or -heterocycloalkyl, said (hetero)cycloalkyl or aryl or heteroaryl groups may be fused with (heterocycloalkyl or aryl or heteroaryl groups.
In a more preferred embodiment according to the invention, R1 is selected from the group consisting of an aryl or heteroaryl group optionally substituted with one or several substituents selected from the group consisting of aryl, heteroaryl, halogen, alkoxy, sulfanyl, straight or branched Cι-C6-alkyl.
R is selected from the group consisting of H, carboxy, acyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted Ci-Cs-alkyl carboxy, substituted or unsubstituted Ci-Cs-alkyl acyl, substituted or unsubstituted Ci-Cs-alkyl alkoxycarbonyl, substituted or unsubstituted Ci-Cs-alkyl aminocarbonyl, substituted or unsubstituted Ci-Cs-alkyl acyloxy, substituted or unsubstituted Ci- Cs-alkyl acylamino, substituted or unsubstituted Ci-Cs-alkyl ureido, substituted or unsubstituted Cj-Cs-alkyl amino, substituted or unsubstituted Ci-Cs-alkyl alkoxy, substituted or unsubstituted Ci-Cs-alkyl sulfanyl, substituted or unsubstituted Ci-Cs-alkyl sulfinyl, substituted or unsubstituted Ci-Cs-alkyl sulfonyl, substituted or unsubstituted Ci-Cs-alkyl sulfonylamino, substituted or unsubstituted Ci-Cs-alkyl sulfonyloxy, substituted or unsubstituted Ci-Cό-alkyl, substituted or unsubstituted C2-C6-alkenyl, substituted or unsubstituted C2-C6-alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Cs-Cs-cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted Cι-C6-alkyl aryl, substituted or unsubstituted C2-C6-alkyl heteroaryl, substituted or unsubstituted Cι-C6-alkyl cycloalkyl, substituted or unsubstituted Cι-C6-alkyl heterocycloalkyl, substituted or unsubstituted C2-C6-alkenyl aryl, substituted or unsubstituted C2-C6-alkenyl heteroaryl, substituted or unsubstituted C2-C6- alkynyl aryl, or substituted or unsubstituted C2-C6-alkynyl heteroaryl.
In a preferred embodiment, R2 is selected from the group consisting of carboxy, acyl, substituted or unsubstituted alkoxycarbonyl, aminocarbonyl, substituted or unsubstituted Ci-Cs-alkyl carboxy, substituted or unsubstituted Ci-Cs-alkyl acyl, substituted or unsubstituted Ci-Cs-alkyl alkoxycarbonyl, substituted or unsubstituted Ci-Cs-alkyl aminocarbonyl, substituted or unsubstituted Ci-Cs-alkyl acyloxy, substituted or unsubstituted Ci-Cs-alkyl acylamino, substituted or unsubstituted Ci-Cs-alkyl ureido, substituted or unsubstituted Cι-C5-alkyl amino, substituted or unsubstituted Ci-Cs-alkyl alkoxy, substituted or unsubstituted Ci-Cs-alkyl sulfanyl, substituted or unsubstituted Ci- Cs-alkyl sulfinyl, substituted or unsubstituted Ci-Cs-alkyl sulfonyl, substituted or unsubstituted Ci-Cs-alkyl sulfonylamino, substituted or unsubstituted Ci-Cs-alkyl sulfonyloxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.
More specifically, R may be a group Cj-C3-alkyl-A-R , wherein :
A is O or N-B-R6.
B is a bond, an amino acid residue (e.g. alanine, phenylalanine, valine, leucine, isoleucine, proline, glycine, methionine, tryptophane, threonine, serine, etc.), (C=0), (C=0)-0, (C=0)- NR7, or S02.
R5, R6 and R7 are independently from each other selected from the group consisting of H, substituted or unsubstituted Cι-C6-alkyl, substituted or unsubstituted C2-C6-alkenyl, substituted or unsubstituted C2-C6-alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-Cs-cycloalkyl or heterocycloalkyl, substituted or unsubstituted C|-C6-alkyl aryl, substituted or unsubstituted Ci-Cβ-alkyl heteroaryl, substituted or unsubstituted Ci-Cό-alkyl cycloalkyl, substituted or unsubstituted Cι-C6-alkyl heterocycloalkyl, substituted or unsubstituted C2-C6-alkenyl aryl or heteroaryl, substituted or unsubstituted C2-C6-alkynyl aryl or -heteroaryl.
R5 and B-R6 (in particular if B is a bond), and similarly R6 and R7 (if B is (C=0)-NR7), together with the respective nitrogen atoms to which they are attached, can optionally form substituted or unsubstituted heterocycloalkyl rings.
In an even more preferred embodiment, R is C |-C3-alkyl-A-R wherein A is O and R is H, or A is N-B-R6 with B being a bond, and R5 and R6 being each independently from each other selected from the group consisting of substituted or unsubstituted Cι-C3-alkyl, e.g. Ci-Cs-alkyl hydroxy, Ci-Cs-alkyl carboxy, Ci-Cs-alkyl aminocarbonyl, Cι-C3-alkyl alkoxycarbonyl, substituted or unsubstituted Cι-C3-alkyl aryl, substituted or unsubstituted Cι-C3-alkyl heteroaryl, substituted or unsubstituted Cι-C3-alkyl cycloalkyl, substituted or unsubstituted Cι-C3-alkyl heterocycloalkyl, substituted or unsubstituted Cι-C3-alkyl hydroxy, substituted or unsubstituted Cι-C3-alkyl carboxy, substituted or unsubstituted Ci- Cs-alkyl aminocarbonyl, substituted or unsubstituted C|-C3-alkyl alkoxycarbonyl.
According to a further preferred embodiment, R" is a substituted or unsubstituted phenyl, pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl.
Said phenyl, pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl moieties may optionally be substituted by at least one substituent selected from the group consisting of H, hydroxy, halogen, carboxy, acyl, aminocarbonyl, acylamino, Ci-Cs-alkyl amino, Ci-Cs-alkyl alkoxy, Ci-Cs-alkyl carboxy, Ci-Cs-alkyl acyl, Ci-Cs-alkyl aminocarbonyl, Ci-Cs-alkyl acylamino, Ci-Cs-alkyl ureido, Ci-Cs-alkyl sulfanyl, C|-C3-alkyl sulfinyl, C|-C3-aIkyl sulfonyl, Ci-Cs-alkyl sulfonylamino. Most preferred substituents are methoxy, carboxy-methoxy, hydroxy- methyl, carboxymethyl, sulfonyloxymethyl, dimethylaminomethyl, 4-morpholinylmethyl, 1-piperidinylmethyl, 1 -pyrrolidinylmethyl, (4-methyl-l-piperazinyl)-methyl, ethoxy, 2- methoxyethoxy, 2-hydroxyethoxy, 2-carboxyethoxy, 2-sulfonyloxy-ethoxy, 2-(dimethyl- amino)ethoxy, 2-(4-morpholinyl)ethoxy, 2-(l-pyrrolidinyl)ethoxy, 2-(l -piperidinyI)ethoxy, 2-(4-methyl-l -piperazinyl)ethoxy, 2-hydroxyethyl, 2-methoxyethyl, 2-carboxyethyl, 2- sulfonyloxyethyl, 2-(dimethylamino)ethyl, 2-(4-morpholinyl)ethyl, 2-(l -pyrrolidinyl)ethyl, 2-( 1 -piperidiny l)ethyl, 2-(4-methyl-l-piperazinyl)ethyl, propoxy, 3-methoxypropoxy, 3- hydroxypropoxy, 3-carboxypropoxy, 3-sulfonyloxypropoxy, 3-(dimethylamino)propoxy, 3- (4-morpholinyl)propoxy, 3 -(1 -pyrrol idinyl)propoxy, 3-(l -piperidiny l)propoxy, 3-(4- methyl-l-piperazinyl)propoxy, 3-hydroxypropyl, 3-methoxypropyl, 3-carboxypropyl, 3- sulfonyloxypropyl, 3-(dimethylamino)propyl, 3-(4-morpholinyl)propyl, 3-(l -pyrrolidinyl)- propyl, 3 -(1 -piperidiny l)propy I, 3-(4-methyl-l-piperazinyl)propyl.
RJ is selected from the group consisting of substituted or unsubstituted C|-C6-alkyl, substituted or unsubstituted C2-C6-alkenyl, substituted or unsubstituted C2-C6-alkynyl, substituted or unsubstituted aryl, heteroaryl, substituted or unsubstituted Cs-Cs-cycloalkyl or substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted Cι-C6-alkyl aryl, substituted or unsubstituted Cι-C6-alkyl heteroaryl, substituted or unsubstituted C1-C3- alkyl cycloalkyl, substituted or unsubstituted Cι-C3-alkyl heterocycloalkyl, substituted or unsubstituted C2-C6-alkenyl-aryl or -heteroaryl, substituted or unsubstituted C2-C6-alkynyl aryl or -heteroaryl, carboxy, cyano, halogen, hydroxy, alkoxy, nitro, acylamino, ureido, sulfonylamino, sulfanyl, or sulfonyl.
m is an integer from 0 to 3 and n is an integer from 0 to 2.
R4 is selected from the group consisting of substituted or unsubstituted Cι-C6-alkyl, substituted or unsubstituted C2-C6-alkenyl, substituted or unsubstituted C2-C6-alkynyl.
In a particularly preferred embodiment, R1 is a phenyl substituted with a group selected from straight or branched C i-Cs-alkyl or aryl, R is selected from the group consisting of d-Cs-alkyl-A-R5 wherein A is O and R5 is H, or A is N-B-R6 with B being a bond and R5 and R6 being each independently selected from the group consisting of Ci-Cs-alkyl, C1-C3- alkyl aryl, C i-Cs-alkyl heteroaryl, Cι-C3-alkyl-hydroxy.
In a more particularly preferred embodiment, R is a biphenyl or a tert-buty\ phenyl group, R2 is d-Cs-alkyl-A-R5, wherein A is O and R5 is H, or A is N-B-R6, R5 and R6 are each independently from each other Cι-C3-alkyl, Cι-C3-alkyl aryl, C i-Cs-alkyl heteroaryl, or Ci- Cs-alkyl hydroxy, B is a bond, RJ is fluorine, m is either 0, 1 , or 2, and n is 0.
In another more particularly preferred embodiment, R1 is a biphenyl or a tert-b y\ phenyl group, R is pyrid-2-yl, carrying one or several substituents selected from the group consisting of H, OH, alkoxy, Ci-Cs-alkyl amino, Ci-Cs-alkyl hydroxy, Ci-Cs-alkyl carboxy, Ci- -alkyl sulfonyloxy, RJ is fluorine, m is either 0, 1 , or 2, and n is 0. Compounds ofthe present invention are in particular those ofthe group consisting of:
(2Λ)-3-([l ,l*-biphenyl]-4-ylsulfonyl)-N-[(75')-3-hydroxy-l-phenylpropyl]-l ,3-thiazolidine- 2-carboxamide
(2^)-3-([l,r-biphenyl]-4-ylsulfonyl)-N-[(7?)-phenyl(2-pyridinyl)methyl]-l ,3-thiazolidine- 2-carboxamide
(27?)-3-[(4-ter/-butylphenyl)sulfonyl]-N-[(7-S -3-hydroxy-l-phenylpropyl]-l,3-thiazolidine- 2-carboxamide
(2-^)-N-[(7-S)-3-hydroxy-l-phenylpropyl]-3-[(4-/ert-pentylphenyl)suIfonyl]-l ,3-thiazo- lidine-2-carboxamide
(2.S)-2-({[3-([l ,l '-biphenyl]-4-ylsulfonyl)- l ,3-thiazolidin-2-yl]carbonyl}amino)-3- phenylpropanoic acid
(2-S)-2-[({3-[(5-chloro-3-methyl-l-benzothien-2-yl)sulfonyl]-l ,3-thiazolidin-2- yl}carbonyl)amino]-3-phenylpropanoic acid
(2-S)-3-([l,l *-biphenyl]-4-ylsulfonyl)-N-((7_S -3-{methyl[2-(2-pyridinyl)ethyl]amino}-l- phenylpropyl)- 1 ,3-thiazolidine-2-carboxamide
(25)-3-([1 , r-biphenyl]-4-ylsulfonyl)-N-[(7- )-l-phenyl-2-propenyl]-l ,3-thiazolidine-2- carboxamide
(2S)-3-([ 1 , 1 '-bipheny l]-4-y lsulfonyl)-N-[(7S 3-(diethylamino)- 1 -phenylpropyl]- 1 ,3- thiazolid ine-2-carboxamide
(2S)-3-([ 1 , 1 '-biphenyl]-4-y lsulfonyl)-N-[(75)-3-hydroxy- 1 -phenylpropyl]- 1 ,3-thiazolid ine- 2-carboxamide (2_S)-3-([l,l'-biphenyl]-4-ylsulfonyl)-N-[(7?)-phenyl(2-pyridinyl)methyl]-l,3-thiazolidine-2- carboxamide
(2-S)-3-([l,l'-biphenyl]-4-ylsulfonyl)-N-{(7-S)-3-[(2-ftιrylmethyl)(methyl)amino]-l- phenylpropyl}- 1 ,3-thiazolidine-2-carboxamide
(21S)-3-([l ,l*-biphenyl]-4-ylsulfonyl)-N-{(7-S)-3-[(2-hydroxyethyl)(methyl)amino]-l- phenylpropyl}-l,3-thiazolidine-2-carboxamide
(2S)-3-([\ , 1 '-bipheny l]-4-ylsulfonyl)-N-{(7£)-3-[2-(2-hydroxyethyl)- 1 -piperidiny I]- 1 - phenylpropyl}- l ,3-thiazolidine-2-carboxamide
(25 -3-([l,l '-biphenyl]-4-ylsulfonyl)-N-{(75)-3-[4-(2-methoxyphenyl)-l-piperazinyl]-1 - phenylpropyl}- l ,3-thiazolidine-2-carboxamide
(2S)-3-[(4-tø^butylphenyl)sulfonyl]-N-[(7S)-3-hydroxy-l -phenylpropyl]- 1 ,3-thiazolidine- 2-carboxamide
(2-S)-3-phenyl-2-{[(3-{[5-(2-pyridinyl)-2-thienyl]sulfonyl}-l ,3-thiazolidin-2-yl)car- bonyl]amino}propanoic acid
(21S)-N-[(7_S)-3-hydroxy- l-phenylpropyl]-3-[(4-fer/'-pentylphenyl)sulfonyl]- 1 ,3- thiazolidine-2-carboxamide
(2S)-N- {(75)-3-[benzy l(methy l)amino]- 1 -pheny Ipropyl} -3-([ 1 , 1 '-bipheny l]-4-y Isulfony I)- 1 ,3-thiazolid ine-2-carboxamide
3-([l , r-biphenyl]-4-ylsulfonyl)-N-(l -phenyl-3-{[(2.S)-tetrahydro-2-furanylmethyl]amino}- propyl)- 1 ,3-thiazolidine-2-carboxamide
3-([l , l '-biphenyl]-4-y Isulfony 1)-N-(1 -pheny 1-3- {[2-(l -piperidiny l)ethyl]amino}propyl)- 1 ,3- thiazolidine-2-carboxamide 3-([ 1 , 1 '-biphenyl]-4-y Isulfony I ■N- 1 -phenyl-3- { [2-(2-pyridinyl)ethyl]amino} propyl)- 1 ,3- thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-y Isulfony 1 ■N-< 1 -phenyl-3- {[2-(3-pyridinyl)ethyl]amino}propyl)- 1 ,3- thiazolidine-2-carboxamide
3-([ 1 , 1 '-biphenyl]-4-ylsulfony 1 -TV- 1 -phenylpropyl)- 1 ,3-thiazolidine-2-carboxamide
3-([l , 1 '-bipheny l]-4-ylsulfony I <-N-< 2,3-difluorobenzy I)- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-y Isulfony 1 -N- 2,4-difluorobenzyl)-l ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-ylsulfony 1 ■N- 2,5-difluorobenzyl)- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-biphenyl]-4-ylsulfony 1 -N-< 2,6-difluorobenzyl)- 1 ,3-thiazolidine-2-carboxamide
3-([l , 1 '-biphenyl]-4-y Isulfony I -TV- 2-chloro-4-fluorobenzyl)- l ,3-thiazolidine-2- carboxamide
3-([ 1 , 1 '-bipheny l]-4-y Isulfony I -TV- 2-fluorobenzyl)- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-y Isulfony 1 >-N- 2-ftιrylmethyl)- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-biphenyl]-4-ylsulfony I <-N~ 2-methoxybenzy I)- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-y Isulfony I ■N- 2-methylbenzyl)- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-y Isulfony 1 ■N- 2-phenylpropyl)- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-ylsulfony 1 ■N- 2-thieny l ethy 1)- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-biphenyl]-4-ylsulfony I ■N- 3,4-difluorobenzyl)- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 *-biphenyl]-4-y lsulfonyl ■N- 3- { [(27?)-2-hydroxy-2-pheny lethy l]amino} - 1- phenylpropyl)- 1 ,3-thiazolidine-2-carboxamide 3-([ 1 , 1 '-bipheny l]-4-y Isulfony l)-N-(3- { [(2S)-2-hydroxypropy l]amino} - 1 -phenylpropyl)- 1 ,3- thiazolidine-2-carboxamide
3-([l,l'-biphenyl]-4-ylsulfonyl)-7V-(3-{[(5-methyl-2-furyl)methyl]amino}-l-phenylpropyl)- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-y Isulfony l)-N-(3- { [2-( 1 H-indol-3-y l)ethyl] amino} - 1 -pheny lpropyl)- 1 ,3-thiazolidine-2-carboxamide
3-([l, -biphenyl]-4-ylsulfonyl)-N-(3-{[2-(l-methyl-2-pyrrolidinyl)ethyl]amino}-l- phenylpropyl)- 1 ,3-thiazolidine-2-carboxamide
3-([l,l'-biphenyl]-4-ylsulfonyl)-N-(3-{[2-(4-mo holinyl)ethyl]amino}-l -phenylpropyl)- l ,3-thiazolidine-2-carboxamide
3-([l,r-biphenyl]-4-ylsulfonyl)-N-(3-{[2-(dimethylamino)ethyl]amino}-l-phenylpropyl)- 1 ,3-thiazolidine-2-carboxamide
3-([l,l'-biphenyl]-4-ylsulfonyl)-N-(3-{[3-(2-oxo-l-pyrrolidinyl)propyl]amino}-l -phenylpropyl)- 1 ,3-thiazolidine-2-carboxamide
3-([l,l'-biphenyl]-4-ylsulfonyl)-N-(3-{[3-(4-morpholinyl)propyl]amino}-l-phenylpropyl)- 1 ,3-thiazolidine-2-carboxamide
3-([l,r-biphenyl]-4-ylsulfonyl)-N-(3-{methyl[(77?)-l -phenylethyl]amino}-l -phenylpropyl)- 1 ,3-thiazolidine-2-carboxamide
3-([l,l'-biphenyl]-4-ylsulfonyl)-N-(3-{methyl[(7-S -l-phenylethyl]amino}-l-phenylpropyl)- l ,3-thiazolidine-2-carboxamide
3-([ 1,1 '-biphenyl]-4-ylsulfonyl)-N-(3-{methyl[2-(2-pyridinyl)ethyl]amino}-l -pheny 1- propyl)-l ,3-thiazolidine-2-carboxamide 3-([l,l'-biphenyl]-4-ylsulfonyl)-N-(3-chloro-4-fluorobenzyl)-l ,3-thiazolidine-2-carbox- amide
3-([l , 1 '-bipheny l]-4-ylsulfonyl)-N-(3-fluorobenzyl)- 1 ,3-thiazolidine-2-carboxamide
3-([l , 1 '-biphenyl]-4-ylsulfonyl)-N-(3-hydroxy-l -phenylpropyl)- 1 ,3-thiazolidine-2- carboxamide
3-([ 1 ,1 '-bipheny l]-4-ylsulfonyl)-N-(3-methylbenzyl)-l,3-thiazolidine-2-carboxamide
3-([l , 1 '-bipheny l]-4-y Isulfony l)-N-(3-phenoxy- 1 -phenylpropyl)- 1 ,3-thiazolidine-2- carboxamide
3-([ 1 , 1 '-biphenyl]-4-y lsulfonyl)-7Vr-(3-pyridinylmethyl)- 1 ,3-thiazolidine-2-carboxamide
3-([l ,l '-biphenyl]-4-y Isulfony l)-N-(4-fluorobenzyl)-l ,3-thiazolidine-2-carboxamide
3-([l , 1 '-bipheny l]-4-ylsulfonyl)-N-(4-phenoxybenzyl)- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-biphenyl]-4-ylsulfony l)-N-[( 1 ,5-dimethy 1- 1 H-pyrrol-2-yl)methyl]- 1 ,3-thiazolidine- 2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-y Isulfony l)-N-[(l -oxido-2-pyridinyl)methyl]- 1 ,3-thiazolidine-2- carboxamide 1 -oxide
3-([ 1 , 1 '-bipheny l]-4-ylsuIfonyl)-N-[(77?)-2-hydroxy- 1 -phenylethy 1]- 1 ,3-thiazol idine-2- carboxamide
3-([ 1 , 1 '-bipheny l]-4-y Isulfony l)-N-[(77?)-3-hydroxy- 1 -phenylpropyl]- 1 ,3-thiazolidine-2- carboxamide
3-([l , -biphenyl]-4-ylsuIfonyl)-N-[(75)-l-phenylethyl]-l ,3-thiazolidine-2-carboxamide 3-([l,l '-biphenyl]-4-y Isulfony l)-N-[(7-S)-3-hydroxy-l -pheny lpropyl]-l , 3-thiazolidine-2- carboxamide
3-([l,l'-biphenyl]-4-ylsulfonyl)-N-[(7?)-{6-[2-(dimethylamino)ethoxy]-2-pyridinyl}- (phenyl)methyl]- 1 ,3-thiazolidine-2-carboxamide
3-([l ,l'-biphenyl]-4-ylsulfonyl)-N-[(7?)-phenyl(2-pyridinyl)methyl]- l,3-thiazolidine-2- carboxamide
3-([ 1 , 1 -bipheny l]-4-y Isulfony l)-N-[(»S)-phenyl(2-pyridiny l)methy I]- 1 ,3-thiazolidine-2- carboxamide
3-([l,l'-biphenyl]-4-ylsulfonyl)-N-[l -(2,6-difluorophenyl)-3-hydroxypropyl]-l ,3-thia- zolidine-2-carboxamide
3-([l ,1 '-bipheny l]-4-y Isulfony l)-N-[l -(2-chlorophenyl)-3-hydroxypropyl]- 1 ,3-thiazolidine- 2-carboxamide
3-([ 1,1 '-bipheny l]-4-y Isulfony l)-N-[l-(2-furyl)-3-hydroxypropy I]- 1 , 3-thiazolidine-2- carboxamide
3-([ 1,1 '-bipheny l]-4-y Isulfony l)-N-[l -(3,4-dich lorophenyl)-3-hydroxypropy I]- 1 , 3- thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-y Isulfony l)-N-[l -(3-chlorophenyl)-3-hydroxypropyl]- 1 ,3-thiazolidine- 2-carboxamide
3-([l , -biphenyl]-4-ylsulfonyl)-N-[l -(3-furyl)-3-hydroxypropyl]- l ,3-thiazolidine-2- carboxamide
3-([ 1 , 1 '-bipheny l]-4-y Isulfony l)-N-[ 1 -(4-chloropheny I)-3-hydroxypropy 1]- 1 ,3-thiazolidine- 2-carboxamide 3-([l , 1 '-bipheny l]-4-ylsulfonyl)-N-[l -(4-chlorophenyl)ethyl]- 1 ,3-thiazolidine-2-carbox- amide
3-([l,l '-bipheny l]-4-ylsulfonyl)-N-[l -(4-fluorophenyl)-3-hydroxypropyl]- 1,3-thiazolidine- 2-carboxamide
3-([l ,l'-biphenyl]-4-ylsulfonyl)-N-[l -(4-fluorophenyl)ethyl]-l ,3-thiazolidine-2-carbox- amide
3-([ 1 , 1 '-bipheny l]-4-ylsulfonyl)-N-[ 1 -phenyl-2-(l -pyrrolidinyl)ethyl]- 1 ,3-thiazolidine-2- carboxamide
3-([ 1 ,1 '-bipheny l]-4-ylsulfonyl)-N-[l -phenyl-3-({[(7-S,27?,3R,55 -2,6,6-trimethylbicyclo- [3.1.1 ]hept-3-yl]methyl}amino)propyl]-l ,3-thiazolidine-2-carboxamide
3-([l ,l '-biphenyl]-4-ylsulfonyl)-N-[l -phenyl-3-(l -piperazinyl)propyl]-l,3-thiazolidine-2- carboxamide
3-([l,l '-biphenyl]-4-ylsulfonyl)-N-[l -phenyl-3-(l-piperidinyl)propyl]-l ,3-thiazolidine-2- carboxamide
3-([l,l'-biphenyl]-4-ylsulfonyl)-N-[l -phenyl-3-(l-pyrrolidinyl)propyl]-l ,3-thiazolidine-2- carboxamide
3-([l,l '-biphenyl]-4-ylsulfonyl)-N-[2-(4-morpholinyl)-l -phenylethyl]-l ,3-thiazolidine-2- carboxamide
3-([l ,l'-biphenyl]-4-ylsulfonyl)-N-[2-(dimethylamino)-l-phenylethyl]-l,3-thiazolidine-2- carboxamide
3-([l,l *-biphenyl]-4-ylsulfonyl)-N-[3-((37?)-3-(hydroxymethyl)-3,4-dihydro-2(l H)-iso- quinolinyl)-l-phenylpropyl]-l,3-thiazolidine-2-carboxamide 3-([l ,l'-biphenyl]-4-ylsulfonyl)-N-[3-((5,S)-3-(hydroxymethyl)-3,4-dihydro-2(lH)- isoquinoliny 1)- 1 -phenylpropyl]- 1 ,3-thiazolidine-2-carboxamide
3-([l ,l*-biphenyl]-4-ylsulfonyl)-N-[3-(l ,3-dioxo-l ,3-dihydro-2H-isoindol-2-yl)-l- phenylpropyl]- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 *-biphenyl]-4-ylsulfonyl)-N-[3-(2,5-dihydro- 1 H-pyrrol- 1 -yl)- 1 -phenylpropyl]- 1 ,3- thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-ylsulfonyl)-N-[3-(3,5-dimethyl- 1 -piperidinyl)- 1 -phenylpropyl]- 1 ,3- thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-ylsulfonyl)-N-[3-(3,6-dihydro- 1 (2H)-pyridinyl)- 1 -phenylpropyl]- 1 ,3- thiazolidine-2-carboxamide
3-([l ,l '-biphenyl]-4-ylsulfonyl)-N-[3-(3-hydroxy- 1 -piperidinyl)- 1 -phenylpropyl]- 1 ,3- thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-y Isulfony l)-N-[3-(3-hydroxy- 1 -pyrrolidinyl)- 1 -pheny lpropy I]- 1 ,3- thiazolidine-2-carboxamide
3-([ 1 ,1 '-bipheny l]-4-ylsulfonyl)-N-[3-(3-methyl- 1-piperidinyl)- 1 -phenylpropyl]- 1,3- thiazolidine-2-carboxamide
3-([ 1 , 1 '-biphenyl]-4-ylsulfonyl)-N-[3-(4-hydroxy- 1 -piperidinyl)- 1 -phenylpropyl]- 1 ,3- thiazolidine-2-carboxamide
3-([ 1 ,1 '-biphenyl]-4-yIsulfonyl)-N-[3-(4-hydroxy-4-phenyl- 1-piperidinyl)- 1 -pheny lpropy 1]- l ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-ylsulfonyl)-N-[3-(4-methy I- 1 -piperazinyl)- 1 -phenylpropyl]- 1 ,3- thiazolidine-2-carboxamide 3-([ 1 , 1 '-biphenyl]-4-ylsulfonyl)-N-[3-(4-morpholiny 1)- 1 -phenylpropyl]- 1 ,3-thiazolidine-2- carboxamide
3-([ 1 , 1 '-bipheny l]-4-ylsulfony l)-N-[3-(diethy lamino)- 1 -phenylpropyl]- 1 ,3-thiazolidine-2- carboxamide
3-([ 1 , 1 '-biphenyl]-4-ylsulfonyl)-N-[3-(dimethylamino)- 1 -phenylpropyl]- 1 ,3-thiazolidine-2- carboxamide
3-([ 1 , 1 '-biphenyl]-4-ylsulfony l)-N- [3 -hydroxy- 1 -(2-methoxyphenyl)propyl]- 1 ,3- thiazolidine-2-carboxamide
3-([l ,l '-biphenyl]-4-ylsulfonyl)-N-[3-hydroxy-l -(2-methylphenyl)propyl]-l ,3-thiazolidine- 2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-y Isulfony I )-N- [3 -hydroxy- 1 -(3-methoxyphenyl)propyl]- 1 ,3- thiazolidine-2-carboxamide
3-([ 1 , 1 '-biphenyl]-4-y lsulfonyl)-N-[3-hydroxy- 1 -(3-pyridinyl)propyl]- 1 ,3-thiazolidine-2- carboxamide
3-([ 1 , 1 '-bipheny l]-4-ylsulfonyl)-N-[3-hydroxy- l-(4-ιnethoxyphenyl)propyl]- 1 ,3- thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-y Isulfony l)-N-[3-hydroxy- 1 -(4-methylphenyl)propy 1]- 1 ,3-th iazolidine- 2-carboxamide
3-([ l ,r-biphenyl]-4-ylsulfonyl)-N-[phenyl(2-pyridinyl)methyl]-l ,3-thiazolidine-2- carboxamide
3-([l ,l '-biphenyl]-4-ylsulfonyl)-N-{ l-phenyI-3-[(2-phenylethyl)amino]propyl}-l ,3- thiazolidine-2-carboxamide 3-([l ,l '-biphenyl]-4-ylsulfonyl)-N-{ l-ρhenyl-3-[(2-phenylpropyl)amino]propyl}-l,3- thiazolidine-2-carboxamide
3-([l ,l'-biphenyl]-4-ylsulfonyl)-N-{ l-phenyl-3-[(2-pyridinylmethyl)amino]propyl}-l,3- thiazolidine-2-carboxamide
3-([l, l'-biphenyl]-4-ylsulfonyl)-N-{l-phenyl-3-[(3-pyridinylmethyl)amino]propyl}-l,3- thiazolidine-2-carboxamide
3-([ 1 ,1 '-bipheny l]-4-y Isulfony 1)-N-{ 1 -pheny l-3-[(tetrahydro-2-furany lmethy l)amino]- propyl}-l ,3-thiazolidine-2-carboxamide
3-([l , -biphenyl]-4-ylsulfonyl)-N-{ l -phenyl-3-[4-(l -pyrrolidinyl)- l-piperidinyl]propyl}- l ,3-thiazolidine-2-carboxamide
3-([l , l '-biphenyl]-4-ylsulfonyl)-N-{3-[(2-furylmethyl)(methyl)amino]-l-phenylpropyl}- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-y Isulfony 1)-N- {3-[(2-fury lmethy l)amino]- 1 -phenylpropyl} - 1 ,3- thiazolidine-2-carboxamide
3-([l , -biphenyl]-4-ylsulfonyl)-N-{3-[(2-hydroxy-2-phenylethyl)(methyl)amino]-l- phenylpropyl}-l ,3-thiazolidine-2-carboxamide
3-([l , l '-biphenyl]-4-ylsulfonyl)-N-{3-[(2-hydroxy-2-phenylethyl)amino]-l-phenylpropyl}- 1 ,3-thiazolidine-2-carboxamide
3-([l ,l '-biphenyl]-4-ylsulfonyl)-N-{3-[(2-hydroxycyclohexyl)amino]-l-phenylpropyl}-l ,3- thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-ylsulfonyl)-N-{3-[(2-hydroxyethyl)(methyl)amino]-l -pheny lpropyl}- 1 ,3-thiazolidine-2-carboxamide 3-([ 1 ,1 '-bipheny l]-4-y Isulfony 1)-N- {3- [(2-hydroxyethyI)amino]-l -phenylpropyl}- 1 ,3- thiazolidine-2-carboxamide
3-([l,l'-biphenyl]-4-ylsulfonyl)-N-{3-[(2-hydroxypropyl)amino]-l -phenylpropyl}- 1 ,3- thiazolidine-2-carboxamide
3-([l,l'-biphenyl]-4-y Isulfony l)-N-{3-[(2/?)-2-(hydroxymethyl)pyrrolidinyl]-l -phenylpropyl} -l ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-y Isulfony 1)-N- {3-[(2jR)-2-(methoxymethy l)pyrro lidinyl]- 1 -pheny 1- propyl}- l ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-biphenyl]-4-y Isulfony l)-N-{3-[(2S)-2-(methoxymethyl)pyrrolidinyl]- 1 -phenyl- propyl} -l ,3-thiazolidine-2-carboxamide
3-([l ,l'-biphenyl]-4-ylsulfonyl)-N-{3-[(3,5-difluorobenzyl)amino]-l -phenylpropyl}- 1 ,3- thiazolidine-2-carboxamide
3-([l ,r-biphenyl]-4-ylsulfonyl)-N-{3-[(3-hydroxy-3-phenylpropyl)(methyl)amino]-l - phenylpropyl}-l ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-ylsulfonyl)-N-{3-[(3-hydroxypropyl)amino]-l -phenylpropyl}- 1 ,3- thiazolidine-2-carboxamide
3-([l , -biphenyl]-4-ylsulfonyl)-N-{3-[(37?)-3-hydroxypyrrolidinyl]-l -phenylpropyl}- 1 , 3- thiazolidine-2-carboxamide
3-([l , -biphenyl]-4-ylsulfonyl)-N-{3-[(4-fluorobenzyl)amino]-l-phenylpropyl}-l ,3- thiazolidine-2-carboxamide
3-([ 1 ,1 '-bipheny l]-4-y Isulfony l)-N-{3-[[3-(dimethylamino)propyl](methyl)amino]-l - phenylpropyl}-l ,3-thiazolidine-2-carboxamide 3-([ 1,1 '-bipheny l]-4-ylsulfonyl)-N-{3-[2-(hydroxymethyl)- 1-piperidinyl]- 1 -phenylpropyl} - l,3-thiazolidine-2-carboxamide
3-([l,l'-biphenyl]-4-ylsulfonyl)-N-{3-[3-(hydroxymethyl)- 1-piperidinyl]- 1 -phenylpropyl} - 1 ,3-thiazolidine-2-carboxamide
3-([l,l'-biphenyl]-4-ylsulfonyl)-N-{3-[4-(2-hydroxyethyl)- 1-piperidinyl]- 1 -phenylpropyl} - 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-y Isulfony 1)-N- (3-[4-(hydroxymethyl)- 1 -piperidinyl]- 1 -phenylpropy 1} - l,3-thiazolidine-2-carboxamide
3-([ 1,1 '-biphenyl]-4-ylsulfonyl)-N-{3-[methyl(2-phenylethyl)amino]-l -phenylpropyl} - 1 ,3- thiazolidine-2-carboxamide
3-[(3',4*-dichloro[l , l *-biphenyl]-4-yl)sulfonyl]-N-[l -(2-furyl)-3-hydroxypropyI]-l ,3- thiazolidine-2-carboxamide
3-[(4'-chloro[ 1 , 1 '-biphenyl]-4-yl)sulfonyl]-N-[ 1 -(2-furyl)-3-hydroxypropy I]- 1 ,3- thiazolidine-2-carboxamide
3-[(4-chlorophenyl)sulfonyl]-N-(2-pyridinylmethyl)-l ,3-thiazolidine-2-carboxamide
3-[(4-chlorophenyl)sulfonyl]-N-{4-[({[(2- ethylhexyl)amino]carbonyl}amino)methyl]benzyl}- l ,3-thiazolidine-2-carboxamide
3-[(4-chlorophenyl)sulfonyl]-N-{4-[({[(2- phenylethyl)amino]carbonyl}amino)methyl]benzyl}- l ,3-thiazolidine-2-carboxamide
3-[(4-chlorophenyl)sulfonyl]-N-{4-[({[(4- methylbenzyl)amino]carbonyl}amino)methyl]benzyl}-l ,3-thiazolidine-2-carboxamide 3-[(4'-fluoro[l,l '-biphenyl]-4-yl)sulfonyl]-N-[l-(2-furyl)-3-hydroxypropyl]-l ,3-thia- zolidine-2-carboxamide
3-[(4-iodophenyl)sulfonyl]-N-{4-[({[(4-methylbenzyl)amino]carbonyl}amino)methyl]- benzyl}-l ,3-thiazolidine-2-carboxamide
3-[(4-tert-butylphenyl)sulfonyl]-N-(l ,2-diphenylethyl)-l ,3-thiazolidine-2-carboxamide
3-[(4-fer/-butylphenyl)sulfonyl]-N-(l -phenylethyl)-l,3-thiazolidine-2-carboxamide
3-[(4-tert-butylphenyl)sulfonyl]-N-(2,3-dihydro-lH-inden-l -yl)-l ,3-thiazolidine-2- carboxamide
3-[(4-tert-butylphenyl)sulfonyl]-N-(2-furylmethyl)-l ,3-thiazolidine-2-carboxamide
3-[(4-ter^butylphenyl)sulfonyl]-N-(2-phenylpropyl)- 1 ,3-thiazolidine-2-carboxamide
3-[(4-/er/-butylphenyl)sulfonyl]-N-(3-hydroxy-l -phenylpropyl)- 1 , 3-thiazolidine-2- carboxamide
3-[(4-^r -butylphenyl)sulfonyl]-N-(3-pyridinylmethyl)-l ,3-thiazolidine-2-carboxamide
3-[(4-fert-buty lphenyl)sulfonyl]-N-[2-( 1 H-indol-3-yl)- 1 -methy lethyl]- 1 ,3-thiazolidine-2- carboxamide
3-[(4-tert-butylphenyl)sulfonyl]-N-{[l -(4-chlorophenyl)cyclopropyl]methyl}-l ,3- thiazolidine-2-carboxamide
3-[(4-ter/^-butylphenyl)sulfonyl]-N-{4-[3-(dimethylamino)propoxy]benzyl}-l ,3- thiazolidine-2-carboxamide
3-{[5-(3-isoxazolyl)-2-thienyl]sυlfonyl}-N-{4-[({[(2-phenylethyl)amino]carbonyl}- amino)methyl]benzyl}- l ,3-thiazolidine-2-carboxamide ethyl {4-[(i,S)-3-({[(25)-3-([l , l'-biphenyl]-4-ylsulfonyl)-l,3-thiazolidin-2-yl]carbonyl}- amino)-3-phenylpropyl]-l -piperazinyl}acetate
methyl [[(3-S)-3-({[(2- )-3-([l,l*-biphenyl]-4-ylsulfonyl)-l,3-thiazolidin-2-yl]carbonyl}- amino)-3-phenylpropyl](methyl)amino]acetate
N-(2,2-diphenylethyl)-3-(8-quinolinylsulfonyl)-l,3-thiazolidine-2-carboxamide
N-(2-aminobenzyl)-3-([l ,l'-biphenyl]-4-ylsuIfonyl)-l ,3-thiazolidine-2-carboxamide
V-(3- { [2-(acetylamino)ethy l]amino} - 1 -pheny lpropy l)-3-([ 1 , 1 '-biphenyl]-4-ylsulfony 1)- 1 ,3- th iazolidine-2-carboxamide
N-(3-amino- 1 -pheny lpropy l)-3-([l , 1 '-biphenyl]-4-ylsulfonyl)- 1 ,3-thiazolidine-2- carboxamide
N-(3-aminobenzyl)-3-[(4-ter^butylphenyl)sulfonyl]-l ,3-thiazolidine-2-carboxamide
N-(3-hydroxy-l -phenylpropyl)-3-[(4-phenoxyphenyl)sulfonyl]-l ,3-thiazolidine-2- carboxamide
N-(4-aminobenzyl)-3-[(4-/ert-butylphenyl)sulfonyl]- l ,3-thiazolidine-2-carboxamide
N-[(77?)-l-benzyl-2-hydroxyethyl]-3-([l , 1 '-bipheny l]-4-y Isulfony 1)- 1 ,3-thiazolidine-2- carboxamide
N-[(6-amino-3-pyridinyl)methyl]-3-[(4-/ert-butylphenyl)sulfonyl]- l ,3-thiazolidine-2- carboxamide
N-[l -(1 ,3-benzodioxol-5-yl)-3-hydroxypropyl]-3-([l , 1 '-biphenyl]-4-ylsulfonyl)- 1 ,3- thiazolidine-2-carboxamide N-[ 1 -( 1 -benzofuran-2-yl)-3-hydroxypropy l]-3-([ 1 , 1 '-bipheny l]-4-ylsulfony 1)- 1 ,3- thiazolidine-2-carboxamide
N-[l -(2-furyl)-3-hydroxypropyl]-3-[(2*-methyl[l,l'-biphenyl]-4-yl)sulfonyl]-l,3- thiazolidine-2-carboxamide
N-[l-(2-furyl)-3-hydroxypropyl]-3-[(4"-methoxy[l,l*-biphenyl]-4-yl)sulfonyl]-l ,3- thiazolidine-2-carboxamide
N-[ 1 -(2-furyl)-3-hydroxypropyl]-3-[(4*-methy 1[ 1 , 1 '-bipheny l]-4-yl)sulfony I]- 1 ,3- thiazolidine-2-carboxamide
N-[3-( 1 -azepanyl)- 1 -phenylpropyl]-3-([ 1 , 1 '-biphenyl]-4-ylsulfonyl)- 1 ,3-thiazolidine-2- carboxamide
N-[3-(4-acetyl- 1 -piperazinyl)- 1 -pheny lpropy l]-3-([l , 1 '-biphenyl]-4-ylsulfonyl)- 1 ,3- thiazolidine-2-carboxamide
N-[3-(4-benzyl-4-hydroxy- 1 -piperidinyl)- l -phenylpropyl]-3-([l , l'-biphenyl]-4-y Isulfony I)- l,3-thiazolidine-2-carboxamide
N-[3-(acetylamino)-l-phenylpropyl]-3-([l ,l '-biphenyl]-4-ylsulfonyl)- l ,3-thiazolidine-2- carboxamide
N-[3-(benzylamino)- 1 -phenylpropyl]-3-([ 1 , 1 '-biphenyl]-4-ylsulfonyl)- 1 ,3-thiazolidine-2- carboxamide
N-[4-({[(hexylamino)carbonyl]amino}methyl)benzyl]-3-(phenylsulfonyl)- l ,3-thiazolidine- 2-carboxamide
N-[4-({[(hexylamino)carbonyl]amino}methyl)benzyl]-3-{[5-(3-isoxazolyl)-2- thienyl]sulfonyl}- l ,3-thiazolidine-2-carboxamide N-{3-[(l-adamantylmethyl)amino]-l-phenylpropyl}-3-([l,l'-biphenyl]-4-ylsulfonyl)-l ,3- thiazolidine-2-carboxamide
N-{3-[(27?)-2-(anilinomethyl)pyrrolidinyl]-l-phenylpropyl}-3-([l,l'-biphenyl]-4- ylsulfonyl)- 1 ,3-thiazolidine-2-carboxamide
N-{3-[(25)-2-(anilinomethyl)pyrrolidinyl]-l-phenylpropyl}-3-([l,l'-biphenyl]-4- ylsulfonyl)- 1 ,3-thiazolidine-2-carboxamide
N-{3-[benzyl(2-hydroxyethyl)amino]-l-phenylpropyl}-3-([l ,r-biphenyl]-4-ylsulfonyl)- 1 ,3-thiazolidine-2-carboxamide
N-{3-[benzyl(methyl)amino]-l-phenylpropyl}-3-([l , l'-biphenyl]-4-ylsulfonyl)-l ,3- thiazolidine-2-carboxamide
N-{4-[({[(2-ethylhexyl)amino]carbonyl}amino)methyl]benzyl}-3-[(4-iodophenyl)- sulfonyl]-l,3-thiazolidine-2-carboxamide
N-benzhydry l-3-([ 1 , 1 '-bipheny l]-4-y Isulfony 1)- 1 ,3-thiazolidine-2-carboxamide
N-benzhydryl-3-(8-quinolinylsulfonyl)-l ,3-thiazolidine-2-carboxamide
N-benzyl{3-[(4-ter/-butylphenyl)sulfonyl]-l ,3-thiazolidin-2-yl}methanamine
N-benzyl-3-([ 1 , 1 '-biphenyl]-4-ylsulfonyl)- 1 ,3-thiazolidine-2-carboxamide
N-benzyl-3-[(4-ter^-butylphenyl)sulfonyl]-l ,3-thiazolidine-2-carboxamide
tert-buty\ 3-{[({3-[(4-terf-butylphenyl)sulfonyl]-l ,3-thiazolidin-2-yl}carbonyl)amino]- methyl} pheny lcarbamate
tert-buty\ 5-{2-[({3-[(4-tert-butylphenyl)sulfonyl]-l ,3-thiazolidin-2-yl}carbonyl)amino]- ethyl}-2-pyridiny lcarbamate (3S)-3-({[(2S)-3-(biphenyl-4-ylsulfonyl)-l,3-thiazolidin-2-yl]carbonyl}amino)-3-(2,6- difluorophenyl)propyl L-valinate
(3S)-3-(2,6-difluorophenyl)-3-[({(2S)-3-[(2'-fluorobiphenyl-4-yl)sulfonyl]- l ,3-thiazolidin- 2-yl}carbonyl)amino]propyl L-valinate
(3S)-3-({[(2S)-3-(biphenyl-4-ylsulfonyl)- l ,3-thiazolidin-2-yl]carbonyl}amino)-3- phenylpropyl L-valinate
(3S)-3-[({(2S)-3-[(2'-fluorobiphenyl-4-yl)sulfonyl]-l ,3-thiazolidin-2-yl}carbonyl)amino]- 3-phenylpropyl L-valinate
3-({[(3S)-3-({[3-(biphenyl-4-ylsulfonyl)-l ,3-thiazolidin-2-yl]carbonyl}amino)-3- phenylpropyl]amino}sulfonyl)benzoic acid
(2S)-N-[(l S)-l -(2,6-difluorophenyl)-3-hydroxypropyl]-3-[(2'-fluorobiphenyl-4- yl)sulfonyl]- 1 ,3-thiazolidine-2-carboxamide
(2S)-3-[(2'-fluorobiphenyl-4-yl)sulfonyl]-N-[(R)-phenyl(pyridin-2-yl)methyl]-l,3- thiazolidine-2-carboxamide
(2S)-3-[(2'-fluorobiphenyl-4-yl)sulfonyl]-N-[(S)-(l -methylpiperidin-4-yl)(phenyl)methyl]- 1 ,3-thiazolidine-2-carboxamide
3-(biphenyl-4-ylsulfonyl)-N-[(2-chloropyridin-4-yl)(phenyl)methyl]-l ,3-thiazolidine-2- carboxamide
3-(biphenyl-4-ylsulfonyl)-N-[(6-hydroxypyridin-3-yl)(phenyl)methyl]-l ,3-thiazolidine-2- carboxamide
(2S)-3-[(2*-fluorobiphenyl-4-yl)sulfonyl]-N-[(R)-ρhenyl(pyridin-4-yl)methyl]- l ,3- thiazolidine-2-carboxamide (2S)-3-[(4-iodophenyl)sulfonyl]-N-[(R)-phenyl(pyridin-2-yl)methyl]-l ,3-thiazolidine-2- carboxamide
3-(biphenyl-4-ylsulfonyl)-N-[[5-(2-hydroxyethyl)-l,2,4-oxadiazol-3-yl](phenyl)methyl]- 1 ,3-thiazolidine-2-carboxamide
methyl 2-methyl-2-(4-{[2-({[(R)-phenyl(pyridin-2-yl)methyl]amino}carbonyl)-l ,3- thiazolidin-3-yl]sulfonyl}phenyl)propanoate
(2S)-3-(biphenyl-4-ylsulfonyl)-N-[(l S)-l -(4-fluorophenyl)-3-hydroxypropyl]-l ,3- thiazolidine-2-carboxamide
3-(biphenyl-4-ylsulfonyl)-N-[(6-chloropyridin-3-yl)(phenyl)methyl]-l ,3-thiazolidine-2- carboxamide
(2S)-3-(biphenyl-4-ylsulfonyl)-N-{(l S)-3-[methyl(methylsulfonyl)amino]-l -phenylpropyl}- l,3-thiazolidine-2-carboxamide
3-{[4-(2-fluoro-l ,l -dimethylethyl)phenyl]sulfonyl}-N-[(R)-phenyl(pyridin-2-yl)methyl]- l ,3-thiazolidine-2-carboxamide
(2S)-3-[(4-bromophenyl)sulfonyl]-N-[(R)-phenyl(pyridin-2-yl)methyl]- 1 ,3-thiazolidine-2- carboxamide
(3S)-3-phenyl-3-[({(2S)-3-[(4-vinylphenyl)sulfonyl]- l ,3-thiazolidin-2-yl}carbonyl)amino]- propyl L-valinate
3-(biphenyl-4-ylsulfonyl)-N-[{5-[2-(dimethylamino)ethoxy]pyridin-2-yl}(phenyl)methyl]- 1 ,3-thiazolidine-2-carboxamide
3-(biphenyl-4-ylsulfonyl)-N-[[6-(dimethylamino)pyridin-3-yl](phenyl)methyl]-l ,3- thiazolidine-2-carboxamide 3-(biphenyl-4-ylsulfonyl)-N-[phenyl(l-L-valylpiperidin-4-yl)methyl]-l,3-thiazolidine-2- carboxamide
Still a further aspect ofthe present invention is the use of the novel compounds of formula (I) as medicament.
