WO2022067573A1 - Composé hétéroaryl-pyrimidinedione substitué par un sulfonamide et son utilisation - Google Patents

Composé hétéroaryl-pyrimidinedione substitué par un sulfonamide et son utilisation Download PDF

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WO2022067573A1
WO2022067573A1 PCT/CN2020/119044 CN2020119044W WO2022067573A1 WO 2022067573 A1 WO2022067573 A1 WO 2022067573A1 CN 2020119044 W CN2020119044 W CN 2020119044W WO 2022067573 A1 WO2022067573 A1 WO 2022067573A1
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alkyl
atoms
compound
group
cycloalkyl
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PCT/CN2020/119044
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Chinese (zh)
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金传飞
钟文和
张英俊
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广东东阳光药业有限公司
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Priority to PCT/CN2020/119044 priority Critical patent/WO2022067573A1/fr
Priority to CN202080103757.7A priority patent/CN116438181A/zh
Publication of WO2022067573A1 publication Critical patent/WO2022067573A1/fr

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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of pharmaceutical technology, and relates to compounds and pharmaceutical compositions for preventing or treating sex hormone-dependent diseases, as well as methods and uses thereof.
  • the present invention describes sulfonamido-substituted heteroarylpyrimidinediones which can act as gonadotropin-releasing hormone receptor antagonists and uses thereof.
  • hypothalamic hormones The secretion of anterior pituitary hormones is feedback-controlled by peripheral hormones secreted from the target organs of the corresponding hormones and by secretory-regulatory hormones from the hypothalamus, which is the upper central organ of the anterior pituitary gland (hereinafter, in the specification). , these hormones are commonly referred to as "hypothalamic hormones").
  • hypothalamic hormones nine hormones have been identified as hypothalamic hormones, including, for example, thyrotropin-releasing hormone (TRH) and gonadotropin-releasing hormone (GnRH, sometimes referred to as LH-RH (luteinizing hormone-releasing hormone)).
  • hypothalamic hormones are thought to exhibit their effects through receptors thought to be present in the anterior pituitary gland; and efforts have been made to find receptor-gene expression specific for these hormones, including in humans of.
  • antagonists or agonists that act specifically and selectively at these receptors should control hypothalamic hormone action and anterior pituitary hormone secretion. Therefore, such antagonists or agonists are expected to prevent or treat anterior pituitary hormone-dependent diseases.
  • GnRH-derived linear peptides US 5,140,009 and US 5,171,835), bicyclic peptide derivatives (Journal of Medicinal Chemistry, Vol.36, pp. 3265-3273 (1993)), a decapeptide compound modified at position 5 or 6 (WO 9846634 A1) and a decapeptide compound modified at position 8 (EP 0277829 B1) and the like.
  • Peptide compounds present many unsolved problems related to oral absorbability, dosage form, dose volume, drug stability, sustained action, and metabolic stability. Therefore, there is a strong need for oral GnRH antagonists, especially antagonists based on non-peptide compounds, which have excellent therapeutic effects on sex hormone-dependent diseases such as prostate cancer, endometriosis, precocious puberty, etc. Not only shows instantaneous pituitary-gonadotropin action (sharp action) but also has excellent oral absorption.
  • the present invention relates to a class of novel sulfonamido-substituted heteroaryl pyrimidinediones, which have unexpectedly excellent GnRH antagonistic activity, and can be used as gonadotropin-releasing hormone receptor antagonists, so that they can be used for prophylaxis Or treat sex hormone-dependent diseases, including but not limited to, prostate cancer, endometriosis, uterine fibroids, precocious puberty, and the like.
  • the compound of the present invention has stable properties, good safety, and has the advantages of pharmacodynamics and pharmacokinetics, such as good brain/plasma ratio, good bioavailability or good metabolic stability, etc. good clinical application prospects.
  • the present invention also provides methods of preparing such compounds and pharmaceutical compositions containing such compounds.
  • the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrated compound represented by formula (I) compound, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
  • R 1 , R 2a , R 2b , R 2c , R 2d , R 3 , R 4 , R 5a , R 5b , R 5c , R 5d , R 5e , Z and R have the meanings as described in the present invention.
  • Z is NH, O, or S.
  • R is wherein X, Y, V, R 6 and R 7 have the meanings as described in the present invention.
  • X is CH or N.
  • Y is CH or N.
  • V is CH or N.
  • R 6 is H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 haloalkyl.
