US20050215605A1 - Thiazolidine carboxamide derivatives as modulators of the prostaglandin f receptor - Google Patents
Thiazolidine carboxamide derivatives as modulators of the prostaglandin f receptor Download PDFInfo
- Publication number
- US20050215605A1 US20050215605A1 US10/508,014 US50801405A US2005215605A1 US 20050215605 A1 US20050215605 A1 US 20050215605A1 US 50801405 A US50801405 A US 50801405A US 2005215605 A1 US2005215605 A1 US 2005215605A1
- Authority
- US
- United States
- Prior art keywords
- thiazolidine
- carboxamide
- biphenyl
- ylsulfonyl
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
-
- 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 of the prostaglandin receptors, particularly of the prostaglandin F 2 ⁇ receptor.
- the present invention is related to novel thiazolidine carboxamide derivatives of formulae (I) and (Ia).
- 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.
- 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:
- 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 binding protein
- 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 of the eicosanoids.
- Prostaglandins (PGs) mediate various physiological processes such as fever generation and inflammation. Aspirin and related drugs act through inhibition of PG biosynthesis.
- 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.
- PGF 2 ⁇ is a major prostaglandin for enhancing uterine contractility.
- EP 1 , EP 2 , EP 4 and FP Specific prostaglandin receptors
- EP 2 and EP 4 receptors results in smooth muscle relaxation whereas activation of the PGF 2 ⁇ -selective receptor (FP receptor) results in contraction.
- the prostaglandin F 2 ⁇ receptor acts via a G protein-coupled receptor, coupled to activation of phospholipase C and increases in IP 3 that release Ca 2+ from intracellular stores. The increases in intracellular calcium that ensue lead to increased contraction of smooth muscle via activation of myosin light chain kinase.
- mice lacking the FP receptor have normal fertility but no labor at term. However healthy pups were delivered by cesarean cut.
- PGF 2 ⁇ is in reproductive biology as a luteolytic agent.
- increased pulsatile serum levels of PGF 2 ⁇ cause apoptotic cell death of the granulosam lutein cells ( Res. Reprod. 16:1-2 (1984) by McCracken).
- 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
- Tsumura & Co proposed prostaglandin F 2 ⁇ 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).
- a phtalide derivative as an active component
- the present invention relates to the use of thiazolidine carboxamide derivatives of formula (II), 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 of the prostaglandin F 2 ⁇ 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 of the 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 of the 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.
- C 1 -C 6 -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.
- C 1 -C 6 -alkyl aryl refers to C 1 -C 6 -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-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl,
- C 1 -C 6 -alkyl heteroaryl refers to C 1 -C 6 -alkyl groups having a heteroaryl substituent, including 2-furylmethyl, 2-thienylmethyl, 2-(1H-indol-3-yl)ethyl and the like.
- C 2 -C 6 -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 ⁇ CH 2 ), n-2-propenyl (allyl, —CH 2 CH ⁇ CH 2 ) and the like.
- C 2 -C 6 -alkenyl aryl refers to C 2 -C 6 -alkenyl groups having an aryl substituent, including 2-phenylvinyl and the like.
- C 2 -C 6 -alkenyl heteroaryl refers to C 2 -C 6 -alkenyl groups having a heteroaryl substituent, including 2-(3-pyridinyl)vinyl and the like.
- C 2 -C 6 -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), propargyl (—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 -C 6 -alkynyl heteroaryl refers to C 2 -C 6 -alkynyl groups having a heteroaryl substituent, including 2-thienylethynyl and the like.
- C 3 -C 8 -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 3 -C 8 -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 1 -C 6 -alkyl cycloalkyl refers to C 1 -C 6 -alkyl groups having a cycloalkyl substituent, including cyclohexylmethyl, cyclopentylpropyl, and the like.
- C 1 -C 6 -alkyl heterocycloalkyl refers to C 1 -C 6 -alkyl groups having a heterocycloalkyl substituent, including 2-(1-pyrrolidinyl)ethyl, 4-morpholinylmethyl, (1-methyl-4-piperidinyl)methyl and the like.
- Carboxy refers to the group —C(O)OH.
- C 1 -C 5 -alkyl carboxy refers to C 1 -C 5 -alkyl groups having an carboxy substituent, including 2-carboxyethyl and the like.
- “Acyl” refers to the group —C(O)R where R includes “C 1 -C 6 -alkyl”, “aryl”, “heteroaryl”,
- C 1 -C 6 -alkyl aryl or “C I—C 6 -alkyl heteroaryl”.
- C 1 -C 5 -alkyl acyl refers to C 1 -C 5 -alkyl groups having an acyl substituent, including 2-acetylethyl and the like.
- “Acyloxy refers to the group —OC(O)R where R includes “C 1 -C 6 -alkyl”, “aryl”, “hetero-aryl”, “C 1 -C 6 -alkyl aryl” or “C 1 -C 6 -alkyl heteroaryl”
- C 1 -C 5 -alkyl acyloxy refers to C 1 -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 “C 1 -C 6 -alkyl” or “aryl” or “hetero-aryl” or “C 1 -C 6 -alkyl aryl” or “C 1 -C 6 -alkyl heteroaryl”.
- Preferred alkoxy groups include by way of example, methoxy, ethoxy, phenoxy and the like.
- C 1 -C 5 -alkyl alkoxy refers to C 1 -C 5 -alkyl groups having an alkoxy substituent, including 2-ethoxyethyl and the like.
- Alkoxycarbonyl refers to the group C(O)OR where R includes H, “C 1 -C 6 -alkyl” or “aryl” or “heteroaryl” or “C 1 -C 6 -alkyl aryl” or “C 1 -C 6 -alkyl heteroaryl”.
- C 1 -C 5 -alkyl alkoxycarbonyl refers to C 1 -C 5 -alkyl groups having an alkoxycarbonyl substituent, including 2-(benzyloxycarbonyl)ethyl and the like.
- Aminocarbonyl refers to the group —C(O)NRR′ where each R, R′ includes independently hydrogen or C 1 -C 6 -alkyl or aryl or heteroaryl or “C 1 -C 6 -alkyl aryl” or “C 1 -C 6 -alkyl hetero-aryl”.