Still a further object of the present invention is a process for preparing l,3-thiazolidine-2- carboxamide derivatives according to formula (I).
The l ,3-thiazolidine-2-carboxamide derivatives exemplified in this invention may be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimisation procedures.
Generally, the l ,3-thiazolidine-2-carboxamide derivatives ofthe present invention may be obtained by several synthetic approaches, using both solution-phase and solid-phase chemistry protocols.
According to one process, illustrated in Scheme 1 below, l ,3-thiazolidine-2-carboxamide derivatives according to the general formula (I), whereby R1, R2, R4, G' and n are as above defined, may be prepared from the corresponding carboxylic acid compounds (III), amines (IV), and sulfonyl chlorides (VI), using standard solution- phase chemistry protocols well known to the practitioner skilled in the art. Intermediates of formula V, wherein PG is a suitable N-protecting group (such as Boc, Fmoc, Cbz, and others), can be obtained from the corresponding carboxylic acid compounds (III) and amines (IV) using standard amide coupling conditions well known to the practitioner skilled in the art. Removal of the 7V- protecting group (e.g., in cases where PG is Boc, using dilute TFA in DCM, or HCl in
Dioxane/DCM mixtures), followed by treatment with sulfonylch rides (VI) in conjunction with a suitable base (such as TEA, DIEA, pyridine, and others), yields products of general formula (I).
Scheme 1
Figure imgf000042_0001
IV
Figure imgf000042_0002
VI
According to another process, illustrated below in Scheme 2, l,3-thiazolidine-2-carboxylic acid derivatives (VII) may be reacted with sulfonyl chlorides (VI), using well known standard solution-phase chemistry protocols, such as e.g. the Schotten-Baumann conditions, affording intermediates of general formula (VIII). The latter can subsequently be reacted with amines (IV) using standard peptide coupling conditions well known to the practitioner skilled in the art, to yield products of general formula (I).
Scheme 2
Figure imgf000042_0003
VII VI VIII
A
Figure imgf000042_0004
VIII IV According to yet another process, illustrated in Scheme 3, l ,3-thiazolidine-2-carboxylic acid ester derivatives (IX) may be reacted with sulfonyl chlorides (VI), followed by saponification of the ester moiety using standard reagents like NaOH, HCl, Boron tribromide, KOSi(CH3)3, or others, to allow isolation ofthe corresponding carboxylic acid intermediates (VIII). The latter are then reacted with amines (IV) using standard amide coupling conditions well known to the practitioner skilled in the art to yield products of general formula (I).
Scheme 3
II
Figure imgf000043_0001
The racemic l,3-thiazolidine-2-carboxylic acid derivatives (III), (VII), and (IX) presented in Schemes 1 -3 are either obtained from commercial sources, or prepared from commercially available starting materials by standard methods detailed in the literature.
The sulfonyl chlorides (VI) presented in Schemes 1-3, wherein R is as above defined, are either commercially available or prepared by standard methods well known to the person skilled in the art, e.g. by treatment ofthe corresponding sulfonic acids (X) with chlorination agents, such as, e.g., SO2CI2, SOCl2, dimethylphosgeniminium chloride, and others, or by treatment of a suitable precursor (XI) with a chlorosulfonylation reagent, such as, e.g. CISO3H (see Scheme 4). Scheme 4
Chlorosulfonylation O o Chlorination agent o O agent 1
HO' Cl ^S R1
XI
VI
The sulfonic acids (X) and precursors (XI) are either obtained from commercial sources or synthesized from commercial starting materials, using standard methods well known to those skilled in the art, of which some are exemplified in Scheme 5 and described hereinafter in the Examples. Thus, e.g., bromobenzenesulfonates (XII) may be reacted with boronic acids (XIII) in presence of a palladium catalyst to yield the sulfonic acids (X). Alternatively, bromobenzenesulfonates (XII) may be converted into the corresponding sulfonic esters (XIV) by treatment with, e.g., thionyl chloride followed by 2-methyl-l - propanol. Sulfonic esters (XIV) can then be transformed in to the corresponding boronic acid derivatives (XV) using, e.g., triisopropylborate in the presence of n-butyllithium. Palladium(O) catalysed cross-coupling between the boronic acid derivatives (XV) and suitable substituted or unsubstituted aryl or heteroaryl halides affords the desired sulfonic acids (X).
Scheme 5
Pd(0)-catalysis
Figure imgf000045_0002
XII XIII
1) socι2 [Hal = Cl, Br, I; R = subst. or unsubst. aryl, heteroaryl] 2) OH
Figure imgf000045_0003
XIV XV
The amine compounds (IV) presented in Schemes 1-3, wherein R and G' are as above defined, are either obtained from commercial sources or made from commercial starting materials using standard protocols well known to the person skilled in the art, as shown in the below Schemes and illustrated hereinafter in the Examples.
In those cases where R and G' are substituted or unsubstituted aryl or heteroaryl moieties, the amine compounds (IV) may be obtained using, e.g., the process shown in Scheme 6. Therein, substituted or unsubstituted aromatic or heteroaromatic aldehydes (XVI) are reacted with commercially available aminoalcohols (XVII) to form the corresponding imines (XV111), followed by addition of a carbanion species (XIX), such as, e.g., a Grignard reagent, organocuprate or organolithium reagents, or others, using standard conditions well known to the person skilled in the art. The resulting secondary amines (XX) can subsequently be converted into the corresponding primary amine analogues (IV) by oxidative cleavage using, e.g., periodic acid, as described hereinafter in the Examples. This process also allows for the obtention of optically pure amines (IV*), by means of using optically active aminoalcohols (XVII*), as described hereinafter in Scheme z. Scheme 6
Figure imgf000046_0001
XVI XVII XVIII XX
G" (oxidative cleavage) G"
HO. {2 ^
H H2N^R2
[R2 = substituted or un¬
XX IV substituted aryl or heteroaryl]
The substituted or unsubstituted aryl and heteroaryl aldehydes (XVI or XVI*) are either obtained from commercial sources, or made by one of the numerous pertinent processes detailed in the literature and well known the person skilled in the art. As an exemplification, one such process is shown in Scheme 7 and described hereinafter in the Examples.
Scheme 7
Figure imgf000046_0002
Others substituted or unsubstituted aryl and heteroaryl aldehydes (XVI*) are either obtained from commercial sources, or made by one of the numerous pertinent processes detailed in the literature and well known the person skilled in the art. As an other exemplification, one such process is shown in Scheme 8 and described hereinafter in the Examples. Scheme 8
Figure imgf000047_0001
XXIV* XXV*
In those cases where R and G' are substituted or unsubstituted aryl or heteroaryl or heterocyclic moieties, the amine compounds (IV) may be obtained using, e.g., the process shown in Scheme 9. Therein, substituted or unsubstituted aromatic (XVII*) are reacted with acyl chlorides (XVIII*) to form the corresponding ketones (XIX*), or by reaction of substituted or unsubstituted lithiated aromatic (XXXXI*) with nitriles derivatives (XXXXII*). The ketones (XIX*) were then treated with hydroxylamine to give the corresponding oxime (XXXXIIF). Subsequent reduction of the oxime (XXXXIir) with an appropriated reductive agent, using standard conditions well known to the person skilled in the art, allow to access to the amine compounds (IV) as described hereinafter in the Examples. Scheme 9
Figure imgf000048_0001
XIX*
droxylamine
Figure imgf000048_0002
XXXXI* XXXXII*
Oxime reduction
Figure imgf000048_0003
Figure imgf000048_0004
[R2 = substituted or un¬
IV substituted aryl or heteroaryl] XXXXIII*
The amines (IV) where R and G' are substituted or unsubstituted aryl or heteroaryl or heterocyclic moieties, can be obtained from the ketone XIX* as shown below in Scheme 10, by treatment with an appropriate amine (XXXXV) to give compound XXXXVI after nucleophile substitution. Following subsequent treatments as outlined above in Scheme 9, the corresponding amines IV were isolated as pure compounds. Scheme 10
NH,
Figure imgf000049_0001
XIX* XXXXV XXXXVI IV
The amine compounds (IV) presented in Schemes 1-3, in which R2 represents a moiety of the general structure Cι-C6-alkyl-A-R5, whereby the substituents A and R5 are as above defined, are either commercially available or may be obtained using, e.g., one of the processes exemplified in Scheme 7-9 and described hereinafter in the Examples. A particularly preferred process consists in the transformation of one functional moiety (R ) into a different one (R ), using any known functional group interconversion protocols. As illustrated in Scheme 11 , and described hereinafter in the Examples, these functional group interconversions can be effected on the level of either the free amines (IV, IV), or the suitably protected amines (XXIV, XXIV), or the l ,3-thiazolidine-2-carboxamide compounds (V, V) or (I, F). The choice of the best synthetic strategy will be governed by the nature of the functional groups to be interconverted, and the compatibility of the required reaction conditions with other functional groups present in the corresponding compounds, as will be well appreciated by the person skilled in the art. Amongst the most preferred starting materials (IV), and the corresponding derivatives (XXIV), (V), and (I), are those wherein R2 is -COOH and/or -CH2COOH, i.e., alpha- and/or beta-amino acids, which are either obtained from commercial sources or made by one of the numerous processes described in the literature. From the intermediates (XXV) derived thereof, in which R is as defined in Scheme 11, a wide range of derivatives, such as e.g. (XXVI)- (XXXVI), in which R4, R5, R6, R7, n, G' and B arc as above defined, can be obtained by reaction sequences including oxidations, reductions, O- and N-alkylations, reductive alkylations and aminations, chain-elongations, Mitsunobu reactions, Acylation, debocylation, Wittig reactions, acylations, sulfonylations and any other appropriate transformations leading to functional group interconversions, some of which being exemplified in Scheme 11. The synthetic examples cited in Scheme 11 are meant to illustrate the concept of functional group interconversion as applied to compounds of general structures (IV), (XXIV), (V), and (I), wherein R, R2 and G' are as defined in the above description and in Scheme 11 , and are not construed to be viewed as limiting the scope of said synthetic approach.
Scheme 11
(functional group
G' interconversion) G"
R 2 N^R2' H H
Figure imgf000051_0001
PG: V-protecting group
Examples:
Reduction G"
Figure imgf000051_0003
Figure imgf000051_0002
XXV XXVI XXVI XXVII
Figure imgf000051_0004
XXVII
Figure imgf000051_0005
xxx
Figure imgf000051_0006
Figure imgf000051_0007
XXVI XXXI XXXI XXXII
HNRSR6 Peptide coupling
Figure imgf000051_0008
a9ent
Figure imgf000051_0009
COOH
XXXVI
Figure imgf000051_0010
The processes outlined in the above Schemes, in particular Schemes 1-3, usually afford mixtures of stereoisomers, such as diastereomers and/or enantiomers, when racemic starting materials (III), (IV), (VII), and/or (IX) are used, due to the presence of at least one, most often two, and in some cases three or more, asymmetric carbon atoms in the compounds of general formula (I). Pure stereoisomers can be obtained from the mixtures by current separation methods, including, e.g., flash chromatography, HPLC, crystallization, and others.
According to another process, less complex mixtures of stereoisomers up to pure stereoisomers can be obtained by using the corresponding optically pure starting materials (HI*), (IV*), (VII*), and/or (IX*) for the syntheses outlined in the above Schemes, in particular Schemes 1-3. Optically pure amines (IV*) are either obtained from commercial sources or made by current methods known to the person skilled in the art, including stereoselective chemical synthesis, chemical resolution, enzymatic resolution, or combinations thereof, as exemplified in Scheme 12 and in the Examples hereinafter. Thus, optically pure amines (IV*) can be obtained, e.g., by adapting the process outlined in Scheme 6 above, by means of using a chiral auxiliary (XVII*), such as, e.g., valinol or others, which are obtained in optically pure form either from commercial sources or by standard methods described in the literature (Scheme 7-9, Example A). Alternatively, as shown in Scheme 12 (Example B), chiral amines (IV*) may be obtained by enzymatic resolution of appropriate racemic precursors (IV), and subsequently transformed into other chiral amines (IV*) by standard functional group interconversion methods, such as those outlined in Scheme 1 1 above. Similarly to the obtention of enantiomerically pure amines (IV*), optically pure l ,3-thiazolidine-2-carboxylic acid derivatives (III*), (VII*), and/or (IX*) can be obtained by stereoselective chemical synthesis, chemical resolution, enzymatic resolution, or combinations thereof. The Examples cited above and shown in Scheme 1 1 are meant to illustrate the preparation of optically pure starting materials, and are not construed to be viewed as limiting the scope of said synthetic approach. Scheme 12
Example A: stereoselective synthesis with chiral auxiliary
Figure imgf000053_0001
XVI XVII* XVIII* XX*
G'
HN R' (oxidative cleavage) G"
[R2 = substituted or un¬
HO. H2N R' substituted aryl or heteroaryl
XX* IV*
Example B: enzymatic resolution of racemic starting materials
Enzyme e.g. Reduction, (e.g. lipase) (see Scheme 8)
Figure imgf000053_0002
Figure imgf000053_0003
Figure imgf000053_0004
IV IV* I
According to yet another process, illustrated in Scheme 13, the carboxylic acid intermediates (VIII) may be reacted with amines (IV) to lead to the corresponding carboxylic acid intermediate (Ta). The primary amide compound (Tb) was isolated after formation of the anydride mixte ofthe carboxylic acid compound (la) and treatment with an excess of ammonia. Dehydratation of the primary amide (lb) with cyanuric chloride allow to accesse to the nitrile derivative (lc), which was subsequently treated with hydroxylamine to give the amidoxime (Id). The amidoxime intermediate (Id) was then reacted with an appropriated carboxylic acid using standard amide coupling conditions and heated up to allow cylisation and formation ofthe final compound oxadiazole using conditions well known to the practitioner skilled in the art to yield products of general formula (I).
Scheme 13
Figure imgf000054_0001
RCOOH Cyclisation
Figure imgf000054_0002
c Id
Figure imgf000054_0003
The processes hitherto outlined describe the synthesis of l,3-thiazolidine-2-carboxamide derivatives of general formula (I) by solution-phase methods. According to yet another approach, l,3-thiazolidine-2-carboxamide derivatives of formula (I), wherein the substituents R , R", R , G' and n are as above defined, are prepared by solid-phase protocols, such as, e.g., that outlined in Schemes 1 -12 and described hereinafter in the Examples. Therein, the filled circles symbolize the resin beads to which the corresponding compounds are linked during the solid phase synthesis. Thus, suitably N-protected 1,3- thiazolidine-2-carboxylic acids (III) are reacted, e.g., with Kaiser oxime resin using, e.g., standard carbodiimide-mediated coupling conditions well known to the practitioner skilled in the art, followed by removal of the protecting group. The resulting intermediates are treated with sulfonyl chlorides (VI) in the presence of a base, affording resin-bound intermediates of general formula (XXXIX). In order to obtain the final compounds of general formula (I), the linkage to the resin is cleaved by prolonged treatment with amines (IV) and, in certain cases, low percentages of a weak acid, such as HO Ac. Other derivatives of formula (I) are prepared using known modifications to, or variations of, the Scheme 14 reaction sequence. Further to the above mentioned Kaiser oxime resin, other suitable reagents, notably resins, known to a person skilled in the art, could be employed for the solid-phase synthesis of compounds of general formula (I).
Scheme 14
Figure imgf000055_0001
XXXVII XXXVIII
Figure imgf000055_0002
XXXVIII VI XXXIX
Figure imgf000055_0003
XXXIX IV
If the above set out general synthetic methods are not applicable to obtaining compounds according to formula (I) and/or to necessary intermediates for the synthesis of compounds of formula (I), suitable methods of preparation known by a person skilled on the art should be used. In general, the synthesis pathways for any individual compound of formula (I) will depend on the specific substitutents of each molecule and upon the ready availability of intermediates necessary; again such factors being appreciated by those of ordinary skill in the art. For all the protection and deprotection methods, see Philip J. Kocienski, in "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994 and, Theodora W. Greene and Peter G. M. Wuts in "Protective Groups in Organic Synthesis'", Wiley- Interscience, 1991. Compounds of this invention can be isolated in association with solvent molecules by crystallization from evaporation of an appropriate solvent. The pharmaceutically acceptable acid addition salts ofthe compounds of formula II, which contain a basic center, may be prepared in a conventional manner. For example, a solution ofthe free base may be treated with a suitable acid, either neat or in a suitable solution, and the resulting salt isolated either by filtration or by evaporation under vacuum ofthe reaction solvent. Pharmaceutically acceptable base addition salts may be obtained in an analogous manner by treating a solution of compound of formula I with a suitable base. Both types of salts may be formed or intercon verted using ion-exchange resin techniques.
A final aspect ofthe present invention are intermediate compounds of the formula (Va)- wherein G' is a phenyl - as used in the method illustrated in Scheme 1 , in particular for preparing compounds of formula (la).
Figure imgf000056_0001
In said formula (Va), PG is H, R2, R3, R4, m and n are as defined above, with the proviso, though, that R2 may not be a hydrogen.
Also intermediate compound of the formula (VIII) are comprised by the present invention,
R '. - ' H \ VIII
N OH
°o 1
wherein R1 is a 1,1 ' -biphenyl or a tert-bu y\ phenyl moiety and R4 and n are as above defined. When employed as pharmaceuticals, thiazolidine carboxamide derivatives ofthe present invention are typically administered in the form of a pharmaceutical composition. Hence, pharmaceutical compositions comprising a compound of formula (II) and a pharmaceutically acceptable carrier, diluent or excipient therefore are also within the scope ofthe present invention. A person skilled in the art is aware of a whole variety of such carrier, diluent or excipient compounds suitable to formulate a pharmaceutical composition.
The compounds ofthe invention, together with a conventionally employed adjuvant, carrier, diluent or excipient may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, or in the form of sterile injectable solutions for parenteral (including subcutaneous use). Such pharmaceutical compositions and unit dosage forms thereof may comprise ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount ofthe active ingredient commensurate with the intended daily dosage range to be employed.
Pharmaceutical compositions containing thiazolidine carboxamide derivatives of this invention can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. Generally, the compounds of this invention are administered in a pharmaceutically effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light ofthe relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response ofthe individual patient, the severity of the patient's symptoms, and the like.
The pharmaceutical compositions ofthe present invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampoules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the thiazolidine carboxamide derivative is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40%) by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any ofthe following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatine; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As above mentioned, the thiazolidine carboxamide derivatives of formula (I) in such compositions is typically a minor component, frequently ranging between 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
The above described components for orally administered or injectable compositions are merely representative. Further materials as well as processing techniques and the like are set out in Part 8 of Remington 's Pharmaceutical Sciences, 17 Edition, 1985, Marck Publishing Company, Easton, Pennsylvania, which is incorporated herein be reference.
The compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can also be found in the incoφorated materials in Remington 's Pharmaceutical Sciences.
In the following the present invention shall be illustrated by means of some examples which are not construed to be viewed as limiting the scope ofthe invention. The following abbreviations are hereinafter used in the accompanying examples: min (min-ute), hr (hour), g (gram), mmol (millimole), m.p. (melting point), eq (equivalents), ml (milliliter), μl (microliters), ACN (acetonitrile), Boc (butoxycarbonyl), Cbz (carboxybenzyl), CDCls (deuterated chloroform), cHex (cyclohexanes), dba (dibenzylidene acetone), DCM (dichloromethane), DEAD (diethylazodicarboxylate, DIC (diisopropyl carbodiimide), DIEA (diisopropyl ethylamine), DMAP (4-dimethylaminopyridine), DMF (dimethylform- amide), DMSO (dimethylsulfoxide), DMSO-^ (deuterated dimethylsulfoxide), EDC (l -(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), EtOAc (ethyl acetate), Et20 (diethyl ether), Fmoc (9-fluorenylmethoxycarbonyl), HOBt (1-hydroxybenzotriazole), K2CO3 (potassium carbonate), MgS0 (magnesium sulfate), MsCl (methylsulfonyl chloride), MTBE (tert-bw\y\ methyl ether), NaH (sodium hydride), NaHCOs (sodium bicarbonate), nBυLi (n- butyl lithium), PCC (pyridinium chlorochromate), PetEther
(petroleum ether), QCI (tetrabutylammonium chloride), rt (room temperature), TBTU (O- benzofriazolyl-N^Λ^N'-tetramethyluroniυm-tetrafluoroborate), TEA (triethyl amine), TFA (trifluoroacetic acid), THF (tetrahydrofuran), TMOF (trimethylorthoformate), TMAD (N,N,N',N'-tetramethylazodicarboxamide), TosCl (toluenesulfonyl chloride).
Examples Intermediate 1 : Preparation of amines of general formula (IVV(1V* : e.g. (-R)-phenyl(2- pyridinyOmethanamine
Figure imgf000060_0001
Method A:
a) Protocol for the formation ofthe imine intermediates (XVIII) / (XVIII*); e.g., (2R)-3- methyl-2-{[(E)-2-pyridinylmethylidene] amino}-! -butanol
Figure imgf000060_0002
Anhydrous MgSθ4 (50 g, 415 mmol, 4.15 eq) and a substituted aryl or heteroaryl carboxaldehyde, e.g. 2-pyridinecarboxaldehyde (9.5 ml, 100 mmol, leq), were added to a solution of (7?)-(-)-2-amino-3 -methyl- 1 -butanol (10.32 g, 100 mmol) in dry DCM (150 ml) at 0° C. The reaction was followed by LC/MS. The mixture was stirred at this temperature for 2h25. MgS04 was filtered off and the DCM removed by evaporation to give the desired product (XVIII*), e.g. (27?)-3-methyl-2-{[(£')-2-pyridinylmethylidene]amino}-l -butanol as a yellowish oil (19.23 g, quantitative yield).
]H NMR (300 MHz, DMSO); Major tautomer: 0.88 (m, 6H, Or (CH^)2); 1.88 (m, IH, C7/(CH3)2); 3.03(m, 2H); 3.66 (m, IH); 4.51 (t, J= 6.0 Hz, IH); 7.43 (m, IH); 7.85 (m, IH); 7.96 (m, IH); 8.23 (s, IH); 8.62 (m, IH). M+(ESI+): 193.
b) Protocol for the silylation of intermediates (XVIII) / (XV III*); e.g. (2R)-3-methyl-N-[(E)- 2-pyridinylmethylidene]-l-[(trimethylsilyl)oxy]-2-butanamine
Figure imgf000061_0001
The imine (XVIII*) resulting from the precedent step, e.g. (27?)-3-methyl-2-{[(£')-2- pyridinylmethylidene]amino}-l -butanol (100 mmol) was dissolved in dry DCM (100 ml). TEA (15.3 ml, 110 mmol, 1.1 eq) and chlorotrimethylsilane (13.9 ml, 110 mmol, l.leq) was added to the stirred solution. The reaction was followed by LC/MS. After 2h30, the reaction was complete. The solvent was removed in vacuo and the residue was taken up in 500 ml Et2θ-Cyclohexane (1 :1) and the solid phase was filtered off. The organic solution was concentrated in vacuo to give the desired product, e.g. (27?)-3-methyl-N-[(-£')-2- pyridinylmethylidene]-l-[(trimethylsilyl)oxy]-2-butanamine as a yellowish oil (25.5g, 96%).
Η NMR (300 MHz, CDC13); 0.0 (s, 9H, Si(CH3)3); 0.89 (s, 6H, CH(C//3)2); 1.93 (m, IH, C /(CH3)2); 3.03 (m, IH); 3.63 (m, IH); 3.83 (m, IH); 7.25 (m, IH); 7.68 (m, IH); 8.0 (m, IH); 8.26 (s, IH); 8.60 (m, IH). M+(ES1+): 265.
c) Asymmetric addition of Grignard reagents; e.g., (2R)-3-methyl-2-{[(R) -phenyl (2- pyridinyl)methyl] amino}- 1 -butanol (XX)/(XX*)
Figure imgf000061_0002
The silylated imine from the previous step, e.g. (2R)-3-methyl-N-[(-£')-2- pyridinylmethylidene]-l-[(trimethylsilyl)oxy]-2-butanamine was dissolved in dry THF (500 ml) and the solution was cooled down to -78° C. A 1 M solution of phenylmagnesiumbromide in THF (200 ml, 200 mmol, 2eq ) was added dropwise while the mixture was stirred by a magnetic bar. The mixture was further stirred 2 hours at -78° C. The temperature was then slowly increased up to room temperature overnight. A sample of the reaction mixture was quenched with aqueous NaHCOs and analysed by LC-MS to detect the O-silylated products. After one night, the mixture was quenched with HCl IM (250 ml) and the mixture was stirred at room temperature until the desilylation was complete (after lh, LC/MS analysis). The aqueous phase was further acidified with the addition of 5M HCl solution (20 ml). The aqueous phase was washed with 300 ml cyclohexane/Et2θ (2: 1), then made basic with 60 ml NaOH 5M at 0° C, and the organic products were extracted with Et2θ, dried (MgS0 ) and concentrated to give the desired product (XX*), e.g. (27?)-3-methyl-2-{[(7?)-phenyl(2-pyridinyl)methyl]amino}-l -butanol as a yellowish oil (22.9 g, 85% yield, d.e. = 99%, determined by ] H NMR).
!H NMR (300 MHz, CDCI3); 0.81 (m, 6H, CH(CH3)2); 1.76 (m, I H, C/ (CH3) ); 2.29 (m, I H); 2.72 (br s, 2H); 3.23-3.60 (m, 2H, CH2OH); 4.87(d, 1 H, NC/ Ar2); 6.97 (m, 2H, H arom.); 7.17 (m, 5H, H arom.); 7.41 (m, 1 H, H arom.); 8.42 (s, I H, H arom. major diastereomer, 99.5%), 8.70 (s, IH, H arom. minor diastereomere, 0.5%). M+(ESI+): 271.
d) Protocol for the deprotection ofthe amines (XX)/(XX*); e.g., (R) -phenyl (2- pyridinyl)methanamine
Figure imgf000062_0001
To a solution of the secondary amines (XX)/(XX*) resulting from the preceding step, e.g. (27?)-3-methyl-2-{[(7?)-phenyl(2-pyridinyl)methyl]amino}-l -butanol (2.9 g, 10.73 mmol) in 25 ml MeOH/THF (9/1) was added methylamine 40% in water (10.2 ml, 1 18 mmol, 1 1 eq). Aqueous periodic acid (8.3 g in 25 ml of water) was added slowly at 0° C to the stirring solution. This thick solution was allowed to stir at room temperature overnight. The reaction was followed by LC/MS. After one night, water (25 ml) was added, the mixture was filtered and the amine extracted 3 times with Et2θ. The organic phase was then dried with MgS04 and evaporated to give the desired products (IV)/(IV*), e.g. (7?)-phenyl(2- pyridinyl)methanamine as a yellowish oil (2.1 g, 95%> yield). This crude primary amine was used without further purification.
Η NMR (300 MHz, CDC13); 2.19 (br s, 2H, N-/-/2); 5.26 (m, IH, NC//Ar2); 7.15-7.44 (m, 7H, H arom.); 7.62 (m, IH, H arom.); 8.58 (s, IH, H arom.). M+(ESI+): 185.
Method B:
a) Protocol for the formation ofthe aldehyde intermediates (XVI*); e.g., 5-[2- (dimethylamino) ethoxy] pyridine-2-carboxaldehyde (Scheme 8)
Figure imgf000063_0001
A mixture of 3-hydroxy-6-methylpyridine (57.5g, 0.529mol), 4-tosylchloride (HOg, 0.58mol) and TEA (lOOmL) in dry DMF (400mL) was heated at 110°C under N2 for 16h. The reaction mixture was cooled down to RT, diluted with water (3L). The resulting precipitate was filtered, washed and dried to give crude [3-(4-tosyloxy)]-6-methylpyridine (102g, 75%) as a white solid. The crude product was used in next reaction without any purification.