  • R 7 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 3-6 cycloalkyl, 3 - a heterocyclic group consisting of 8 atoms, a C 6-10 aryl group or a heteroaryl group consisting of 5-10 atoms.
  • R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, hydroxy substituted C 1 -C 6 alkyl, cyano substituted C 1 -C 6 alkyl, amino substituted C 1 -C 6 alkyl, C 3-6 cycloalkyl , a heterocyclic group consisting of 3-8 atoms, a C 6-10 aryl group or a heteroaryl group consisting of 5-10 atoms.
  • R 3 and R 4 are each independently H, D, -OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3-6 cycloalkyl, heterocyclic group consisting of 3-8 atoms, C 6-10 aryl, 5- Heteroaryl group consisting of 10 atoms, C 3-6 cycloalkyl C 1-6 alkylene group, (heterocyclic group consisting of 3-8 atoms) C 1-6 alkylene group, C 6-10 aryl group C 1-6 alkylene or (heteroaryl consisting of 5-10 atoms) C 1-6 alkylene.
  • R 6 is H, D, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, or C 1 -C 4 haloalkyl.
  • R 6 is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl, 1-methylpropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, -CHF 2 or -CF 3 .
  • R 7 is C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, C 3-6 cycloalkyl, 3 - a heterocyclic group consisting of 6 atoms, a C 6-10 aryl group or a heteroaryl group consisting of 5-6 atoms.
  • R 7 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl, 1-methylpropyl, vinyl, propylene group, allyl, ethynyl, propynyl, propargyl, -CHF 2 , -CF 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, pyrrolidinyl, Tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, Thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyra
  • R 1 is C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, hydroxy substituted C 1 -C 4 alkyl, cyano substituted C 1 -C 4 alkyl, amino substituted C 1 -C 4 alkyl, C 3-6 cycloalkyl , a heterocyclic group consisting of 3-6 atoms, a C 6-10 aryl group or a heteroaryl group consisting of 5-6 atoms.
  • R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl, 1-methylpropyl, vinyl, propylene group, allyl, ethynyl, propynyl, propargyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, isopropoxy, -OCF 3 , hydroxymethyl, 2-hydroxyethyl, -CH 2 CN, -CH 2 CH 2 CN, -CH 2 CH 2 CH2CN , -CH2NH2 , -CH2CH2NH2 , -CH2CH2CH2NH2 , cyclopropyl , cyclobutyl , cyclopen
  • R 3 and R 4 are each independently H, D, -OH, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 3-6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 aryl, 5- Heteroaryl group consisting of 6 atoms, C 3-6 cycloalkyl C 1-4 alkylene group, (heterocyclic group consisting of 3-6 atoms) C 1-4 alkylene group, C 6-10 aryl group C 1-4 alkylene or (heteroaryl consisting of 5-6 atoms) C 1-4 alkylene.
  • R3 and R4 are each independently H, D, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl , 1-methylpropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, -CHF 2 , -CF 3 , methoxy, ethoxy, isopropoxy , -OCF 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl , naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,
  • the compound of the present invention is a compound represented by formula (II) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide of the compound represented by formula (II) , hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
  • R 1 , R 3 , R 4 , R 6 , R 7 , X and Y have the meanings as described in the present invention.
  • the compound of the present invention is a compound represented by formula (III) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide of the compound represented by formula (III) , hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
  • R 1 , R 3 , R 4 , R 6 , R 7 and V have the meanings as described in the present invention.
  • the compound described in the present invention is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide of a compound having one of the following structures , hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound disclosed herein.
  • compositions of the present invention further comprise pharmaceutically acceptable excipients, carriers, adjuvants or any combination thereof.
  • the present invention relates to the use of the compounds or pharmaceutical compositions disclosed in the present invention in the preparation of medicaments for preventing or treating sex hormone-dependent diseases.
  • the sex hormone-dependent disease of the present invention is sex hormone-dependent cancer, bone metastases of sex hormone-dependent cancer, prostatic hypertrophy, uterine fibroids, endometriosis, uterine fibroids, precocious puberty, Amenorrhea, Premenstrual Syndrome, Dysmenorrhea, Polylocular Ovarian Syndrome, Polycystic Ovary Syndrome, Acne, Alopecia, Alzheimer's Disease, Infertility, Irritable Bowel Syndrome, Hormone-Independent LH-RH (luteinizing hormone-releasing hormone) sensitive benign or malignant tumors or flushing.