- C 1 -C 5 -alkyl aminocarbonyl refers to C 1 -C 5 -alkyl groups having an aminocarbonyl substituent, including 2-(dimethylaminocarbonyl)ethyl and the like.
- “Acylamino” refers to the group —NRC(O)R′ where each R, R′ is independently hydrogen or “C 1 -C 6 -alkyl” or “aryl” or “heteroaryl” or “C 1 -C 6 -alkyl aryl” or “C 1 -C 6 -alkyl heteroaryl”.
- C 1 -C 5 -alkyl acylamino refers to C 1 -C 5 -alkyl groups having an acylamino substituent, including 2-(propionylamino)ethyl and the like.
- “Ureido” refers to the group —NRC(O)NR′R′′ where each R, R′, R′′ is independently hydrogen or “C 1 -C 6 -alkyl” or “aryl” or “heteroaryl” or “C 1 -C 6 -alkyl aryl” or “C 1 -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 hetero-cycloalkyl ring.
- C 1 -C 5 -alkyl ureido refers to C 1 -C 5 -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 1 -C 6 -alkyl” or “aryl” or “heteroaryl” or “C 1 -C 6 -alkyl aryl” or “C 1 -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.
- C 1 -C 5 -alkyl amino refers to C 1 -C 5 -alkyl groups having an amino substituent, including 2-(1-pyrrolidinyl)ethyl and the like.
- Ammonium refers to a positively charged group —N + RR′R′′, where each R,R′,R′′ is independently “C 1 -C 6 -alkyl” or “C 1 -C 6 -alkyl aryl” or “C 1 -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 —OSO 2 —R wherein R is selected from H, “C I—C 6 -alkyl”, “C 1 -C 6 -alkyl” substituted with halogens, e.g., an —OSO 2 —CF 3 group, “aryl”, “heteroaryl”, “C 1 -C 6 -alkyl aryl” or “C 1 -C 6 -alkyl heteroaryl”.
- C 1 -C 5 -alkyl sulfonyloxy refers to C 1 -C 5 -alkyl groups having a sulfonyloxy substituent, including 2-(methylsulfonyloxy)ethyl and the like.
- “Sulfonyl” refers to group “—SO 2 —R” wherein R is selected from H, “aryl”, “heteroaryl”, “C 1 -C 6 -alkyl”, “C 1 -C 6 -alkyl” substituted with halogens, e.g., an —SO 2 —CF 3 group, “C 1 -C 6 -alkyl aryl” or “C 1 -C 6 -alkyl heteroaryl”.
- C 1 -C 5 -alkyl sulfonyl refers to C 1 -C 5 -alkyl groups having a sulfonyl substituent, including 2-(methylsulfonyl)ethyl and the like.
- “Sulfinyl” refers to a group “—S(O)—R” wherein R is selected from H, “C 1 -C 6 -alkyl”, “C 1 -C 6 -alkyl” substituted with halogens, e.g., an —SO—CF 3 group, “aryl”, “heteroaryl”, “C 1 -C 6 -alkyl aryl” or “C 1 -C 6 -alkyl heteroaryl”.
- C 1 -C 5 -alkyl sulfinyl refers to C 1 -C 5 -alkyl groups having a sulfinyl substituent, including 2-(methylsulfinyl)ethyl and the like.
- “Sulfanyl” refers to groups —S—R where R includes “C 1 -C 6 -alkyl” or “aryl” or “hetero-aryl” or “C 1 -C 6 -alkyl aryl” or “C 1 -C 6 -alkyl heteroaryl”.
- Preferred sulfanyl groups include methylsulfanyl, ethylsulfanyl, and the like.
- C 1 -C 5 -alkyl sulfanyl refers to C 1 -C 5 -alkyl groups having a sulfanyl substituent, including 2-(ethylsulfanyl)ethyl and the like.
- “Sulfonylamino” refers to a group —NRSO 2 —R′ where each R, R′ is independently hydrogen or “C 1 -C 6 -alkyl” or “aryl” or “heteroaryl” or “C 1 -C 6 -alkyl aryl” or “C 1 -C 6 -alkyl heteroaryl”.
- C 1 -C 5 -alkyl sulfonylamino refers to C 1 -C 5 -alkyl groups having a sulfonylamino substituent, including 2-(ethylsulfonylamino)ethyl and the like.
- groups can optionally be substituted with from 1 to 5 substituents selected from the group consisting of “C 1 -C 6 -alkyl”, “C 2 -C 6 -alkenyl”, “C 2 -C 6 -alkynyl”, “cyclo-alkyl”, “heterocycloalkyl”, “C 1 -C 6 -alkyl aryl”, “C 1 -C 6 -alkyl heteroaryl”, “C 1 -C 6 -alkyl cycloalkyl”, “C 1 -C 6 -alkyl heterocycloalkyl”, “amino”, “ammonium”, “acyl”, “acyloxy”, “acylamino”, “aminocarbonyl”, “alkoxycarbonyl”, “ureido”, “aryl”, “heteroaryl”, “sulfinyl”, “sulfonyl”, “alkoxy”, “sulfanyl”, “halogen”, “carboxy”, trihalomethyl, cyan
- 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 of the 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 formed 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, ni
- 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 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkyl aryl, C 1 -C 6 -alkyl heteroaryl, cycloalkyl, heterocycloalkyl, and Z is a counterion, including chloride, bromide, iodide, —O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, fumarate,
- “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 synthesis, 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 of the 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) 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.
- G is selected from the group consisting of substituted or unsubstituted C 1 -C 6 -alkyl aryl, substituted or unsubstituted C 1 -C 6 -alkyl heteroaryl, substituted or unsubstituted C 1 -C 6 -alkyl cycloalkyl, substituted or unsubstituted C 1 -C 6 -alkyl heteroaryl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 3 -C 8 -cycloalkyl or -heterocycloalkyl, said cycloalkyl or aryl or heteroaryl groups may be fused with cycloalkyl or aryl or heteroaryl groups.