To a solution of [3-(4-tosyloxy)]-6-methylpyridine (lOOg, 0.38mol) in dry CHCI3 (2L) was added MCPBA (50% w/w, 200g, 0.57mol) in one portion. The reaction mixture was refluxed for 4h, cooled to RT and filtered off the solid. The filtrate was washed with 20%
Na2C03 solution (3xlL), dried over Na2S04 and concentrated to give 6-methyl-3-(4- tosyloxy)pyridine-7V-oxide (85g, 80%) as a solid. The crude product was used in the next step without further purification.
To a solution of acetic anhydride (500mL) heated at 90°C, was added 6-methyl-3-(4- tosyloxy)pyridine-N-oxide (80g) in small portions over a period of 2h. The reaction mixture was refluxed for 16h under N2. Acetic anhydride was distilled off. The resulting crude product was purified by column chromatography over silica gel (gradient petroleum ether/CH2Cl2, 7:3 to 3:7) to give 3-tosyloxy-6-acetoxymethylpyridine (55g, 57%) as a liquid.
A mixture of 3-tosyloxy-6-acetoxymethylpyridine (50g, 0.148mol) and NaOH (25g, 0.62mol) in 150mL of water was refluxed for 15h. The reaction mixture was cooled to RT and neutralized with con. HCl. The solvent was evaporated under vacuum affording a solid residue, which was suspended in ethyl acetate (750mL) and heated to 60°C for 30 min. with stirring. The suspended material was filtered off and the filtrate was concentrated to give 5- hydroxy-2-hydroxymethylpyridine (15g, 80%) as a pale yellow solid. It was used in next step without further purification.
A mixture of 5-hydroxy-2-hydroxymethylpyridine (14g) and Mnθ2 (100g) in isopropylalcohol (600mL) was stirred under N2 for 20h. The reaction mixture was filtered and filtrate concentrated under vacuum affording a crude product as a solid (12g). It was suspended in acetone/acetonitrile (25mL each) and the solid residue was filtered off. It was washed with cold acetone/acetonitrile 1 : 1 mixture to give pure 5-hydroxypyridine-2- carboxaldehyde (3g) as a solid.
A mixture of the above 5-hydroxypyridin-2-carboxaldehyde (4g, 0.032mol), K2CO3 (14g, 0.097mol) in THF (l OOmL) was heated at 60°C for 2h under N2. 2- Dimethylaminoethylchloride was freshly prepared from the corresponding HCl salt (9.4g, 0.06mol) to which was added drop-wise 20% NaOH solution (2 equivalent) at 0°C. It was then added drop-wise to the above reaction mixture at 60°C. The reaction mixture was allowed to stir 6h at the same temperature. Upon completion, the reaction mixture was cooled down to RT, the solid was filtered off and the filtrate was concentrated under vacuum to give expected crude product. It was then purified by column chromatography over silica gel (gradient methanol in chloroform from 0.1% to 2%>) to give the desired aldehyde (XVI*), e.g., 5 -[2-(dimethylamino) ethoxy] pyridine-2-carboxaldehyde (3.25g, 51%)) as a colorless liquid.
b) Protocol for the preparation ofthe amines (IV and IV*); e.g., [2-({6-[(R)- amino(phenyl)methyl]pyridin-3-yl}oxy)ethyl]dimethylamine.
Figure imgf000065_0001
Steps a) to d) described in method A were applied to the aldehyde (XVI*) from the previous step, e.g., 5-[2-(dimethylamino) ethoxy] pyridine-2-carboxaldehyde, affording the desired amine (IV, IV*), e.g., [2-({6-[(R)-amino(phenyl)methyl]pyridin-3- yl}oxy)ethyl]dimethylamine (165 mg, 96% yield). This crude primary amine was used without further purification.
M+(ESI+): 271.
Intermediate 2: Preparation of racemic amines of general formula (IV); e.g., [(6- chloropyridin-3-yl)(phenyl)methyl]amine; [(2-chloropyridin-4-yl (phenyl)methyl]amine; 5- [amino(phenyl)methyl]pyridin-2-ol; 5-[amino(phenyl)methyl]-N,N-dimethylpyridin-2- amine: [(1 -methylpiperidin-4-yl)(phenyl)methyl]amine.
Method A: a) Protocol for the formation ofthe ketone intermediates (XIX*); e.g., (6-chloropyridin-3- yl)(phenyl)methanone.
Figure imgf000066_0001
A carboxylic acid, e.g., 6-Chloronicotinic acid (3.151 g, 20 mmol) was dissolved in dry DCM. The mixture was cooled down to 0°C. Oxalyl chloride (2.58 mL, 30 mmol) followed by DMF (77 μL) were added. The mixture was stirred at 0°C for lh30, then at RT overnight. The solvents were evaporated. The crude product was dissolved in toluene and the solvents were evaporated again to give the corresponding acid chloride (XVIII*), e.g., 6-chloronicotinoyl chloride (2.886 g, 82% yield). It was dissolved in benzene (50 mL) and A1C13 (5.248 g, 39.4 mmol) was added. The mixture was stirred overnight at 80°C. After cooling down to RT, water was added. The two phases were separated and the aqueous layer was extracted with two portions of ethyl acetate. Combined organic layers were washed with brine and dried over MgS04, filtrated and concentrated to give the desired product (XIX*), e.g., (6-chloropyridin-3-yl)(phenyl)methanone as a yellowish oil (3.884 g, 67% yield). It was used in the next step without further purification.
'H NMR (300 MHz, CDC13); 7.41 -7.57 (m, 3H, H arom.); 7.64 (m, IH, H arom.); 7.73- 7.83 (m, 2H, H arom.); 8.08 (dd, J = 3.0, 9.0 Hz, IH, H pyridine.); 8.76 (d, J = 3.0 Hz, IH, H pyridine). M+(ESI+): 218.
b) Protocol for the formation of the oxime intermediates (XXXXIII*); e.g., (6- chloropyridin-3-yl)(phenyl)methanone oxime.
Figure imgf000067_0001
The ketone issued from the precedent step (XIX*), e.g., (6-chloropyridin-3- yl)(phenyl)methanone (435 mg, 2 mmol), was dissolved in EtOH (40 mL). DIEA (1.027 L, 6 mmol) and hydroxylamine hydrochloride (417 mg; 6 mmol) were added. The mixture was heated under reflux overnight. The solvents were removed. The resulting crude mixture was dissolved in ethyl acetate (40 mL) and was washed with three portions of water. The organic layer was dried over magnesium sulfate, filtrated and evaporated to give the desired product (XXXXIII*), e.g., (6-chloropyridin-3-yl)(phenyl)methanone oxime (413 mg, 89% yield). It was used in the next step without further purification.
lR NMR (300 MHz, CDC13); 7.22-7.52 (m, 6H, H arom.); 7.75 (m, IH, H arom.); 8.45 (d, J = 3.0 Hz, IH, H pyridine). M+(ESI+): 233. M"(ESF): 231.
c) Protocol for the reduction of the oxime into the primary amine intermediates (IV); e.g., [(6-chloropyridin-3-yl)(phenyl)methyl]amine.
Figure imgf000067_0002
The oxime obtained from the precedent step (XIX*), e.g., (6-chloropyridin-3- yl)(phenyl)methanone oxime (368 mg, 1.58 mmol) was dissolved in glacial acetic acid (20 mL). Metallic Zn (1.034 g, 15.8 mmol) was added in portions at RT. The reaction was followed by LC-MS. After a complete reduction ofthe oxime functionality, the reaction mixture was filtered and the solvents were evaporated. The crude residue was dissolved in DCM and was washed with three portions of NaHCθ3 sat. It was then dried over MgS04, filtrated and evaporated. It was further purified by column chromatography over silica gel (DCM/MeOH 20: 1 with 2% of NH4OH) to give the desired product (IV), e.g, [(6- chloropyridin-3-yl)(phenyl)methyl]amine (188 mg, 54% yield).
Η NMR (300 MHz, CDC13); 5.18 (s, IH, C7_/NH2); 7.14-7.32 (m, 6H, H arom.); 7.61 (dd, J = 3.0,6.0 Hz, IH, H pyridine.); 8.37 (d, J= 3.0 Hz, I H, H pyridine). M+(ESI+): 219.
Method B:
a) Protocol for the aromatic substitution of intermediates (XIX*); e.g., (6-chloropyridin-3- yl)(phenyl)methanone with sodium alcolate, affording ketone intermediates (XIX*); e.g. , (6-tørt-butoxypyridin-3-y l)(pheny l)methanone.
Figure imgf000068_0001
b) In a 5 mL flask for microwave reaction were added NaH 55-65% in oil (192 mg, 4.4 mmol) and dry THF (2 mL), followed by the alcohol, e.g., t-butanol.. The mixture was heated 30 min at 60°C. Intermediates (XIX*); e.g., (6-chloropyridin-3-yl)(phenyl)- methanone (435 mg, 2 mmol) was dissolved in dry THF (2 mL) and added to the alcoholate solution prepared previously. This mixture was heated 40 min under microwave at 100°C. As the reaction was complete, water and ethyl acetate were added. The phases were separated and the aqueous phase was extracted with two portions of ethyl acetate. Combined organic layers were dried over MgS04, filtrated and evaporated affording the expected product (XIX*), e.g., (6-/ert-butoxypyridin-3- yl)(phenyl)methanone (191 mg, 37% yield).
Η NMR (300 MHz, CDC13); 1.62 (s, 9H, /Bu); 6.72 (d, J= 6.0 Hz, IH, H arom.); 7.42- 7.53 (m, 2H, H arom.); 7.58 (m, I H, H arom.); 7.71-7.80 (m, 2H, H arom.); 8.05 (dd, J = 3.0, 9.0 Hz, IH, H pyridine.); 8.37 (d, J= 3.0 Hz, IH, H pyridine). [M-tBu+H]+ (ESI+): 200. M"(ESL): 255.
c) Protocol for the preparation ofthe primary amine intermediates (IV); e.g., 5- [amino(phenyl)methyl]pyridin-2-ol.
Figure imgf000069_0001
The protocole described in Method A step b) and c) was applied to the intermediate (XIX*); e.g. (6-fcrt-butoxypyridin-3-yl)(phenyl)methanone, affording the desired amine (IV), e.g., 5-[amino(phenyl)methyl]pyridin-2-ol (160 mg, quantitative yield). During the reduction step with Zn in AcOH, the t-butyl group has been cleaved, affording directly the corresponding pyridin-2-ol. This crude primary amine was used without further purification.
M+(ESI+): 201.
Method C:
d) Protocol for the aromatic substitution of intermediates (XIX*); e.g., (6-chloropyridin-3- yl)(phenyl)methanone with amine, affording ketone intermediates (XIX*); e.g., (6-N,N- dimethylaminopyridin-3-yl)(phenyl)mcthanonc.
Figure imgf000069_0002
In a 5 mL flask for microwave reaction, intermediates (XIX*); e.g., (6-chloropyridin-3- yl)(phenyl)methanone (217 mg, 1 mmol) was added together with dry THF (1.5mL) and 2M solution of dimethylamine in THF (3 mL, 6 eq). This mixture was heated 120 min under microwave at 180°C. As the reaction was complete, water was added. The aqueous solution was basified with NaOH 5M to pH 8. It was then extracted with three portions of ethyl acetate. Combined organic phases were dried over MgS04, filtrated and evaporated, affording the expected product (XXXXVI), e.g., (6-NN-dimethylaminopyridin-3- yl)(phenyl)methanone (88 mg, 39% yield).
Η NMR (300 MHz, CDC13); 3.19 (s, 6H, NMe2); 6.56 (d, J= 9.0 Hz, I H, H arom.); 7.40- 7.49 (m, 2H, H arom.); 7.53 (m, IH, H arom.); 7.68-7.76 (m, 2H, H arom.); 8.04 (dd, J= 3.0, 9.0 Hz, I H, H pyridine.); 8.60 (d, J= 3.0 Hz, I H, H pyridine). M+ (ESI+): 227.
e) Protocol for the preparation of the primary amine intermediates (IV); e.g., 5- [amino(phenyl)methyl]-N,N-dimethylpyridin-2-amine.
Figure imgf000070_0001
The protocole described in Method A step b) and c) was applied to the intermediate
(XXXXVI); e.g., (6-N,/V-dimethylaminopyridin-3-yl)(phenyl)methanone, affording the desired amine (IV), e.g., 5-[amino(phenyl)methyl]-N,iV-dimethylpyridin-2-amine (136 mg, 83% yield). This crude primary amine was used without further purification.
Η NMR (300 MHz, CDC13); 2.13 (br s, 2H, N 2); 2.99 (s, 6H, NMe2); 5.06 (s, IH, C//NH2), 6.41 (d, J= 9.0 Hz, IH, H arom.); 7.10-7.41 (m, 6H, H arom.); 8.09 (d, J= 3.0 Hz, IH, H pyridine). M+ (ESI+): 228. Method D: a) Protocol for boc protection of the amino ketone intermediates (XIX*); e.g., phenyl(ρiperidin-4-yl)methanone.
Figure imgf000071_0001
b) The amino ketone intermediate XIX*, e.g. pheny l(piperidin-4-yl)methanone
hydrochloride (1.129 g, 5 mmol) was suspended in DCM (25 mL). DIEA (0.94 mL, 5.5 mmol) was added and the resulting inhomogeneous mixture was cooled down to 0°C. Di- tert-butyl dicarbonate (1.20 g, 5.5 mmol) was added as a solid. The mixture was stirred 5 min at 0°C and lh at RT. As the reaction was complete, it was washed with HCl IN aqueous solution then with NaHC03 sat, brine and dried over MgS04. After filtration and evaporation, the expected product (XIX*), e.g., tert-butyl 4-benzoylpiperidine- 1 - carboxylate (1.333 g, 92% yield) was obtained as a white solid.
Η NMR (300 MHz, CDC13); 1.44 (s, 9H, Boc); 1.59-1.76 (m, 2H); 1.76-1.88 (m, 2H), 2.87 (m, 2H); 3.38 (m, IH); 4.14 (m, 2H); 7.41-7.49 (m, 2H, H arom.); 7.55 (m, IH, H arom.); 7.88-7.95 (m, 2H, H arom.). [M-tBu+H]+ (ESI+): 234. M"(ESr): 288.
c) Protocol for formation of the oxime intermediate (XXXXIII*); e.g., tert-butyl 4-[(Z)- (hydroxyimino)(phenyl)methyl]piperidine- 1 -carboxylate.
Figure imgf000071_0002
The procedure described in the method A step b) was followed, starting from intermediate XVIII*, e.g., tert-butyl 4-benzoylpiperidine- 1 -carboxylate (1,0 g, 3.46 mmol), affording the desired product XXXXIII*, e.g., tert-bu y\ 4-[(Z)-
(hydroxyimino)(phenyl)methyl]piperidine-l -carboxylate in 94% yield and 97%o HPLC purity. It was used in the next step without further purification.
1H NMR (300 MHz, CDCls); 1.42 (s, 9H, Boc); 1.35-1.58 (m, 2H); 1.58-1.84 (m, 2H), 2.62 (m, IH, major isomer), 2.63-2.82 (m, 2H); 3.39 (m, IH, minor isomer); 4.12 (m, 2H); 7.20- 7.51 (m, 5H, H arom.). [M-tBu+H]+ (ESI+): 249. M (ESF): 303.
d) Protocol for the reduction ofthe oxime intermediate XXXXIII* into the primary amine (IV); e.g., tert-buty\ 4-[amino(phenyl)methyl]piperidine-l-carboxylate.
Figure imgf000072_0001
The oxime intermediate XXXXIII*, e.g., tert-b ty] 4-[(Z)-
(hydroxyimino)(phenyl)methyl]piperidine-l -carboxylate, was dissolved in MeOH. Pd/C (10%) was added and the mixture was placed under 30 bar of H2 overnight. As the reduction was complete, the solution was filtered through celite and the solvents were evaporated, affording the crude the primary amine. It was dissolved in Et20 and extracted with 3 portions of HCl I N. Combined acidic fractions were washed with one portion of Et2θ. It was then basified with NaOH 5N. The basic aqueous phase was extracted with 3 portions of ether. Combined organic phases were dried over MgSθ4, filtrated and evaporated, affording the primary amine IV, e.g., tert-bu y\ 4- [amino(phenyl)methyl]piperidine-l -carboxylate (729 mg, 68% yield), which was used in the next step without further purification. Η NMR (300 MHz, CDCls); 0.93-1.30 (m, 2H); 1.42 (s, 9H, Boc); 1.62 (m, IH); 1.82-1.98 (m, 2H); 2.59 (m, 2H), 3.61 (d, J= 9.0 Hz, I H); 4.10 (m, 2H); 7.19-7.35 (m, 5H, H arom.). NT" (ESI+): 291.
e) Protocol for the reduction of boc group into tertiary amine (XXXII); e.g., 1-(1- methylpiperidin-4-yl)-l -pheny lmethanamine.
Figure imgf000073_0001
Intermediate XXXI, e.g. tørt-butyl 4-[amino(phenyl)methyl]piperidine-l -carboxylate (1.0 g, 3.44 mmol) was dissolved in dry THF (50 mL). LiAlH4 (261 mg, 6.89 mmol) was added in portions. The reaction was heated under reflux overnight. As the reaction was completed, it was quenched with dropwise addtion of water (5 mL), followed by NaOH IN (5 mL) and H20 (5 mL). The suspension thus obtained was extracted with ethyl acetate, dried over MgSθ4 and evaporated, affording the crude product. It was further purified by flash chromatograpy (DCM/MeOH 20: 1 with 2% NH4OH) to give the tertiary amine XXX11, e.g., l-(l-methylpiperidin-4-yl)-l -pheny lmethanamine (444.6 mg, 63% yield).
' H NMR (300 MHz, CDC13); 1.12-1.53 (m, 4H); 1.62 (br s, 2H, N// ); 1.77 (m, IH); 1.83- 2.03 (m, 2H); 2.22 (s, 3H, CH3); 2.75 (ra, IH), 2.91 (m, IH), 3.60 (d, J= 6.0 Hz, IH); 7.18- 7.35 (m, 5H, H arom.). M+ (ESI+): 204.
f) Enantiomers separation of intermediate (XXXII); e.g., l-(l-methylpiperidin-4-yl)-l- phenylmethanamine, by chromatography on chiral support.
Both enantiomcr of intermediate XXXII, e.g. l-(l-methylpiperidin-4-yl)-l- phenylmethanamine (5.00 g), were separated on chiral column (Chiralcell OD-H, 250 mm x 20 mm; 5 μm granulometry, Chiral Technologies Europe). Divided in 35 injections, enantiomer (R) (2.344 g, r.t. = 5.897 min) and enantiomer (S) (2.552 g, r.t. = 7.898 min) were isolated both with e.e. >99.8 % (determined on analytical Chiralcell OD-H, 250 x 4.6 mm, 5 μm granulometry, Chiral Technologies Europe) and 98% yield. Absolute configuration of each enantiomer was established by correlation with biological activity of the final products, knowing that products XXXII bearing (S)-2-substituted benzylamine were more active than the one bearing (R)-2-substituted benzylamine.
l-(2-chloropyridin-4-yl)-l-phenylmethanamine
Following the general Method A, starting from 2-chloroisonicotinic acid, the title compound was obtained in 62% yield.
Figure imgf000074_0001
'H NMR (300 MHz, CDC13); 1.69 (s, 2H, N#2); 5.08 (s, IH, CHNH2); 7.12-7.31 (m, 6H, H arom.); 7.34 (br s, 1 H, H pyridine.); 8.20 (d, J = 6.0 Hz, IH, H pyridine). M+(ESI+): 219.
Figure imgf000074_0002
Intermediate 3: Preparation of amino alcohols of general formula (XXVI); e.g.. 3-amino-3- (2,4-dimethylphenyl -l -propanol; 3-amino-3-(2-fluorophenyl)-l -propanol; 3-amino-3-(4- fluorophenyl)- 1 -propanol; 3-amino-3-(2,6-difluorophenyl)-l -propanol; 3-amino-3-(2- methylphenylVl -propanol; 3-amino-3-(2-methoxyphenyl -l-propanol; 3-amino-3-(4- methylphenylV 1 -propanol; 3 -amino-3 -(2,3 -difluorophenyl)- 1 -propanol; 3-amino-3 -(4- methylphenyl -l -propanol; 3-amino-3-(4-methoxyphenyl -l-propanol; 3-Amino-3-(2,4- dimethylphenylV 1 -propanol.
Method A:
To a suspension of sodium borohydride (0.585g, 15.47mmol) in dry THF (20ml) was added the corresponding amino acid (XXV), e.g., 3-(2,4-dimethylphenyl)-β-alanine (1.25g, 6.45mmol) in dry THF (20ml). The reaction mixture was stirred under inert atmosphere and cooled down to zero degree in an ice bath. A solution of iodine (1.64g, 6.45mmol) dissolved in dry THF (10ml) was added dropwise over a period of 30min resulting in a vigorous evolution of hydrogen. After the addition of iodine was completed and gas evolution ceased, the flask was heated to reflux for 18 hours and then cooled to room temperature, methanol (100ml) was added cautiously until the mixture became clear. After stirring further 30min, the solvent were removed, yielding a white paste which was dissolved by addition of 150ml of 20%) aqueous KOH. The solution was stirred for 4h and extracted with DCM (3x150ml). The organic layer were dried over sodium sulfate and concentrated in vacuo to give the desired aminoalcohol compounds (XXVI), e.g., 3-amino- 3-(2,4-dimethylphenyl)-l-propanol as a yellowish oil (0.85g, 74%).
Figure imgf000075_0001
Η NMR (300 MHz, CDC13) : 1.82 (m, IH), 2.00 (m, IH), 2.27 (s, 3H), 2.30 (s, 3H), 3.50 (brs, 2H), 3.78 (m, 2H), 4.48 (m, IH), 6.95 (s, IH), 7.02 (d, J = 7.9 Hz, IH), 7.34 (d, J = 7.9 Hz, IH)
Method B:
A solution of lithium aluminium hydride (2.5 ml of a 1 M solution in THF) was slowly added to the amino acid (XXV), e.g., 3-(2-fluorophenyl)-β-alanine (272mg, 1.65mmol) in THF (4ml) at 0°C. The mixture was stirred at r.t. for 8 h and quenched with 0.6 ml water, 0.6 ml IN NaOH and 0.6 ml water. The suspension thus obtained was filtered, dried with a Na2Sθ4 cartridge and concentrated under reduced pressure. This crude product (XXVI), e.g., 3-amino-3-(2-fluorophenyl)-l -propanol (131mg, 69%) was directly engaged in the following step.
Method C: Preparation of amines of general formula (IV*VIV* by enzymatic resolution ;e.g. (SV3- amino-3-(2,4-difluorophenyP-l -propanol and (RV3-amino-3-(2.4-difluorophenyl -l- propanol
a) Enzymatic resolution :
Ethyl-3-amino-3-(2,4-difluorophenyl)-l-propanoate (5.3g, 23mmol) was suspended in a phosphate buffer (15 ml, pH = 8.2) and gently stirred before the addition of lipase Amano PS (313 mg). The mixture was then stirred at room temperature and the pH maintained at 8.2 by addition of NaOH IN when necessary. The saponification was monitored by chiral HPLC (column CHIRALPAK AD ; hexane/IS OH/TEA 95:5:0. l)and the reaction was stopped just before the complete consumption of the S enantiomer. The mixture was filtered and NaOH IN was added to the filtrate. Which was then extracted twice with DCM. Combined organic layer were washed with brine, dried over magnesium sulfate, filtrated and concentrated to give 2.72 g of the pure R-ethyl-3-amino-3-(2,4- difluorophenyl)-l-propanoate (chiral HPLC : Rt = 9.8 mn; ee = 99%); Η-RMN (CDC13): 7.40 (m, IH) ; 6.80 (m, 2H) ; 4.60 (m, I H) ; 4.10 (m, 2H) ; 1.93 (m, 2H) ; 1.25 (m, 3H)). The aqueous phase was lyophilized and redissolved in HCl IN. It was filtered through a SCX cartridge, suspended in MeOH/ACN 3: 1 , filtered and concentrated to give the pure S- 3-amino-3-(2,4-difluorophenyl)-l-propanoic acid as a nice white powder (Η-RMN (D20): 7.43 (q, I H) ; 7.00 (m, 2H) ; 4.93 (s, I H) ; 3.25 (s, 2H) ; 3.00 (m, 2H). The enantiomeric purity of the acid was controlled by preparation of the methyl ester derivative with TMS- diazomethane and chiral HPLC analysis using a CHIRALCEL OD-H column with hexane/ISOH/TEA 95:5:0.1 as eluant. Rt (S enantiomer) = 10.0 min; Rt (R enantiomer) = 9.4 min. ee of the above described S-enantiomer = 95.5%.
b) reduction to the alcohol
(S)-3-amino-3-(2.4-difluorophenvπ-l -propanol
Figure imgf000077_0001
(S)-3-amino-3-(2,4-difluorophenyl)-l -propanol was obtained following the general method C as described for intermediate 2 from (S)-3-amino-3-(2,4-difluorophenyl)-l-propanoic acid.
Η NMR (CDCls): 7.30 (m, IH) ; 6.83 (m, 2H) ; 4.37 (m, IH) ; 3.82 (m, 2H) ; 1.90 (m, 4H).
(R)-3-amino-3-(2,4-difluorophέnyl)- 1 -propanol
Figure imgf000077_0002
(R)-3-amino-3-(2,4-difluorophenyl)-l -propanol was obtained following the general method B as described for intermediate 2 from Ethyl (R)-3-amino-3-(2,4-difluorophenyl)-l - propanoate.
Method D:
The amino acid (XXV), e.g., 3-(4-fluorophenyl)-β-alanine (1 eq.) was dissolved in dry THF (30 vol.) and BH .DMS (2.5eq) was added. The mixtures were then refluxed between 2h00 and 24h00 until total disappearance of the starting material by LC-MS analysis. The reaction was then quenched by adding MeOH slowly and the mixture was stirred for lh at room temperature. The solvents were then removed by evaporation and 15 ml of aq.KOH solution (20%) was added. The compounds were then extracted with DCM and dried with Na2S0 , filtered and the DCM removed. The yields of desired compounds (XXVI), e.g., 3- (4-fluorophenyl)-β-aIanine, varied between 70 and 90%.
Figure imgf000078_0001
Η NMR (360 MHz, DMSO); 1.53 (s, 9H), 3.62-3.63 (d, 2H), 5.33-5.44 (s, 2H) 7.10(t, IH), 8.94 (s, IH).
Similarly, using one of these three methods, and starting from the appropriate commercial amino acids (XXV), the following, related amino alcohol intermediates (XXVI) were obtained:
3-amino-3-(2,6-diflυorophenyl -l -propanol:
Following the general Method B, starting from 3-(2,6-difluorophenyl)-β-alanine, the title compound was obtained in 60% yield.
Figure imgf000078_0002
Η NMR (300 MHz, CDC13) : 1.71(d, J = 13.9 Hz, IH), 2.20 (m, IH), 3.12 (m, 2H), 3.80 (m, 2H), 4.44 (d, J = 10.5 Hz, IH), 6.81 (m, 2H), 7.19 (m, IH).
3-amino-3-(2-methylphenyl -l -propanol:
Following the general Method B, starting from 3-(2-methylphenyl)-β-alanine, the title compound was obtained in 80% yield.
Figure imgf000079_0001
Η NMR (300 MHz, CDC13) : 1.84 (m, 2H), 2.28 (s, 3H), 3.07 (brs, 2H), 3.77 (m, 2H), 4.35 (dd, J = 9.0 and 3.8 Hz, IH), 7.08-7.38 (m, 4H). 3-amino-3-(2-methoxyphenyl)-l -propanol:
Following the general Method B, starting from 3-(2-methoxyphenyl)-β-alanine, the title compound was obtained in 70% yield.
Figure imgf000079_0002
Η NMR (300 MHz, CDC13) : 1.77 (m, IH), 2.10 (m, IH), 3.50 (brs, 2H), 3.78 (m, 5H), 4.39 (dd, J = 9.8 and 3.8 Hz, IH), 6.86 (m, 2H), 7.20 (m, 2H).
3-Amino-3-(2.4-dimethylphenyl -l -propanol:
Following the general Method B, starting from 3-(2,4-dimethylphenyl)-β-alanine, the title compound was obtained in 88% yield.
Figure imgf000079_0003
Η NMR (300 MHz, CDCI3) : 1.82 (m, IH), 2.00 (m, I H), 2.27 (s, 3H), 2.30 (s, 3H), 3.50 (brs, 2H), 3.78 (m, 2H), 4.48 (m, IH), 6.95 (s, IH), 7.02 (d, J = 7.9 Hz, IH), 7.34 (d, J = 7.9 Hz, IH) Intermediate 4: Preparation of non-commercial secondary amines; e.g., 2-[(2- furylmethyOaminojethanol; methyl 3-(methylamino)propanoate.
Method A:
An aldehyde, e.g. , 2-furfuraldehyde (2g, 20.82mmol), and an amine, e.g., 2-aminoethanoI, (1.65g, 27.06mmol) were poured together in a mixture 1 :1 TMOF:DCE (50ml) and the reaction mixture was cooled down to zero degree. The reducing agent NaBH(OAc)s (6.18g, 29.14mmol) was added in 4 subsequent portions over a 5min period, the reaction mixture was allowed to gradually warm to room temperature and stirred for 16 hours. The solvents was removed from the reaction in vacuo and the residue was partitioned between dichloromethane (150ml) and saturated bicarbonate solution (50ml). After separation, the organic layer was washed with saturated bicarbonate solution (50ml) and brine (50ml). The combined organic layers were then dried over sodium sulphate, filtered and the solvent removed in vacuo. The desired secondary amines, e.g., 2-[(2-furylmethyl)amino]ethanol, were obtained as a yellowish oil (1.82g, 62%).
Figure imgf000080_0001
H
Η NMR (300 MHz, CDC13); 2.71 (m, CH2N, 2H), 3.25 (s, CH2N, 2H), 3.65 (m, CH20, 2H), 4.98 (s, NH, IH), 6.16 (s broad, CH=, IH), 6.25 (s broad, CH=, IH), 7.3 (s broad, CH=, IH); M+(ESI+): 142.5; M"(ESF): 140.1.
Method B:
Methyl acrylate (3.1g, l eq, 36mmol) was dissolved in CHCI3 (50ml) and methyl amine (1.68g, 1.5eq, 56mmol) was added in one portion. The reaction mixture was stirred and heated to 40°C for 12h. The solvents evaporated at the pump to give a yellowish oil, methyl 3-(methylamino)propanoate (3.6g, 85.3% yield).
Figure imgf000081_0001
Η NMR (300 MHz, CDC13); 2.50 (s, CH3N, 3H), 2.51 (m, CH2N, 2H), 2.85 (m, CH2C(0),
Figure imgf000081_0002
Intermediate 5: Preparation of non-commercial sulfonyl chlorides (VI) and/or sulfonic acids (X); e.g., 4'-methoxy[l,r-biphenyl]-4-sulfonyl chloride; 4'-chloro[l,r-biphenyl]-4- sulfonyl chloride; 3 '-chloro[U'-biphenyl] -4- sulfonyl chloride; 3'-methyl[l,l'-biphenyl]-4- sulfonyl chloride; 2 '-chloro[l.r-biphenyl] -4- sulfonyl chloride; 2'-methyl[l.r-biphenyl]-4- sulfonyl chloride; 4 '-methyl [1,1 '-biphenyl] -4- sulfonyl chloride; 4'-methoxy[l ,r-biphenyl]- 4-sulfonyl chloride; 4'-methoxy[l,l'-biphenyl]-4-sulfonyl chloride; sodium 4-(3- pyridinyDbenzenesulfonate.
Figure imgf000081_0003
Method A:
a) 4-methoxyphenylboronic acid:
To a solution of 4-bromoanisole (lOOg, 0.53mol) in dry THF (IL), BuLi (494ml, 0.64mol) was added slowly at -78°C and stirred for 2h. To this was added n-butylborate
(147g, 0.64mol) slowly over 30min and stirred at RT for 12h. After completion, the reaction mixture was quenched with water (400ml), acidified with 1.5N HCl and filtered off the solid precipitate. The solid was washed with water and dried to give 4- methoxyphenylboronic acid (75g, 92%).
b) 4'-methoxy [1,1 '-biphenyl] -4-sulfonic acid:
A mixture of 4-methoxyphenylboronic acid (35g, 0.23mol), sodium-4-bromobenzene- sulfonate (50g, 0.19mol) and Na2CC.3 (200g) were taken in toluene (1000ml) and water (500ml). To this was added Pd(PPh3)4 (1 lg, 0.01 lmol) and the reaction mixture was refluxed for 12h under N2 atmosphere. The reaction mixture was cooled, filtered off the solid residue, washed with toluene and acidified with 6N HCl. The solid precipitate was filtered and dried to give 4'-methoxy[l,l'-biphenyl]-4-sulfonic acid (45g, 88%).
c) 4 '-methoxy[l, 1 ' -biphenyl] -4-sulfonyl chloride:
To a mixture of 4'-tnethoxy[l , l '-biphenyl]-4-sulfonic acid (30g, 0.1 lmol) and thionylchloride (90ml), DMF (1ml) was added and the reaction mixture was refluxed for 6h. Excess thionylchloride was distilled off and the crude was purified by column chromatography over silica gel (pet. ether/CHC , 1 : 1 ) to give 4'-methoxy[l, r-biphenyl]-4- sulfonyl chloride (30g, 95%).
Η NMR (300 MHz, CDC13); 3.9 (CH30, s, 3H), 7.31 (AB system, J = 6Hz, 2xH7, 2xH6), 7.95 (AB system, J = 6Hz, 2xH2, 2xH3); M+(ESI+): 283.2; MXESF): 281.6.
Similarly, using the appropriate commercial boronic acids and arylbromides, other related sulfonyl chlorides as mentioned above were obtained.
Figure imgf000082_0001
Method B:
a) isobutyl 4-bromobenzenesulfonate:
4-bromobenzenesulfonyl chloride 850g, 0.19mol) was suspended in 2-propanol (45ml, 3eq) and the slurry was cooled to less then 10°C. Pyridine (32ml, 2eq) was added in portions while maintaining the reaction temperature below 10 C. After reaction completion (ca. 3 hours), 11ml of glacial acetic acid followed by 250ml of methyl tert-butyl ether (MTBE) were added. The layers were separated and the rich organic layer was successively washed with 125ml of IN aqueous hydrochloric acid and 150ml of saturated sodium bicarbonate solutions. The rich MTBE solution was solvent exchanged into hexane (i.e., the addition of hexane with concurrent distillation of MTBE) to induce crystallisation. The crystal slurry was filtered, washed and dried in vacuo at no more than 25°C, to give 48g (87% yield) of isobutyl 4-bromobenzenesulfonate.
b) 4-(isobutoxysulfonyl)phenylboronic acid:
To a solution of isobutyl 4-bromobenzenesulfonate (56g, 200mmol) in 280ml of THF was added triisopropylborate (84ml, 1.82eq) and the reaction mixture was cooled to less than - 65°C. To the cooled solution, n-butyllithium (144ml, 0.9eq, 1.07 M in hexanes) was slowly addded while maintaining the temperature below -65°C. The reaction mixture was stirred for at least 0.5hours and then was quenched with IM sulfuric acid (200ml). The reaction mixture was allowed to warm to ca. 20°C. The layers were separated and the rich organic layer containing 35g (92% yield) of 4-(isobutoxysulfonyl)phenylboronic acid was used without further purification in the next step.
c) sodium 4-(3-pyridinyl)benzenesulfonate:
The THF-Hexane-MTBE solution containing 23g (93.3mmol) of 4-(isobutoxysulfonyl) phenylboronic acid was concentrated to a concentration of ca. 7ml/g. A portion of this solution containing ca. 4.7g (19mmol, 0.26eq) was added to a solution of 15.4g (75mmol) of 3-iodopyridine dissolved in 100ml of degassed tetrahydrofuran. To this solution, tris(dibenzylidene acetone) dipalladium (0) (0.5g, 0.6mol%) and degassed aqueous sodium carbonate solution (300ml, 3eq) were added. The reaction mixture was heated to ca. 50°C to initiate the coupling reaction. During the reaction, Pd2(dba)s (0.5g per addition) and rich organic concentrate containing 4-(isobutoxysulfonyl)phenylboronic acid (4.7g, 0.26eq per addition) were added in several portions until all the 3-iodopyridine was consumed. The reaction mixture was further heated at ca. 55°C for an additional 4hours. The reaction mixture was filtered and washed with methyl-fe -butyl ether. The pH of the product-rich aqueous solution was adjusted to ca. 4, treated with trithiacyanuric acid (l g) and filtered to remove Pd containing by-products. The pH of the product-rich aqueous solution was adjusted to ca. 7 and was saturated with solid NaCl (1 18g) to initiate the xrystallisation of the product. The salted-out product was dried in vacuo at less than 70oC. For recrystallization, the dried product was dissolved in 350ml of 190 proof ethanol at ca. 75°C. The solution was filtered and concentrated to ca. 100ml and cooled to ca. 30°C to initiate crystallization. About 200ml of MTBE was added to maximize the yield. The crystal slurry was filtered, washed and dried in vacuo less than 70°C, to give 13.4g (70% yield) of sodium 4-(3-pyridinyl)benzenesulfonate.
Η NMR (300 MHz, DMSO); 7.45 (AB system, J = 6Hz, 2xH3, 2xH4), 7.8 (dd, J = 4Hz, J = 6Hz, H'°), 8.71 (dά, J = 7Hz, J = 1Hz, H1 1), 8.81 (dd, J = 6Hz, J = 1Hz, H9), 9.19 (d, J = 1 Hz, H7); M+(ESI+): 236.2; M"(ESF): 234.2.