  • the present invention relates to the use of a compound or pharmaceutical composition disclosed herein in the manufacture of a medicament useful as a reproduction regulator, contraceptive, ovulation inducer, or the Drugs are used to prevent recurrence of sex hormone-dependent cancers after surgery.
  • the present invention relates to the use of a compound or a pharmaceutical composition disclosed in the present invention in the preparation of a medicament for antagonizing gonadotropin-releasing hormone (GnRH).
  • GnRH gonadotropin-releasing hormone
  • the present invention relates to methods for the preparation, isolation and purification of compounds of formula (I), formula (II) or formula (III).
  • the biological test results show that the compounds of the present invention have strong antagonistic activity to gonadotropin-releasing hormone (GnRH), so the compounds provided by the present invention can be used as better GnRH antagonists.
  • GnRH gonadotropin-releasing hormone
  • any embodiment of any aspect of the invention may be combined with other embodiments so long as they do not appear to be inconsistent.
  • any technical feature may be applicable to that technical feature in other embodiments, as long as they do not contradict.
  • the articles “a”, “an” and “the” are intended to include “at least one” or “one or more” unless stated otherwise or otherwise clearly contradicted by context.
  • these articles refer to articles of one or more than one (ie, at least one) object.
  • a component refers to one or more components, ie, there may be more than one component contemplated for use or use in the implementation of the described embodiments.
  • patient refers to humans (including adults and children) or other animals. In some embodiments, “patient” refers to a human.
  • stereoisomers refers to compounds that have the same chemical structure, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric (cis/trans) isomers, atropisomers, and the like.
  • tautomer or "tautomeric form” refers to structural isomers having different energies that are interconvertible through a low energy barrier. A chemical equilibrium of tautomers can be achieved if tautomerism is possible (eg, in solution).
  • protontautomers also known as prototropic tautomers
  • prototropic tautomers include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization.
  • “Pharmaceutically acceptable” means compounds, materials, compositions, and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation, allergy, or compatibility with reasonable The benefit/risk ratio is symmetric with other problems and complications and is effective for the intended use.
  • C1 - C6 alkyl specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl groups.
  • linking substituents are described.
  • the Markush variables listed for that group should be understood to be the linking group.
  • the Markush group definition for that variable recites “alkyl” or “aryl”, it should be understood that the “alkyl” or “aryl” respectively represents the linking An alkylene group or an arylene group.
  • halogen and “halo” are used interchangeably herein to refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • alkyl or “alkyl group” used in the present invention refers to a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group can be optionally is substituted with one or more substituents described herein.
  • alkyl groups contain 1-6 carbon atoms; in other embodiments, alkyl groups contain 1-4 carbon atoms; in still other embodiments, alkyl groups contain 1 -3 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me, -CH3 ), ethyl (Et, -CH2CH3), n - propyl (n - Pr, -CH2CH2CH3 ) ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH ) (CH 3 ) 2 (2-methylpropyl)), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 (1-methylpropyl)), tert-butyl (t-Bu , -C(CH 3 ) 3 ), etc.
  • alkylene refers to a saturated divalent hydrocarbon radical obtained by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbon. Unless otherwise specified, alkylene groups contain 1-10 carbon atoms. In some embodiments, the alkylene group contains 1-6 carbon atoms; in other embodiments, the alkylene group contains 1-4 carbon atoms; in still other embodiments, the alkylene group The group contains 1-2 carbon atoms. Such examples include, but are not limited to, methylene ( -CH2- ), ethylene ( -CH2CH2- ) , propylene ( -CH2CH2CH2- ) , isopropylene (-CH( CH3 )CH2- ) , etc.
  • the alkylene group is optionally substituted with one or more substituents described herein.
  • alkenyl refers to a linear or branched monovalent hydrocarbon group containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e., a carbon-carbon sp 2 double bond, wherein the alkenyl group A group can be optionally substituted with one or more substituents described herein, including the “cis” and “trans” positions, or the "E” and “Z” positions.
  • the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 -4 carbon atoms.
  • alkynyl refers to a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one site of unsaturation, i.e., a carbon-carbon sp triple bond, wherein the alkynyl group Can be optionally substituted with one or more of the substituents described herein.
  • the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 -4 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH2C ⁇ CH), 1 -propynyl (ie, propynyl, -C ⁇ C -CH 3 ), etc.