- R 1 is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 3 -C 8 -cycloalkyl or -heterocycloalkyl, said (hetero)cycloalkyl or aryl or heteroaryl groups may be fused with (hetero)-cycloalkyl or aryl or heteroaryl groups.
- R 2 is H, carboxy, acyl, alkoxycarbonyl, aminocarbonyl, substituted or unsubstituted C 1 -C 5 -alkyl carboxy, substituted or unsubstituted C 1 -C 5 -alkyl acyl, substituted or unsubstituted C 1 -C 5 -alkyl alkoxycarbonyl, substituted or unsubstituted C 1 -C 5 -alkyl aminocarbonyl, substituted or unsubstituted C 1 -C 5 -alkyl acyloxy, substituted or unsubstituted C 1 -C 5 -alkyl acylamino, substituted or unsubstituted C 1 -C 5 -alkyl ureido, substituted or unsubstituted C 1 -C 5 -alkyl amino, substituted or unsubstituted C 1 -C 5 -alkyl alkoxy, substituted or unsubstitute
- R 2 and G may form a C 3 -C 8 -cycloalkyl ring.
- R 4 is selected from the group consisting of substituted or unsubstituted C 1 -C 6 -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 of the activity of prostaglandins and particularly prostaglandin F 2 ⁇ . 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 F 2 ⁇ . Said treatment involves the modulation—notably the inhibition or the down regulation—of the prostaglandin function.
- a further aspect of the 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 C 3 -C 8 -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 (Ia):
- Formulae (I), (Ia) 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 -C 8 -cycloalkyl or -heterocycloalkyl, said (hetero)cycloalkyl or aryl or heteroaryl groups may be fused with (hetero)cycloalkyl 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 1 -C 6 -alkyl.
- R 2 is selected from the group consisting of H, carboxy, acyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted C 1 -C 5 -alkyl carboxy, substituted or unsubstituted C 1 -C 5 -alkyl acyl, substituted or unsubstituted C 1 -C 5 -alkyl alkoxycarbonyl, substituted or unsubstituted C 1 -C 5 -alkyl aminocarbonyl, substituted or unsubstituted C 1 -C 5 -alkyl acyloxy, substituted or unsubstituted C 1 -C 5 -alkyl acylamino, substituted or unsubstituted C 1 -C 5 -alkyl ureido, substituted or unsubstituted C 1 -C 5 -alkyl amino, substituted or unsubstit
- R 2 is selected from the group consisting of carboxy, acyl, substituted or unsubstituted alkoxycarbonyl, aminocarbonyl, substituted or unsubstituted C 1 -C 5 -alkyl carboxy, substituted or unsubstituted C 1 -C 5 -alkyl acyl, substituted or unsubstituted C 1 -C 5 -alkyl alkoxycarbonyl, substituted or unsubstituted C 1 -C 5 -alkyl aminocarbonyl, substituted or unsubstituted C 1 -C 5 -alkyl acyloxy, substituted or unsubstituted C 1 -C 5 -alkyl acylamino, substituted or unsubstituted C 1 -C 5 -alkyl ureido, substituted or unsubstituted C 1 -C 5 -alkyl amino, substituted or unsubstituted C 1 -C 5 -al
- R 2 may be a group C 1 -C 3 -alkyl-A-R 5 , wherein:
- A is O or N-B-R 6 .
- B is a bond, an amino acid residue (e.g. alanine, phenylalanine, valine, leucine, isoleucine, proline, glycine, methionine, tryptophane, threonine, serine, etc.), (C ⁇ O), (C ⁇ O)—O, (C ⁇ O)—NR 7 , or SO 2 .
- 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 1 -C 6 -alkyl, substituted or unsubstituted C 2 -C 6 -alkenyl, substituted or unsubstituted C 2 -C 6 -alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 3 -C 8 -cycloalkyl or heterocycloalkyl, substituted or unsubstituted C 1 -C 6 -alkyl aryl, substituted or unsubstituted C 1 -C 6 -alkyl heteroaryl, substituted or unsubstituted C 1 -C 6 -alkyl cycloalkyl, substituted or unsubstituted C 1 -C 6 -alkyl heterocycloalkyl, substituted or unsubstit
- R 5 and B-R 6 in particular if B is a bond
- R 6 and R 7 if B is (C ⁇ O)—NR 7
- 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 2 is C 1 -C 3 -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 from each other selected from the group consisting of substituted or unsubstituted C 1 -C 3 -alkyl, e.g.
- R 2 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, C 1 -C 3 -alkyl amino, C 1 -C 3 -alkyl alkoxy, C 1 -C 3 -alkyl carboxy, C 1 -C 3 -alkyl acyl, C 1 -C 3 -alkyl aminocarbonyl, C 1 -C 3 -alkyl acylamino, C 1 -C 3 -alkyl ureido, C 1 -C 3 -alkyl sulfanyl, C 1 -C 3 -alkyl sulfinyl, C 1 -C 3 -alkyl sulfonyl, C 1 -C 3 -
- substituents are methoxy, carboxy-methoxy, hydroxymethyl, carboxymethyl, sulfonyloxymethyl, dimethylaminomethyl, 4-morpholinylmethyl, 1-piperidinylmethyl, 1-pyrrolidinylmethyl, (4-methyl-1-piperazinyl)-methyl, ethoxy, 2-methoxyethoxy, 2-hydroxyethoxy, 2-carboxyethoxy, 2-sulfonyloxy-ethoxy, 2-(dimethylamino)ethoxy, 2-(4-morpholinyl)ethoxy, 2-(1-pyrrolidinyl)ethoxy, 2-(1-piperidinyl)ethoxy, 2-(4-methyl-1-piperazinyl)ethoxy, 2-hydroxyethyl, 2-methoxyethyl, 2-carboxyethyl, 2-sulfonyloxyethyl, 2-(dimethylamino)ethyl, 2-(4-morpholinyl)ethoxy
- R 3 is selected from the group consisting of substituted or unsubstituted C 1 -C 6 -alkyl, substituted or unsubstituted C 2 -C 6 -alkenyl, substituted or unsubstituted C 2 -C 6 -alkynyl, substituted or unsubstituted aryl, heteroaryl, substituted or unsubstituted C 3 -C 8 -cycloalkyl or substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted C 1 -C 6 -alkyl aryl, substituted or unsubstituted C 1 -C 6 -alkyl heteroaryl, substituted or unsubstituted C 1 -C 3 -alkyl cycloalkyl, substituted or unsubstituted C 1 -C 3 -alkyl heterocycloalkyl, substituted or unsubstituted C 2 -C 6 -alkeny
- n is an integer from 0 to 2.