Other related sulfonyl chlorides or sulfonyl acids as mentioned above were obtained such as benzeneacetic acid, 4-(chlorosulfonyl)-alpha,alpha-dimethyl-, methyl ester
Figure imgf000084_0001
Method C:
a) 2 -methy 1-2 -phenyl propanoic methyl ester: The 2-methyl-2-phenyl propanoic acid (1.045g, 6.36mmol) was dissolved in 10 mL od Toluene/MeOH (1 : 1). Trimethylsilyl)diazomethane (9.54mL in a solution 2M in hexane, 19.08mmol, 3eq) was added. The reaction mixture was stirred overnight at room temperature, then the solution was evaporated under vacuum et the residue dissolved in EtOAc. The organic layer was washed with NaHC03 sat., NaCl sat., and dried over MgS04. The solvent was evaporated to give a colorless (1.lg, quantitative yield). Η-RMN (CDCI3) δ 7.22-7.34 (m, 5H) ; 3.66 (s, 3H) ; 1.59 (s, 6H).
b) benzeneacetic acid, 4-(chlorosulfonyl)-alpha,alpha-dimethyl-, methyl ester: 2-methyl-2-phenyl propanoic methyl ester (l .lg, 6.17mmol) was dissolved in 20mL of anhydrous DCM and the reaction mixture was cooled down to -78°C. The chlorosulfonic acid (2.05mL, 30.86mmol, 5eq) dissolved in 10 mL of anydrous DCM was added dropwise during a period of 2h. The reaction mixture was stirred overnight at room temperature. The reaction was quenched by addition of ice and the product extracted with DCM (3x5 OmL) The organic layer was washed with NaCl sat, dried over MgS04, evaporated to give an oil (l g, yield: 59%, HPLC purity: 84%)
Η-RMN (CH2C12) δ 7.99 (d, J = 9.1 , 2H) ; 7.58 (d, J = 8.7, 2H) ; 3.69 (s, 3H) ; 1.56 (s, 6H). MS (ESI -) : 275.15
Intermediate 6: Thiazolidine intermediates of general formula (V); e.g.. tert-buty\ 2- ({[( l-Sr)-3-hydroxy-l-phenylpropyl]amino}carbonyπ- l ,3-thiazolidine-3-carboxylate
Figure imgf000085_0001
Commercial 3-(tert-butoxycarbonyl)-l,3-thiazolidine-2-carboxylic acid (III) (lg, 4.29mmol) was dissolved in dry THF (50ml). A mechanical stirrer was placed in the flask and the solution stirred vigorously. The solution was cooled down to -25°C and N-methyl moφholine (1.084g, 10.72mmol) was added in dry TFIF (5ml). A solution of isobutyl- chloroformate (0.615g, 4.5mmol) in dry THF (10ml) was then added dropwise over a period of 10 minutes with continued vigorous stirring, the reaction's exotherm being maintained at the optimal temperature of -25°C by the use of a dry-acetone bath . After the complete addition ofthe chloroformate, the reaction mixture was stirred at -25°C for 30min after which time an amine (IV)/(IV*), e.g., (3-S -3-amino-3-phenyl-l -propanol (0.778g, 5.14mmol) was added drop-wise over a period of lOmin. The reaction mixture was allowed to gradually warm to room temperature and stirred overnight. The solvent was removed and the residue re-dissolved in ethyl acetate (150ml). The organic layer was washed subsequently with a saturated solution of ammonium chloride (100ml), saturated bicarbonate (100ml) and brine (100ml). Organics then dried with magnesium sulfate and concentrated in vacuo. The product (V), e.g.,
Figure imgf000086_0001
2-({[(l_S)-3-hydroxy-l -pheny 1- propyl]amino}carbonyl)-l,3-thiazolidine-3-carboxylate, was finally obtained as a white foam (1.5g, 95%). The antipodal intermediate, tert-bx\Xy\ 2-( {[(l<S)-3-hydroxy-l -pheny 1- propyl]amino}carbonyl)- l ,3-thiazolidine-3-carboxylate, as well as the racemic intermediate, rt-butyl 2-({[3-hydroxy-l-phenylpropyl]amino}carbonyl)-l ,3-thiazolidine-3- carboxylate were made according to the same protocol, starting from commercial (37?)-3- amino-3-phenylpropan-l-ol or 3-amino-3-phenylpropan-l-ol, respectively.
lU NMR (300MHz, CDC13); 1.72 (s, 9H), 2.1 -2.55 (m, CH2, 2H), 3.2-3.6 (m, CH2S, 2H), 3.9-4.25 (m, CH20, CH2N, 4H), 5.49 (m, CH, I H), 5.51 (s, CH, I H), 6.85(s broad, NH, IH), 7.5-7.7 (m, CH(Ar), 5H); M+(ESI+): 367.1.
According to the general method outlined above for the synthesis of Intermediates 6, starting from commercial 3-(tert-butoxycarbonyl)- 1 ,3-thiazolidine-2-carboxylic acid (III) and the appropriate commercial amines (IV), the following, related intermediates (V) were obtained:
Figure imgf000086_0002
tert-butyl 2-({[(17?)-2-hydroxy-l-phenylethyl]amino}carbonyl)-l ,3-thiazolidine-3- carboxylate: Η NMR (300MHz, CDC13); 1.7 (s, 9H), 3.2-3.6 (m, CH2S, 2H), 3.7-4.0 (m, CH20, CH2N, 4H), 5.1 (m, CH, IH), 5.5 (s, CH, IH), 6.8 (s broad, NH, IH), 7.5-7.7 (m, CH(Ar), 5H); M+(ESI+): 353.4.
Figure imgf000087_0001
tert-butyl 2-( { [2-(dimethylamino)- 1 -phenylethyl] amino } carbonyl)- 1 ,3-thiazolidine-3- carboxylate: Η NMR (300MHz, CDC13); 1.4 (s, 9H), 2.28 (s, CH3N, 6H), 2.4-2.7 (m, CH2N, 2H), 2.9-3.3 (m, CH2S, 2H), 3.7-4.0 (m, CH2N, 2H), 4.85 (m, CH, IH), 5.3 (s broad, CH, IH), 7.2-7.4 (m, CH(Ar), 5H); M+(ESI+): 380.5.
Figure imgf000087_0002
tert-butyl 2-( { [(7?)-phenyl(2-pyridinyl)methyl]amino} carbonyl)- 1 ,3-thiazolidine-3- carboxylate: Η NMR (300MHz, CDCI3); 1.5 (m, 9H), 3.2-3.4 (m, CH2S, 2H), 3.7-4.0 (m, CH2N, 2H), 5.3 (m, CH, IH), 6.1 (s, CH, IH), 6.8 (s broad, NH, IH), 7.0-7.3 (m, CH(Ar), 7H), 7.6 (m, CH(Pyr), IH), 8.1 (m, CH(Pyr), IH); M+(ESI+): 400.2.
Figure imgf000087_0003
tert-butyl (2S)-2-({[(lS)-3-hydroxy-l-phenylpropyl]amino}carbonyl)-l,3-thiazolidine-3- carboxylate: Η NMR (300MHz, CDCI3); 1.5 (m, 9H), 3.2-3.45 (m, CH2S, 2H), 3.7-3.9 (m, CH2N, 2H), 5.3 (m, CH, IH), 6.1 (s, CH, IH), 6.8 (s broad, NH, IH), 7.0-7.3 (m, CH(Ar), 7H), 7.6 (m, CH(Pyr), IH), 8.1 (m, CH(Pyr), IH); M+(ESI+): 400.2. CH(Pyr), IH); M+(ESI+): 400.5.
Figure imgf000088_0001
tert-butyl (2S)-2-({[(l S)- l-(4-fluorophenyl)-3-hydroxypropyl]amino}carbonyl)- 1 ,3- thiazolidine-3-carboxylate: Η NMR (300MHz, CDC13); 1.5 (s, 9H), 2.1-2.52 (m, CH2, 2H), 3.25-3.6 (m, CH2S, 2H), 3.9-4.15 (m, CH20, CH2N, 4H), 5.45 (m, CH, IH), 5.50 (s, CH, IH), 6.75(s broad, NH, IH), 7.5-7.6 (m, CH(Ar), 4H); M+(ESI+): 385.5.
Figure imgf000088_0002
tert-butyl (2S)-2-({[(lS)-l-(2,6-difluorophenyl)-3-hydroxypropyl]amino}carbonyl)-l,3- thiazolidine-3-carboxylate: Η NMR (300MHz, CDCI3); 1.7 (s, 9H), 2.1-2.5 (m, CH2, 2H), 3.2-3.5 (m, CH2S, 2H), 3.9-4.15 (m, CH20, CH2N, 4H), 5.40 (m, CH, IH), 5.45 (s, CH, I H), 6.8(s broad, NH, IH), 7.5-7.5 (m, CH(Ar), 3H); M '(ESI+): 403.2.
Figure imgf000088_0003
tert-butyl (2S)-2-({[(lS)-l -(2,4-difluorophenyl)-3-hydroxypropyl]amino}carbonyl)-l ,3- thiazolidine-3-carboxylate: 'H NMR (300MHz, CDC13); 1.65 (s, 9H), 2.1-2.55 (m, CH2, 2H), 3.2-3.56 (m, CH2S, 2H), 3.9-4.27 (m, CH20, CH2N, 4H), 5.46 (m, CH, IH), 5.6 (s, CH, 1 H), 6.8(s broad, NH, 1 H), 7.5-7.7 (m, CH(Ar), 4H); M+(ESI+): 403.8.
Figure imgf000089_0001
tert-butyl (2S)-2-( { [( 1 S)-3-hydroxy- 1 -phenylpropyl]amino} carbonyl)- 1 ,3-thiazolidine-3- carboxylate: Η NMR (300MHz, CDC13); 1.7 (s, 9H), 2.1-2.5 (m, CH2, 2H), 3.2-3.6 (m, CH2S, 2H), 3.9-4.25 (m, CH20, CH2N, 4H), 5.47 (m, CH, I H), 5.49 (s, CH, IH), 6.85(s broad, NH, IH), 7.5-7.7 (m, CH(Ar), 5H); M+(ESI+): 367.2.
Intermediate 7: e.g.. methyl 3-([l,r-biphenyl]-4-ylsulfonyl)-l ,3-thiazolidine-2-carboxylate
Figure imgf000089_0002
Commercial l,3-thiazolidine-2-carboxylic acid methyl ester hydrochloride (IX) (3g, 16.33mmol) was dissolved in DCM dry (50ml) and the solution was cooled down to zero degree. Triethylamine (4.96g, 49mmol) was added in DCM (10ml) followed by the sulfonyl chloride (4.13g, 16.33mmol) in DCM (50ml). The reaction mixture was stirred for 24h at room temperature. Aminomethyl polystyrene resin (lg, 3.3mmol/g) was added to the reaction mixture and stirred for two hours before filtering at the pump. The organic solution was washed with saturated solution of ammonium chloride (100ml) and brine (100ml). The organic layer was then dried with magnesium sulfate and concentrated in vacuo (crude yield 70%). Silica gel chromatography, eluting with 15% ethyl acetate in hexanes gave the desired compound as a white solid, methyl 3-([l,l'-biphenyl]-4-ylsulfonyl)-l,3- thiazolidine-2-carboxylate (2.98g, 50% yield).
Η NMR (300MHz, CDCI3); 2.7-3.1 (m, CH2S, 2H), 3.7 (s, CH3O, 3H), 3.8-4.0 (m, CH2N, 2H), 5.2 (m, CH, IH), 5.5 (s, CH, IH), 7.4-8.0 (m, CH(Ar), 9H); MχESI~): 362.5. Intermediate 8: Thiazolidine intermediates of general formula (VIII); e.g., 3-([l ,l '- biphenyl]-4-ylsulfonyl)-l ,3-thiazolidine-2-carboxylic acid and
Figure imgf000090_0001
Method A:
A stirred solution of l,3-thiazolidine-2-carboxylic acid (VII) (6.0g, 45.1mmol, leq) in dioxane (60ml, lOvol), IM aqueous sodium carbonate solution (90ml, 15vol) and water (50ml, 8.3vol) was treated at RT over 50 minutes with a solution of a sulfonyl chloride (VI), e.g., [l,l '-biphenyl]-4-sulfonyl chloride (12. Og, 47.5mmol, 1.05eq) in dioxane (50ml, 8.3 vol w.r.t. thiazolidine input). The thick white suspension which resulted was stirred (poorly) for 2.5hrs, when TLC (silica, 1 : 1 EtOAc/hexane, 1% AcOH) showed a negligible amount of sulphonyl chloride remaining. The reaction mixture was cooled to 10°C and filtered, solids washed with water (50ml), and the filter cake sucked "dry" overnight. The wet filter cake (32mg) was stirred in water (165ml) and dioxane (160ml), and warmed to ca. 60°C, giving a clear colorless solution, (pH ca.7), which was stirred at about this temperature while adding 2M HCl (13ml) to give a pH of 2. The resulting suspension was stirred while cooling to 10°C, aged for a few minutes then filtered and solids washed with water (3 x 20ml). The product of general structure (VIII), e.g., 3-([l ,l'-biphenyl]-4- ylsulfonyl)-l,3-thiazolidine-2-carboxylic acid, was dried in vacuo at 45°C giving 11.01 g (70%).
Η NMR (300MHz, OMSO-d6); 2.6-3.1 (m, CH2S, 2H), 3.6-3.9 (m, CH2N, 2H) 5.45 (s, CH, IH), 7.4-8.0 (m, CH(Ar), 9H); M"(ESI"): 348.0.
Figure imgf000091_0001
Following the same method A, starting from benzeneacetic acid, 4-(chlorosulfonyl)- alpha,alpha-dimethyl-, methyl ester , the compound 2-thiazolidinecarboxylic acid, 3-[[4-(2- methoxy-l,l-dimethyl-2-oxoethyl)phenyl]sulfonyl]- was obtained in 63% yield and 93% HPLC purity.
Η-RMN (CDC13) δ 7.83 (d, Jd = 8.67, 2H) ; 7.50 (d, Jd = 8.67, 2H) ; 5.47 (s, IH) ; 3.78- 3.90 (m, 2H) ; 3.68 (s, 3H) ; 3.19 (td, Jt = 6.03, Jd = 10.55, IH) ; 2.80 (td, Jt = 6.41, Jd - 10.55, IH) ; 1.61 (s, 6H)
Method B:
A solution was made containing Intermediate 6, e.g., methyl 3-([l, l '-biphenyl]-4- ylsulfonyl)-l,3-thiazolidine-2-carboxylate (2.0g, 5.5mmol, leq), in dry DCM (50ml). The flask was cooled down to -20°C in a dry-acetone bath. A solution of boron tribromide (5.55g, 22.0mmol) in dry DCM (30ml) was added drop wise over a period of 10 minutes. The reaction mixture was stirred for lh at 0°C. The reaction mixture was diluted with DCM (50ml) and washed with a IM HCl solution (2x50ml) and with brine (50ml) before drying over magnesium sulfate, filtering and removal of solvent in vacuo. The desired product of general structure (VIII), e.g., 3-([l,l'-biphenyl]-4-ylsulfonyl)-l,3-thiazolidine-2-carboxylic acid, was isolated as a white powder (1.8g, 94%).
Intermediate 9: Thiazolidine intermediates of general formula (XXVIII); e.g., (3S)-3- ( { \(2S)-3-(\\ .1 '-biphenyll-4- ylsulfonyl)- 1.3 -thiazolidin-2-yl]carbonyU amino V3- phenylpropyl methanesulfonate; 3-({[3-([l,r-biphenyl]-4-ylsulfonyl)-1.3-thiazolidin-2- yllcarbonyll amino)-3 -phenylpropyl methanesulfonate.
Figure imgf000092_0001
Intermediates of general structure (XXVI), e.g., (2-S -3-([l,r-biphenyl]-4-ylsulfonyl)-iV- [(liS -3-hydroxy-l -phenylpropyl]- l,3-thiazolidine-2-carboxamide or 3-([l,l'-biphenyl]-4- ylsulfonyl)-N-(3 -hydroxy- 1 -phenylpropyl)- 1, 3 -thiazolidine-2-carboxamide (3.5g, 7.25mmol), were dissolved in dry DCM (20ml) at 0°C and TEA (2.2g, 21.76mmol) was added followed by MsCI (lg, 8.7mmol) in 10ml of DCM. The reaction mixture was stirred for 4h at r.t., then washed with saturated NH4CI and brine. The organic layer was dried over Na2Sθ4, and the solvents evaporated. The crude products of general structure (XXVIII), e.g., (3tS)-3-({[(25)-3-([l,l'-biphenyl]-4-ylsulfonyl)-l,3-thiazolidin-2-yl]carbonyl}amino)- 3 -phenylpropyl methanesulfonate and 3-({[3-([l,l'-biphenyl]-4-ylsulfonyl)-l,3-thiazolidin- 2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate were directly utilized for the next reaction.
Η NMR (300MHz, CDCI3); 2.0-2.25 (m, 2H), 2.25-2.8 (m, CH2S, 2H), 2.87 (s broad, CH3, 3H), 3.5-4.2 (m, CH2N, CH20, 4H), 5.03 (m, CH, IH), 5.15 (s broad, CH, IH), 7.2-8.0 (m, CH(Ar), 14H).
Intermediate 10: Thiazolidine intermediates of general formula (XXXI); e.g., (2-SV-/V-[(l-Sy 3-amino- 1 -phenylpropyl]-3-([ 1 , 1 '-biphenyl]-4-ylsulfonyl)- 1 ,3-thiazolidine-2-carboxamide and N-[3-amino- 1 -phenylpropyl]-3-([ 1 , 1 '-biphenyl]-4-ylsulfonyl)- 1 ,3-thiazolidine-2- carboxamide.
Figure imgf000093_0001
a) Mitsunobu-reaction using phthalimide, e.g., 3 -([ 1,1 ' -biphenyl] -4-ylsulfonyl)-N-[ 3 -(1,3- dioxo-1, 3-dihydro-2H-isoindol-2-yl)- 1 -phenylpropyl]- 1 ,3-thiazolidine-2-carboxamide.
Intermediates of general structure (XXVI), e.g., 3-([l, -biphenyl]-4-ylsulfonyl)-7V-(3- hydroxy- 1 -phenylpropyl)- 1, 3 -thiazolidine-2-carboxamide (l.Og, l .Oeq, 2.07mmol) were dissolved in 20 ml dry THF under nitrogen. Phthalamide (395mg, 1.5eq, 2.69mmol), diethylazodicarboxylate (470mg, 1.5eq, 2.69mmol) and polymer bound triphenyl phosphine (l .Og, 1.5eq, 2.70mmol) were then added and the reaction mixture was shaken for 12 hours at RT. The triphenyl phosphine resin was filtered off and the THF solution evaporated in vacuo. The residue was taken up in DCM and washed twice with a saturated sodium carbonate solution and then water. The organic layer was dried with magnesium sulfate and concentrated in vacuo to give a crude product which was purified on silica gel using cyclohexane/ethyl acetate(7/3) as eluent, to obtain the desired products, e.g. , 3-([l,l'- biphenyl]-4-ylsulfonyl)-N-[3-( 1 ,3 -dioxo- 1 ,3-dihydro-2H-isoindol-2-yl)- 1 -phenylpropyl] - l,3-thiazolidine-2-carboxamide in 57% yield as a white oil in 96 % purity by HPLC.
Η NMR (400MHz, CDCl3); 2.10-2.40 (m, 2H, CH2), 2.509-2.61 (m, IH, CH2S), 2.90-3.30 (m, IH, CH2S), 3.69-3.93 (m, 4H, CH2N), 5.06 (m, IH, CH), 5.32 (s, IH, CH), 6.39 (m, IH, NH), 7.05-7.67 (m, 16H, CH(Ar)), 7.71 -7.81 (m, 2H, CH(Ar)); M+(ESI+): 612.6; M" (ESF): 610.71.
b) Hydrazinolvsis, e.g., N-[3-amino-l-phenylpropyl]-3-([l,l '-biphenyl]-4-yIsulfonyl)-l,3- th iazo lidine- 2-carboxam ide The intermediates from the previous step, e.g., 3-([l,l '-biphenyl]-4-ylsulfonyl)-N-[3-(l,3- dioxo-l,3-dihydro-2 /-isoindol-2-yl)-l-phenylpropyl]-l ,3-thiazolidine-2-carboxamide (400mgs, 1.Oeq, 0.65mmol) were dissolved in a mixture of EtOH/THF (15/1) at room temperature. 1.5 ml of hydrazine was introduced and reaction mixture heated up to 70C for 12 hours. The corresponding phthalhydrazide precipitate was filtered off, rinsed with DCM and the organic solvents concentrated in vacuo. The residue was taken up in ethylacetate (20 ml), washed several times with a sodium hydrogeno carbonate solution (10%), dried with magnesium sulfate. The organic solvents were then concentrated in vacuo to give a crude compound, which was purified by flash chromatography using DCM/MeOH (98/2) as eluent, affording the desired compounds, e.g., N-[3-amino-l-phenylpropyl]-3-([l ,1 '- biphenyl]-4-ylsulfonyl)-l ,3-thiazolidine-2-carboxamide was obtained in 70% yield as a white oil in 98% purity by HPLC.
Η NMR (400MHz, CDC13); 1.88 (m, 2H, CH2), 2.40 (m, 2H, NH2), 2.48-2.50 (m, IH, CH2S), 2.89-2.90 (m, IH, CH2S), 3.20-3.53 (m, 2H, CH2), 3.70-3.90 (m, 2H, CH2N), 5.10 (m, 1 H, CH), 5.27 (s, 1 H, CH), 6.45 (m, 1 H, NH), 7.19-7.88 (m, 14H, CH(Ar)); M+(ESI+): 482.47; M"(ESF): 480.88.
Intermediate 1 1 : Substituted aryl and heteroaryl aldehyde derivatives of general formula (XVI): e.g., 6-[2-(dimethylamino)ethoxy]-2-pyridinecarbaldehyde.
Figure imgf000094_0001
a) N-{2-[(6-bromo-2-pyridinyl)oxy]ethyl}-N,N-dimethylamine (XXIII):
2-dimethylaminoethanol (2 mL, 20 mmol) was added at rt to a suspension of NaH (oil was not removed) in dry DMF (3 mL). The mixture was stirred at rt for 2 hours and lh at 60°C. Then commercial 2,6-dibromopyridine (6.16 g, 26 mmol, 1.3eq) was added at rt and the whole was stirred at rt overnight. The crude mixture was dissolved in some Et20 and was extracted with 2 portions of citric acid 30%. Combined aqueous phases were washed with 2 portions of Et20. The aqueous phase was basified with NaOH 5N at 0°C and was extracted with 3 portions of Et20. Combined organic phases was dried over MgS04, filtrated and evaporated. As some DMF remained, HCl in Et20 was added. The solvents were evaporated and the resulting solid was put at the pump for 4 hours. It was dissolved in H20 and basified with NaOH 5M. The desired product (the base) was extracted with 3 portions of Et2θ. Combined organic layers were dried over MgS04, filtrated and evaporated to give the desired product (XXIII), 7V-{2-[(6-bromo-2-pyridinyl)oxy]ethyl}-N,N-dimethylamine (4.4309 g, 18.076 mmol, 90.4%).
' H ΝMR (360 MHZ, CDCI3); 2.16 (S, 6H); 2.53 (m, 2H); 4.23 (m, 2H); 6.58 (m, I H); 6.88 (m, IH); 7.24 (m, I H); M+(ESI+): 245.2/247.2
b) 6-[2-(dimethylamino)ethoxy]-2-pyridinecarbaldehyde:
n-BuLi 2.5 M in hexane (1.2 mL, 3 mmol, 3eq) was added at -70°C to a solution ofthe product from the previous step, N-{2-[(6-bromo-2-pyridinyl)oxy]ethyl}-N,N- dimethylamine (245 mg, lmmol) in dry THF (10 mL). The reaction mixture was stirred at - 70°C for 1 h30 min. Ethyl formate (freshly distilled over P205) was added at -70°C, and the reaction mixture was stirred at -70°C for 2 hours. The reaction was quenched with addition of water. The reaction mixture was extracted with 3 portions of DCM. Combined organic phase were dried with MgS04, filtrated and evaporated to give the desired product, 6- [2- (dimethylamino)ethoxy]-2-pyridinecarbaldehyde (192 mg, 0.988 mmol, 99%).
' H NM (360 MHz, CDC13); 2.24 (s, 6H); 3.62 (m, 2H); 4.41 (m, 2H); 6.91 (d, I H, J=6Hz); 7.44 (m, I H); 7.60 (t, I H, J=6Hz); 9.81 (s, I H).
Example 1 : General protocols for the solution- phase synthesis of l ,3-thiazolidine-2- carboxamide derivatives of general formula (I); e.g., 3-([ l , r-biphenyl]-4-y Isulfony D-N- [( 1 -Sr)-3-hydroxy- 1 -phenylpropyl]- l ,3-thiazolidine-2-carboxamide; (2 r)-3-([l .l '-biphenyl]- 4-y Isulfony \)-N-[( 1 f)-3-hydroxy- 1 -pheny Ipropyll- 1 ,3-thiazolidine-2-carboxamide: (27?)-3- rπ,l '-biphenyl]-4-v Isulfony0-N-[(1 y)-3-hydroxy- 1 -phenylpropyl]- 1 ,3-thiazolidine-2- carboxamide. (2S -3-(l.r-biphenyl-4-ylsulfonyl)-N-[(R)-phenyl(pyridin-2-yl methyll-1.3- thiazolidine-2-carboxamide.
Strategy 1:
N-methyl moφholine (NMM) (3.24g, 2.5eq, 32.15mmol) was added to a solution of a compound of general formula (VIII) (Intermediate 8, 4.50g, leq, 12.86mmol), e.g., 3-([l,l '- biphenyl]-4-ylsulfonyl)-l ,3-thiazolidine-2-carboxylic acid, in dry THF (100ml) and the reaction mixture was cooled down to -25°C. To the reaction mixture was then added drop wise, over a period of 5 minutes, isobutyl chloroformate (1.84g, 1.05eq, 13.50mmol) in solution in dry THF (20ml). The resulting mixture was stirred at -25°C for 30minutes, after which time an amine of general formula (IV) or (IV*) (commercial or Intermediate 2, 2.14g, l .leq, 14.15mmol), e.g., (3-S)-3-amino-3-phenyl-l -propanol, was added in dry THF (20ml) over a period of 5 minutes. The mixture was allowed to gradually warm to room temperature and stirred overnight at room temperature. The solvent was removed and the residue re-dissolved in ethyl acetate (200ml). The organic layer was washed subsequently with a saturated solution of ammonium chloride (100ml), saturated bicarbonate (100ml) and brine (100ml). The combined organic phases were dried with magnesium sulfate and concentrated in vacuo, yielding the crude product of general formula (I), e.g., 3-([l ,l '- biphenyl]-4-ylsulfonyl)-N-[(lJS)-3-hydroxy-l -phenylpropyl]- l ,3-thiazolidine-2- carboxamide, as a white solid (6.2 l g, 96%). Silica gel chromatography, eluting in isocratic conditions (50% ethyl acetate in hexanes), which gave the separation ofthe desired two pure diastereoisomers of general formula (I), e.g., (2S)-3-([ l , l '-biphenyl]-4-y Isulfony 1)-N- [(l-S)-3-hydroxy-l -pheny lpropy l]-l ,3-thiazolidine-2-carboxamide (more polar compound, 3.1 g), and (27?)-3-([l , 1 *-biphenyl]-4-ylsulfonyl)-N-[(l 5)-3-hydroxy-l -phenylpropyl]- 1 ,3- thiazolidine-2-carboxamide (less polar compound, 3.0g).
Strategy 2:
a) Protocol for the Η -deprotection step
Method A: A solution was made containing a compound of general structure (V) (Intermediate 6, 0.788 g, 2.15 mmol), e.g., tert-butyl 2-({[(l_ )-3-hydroxy-l-phenylpropyl]amino}carbonyl)- 1 , 3 -thiazolidine-3 -carboxy late, in anhydrous DCM (50 ml). At 0°C, 4M HCl solution in dioxane (50ml) was added, or alternatively, HCl gas, previously dried with a H2S04 cc trap, was bubbled slowly through the reaction and deprotection was monitored by TLC using cyclohexane/ethyl acetate (1/1) and stained with a pancaldi solution. After approximately 45 minutes, TLC showed no remaining starting materiel and DCM was then evaporated in vacuo without heating to avoid salt decomposition. More DCM (20 ml) was then added and evaporated again in vacuo to remove remaining potential HCl (2-3 times). The desired product, e.g., N-[(l»S)-3-hydroxy-l-phenylpropyl]- l ,3-thiazolidine-2-carboxamide hydrochloride, was isolated as a white solid and used for the next step without further purification and characterization.
Method B:
In a 6L 4-neck flask, was added a solution containing a compound of general structure (V) (Intermediate 6, 60g g, 150.18 mmol), e.g., tert-butyl (2S)-2-({[(R)-ρhenyl(pyridin-2- yl)methyl]amino}carbonyl)-l ,3-thiazolidine-3-carboxylate, in DCM under argon atmosphere ( 1250 ml). At -30°C, a solution of HCl cone. (627mL, 7509mmol) was added slowly during a period of 40minutes. The reaction mixture was stirred at -30°C for 3h30. The reaction was kept at -30°C and a solution of IL of ΝAOH I M was added followed by 1250mL of ΝaOH 5M so that to obtain pH=5 . The last 50 mL of 5M ΝaOH solution were added at -10°C due to formation if ice in the flask.. The slurry was extracted with DCM (5x 500mL) and dried over MgS04 and evaporated to almost dryness. The desired product, e.g. , (2S)-Ν-[(R)-phenyl(pyridin-2-yl)methyl]- 1 ,3-thiazolidine-2-carboxamide hydrochloride, was isolated and used for the next step without further purification and shows no trace of racemisation.
b) Protocols for the N -capping step Method A: To a solution ofthe product from the previous step, e.g., N- [(\S)-3 -hydroxy- 1 - phenylpropyl]-l,3-thiazolidine-2-carboxamide hydrochloride (636mg, leq, 2.1 mmol) in DCM (50ml) was added a compound of general structure (VI) (commercial or Intermediate 4, 543mg, leq, 2.15mmol), e.g., [l,l'-biphenyl]-4-sulfonyl chloride, followed by TEA (1.74g, 8eq, 17.2mmol) in dry DCM (50ml) and the reaction mixture was stirred overnight at room temperature. Aminomethyl polystyrene resin (250mg) was added to the reaction mixture and stirred for one hour before filtering at the pump. The solution was washed with citric acid (aq) (2 x 50ml), then dried over MgS04, and evaporated in vacuo. The product of general structure (1), e.g., 3-([l ,r-biphenyl]-4-ylsulfonyl)-N-[(l,S)-3-hydroxy-l- pheny lpropy 1]- 1 , 3 -thiazolidine-2-carboxamide, was purified by Silica gel chromatography, eluting in isocratic conditions (50% ethyl acetate in hexanes), which gave the separation of the desired two pure diastereoisomers of general formula (I), e.g., (2-S)-3-([l ,l '-biphenyl]-4- ylsulfonyl)-N-[(l_S)-3-hydroxy-l-phenylpropyl]-l,3-thiazolidine-2-carboxamide (more polar compound, 300mg) «t7t (27?)-3-([l,r-biphenyl]-4-ylsulfonyl)-N-[(1 )-3-hydroxy-l- phenylpropyl]- 1 ,3-thiazolidine-2-carboxamide (less polar compound, 31 Omg), corresponding to an overall yield of 60%>.
Method B: To a solution of a compound of general structure (X) (commercial or Intermediate 4, 504mg, l eq, 2.1 mmol), e.g., [l ,l'-biphenyl]-4-sulfonic acid, in dry THF (20ml), at 0°C, was drop wise added thionyl chloride (580mg, 2eq, 4.3mmol) in dry THF solution (10ml). The reaction mixture was stirred at room temperature over a 2h period. The excess of thionyl chloride was then evaporated in vacuo and the crude product of general formula (VI), e.g., [l ,l'-biphenyl]-4-sulfonyl chloride, was then directly added to a solution of N-[(l -S)-3-hydroxy-l -phenylpropyl]- l ,3-thiazolidine-2-carboxamide hydrochloride (636mg, leq, 2.1 mmol) in DCM (50ml). To the reaction mixture, TEA (1.74g, 17.2mmol) was added in dry DCM (50ml) and the reaction mixture was stirred overnight at room temperature. Aminomethyl polystyrene resin (25 Omg) was added to the reaction mixture and stirred for one hour before filtering at the pump. The solution was washed with citric acid (aq) (2 x 50ml) and then dried over MgS04, and evaporated in vacuo. The product of general structure (I), e.g. , 3-([l, r-biphenyl]-4-ylsulfonyl)- V-[(15)-3- hydroxy-1 -pheny lpropy l]-l,3-thiazolidine-2-carboxamide, was purified by Silica gel chromatography, eluting in isocratic conditions (50% ethyl acetate in hexanes), which gave the separation ofthe desired two pure diastereoisomers of general formula (I), e.g., (25)-3- ([1 ,1 '-biphenyl]-4-ylsulfonyl)-N-[(15)-3-hydroxy- 1 -phenylpropyl]- 1 ,3-thiazolidine-2- carboxamide (more polar compound, 280mg) and (27?)-3-([l,T-biphenyl]-4-ylsulfonyl)-N- [(15)-3-hydroxy-l-phenylpropyl]- l,3-thiazolidine-2-carboxamide (less polar compound, 300mg), corresponding to an overall yield of 58%>.
Method C: In a 3 L 4 necks flask was dissolved (2S)-N-[(R)-phenyl(pyridin-2-yl)methyl]- l,3-thiazolidine-2-carboxamide hydrochloride (50.4g, 150mmol) in 1800 mL of dry THF under argon at -30°C. When the temperature was reached, NMM (198mL, 182mmol) was added slowly, followed by (1.8g, 15mmol) of DMAP. The sulfonyl chloride, e.g., [ 1 ,1 '- biphenyl]-4-sulfonyl chloride dissolved in 445mL of anhydrous THF, was then added over a period of 30min at -30°C. The reaction was stirred overnight and allow to warm to room temperature. The solvents were evaporated under vacuum (temperature ofthe bath = 35°C) and the resulting oily-solid slightly pink mixture was dissolved in 2L of AcOEt and this mixture was extracted with 2x500mL of NH4C1 sat, NaHCOs sat. and NaCl sat. The organic layer was dried over MgSθ4 and evaporated to give 1 OOg of crude product. No racemisation was detected by chiral HPLC (WhelkOl (S, S) hexane/EtOH 5/5 0.1% TEA). The crude product was purified by flash chromatography to give 41.45g ofthe desired product (2S)-3-( 1 ,1 '-biphenyl-4-y Isulfony l)-N-[(R)-phenyl(pyridin-2-yl)methyl]- 1 ,3- thiazolidine-2-carboxamide as a white solid. Yield: 53.5%.
Figure imgf000099_0001
(2S)-3-([ 1 , 1 '-biphenyl]-4-ylsulfonyl)-N-[( 1 S 3 -hydroxy- 1 -phenylpropyl]- 1 ,3-thiazolidine- 2-carboxamide. Η NMR (300MHz, CDC13); 1.8-2.3 (m, 2H), 2.55-3.15 (m, CH2S, 2H), 3.6-3.60-4.0 (m, CH2N, CH20, 4H), 5.2-5.3 (m, CH, I H), 5.35 (s, CH, 0.5H), 5.37 (s, CH, 0.5 H), 7.2-8.0 (m, CH(Ar), 14H); M+(ESI+): 483.1; MXESF) 481.1.
Figure imgf000100_0001
(27?)-3-([ 1,1 '-biphenyl] -4-ylsulfonyl)-N-[(l-S)-3 -hydroxy- 1 -phenylpropyl] -1 ,3 -thiazolidine- 2-carboxamide. Η NMR (300MHz, CDCI3); 1.8-2.25 (m, 2H), 2.55-3.15 (m, CH2S, 2H), 3.65-3.8 (m, CH2N, 2H), 3.65-4.0 (m, CH20, 2H), 5.2 (m, CH, IH), 5.36 (s, CH, IH), 7.2- 8.0 (m, CH(Ar), 14H); M+(ESI+): 483.1; MXESF) 481.2.
Figure imgf000100_0002
(27?)-3 -([1,1 '-biphenyl] -4-ylsulfonyl)-N-[(l-S)-3 -hydroxy- 1 -pheny lpropy 1]- 1,3 -thiazolidine- 2-carboxamide. 'H NMR (300MHz, CDC13); 1.85-2.3 (m, 2H), 2.55-3.15 (m, CH2S, 2H), 3.65-3.9 (m, CH2N, CH20, 4H), 5.2-5.3 (m, CH, IH), 5.37 (s, CH, IH), 7.25-8.0 (m, CH(Ar), 14H); M+(ES1+): 483.0; MXESF) 481.0.
Example 2: 3-([ 1 , 1 '-biphenyll-4-ylsulfonvn-N- ( lR)-2-hvdroxy- 1 -phenylethyll- 1.3- thiazolidine-2-carboxamide.
Following the general strategies and protocols outlined in Example 1, starting from 3- ([l,l '-biphenyl]-4-ylsulfonyl)-l,3-thiazolidine-2-carboxylic acid (Intermediate 8) and commercial (27?)-2-amino-2-phenylethanol, the title compound was obtained in 98% purity by HPLC.
Figure imgf000101_0001
Η NMR (300MHz, CDC13); 2.4-2.9 (m, CH2S, 2H), 3.5-3.7 (m, CH2N, 2H), 3.7-3.9 (m, CH20, 2H), 4.9 (m, CH, IH), 5.2 (s, CH, IH), 7.1-7.9 (m, CH(Ar), 14H); M+(ESI+): 469.2; MXESF) 467.1.
Example 3 : 3-([ 1 , 1 '-biphenyl]-4-ylsulfonyl)-N-[(7?)-phenyl(2-pyridinyl)methyl]- 1 ,3- thiazolidine-2-carboxamide.
Following the general strategies and protocols outlined in Example 1, starting from 3- ([l,l '-biphenyl]-4-ylsulfonyl)-l,3-thiazolidine-2-carboxylic acid (Intermediate 8) and (7?)- phenyl(2-pyridinyl)methanamine (Intermediate 1), the title compound was obtained in 96% purity by HPLC.
Figure imgf000101_0002
Η NMR (300MHz, CDCI3); 2.5-3.0 (m, CH2S, 2H), 3.6-4.0 (m, CH2N, 2H), 5.41 (s, CH, 0.5H), 5.42 (s, CH, 0.5H), 6.07 (m, CH, IH), 5.2 (s, CH, IH), 7.1-7.8 (m, CH(Ar), 16H), 7.8-7.9 (m, CH, IH), 8.5-8.6 (m, CH, IH); M+(ES1+): 516.3; MXESF) 514.1.
Example 4: 3-([l .1 '-biphenyπ-4-ylsulfonvD-N-[ 1 -(4-fluorophenyl)-3-hydroχypropyll- 1 ,3- thiazolidine-2-carboxamide. Following the general strategies and protocols outlined in Example 1 , starting from 3- ([l ,l '-biphenyl]-4-y Isulfony I)- l ,3-thiazolidine-2-carboxy lie acid (Intermediate 8) and 3- amino-3-(4-fluorophenyl)-l -propanol (Intermediate 2), the title compound was obtained in 92% purity by HPLC.