  • alkoxy means that an alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain 1-12 carbon atoms. In some embodiments, the alkoxy group contains 1-6 carbon atoms; in other embodiments, the alkoxy group contains 1-4 carbon atoms; in still other embodiments, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy groups may be optionally substituted with one or more substituents described herein.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-propoxy, n -PrO, n-propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (isopropoxy, i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1- Butoxy (n-BuO, n-butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH (CH 3 ) 2 ), 2-butoxy (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC( CH3 ) 3 ), and the like.
  • alkylthio means that an alkyl group is attached to the remainder of the molecule through a sulfur atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkylthio group contains 1-12 carbon atoms. In some embodiments, alkylthio groups contain 1-6 carbon atoms; in other embodiments, alkylthio groups contain 1-4 carbon atoms; in still other embodiments, alkylthio groups The group contains 1-3 carbon atoms. The alkylthio group may be optionally substituted with one or more substituents described herein. Examples of alkylthio groups include, but are not limited to, methylthio (MeS, -SCH3 ), ethylthio ( EtS , -SCH2CH3 ), and the like.
  • alkylamino or “alkylamino” describe an amino group independently substituted with one or two alkyl groups, respectively, including “N-alkylamino” and “N,N-dialkylamino", where the alkyl group has the meaning as defined in the present invention.
  • Suitable alkylamino groups may be monoalkylamino or dialkylamino, examples of which include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N,N -Dimethylamino (dimethylamino), N,N-diethylamino (diethylamino), etc.
  • the alkylamino group is optionally substituted with one or more substituents described herein.
  • hydroxy-substituted alkyl means that an alkyl group is substituted with one or more hydroxyl groups (-OH), wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the hydroxy-substituted alkyl groups contain 1-12 carbon atoms.
  • hydroxy-substituted alkyl groups contain 1-6 carbon atoms, eg, hydroxy-substituted C1 - C6 alkyl; in other embodiments, hydroxy-substituted alkyl groups contain 1 -4 carbon atoms, eg, hydroxy-substituted C1 - C4 alkyl; in yet other embodiments, hydroxy-substituted alkyl groups contain 1-3 carbon atoms, eg, hydroxy-substituted C1 -C 3 alkyl.
  • Such examples include, but are not limited to, hydroxymethyl, hydroxyethyl (eg 2-hydroxyethyl), 2-hydroxy-1-propyl, 3-hydroxy-1-propyl, 2,3-dihydroxy Propyl and so on.
  • cyano-substituted alkyl means that an alkyl group is substituted with one or more cyano groups (-CN), wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the cyano-substituted alkyl groups contain 1-12 carbon atoms.
  • cyano-substituted alkyl groups contain 1-6 carbon atoms, eg, cyano-substituted C1 - C6 alkyl groups; in other embodiments, cyano-substituted alkyl groups groups contain 1-4 carbon atoms, eg, cyano-substituted C1 - C4 alkyl; in yet other embodiments, cyano-substituted alkyl groups contain 1-3 carbon atoms, eg, cyano Substituted C 1 -C 3 alkyl.
  • Such examples include, but are not limited to, cyanomethyl (-CH2CN), cyanoethyl (eg 2 -cyanoethyl, -CH2CH2CN ), 2 -cyano-1-propane (-CH 2 CH(CN)CH 3 ), 3-cyano-1-propyl (-CH 2 CH 2 CH 2 CN), 2,3-dicyanopropyl (-CH 2 CH(CN) CH 2 CN) and so on.
  • cyanomethyl -CH2CN
  • cyanoethyl eg 2 -cyanoethyl, -CH2CH2CN
  • 2 -cyano-1-propane -CH 2 CH(CN)CH 3
  • 3-cyano-1-propyl -CH 2 CH 2 CH 2 CN
  • 2,3-dicyanopropyl -CH 2 CH(CN) CH 2 CN
  • amino-substituted alkyl means that an alkyl group is substituted with one or more amino groups ( -NH2 ), wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the amino-substituted alkyl groups contain 1-12 carbon atoms.
  • amino-substituted alkyl groups contain 1-6 carbon atoms, eg, amino-substituted C1 - C6 alkyl groups; in other embodiments, amino-substituted alkyl groups contain 1 -4 carbon atoms, eg, amino-substituted C1 - C4 alkyl; in yet other embodiments, amino-substituted alkyl groups contain 1-3 carbon atoms, eg, amino-substituted C1 -C 3 alkyl.