- R 4 is selected from the group consisting of substituted or unsubstituted C 1 -C 6 -alkyl, substituted or unsubstituted C 2 -C 6 -alkenyl, substituted or unsubstituted C 2 -C 6 -alkynyl.
- R′ is a phenyl substituted with a group selected from straight or branched C 1 -C 5 -alkyl or aryl
- R 2 is selected from the group consisting of C 1 -C 3 -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 C 1 -C 3 -alkyl, C 1 -C 3 -alkyl aryl, C 1 -C 3 -alkyl heteroaryl, C 1 -C 3 -alkyl-hydroxy.
- R 1 is a biphenyl or a tert-butyl phenyl group
- R 2 is C 1 -C 3 -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 1 -C 3 -alkyl, C 1 -C 3 -alkyl aryl, C 1 -C 3 -alkyl heteroaryl, or C 1 -C 3 -alkyl hydroxy
- B is a bond
- R 3 is fluorine
- m is either 0, 1, or 2
- n is 0.
- R 1 is a biphenyl or a tert-butyl phenyl group
- R 2 is pyrid-2-yl, carrying one or several substituents selected from the group consisting of H, OH, alkoxy, C 1 -C 3 -alkyl amino, C 1 -C 3 -alkyl hydroxy, C 1 -C 3 -alkyl carboxy, C 1 -C 3 -alkyl sulfonyloxy
- R 3 is fluorine
- m is either 0, 1, or 2
- n is 0.
- Still a further aspect of the 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 1,3-thiazolidine-2-carboxamide derivatives according to formula (I).
- 1,3-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.
- 1,3-thiazolidine-2-carboxamide derivatives of the present invention may be obtained by several synthetic approaches, using both solution-phase and solid-phase chemistry protocols.
- 1,3-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.
- 1,3-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).
- 1,3-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 of the 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).
- 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 of the corresponding sulfonic acids (X) with chlorination agents, such as, e.g., SO 2 Cl 2 , SOCl 2 , dimethylphosgeniminium chloride, and others, or by treatment of a suitable precursor (XI) with a chlorosulfonylation reagent, such as, e.g ClSO 3 H (see Scheme 4).
- chlorination agents such as, e.g., SO 2 Cl 2 , SOCl 2 , dimethylphosgeniminium chloride, and others
- a suitable precursor (XI) such as, e.g ClSO 3 H (see Scheme 4).
- 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-1-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(0) 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 (XVIII), 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. 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 (XXXXIII′). Subsequent reduction of the oxime (XXXXIII′) 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.
- amines (IV) where R 2 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.
- 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 1,3-thiazolidine-2-carboxamide compounds (V, V′) or (I, I′).
- 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 (III*), (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 11 above.
- optically pure 1,3-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 11 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.
- the carboxylic acid intermediates (VIII) may be reacted with amines (IV) to lead to the corresponding carboxylic acid intermediate (Ia).
- the primary amide compound (Ib) was isolated after formation of the anydride mixte of the carboxylic acid compound (Ia) and treatment with an excess of ammonia. Dehydratation of the primary amide (Ib) with cyanuric chloride allow to accesse to the nitrile derivative (Ic), 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 of the final compound oxadiazole using conditions well known to the practitioner skilled in the art to yield products of general formula (I).
- 1,3-thiazolidine-2-carboxamide derivatives of general formula (I) by solution-phase methods.
- 1,3-thiazolidine-2-carboxamide derivatives of formula (I), wherein the substituents R 1 , R 2 , R 4 , 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 HOAc.
- 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 of the compounds of formula II which contain a basic center, may be prepared in a conventional manner.
- a solution of the 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 of the 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 interconverted using ion-exchange resin techniques.
- a final aspect of the 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 (Ia).
- 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.
- intermediate compound of the formula (VIII) are comprised by the present invention, wherein R′ is a 1,1′-biphenyl or a tert-butyl phenyl moiety and R 4 and n are as above defined.
- compositions comprising a compound of formula (II) and a pharmaceutically acceptable carrier, diluent or excipient therefore are also within the scope of the present invention.
- a pharmaceutically acceptable carrier, diluent or excipient therefore are also within the scope of the 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 of the 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 of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
- compositions of the 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 of the 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 incorporated materials in Remington's Pharmaceutical Sciences.
- the imine (XVIII*) resulting from the precedent step e.g. (2R)-3-methyl-2- ⁇ [(E)-2-pyridinylmethylidene]amino ⁇ -1-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, 1.1 eq) was added to the stirred solution.
- the reaction was followed by LC/MS. After 2 h30, the reaction was complete. The solvent was removed in vacuo and the residue was taken up in 500 ml Et 2 O-Cyclohexane (1:1) and the solid phase was filtered off.
- silylated imine from the previous step e.g. (2R)-3-methyl-N-[(E)-2-pyridinylmethylidene]-1-[(trimethylsilyl)oxy]-2-butanamine was dissolved in dry THF (500 ml) and the solution was cooled down to ⁇ 78° C.
- a 1M solution of phenylmagnesiumbromide in THF 200 ml, 200 mmol, 2 eq
- 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 NaHCO 3 and analysed by LC-MS to detect the O-silylated products. After one night, the mixture was quenched with HCl 1M (250 ml) and the mixture was stirred at room temperature until the desilylation was complete (after 1 h, 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.
- 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.
- [(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.
- 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 1 h30, 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
- 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 of the 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 NaHCO 3 sat. It was then dried over MgSO 4 , filtrated and evaporated.
- intermediates (XIX*); e.g., (6-chloropyridin-3-yl)(phenyl)methanone (217 mg, 1 mmol) was added together with dry THF (1.5 mL) 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.