Figure imgf000102_0001
Η NMR (400MHz, CDC13); 1.8-2.15 (m, CH2, 2H), 2.5-2.9 (m, CH2S, 2H), 3.5-3.8 (m, CH2N, CH20, 4H), 5.15 (m, CH, IH), 5.25 (s, CH, IH), 7.1 -7.9 (m, CH(Ar), 13H); M+(ESI+): 501.3.
Example 5 : 3-([ 1 , 1 '-biphenyl] -4- ylsulfonyU-N- [ 1 -(3-furyl)-3-hydroxypropyl]- 1 ,3- thiazolidine-2-carboxamide.
Following the general strategies and protocols outlined in Example 1 , starting from 3- ([l, l '-biphenyl]-4-ylsulfonyl)-l,3-thiazolidine-2-carboxylic acid (Intermediate 8) and 3- amino-3-(3-furyl)-l -propanol (Intermediate 2), the title compound was obtained in 98% purity by HPLC.
Figure imgf000102_0002
Η NMR (400MHz, CDCI3); 1.7-2.2 (m, CH2, 2H), 2.5-2.9 (m, CH2S, 2H), 3.6-3.8 (m, CH2N, CH20, 4H), 5.12 (m, CH, IH), 5.21 (s, CH, IH), 6.25-6.35 (d, CH(furyl), IH), 6.9- 7.1 (m, CH(furyl), IH), 7.3-7.9 (m, CH(Ar), 10H); M+(ESI+): 473.1; MXESF): 471.1. Example 6: 3-(ri, r-biphenyl]-4-ylsulfonylVN-ri -(2-chlorophenyπ-3-hydroxypropyl]- 1.3- thiazolidine-2-carboxamide.
Following the general strategies and protocols outlined in Example 1, starting from 3- ([l,r-biphenyl]-4-ylsulfonyl)-l ,3-thiazolidine-2-carboxylic acid (intermediate 8) and 3- amino-3-(2-chlorophenyl)-l-propanol (Intermediate 2), the title compound was obtained in 94% purity by HPLC.
Figure imgf000103_0001
Η NMR (400MHz, CDC13); 1.95-2.15 (m, CH2, 2H), 2.5-2.9 (m, CH2S, 2H), 3.6-3.8 (m, CH2N, CH20, 4H), 5.28 (s, CH, 0.5H), 5.29 (s, CH, 0.5H), 5.4-5.5 (m, CH, IH), 7.1-7.9 (m, CH(Ar), 13H); M+(ES1+): 517.3.
Example 7: 3-([ 1 , 1 '-biphenyl] -4-ylsulfonyl -N-[ 1 -(3-chlorophenyl)-3-hydroxypiOpyl]- 1 ,3- thiazolidine-2-carboxamide.
Following the general strategies and protocols outlined in Example 1, starting from 3- ([l,r-biphenyl]-4-ylsulfonyl)-l,3-thiazolidine-2-carboxylic acid (Inteπnediate 8) and 3- amino-3-(2-chlorophenyl)-l -propanol (Intermediate 2), the title compound was obtained in 99% purity by HPLC.
Figure imgf000103_0002
Η NMR (400MHz, CDC13); 1.8-2.2 (m, CH2, 2H), 2.55-3.0 (m, CH2S, 2H), 3.6-3.8 (m, CH2N, CH20, 4H), 5.1-5.2 (m, CH, IH), 5.24 (s, CH, 0.5H), 5.28 (s, CH, 0.5H), 7.2-7.9 (m, CH(Ar), 13H); M+(ESI+): 517.1 ; MXESF): 514.8.
Example 8: N-ri-π.3-benzodioxol-5-ylV3-hvdroxypropyl]-3-([l .r-biphenyl]-4- ylsulfonyO- 1 ,3-thiazolidine-2-carboxamide.
Following the general strategies and protocols outlined in Example 1 , starting from 3- ([l,l '-biphenyl]-4-y Isulfony I)- l ,3-thiazolidine-2-carboxylic acid (Intermediate 8) and 3- amino-3-(l ,3-benzodioxol-5-yl)-l-propanol (Intermediate 2), the title compound was obtained in 92% purity by HPLC.
Figure imgf000104_0001
Η NMR (400MHz, CDCI3); 1.7-2.2 (m, CH2, 2H), 2.45-3.0 (m, CH2S, 2H), 3.6-3.95 (m, CH2N, CH20, 4H), 5.0-5.1 (m, CH, IH), 5.26 (s, CH, 0.5H), 5.28 (s, CH, 0.5H), 5.87 (s, CH, IH), 5.89 (s, CH, IH), 6.8-7.9 (m, CH(Ar), 12H); M+(ESI+): 527.1; MXESF): 525.0.
Example 9: 2,S -3-[(4-fert-butylphenynsulfonyl1-N- (lty)-3-hydroxy-l-phenylpropyl]-1.3- thiazolidine-2 -carboxamide.
Following the general strategies and protocols outlined in Example 1, starting from 3-[(4- ter/-butylphenyl)sulfonyl]-l ,3-thiazolidine-2-carboxylic acid (Intermediate 8) and commercial (3-S -3-amino-3-phenyl-l -propanol, the title compound was obtained in 98% purity by HPLC.
Figure imgf000105_0001
Η NMR (400MHz, CDC13); 1.27 (s, CH3, 9H), 1.65-2.15 (m, CH2, 2H), 2.45-2.95 (m, CH2S, 2H), 3.6-3.95 (m, CH2N, CH20, 4H), 5.1-5.2 (m, CH, IH), 5.26 (s, CH, IH), 7.3-7.7 (m, CH(Ar), 9H); M+(ESI+): 463.1; M (ESF): 461.6.
Example 10: (25f)-N-[(1 f)-3-hydroxy-l-phenylpropyl]-3-[(4-fert-pentylphenyl)sulfonyl]- 1 ,3-thiazolidine-2-carboxamide.
Following the general strategies and protocols outlined in Example 1, starting from 3-[(4- ter/-pentylphenyl)sulfonyl]-l,3-thiazolidine-2-carboxylic acid (Intermediate 8) and commercial (3S)-3-amino-3-phenyl-l -propanol, the title compound was obtained in 99% purity by HPLC.
Figure imgf000105_0002
Η NMR (400MHz, CDCI3); 0.63 (t, J = 7.3Hz, 3H), 1.29 (s, CH3, 6H), 1.65 (q, J = 7.4Hz, 2H), 1.88 (m, CH2, I H), 2.19 (m, CH2, I H), 2.5 (m, CH2S, I H), 2.94 (dt, J =12Hz and 5.6Hz, CH2S, IH), 3.65-3.87 (m, CH2N, CH20, 4H), 5.2 (td, J = 6.6Hz and 3.8Hz, CH, 1 H), 5.32 (s, CH, 1 H), 7.25-7.8 (m, CH(Ar), 9H); M+(ESI+): 477.2; MXESF): 475.0.
Example 11 : 3-([l,r-biphenyl]-4-ylsulfonyl)-N-[l-(2-fluorophenyl)-3-hydroxypropyl]-l,3- thiazolidine-2-carboxamide. Following the general strategies and protocols outlined in Example 1 , starting from 3- ([l, -biphenyl]-4-ylsulfonyl)-l,3-thiazolidine-2-carboxylic acid (Intermediate 8) and 3- amino-3-(2-fluorophenyl)-l -propanol (Intermediate 2), the title compound was obtained in 96% purity by HPLC.
Figure imgf000106_0001
Η NMR (400MHz, CDCL); 2.24 (m, 3H), 2.25 (m, IH), 2.95 (m, IH), 3.63-3.90 (m, 4H), 5.31 (m, 2H), 6.99-7.86 (m, 13H).; M+(ESI+): 501; M (ESF): 499.
Example 12: 3-([l , 1 '-biphenyl] -4-y Isulfony l)-N-[ 1 -(2-methylphenyl)-3-hydroxypropyl]- 1 ,3-thiazolidine-2-carboxamide.
Following the general strategies and protocols outlined in Example 1, starting from 3- ([l,r-biphenyl]-4-ylsulfonyl)-l,3-thiazolidinc-2-carboxylic acid (Intermediate 8) and 3- amino-3 -(2 -methylphenyl)- 1 -propanol (Intermediate 2), the title compound was obtained in 98% purity by HPLC.
Figure imgf000106_0002
Η NMR (300MHz, CDC13); 1.86 (m, IH), 2.09 (m, IH), 2.36 (s, 3H), 2.57 (m, IH), 2.99 (m, IH), 3.72-3.92 (m, 4H), 5.31-5.40 (m, 2H), 7.19-7.88 (m, 13H); M+(ESI+): 497; M" (ESF): 495. Example 13: 3-(IT .r-biphenyl]-4-ylsulfonyl)-N-ri-(2-methoxyphenv0-3-hvdroxypropyll- 1 ,3-thiazolidine-2-carboxamide.
Following the general strategies and protocols outlined in Example 1 , starting from 3- ([l ,r-biphenyl]-4-ylsulfonyl)-l ,3-thiazolidine-2-carboxylic acid (Intermediate 8) and 3- amino-3-(2-methoxyphenyl)-l -propanol (Intermediate 2), the title compound was obtained in 87%o purity by HPLC.
Figure imgf000107_0001
Η NMR (300MHz, CDC13); 2.00 (m, 2H), 2.57 (m, IH), 2.87-2.98 (m, 2H), 3.62-3.70 (m, 3H), 3.92 (m, 0.4H), 3.92 (s, 1.8H), 3.98 (s, 1.2H), 4.04 (m, 0.6H), 5.23 (m, IH), 5.43 (m, IH), 6.92 (m, 2H), 7.22-7.45 (m, 2H), 7.46 (m, 3H), 7.60 (m, 2H), 7.77 (m, 2H), 7.90 (m, 2H), 8.26 (d, J = 11.7 Hz, 0.6H), 8.47 (d, J = 9.8 Hz, 0.4H); M+(ESI+): 513; M (ESF): 51 1.
Example 14: 3-([l,r-biphenyl]-4-ylsulfonyf)-N-[l -(2,6-difluorophenyl)-3-hydroxypropyl]- 1 ,3-thiazolidine-2-carboxamide.
Following the general strategies and protocols outlined in Example 1, starting from 3- ([1,1 ' -biphenyl] -4-ylsulfonyl)-l ,3-thiazolidine-2-carboxylic acid (Intermediate 8) and 3- amino-3-(2,6-difluorophenyl)-l -propanol (Intermediate 2), the title compound was obtained in 80% purity by HPLC.
Figure imgf000107_0002
Η NMR (300MHz, CDC13); 2.01 (m, 2H), 2.69 (m, I H), 3.00 (m, I H), 3.69-3.96 (m, 4H), 4.32 (m, 0.5H), 5.36 (m, IH), 5.62 (m, IH), 6.91-7.91 (m, 13H).; M+(ESI+): 519; MXESF): 517.
Example 15: 3-([l , 1 '-biphenyl]-4-ylsulfonyO-N-[l -(2,4-dimethylpheny0-3-hydroxypropyl]- 1 ,3-thiazolidine-2-carboxamide.
Following the general strategies and protocols outlined in Example 1 , starting from 3- ([l ,l '-biphenyl]-4-ylsulfonyl)-l ,3-thiazolidine-2-carboxylic acid (Intermediate 8) and 3- amino-3-(2,4-dimethylphenyl)-l -propanol (Intermediate 2), the title compound was obtained in 94.9% purity by HPLC.
Figure imgf000108_0001
Η NMR (300MHz, CDCI3); 1.94 (m, IH), 2.09 (m, IH), 2.30 (m, 6H), 2.56 (m, IH), 2.87 (m, 0.5H), 2.99 (m, 0.5H), 3.70 (m, 3H), 391 (m, IH), 5.31-5.37 (m, 2H), 6.76 (m, 2H), 6.99 (m, 2H), 7.45-7.93 (m, 9H).; MXESF): 511. MXEST): 509.
Example 16: General protocols for the solution-phase synthesis of l ,3-thiazolidine-2- carboxamide derivatives of general formula (I) from intermediates of general formula (XXVIII) (Intermediates 8)
Methods for the nucleophile substitution ofthe mesylate group in compounds of general structure (XXVIII) (Intermediate 9) by primary or secondary amines include:
Method A (displacement by secondary amines):
The mesylate derivative of general formula (XXVIII) (Intermediate 8, leq.) and LiBr (l ,5eq) were dissolved in a mixture of acetonitrile/2-butanone (1 :1) (e.g., dilution 500mg in 10ml of solvents) and agitated for 20min at room temperature. To this solution was added TEA (leq) and the amine of general structure HNR5R6 (3-4eq) in 10ml acetonitrile/2- butanone (1 : 1). The reaction mixture was heated at reflux (80°C) for 16h. The reaction mixture was cooled down to room temperature and evaporated in vacuo, redissolved in EtOAc (50ml) and washed with an aqeous solution of NaHCOs sat.. The organic phase was dried over Na2S0 . The crude product of general formula (I) was purified on FC with an appropriated gradient EtOAc: CycloHexane: MeOH.
Method B (displacement by primary amines):
The mesylate derivative of general formula (XX VIII) (Intermediate 8, leq.) was dissolved in dry THF (e.g., dilution 760mg in 76ml of THF). Sodium iodide (10 eq.), anhydrous potassium carbonate (2eq.) and the amine of general structure HNR5R6 (3.5eq.) were added and the reaction mixtures were shaken at room temperature for 6 days. Potassium carbonate and sodium iodide were filtered and the THF evaporated. The residue was dissolved in DCM and Ameba (aminomethylbenzylaldehyde) resin (2 eq.) was added to the flask. The reaction was shaken at room temperature over night. The resin was filtered and the solvent removed. The compounds were analyzed by LC-MS. When the purity was <60%, the compound was further purified using amberlyst 15 resin in MeOH. The reaction mixture was shaken at room temperature for 2 days. The resin was filtered and washed with methanol. The final product of general structure (I) was then released using concentrated HCl/MeOH (1/1 ) over night.
Example 17: (2S)-3-(\ 1.1 '-bipheny l]-4-v Isulfony \)-N- U 1 -SV3-[(2-fury lmethy lϊmethy IV amino]-! -phenylpropyl}- l,3-thiazolidine-2-carboxamide.
Following the general method A as outlined in Example 16, starting from (3S)-3-({[(2S)-3- ([l ,l '-biphenyl]-4-ylsulfonyl)-l ,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and 2-furyl-N-methylmethanamine, the title compound was obtained in 98.2% purity by HPLC.
Figure imgf000110_0001
Η NMR (300MHz, CDC13); Η NMR (300MHz, CDC13); 1.85-2.2 (m, 2H), 2.5 (s, CH3N, 3H), 2.45-3.00 (m, CH2S, 2H), 2.7-3.0 (m, CH2N, 2H), 3.6 (m, CH2N, 2H), 4.2 (m, CH2N, 2H), 4.7 (m, CH, IH), 5.3 (s, CH, IH), 6.37 (m, CH(furyl), IH), 6.56 (m, CH(furyl), IH), 7.05-8.0 (m, CH(Ar), 15H), 8.7 (m, NH, IH); M+(ESI+): 576.1; MXESF): 573.8.
Example 18: (2tSf)-3-(ri.l,-biphenyl]-4-ylsulfonyl)-N-r(l-y)-3-(diethylamino)-l -phenylpropyl]-!, 3-thiazolidine-2-carboxamide.
Following the general method A as outlined in Example 16, starting from (3S)-3-({[(2S)-3- ([l,l'-biphenyl]-4-ylsulfonyl)-l,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and N, V-diethylamine, the title compound was obtained in 98.6% purity by HPLC.
Figure imgf000110_0002
Η NMR (400MHz, DMSO); 1.05 (t, J - 7.3Hz, 6H), 1.88 (m, CH2, 2H), 2.79-2.81 (m, CH2N, 6H), 3.05 (m, CH2S, IH), 3.05-3.50 (broad, H20), 3.81 (m, CH2N, 2H), 4.86 (td, J = 6.6Hz and 3.8Hz, CH, IH), 5.44 (s, CH, IH), 6.58 (s, CH2, 2H), 7.24-7.33 (m, CH(Ar), 5H); 7.53 (m, CH(Ar), 3H), 7.76 (m, CH(Ar), 2H), 7.95 (m, CH(Ar), 4H), 8.68 (m, IH, NH); M+(ESI+): 538.0; MXESF): 536.0. 10
Example 19: (2-y -N-((l-S,)-3-rbenzyl(methvnaminol-l-phenylpropyl}-3-(ri.l'-biphenyl]-4- ylsulfonvD- 1 ,3-thiazolidine-2-carboxamide.
Following the general method A as outlined in Example 16, starting from (3S)-3-({[(2S)-3- ([l ,l '-biphenyl]-4-ylsulfonyl)-l,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and N-methyl(phenyl)methanamine, the title compound was obtained in 98% purity by HPLC.
Figure imgf000111_0001
Η NMR (300MHz, CDC13); 1.75-2.1 (m, 2H), 2.2 (s, CH3N, 3H), 2.3-2.9 (m, CH2S, 2H), 3.3-3.5 (m, CH2N, 2H), 3.6 (s, CH2N, 2H), 3.9 (m, CH2N, 2H), 5.0 (m, CH, IH), 5.3 (s, CH, IH), 7.0-8.0 (m, CH(Ar), 19H), 8.6 (m, NH, IH); M+(ESI+): 586.2; M (ESF): 583.8.
Example 20: (2S)-3-(\\ ,l'-biphenyl]-4-ylsulfonyl)-N-(( 1-^-3--! methyl[2-(2-pyridinyl)ethyl]- aminol - 1 -phenylpropyl)- 1 ,3 -thiazolidine-2-carboxamide.
Following the general method A as outlined in Example 16, starting from (3S)-3-({[(2S)-3- ([1,1 '-biphenyl]-4-ylsulfonyl)- 1 ,3-thiazolidin-2-yl]carbonyl } amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and N-methyl-2-(2-pyridinyl)ethanamine, the title compound was obtained in 100% purity by FIPLC.
Figure imgf000111_0002
1 1
Η NMR (400MHz, DMSO); 1.75 (m, CH2, 6H), 2.18 (s, CH3, 3H), 2.36 (m, CH, IH), 2.50 (m, CHS, I H), 2.55-2.85 (m, CH, 3H), 2.95 (m, CHS, IH), 2.37 (m, CH2, 2H), 3.67-3.74 (m, 2H, CH2N), 4.70 (s, CH, IH), 5.34 (s, CH, I H), 6.47 (s, 2H, H vinyl), 7.14-7.25 (m, CH(Ar), 7H); 7.40-7.49 (m, CH(Ar), 3H), 7.50-7.70 (m, CH(Ar), 3H), 7.83 (m, CH(Ar), 4H), 8.33 (m, CH(Ar), IH), 8.58 (m, IH, NH); M+(ESI+): 601 ; M (ESF): 599
Example 21 : (2S)-3-(\\ .1 '-biphenyll-4-ylsulfonyn-N- {( 1 -SV3-[(2-hydroxyethvn(methviy amino]-l-phenylpropyl}-1 ,3-thiazolidine-2-carboxamide.
Following the general method A as outlined in Example 16, starting from (3S)-3-({[(2S)-3- ([l, r-biphenyl]-4-ylsulfonyl)-l ,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and 2-(methylamino)ethanol, the title compound was obtained in 94.3% purity by HPLC.
Figure imgf000112_0001
Η NMR (300MHz, CDC13); 1.8-2.2 (m, 2H), 2.36 (s, CH3N, 3H), 2.45-3.05 (m, CH2S, 2H), 2.6-2.7 (m, CH2N, 4H), 3.7 (m, CH20, 2H), 3.7-4.1 (m, CH2N, 2H), 5.1-5.25 (m, CH, I H), 5.48 (s, CH, IH), 7.25-8.0 (m, CH(Ar), 14H), 8.55 (m, NH, IH); M+(ESθ: 540.2; M- (ESF): 537.99.
Example 22: methyl [[(3S)-3-({[(2-Sf)-3-([l .1 '-biphenyl]-4-ylsulfonyn-l .3-thiazolidin-2- yl] carbony 1 } amino)-3 -pheny lpropy 1] (methy Damino] acetate .
Following the general method A as outlined in Example 16, starting from (3S)-3-({[(2S)-3- ([1,1 '-biphenyl] -4-ylsulfonyl)-l ,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and methyl (methylamino)acetate, the title compound was obtained in 98.9% purity by HPLC. 12
Figure imgf000113_0001
Η NMR (300MHz, CDC13); 1.8-2.2 (m, 2H), 2.4 (s, CH3N, 3H), 2.5-3.0 (m, CH2S, 2H), 2.6-2.7 (m, CH2N, 2H), 3.4 (s, CH2N, 2H), 3.69 (s, CH30, 3H), 3.7-4.0 (m, CH2N, 2H), 5.1 (m, CH, IH), 5.49 (s, CH, I H), 7.2-8.0 (m, CH(Ar), 14H), 8.6 (m, NH, IH); M+(ESI+): 568.2; MXESF): 565.8.
Example 23 : 3 -([1,1 '-biphenyl] -4-ylsulfonyl)-N-[ 1 -phenyl-3 -( 1 -pyrrolidinyDpropyl]- 1 ,3- thiazolidine-2-carboxamide.
Following the general method A as outlined in Example 16, starting from 3-({[3-([l,T- biphenyl]-4-ylsulfonyl)-l ,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and pyrrolidine, the title compound was obtained in 99.2% purity by HPLC.
Figure imgf000113_0002
Η NMR (300MHz, CDC13); 2.15-2.4 (m, CH2, 6H), 2.45-3.05 (m, CH2S, 2H), 2.5-3.5 (m, CH2N, 6H), 3.9-4.25 (m, CH2N, 2H), 5.2 (m, CH, IH), 5.5 (s, CH, IH), 7.2-8.0 (m, CH(Ar), 14H), 8.5 (m, NH, IH); M+(ESI+): 536.3; MXESF): 534.2.
Example 24 : 3-([ 1 , 1 '-biphenyl] -4- ylsulfonylVN- [3 -(dimethylaminoV 1 -phenylpropyl] -1,3- thiazolidine-2-carboxamide. Following the general method A as outlined in Example 16, starting from 3-({[3-([l ,l' biphenyl]-4-ylsulfonyl)-l ,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and V,N-dimethylamine, the title compound was obtained in 99.6%o purity by HPLC.
Figure imgf000114_0001
Η NMR (300MHz, CDC13); 2.2-2.7 (m, CH2, 2H), 2.45-3.00 (m, CH2S, 2H), 2.7 (s, CH3N, 3H), 2.9 (s, CH3N, 3H), 3.5-3.9 (m, CH2N, 2H), 4.0-4.25 (m, CH2N, 2H), 5.0 (m, CH, IH), 5.3 (s, CH,1 H), 7.2-8.0 (m, CH (Ar), 14H), 8.5 (m, NH, I H); M+(ESI+): 510.2; MXESF): 508.1.
Example 25: -V-[3-(l-azepanyl)-l-phenylpropyl]-3-([l,r-biphenyl]-4-ylsulfonyl)-l,3- thiazolidine-2-carboxamide.
Following the general method A as outlined in Example 16, starting from 3-({[3-([l ,l'- biphenyl]-4-ylsulfonyl)-l,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and azepane, the title compound was obtained in 99.1% purity by HPLC.
Figure imgf000114_0002
M+(ESI+): 564.3; MXESF): 562.3. 14
Example 26: 3-(\ 1.1 '-biphenyll-4-ylsulfonylVN-l 1 -phenyl-3-( 1 -piperidinvDpropyl]- 1.3- thiazolidine-2-carboxamide.
Following the general method A as outlined in Example 16, starting from 3-({[3-([l ,F- biphenyl]-4-ylsulfonyl)-l,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and piperidine, the title compound was obtained in 99.5% purity by HPLC.
Figure imgf000115_0001
M+(ESI+): 550.3; MXESF): 548.2.
Example 27: 3-([l ,l'-biphenyl]-4-ylsulfonyl)-N-[3-(4-moφholinyπ-l-phenylpropyl]-l,3- thi azolidine-2 -carboxamide .
Following the general method A as outlined in Example 16, starting from 3-({[3-([l ,l '- biphenyl]-4-ylsulfonyl)-l,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and moφholine, the title compound was obtained in 99.3% purity by HPLC.
Figure imgf000115_0002
M+(ESI+): 552.3; MXESF): 550.2. Example 28: 3-( l . l'-biphenyll-4-ylsulfonyn-N-(3-r 2-hvdroχy-2-phenylethylϊmethyn- amino]-! -pheny lpropy -1.3-thiazolidine-2-carboxamide.
Following the general method A as outlined in Example 16, starting from 3-({[3-([l,l'- biphenyl]-4-ylsulfonyl)-l ,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and 2-(methylamino)-l -pheny lethanol, the title compound was obtained in 82%> purity by HPLC.
Figure imgf000116_0001
M+(ESI+): 616.3; MXESF): 614.9.
Example 29: 3-([l,r-biphenyl]-4-ylsulfonyl)-N-{3-[(3-hydroxy-3-phenylpropyl (methyl)- amino]- 1 -phenylpropyl} - 1 ,3-thiazolidine-2-carboxamide.
Following the general method A as outlined in Example 16, starting from 3-({[3-([l,l'- biρhenyl]-4-ylsulfonyl)-l,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and 3-(methylamino)-l -phenyl- 1 -propanol, the title compound was obtained in 85% purity by HPLC.
Figure imgf000116_0002
M (ESI+): 630.4; M (ESI ): 628.2.
Example 30: 3-(π ,r-biphenyl1-4-ylsulfonyπ-N-(3-[(2-hydroxycvclohexyπamino]-l- phenylpropy - 1 ,3-thiazolidine-2-carboxamide.
Following the general method B as outlined in Example 16, starting from 3-({[3-([l,l '- biphenyl]-4-ylsulfonyl)-l,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and 2-aminocyclohexanol, the title compound was obtained in 99% purity by HPLC.
Figure imgf000117_0001
M+(ESI+): 580.6; MXESF): 578.8.
Example 31 : iV-[3-(benzylamino)- 1 -phenylpropyl] -3 -([ 1 , 1 '-biphenyl] -4-ylsulfonyl)- 1 ,3- thiazolidine-2 -carboxamide .
Following the general method B as outlined in Example 16, starting from 3 -({[3 -([1,1'- biphenyl]-4-ylsulfonyl)-l,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and benzylamine, the title compound was obtained in 99% purity by HPLC.
Figure imgf000117_0002
M+(ESI+): 571.8; M (ESF): 569.99.
Example 32: 3-([l.1 '-bipheny ll-4-ylsulfonyn-N-(l -phenyl-3- { [2-(2-pyridinvnethyl]- amino} propyl)- 1 , 3 -thiazolidine-2-carboxamide.
Following the general method B as outlined in Example 16, starting from 3-({[3-([l ,l '- biphenyl]-4-ylsulfonyl)-l,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and 2-(2-pyridinyl)ethanamine, the title compound was obtained in 97.4% purity by HPLC.
Figure imgf000118_0001
M+(ESI+): 586.9; M (ESF): 585.3.
Example 33: General protocols for the solid-phase synthesis of l,3-thiazolidine-2- carboxamide derivatives of general formula (I)
a) Loading step
A solution of an suitably protected intermediate of general formula (III), e.g., 3-(tert- butoxycarbonyl)-l,3-thiazolidine-2-carboxylic acid (8.6g, 35.7mmol) in dry DCM (100ml) was added to Kaiser oxime resin (lOg, 11.9mmol) suspended in dry DCM (100ml).
Diisopropylcarbodiimide (4.5g, 35.7mmol) was then added to the suspension and shaken overnight at ambient temperature. The resin was then filtered at the pump and washed sequentially with NMP, DCM, MeOH and finally diethyl ether before being dried at 40°C in vacuo.
b) Η -deprotection step The resin obtained in the previous loading step was shaken with a 20% solution of trifluoroacetic acid in dichloromethane (100ml) for 30 minutes prior to filtering at the pump and washing sequentially with aliquots of NMP, DCM, MeOH and finally diethyl ether before being dried at room temperature in vacuo.
c) N-capping step
The resin from the previous deprotection step was transferred into a 96-well filter-plate (approx. 50mg of dry resin/well; Loading 0.93mmol/g; 0.047mmol) and each well treated with a sulfonyl chloride (VI) (0.140mmol, 3eq) and diisopropylethylamine (0.140mmol, 3eq) in NMP (1 ml), overnight. The plate was then sealed and shaken overnight at ambient temperature. After this time, the resin aliquots were filtered, washed sequentially with aliquots of NMP, DCM and finally diethyl ether before being dried at room temperature in vacuo.
d) Cleavage step
Amines (IV) (e.g., from commercial sources, or Intermediates 1 or Intermediates 2, 0.042mmol) were added to suspensions of the functional ised oxime resin batches from the previous step (50mg, 0.047mmol) in DCM (0.5- lml), and the plates sealed and shaken over the weekend period (~66 hours) at ambient temperatures. After filtration, the resultant solvent was evaporated in vacuo to give the products of general formula (1), which were analyzed by HPLC and mass spectroscopy. In cases where an N-Boc-protecting group was present on the final product, a solution of 25%>TFA in DCM (3ml) was added to the crude compound and stirred at ambient temperatures for 40min. The solvent was then removed in vacuo to give the corresponding final, N-deprotected products, again of general formula (I).
Example 34: N-benzyl-3-([l , l '-biphenyl]-4-y Isulfony 1)-1 , 3-th iazolidine-2-carboxamide.
Following the general solid phase method as outlined Example 33, starting from 3-(tert- butoxycarbonyl)- l ,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, [l , l '-biphenyl]-4- sulfonyl chloride and benzylamine, the title compound was obtained in 97% purity by HPLC.
Figure imgf000120_0001
Η NMR (400MHz, CDC13); 2.6-3.1 (m, CH2S, 2H), 3.7-4.1 (m, CH2N, 2H), 4.6-4.7 (m, NCH2Ar, 2H), 5.6 (s, CH, IH), 7.3-8.15 (m, CH(Ar), 14H); M+(ESI+): 439.1; MXESF): 437.0.
Example 35: N-benzyl-3-[(4-tert-butylphenyl)sulfonyl]-l,3-thiazolidine-2-carboxamide.
Following the general solid phase method as outlined Example 33, starting from 3-(tert- butoxycarbonyl)-l,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, 4-tert- butylbenzenesulfonyl chloride and benzylamine, the title compound was obtained in 97.1% purity by HPLC.
Figure imgf000120_0002
Η NMR (300MHz, CDC13); 1.1 (s, CH3, 3H), 2.3-2.8 (m, CH2S, 2H), 3.5-3.8 (m, CH2N, 2H), 4.2-4.4 (m, NCH2Ar, 2H), 5.2 (s, CH, IH), 7.0-7.65 (m, CH(Ar), 9H); M+(ES1+): 419.8; MXESF): 417.4.
Example 36: 3-([l,r-biphenyl]-4-ylsulfonyl)-N-(4-methoxybenzyl)-l,3-thiazolidine-2- carboxamide.
Following the general solid phase method as outlined Example 33, starting from 3-(tert- butoxycarbonyl)-l,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, 1,1 '-bipheny 1-4- sulfonyl chloride and 4-methoxyphenyl)methanamine, the title compound was obtained in 98% purity by HPLC.
Figure imgf000121_0001
Η NMR (400MHz, CDC13); 2.6-3.1 (m, CH2S, 2H), 3.7-4.1 (m, CH2N, 2H), 3.8 (s, CH3O, 3H), 4.6-4.7 (m, NCH2Ar, 2H), 5.6 (s, CH, IH), 7.3-8.1 (m, CH(Ar), 13H); M+(ESI+): 469.1; MXESF): 467.4.
Example 37: 3-([l ,l'-biphenyl]-4-ylsulfonyl)-N-(2-thienylmethyl)-l ,3-thiazolidine-2- carboxamide.
Following the general solid phase method as outlined Example 33, starting from 3-(tert- butoxycarbonyl)- 1,3 -thiazolidine-2 -carboxy lie acid, Kaiser oxime resin, l,l'-biphenyl-4- sulfonyl chloride and 2-thienylmethanamine, the title compound was obtained in 94% purity by HPLC.
Figure imgf000121_0002
Η NMR (400MHz, CDCI3); 2.55-3.1 (m, CH2S, 2H), 3.65-4.05 (m, CH2N, 2H), 4.6-4.85 (m, NCH2Ar, 2H), 5.5 (s, CH, 2H), 6.95-8.05 (m, CH(Ar), 12H); M+(ESI+): 445.1 ; MXESF): 443.1.
Example 38: 3-([l.r-biphenyl]-4-ylsulfonyl)-N-(2-furylmethyl - 3-thiazolidine-2- carboxamide. Following the general solid phase method as outlined Example 33, starting from 3-(tert- butoxycarbonyl)-l,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, l ,l'-biphenyl-4- sulfonyl chloride and 2-furylmethanamine, the title compound was obtained in 92.2%> purity by HPLC.
Figure imgf000122_0001
Η NMR (300MHz, CDC13); 2.6-3.1 (m, CH2S, 2H), 3.8-4.3 (m, CH2N, 2H), 4.6-4.75 (m, NCH2Ar, 2H), 5.7 (s, CH, 2H), 6.6 (m, CH(furyl), 2H), 7.45-8.3 (m, CH(Ar), 10H); M+(ESI+): 429.5; MXESF): 427.5.
Example 39: 3-([l,r-biphenyl]-4-ylsulfonyl)-N-(4-fluorobenzyl)-l,3-thiazolidine-2- carboxamide.
Following the general solid phase method as outlined Example 33, starting from 3-(tert- butoxycarbonyl)-l ,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, l,l'-biphenyl-4- sulfonyl chloride and (4-fluorophenyl)methanamine, the title compound was obtained in 92% purity by HPLC.
Figure imgf000122_0002
Η NMR (400MHz, CDC13); 2.65-3.1 (m, CH2S, 2H), 3.7-4.1 (m, CH2N, 2H), 4.6-4.7 (m, NCH2Ar, 2H), 5.6 (s, CH, IH), 6.9-7.9 (m, CH(Ar), 13H); M+(ESI+): 457.4; MXESF): 455.2. Example 40: N-benzhvdryl-3-(π ,r-biphenvH-4-ylsulfonvD- 1.3-thiazolidine-2- carboxamide.
Following the general solid phase method as outlined Example 33, starting from 3-(tert- butoxy-carbonyl)-l ,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, l ,l'-biphenyl-4- sulfonyl chloride and benzhydrylamine, the title compound was obtained in 98.5%> purity by HPLC.
Figure imgf000123_0001
Η NMR (400MHz, CDC13); 2.3-2.9 (m, CH2S, 2H), 3.5-3.9 (m, CH2N, 2H), 5.3 (s, CH, IH), 6.2 (s x2, NCHAr, IH), 7.3-8.15 (m, CH(Ar), 19H); M+(ESI+): 515.3; MXESF): 513.7.
Example 41 : 3-([l,r-biphenyl1-4-ylsulfonyl -N-[l-(4-fluoroρhenyl)ethyl]-l,3-thiazolidine- 2-carboxamide.
Following the general solid phase method as outlined Example 33, starting from 3-(tert- butoxycarbonyl)-l,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, l,l'-biphenyl-4- sulfonyl chloride and 1 -(4-fluorophenyl)ethanamine, the title compound was obtained in 85% purity by HPLC.
Figure imgf000123_0002
M+(ESf): 471.2; MXESF): 469.0. Example 42: 3-(IT .1 '-biphenyll^-ylsulfonyD-N-^-methylbenzviy 1 ,3-thiazolidine-2- carboxamide.
Following the general solid phase method as outlined Example 33, starting from 3-(tert- butoxycarbonyl)-l,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, l,l'-biphenyI-4- sulfonyl chloride and (2-methylphenyl)methanamine, the title compound was obtained in 99% purity by HPLC.
Figure imgf000124_0001
M+(ESI+): 453.2; MXESF): 451.0.
Example 43 : 3-([ 1 , 1 '-biphenyl] -4-ylsulfonyl -N-(2,6-difluorobenzyl)- 1 ,3-thiazolidine-2- carboxamide.
Following the general solid phase method as outlined Example 33, starting from 3-(tert- butoxycarbonyl)-l ,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, l,l'-biphenyl-4- sulfonyl chloride and 2,6-difluorophenyl)methanamine, the title compound was obtained in 85% purity by HPLC.
Figure imgf000124_0002
M+(ES1+): 475.2; MXESF): 473.0.
Example 44: 3-(ri,r-biphenyll-4-ylsulfonylVN-(2,3-difluorobenzyl)-1.3-thiazolidine-2- carboxamide. Following the general solid phase method as outlined Example 33, starting from 3-(tert- butoxycarbonyl)-l,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, l ,l '-biphenyl-4- sulfonyl chloride and 2,3-difluorophenyl)methanamine, the title compound was obtained in 93.4% purity by HPLC.
Figure imgf000125_0001
M+(ESI+): 475.4; MXESF): 472.6.
Example 45 : 3-([ 1 , 1 '-biphenyl] -4-ylsulfonyl)-N-(2-methoxybenzyl)- 1 ,3-thiazolidine-2- carboxamide.
Following the general solid phase method as outlined Example 33, starting from 3-(tert- butoxycarbonyl)-l ,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, l, l'-biphenyl-4- sulfonyl chloride and (2-methoxyphenyl)methanamine, the title compound was obtained in 98.5% purity by HPLC.
Figure imgf000125_0002
Η NMR (400MHz, CDC13); 2.6-3.1 (m, CH2S, 2H), 3.7-4.1 (m, CH2N, 2H), 3.8 (s, CH30, 3H), 4.6-4.7 (m, NCH2Ar, 2H), 5.6 (s, CH, IH), 7.3-8.1 (m, CH(Ar), 13H); M+(ESI+): 469.2; MXEST): 467.6.
Example 46: 3-([l.r-biphenyll-4-ylsulfonvπ-N-(2-chlorobenzyl -1.3-thiazolidine-2- carboxamide. Following the general solid phase method as outlined Example 33, starting from 3-(tert- butoxycarbonyl)-l,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, l,l '-biphenyl-4- sulfonyl chloride and (2-chlorophenyl)methanamine, the title compound was obtained in 85% purity by HPLC.
Figure imgf000126_0001
M+(ESI+): 473.3; M (ESI ): 470.2.
Example 47: 3-([l.r-biphenyl]-4-ylsulfonyπ-N-(2-fluorobenzyl)-l,3-thiazolidine-2- carboxamide.
Following the general solid phase method as outlined Example 33, starting from 3-(tert- butoxycarbonyl)- l,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, 1 , l'-biphenyl-4- sulfonyl chloride and (2-fluorophenyl)methanamine, the title compound was obtained in 88.6% purity by HPLC.