  • Such examples include, but are not limited to, aminomethyl ( -CH2NH2 ), aminoethyl (eg 2 -aminoethyl, -CH2CH2NH2 ) , 2 -amino-1-propyl ( -CH2CH( NH2 ) CH3 ), 3 -amino- 1 -propyl ( -CH2CH2CH2NH2 ), 2,3 - diaminopropyl (-CH2CH( NH2 ) CH 2 NH 2 ) and so on.
  • aminomethyl -CH2NH2
  • aminoethyl eg 2 -aminoethyl, -CH2CH2NH2
  • 2 -amino-1-propyl -CH2CH( NH2 ) CH3
  • 3 -amino- 1 -propyl -CH2CH2CH2NH2
  • 2,3 - diaminopropyl -CH2CH( NH2 ) CH 2
  • haloalkyl or “haloalkoxy” means that an alkyl or alkoxy group is substituted with one or more halogen atoms, wherein the alkyl and alkoxy groups have the meaning as described herein, such that Examples include, but are not limited to, -CHF2 , -CF3 , -CHFCH2F , -CF2CHF2 , -CH2CHF2 , -CH2CF3 , -CH2CF2CHF2 , -OCHF2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 and the like.
  • C 1 -C 6 haloalkyl comprises fluorine substituted C 1 -C 6 alkyl; in other embodiments, C 1 -C 4 haloalkyl comprises fluorine substituted C 1 -C 4 alkyl ; In still other embodiments, the C 1 -C 2 haloalkyl group comprises a fluorine substituted C 1 -C 2 alkyl group.
  • cycloalkyl denotes a saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 ring carbon atoms.
  • the cycloalkyl group contains 3-10 ring carbon atoms, such as C 3-10 cycloalkyl; in other embodiments, the cycloalkyl group contains 3-8 ring carbon atoms, such as C 3- 8 cycloalkyl; in yet other embodiments, cycloalkyl contains 3-6 ring carbon atoms, eg, C3-6 cycloalkyl.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • C 3-8 cycloalkyl includes C 3-6 cycloalkyl; the C 3-6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl .
  • the cycloalkyl group may be optionally substituted with one or more substituents described herein.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system comprising 3-12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms; wherein the Heterocyclyl groups are non-aromatic and do not contain any aromatic rings.
  • Ring sulfur atoms can optionally be oxidized to S-oxides.
  • Ring nitrogen atoms can optionally be oxidized to N-oxides.
  • heterocyclyl is used interchangeably with the term “heterocycle.”
  • the heterocyclyl group can be composed of 3-8 atoms or 3-6 atoms, the atoms are optionally selected from C, N, O or S and at least one atom is N, O or S; wherein, the heterocyclic group composed of 3-8 atoms includes a heterocyclic group composed of 3-6 atoms; the heterocyclic group composed of 3-6 atoms includes a heterocyclic group composed of 3-5 atoms Heterocyclyl.
  • the heterocyclic group consisting of 3-6 atoms includes, but is not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl , tetrahydrothienyl, thiazolidinyl, pyrazolidine, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl and the like.
  • the heterocyclyl group may be optionally substituted with one or more substituents described herein.
  • aryl refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring is aromatic , and has one or more points of attachment to the rest of the molecule.
  • aryl is used interchangeably with the term “aromatic ring” or "aromatic ring”.
  • Examples of aryl groups may include phenyl, indenyl, 2,3-dihydro-1H-indenyl, naphthyl, and anthracenyl.
  • the aryl group may be optionally substituted with one or more substituents described herein.
  • the group “ C6-10 aryl” refers to an aryl group containing 6-10 ring carbon atoms.
  • heteroaryl refers to monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring is aromatic, and At least one ring contains 1, 2, 3 or 4 ring heteroatoms selected from nitrogen, oxygen, sulfur, and the heteroaryl group has one or more points of attachment to the rest of the molecule.
  • the heteroaryl group may be attached to the remainder of the molecule (eg, the host structure in the formula) through any reasonable site (which may be C or N).
  • heteroaryl may be used interchangeably with the terms “heteroaromatic ring” or “heteroaromatic”.
  • the heteroaryl group may be optionally substituted with one or more substituents described herein.