- step b) 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-butyl 4-[(Z)-(hydroxyimino)(phenyl)methyl]piperidine-1-carboxylate in 94% yield and 97% HPLC purity. It was used in the next step without further purification.
- intermediate XVIII* e.g., tert-butyl 4-benzoylpiperidine-1-carboxylate (1,0 g, 3.46 mmol)
- XXXXIII* e.g., tert-butyl 4-[(Z)-(hydroxyimino)(phenyl)methyl]piperidine-1-carboxylate in 94% yield and 97% HPLC purity. It was used
- the oxime intermediate XXXXIII* e.g., tert-butyl 4-[(Z)-(hydroxyimino)(phenyl)methyl]piperidine-1-carboxylate, was dissolved in MeOH. Pd/C (10%) was added and the mixture was placed under 30 bar of H 2 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 Et 2 O and extracted with 3 portions of HCl 1N. Combined acidic fractions were washed with one portion of Et 2 O. It was then basified with NaOH 5N. The basic aqueous phase was extracted with 3 portions of ether.
- Protocol for the reduction of boc group into tertiary amine e.g., 1-(1-methylpiperidin-4-yl)-1-phenylmethanamine.
- the amino acid (XXV), e.g., 3-(4-fluorophenyl)- ⁇ -alanine (1 eq.) was dissolved in dry THF (30 vol.) and BH 3 .DMS (2.5eq) was added. The mixtures were then refluxed between 2 h00 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 1 h 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 SO 4 , filtered and the DCM removed. The yields of desired compounds (XXVI), e.g. 3-(4-fluorophenyl)- ⁇ -alanine, varied between 70 and 90%.
- Methyl acrylate (3.1 g, 1 eq, 36 mmol) was dissolved in CHCl 3 (50 ml) and methyl amine (1.68 g, 1.5eq, 56 mmol) was added in one portion. The reaction mixture was stirred and heated to 40° C. for 12 h. The solvents evaporated at the pump to give a yellowish oil, methyl 3-(methylamino)propanoate (3.6 g, 85.3% yield).
- 4-bromobenzenesulfonyl chloride 850 g, 0.19 mol was suspended in 2-propanol (45 ml, 3eq) and the slurry was cooled to less then 10° C. Pyridine (32 ml, 2eq) was added in portions while maintaining the reaction temperature below 10° C. After reaction completion (ca. 3 hours), 11 ml of glacial acetic acid followed by 250 ml of methyl tert-butyl ether (MTBE) were added. The layers were separated and the rich organic layer was successively washed with 125 ml of 1N aqueous hydrochloric acid and 150 ml of saturated sodium bicarbonate solutions.
- 2-propanol 45 ml, 3eq
- Pyridine 32 ml, 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 48 g (87% yield) of isobutyl 4-bromobenzenesulfonate.
- the THF-Hexane-MTBE solution containing 23 g (93.3 mmol) of 4-(isobutoxysulfonyl) phenylboronic acid was concentrated to a concentration of ca. 7 m]/g.
- a portion of this solution containing ca. 4.7 g (19 mmol, 0.26eq) was added to absolution of 15.4 g (75 mmol) of 3-iodopyridine dissolved in 100 ml of degassed tetrahydrofuran.
- tris(dibenzylidene acetone) dipalladium (0) (0.5 g, 0.6 mol %) and degassed aqueous sodium carbonate solution 300 ml, 3eq
- the reaction mixture was heated to ca. 50° C. to initiate the coupling reaction.
- Pd 2 (dba) 3 0.5 g per addition
- rich organic concentrate containing 4-(isobutoxysulfonyl)phenylboronic acid 4.7 g, 0.26 eq per addition
- the reaction mixture was further heated at ca. 55° C. for an additional 4 hours.
- the reaction mixture was filtered and washed with methyl-tert-butyl ether.
- the pH of the product-rich aqueous solution was adjusted to ca. 4, treated with trithiacyanuric acid (1 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 (118 g) to initiate the xrystallisation of the product.
- the salted-out product was dried in vacuo at less than 70° C.
- the dried product was dissolved in 350 ml of 190 proof ethanol at ca. 75° C.
- tert-butyl 2-( ⁇ [(1S)-3-hydroxy-1-phenylpropyl]amino ⁇ carbonyl)-1,3-thiazolidine-3-carboxylate as well as the racemic intermediate, tert-butyl 2-( ⁇ -hydroxy-1-phenylpropyl]amino ⁇ carbonyl)-1,3-thiazolidine-3-carboxylate were made according to the same protocol, starting from commercial (3R)-3-amino-3-phenylpropan-1-ol or 3-amino-3-phenylpropan-1-ol, respectively.
- reaction mixture was diluted with DCM (50 ml) and washed with a 1M HCl solution (2 ⁇ 50 ml) and with brine (50 ml) before drying over magnesium sulfate, filtering and removal of solvent in vacuo.
- 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
- 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-([1,1′-biphenyl]-4-ylsulfonyl)-N-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-phenylpropyl]-1,3-thiazolidine-2-carboxamide in 57% yield as a white oil in 96% purity by HPLC.
- Hydrazinolysis e.g., N-[3-amino-1-phenylpropyl]-3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidine-2-carboxamide
- N-methyl morpholine (NMM) (3.240g, 2.5eq, 32.15 mmol) was added to a solution of a compound of general formula (VIII) (Intermediate 8, 4.50 g, 1 eq, 12.86 mmol), e.g., 3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidine-2-carboxylic acid, in dry THF (100 ml) 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 (1.84 g, 1.05eq, 13.50 mmol) in solution in dry THF (20 ml).
- the desired product e.g., N-[(1S)-3-hydroxy-1-phenylpropyl]-1,3-thiazolidine-2-carboxamide hydrochloride, was isolated as a white solid and used for the next step without further purification and characterization.
- Aminomethyl polystyrene resin 250 mg 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 ⁇ 50 ml), then dried over MgSO 4 , and evaporated in vacuo.
- Method B To a solution of a compound of general structure (X) (commercial or Intermediate 4, 504 mg, 1 eq, 2.1 mmol), e.g., [1,1′-biphenyl]-4-sulfonic acid, in dry THF (20 ml), at 0° C., was drop wise added thionyl chloride (580 mg, 2eq, 4.3 mmol) in dry THF solution (10 ml). The reaction mixture was stirred at room temperature over a 2 h period.