Figure imgf000126_0002
M+(ESI+): 457.03; MXESF): 455.4.
Example 48: General protocols for the solution-phase synthesis of 1.3-thiazolidine-2- carboxamide derivatives of general formula (XXX111); e.g., N-[3-(acetylamino)-l- phenylpropyl]-3-([l,r-biphenyl]-4-ylsulfonyl -1.3-thiazolidine-2-carboxamide: 3-flT,l'- biphenyl1-4-ylsulfonyπ-N-{3-r(methylsulfonyπamino]-l-ρhenylpropy -l,3-thiazolidine-2- carboxamide.
Thiazolidine intermediates of general formula (XXXI) (Intermediate 10) or (XXXII), e.g., N-[3-amino-l-phenylpropyl]-3-([l, l'-biphenyl]-4-ylsulfonyl)-l ,3-thiazolidine-2- carboxamide, were reacted with
an acid chloride, R6COCI, with an appropriate base or an acid, R6COOH, with a peptide coupling agent and optionally a base
a sulfonyl chloride, R6S02C1, with an appropriate base
an isocyanate, R6NCO, or triphosgene, followed by an amine, R6R7NH
- a chloroformate, R6OCOCl, with an appropriate base
Thus, e.g. , N-[3-amino-l-phenylpropyl]-3-([l ,r-biphenyl]-4-ylsulfonyl)-l ,3-thiazolidine-2- carboxamide (Intermediate 9, 50mgs, 1.Oeq, O.l Ommol) was dissolved in 5 ml DCM in presence of 30μl triethylamine. Acetyl chloride (l Oμl, 1. l eq, 0.1 l mol) was introduced slowly at 0°C and the reaction mixture stirred for 30 minutes. It was then hydrolyzed by addition of aqueous sodium carbonate (10%) (5ml), and the compound extracted with
DCM. The organic phase was dried with magnesium sulfate and concentrated in vacuo to give a crude compound, which was readily purified by flash chromatography using DCM/MeOH (99/1 ) as eluent, to obtain the desired compound of general formula (XXXIII), e.g., N-[3-(acetylamino)-l-phenylpropyl]-3-([l ,l '-biphenyl]-4-ylsulfonyl)- l ,3- thiazolidine-2-carboxamide in 80% yield as a white gum in 99.5% purity by HPLC.
Figure imgf000127_0001
'H NMR (400MHz, CDC13); 1.80-2.10 (m, 6H, CH3, CH2S, CH2), 2.54 (m, IH, CH2S), 2.97-3.10 (m, 2H, CH2), 3.50-3.90 (m, 3H, NH, CH2N), 5.0-5.10 (m, IH, CH), 5.24 (s, I H, CH), 5.98-6.11 (m, 1H, NH), 7.25-7.89 (m, 14H, CH(Ar)); M+(ESI+): 523.71 ; M (ESF): 522.05.
Alternatively, thiazolidine intermediates of general structure (XXXI) or (XXXII), e.g., N- [3-amino-l -phenylpropyI]-3-([l ,r-biphenyl]-4-ylsulfonyl)-l ,3-thiazolidine-2-carboxamide (Intermediate 9, 50mgs, 1.Oeq, O.l Ommol), were dissolved in 10ml DCM in presence of 30μl of triethylamine at 0°C. Methane sulfonylchloride (l Oμl, 1.leq, 0.1 lmol) was introduced slowly and reaction mixture was stirred at 0°C for 30 minutes. It was then hydrolyzed with aqueous sodium carbonate (10%) and the compound extracted with DCM. The organic phase was dried with magnesium sulfate, and concentrated in vacuo to give a crude compound, which was purified by flash chromatography using cyclohexane/ethyl- acetate (1/1 ) as eluent, to obtain the desired compounds of general structure (XXXIII), e.g., 3-([l ,l '-biphenyl]-4-ylsulfonyl)-N-{3-[(methylsulfonyl)amino]-l -phenylpropyl} -1 ,3- thiazolidine-2-carboxamide, was obtained as a white gum in 95% yield and 99.6% purity by HPLC.
Figure imgf000128_0001
Η NMR (400MHz, CDC13); 1.80-2.10 (m, 3H, CH2S, CH2), 2.88 (s, 3H, CH3), 3.0-3.50 (m, 3H, CH2S, CH2), 3.70-3.85 (m, 2H, CH2N), 4.45 (m, IH, NH), 5.13-5.21 (m, IH, CH), 5.35 (s, IH, CH), 6.86-6.94 (m, IH, NH), 7.35-8.10 (m, 14H, CH(Ar)); M+(ES1+): 560.21; MXESF): 558.47. Example 49: General protocols for the solution-phase synthesis of 1 ,3-thiazolidine-2- carboxamide derivatives of general formula (XXVIO; e.g.. 3-(π ,r-biphenyl]-4-ylsulfonylV N-[3-phenoxy-l-phenylpropyl]-l ,3-thiazolidine-2-carboxamide.
Thiazolidine intermediates of general structure (XXVI), e.g., 3-([ 1,1 '-bipheny l]-4- ylsulfonyl)-N-(3-hydroxy-l-phenylpropyl)-l,3-thiazolidine-2-carboxamide (1.0 g, 1 .0 eq, 2.07 mmol) was dissolved in 20 ml dry THF under nitrogen. Phenol (252 mg, 1.5 eq, 2.69 mmol), diethylazodicarboxylate (470mg, 1.5 eq, 2.69 mmol) and triphenyl phosphine polymer bound (1.0 g, 1.5 eq, 2.70 mmol) were then added and the reaction mixture was shaken for 12 hours at RT. Triphenyl phosphine resin was filtered off and the THF solution evaporated in vacuo. The residue was taken up in DCM and washed twice with saturated sodium carbonate solution and then water. The organic layer was dried with magnesium sulfate and concentrated in vacuo to give a crude product which was purified on silica gel using cyclohexane/ethyl acetate(8/2) as eluent, affording the desired products of general structure (XXVII), e.g., 3-([l ,r-biphenyl]-4-ylsulfonyl)-N-[3-phenoxy-l-phenylpropyl]- l ,3-thiazolidine-2-carboxamide as a white oil in 40%> yield and 95.5 % purity by HPLC.
Figure imgf000129_0001
Η NMR (400MHz, CDC13); 2.22-2.40 (m, 2H, CH2), 2.41-2.50 (m, IH, CH2S), 2.78-2.81 (m, IH, CH2S), 3.56-3.93 (m, 4H, CH2N, CH20), 5.21 (m, IH, CH), 5.31 (s, IH, CH), 6.79-6.92 (m, 4H, CH(Ar) and NH), 7.20-7.85 (m, 16H, CH(Ar)); M+(ESI+): 559.39; M" (ESI ): 557.61.
Example 50: 3-(biphenyl-4-ylsulfonyl)-N-r(2-chloropyridin-4-yl)(phenvπmethyl]-l .3- thiazolidine-2-carboxamide. Following the general strategies and protocols outlined in Example 1 , starting from 3- ([l , -biphenyl]-4-ylsulfonyl)-l ,3-thiazolidine-2-carboxylic acid (Intermediate 8) and l-(2- chloropyridin-4-yl)-l-phenylmethanamine (Intermediate 2), the title compound was obtained in 98%o purity by HPLC.
Figure imgf000130_0001
Η NMR (300MHz, CDC13); 2.58 (m, IH), 2.93 (m, IH), 3.77 (m, 2H), 5.28 (s, 0.5H), 5.31 (s, 0.5H), 6.07 (m, IH), 7.13 (m, 4H), 7.37 (m, 7H), 7.55 (m, 2H), 7.71 (m, 2H), 7.87 (m, 2H), 8.30 (m, IH). M^ESI÷): 550 ; MXESF): 548.
Example 51 : 3-(biphenyl-4-ylsulfonylVN-[(6-chloropyridin-3-yl)(phenyl)methyl]- 1 ,3- thiazolidine-2-carboxamide.
Following the general strategies and protocols outlined in Example 1, starting from 3- ([l,l '-biphenyl]-4-ylsulfonyl)-l ,3-thiazolidine-2-carboxylic acid (Intermediate 8) and [(6- chloropyridin-3-yl)(phenyl)methyl]amine (Intermediate 2), the title compound was obtained in 99% purity by HPLC.
Figure imgf000130_0002
Η NMR (300MHz, CDC13); 2.60 (m, IH), 2.94 (m, IH), 3.72 (m, IH), 3.86 (m, IH), 5.31 (s, 0.5H), 5.36 (s, 0.5H), 6.21 (m, IH), 7.36 (m, 1 IH), 7.60 (m, 2H), 7.76 (m, 2H), 7.90 (m, 2H), 8.34 (m, IH). M+(ESI+): 550 ; MXESF): 548. Example 52: 3-(biphenyl-4-ylsulfonylV V-[(6-hydroxypyridin-3-yl¥phenyπmethyl]- 1.3- thiazolidine-2-carboxamide.
Following the general strategies and protocols outlined in Example 1 , starting from 3- ([l ,l '-biphenyl]-4-ylsulfonyl)-l,3-thiazolidine-2-carboxylic acid (Intermediate 8) and 5- [amino(phenyl)methyl]pyridin-2-ol (Intermediate 2), the title compound was obtained in 99% purity by HPLC.
Figure imgf000131_0001
Η NMR (300MHz, DMSO-d6); 2.58 (m, IH), 2.97 (m, IH), 3.69 (m, 2H), 5.41 (m, IH), 5.65 (m, IH), 6.18 (m, IH), 7.20 (m, 10H), 7.60 (m, 2H), 7.77 (m, 4H), 8.73 (m, IH), 11.37 (br s, 1 H). M+(ESI+): 532 ; MXESF): 530.
Example 53: 3-(biphenyl-4-ylsulfonyl)-N-[[6-(dimethylamino)pyridin-3- yl](phenyl)methyl]-l,3-thiazolidine-2-carboxamide.
Following the general strategies and protocols outlined in Example 1, starting from 3- ([l ,l '-biphenyl]-4-ylsulfonyl)-l ,3-thiazolidine-2-carboxylic acid (Intermediate 8) and 5- [amino(phenyl)methyl]-N,N-dimethylpyridin-2-amine (Intermediate 2), the title compound was obtained in 98% purity by HPLC.
Figure imgf000131_0002
Η NMR (300MHz, CDC13); 2.61 (m, IH), 2.99 (m, 1H), 3.15 (s, 6H), 3.72 (m, I H), 3.90 (s, IH), 5.36 (s, 0.5H), 5.39 (s, 0.5H), 6.10 (m, I H), 6.56 (m, IH), 7.13 (m, IH), 7.28 (m, 6H), 7.46 (m, 3H), 7.60 (m, 2H), 7.73 (m, 2H), 7.91 (m, 2H), 8.02 (m, 0.5H), 8.09 (m, 0.5H). lvf(ESI+): 559 ; M (ESF): 558.
Example 54: 3-(biphenyl-4-ylsulfonyl -N-[(R)-{5-[2-(dimethylamino ethoxy]pyridin-2- yl|(phenyl)methyl]-l,3-thiazolidine-2-carboxamide.
Following the general strategies and protocols outlined in Example 1 , starting from 3- ([l, r-biphenyl]-4-ylsulfonyl)-l ,3-thiazolidine-2-carboxylic acid (Intermediate 8) and [2- ({6-[(R)-amino(phenyl)methyl]pyridin-3-yl}oxy)ethyl]dimethylamine (Intermediate 2), the title compound was obtained in 99% purity by HPLC.
Figure imgf000132_0001
Η NMR (300MHz, CDC13); 2.63 (m, 7H), 2.99 (m, 3H), 3.71 (m, IH), 4.02 (m, IH), 4.26 (br s, 2H), 5.48 (s, 0.5H), 5.49 (s, 0.5H), 6.02 (s, 0.5H), 6.05 (s, 0.5H), 7.25 (m, 6H), 7.44 (m, 4FI), 7.58 (m, 2FI), 7.70 (m, 2H), 7.93 (m, 2H), 8.33 (m, 2H). M'(ESI+): 603 ; MXESF): 601.
Example 55: 4-r(-S -r({r2^-3-[(2'-fluorobiphenyl-4-vnsulfonyll-l,3-thiazolidin-2- yU carbonyDamino] (pheny Dmethyl]- 1 -methylpiperidinium methanesulfonate.
Following the strategies and protocols outlined in Example 1 , the title compound was obtained in 99% purity by HPLC.
Figure imgf000133_0001
Η NMR (300MHz, DMSO-c 6); 1.40 (m, 2H), 1.92 (m, 2H), 2.29 (s, 3H), 2.70 (m, 3H), 3.06 (m, IH), 3.31 (m, 4H), 3.82 (m, 2H), 4.58 (m, IH), 5.50 (s, IH), 7.34 (m, 7H), 7.56 (m, 2H), 7.90 (m, 4H), 8.57 (m, IH), 9.10 (m, IH). M+(ESI+): 554 ; MXESF): 552.
Example 56: benzeneacetic acid, alpha,alpha-dimethyl-4-[[2-[[[(R)-phenyl-2- pyridinylmethyl]amino]carbonyl]-3-thiazolidinyl]sulfonyl]-, methyl ester
Following the general strategies and protocols outlined in Example 1 , starting from 2- thiazolidinecarboxylic acid, 3-[[4-(2-methoxy-l ,l-dimethyl-2-oxoethyl)phenyl] sulfonyl] - (Intermediate 8) and (7?)-phenyl(2-pyridinyl)methanamine (Intermediate 1), the title compound was obtained in 91% purity by HPLC.
Figure imgf000133_0002
Η NMR (300MHz, CDC13); δ 8.63 (s, I H) ; 7.82-7.91 (m, 3H) ; 7.33-7.51 (m, 9H) ; 6.2 (s, IH) ; 5.65 (s, IH) ; 3.88 (m, 2H) ; 3.66 (s, 3H) ; 3.10 (m, IH) ; 2.65 (m, IH) ; 1.6 (s, 6H)
. M+(ESI+): 540.1 ; MXESF): 538.0. Example 57: Preparation of product la. e.g. (i r3-(biphenyl-4-y lsulfonyl)- 1, 3-thiazolidin-2- yl]carbonyl}aminoXphenyOacetic acid.
Figure imgf000134_0001
Intermediate VIII (Scheme 3), e.g., 3-(biphenyl-4-ylsulfonyl)-l ,3-thiazolidine-2-carboxylic acid (1.747 g, 5 mmol) was dissolved in DCM (20 mL). The resulting solution was cooled down to -10°C and oxalyl chloride (0.645 mL, 7.5 mmol) was added slowly. DMF (0.1 mL) was added carefully. The reaction mixture was allowed to warm to RT over lh and stirred an additional hour at RT. As the reaction was complete, the solvents were evaporated. Toluene was added and evaporated to remove residual oxalyl chloride. This process was repeated twice, affording intermediate XXX, e.g., 3-(biphenyl-4-ylsulfonyl)- l ,3-thiazolidine-2-carbonyl chloride as a yellow solid (1.839 g, quantitative yield).
α-Aminophenylacetic acid (831 mg, 5.5 mmol) was dissolved in water (20 mL). TEA (2.77 mL, 20 mmol) was added carefully. THF (25 mL) was added to reaction mixture. The reaction mixture was cooled to 0°C. Acid chloride previously prepared XXX, e.g. 3- (biphenyl-4-ylsulfonyl)-l,3-thiazolidine-2-carbonyl chloride dissolved in THF (25 mL) was added dropwise. The reaction mixture was stirred 15 min at 0°C and overnight at RT. Solvents were concentrated and the resulting aqueous fraction was acidified with HCl 5N and extracted with 3 portions of EtOAc. Combined organic phases were dried over MgS04, filtrated and evaporated. The crude product was recrystallized in acetone/Et20 mixture, affording carboxylic acid la, e.g., ({[3-(biphenyl-4-ylsulfonyl)-l,3-thiazolidin-2- yl]carbonyl}amino)(phenyl)acetic acid in 97% purity by HPLC (943 mg, 39% yield). 'H NMR (300MHz, DMSO-d6); 2.68 (m, I H), 3.08 (m, IH), 3.84 (m, 2H), 5.30 (m, I H), 5.76 (s, 0.5H), 5.82 (s, 0.5H), 7.44 (m, 8H), 7.78 (m, 2H), 7.93 (m, 4H), 8.91 (m, IH), 13.10 (br s, IH). M+(ESI+): 483 ; MXESF): 481.
Example 58: Preparation of product lb. e.g. N-(2-amino-2-oxo-l -pheny lethyl)-3-(biphenyl- 4-ylsulfonyl)- 1 ,3-thiazolidine-2-carboxamide.
Figure imgf000135_0001
Compound la, e.g., ({[3-(biphenyl-4-ylsulfonyl)-l,3-thiazolidin-2-yl]carbonyl}amino)- (phenyl)acetic acid (500 mg, 1.04 mmol) was dissolved in THF (10 mL). Ammonia in dioxane (0.5N, 3.11 mL, 1.55 mmol) was added followed by HOBt (210 mg, 1.55 mmol) and DMAP (6 mg, 0.05 mmol). EDC.HCl (298 mg, 1.55 mmol) was finally added. The mixture was stirred for 5 hours at RT. As the reaction was complete, it was diluted with EtOAc, washed with 5% citric acid, NΗ4CI sat, NaHCθ3 sat, brine and dried over MgSθ4. After filtration and evaporation ofthe solvents, the resulting crude product was purified by flash chromatography (Cyclohexane/EtOAc, gradient from 1 : 1 to 0:1). Compound lb, e.g. N-(2-amino-2-oxo-l-phenylethyl)-3-(biphenyl-4-ylsulfonyl)-l,3-thiazolidine-2- carboxamide, was isolated in 90% purity by HPLC (349 mg, 80% yield).
Η NMR (300MHz, DMSO-d6); 2.64 (m, IH), 3.04 (m, IH), 3.78 (m, 2H), 5.34 (m, IH), 5.84 (m, IH), 7.29 (m, 4H), 7.47 (m, 4H), 7.76 (m, 2H), 7.90 (m, 4H), 8.77 (m, IH). M+(ESI+): 482 ; MXESF): 480. Example 59: Preparation of product lc. e.g. 3-(biphenyl-4-ylsulfonyQ-N-[cyano(phenyl - methy 1]- 1 ,3-thiazolidine-2-carboxamide.
Figure imgf000136_0001
To a stirred solution of compound lb, e.g., N-(2-amino-2-oxo-l-phenylethyl)-3-(biphenyl- 4-ylsulfonyl)- 1, 3 -thiazolidine-2-carboxamide (385 mg, 0.8 mmol) in DMF (1 mL) at RT was added cyanuric chloride (74 mg, 0.4 mmol) in one portion. After one night, the reaction was done. Water (3 mL) was added and a precipitate was formed. The aqueous phase was extracted with two portions of EtOAc (5 mL). Combined organic phases were washed with 5% aqueous sodium bicarbonate, with water, dried over MgSθ4 and concentrated under reduced pressure. A light yellow solid was isolated and was purified by flash chromatography (Cyclohexane/EtOAc gradient form 8:2 to 1 : 1), affording product lc, e.g., 3 -(bipheny l-4-ylsulfonyl)-N-[cyano(phenyl)methyl]- 1 ,3-thiazolidine-2-carboxamide (257 mg, 69% yield) in 100% purity by HPLC.
Η NMR (300MHz, CDC ); 2.61 (m, IH), 2.99 (m, IH), 3.72 (m, 2H), 5.35 (s, 0.5H), 5.41 (s, 0.5H), 6.06 (m, 0.5H), 6.17 (m, 0.5H), 7.17 (m, IH), 7.47 (m, 8H), 7.61 (m, 2H), 7.77 (m, 2H), 7.91 (m, 2H). M+(ESI+): 464 ; MXESF): 462.
Example 60: Preparation of product I, e.g. 3-(biphenyl-4-ylsulfonyl)-7V-[[5-(2- hydroxyethyl)-l ,2,4-oxadiazol-3-yl](phenyl)methyl]-l ,3-thiazolidine-2-carboxamide.
Figure imgf000137_0001
Triethylamine (92 μl, 0.66 mmol) was slowly added to a suspension of product lc, e.g., 3- (biphenyl-4-ylsulfonyl)-N-[cyano(phenyl)methyl]-l,3-thiazolidine-2-carboxamide, and hydroxylamine.hydrochloride (46 mg, 0.66 mmol) in ethanol (5 mL), under stirring. The reaction mixture was heated under reflux for 16h, and then cooled to RT. The solvents were removed and the resulting solid was suspended in water and extracted with three protions of EtOAc. Combined organic phases were dried over MgS04, filtrated and evaporated, affording intermediate Id, e.g., N-[(17?,2Z)-2-amino-2-(hydroxyimino)-l-phenylethyl]-3- (biphenyl-4-ylsulfonyl)-l,3-thiazolidine-2-carboxamide (272 mg, quantitative yield) which was directly used in the next step.
Η NMR (300MHz, CDC13); 2.35 (br s, 2H), 2.55 (m, 2H), 3.00 (m, IH), 3.60-3.93 (m, 2H), 5.30 (s, 0.5H), 5.40 (s, 0.5H),), 5.64 (m, IH) 7.05-8.17 (m, 14H, H arom.). M+(ESI+): 497. MXESF): 495.
Carboxylic acid , e.g., 3-tert-butoxypropionic acid (35 mg, 0.24 mmol), was dissolved in THF (2 mL). The resulting solution was cooled down to -15°C. NMM (84 μL, 0.76 mmol), followed by isobutyl chloroformate (33 μL, 0.25 mmol), were added. The mixture was stirred at -15°C for 30 min. Intermediate Id, e.g. N-[(17?,2Z)-2-amino-2-(hydroxyimino)-l- phenylethyl]-3-(biphenyl-4-ylsulfonyl)-l,3-thiazolidine-2-carboxamide (108 mg, 0.22 mmol) in THF (2 mL) was added dropwise. The mixture was stirred overnight, letting the temperature increasing up to RT. Solvents were evaporated. The resulting oil was dissolved in AcOEt, and washed with sat NH4CI and sat NaHCOs. Aqueous phases were extracted with two portions of AcOEt. Combined organic phases were dried over MgS04, filtrated and evaporated, affording intermediate Id', e.g. 3-(biphenyl-4-ylsulfonyl)-N-[(2-£)-2-[(3- te -butoxypropanoy l)amino]-2-(hydroxyimino)- 1 -phenylethyl]- 1 ,3-thiazolidine-2- carboxamide (1 18 mg, 86% yield), which was directly used in the next step.
M+(ESI+): 625. M (ESF): 623.
Intermediate Id', e.g., 3-(biphenyl-4-ylsulfonyl)-N-[(2£)-2-[(3-te - butoxypropanoyl)amino]-2-(hydroxyimino)-l -phenylethyl]- 1 ,3-thiazolidine-2-carboxamide (1 18 mg, 0.19 mmol), was suspended in dry toluene. Pyridine (46 μL, 0.56 mmol) was added. The mixture was stirred under reflux. After 7 hours the reaction was complete and the solvents were evaporated.
The crude residue was dissolved in EtOAc, and washed with two portions of brine.
Combined aqueous phases were extracted with two portions of EtOAc. Combined organic phases were dried over MgS04, filtrated and evaporated. The crude product was dissolved in DCM (2.5 mL) and TFA (0.5 mL) was added at 0°C. The mixture was stirred 15 min at 0°C then overnight at RT. Solvents were evaporated. The crude oil was stirred 5 hours in MeOH, in order to hydrolyze the trifluoroacetic ester formed. After evaporation of the solvents, the desired product was purified by flash chromatography (Cylclohexane/EtOAc, gradient from 8:2 to 0: 1), affording product I, e.g. 3-(biphenyl-4-ylsulfonyl)-N-[[5-(2- hydroxyethyl)-l ,2,4-oxadiazoI-3-yl](phenyl)methyl]-l,3-thiazolidine-2-carboxamide (25 mg, 24% yield over three steps) in 100% purity by HPLC.
'H ΝMR (300MHz, CDCls); 1.85 (br s, IH), 2.62 (m, I H), 3.07 (m, 3H), 3.75 (m, I H),
4.00 (m, 3H), 5.38 (s, 0.5H), 5.44 (s, 0.5H), 6.37 (m, I H), 7.40 (m, 8H), 7.66 (m, 5H), 7.91 (m, 2H). M+(ESI+): 551 ; MXESF): 549.
Example 61 : Preparation of product XXX, e.g. 2-thiazolidinecarboxamide, 3-[[4-(2-fluoro- l,l -dimethylethyπphenyl]sulfonyl]-Ν-[(RVphenyl-2-pyridinylmethyl]-
Figure imgf000139_0001
The compound benzeneacetic acid, alpha,alpha-dimethyl-4-[[2-[[[(R)-phenyl-2-pyridinyl- methyl]amino]carbonyl]-3-thiazolidinyl]sulfonyl]-, methyl ester (Example X) (54 mg, O.lmmol) was dissolved in 3mL of anhydrous THF. The solution was cooled down to zero degree and LiBH4 was added (3mg, 0.15mmol, 1.5eq). The reaction mixture was agitated for 2h. The reaction mixture was quenched by addition of H2O. The organic solvent was evaporated under reduced pressure, and the residue redissolved in EtOAc. The organic layer was washed with NaHCθ3 sat., NaCl sat, dried over MgS04, and evaporated in vacuo to give 2-thiazolidinecarboxamide, 3-[[4-(2-hydroxy-l,l-dimethylethyl)phenyl] sulfonyl]-N-[(R)-phenyl-2-pyridinylmethyl]- as a colorless oil (44mg, yield : 86%).
Η NMR (300MHz, CDCI3); δ 8.07 (m, 2H) ; 7.82-7.97 (m, 3H) ; 7.28-7.58 (m, 9H) ; 6.26 (s, IH) ; 3.86 (m, 2H) ; 3.36 (d, 2H) ; 3.635 (m, IH) ; 2.71 (m, IH) ; 1.36 (s,lH) M+(ES1+): 512.4. MXESF): 510.3. The compound 2-thiazolidinecarboxamide, 3-[[4-(2-hydroxy-l ,l-dimethylethyl)phenyl] sulfonyl]-N-[(R)-phenyl-2-pyridinylmethyl]- (43mg, 0.08mmol) was dissolved in 2mL anhydrous DCM. The solution was cooled down to -78°C, and DAST (0.02mL, 0.17mmol, 2eq) was added. The reaction mixture was stirred for 24h at -78°C and warmed to room temperature. The reaction was quenched by addition of NaHCC.3 sat. and agitated for lh. The product was extracted with DCM (50mL). The organic layer was dried over MgS04 and evaporated. The residue was purified by with EtOAc/cHex, 40:60) to give compound 2-thiazolidinecarboxamide, 3-[[4-(2-fluoro-l,l-dimethylethyl)phenyl]sulfonyl]-N-[(R)- phenyl-2-pyridinylmethyl]- as an orange oil (14.8mg, yield : 36%, 98.1 HPLC purity). Η-RMN (CH2CI2) δ 8.58 (m, 2H) ; 7.83 (t, Jt = 8.29, 2H) ; 7.65 (m, IH) ; 7.19-7.40 (m, 9H) ; 6.10 (s, IH) ; 5.46 (s, IH) ; 3.95-4.06 (m, IH) ; 3.65-3.78 (m, IH) ; 2.92-2.99 (m, 3H) ; 2.55-2.64 (m, IH) ; 1.25-1.37 (m, 6H). 19F-RMN (CH2C12) δ -138.6. M+(ESI+): 514.2 ; M" (ESF): 512.2
Example 62: (2SV3-(l,l,-biphenyl-4-ylsulfonylVN-[(RVphenyl(pyridin-2-ynmethyl]-l ,3- thiazolidine-2-carboxamide
Following the general strategies and protocols outlined in Example 1, starting from tert- butyl (2S)-2-({[(R)-phenyl(pyridin-2-yl)methyl]amino}-carbonyl)-l,3-thiazolidine-3- carboxylate (Intermediate 6) and [l ,l'-biphenyl]-4-sulfonyl chloride, the title compound was obtained in 99% purity by HPLC.
M+(ESI+): 516 ; MXESF): 514.
Figure imgf000140_0001
Example 63: (2S -3-r(2'-fluorobiphenyl-4-yl sulfonvn-N-r(R -phenyl(pyridin-2-yl)methyl]- 1 ,3-thiazolidinc-2-carboxamide. Following the general strategies and protocols outlined in Example 1, starting from tert-butyl (2S)-2-({[(R)-phenyl(pyridin-2-yl)methyl]amino}- carbonyl)-l, 3 -thiazolidine-3 -carboxylate (Intermediate 6) and 2'-fluorobiphenyl-4- yl)sulfonyl chloride, the title compound was obtained in 99% purity by HPLC.
M+(ESI+): 534.6 ; M (ESF): 532.9.
Figure imgf000141_0001
Example 64: (2 S)-3 -(bipheny 1-4-y Isulfony 1 -N-[(1 S)-l-(4-fluorophenyl)-3-hydroxypropyl]- 1 ,3-thiazolidine-2-carboxamide.
Following the general strategies and protocols outlined in Example 1 , starting from tert- butyl (2S)-2-({[(l S)-3-hydroxy-l -phenylpropyl]amino}
carbonyl)-l , 3 -thiazolidine-3 -carboxylate (Intermediate 6) and [l,l'-biphenyl]-4-sulfonyl chloride, the title compound was obtained in 98% purity by HPLC.
M+(ESI+): 501.6 ; MXESF): 499.2.
Figure imgf000141_0002
Example 65 : 3-( 1 , 1 '-biphenyl-4-ylsulfonyl -N-[ 1 -(2,6-difluorophenyl)-3-hydroxypropyl]- 1 ,3-thiazolidine-2-carboxamide.
Following the general strategies and protocols outlined in Example 1 , starting tert-butyl (2S)-2-({[(lS)-l-(2,6-difluorophenyl)-3-hydroxypropyl]amino}carbonyl)-l,3-thiazolidine- 3-carboxylate (Intermediate 6) and [l ,l'-biphenyl]-4-sulfonyl chloride, the title compound was obtained in 99% purity by HPLC.
M+(ESI+): 519.9 ; MXESF): 517.8
Figure imgf000142_0001
Example 66: (2S)-N-[(1 S)-l-(4-fluorophenyl -3-hvdroxypropyl]-3-[(2'-fluorobiphenyl-4- vDsulfonyl]- 1 ,3-thiazolidine-2-carboxamide.
Following the general strategies and protocols outlined in Example 1 , starting tert-butyl (2S)-2-({[(lS)-l-(2,6-difluorophenyl)-3-hydroxypropyl]amino}carbonyl)-l,3-thiazolidine- 3-carboxylate (Intermediate 6) and 2'-fluorobiphenyl-4-yl)sulfonyl chloride, the title compound was obtained in 99% purity by HPLC.
M+(ESI+): 537.9 ; MXESF): 535.9.
Figure imgf000142_0002
Example 67: (2S)-3-[(2,-flυoro-l ,l '-biphenyl-4-ynsulfonyll-N-[(lS -3-hydroxy-l- phenylpropyl]-l,3-thiazolidine-2-carboxamide.
Following the general strategies and protocols outlined in Example 1 , starting tert-butyl (2S)-2-({[(lS)-3-hydroxy-l-phenylpropyl]amino}carbonyl)-l,3-thiazolidine-3-carboxylate (Intermediate 6) and [l ,l '-biphenyl]-4-sulfonyl chloride, the title compound was obtained in 98% purity by HPLC.
Iv CESI4): 501.9 ; MXESF): 499.5.
Figure imgf000143_0001
Example 68: General protocols for the solution-phase synthesis of l,3-thiazolidine-2- carboxamide derivatives of general formula (I); e.g.. (3S -3-({[(2S)-3-(biphenyl-4- ylsulfonyl -l,3-thiazolidin-2-yl]carbonyl}amino)-3-(2,6-difluorophenyl)propyl L-valinate, (3S -3-(2.6-difluorophenylV3-r({(2S)-3-[(2'-fluorobiphenyl-4-yl sulfonyl]-1.3-thiazolidin- 2-yl}carbonyl)amino]propyl L-valinate, (3S)-3-({[(2S -3-(biphenyl-4-ylsulfonyl -l,3- thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl L-valinate, (3S)-3-[({(2S)-3-[(2'- fluorobiphenyl-4-yl)sulfonyI]-l,3-thiazolidin-2-yl}carbonyl)amino]-3-phenylpropyl L- valinate.
(2S)-N-[(l S)-l-(4-fluorophenyl)-3-hydroxypropyl]-3-[(2'-fluorobiphenyl-4-yl)sulfonyl]- l,3-thiazolidine-2-carboxamide (2.48g, 4.62mmol) was dissolved in 40mL of DMF:DCM (1 : 1) and DMAP (846mg, 6.93mmol) was added. To this solution was added a 5-min pre- incubated solution of HOBt (937mg, 6.93mmol), EDC (1.35g, 6.93mmol) and Boc-L- valine (1.5g, 6.93mmol). The reaction mixture was agitated for 16h at room temperature. The reaction mixture was diluted with DCM (200mL) and washed with citric acid 5%, NH4C1 sat, NaHCθ3 sat and brine. The organic layer was dried over MgSθ4 and evaporated. The residue was purified by FC 10:90 to 50:50 (EtOAc xyclohexane) to give the desired product (3S)-3-(2,6-difluorophenyl)-3-[({(2S)-3-[(2'-fluorobiphenyl-4- yl)sulfonyl]-l,3-thiazolidin-2-yl}carbonyl)amino]propyl N-(tert-butoxycarbonyl)-L- valinate a white solid (3.04g, 89.4%).
Compound (3S)-3-(2,6-difluorophenyl)-3-[({(2S)-3-[(2'-fluorobiphenyl-4-yl)sulfonyl]- 1,3- thiazolidin-2-yl} carbonyl)amino]propyl N-(tert-butoxycarbonyl)-L-valinate (3.04g, 4.13mmol)was dissolved in DCM (33mL) at 0 degree and 66mL of 4M HCl in dioxane was added. The reaction was stirred at 0 degree for l h and at r.t. for 3h. The solvent was evaporated and the residue redissolved in DCM and washed with 10%NaHCθ3 and brine. The organic layer was dried over MgSθ4 and evaporated to give a white foam. The foam was redissolved in THF and leq of methanesulfonic acid (345mg) was added, the precipitate was filtered and dried to give the desired product (3S)-3-(2,6-difluorophenyl)-3- [({(2S)-3-[(2'-fluorobiphenyl-4-yl)sulfonyl]-l,3-thiazolidin-2-yl}carbonyl)amino]propyl L- valinate as a white solid (2.53g, 83.7% yield).
M+(ESI+): 636.7; MXESF): 634.3.
Figure imgf000144_0001
Example 69: (3SV3-(([(2S)-3-(biphenyl-4-ylsulfonyl -l,3-thiazolidin-2-yl]carbonyl}- amino)-3-(2,6-difluorophenyl)propyl L-valinate.
Following the general strategies and protocols outlined in Example 68, starting from 3- (l,r-biphenyl-4-ylsulfonyl)-N-[l-(2,6-difluorophenyl)-3-hydroxypropyl]-l,3-thiazolidine- 2-carboxamide (Example 65), the title compound was obtained in 99% purity by HPLC.
M+(ESI+): 618.9; MXESF): 616.5.
Figure imgf000144_0002
Example 70: (3SV3-(U(2S -3-(biphenyl-4-ylsulfonvn-l ,3-thiazolidin-2-yllcarbonyU- amino)-3-phenylpropyl L-valinate.
Following the general strategies and protocols outlined in Example 68, starting from (25)- 3-([l ,l'-biphenyl]-4-ylsulfonyl)-N-[(l S)-3-hydroxy- 1 -phenylpropyl]- l,3-thiazolidine-2- carboxamide (Example 1), the title compound was obtained in 99% purity by HPLC.
M+(ESI+): 582.9; M (ESF): 581.3.
Figure imgf000145_0001
Example 71 : (3S -3-[({(2S -3-r(2'-fluorobiphenyl-4-yl sulfonyll-1.3-thiazolidin-2- yl } carbonyDamino]- 3 -phenylpropyl L-valinate.
Following the general strategies and protocols outlined in Example 68, starting from (2S)- 3-[(2'-fluoro-l , l'-biphenyl-4-yl)sulfonyl]-N-[(l S)-3-hydroxy- 1 -phenylpropyl]- 1 ,3- thiazolidine-2-carboxamide (Example 67), the title compound was obtained in 99% purity by HPLC.
M' (ESI '): 600.8; MXESF): 598.6.
Figure imgf000145_0002
Example 72: (2SV3-(l .l'-biphenyl-4-ylsulfonyn-N-r(lS -3-hydroχy-l-(2.4-difluoro- phenyPpropyl]- 1 ,3-thiazolidine-2-carboxamide.
Following the general strategies and protocols outlined in Example 1 , starting tert-butyl (2S)-2-({[(lS)-l-(2,4-difluorophenyl)-3-hydroxypropyl]amino}carbonyl)-l ,3-thiazolidine- 3-carboxylate (Intermediate 6) and [l, l'-biphenyl]-4-sulfonyl chloride, the title compound was obtained in 98%> purity by HPLC.
M+(ESI+): 519.6; MXESF): 517.6.
Figure imgf000146_0001
Example 73: Preparation of a pharmaceutical formulation
Formulation 1 - Tablets
A l ,3-thiazolidine-2-carboxamide compound of formula (II) is admixed as a diy powder with a dry gelatin binder in an approximate 1 :2 weight ration. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of active l,3-thiazolidine-2-carboxamide compound per tablet) in a tablet press.
Formulation 2 - Capsules
A l,3-thiazolidine-2-carboxamide compound of formula (II) is admixed as a dry powder with a starch diluent in an approximate 1 : 1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active l,3-thiazolidine-2-carboxamide compound per capsule).
Formulation 3 - Liquid A l,3-thiazolidine-2-carboxamide compound of formula (II), sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously prepared solution of microcrystalline cellulose and sodium carboxymethyl cellulose (1 1 :89) in water. Sodium benzoate, flavor, and color are diluted with water and added with stirring. Sufficient water is then added.
Formulation 4 - Tablets A l,3-thiazolidine-2-carboxamide compound of formula (II) is admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of active l ,3-thiazolidine-2-carboxamide compound) in a tablet press.
Formulation 5 - Injection A l ,3-thiazolidine-2-carboxamide compound of formula (II) is dissolved in a buffered sterile saline injectable aqueous medium to provide a satisfactory concentration.