  • the heteroaryl group is a heteroaryl group of 5-10 atoms, meaning that the heteroaryl group contains 1-9 ring carbon atoms and 1, 2, 3, or 4 atoms selected from O, S, and N Ring heteroatom; in other embodiments, heteroaryl is a heteroaryl group consisting of 5-6 atoms, meaning that the heteroaryl group contains 1-5 ring carbon atoms and 1, 2, 3, or 4 selected from O , S, and N ring heteroatoms; examples of heteroaryl groups of 5-6 atoms include, but are not limited to, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, Pyridyl, pyrimidinyl, pyridazinyl
  • j-k atoms means that the cyclic group consists of j-k ring atoms, and the ring atoms include carbon atoms and/or heteroatoms such as O, N, S, P, etc.; the j and k Each is independently any non-zero natural number, and k>j; the "j-k” includes j, k and any natural number in between.
  • “consisting of 3-8 atoms”, “consisting of 3-6 atoms”, “consisting of 5-10 atoms” or “consisting of 5-6 atoms” means that the cyclic group consists of 3 -8 (ie, 3, 4, 5, 6, 7, or 8), 3-6 (ie, 3, 4, 5, or 6), 5-10 (ie, 5, 6, 7, 8, 9, or 10 ) or 5-6 (ie, 5 or 6) ring atoms including carbon atoms and/or heteroatoms such as O, N, S, P, etc.
  • cycloalkylalkylene means said cycloalkyl, heterocyclyl, aryl or
  • the heteroaryl groups are each independently attached to the remainder of the molecule through an alkylene group, wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl and alkylene groups all have the meanings described herein.
  • examples of arylalkylene groups include, but are not limited to, phenylmethylene, phenylethylene, phenylpropylene, and the like.
  • the cycloalkylalkylene, heterocyclylalkylene, arylalkylene, heteroarylalkylene are each independently optionally substituted with one or more substituents described herein.
  • prodrug refers to the conversion of a compound into a compound of formula (I), formula (II) or formula (III) in vivo. Such conversion is effected by hydrolysis of the prodrug in blood or enzymatic conversion to the parent structure in blood or tissue.
  • the prodrug compounds of the present invention can be esters.
  • esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonate esters , carbamates and amino acid esters.
  • a compound of the present invention contains a hydroxyl group, which can be acylated to give the compound in prodrug form.
  • Other prodrug forms include phosphates, such as these phosphates are phosphorylated by the hydroxyl group on the parent.
  • Metal refers to a product obtained by metabolism of a specific compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and their activity can be characterized using assays as described herein. Such products may be obtained by subjecting the administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
  • pharmaceutically acceptable salts refer to organic and inorganic salts of the compounds of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.
  • Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups including hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or obtained by other methods such as ion exchange method described in books and literature these salts.
  • the present invention also contemplates quaternary ammonium salts formed from any compound containing an N-group.
  • Water- or oil-soluble or dispersible products can be obtained by quaternization.
  • Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations that resist the formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1 -C 8 sulfonates and aromatic sulfonates.
  • a “solvate” of the present invention refers to an association of one or more solvent molecules with a compound of the present invention.
  • Solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or mixtures thereof.
  • hydrate refers to an association in which the solvent molecule is water.
  • the term "hydrate" may be used.
  • one molecule of the compound of the present invention may be associated with one molecule of water, such as a monohydrate; in another embodiment, one molecule of the compound of the present invention may be associated with more than one molecule of water, such as a dihydrate In yet another embodiment, one molecule of a compound of the present invention may be associated with less than one molecule of water, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the bioavailability of the non-hydrated form of the compounds.
  • any disease or disorder in some embodiments refers to ameliorating the disease or disorder (ie, slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, “treating” refers to alleviating or improving at least one physical parameter, including a physical parameter that may not be perceived by a patient. In other embodiments, “treating” refers to modulating a disease or disorder physically (eg, stabilizing an observable symptom) or physiologically (eg, stabilizing a physical parameter), or both. In other embodiments, “treating” refers to preventing or delaying the onset, occurrence or worsening of a disease or disorder.
  • prevent refers to a reduction in the risk of acquiring a disease or disorder (ie: stopping the development of at least one clinical symptom of a disease in a subject who may be facing or predisposed to facing the disease, but also not experience or exhibit symptoms of disease).
  • terapéuticaally effective amount refers to an amount of a compound that, when administered to a subject to treat a disease, is sufficient to effect the treatment of such disease.