- thionyl chloride 580 mg, 2eq, 4.3 mmol
- Aminomethyl polystyrene resin 250 mg 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 ⁇ 50 ml) and then dried over MgSO 4 , and evaporated in vacuo.
- sulfonyl chloride e.g., [1,1′-biphenyl]-4-sulfonyl chloride dissolved in 445 mL of anhydrous THF
- the mesylate derivative of general formula (XXVIII) (Intermediate 8, 1 eq.) was dissolved in dry THF (e.g., dilution 760 mg in 76 ml 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 MeOU.
- 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 16 Following the general method A as outlined, in Example 16, starting from 3-( ⁇ [3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl ⁇ amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and morpholine, the title compound was obtained in 99.3% purity by HPLC.
- the resin obtained in the previous loading step was shaken with a 20% solution of trifluoroacetic acid in dichloromethane (100 ml) 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.
- the resin from the previous deprotection step was transferred into a 96-well filter-plate (approx. 50 mg of dry resin/well; Loading 0.93 mmol/g; 0.047 mmol) and each well treated with a sulfonyl chloride (VI) (0.140 mmol, 3eq) and diisopropylethylamine (0.140 mmol, 3 eq) 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
- Amines (IV) (e.g., from commercial sources, or Intermediates 1 or Intermediates 2, 0.042 mmol),were added to suspensions of the functionalised oxime resin batches from the previous step (50 mg, 0.047 mmol) in DCM (0.5-1 ml), 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 (I), 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 (3 ml) was added to the crude compound and stirred at ambient temperatures for 40 min. The solvent was then removed in vacuo to give the corresponding final, N-deprotected products, again of general formula (I).
- Example 33 Following the general solid phase method as outlined Example 33, starting from 3-(tert-butoxycarbonyl)-1,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, [1,1′-biphenyl]-4-sulfonyl chloride and benzylamine, the title compound was obtained in 97% purity by HPLC.
- Example 33 Following the general solid phase method as outlined Example 33, starting from 3-(tert-butoxycarbonyl)-1,3-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 33 Following the general solid phase method as outlined Example 33, starting from 3-(tert-butoxycarbonyl)-1,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, 1,1′-biphenyl-4-sulfonyl chloride and 4-methoxyphenyl)methanamine, the title compound was obtained in 98% purity by HPLC.
- Example 33 Following the general solid phase method as outlined Example 33, starting from 3-(tert-butoxycarbonyl)-1,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, 1,1′-biphenyl-4-sulfonyl chloride and 2-thienylmethanamine, the title compound was obtained in 94% purity by HPLC,
- Example 33 Following the general solid phase method as outlined Example 33, starting from 3-(tert-butoxycarbonyl)-1,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, 1,1′-biphenyl-4-sulfonyl chloride and 2-furylmethanamine, the title compound was obtained in 92.2% purity by HPLC.
- Example 33 Following the general solid phase method as outlined Example 33, starting from 3-(tert-butoxycarbonyl)-1,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, 1,1′-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)-1,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, 1,1′-biphenyl-4-sulfonyl chloride and benzhydrylamine, the title compound was obtained in 98.5% purity by HPLC.
- Example 33 Following the general solid phase method as outlined Example 33, starting from 3-(tert-butoxycarbonyl)-1,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, 1,1′-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)-1,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, 1,1′-biphenyl-4sulfonyl chloride and (2-methylphenyl)methanamine, the title compound was obtained in 99% purity by HPLC.
- Example 33 Following the general solid phase, method as outlined Example 33, starting from 3-(tert-butoxycarbonyl)-1,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, 1,1′-biphenyl-4-sulfonyl chloride and 2,6-difluorophenyl)methanamine, 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)-1,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, 1,1′-biphenyl-4-sulfonyl chloride and 2,3-difluorophenyl)methanamine, the title compound was obtained in 93.4% purity by HPLC.
- Example 33 Following the general solid phase method as outlined Example 33, starting from 3-(tert-butoxycarbonyl)-1,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin; 1,1′-biphenyl-4-sulfonyl chloride and (2-methoxyphenyl)methanamine, the title compound was obtained in 98.5% purity by HPLC.
- Example 33 Following the general solid phase method as outlined Example 33, starting from 3-(tert-butoxycarbonyl)-1,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, 1,1′-biphenyl-4-sulfonyl chloride and (2-chlorophenyl)methanamine, 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)-1,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, 1,1′-biphenyl-4-sulfonyl chloride and (2-fluorophenyl)methanamine, the title compound was obtained in 88.6% purity by HPLC.
- N-[3-amino-1-phenylpropyl]-3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidine-2-carboxamide (Intermediate 9, 50 mgs, 1.0eq, 0.10 mmol) was dissolved in 5 ml DCM in presence of 30 ⁇ l triethylamine.
- Acetyl chloride (10 ⁇ l, 1.1 eq, 0.11 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%) (5 ml), and the compound extracted with DCM.
- thiazolidine intermediates of general structure (XXXI) or (XXXII), e.g., N-[3-amino-1-phenylpropyl]-3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidine-2-carboxamide (Intermediate 9, 50 mgs, 1.0 eq, 0.10 mmol), were dissolved in 10 ml DCM in presence of 30 ⁇ l of triethylamine at 0° C. Methane sulfonylchloride (10 ⁇ l, 1.1 eq, 0.11 mol) was introduced slowly and reaction mixture was stirred at 0° C. for 30 minutes.
- Thiazolidine intermediates of general structure (XXVI), e.g., 3-([1,1′-biphenyl]-4-ylsulfonyl)-N-(3-hydroxy-1-phenylpropyl)-1,3-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 (470 mg, 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 2 Following the strategies and protocols outlined in Example 1, the title compound was obtained in 99% purity by HPLC.
- product Ia e.g. ( ⁇ [3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl ⁇ amino)(phenyl)acetic acid
- intermediate XXX e.g., 3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carbonyl chloride as a yellow solid (1.839 g, quantitative yield).