Example 51 : Biological assays
The compounds of formula (II), were be subjected to the following in vitro and in vivo biological assays:
1) In vitro competition binding assay on human Prostaglandin F2a receptor using a Scintillating Proximity Assay (SPA)
This assay allows to determine the binding affinity ofthe test compounds of formula (II) for the human Prostaglandin F2α receptor:
a) Preparation of Prostaglandin F?» receptor:
Human Prostaglandin F α receptor (full-length cDNA) was subcloned into the pCEP4
(Invitrogen) vector and transfected together with the hygromycin resistance gene into HEK 293 EBNA cells by Calcium-phosphate co-precipitation method. Antibiotic resistant cells were grown under constant selection pressure in DMEM /F-12 medium supplemented with 2%> fetal calf serum , 4 mM L-Glutamine and 8ml/l Insulin-Transferrin-Selenium-mix (all Invitrogen)and 300μg/ml hygromycin at 37°C in a humidified atmosphere of 5%> CO2 in air. At 48h before harvesting, receptor expression was enhanced by adding 5 mM of Na- butyrate. Cells were washed twice with phosphate buffer saline, harvested and pelleted by centrifugation.
Cell pellet was lysed by Dounce homogenisation in 250mM sucrose, 25mM Tris-HCI pH 7.5, lOmM MgC , ImM EDTA containing proteases inhibitors according to the manufacturer (Boehringer Mannheim) at 4°C. The lysate was centrifuged at lOOOg, 4°C for lOmin and the supernatant was centrifuged at 160000g, 4°C for 60min. The membranes pellets were resuspended in binding buffer (l OmM MES pH 6.2, lOmM MgCl2, I mM EDTA containing proteases inhibitors), frozen in dry ice ethanol and stored at -80°C.
b) Determination of the binding affinity values for test compounds:
In vitro competition binding with Scintillation proximity assay (SPA) was performed in Corning NBS 96 wells plates. Briefly, lOOμl of binding buffer containing 15 to 30μg of purified membranes, 4mg/ml of wheat-germ agglutinin (WGA) SPA beads and 1 to 2 nM of JH PGF2-alpha (determined by Scatchard analysis) in 1 % DMSO was incubated for 2 hours at room temperature. Non-specific binding was determined in the presence of 1 μM of non-radioactive Prostaglandin F2α. The concentrations of compounds (antagonist) used to compete with the radioactive ligand (agonist) were l OμM, 3μM, l μM, 300nM, l OOnM, 30nM, l OnM, InM, l OOpM, l OpM. The radioactivity was counted on a Microbeta plate counter and the binding data were analysed using the iterative, non- linear, curve-fitting program, "Prism" (GraphPad Software, Inc).
c) Results - Discussion:
The tested compounds according to formula (II) induced an inhibition (illustrated by K, values) ofthe binding of Prostaglandin F2 to its receptor of less than 10 μM. The binding affinity of preferred compounds of formula (II) to human Prostaglandin F2α receptor is illustrated in the below Table 1 by means ofthe corresponding inhibition constants K. From the values shown in Table 1 , it can be conclued that said test compounds according to formula (II) do show a significant binding to the Prostaglandin F20. receptor.
Table 1. Binding affinities of test compounds of general formula (II) to human Prostaglandin F α receptor, as determined in the scintillation proximity competition binding assay (against Prostaglandin F2α as radioligand).
Figure imgf000150_0001
Figure imgf000151_0001
2) In vitro functional assay 1: Inhibition of Prostaglandin F2a induced IP 3 (Inositol
Triphosphate) Synthesis in HEK/EBNA-cells expressing the Prostaglandin F2a receptor
The interaction of Prostaglandin F2 with its receptor leads to IP3 synthesis, a second messenger for Ca release from sarcoplasmatic reticulum, involved in the process triggering uterine contractions. The present assay described hereinafter can be used to show the inhibition ofthe Prostaglandin F2α/Prostaglandin F2α receptor mediated IP3 synthesis by test compounds of formula (II).
a) Materials:
293-EBNA cells and pCEP4 vector were purchased from Invitrogen; Fetal Bovine Serum from Cansera; Hygromycin B from Roche Molecular Biochemicals; DMEM-F12 medium, L-Glutamine from Life Technologies Inc.; [ H] Inositol from Perkin Elmer Life Sciences; Prostaglandin F2« (PGF2«) from Sigma, AG1 -X8 chromatography columns from BioRad, 96 well black/white plates from Corning Inc.
b) Constructs:
The cDNAs of the human Prostaglandin F2 receptor (hFP) and ofthe rat Prostaglandin F2α receptor (rFP) receptors were subcloned into the expression vector pCEP4 to generate pCEP4hFPuno and pCEP4rFP respectively.
c) Cell culture and transfection:
293-EBNA cells were grown in DMEM-F12 medium supplemented with 2% fetal bovine serum and 4 mM L-glutamine. Cells were transfected by the calcium phosphate precipitation method with the appropriate plasmid and selected for hygromycinB resistance. The surviving colonies were assayed for their ability to retain specific [3H] PGF2α binding. Selected clones were maintained in DMEM-F12 medium supplemented with 4 mM L- glutamine, 300μg/ml hygromycinB and 2%> fetal bovine serum (10% for cells expressing rFP).
d) Inositol Phosphate measurements:
Cells were detached with PBS/EDTA, washed with inositol-free DMEM-F12 medium and seeded at 80000 cells/well in a Poly-L-Lysine precoated 12 well plate. Cells were labelled with W Ό-[JH] Inositol at 4 μCi/ml in inositol-free DMEM-F12 supplemented with 1 % fetal bovine serum, 4 mM L-glutamine and 300μg/ml hygromycinB. After 24 hours (rFP expressing cells) or 40 hours (hFP expressing cells), the medium was removed and cells were pre-incubated for 10 min in assay buffer (DMEM-F12 without Inositol, 20mM Hepes, 0.1 %BSA) containing 20 mM LiCI at 37°C. For agonist dose response, cells were then stimulated for 1 hour at room temperature with increasing concentration of PGF2α, in assay buffer. For IC50 determination of the compounds, cells were incubated with increasing concentrations of test compounds for 10 min at room temperature prior to addition of 30 nM PGF2α (about 2X the EC50) and further incubation for 1 hour. For agonist activity determination of the test compounds themselves, the test compounds were added to the cells at 10 μM and 1 μM for 1 hour at room temperature.
In the course of the three above mentioned experiments, the reaction was stopped by addition of 1 ml of stop solution (2.4% perchloric acid) for 10 min. 800 μl were then transferred to 400 μl of neutralising solution (0.72N KOH, 0.6 M KHCO3), vortexed, and sedimented for at least 2 hours at 4°C. After centrifugation of 15 min. at 2500 g, 1 ml of the supernatant was loaded on a chomatography column, followed by two washes with 10 ml of water. The IP3 to be quantified were eluted with 3 ml elution buffer (IM ammonium formate, 0.1 M formic acid) and radioactivity was counted on a Beckman LS6000TA scintillation counter to measure the amount of phosphorylated [JH] inositol. e) Results and discussion:
The activities ofthe thiazolidine compounds of formula (II) were assessed using the above described in vitro biological assay. Representative values for some example compounds are given in Table 2 below. The values refer to the capacity ofthe example compounds according to fonnula (II) to effectively antagonize Prostaglandin F2α- induced IP3-synthesis mediated by the Prostaglandin F2« receptor. From the values shown in Table 2, it can be derived that said example test compounds according to formula (II) do exhibit a significant activity as Prostaglandin F2 receptor antagonists, as illustrated by IC50 values of generally less than 2 μM.
Table 2. Inhibition of 1P3 synthesis in HEK EBNA cells expressing the human Prostaglandin F2α receptor, by thiazolidine antagonists of general formula (II).
Figure imgf000155_0001
3) In vitro functional assay 2: Inhibition of Prostaglandin F2a induced Ca -mobilization in HEK/EBNA-cells expressing the Prostaglandin F2a receptor, as measured by FLIPR® (Fluorimetric Imaging Plate Reader).
a) Calcium mobilisation measurements by FLIPR (Fluorometric Imaging Plate Reader)
HEK EBNA cells were seeded at 60000 cells/well in a Poly-L-Lysine precoated black/white bottom 96 well plate. 24 hours later cells were loaded with 4.5 nM Fluo-4 in DMEM-F 12 without fetal calf serum for 1 -2 hours at 37°C. For Prostaglandin F2α dose response or agonist activity measurement of compounds - after a wash with FLIPR buffer (10 mM Hepes, 145 mM NaCl, 5 mM KCl, 1 mM MgCl2, 10 mM glucose, pH 7.4) - cells were stimulated with increasing concentration of Prostaglandin F2α or test compounds of formula (II). Calcium mobilisation was then measured on the FLIPR for 4 min. For IC50 determination of the molecules, increasing concentrations of test compounds were added to the cells 30 min prior to the wash step. After the wash with FLIPR buffer, increasing concentrations of test compounds were added to the cells in FLIPR buffer and calcium mobilisation was measured for 1 min. Then the cells were stimulated with a concentration of 2 times the EC50 of Prostaglandin F2α and calcium mobilisation was measured for 4 min.
b) Results and Discussion:
The activities of the thiazolidine derivatives according to formula (II) were assessed using the above described in vitro biological assay. Representative values for some example compounds are given in Table 3 below. The values refer to the capacity ofthe example compounds according to formula (II) to effectively antagonize Prostaglandin F2α-induced intracellular Ca"+-mobilization mediated by the Prostaglandin F α-receptor. From the IC50- values shown in Table 3 it can be derived that said example test compounds according to formula (II) do exhibit a significant activity as Prostaglandin F2α receptor antagonists, as illustrated by IC50 values of generally less than 2 μM.
Table 3. Inhibition of Ca -mobilization in HEK EBNA cells expressing the human Prostaglandin F20C receptor, by thiazolidine antagonists of general formula (II).
Figure imgf000157_0001
4) In vivo assay Reduction of uterine contractile activity in rats
a) PGF^- or fluprostenol-induced uterine contractions in non-pregnant rats
(i) Preparation of the experiment:
Non-pregnant Sprague Dawley female rats (Charles River, Calco, Italy) weighing 200-300 g were used. They received an i.p. injection of 250 μg/kg diethylstilbestrol (DES) 18 and 24 hours before the experiment. On the day of the experiment, they were anaesthetised with urethane (1.05 g/kg, i.p.) and placed on a homeothermic operating table. The trachea was then isolated and cannulated with a suitable polyethylene (PE) tubing. A midline incision at the hypogastrium level was made, one uterine horn exposed and its tubal end closed (near the ovary) by a ligature with surgical silk. About 3 cm posteriorly to the first tie, the uterine horn wall was incided (close to the uterus body) and a PE240 tubing was inserted into the lumen and secured with surgical silk. After filling the internal cavity with 0.2 ml of sterile physiological saline solution, the catheter was connected to an amplifying/recording system (MacLab, ADlnstruments Pty Ltd, Castle Hill, Australia) via a P23ID Gould Statham pressure transducer. One jugular vein was then isolated and cannulated with a PE60 catheter connected to a butterfly needle for the intravenous administration of Prostaglandin F (Sigma Chem. co., St. Louis, MO, USA) and (±)fluprostenol (Cayman Chemicals, Ann Arbor, MI, USA) or test compounds. For the oral administration, the oesophagus was cannulated with a PE90 catheter.
For obtaining information regarding the test compound plasma levels, 2, 30, 90 and 210 minutes after the intravenous administration or 30, 60, 120 and 210 minutes after the oral administration, 0.5-ml blood samples were withdrawn from the carotid artery previously cannulated with a PE60 catheter. Plasma was then obtained by standard laboratory procedure and the resulting samples were stored at -20°C for successive determinations.
After a suitable stabilization period, repeated administrations of Prostaglandin F2α (by a l Omin intravenous infusion) or fluprostenol (by intravenous bolus) were performed every 35 minutes for 9 times totally. The contractile response obtained from the third Prostaglandin F2α or fluprostenol injection was set as 100%. Five minutes before the fourth injection of Prostaglandin F2α and (±) fluprostenol, the test compound of formula (II) (i.e. a FP antagonist) was injected intravenously as a 5-min infusion.
(ii) Results and discussion:
As each administration of Prostaglandin F2α or fluprostenol induced a train of uterine contractions, the resulting contractile response was quantified by measuring the area under the curve (AUC) ofthe changes in intraluminal uterine pressure (by Chart V4.04 for Windows software, PowerLab ADInstruments, Castle Hill, Australia) over the first 15 minutes ofthe 35-min post-injection period (Prostaglandin F2α-induced uterine contractions) or the whole 35-min (for fluprostenol). Percent variations of AUCs determined after each Prostaglandin F2 or fluprostenol injection were calculated in comparison to the AUC obtained with the third injection (set as 100%) of Prostaglandin F2 or fluprostenol. The effect ofthe test compound was expressed at each time-point as the percent inhibition ofthe above variation values after the administration of each dose of test compound compared to that obtained at the corresponding time-point in the group receiving the vehicle alone. From the inhibition values obtained for each dose-group at the peak effect, a dose-response curve was plotted and, when possible, the relative ED50 value calculated (by S-Plus 2000 v. 4.6 statistical software, Mathsoft, Inc. Seattle, Washington, USA).
Compound (2S)-3-[(l ,l '-biphenyl-4-ylsulfonyl)-N-[(75)-3-hxdroxy-l -phenylpropyl]- 1 , 3- thiazolidine-2-carboxamide for instance for instance, 40 minutes after administration by i.v. route, caused inhibition of uterine contractions of 26%, at a cumulative dose of 30mg/kg.
b) Spontaneous uterine contractions in late-term pregnant rats:
(i) Preparation ofthe experiment:
Late-term pregnant (19-21 days of gestation) Sprague Dawley female rats (Charles River, Calco, Italy) weighing 350-400 g were anesthetised with urethane (1.05 g/kg, i.p.) and placed on a homeothermic operating table. The trachea was isolated and cannulated with a suitable polyethylene (PE) tubing. A midline incision at the hypogastrium level was made, one pregnant uterine horn exposed and its tubal end closed (near the ovary) by a ligature with surgical silk. In the correspondence ofthe last foetus near the above-mentioned ovary, the uterine horn wall was incided taking care not to injure the adjacent placenta, and a PE240 tubing with a latex balloon (9 mm length when empty, capacity 0.1 ml; Radnoti, Monrovia, CA, USA) on the top was inserted into the lumen and secured with surgical silk. After filling the internal cavity ofthe latex balloon with 0.1 ml of sterile physiological saline solution, the catheter was connected to an amplifying/recording system (MacLab, ADInstruments Pty Ltd, Castle Hill, Australia) via a P23ID Gould Statham pressure transducer. One jugular vein was then isolated and cannulated with a PE60 catheter connected to a butterfly needle for the intravenous administration ofthe vehicle or test compounds.
After a suitable stabilization period, vehicle or increasing doses ofthe test compound were administered by a 10-min intravenous infusion. Each dose administration was followed by a 30-min recovery period.
(ii) Results and discussion:
The spontaneous contractile response of the uterus was quantified by evaluating the area under the curve (AUC) of the changes in the intra-luminal uterine pressure over time (by Chart V4.04 for Windows software, PowerLab ADInstruments, Castle Hill, Australia). The effect of the test compound on the spontaneous uterine contraction was evaluated as the percent variation ofthe AUC calculated in a 10-min interval following the administration of each dose of test compound as compared to the AUC in a 10-min interval before the administration ofthe first dose of test compound (basal value). When possible, a dose- response curve (of peak effect) was plotted and the relative ED50 value calculated (by S- Plus 2000 v. 4.6 statistical software, Mathsoft, Inc. Seattle, Washington, USA).
Compound (2S)-3-[(\ , P-biphenyl-4-ylsulfonyl)-N-[(7-S)-3-hxdroxy-l -pheny lpropy 1]- 1,3- thiazolidine-2-carboxamide for instance, upon administration by i.v. route (infusion over 10 minutes), caused inhibition of uterine contractions of >50%>, at a cumulative dose of 30mg/kg - with a calculated ED50 value) of 28 mg/kg or 2.8mg/kg/min, in the experiment outlined above.

Claims

Claims
1. Use of a compound according to formula Tl
Figure imgf000161_0001
as well as its geometrical isomers, its optically active forms as enantiomers, diastereo- mers and its racemate forms, as well as pharmaceutically acceptable salts and pharmaceutically active derivatives thereof, wherein
G is selected from the group consisting of Ci-Cό-alkyl aryl, Cι-C6-alkyl heteroaryl, Ci- C6-alkyl cycloalkyl, Cι-C6-alkyl heteroaryl, aryl, heteroaryl, C3-C8-cycloalkyl or - heterocycloalkyl, said cycloalkyl or aryl or heteroaryl groups may be fused with a cycloalkyl or aryl or heteroaryl group;
R1 is selected from the group consisting of aryl, heteroaryl, C3-Cs-cycloalkyl or a 3 to 8 membered heterocycloalkyl, said (hetero)cycloalkyl or aryl or heteroaryl groups may be fused with a (hetero)cycloalkyl or aryl or heteroaryl group;
R is selected from the group consisting of H, carboxy, acyl, alkoxycarbonyl, aminocarbonyl, Ci-Cs-alkyl carboxy, Ci-Cs-alkyl acyl, Ci-Cs-alkyl alkoxycarbonyl, Ci-Cs-alkyl aminocarbonyl, Ci-Cs-alkyl acyloxy, Ci-Cs-alkyl acylamino, Ci-Cs-alkyl ureido, Ci-Cs-alkyl amino, Cι-C5-alkyl alkoxy, Ci-Cs-alkyl sulfanyl, Ci-Cs-alkyl sulfinyl, Cj-Cs-alkyl sulfonyl, Ci-Cs-alkyl sulfonylamino, -Cs-alkyl sulfonyloxy, Ci- C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, aryl, heteroaryl, C3-C8-cycloalkyl, 3-8 membered heterocycloalkyl, Cι-C6-alkyl aryl, C2-C6-alkyl heteroaryl, Cι-C6-alkyl cycloalkyl, Cι-C6-alkyl heterocycloalkyl, C2-C6-alkenyl aryl, C2-C6-alkenyl heteroaryl, C2-C6-alkynyl aryl, or C2-C6-alkynyl heteroaryl; or
R and G may form a Cs-Cg-cycloalkyl ring;
R4 is selected from the group consisting of Cι-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl;
n is an integer from 0 to 2;
for the preparation of a medicament for the prophylaxis and/or treatment of dysmenorrhea, preterm labor, premature birth and for stopping labor prior to cesarean delivery.
2. Use according to claim 1 , wherein G is an aryl group.
3. Use of compounds according to claims 1 or 2, for the inhibition of a prostaglandin receptor.
4. Use according to of claim 3, wherein said prostaglandin receptor is the prostaglandin F2 receptor.
5. Thiazolidine carboxamide derivatives according to formula (I),
Figure imgf000162_0001
as well as its geometrical isomers, its optically active forms as enantiomers, diasterec- mers and its racemate forms, as well as pharmaceutically acceptable salts and pharmaceutically active derivatives thereof, wherein G' is selected from the group consisting of aryl, heteroaryl, Cs-Cg-cycloalkyl or 3 to 8 membered heterocycloalkyl, said cycloalkyl or aryl or heteroaryl groups may be fused with cycloalkyl or aryl or heteroaryl groups;
R1, R2, R4 and n are as defined in claim 1.
6. Thiazolidine carboxamide derivatives according to claim 5, said compounds having formula (la):
Figure imgf000163_0001
as well as its geometrical isomers, its optically active forms as enantiomers, diasterec- mers and its racemate forms, as well as pharmaceutically acceptable salts and pharmaceutically active derivatives thereof, wherein
R1, R2, R4 and n are as defined in claim 1 ;
R3 is selected from the group consisting of Cι-C -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, aryl, heteroaryl, C3-C8-cycloalkyl or heterocycloalkyl, Cι-C6-alkyl aryl, Cι-C6-alkyl heteroaryl, Cι-C3-alkyl cycloalkyl, Cι-C3-alkyl heterocycloalkyl, C2-C6-alkenyl-aryl or -heteroaryl, C2-C6-alkynyl aryl or -heteroaryl, carboxy, cyano, halogen, hydroxy, Ci-
C6-alkoxy, nitro, acylamino, ureido, sulfonylamino, sulfanyl, or sulfonyl;
m is an integer from 0 to 3.
7. A thiazolidine carboxamide derivative according to claim 5 or 6 wherein R1 is selected from the group consisting of an aryl or heteroaryl group optionally substituted with at least one moiety selected from the group consisting of aryl, heteroaryl, halogen, alkoxy, sulfanyl, straight or branched Cι-C -alkyl.
8. A thiazolidine carboxamide derivative according to any of claims 5 to 7, whereby R is a group Ci-Cs-alkyl-A-R5, wherein
A is O or a moiety of the formula N-B-R6; wherein
B is selected from the group consisting of a bond, an amino acid residue, (C=0), (CO)-O, (C=0)-NR7, or S02;
R , R and R are independently from each other selected from the group consisting of H, Ci-Cό-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, aryl, heteroaryl, Cs-Cs-cycloalkyl or heterocycloalkyl, Ci-Cό-alkyl aryl, Ci-Cό-alkyI heteroaryl, Cι-C6-alkyl cycloalkyl, C|-
C6-alkyl heterocycloalkyl, C2-C6-alkenyl aryl or heteroaryl, C2-C6-alkynyl aryl or - heteroaryl, or
R6 and R7, or R5 and B-R6 together with the respective nitrogen atoms to which they are attached, may optionally form a substituted or unsubstituted heterocycloalkyl ring.
9. A thiazolidine carboxamide derivative according to claim 8, wherein R" is C ι-C3-alkyl- A-R5 wherein A is O and R5 is H, or A is N-B-R6 with B being a bond, and R5 and R6 being each independently from each other selected from the group consisting of C1-C3- alkyl, including Cι-C3-alkyl hydroxy, Ci-Cs-alkyl carboxy, Ci-Cs-alkyl aminocarbonyl, Ci-Cs-alkyl alkoxycarbonyl, Ci-Cs-alkyl aryl, C|-C3-alkyl heteroaryl, C1-C3- alkyl cycloalkyl, C|-C3-alkyl heterocycloalkyl.
10. A thiazolidine carboxamide derivative according to claim 7, wherein R" is selected from the group consisting of phenyl, pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl.
1 1. A thiazolidine carboxamide derivative according to any of claim 5 to 9, wherein R is a phenyl substituted with a group selected from the group consisting of a straight or branched Ci-Cs-alkyl or aryl, R2 is selected from the group consisting of Cι-C3-alkyl- A-R5 wherein A is O and R5 is H, or A is N-B-R6 with B being a bond and R5 and R6 being each independently selected from the group consisting of Cι-C3-alkyl, Ci-Cs- alkyl aryl, Cι-C3-alkyl heteroaryl, Ci-Cs-alkyl- hydroxy.
12. A thiazolidine carboxamide derivative according to claim 1 1 wherein R1 is a biphenyl or a tert-butyl phenyl group, R is Ci-Cs-alkyl-A-R , wherein A is O and R is H, or A is N-B-R6, R5 and R6 are each independently from each other Ci-Cs-alkyl, Ci-Cs-alkyl aryl, Cι-C3-alkyl heteroaryl, or Cι-C3-alkyl hydroxy, B is a bond, R is fluorine, m is either 0, 1 , or 2, and n is 0.
13. A thiazolidine carboxamide derivative according to any of the preceding claims selected in the group consisting of :
(27?)-3-([l , l '-biphenyl]-4-ylsulfonyl)-N-[(7,S)-3-hydroxy- l -phenylpropyl]- 1 ,3- thiazolidine-2-carboxamide
(27?)-3-([l , r-biphenyl]-4-ylsulfonyl)-N-[(7?)-phenyl(2-pyridinyl)methyl]- l ,3- thiazolidine-2-carboxamide
(2-R)-3-[(4-fert-butylphenyl)sulfonyl]-N-[(75)-3-hydroxy-l -phenylpropyl]- 1 ,3- thiazolidine- 2-carboxamide
(27?)-N-[(7.S)-3-hydroxy-l -phenylpropyl]-3-[(4-tert-pentylphenyl)sulfonyl]- l ,3- thiazolidine-2-carboxamide
(2,S)-2-({[3-([l , r-biphenyl]-4-ylsulfonyl)-l ,3-thiazolidin-2-yl]carbonyl}amino)-3- phenylpropanoic acid
(25)-2-[({3-[(5-chloro-3-methyl- l-benzothien-2-yl)sulfonyl]- 1 ,3-thiazolidin-2- yl}carbonyl)amino]-3-phenylpropanoic acid (25)-3-([l ,l'-biphenyl]-4-ylsulfonyl)-N-((75)-3-{methyl[2-(2-pyridinyl)ethyl]amino}- 1 -phenylpropyl)- 1 ,3-thiazolidine-2-carboxamide
(2S)-3-([l , 1 '-biphenyl]-4-ylsulfonyl)-7V-[(7S)-l -pheny 1-2-propenyl]- 1 ,3-thiazolidine-2- carboxamide
(2-S)-3-([l ,l '-biphenyl]-4-ylsulfonyl)-N-[(7-S)-3-(diethylamino)-l-phenylpropyl]-l ,3- thiazolidine-2-carboxamide
(2S)-3-([ 1 , 1 '-bipheny l]-4-y Isulfony l)-N-[(75)-3-hydroxy- 1 -phenylpropyl]- 1 ,3- thiazolidine-2-carboxamide
(2S)-3-([ 1 , l *-bipheny l]-4-y lsulfonyl)-N-[(7?)-phenyl(2-pyridinyl)methy I]- 1 ,3- thiazolidine-2-carboxamide
(2S)-3-([ 1 , 1 '-biphenyl]-4-ylsulfonyl)-N-{(75)-3-[(2-furylmethyl)(methyl)amino]- 1 - pheny lpropyl}- 1 ,3-thiazolidine-2-carboxamide
(2S)-3-([ 1 , 1 '-bipheny l]-4-ylsulfonyl)-N-{(7 )-3-[(2-hydroxyethyl)(methyl)amino]- 1 - phenylpropyl}- 1 ,3-thiazolidine-2-carboxamide
(2S)-3-([ 1 , 1 '-biphenyl]-4-y lsulfonyl)-N-{(75)-3-[2-(2-hydroxyethyl)- 1 -piperidinyl]- 1 - phenylpropyl}- l ,3-thiazolidine-2-carboxamide
(2S)-3-([ 1 , 1 '-biphenyl]-4-y lsulfonyl)-N-{(75)-3-[4-(2-methoxyphenyl)- 1 -piperazinyl]- l-phenylpropyl}- l ,3-thiazolidine-2-carboxamide
(25)-3-[(4-ter/-butylphenyl)sulfonyl]-N-[(7-S)-3-hydroxy-l -phenylpropyl]- 1 ,3- thiazolidine-2-carboxamide
(2-S)-3-phenyl-2-{[(3-{[5-(2-pyridinyl)-2-thienyl]sulfonyl}-l ,3-thiazolidin-2- yl)carbonyl]amino}propanoic acid (25)-7V-[(7-S)-3-hydroxy-l-phenylpropyl]-3-[(4-/err-pentylphenyl)sulfonyl]-l ,3- thiazolidine-2-carboxamide
(2-S)-N-{(75)-3-[benzyl(methyl)amino]-l-phenylpropyl}-3-([l ,l '-biphenyl]-4- ylsulfonyl)- 1 ,3-thiazolidine-2-carboxamide
3-([l , l '-biphenyl]-4-ylsulfonyl)-N-(l -phenyl-3- {[(2lS)-tetrahydro-2-furanylmethyl]- amino} propyl)- l ,3-thiazolidine-2-carboxamide
3-([l ,l '-biphenyl]-4-y Isulfony 1)-N-(1 -phenyl-3- {[2-(l -piperidinyl)ethyl]amino}- propyl)- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-ylsulfonyl)-N-(l -pheny 1-3- { [2-(2-pyridinyl)ethy l]amino} propyl)- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-biphenyl]-4-y Isulfony 1)-N-(1 -pheny 1-3- {[2-(3-pyridiny l)ethyl] amino} propyl)- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-y Isulfony l)-N-( 1 -phenylpropyl)- 1 ,3-thiazolidine-2-carboxamide
3-([l ,l '-biphenyl]-4-ylsulfonyl)-N-(2,3-difluorobenzyl)-l ,3-thiazolidine-2-carbox- amide
3-([ 1 , 1 '-biphenyl]-4-ylsulfonyl)-N-(2,4-difluorobenzyl)- 1 ,3-thiazolidine-2-carbox- amide
3-([ 1 , 1 '-biphenyl]-4-ylsulfonyl)-N-(2,5-difluorobenzyl)- 1 ,3-thiazolidine-2-carbox- amide
3-([ 1 , 1 '-biphenyl]-4-ylsulfonyl)-N-(2,6-difluorobenzy 1)- 1 ,3-thiazolidine-2-carbox- amide 3-([l ,l'-biphenyl]-4-ylsulfonyl)-N-(2-chloro-4-fluorobenzyl)-l ,3-thiazolidine-2- carboxamide
3-([l ,l'-biphenyl]-4-ylsulfonyl)-N-(2-fluorobenzyl)-l,3-thiazolidine-2-carboxamide
3-([l ,l'-biphenyl]-4-ylsulfonyl)-N-(2-furylmethyl)-l,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-ylsulfony l)-N-(2-methoxybenzy 1)- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-biphenyl]-4-ylsulfony l)-N-(2-methylbenzy 1)- 1 ,3-thiazolidine-2-carboxamide
3-([l ,l'-biphenyl]-4-ylsulfonyl)-N-(2-phenylpropyl)-l,3-thiazolidine-2-carboxamide
3-([l ,l '-biphenyl]-4-ylsulfonyl)-N-(2-thienylmethyl)-l,3-thiazolidine-2-carboxamide
3-([l ,r-biphenyl]-4-ylsulfonyl)-N-(3,4-difluorobenzyl)-l ,3-thiazolidine-2-carbox- amide
3-([ 1 , 1 '-biρhenyl]-4-y Isulfony l)-N-(3- { [(27?)-2-hydroxy-2-pheny lethy l]amino} - 1 - phenylpropyl)- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-ylsulfonyl)-N-(3- { [(2-S)-2-hydroxypropy l]amino} - 1 -phenylpropyl)- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-biphenyl]-4-ylsulfonyl)-N-(3- { [(5-methyl-2-furyl)methyl]amino} - 1-phenyl- propyl)-l ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-ylsulfonyl)-N-(3- { [2-( 1 H-indol-3-y l)ethyl]amino} - 1 -pheny 1- propyl)- l ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-y Isulfony l)-N-(3- { [2-( 1 -methy 1-2-pyrrolidiny l)ethy l]amino} - 1 - phenylpropyl)- 1 ,3-thiazolidine-2-carboxamide 3-([ 1 , 1 '-bipheny l]-4-ylsulfonyl)-/V-(3- { [2-(4-moφholiny l)ethy l]amino} - 1 - phenylpropyl)- 1 ,3-thiazolidine-2-carboxamide
3-([l ,l'-biphenyl]-4-ylsulfonyl)-N-(3-{[2-(dimethylamino)ethyl]amino}-l- phenylpropyl)- 1 ,3-thiazolidine-2-carboxamide
3-([l ,l '-biphenyl]-4-ylsulfonyl)-N-(3-{[3-(2-oxo-l-pyrrolidinyl)propyl]amino}-l- phenylpropyl)- 1 ,3-thiazolidine-2-carboxamide
3-([l ,l '-biphenyl]-4-ylsulfonyl)-N-(3-{[3-(4-moφholinyl)propyl]amino}-l - phenylpropyl)- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 *-biphenyl]-4-ylsulfonyl)-N-(3- {methyl[(77?)- l-phenylethyl]amino}- 1- phenylpropyl)- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 *-biphenyl]-4-ylsulfony l)-N-(3- {methy \[(1S)- 1 -pheny lethy l]amino}- 1 - phenylpropyl)- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-biphenyl]-4-y lsulfonyl)-N-(3- {methy l[2-(2-pyridinyl)ethy l]amino}- 1 - phenylpropyl)- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-biphenyl]-4-ylsulfonyl)-N-(3-chloro-4-fluorobenzyl)-l ,3-thiazolidine-2- carboxamide
3-([ 1 , 1 '-bipheny l]-4-y Isulfony l)-N-(3-fluorobenzy 1)- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-biphenyl]-4-y Isulfony l)-N-(3-hydroxy- 1 -phenylpropyl)- 1 ,3-th iazolidine-2- carboxamide
3-([ 1 , 1 '-biphenyl]-4-ylsulfonyl)-N-(3-methylbenzyl)- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-biphenyl]-4-y lsulfonyl)-N-(3-phenoxy- 1 -phenylpropyl)- 1 ,3-thiazolidine-2- carboxamide 3-([ 1 , 1 '-biphenyl]-4-ylsulfonyl)-N-(3-pyridiny lmethy I)- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-y Isulfony l)-N-(4-fluorobenzy 1)- 1 ,3-thiazolidine-2-carboxamide
3-([l ,l'-biphenyl]-4-ylsulfonyl)-N-(4-phenoxybenzyl)-l ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 *-biphenyl]-4-y Isulfony l)-N-[( 1 ,5-dimethy I- 1 H-pyrrol-2-y l)methy 1]- 1 ,3- thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-ylsulfonyl)-N-[(l -oxido-2-pyridinyl)methyl]- 1 ,3-thiazolidine-2- carboxamide 1 -oxide
3-([ 1 , 1 '-biphenyl]-4-ylsulfonyl)-N-[(77?)-2-hydroxy- 1 -phenylethyl]- 1 ,3-thiazolidine-2- carboxamide
3-([l ,l'-biphenyl]-4-ylsulfonyl)-N-[(7-R)-3-hydroxy-l-phenylpropyl]- l ,3-thiazolidine-
2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-ylsulfonyl)-N-[(75)- 1 -phenylethyl]- 1 ,3-thiazolidine-2-carbox- amide
3-([ 1 , 1 '-bipheny l]-4-ylsulfonyl)-N-[(7-S)-3-hydroxy- 1 -phenylpropyl]- 1 ,3-thiazolidine- 2-carboxamide