  • a “therapeutically effective amount” can vary depending on the compound, the disease and severity, and the condition, age, weight, sex, etc. of the subject to be treated.
  • stereochemistry of any particular chiral atom when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated within the present invention and are included in the present invention as compounds disclosed herein .
  • stereochemistry is indicated by a solid wedge or a dashed line representing a particular configuration, then the stereoisomers of that structure are well defined and defined.
  • Nitrogen oxides of the compounds of the present invention are also included within the scope of the present invention. Oxidation of the corresponding nitrogen-containing basic species can be accomplished by using common oxidizing agents such as hydrogen peroxide at elevated temperature in the presence of an acid such as acetic acid, or by reaction with a peracid in a suitable solvent, such as in dichloromethane , ethyl acetate or methyl acetate react with peracetic acid, or react with 3-chloroperoxybenzoic acid in chloroform or dichloromethane to prepare nitrogen oxides of the compounds of the present invention.
  • common oxidizing agents such as hydrogen peroxide at elevated temperature in the presence of an acid such as acetic acid, or by reaction with a peracid in a suitable solvent, such as in dichloromethane , ethyl acetate or methyl acetate react with peracetic acid, or react with 3-chloroperoxybenzoic acid in chloroform or dichloromethane to prepare nitrogen oxides of the
  • compositions of formula (I), formula (II) or formula (III) may exist in the form of salts.
  • the salt refers to a pharmaceutically acceptable salt.
  • pharmaceutically acceptable means that a substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated with it.
  • the salt is not necessarily a pharmaceutically acceptable salt, but can be used for the preparation and/or purification of the compound represented by formula (I), formula (II) or formula (III) and/or with Intermediates for separating enantiomers of compounds represented by formula (I), formula (II) or formula (III).
  • Isotopically enriched compounds have the structures depicted by the general formulae given herein, except that one or more atoms are replaced by atoms having a selected atomic weight or mass number.
  • Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O , 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • the present invention relates to intermediates for the preparation of compounds of formula (I), formula (II) or formula (III).
  • the present invention provides a pharmaceutical composition, comprising a compound represented by formula (I), formula (II) or formula (III) or its individual stereoisomers, racemic or non-racemic mixtures of isomers or A pharmaceutically acceptable salt or solvate thereof.
  • the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant or excipient, and optionally, other therapeutic and/or prophylactic ingredients.
  • Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described in detail in, for example, Ansel H.C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, Philadelphia; Gennaro A.R. et al ., Remington: The Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe R.C., Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.
  • compositions of the present invention may exist in free form or, where appropriate, in the form of their pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of these esters, or can provide, directly or indirectly, the invention described herein when administered to a patient in need thereof. Any additional adducts or derivatives of the compound or its metabolites or residues.
  • Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form chosen. Furthermore, pharmaceutically acceptable excipients can be selected based on their particular function in the composition. Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents , solvent, co-solvent, suspending agent, emulsifier, sweetener, flavoring agent, taste masking agent, coloring agent, anti-caking agent, humectant, chelating agent, plasticizer, tackifier, antioxidant, Preservatives, stabilizers, surfactants and buffers.
  • diluents fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents , solvent, co-solvent, suspending agent, emulsifier, sweetener, flavoring agent, taste masking agent, coloring agent,
  • compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. A description of some commonly used methods in the art can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • the present invention relates to a process for preparing a pharmaceutical composition
  • a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof, the process comprising Mix various ingredients.
  • Pharmaceutical compositions containing compounds of the present disclosure can be prepared by mixing, for example, at ambient temperature and atmospheric pressure.
  • dosage forms include those suitable for the following routes of administration: (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, Solutions, emulsions, sachets, and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches (4) rectal administration, such as suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes , sprays, foams and gels.
  • routes of administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, Solutions, emulsions, sachets, and cachets
  • parenteral administration such as sterile solutions, suspensions, and reconstituted powders
  • transdermal administration such as
  • the compounds disclosed herein can be formulated into oral dosage forms. In other embodiments, the compounds disclosed herein may be formulated in a dosage form for inhalation. In other embodiments, the compounds disclosed herein may be formulated for nasal administration. In yet other embodiments, the compounds disclosed herein can be formulated for transdermal administration. In still some embodiments, the compounds disclosed herein can be formulated for topical administration.
  • compositions provided by the present invention can be provided as compressed tablets, triturated tablets, chewable lozenges, fast-dissolving tablets, recompressed tablets, enteric-coated tablets, sugar-coated or film-coated tablets.