- product Ib e.g. N-(2-amino-2-oxo-1-phenylethyl)-3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carboxamide
- Compound Ia e.g., ( ⁇ [3-(biphenyl-4-ylsulfonyl)-1,3-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.
- Triethylamine (92 ⁇ l, 0.66 mmol) was slowly added to a suspension of product Ic, e.g., 3-(biphenyl-4-ylsulfonyl)-N-[cyano(phenyl)methyl]-1,3-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 16 h, and then cooled to RT. The solvents were removed and the resulting solid was suspended in water and extracted with three protions of EtOAc.
- 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.
- product I e.g. 3-(biphenyl-4-ylsulfonyl)-N-[[5-(2-hydroxyethyl)-1,2,4-oxadiazol-3-yl](phenyl)methyl]-1,3-thiazolidine-2-carboxamide (25 mg, 24% yield over three steps) in 100% purity by HPLC.
- 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, 0.1 mmol) was dissolved in 3 mL of anhydrous THF. The solution was cooled down to zero degree and LiBH4 was added (3 mg, 0.15 mmol, 1.5eq). The reaction mixture was agitated for 2 h. 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.
- Example 65 Following the general strategies and protocols outlined in Example 68, starting from 3-(1,1′-biphenyl-4-ylsulfonyl)-N-[1-(2,6-difluorophenyl)-3-hydroxypropyl]-1,3-thiazolidine-2-carboxamide (Example 65), the title compound was obtained in 99% purity by HPLC.
- Example 1 Following the general strategies and protocols outlined in Example 68, starting from (2S)-3-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1S)-3-hydroxy-1-phenylpropyl]-1,3-thiazolidine-2-carboxamide (Example 1), the title compound was obtained in 99%,purity by HPLC.
- Example 67 Following the general strategies and protocols outlined in Example 68, starting from (2S)-3-[(2′-fluoro-1,1′-biphenyl-4-yl)sulfonyl]-N-[(1S)-3-hydroxy-1-phenylpropyl]-1,3-thiazolidine-2-carboxamide (Example 67), the title compound was obtained in 99% purity by HPLC.
- a 1,3-thiazolidine-2-carboxamide compound of formula (II) is admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight 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 1,3-thiazolidine-2-carboxamide compound per tablet) in a tablet press.
- a 1,3-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 1,3-thiazolidine-2-carboxamide compound per capsule).
- a 1,3-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 (11:89) in water.
- Sodium benzoate, flavor, and color are diluted with water and added with stirring. Sufficient water is then added.
- a 1,3-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 1,3-thiazolidine-2-carboxamide compound) in a tablet press.
- a 1,3-thiazolidine-2-carboxamide compound of formula (II) is dissolved in a buffered sterile saline injectable aqueous medium to provide a satisfactory concentration.
- This assay allows to determine the binding affinity of the test compounds of formula (II) for the human Prostaglandin F 2 ⁇ receptor:
- Human Prostaglandin F 2 ⁇ 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 8 ml/l Insulin-Transferrin-Selenium-mix (all Invitrogen) and 300 ⁇ g/ml hygromycin at 37° C. in a humidified atmosphere of 5% CO 2 in air.
- 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 250 mM sucrose, 25 mM Tris-,HCl pH 7.5, 10 mM MgCl 2 , 1 mM EDTA containing proteases inhibitors according to the manufacturer (Boehringer Mannheim) at 4° C.
- the lysate was centrifuged at 1000 g, 4° C. for 10 min and the supernatant was centrifuged at 160000 g, 4° C. for 60 min.
- the membranes pellets were resuspended in binding buffer (10 mM MES pH 6.2, 10 mM MgCl 2 , 1 mM EDTA containing proteases inhibitors), frozen in dry ice ethanol and stored at ⁇ 80° C.
- SPA Scintillation proximity assay
- the concentrations of compounds (antagonist) used to compete with the radioactive ligand (agonist) were 10 ⁇ M, 3 ⁇ M, 1 ⁇ M, 300 nM, 100 nM, 30 nM, 10 nM, 100 nM, 100 pM, 10 pM.
- 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).
- the tested compounds according to formula (II) induced an inhibition (illustrated by K i values) of the binding of Prostaglandin F 2 ⁇ to its receptor of less than 10 ⁇ M.
- the binding affinity of preferred compounds of formula (II) to human Prostaglandin F 2 ⁇ receptor is illustrated in the below Table 1 by means of the corresponding inhibition constants K i . 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 F 2 ⁇ receptor.
- Prostaglandin F 2 ⁇ The interaction of Prostaglandin F 2 ⁇ with its receptor leads to IP3 synthesis, a second messenger for Ca 2+ release from sarcoplasmatic reticulum, involved in the process triggering uterine contractions.
- the present assay described hereinafter can be used to show the inhibition of the Prostaglandin F 2 ⁇ /Prostaglandin F 2 , receptor mediated IP3 synthesis by test compounds of formula (I).
- 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.; [ 3 H] Inositol from Perkin Elmer Life Sciences; Prostaglandin F 2 ⁇ (PGF 2 ⁇ .) from Sigma, AG1-X8 chromatography columns from BioRad, 96 well black/white plates from Corning Inc.
- the cDNAs of the human Prostaglandin F 2 ⁇ receptor (hFP) and of the rat Prostaglandin F 2 ⁇ receptor (rFP) receptors were subcloned into the expression vector pCEP4 to generate pCEP4hFPuno and pCEP4rFP respectively.
- 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 [ 3 H] PGF 2 ⁇ binding. Selected clones were maintained in DMEM-F12 medium supplemented with 4 mM L-glutamine, 300 ⁇ g/ml hygromycinB and 2% fetal bovine serum (10% for cells expressing rFP).
- Cells were detached with PBS/EDTA, washed with inositol-free DMEM-F-12 medium and seeded at 80000 cells/weal in a Poly-1-Lysine precoated 12 well plate. Cells were labelled with myo-[ 3 H] Inositol at 4 ⁇ Ci/ml in inositol-free DMEM-F12 supplemented with 1% fetal bovine serum, 4 mM L-glutamine and 300 ⁇ g/ml hygromycinb.