3-([l ,l *-biphenyl]-4-ylsulfonyl)-N-[(7?)-{6-[2-(dimethylamino)ethoxy]-2-pyridinyl}- (phenyl)methy I]- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-y Isulfony l)-N-[(7?)-phenyl(2-pyridinyl)methy I]- 1 ,3-thiazolidine-2- carboxamide
3-([ 1 , 1 '-bipheny l]-4-ylsulfonyl)-N-[(-S)-phenyl(2-pyridinyl)methyl]- 1 ,3-thiazol idine-2- carboxamide 3-([ 1 , 1 '-bipheny l]-4-ylsulfonyl)-N-[l -(2,6-difluorophenyl)-3-hydroxypropy 1]- 1 ,3- thiazolidine-2-carboxamide
3-([ 1 , 1 '-biphenyl]-4-ylsulfonyl)-7V-[l -(2-chlorophenyl)-3-hydroxypropyl]- 1 ,3- thiazolidine-2-carboxamide
3-([ 1 , 1 '-biphenyl]-4-ylsulfonyl)-N-[ 1 -(2-fury l)-3-hydroxypropyl]- 1 ,3-thiazolidine-2- carboxamide
3-([ 1 , 1 '-bipheny l]-4-ylsulfonyl)-N-[ 1 -(3,4-dichloropheny l)-3-hydroxypropy 1]- 1 ,3- thiazolidine-2-carboxamide
3-([ 1 , 1 '-biphenyl]-4-y Isulfony l)-N-[l -(3-chlorophenyl)-3-hydroxypropyl]- 1 ,3- thiazolidine-2-carboxamide
3-([ 1 , 1 '-biphenyl]-4-y Isulfony l)-7V-[l -(3-furyl)-3-hydroxypropy 1]- 1 ,3-thiazolidine-2- carboxamide
3-([ 1 ,1 '-bipheny l]-4-ylsulfonyl)-N-[l -(4-chloropheny l)-3-hydroxypropyl]- 1 ,3- thiazolidine-2-carboxamide
3-([ 1 , 1 '-biphenyl]-4-y Isulfony l)-N-[l -(4-chloropheny l)ethy 1]- 1 ,3-thiazolidine-2- carboxamide
3-([l , 1 '-biphenyl]-4-ylsulfonyl)-N-[l -(4-fluorophenyl)-3-hydroxypropyl]- 1 ,3- thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-y Isulfony l)-N-[ 1 -(4-fluorophenyl)ethyl]- 1 ,3-thiazolidine-2- carboxamide
3-([ 1 , 1 '-bipheny l]-4-ylsulfonyl)-N-[ 1 -pheny l-2-( 1 -pyrrolidiny l)ethy 1]- 1 ,3-thiazolidine- 2-carboxamide 3-([l,l*-biphenyl]-4-ylsulfonyl)-N-[l -phenyl-3-({[(7-S,27?,37?,55)-2,6,6-trimethyl- bicyclo[3.1.1 ]hept-3-yl]methyl}amino)propyl]- 1 ,3-thiazolidine-2-carboxamide
3-([l ,l '-biphenyl]-4-ylsulfonyl)-7V-[l-phenyl-3-(l-piperazinyl)propyl]-l ,3-thiazolidine- 2-carboxamide
3-([l ,l '-biphenyI]-4-ylsulfonyl)-N-[l-phenyl-3-(l-piperidinyl)propyl]-l ,3-thiazolidine-
2-carboxamide
3-([l , r-biphenyl]-4-ylsulfonyl)-7V-[l -phenyl-3-(l-pyrrolidinyl)propyl]-l ,3- th iazol idine-2-carboxam ide
3-([l ,l '-biphenyl]-4-ylsulfonyl)-N-[2-(4-morpholinyl)-l-phenylethyl]-l ,3-thiazolidine- 2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-y lsulfonyl)-N-[2-(dimethy lamino)- 1 -phenylethyl]- 1 ,3-thiazo- lidine-2-carboxamide
3-([ 1 ,1 '-bipheny l]-4-ylsulfonyl)-N-[3-((37?)-3-(hydroxymethyl)-3,4-dihydro-2( l H)- isoquinolinyl)-l-phenylpropyl]-l ,3-thiazolidine-2-carboxamide
3-([l ,l *-biphenyl]-4-ylsulfonyl)-N-[3-((3-S)-3-(hydroxymethyl)-3,4-dihydro-2(l H)- isoquinoliny I)- 1 -phenylpropyl]- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-biphenyl]-4-ylsulfonyl)-N-[3-( 1 ,3-dioxo- 1 ,3-dihydro-2H-isoindol-2-yl> 1 - pheny Ipropyl]- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-biphenyl]-4-y lsulfonyl)-N-[3-(2,5-dihydro- 1 H-pyrrol- 1 -yl)- 1 -pheny Ipropyl]- 1 ,3-thiazolidine-2-carboxamide
3-([l ,l '-biphenyl]-4-yIsulfonyl)-N-[3-(3,5-dimethy I- 1 -piperidinyl)- 1 -phenylpropyl]- l ,3-thiazolidine-2-carboxamide 3-([ 1 , 1 '-biphenyl]-4-ylsulfonyl)-N-[3-(3,6-dihydro- 1 (2H)-pyridiny I)- 1 -phenylpropy 1]- 1 ,3-thiazolidine-2-carboxamide
3-([l ,l'-biphenyl]-4-ylsulfonyl)-iV-[3-(3-hydroxy- 1-piperidinyl)- 1 -phenylpropyl]- 1 ,3- thiazolidine-2-carboxamide
3-([l ,l'-biphenyl]-4-ylsulfonyl)-N-[3-(3-hydroxy-l-pyrrolidinyl)-l-phenylpropyl]-l ,3- thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-y Isulfony l)-N-[3-(3-methy I- 1 -piperidinyl)- 1 -phenylpropyl]- 1 ,3- thiazolidine-2-carboxamide
3-([ 1 , 1 '-biphenyl]-4-ylsulfonyl)-N-[3-(4-hydroxy- 1-piperidinyl)- 1 -phenylpropyl]- 1 ,3- thiazolidine-2-carboxamide
3-([ 1 , 1 '-biphenyl]-4-y Isulfony l)-N-[3-(4-hydroxy-4-pheny I- 1 -piperidinyl)- 1 - phenylpropyl]- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-y lsulfonyl)-N-[3-(4-methy 1- 1 -piperazinyl)- 1 -phenylpropyl]- 1 ,3- thiazolidine-2-carboxamide
3-([l , 1 '-biphenyl]-4-y lsulfonyl)-N-[3-(4-moφholiny 1)- 1 -phenylpropyl]- 1 ,3-thiazo- lidine-2-carboxamide
3-([l ,l '-biphenyl]-4-y Isulfony l)-N-[3-(diethy lam ino)-l -phenylpropy I]- 1 ,3-thiazolidine- 2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-y Isulfony l)-N-[3-(dimethylamino)- 1 -phenylpropyl]- 1 ,3-thia- zolidine-2-carboxamide
3-([l , 1 '-biphenyl]-4-y lsulfonyl)-N-[3-hydroxy- 1 -(2-methoxyphenyl)propy I]- 1 ,3- thiazolidine-2-carboxamide 3-([ 1 , 1 '-biphenyl]-4-ylsulfonyl)-N-[3-hydroxy- 1 -(2-methylphenyl)propy 1]- 1 ,3- thiazolidine-2-carboxamide
3-([ 1 , 1 '-biphenyl]-4-ylsulfony 1)-N- [3 -hydroxy- 1 -(3-methoxypheny l)propyl]- 1 ,3- thiazolidine-2-carboxamide
3-([l ,l'-biphenyl]-4-ylsulfonyl)-N-[3-hydroxy-l-(3-pyridinyl)propyl]-l ,3-thiazolidine-
2-carboxamide
3-([ 1 ,1 '-biphenyl]-4-ylsulfony 1)-N- [3 -hydroxy- 1 -(4-methoxyphenyl)propyl]- 1 ,3- thiazolidine-2-carboxamide
3-([ 1 , 1 '-biphenyl]-4-ylsulfonyl)-N-[3-hydroxy- 1 -(4-methylphenyl)propy 1]- 1 ,3- thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-y Isulfony l)-N-[pheny l(2-pyridiny l)methy 1]- 1 ,3-thiazolidine-2- carboxamide
3-([l ,l '-biphenyl]-4-ylsulfonyl)-N-{ l -phenyl-3-[(2-phenylethyl)amino]propyl}-l ,3- thiazolidine-2-carboxamide
3-([l ,l '-biphenyl]-4-ylsulfonyl)-N-{ l -phenyl-3-[(2-phenylpropyl)amino]propyl}- l ,3- thiazolidine-2-carboxamide
3-([l ,l '-biphenyl]-4-ylsulfonyl)-N-{l -phenyl-3-[(2-pyridinylmethyl)amino]propyl}- 1 ,3-thiazolidine-2-carboxamide
3-([l ,r-biphenyl]-4-ylsulfonyl)-N-{ l-phenyl-3-[(3-pyridinylmethyl)amino]propyl}- 1 ,3-thiazolidine-2-carboxamide
3-([l ,l '-biphenyl]-4-y Isulfony 1)-N-{ 1 -pheny l-3-[(tetrahydro-2-furany lmethy l)amino]- propyl}-l ,3-thiazolidine-2-carboxamide 3-([l ,l '-biphenyl]-4-ylsulfonyl)-N-{ l -phenyl-3-[4-(l -pyrrolidinyl)- 1 -piperidiny 1]- propyl}-l,3-thiazolidine-2-carboxamide
3-([l,r-biphenyl]-4-ylsulfonyl)-N-{3-[(2-furylmethyl)(methyl)amino]-l -phenylpropyl}- l ,3-thiazolidine-2-carboxamide
3-([l ,l '-biphenyl]-4-ylsulfonyl)-N-{3-[(2-furylmethyl)amino]-l-phenylpropyl}-l,3- thiazolidine-2-carboxamide
3-([l ,r-biphenyl]-4-ylsulfonyl)-N-{3-[(2-hydroxy-2-phenylethyl)(methyl)amino]-l- phenylpropyl}-l ,3-thiazolidine-2-carboxamide
3-([l ,l '-biphenyl]-4-ylsulfonyl)-N-{3-[(2-hydroxy-2-phenylethyl)amino]-l-phenyl- propyl}- l,3-thiazolidine-2-carboxamide
3-([l ,l '-biphenyl]-4-ylsulfonyl)-N-{3-[(2-hydroxycyclohexyl)amino]-l -pheny lpropyl}- 1 ,3-thiazolidine-2-carboxamide
3-([l ,l '-biphenyl]-4-y Isulfony l)-N-{3-[(2-hydroxyethyI)(methyl)amino]-l -pheny 1- propyl}-l ,3-thiazolidine-2-carboxamide
3-([l ,r-biphenyl]-4-ylsulfonyl)-N-{3-[(2-hydroxyethyl)amino]-l -phenylpropyl}- 1 ,3- thiazolidine-2-carboxamide
3-([l ,l '-biphenyl]-4-ylsulfonyl)-N-{3-[(2-hydroxypropyl)amino]-l -phenylpropyl}- 1 ,3- thiazolidine-2-carboxamide
3-([l , 1 *-biphenyl]-4-ylsulfonyl)-N-{3-[(27?)-2-(hydroxymethyl)pyrrolidinyl]- 1 - pheny Ipropyl}- 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-y Isulfony 1)-N- {3-[(27?)-2-(methoxymethy l)ρyrrolidiny 1]- 1 - phenylpropyl}- l ,3-thiazolidine-2-carboxamide 3-([l ,l'-biphenyl]-4-ylsulfonyl)-N-{3-[(25)-2-(methoxymethyl)pyrrolidinyl]-l - phenylpropyl}-l,3-thiazolidine-2-carboxamide
3-([l ,l'-biphenyl]-4-ylsulfonyl)-N-{3-[(3,5-difluorobenzyl)amino]-l-phenylpropyl}- 1 ,3-thiazolidine-2-carboxamide
3-([l ,l'-biphenyl]-4-ylsulfonyl)-N-{3-[(3-hydroxy-3-phenylpropyl)(methyl)amino]-l- phenylpropyl}-l ,3-thiazolidine-2-carboxamide
3-([l,l '-biphenyl]-4-ylsulfonyl)-N-{3-[(3-hydroxypropyl)amino]-l -phenylpropyl}- 1 ,3- thiazolidine-2-carboxamide
3-([ 1 , 1 '-biphenyl]-4-ylsulfonyl)-N-{3-[(37?)-3-hydroxypyrrolidinyl]- 1 -phenylpropyl }- l,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-biphenyl]-4-y lsulfonyl)-N-{3-[(4-fluorobenzyl)amino]- 1 -phenylpropy 1}- 1 ,3- thiazolidine-2-carboxamide
3-([ 1 ,1 '-bipheny l]-4-y Isulfony l)-N-{3-[[3-(dimethylamino)propyl](methyl)amino]-l - phenylpropyl}-l,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-biphenyl]-4-ylsulfonyl)-N-{3-[2-(hydroxymethyl)- 1 -piperidinyl]- 1 -pheny 1- propyl}-l ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-y Isulfony 1)-N- {3-[3-(hydroxymethy 1)- 1 -piperidiny 1]- 1 -pheny 1- propyl}-l ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-biphenyl]-4-y lsulfonyl)-N- {3-[4-(2-hydroxyethy 1)- 1 -piperidinyl]- 1 -phenyl- propyl} - 1 ,3-thiazolidine-2-carboxamide
3-([ 1 , 1 '-bipheny l]-4-y Isulfony 1)-N- {3-[4-(hydroxymethyl)- 1 -piperidiny 1]- 1 -pheny 1- propyl}-l ,3-thiazolidine-2-carboxamide 3-([l ,l'-biphenyl]-4-ylsulfonyl)-N-{3-[methyl(2-phenylethyl)amino]-l -pheny Ipropyl}- 1 ,3-thiazolidine-2-carboxamide
3-[(3*,4'-dichloro[ 1 , 1 '-biphenyl ]-4-y l)sulfonyl]-N-[ 1 -(2-furyl)-3-hydroxypropy 1]- 1 ,3- thiazolidine-2-carboxamide
3-[(4'-chloro[l ,l '-biphenyl]-4-yl)sulfonyl]-N-[l-(2-flιryl)-3-hydroxypropyl]-l,3- thiazolidine-2-carboxamide
3-[(4-chlorophenyl)sulfonyl]-N-(2-pyridinylmethyl)- l,3-thiazolidine-2-carboxamide
3-[(4-chIorophenyl)sulfonyl]-N-{4-[({[(2- ethylhexyl)amino]carbonyl}amino)methyl]benzyl}- l,3-thiazolidine-2-carboxamide
3-[(4-chlorophenyl)sulfonyl]-N-{4-[({[(2- phenyIethyl)amino]carbonyl}amino)methyl]benzyl}- l ,3-thiazolidine-2-carboxamide
3-[(4-chlorophenyl)sulfonyl]-N-{4-[({[(4- methylbenzyl)amino]carbonyl}amino)methyl]benzyl}- l ,3-thiazolidine-2-carboxamide
3-[(4'-fluoro[l ,l *-biphenyl]-4-yl)sulfonyl]-N-[l -(2-furyl)-3-hydroxypropyl]- l ,3- thiazolidine-2-carboxamide
3-[(4-iodophenyl)sulfonyl]-N-{4-[({[(4-methylbenzyl)amino]carbonyl}amino)methyl]- benzyl}-l ,3-thiazolidine-2-carboxamide
3-[(4-fer/-butylphenyl)sulfonyl]-N-(l ,2-diphenylethyl)-l ,3-thiazolidine-2-carboxamide
3-[(4-rer?-butylphenyl)sulfonyl]-N-(l -pheny lethyl)-l ,3-thiazolidine-2-carboxamide
3-[(4-terr-butylphenyl)sulfonyl]-N-(2,3-dihydro-l H-inden-l -yl)-l ,3-thiazolidine-2- carboxamide 3-[(4-;ert-butylphenyl)sulfonyl]-V-(2-furylmethyl)-l ,3-thiazolidine-2-carboxamide
3-[(4-?ert1-butylphenyl)sulfonyl]-N-(2-phenylpropyl)-l,3-thiazolidine-2-carboxamide
3-[(4-tør/-butylphenyl)sulfonyl]- V-(3-hydroxy- 1 -phenylpropyl)- 1 ,3-thiazolidine-2- carboxamide
3-[(4-ter^butylphenyl)sulfonyl]-N-(3-pyridinylmethyl)- 1 ,3-thiazolidine-2-carboxamide
3-[(4-te^-butylphenyl)sulfonyl]-N-[2-(l H-indol-3-yl)-l-methylethyl]-l ,3-thiazolidine- 2-carboxamide
3-[(4-tert-butylphenyl)sulfonyl]-N-{[l -(4-chlorophenyl)cyclopropyl]methyl}-l ,3- thiazolidine-2-carboxamide
3-[(4-/er/-butylphenyl)sulfonyl]-N-{4-[3-(dimethylamino)propoxy]benzyl}-l,3- thiazolidine-2-carboxamide
3-{[5-(3-isoxazolyl)-2-thienyl]sulfonyl}-N-{4-[({[(2-phenylethyl)amino]carbonyl}- amino)methyl]benzyl}-l ,3-thiazolidine-2-carboxamide
ethyl {4-[(3S)-3-({ [(2S)-3-([\ ,\ '-bipheny l]-4-ylsulfonyl)- 1 , 3-thiazolidin-2-yl]- carbonyl}amino)-3-phenylpropyl]-l-piperazinyl}acetate
methyl [[(35)-3-({[(21S)-3-([l ,r-biphenyl]-4-ylsulfonyl)- l ,3-thiazolidin-2-yl]- carbonyl}amino)-3-phenylpropyl](methyl)amino]acetate
N-(2,2-diphenylethyl)-3-(8-quinoliny Isulfony I)- l ,3-thiazolidine-2-carboxamide
N-(2-aminobenzyl)-3-([l , l '-biphenyl]-4-ylsulfonyl)-l ,3-thiazolidine-2-carboxamide
N-(3- { [2-(acety lamino)ethy l]amino} - 1 -phenylpropy l)-3-([ 1 , 1 '-bipheny l]-4-ylsulfony 1)-
1 ,3-thiazolidine-2-carboxamide 7V-(3-amino- 1 -phenylpropyl)-3-([ 1 , 1 '-biphenyl]-4-ylsulfony 1)- 1 ,3-thiazolidine-2- carboxamide
V-(3-aminobenzyl)-3-[(4-ter?-butylphenyl)sulfonyl]-l ,3-thiazolidine-2-carboxamide
N-(3-hydroxy-l-phenylpropyl)-3-[(4-phenoxyphenyl)sulfonyl]-l ,3-thiazolidine-2- carboxamide
N-(4-aminobenzyl)-3-[(4-ter?-butylphenyl)sulfonyl]-l ,3-thiazolidine-2-carboxamide
N-[(1R)- 1 -benzyl-2-hydroxyethyl]-3-([l , 1 '-biρhenyl]-4-ylsulfonyl)- 1 ,3-thiazolidine-2- carboxamide
N-[(6-amino-3-pyridinyl)methyl]-3-[(4-/e t-butylphenyl)sulfonyl]- l ,3-thiazolidine-2- carboxamide
N-[1-(l ,3-benzodioxol-5-yl)-3-hydroxypropyl]-3-([l , l '-biphenyl]-4-ylsulfonyl)-l ,3- thiazolidine-2-carboxamide
N-[ 1 -( 1 -benzofuran-2-yl)-3-hydroxypropyl]-3-([ 1 , 1 '-bipheny l]-4-ylsulfonyl)- 1 ,3- thiazolidine-2-carboxamide
N-[ 1 -(2-furyl)-3-hydroxypropyl]-3-[(2'-methyl[ 1 , 1 '-bipheny l]-4-y l)sulfony 1]- 1 ,3- thiazolidine-2-carboxamide
N-[ 1 -(2-furyl)-3-hydroxypropy l]-3-[(4'-methoxy[l , 1 '-biphenyl]-4-yl)sulfonyl]- 1 ,3- th iazolidine-2-carboxamide
7V-[ 1 -(2-furyl)-3-hydroxypropyl]-3-[(4'-methy 1[1 , 1 '-bipheny l]-4-yl)sulfony 1]- 1 ,3- thiazolidine-2-carboxamide
N-[3-(l -azepanyl)- l-phenylpropyl]-3-([l ,r-biphenyl]-4-ylsulfonyl)-l ,3-thiazolidine-2- carboxamide N-[3-(4-acetyl-l -piperazinyl)- 1 -phenylpropy l]-3-([ 1 ,1 '-biphenyl]-4-y Isulfony 1)- 1,3- thiazolidine-2-carboxamide
TV-[3-(4-benzyl-4-hydroxy- 1 -piperidinyl)- 1 -phenylpropy l]-3-([ 1 , 1 '-biphenyl]-4- ylsulfonyl)- 1 ,3-thiazolidine-2-carboxamide
N-[3-(acetylamino)-l-phenylρropyl]-3-([l ,l'-biphenyl]-4-ylsulfonyl)-l ,3-thiazolidine-
2-carboxamide
N-[3-(benzy lam ino)-l -phenylpropy l]-3-([ 1 , 1 '-biphenyl]-4-ylsulfonyl)- 1 ,3-thiazolidine- 2-carboxamide
N-[4-({[(hexylamino)carbonyl]amino}methyl)benzyl]-3-(phenylsulfonyl)-l ,3-thia- zolidine-2-carboxamide
N-[4-({[(hexylamino)carbonyl]amino}methyl)benzyl]-3-{[5-(3-isoxazolyl)-2-thienyl]- sulfonyI}- l ,3-thiazolidine-2-carboxamide
7V-{3-[( 1 -adamanty lmethy l)amino]-l -phenylpropy l}-3-([l ,l'-biphenyl]-4-ylsulfonyl)- 1 ,3-thiazolidine-2-carboxamide
N-{3-[(27?)-2-(anilinomethyl)pyrrolidinyl]-l -phenylpropyl}-3-([l ,r-biphenyl]-4- ylsulfonyl)- 1 ,3-thiazolidine-2-carboxamide
N-{3-[(2lS)-2-(anilinomethyl)pyrrolidinyl]-l -phenylpropyl}-3-([l , r-biphenyl]-4- ylsulfonyl)- 1 ,3-thiazolidine-2-carboxamide
TV- {3-[benzyl(2-hydroxyethyl)amino]-l -pheny lpropyl}-3-([l , l '-biphenyl]-4-yl- sulfonyl)- 1 ,3-thiazolidine-2-carboxamide
TV- {3-[benzyl(methy l)amino]- 1 -phenylpropyl}-3-([l , 1 '-bipheny l]-4-ylsulfony 1)- 1 ,3- thiazolidine-2-carboxamide N-{4-[({[(2-ethylhexyl)amino]carbonyl}amino)methyl]benzyl}-3-[(4-iodophenyl)- sulfonyl]- 1 ,3-thiazolidine-2-carboxamide
TV-benzhydryl-3-([ 1 , 1 '-bipheny l]-4-ylsulfonyl)- 1 ,3-thiazolidine-2-carboxamide
N-benzhydryl-3-(8-quinolinylsulfonyl)-l ,3-thiazolidine-2-carboxamide
N-benzyl{3-[(4-tert-butylphenyl)sulfonyl]-l ,3-thiazolidin-2-yl}methanamine
N-benzyl-3-([ 1 , 1 '-biphenyl]-4-y Isulfonyl)- 1 ,3-thiazolidine-2-carboxamide
N-benzyl-3-[(4-fer^butylphenyl)sulfonyl]-l,3-thiazolidine-2-carboxamide
tert-butyl 3-{[({3-[(4-/ert-butylphenyl)sulfonyl]- l ,3-thiazolidin-2-yl}carbonyl)amino]- methyl} pheny lcarbamate
tert-butyl 5-{2-[({3-[(4-tert-butylphenyl)sulfonyl]-l ,3-thiazolidin-2-yl}carbonyl)- amino]ethyl}-2-pyridinylcarbamate
(3S)-3-({[(2S)-3-(biphenyl-4-ylsulfonyl)-l,3-thiazolidin-2-yl]carbonyl}amino)-3-(2,6- difluorophenyl)propyl L-valinate
(3S)-3-(2,6-difluorophenyl)-3-[({(2S)-3-[(2'-fluorobiphenyl-4-yl)sulfonyl]-l ,3- thiazolidin-2-yl}carbonyl)amino]propyl L-valinate
(3S)-3-({[(2S)-3-(biphenyl-4-ylsulfonyl)- l ,3-thiazolidin-2-yl]carbonyl}amino)-3- phenylpropyl L-valinate
(3S)-3-[({(2S)-3-[(2*-fluorobiphenyl-4-yl)sulfonyl]-l ,3-thiazolidin-2- yl}carbonyl)amino]-3-phenylpropyl L-valinate
(2S)-3-(biphenyl-4-ylsulfonyl)-N-[(l S)-l-(4-fluorophenyl)-3-hydroxypropyl]- 1,3- thiazolidine-2-carboxamide 3-({[(3S)-3-({[3-(biphenyl-4-ylsulfonyl)-l ,3-thiazolidin-2-yl]carbonyl}amino)-3- phenylpropyl]amino} sulfonyl)benzoic acid
(2S)-N-[(l S)-l-(2,6-difluorophenyl)-3-hydroxypropyl]-3-[(2'-fluorobiphenyl-4- yl)sulfonyl]- 1 ,3-thiazolidine-2-carboxamide
(2S)-3-[(2'-fluorobiphenyl-4-yl)sulfonyl]-N-[(R)-phenyl(pyridin-2-yl)methyl]-l ,3- thiazolidine-2-carboxamide
(2S)-3-[(2'-fluorobiphenyl-4-yl)sulfonyl]-N-[(S)-(l-methylpiperidin-4- yl)(phenyl)methyl]- 1 ,3-thiazoIidine-2-carboxamide
3-(biphenyl-4-ylsulfonyl)-N-[(2-chloropyridin-4-yl)(phenyl)methyl]-l ,3-thiazolidine- 2-carboxamide
3-(biphenyl-4-ylsulfonyl)-N-[(6-hydroxypyridin-3-yl)(phenyl)methyl]-l ,3- thiazolidine-2-carboxamide
(2S)-3-[(2'-fluorobiphenyl-4-yl)sulfonyl]-N-[(R)-phenyl(pyridin-4-yl)methyl]-l ,3- thiazolidine-2-carboxamide
(2S)-3-[(4-iodophenyl)sulfonyl]-N-[(R)-phenyl(pyridin-2-yl)methyl]- 1 ,3-thiazolidine-
2-carboxamide
3-(biphenyl-4-ylsulfonyl)-N-[[5-(2-hydroxyethyl)-l ,2,4-oxadiazol-3- yl](phenyl)methyl]- 1 ,3-thiazolidine-2-carboxamide
methyl 2-methyl-2-(4-{[2-({[(R)-phenyl(pyridin-2-yl)methyl]amino}carbonyl)- l ,3- thiazolidin-3-yl]sulfonyl}phenyl)propanoate
3-(biphenyl-4-ylsulfonyl)-N-[(6-chloropyridin-3-yl)(phenyl)methyl]- l ,3-thiazolidine- 2-carboxamide (2S)-3-(biphenyl-4-ylsulfonyl)-N-{(l S)-3-[methyl(methylsulfonyl)amino]-l- phenylpropyl}-l ,3-thiazolidine-2-carboxamide
3-{[4-(2-fluoro-l ,l-dimethylethyl)phenyl]sulfonyl}-N-[(R)-phenyl(pyridin-2- yl)methyl]- 1 ,3-thiazolidine-2-carboxamide
(2S)-3-[(4-bromophenyl)sulfonyl]-N-[(R)-phenyl(pyridin-2-yl)methyl]- 1 ,3- thiazolidine-2-carboxamide
(3S)-3-phenyl-3-[({(2S)-3-[(4-vinylphenyl)sulfonyl]-l ,3-thiazolidin-2- yl}carbonyl)amino]propyl L-valinate
3-(biphenyl-4-ylsulfonyl)-N-[{5-[2-(dimethylamino)ethoxy]pyridin-2- yl}(phenyl)methyl]-l ,3-thiazolidine-2-carboxamide
3-(biphenyl-4-ylsulfonyl)-N-[[6-(dimethylamino)pyridin-3-yl](phenyl)methyl]- l ,3- thiazolidine-2-carboxamide
3-(biphenyl-4-ylsulfonyl)-N-[phenyl(l -L-valylpiperidin-4-yl)methyl]-l ,3-thiazolidine- 2-carboxamide
14. A thiazolidine carboxamide derivative according to any of claims 5 to 13 for use as a medicament.
15. A pharmaceutical composition containing at least one thiazolidine carboxamide derivative according to any of claims 5 to 13 and a pharmaceutically acceptable carrier, diluent or excipient thereof.
16. A method of preparing a thiazolidine carboxamide derivative of formula (la) according to any of claims 6 to 13, comprising the following step :
Figure imgf000184_0001
VI
wherein PG, G', R1, R2, R4, m and n are as above-defined.
17. A method of preparing a thiazolidine carboxamide derivative of formula (la) according to any of claims 6 to 13, comprising the following step:
Peptide coupling
Figure imgf000184_0002
Figure imgf000184_0003
VIII IV
wherein G', R1, R2, R4, m and n are as above-defined.
18. An intermediate compound of the formula Va,
PG
wherein PG is H, R2, R4, n and m are as defined in any of claims 6 to 13, with the proviso that R" may not be a hydrogen.
9. An intermediate compound ofthe formula VIII,
Figure imgf000185_0001
wherein R! is a 1 , 1 ' -biphenyl or a tert-butyl phenyl moiety and R and n are as defined in any of claims 6 to 13.
PCT/EP2003/050083 2002-03-28 2003-03-27 Thiazolidine carboxamide derivatives as modulators of the prostaglandin f receptor WO2003082278A1 (en)

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* Cited by examiner, † Cited by third party
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WO2005100519A1 (en) * 2004-04-09 2005-10-27 Archer-Daniels-Midland Company Method of preparing fatty acid alkyl esters from waste or recycled fatty acid stock
US7176222B2 (en) 2004-07-27 2007-02-13 Cytokinetics, Inc. Syntheses of ureas
US7399866B2 (en) 2003-01-14 2008-07-15 Cytokinetics, Inc. Compounds, compositions, and methods
US7718657B2 (en) 2005-12-16 2010-05-18 Cytokinetics, Inc. Certain indanyl urea modulators of the cardiac sarcomere
US7825120B2 (en) 2005-12-15 2010-11-02 Cytokinetics, Inc. Certain substituted ((piperazin-1-ylmethyl)benzyl)ureas
US7989455B2 (en) 2005-12-19 2011-08-02 Cytokinetics, Inc. Compounds, compositions and methods
US8101617B2 (en) 2004-06-17 2012-01-24 Amgen, Inc. Disubstituted ureas and uses thereof in treating heart failure
EP2459187A1 (en) * 2009-07-29 2012-06-06 Duke University Compositions and methods for inhibiting hair growth
US8415480B2 (en) 2002-03-28 2013-04-09 Merck Serono Sa Thiazolidine carboxamide derivatives as modulators of the prostaglandin F receptor
US8445495B2 (en) 2005-12-15 2013-05-21 Cytokinetics, Inc. Certain Chemical entities, compositions and methods
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US8778941B2 (en) 2011-06-24 2014-07-15 Amgen Inc. TRPM8 antagonists and their use in treatments
US8952009B2 (en) 2012-08-06 2015-02-10 Amgen Inc. Chroman derivatives as TRPM8 inhibitors
WO2015060368A1 (en) 2013-10-23 2015-04-30 武田薬品工業株式会社 Heterocyclic compound
US9145380B2 (en) 2007-12-20 2015-09-29 Astrazeneca Ab Bis-(sulfonylamino) derivatives for use in therapy
US9447055B1 (en) 2016-01-04 2016-09-20 Merck Serono S.A. α-amino esters of hydroxypropylthiazolidine carboxamide derivative and salt form, crystal polymorph thereof
WO2017118641A1 (en) * 2016-01-04 2017-07-13 Merck Serono S.A. L-valinate of hydroxypropylthiazolidine carboxamide derivative and salt form, crystal polymorph thereof
US20190000812A1 (en) * 2016-01-04 2019-01-03 ObsEva S.A. Alpha-amino esters of hydroxypropylthiazolidine carboxamide derivative and salt form, crystal polymorph thereof
EP3560917A4 (en) * 2016-12-22 2019-11-20 Guangzhou Chinaray Optoelectronic Materials Ltd. Polymer containing furan crosslinking group and use thereof
EA039545B1 (en) * 2016-10-13 2022-02-09 Обсева С.А. Methods of preventing preterm labor using a combination of a pgf2 inhibitor and a tocolytic agent
US11534428B1 (en) 2018-05-16 2022-12-27 Xoma (Us) Llc Compositions and methods for delaying the incidence of labor

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103755737A (en) * 2006-02-07 2014-04-30 株式会社·R-技术上野 Method for preparing prostaglandin derivative
EP4243817A1 (en) 2020-11-16 2023-09-20 Xoma (Us) Llc Compositions and methods for the treatment or prevention of preterm labor
WO2022125876A1 (en) * 2020-12-11 2022-06-16 Olsen Elise A Compositions and methods for inhibiting hair growth

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5338755A (en) * 1990-07-31 1994-08-16 Elf Sanofi N-sulfonylindoline derivatives, their preparation and the pharmaceutical compositions in which they are present
WO1998008822A1 (en) * 1996-08-28 1998-03-05 The Procter & Gamble Company 1,3-diheterocyclic metalloprotease inhibitors
WO1999006390A1 (en) * 1997-07-31 1999-02-11 Elan Pharmaceuticals, Inc. Carbamyloxy compounds which inhibit leukocyte adhesion mediated by vla-4

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4016270A (en) * 1975-10-31 1977-04-05 Alza Corporation Method for treating dysmenorrhea with a uterine therapeutic system
JPH0662529B2 (en) * 1984-07-13 1994-08-17 三共株式会社 Amino acid derivative
JPS6450818A (en) * 1987-08-20 1989-02-27 Tsumura & Co Prostaglandin f2alpha-inhibitor
US6271201B1 (en) * 1993-07-15 2001-08-07 Board Of Regents, The University Of Texas System Methods for the selective regulation of placental prostanoids and inhibition of labor using IGF-I
KR20010022413A (en) * 1997-07-31 2001-03-15 진 엠. 듀발 Benzyl compounds which inhibit leukocyte adhesion mediated by VLA-4
US6645939B1 (en) * 1997-11-24 2003-11-11 Merck & Co., Inc. Substituted β-alanine derivatives as cell adhesion inhibitors
ZA200406763B (en) * 2002-03-28 2005-09-30 Applied Research Systems Thiazolidine carboxamide derivatives as modulatorsof the prostaglandin F receptor.

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5338755A (en) * 1990-07-31 1994-08-16 Elf Sanofi N-sulfonylindoline derivatives, their preparation and the pharmaceutical compositions in which they are present
WO1998008822A1 (en) * 1996-08-28 1998-03-05 The Procter & Gamble Company 1,3-diheterocyclic metalloprotease inhibitors
WO1999006390A1 (en) * 1997-07-31 1999-02-11 Elan Pharmaceuticals, Inc. Carbamyloxy compounds which inhibit leukocyte adhesion mediated by vla-4

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8415480B2 (en) 2002-03-28 2013-04-09 Merck Serono Sa Thiazolidine carboxamide derivatives as modulators of the prostaglandin F receptor
US7399866B2 (en) 2003-01-14 2008-07-15 Cytokinetics, Inc. Compounds, compositions, and methods
US7491826B2 (en) 2003-01-14 2009-02-17 Cytokinetics, Inc. Compounds, compositions and methods
WO2005100519A1 (en) * 2004-04-09 2005-10-27 Archer-Daniels-Midland Company Method of preparing fatty acid alkyl esters from waste or recycled fatty acid stock
US7705170B2 (en) 2004-04-09 2010-04-27 Archer-Daniels-Midland Company Method of preparing fatty acid alkyl esters from waste or recycled fatty acid stock
US8871769B2 (en) 2004-06-17 2014-10-28 Cytokinetics, Inc. Ureas and their use in the treatment of heart failure
US8513257B2 (en) 2004-06-17 2013-08-20 Cytokinetics, Incorporated Ureas and their use in the treatment of heart failure
US9643925B2 (en) 2004-06-17 2017-05-09 Cytokinetics, Incorporated Compounds, compositions and methods
US8101617B2 (en) 2004-06-17 2012-01-24 Amgen, Inc. Disubstituted ureas and uses thereof in treating heart failure
US8110595B2 (en) 2004-06-17 2012-02-07 Cytokinetics, Inc. Ureas and their use in the treatment of heart failure
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US10385023B2 (en) 2004-06-17 2019-08-20 Cytokinetics, Inc. Compounds, compositions and methods
US10035770B2 (en) 2004-06-17 2018-07-31 Cytokinetics, Incorporated Compounds, compositions and methods
US9150564B2 (en) 2004-06-17 2015-10-06 Cytokinetics, Inc. Compounds, compositions and methods
US7176222B2 (en) 2004-07-27 2007-02-13 Cytokinetics, Inc. Syntheses of ureas
US8445495B2 (en) 2005-12-15 2013-05-21 Cytokinetics, Inc. Certain Chemical entities, compositions and methods
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US7825120B2 (en) 2005-12-15 2010-11-02 Cytokinetics, Inc. Certain substituted ((piperazin-1-ylmethyl)benzyl)ureas
US8653081B2 (en) 2005-12-16 2014-02-18 Cytokinetics, Inc. Certain chemical entities, compositions, and methods
US8410108B2 (en) 2005-12-16 2013-04-02 Cytokinetics, Inc. Certain chemical entities, compositions and methods
US7718657B2 (en) 2005-12-16 2010-05-18 Cytokinetics, Inc. Certain indanyl urea modulators of the cardiac sarcomere
US7989455B2 (en) 2005-12-19 2011-08-02 Cytokinetics, Inc. Compounds, compositions and methods
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US20120245205A1 (en) * 2009-07-29 2012-09-27 Delong Mitchell A Compositions and methods for inhibiting hair growth
US10159634B2 (en) 2009-07-29 2018-12-25 Elise A. Olsen Compositions and methods for inhibiting hair growth
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US8778941B2 (en) 2011-06-24 2014-07-15 Amgen Inc. TRPM8 antagonists and their use in treatments
US9096527B2 (en) 2011-06-24 2015-08-04 Amgen Inc. TRPM8 antagonists and their use in treatments
US8710043B2 (en) 2011-06-24 2014-04-29 Amgen Inc. TRPM8 antagonists and their use in treatments
US8952009B2 (en) 2012-08-06 2015-02-10 Amgen Inc. Chroman derivatives as TRPM8 inhibitors
WO2015060368A1 (en) 2013-10-23 2015-04-30 武田薬品工業株式会社 Heterocyclic compound
US20190000812A1 (en) * 2016-01-04 2019-01-03 ObsEva S.A. Alpha-amino esters of hydroxypropylthiazolidine carboxamide derivative and salt form, crystal polymorph thereof
AU2017205670B2 (en) * 2016-01-04 2021-05-20 Merck Serono S.A. L-valinate of hydroxypropylthiazolidine carboxamide derivative and salt form, crystal polymorph thereof
US10259795B2 (en) 2016-01-04 2019-04-16 Merck Serono S.A. Alpha-amino esters of hydroxypropylthiazolidine carboxamide derivative and salt form, crystal polymorph thereof
US9447055B1 (en) 2016-01-04 2016-09-20 Merck Serono S.A. α-amino esters of hydroxypropylthiazolidine carboxamide derivative and salt form, crystal polymorph thereof
JP7377588B2 (en) 2016-01-04 2023-11-10 オブセヴァ エス．エー． Alpha-amino esters of hydroxypropylthiazolidine carboxamide derivatives and their salt forms and crystal polymorphs
US10555934B2 (en) 2016-01-04 2020-02-11 ObsEva S.A. Alpha-amino esters of hydroxypropylthiazolidine carboxamide derivative and salt form, crystal polymorph thereof
EA036990B1 (en) * 2016-01-04 2021-01-25 Мерк Сероно С.А. (3s)-3-({[(2s)-3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}amino)-3-(4-fluorophenyl)propyl l-valinate and salt form, crystal polymorph thereof
IL260286A (en) * 2016-01-04 2018-07-31 ObsEva SA Alpha-amino esters of hydroxypropylthiazolidine carboxamide derivative and salt form, crystal polymorph thereof
AU2017205254B2 (en) * 2016-01-04 2021-05-20 Xoma (Us) Lcc Alpha-amino esters of hydroxypropylthiazolidine carboxamide derivative and salt form, crystal polymorph thereof
WO2017118639A1 (en) * 2016-01-04 2017-07-13 ObsEva S.A. Alpha-amino esters of hydroxypropylthiazolidine carboxamide derivative and salt form, crystal polymorph thereof
US9834528B2 (en) 2016-01-04 2017-12-05 Merck Serono S.A. Alpha-amino esters of hydroxypropylthiazolidine carboxamide derivative and salt form, crystal polymorph thereof
AU2021218009B2 (en) * 2016-01-04 2023-06-22 Merck Serono S.A. L-valinate of hydroxypropylthiazolidine carboxamide derivative and salt form, crystal polymorph thereof
WO2017118641A1 (en) * 2016-01-04 2017-07-13 Merck Serono S.A. L-valinate of hydroxypropylthiazolidine carboxamide derivative and salt form, crystal polymorph thereof
EP4144351A1 (en) * 2016-01-04 2023-03-08 ObsEva S.A. Hydroxypropylthiazolidine carboxamide derivatives as inhibitors of the prostaglandin f receptor
US11524003B2 (en) 2016-01-04 2022-12-13 ObsEva S.A. Alpha-amino esters of hydroxypropylthiazolidine carboxamide derivative and salt form, crystal polymorph thereof
EP4140988A1 (en) * 2016-01-04 2023-03-01 Merck Serono S.A. L-valinate of hydroxypropylthiazolidine carboxamide derivative and salt form, crystal polymorph thereof
EA039545B1 (en) * 2016-10-13 2022-02-09 Обсева С.А. Methods of preventing preterm labor using a combination of a pgf2 inhibitor and a tocolytic agent
US11289654B2 (en) 2016-12-22 2022-03-29 Guangzhou Chinaray Optoelectronic Materials Ltd. Polymers containing furanyl crosslinkable groups and uses thereof
EP3560917A4 (en) * 2016-12-22 2019-11-20 Guangzhou Chinaray Optoelectronic Materials Ltd. Polymer containing furan crosslinking group and use thereof
US11534428B1 (en) 2018-05-16 2022-12-27 Xoma (Us) Llc Compositions and methods for delaying the incidence of labor

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EP1487442B1 (en) 2010-12-01
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US20080255094A1 (en) 2008-10-16
PL372919A1 (en) 2005-08-08
DE60335175D1 (en) 2011-01-13
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US20090215749A9 (en) 2009-08-27
EA007328B1 (en) 2006-08-25
ATE489951T1 (en) 2010-12-15
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EA200401270A1 (en) 2005-02-24
US8415480B2 (en) 2013-04-09

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