- test compounds were added to the cells at 10 ⁇ M and 1 ⁇ M for 1 hour at room temperature.
- reaction was stopped by addition of 1 ml of stop solution (2.4% perchloric acid) for 10 min. 800 ⁇ l were then transferred to 400 ⁇ l of neutralising solution (0.72N KOH, 0.6 M KHCO 3 ), 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.
- IP3 to be quantified were eluted with 3 ml elution buffer (1M ammonium formate, 0.1M formic acid) and radioactivity was counted on a Beckman LS6000TA scintillation counter to measure the amount of phosphorylated [ 3 H] inositol.
- the activities of the 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 of the example compounds according to formula (II) to effectively antagonize Prostaglandin F 2 ⁇ -induced IP3-synthesis mediated by the Prostaglandin F 2 ⁇ 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 F 2 ⁇ receptor antagonists, as illustrated by IC 50 values of generally less than 2 ⁇ M.
- 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-F12 without fetal calf serum for 1-2 hours at 37° C.
- Calcium mobilisation was then measured on the FLIPR for 4 min.
- increasing concentrations of test compounds were added to the cells 30 min prior to the wash step.
- increasing concentrations of test compounds were added to the cells in FLIPR buffer and calcium mobilisation was measured for 1 min.
- the cells were stimulated with a concentration of 2 times the EC 50 of Prostaglandin F 2 ⁇ and calcium mobilisation was measured for 4 min.
- 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 of the example compounds according to formula (II) to effectively antagonize-Prostaglandin F 2 ⁇ -induced intracellular Ca 2+ -mobilization mediated by the Prostaglandin F 2 ⁇ -receptor. From the IC 50 -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 F 2 ⁇ receptor antagonists, as illustrated by IC 50 values of generally less than 2 ⁇ M.
- Non-pregnant Sprague Dawley female rats (Charles River, Calco, Italy) weighing 200-300 g were used. They received an i.p. injection of 250 ⁇ g/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.
- PE polyethylene
- 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.
- 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 of Prostaglandin F 2 ⁇ (Sigma Chem. co., St. Louis, Mo., USA) and ( ⁇ )fluprostenol (Cayman Chemicals, Ann Arbor, Mich., USA) or test compounds.
- the oesophagus was cannulated with a PE90 catheter.
- 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.
- the resulting contractile response was quantified by measuring the area under the curve (AUC) of the changes in intraluminal uterine pressure (by Chart V4.04 for Windows software, PowerLab ADInstruments, Castle Hill, Australia) over the first 15 minutes of the 35-min post-injection period (Prostaglandin F 2 ⁇ -induced uterine contractions) or the whole 35-min (for fluprostenol). Percent variations of AUCs determined after each Prostaglandin F 2 ⁇ or fluprostenol injection were calculated in comparison to the AUC obtained with the third injection (set as 100%) of Prostaglandin F 2 ⁇ or fluprostenol.
- AUC area under the curve
- the effect of the test compound was expressed at each time-point as the percent inhibition of the 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 ED 50 value calculated (by S-Plus 2000 v. 4.6 statistical software, Mathsoft, Inc. Seattle, Wash., USA).
- the trachea was isolated and cannulated with a suitable polyethylene (PE) tubing.
- PE polyethylene
- the uterine horn wall was included 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, Calif., USA) on the top was inserted into the lumen and secured with surgical silk.
- 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 of the vehicle or test compounds.
- test compound After a suitable stabilization period, vehicle or increasing doses of the test compound were administered by a 10-min intravenous infusion. Each dose administration was followed by a 30-min recovery period.
- 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 overtime (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 of the 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 of the first dose of test compound (basal value).
- 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, Wash., USA).
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US20080255094A1 (en) * | 2002-03-28 | 2008-10-16 | Laboratoires Serono S.A. | Thiazolidine carboxamide derivatives as modulators of the prostaglandin f receptor |
WO2022125876A1 (en) * | 2020-12-11 | 2022-06-16 | Olsen Elise A | Compositions and methods for inhibiting hair growth |
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CA3045407C (en) | 2009-07-29 | 2024-03-12 | Elise A. Olsen | Compositions and methods for inhibiting hair growth |
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AU2017205670B2 (en) * | 2016-01-04 | 2021-05-20 | Merck Serono S.A. | L-valinate 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 |
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US11289654B2 (en) | 2016-12-22 | 2022-03-29 | Guangzhou Chinaray Optoelectronic Materials Ltd. | Polymers containing furanyl crosslinkable groups and uses thereof |
US11534428B1 (en) | 2018-05-16 | 2022-12-27 | Xoma (Us) Llc | Compositions and methods for delaying the incidence of labor |
US20240024294A1 (en) | 2020-11-16 | 2024-01-25 | Xoma (Us) Llc | Compositions and methods for the treatment or prevention of preterm labor |
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US20080255094A1 (en) | 2008-10-16 |
US8415480B2 (en) | 2013-04-09 |
CN100484524C (zh) | 2009-05-06 |
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HRP20040759A2 (en) | 2004-12-31 |
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KR20040095311A (ko) | 2004-11-12 |
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AU2003240757B2 (en) | 2008-07-03 |
UA78021C2 (en) | 2007-02-15 |
MXPA04009374A (es) | 2005-01-25 |
ATE489951T1 (de) | 2010-12-15 |
ES2360882T3 (es) | 2011-06-10 |
AU2003240757A1 (en) | 2003-10-13 |
US20090215749A9 (en) | 2009-08-27 |
EA007328B1 (ru) | 2006-08-25 |
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Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:APPLIED RESEARCH SYSTEMS ARS HOLDING N.V.;REEL/FRAME:019808/0379 |
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Owner name: MERCK SERONO SA, SWITZERLAND Free format text: CHANGE OF NAME;ASSIGNOR:LABORATOIRES SERONO SA;REEL/FRAME:023599/0944 Effective date: 20081212 Owner name: MERCK SERONO SA,SWITZERLAND Free format text: CHANGE OF NAME;ASSIGNOR:LABORATOIRES SERONO SA;REEL/FRAME:023599/0944 Effective date: 20081212 |