  • compositions provided by the present invention can be provided in soft capsules or hard capsules, which can be prepared from gelatin, methylcellulose, starch or calcium alginate.
  • compositions provided by the present invention can be parenterally administered by injection, infusion or implantation for local or systemic administration.
  • Parenteral administration as used in the present invention includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.
  • compositions provided herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and in liquid prior to injection Solid forms are prepared as solutions or suspensions.
  • dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical sciences (see Remington: The Science and Practice of Pharmacy, supra).
  • compositions disclosed herein can be formulated into any dosage form suitable for inhalation administration to a patient, such as dry powder, aerosol, suspension or solution compositions.
  • compositions suitable for transdermal administration may be prepared as discrete patches intended to remain in intimate contact with the epidermis of a patient for an extended period of time.
  • the active ingredient can be delivered from the patch by iontophoresis, as generally described in Pharmaceutical Research, 3(6), 318 (1986).
  • compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the compounds and pharmaceutical compositions provided by the present invention have excellent GnRH antagonistic activity and low toxicity (eg, acute toxicity, chronic toxicity, genotoxicity, reproduction toxicity, cardiotoxicity, drug interactions, and carcinogenicity). Also, the compound or pharmaceutical composition is excellent in oral absorbability, sustainability of action, stability and pharmacokinetics. Furthermore, the compounds or pharmaceutical compositions are rarely affected by plasma components.
  • the compounds or pharmaceutical compositions of the present invention can be safely used in mammals (eg, humans, monkeys, bovines, horses, dogs, cats, rabbits, rats and mice, etc.) by utilizing GnRH receptor antagonism to Control plasma sex hormone concentrations to inhibit gonadotropin secretion, thereby preventing and/or treating diseases that are dependent on male or female hormones and diseases caused by excess of these hormones.
  • mammals eg, humans, monkeys, bovines, horses, dogs, cats, rabbits, rats and mice, etc.
  • the compounds or pharmaceutical compositions of the present invention are suitable for preventing and/or treating sex hormone-dependent cancers (eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.), bone metastases of sex hormone-dependent cancers, prostate cancer Hypertrophy, uterine fibroids, endometriosis, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, multilocular ovary syndrome, polycystic ovary syndrome, acne, Alopecia, Alzheimer's disease (Alzheimer's disease, Alzheimer's type and its mixed type senile dementia), etc.
  • sex hormone-dependent cancers eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.
  • sex hormone-dependent cancers eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.
  • bone metastases of sex hormone-dependent cancers
  • the compounds of the present invention are also suitable for modulating male and female reproduction (eg, pregnancy regulators and menstrual cycle regulators, etc.).
  • the compounds or pharmaceutical compositions of the present invention may also be used as male or female contraceptives or as ovulation inducers in females. Based on the rebound effect after drug withdrawal, the compounds or pharmaceutical compositions of the present invention can be used to treat infertility. Also, the compounds or pharmaceutical compositions of the present invention can be used as agents for the prevention and/or treatment of hormone-independent and LH-RH-sensitive benign or malignant tumors.
  • the compound or pharmaceutical composition of the present invention can be used as an agent for preventing and/or treating irritable bowel syndrome and preventing postoperative recurrence of hormone-dependent cancer (agent for preventing postoperative recurrence of prostate cancer; preventing before or after menopause) Agents for the recurrence of breast or ovarian cancer after surgery; in particular for the prevention of premenopausal breast or ovarian cancer recurrence after surgery).
  • the compounds or pharmaceutical compositions of the present invention are suitable for use in animal husbandry for regulating estrus, improving meat quality and promoting animal growth.
  • the compounds of the present invention are also suitable for use in fishspawning promoters.
  • the compounds or pharmaceutical compositions of the present invention may also be used to inhibit transient increases in plasma testosterone concentrations (flare phenomenon) observed with administration of GnRH superagonists such as leuprolide acetate Instantaneous rise.
  • GnRH superagonists such as leuprolide acetate Instantaneous rise.
  • the compounds of the present invention can be combined with leuprolide acetate, gonadorelin, buserelin, triptorelin, goserelin, nafarelin ), histrelin (histrelin), deslorelin (deslorelin), meterelin (meterelin) and lecirelin (lecirelin) and other super agonists in combination.
  • leuprolide acetate is especially preferred.
  • the compounds or pharmaceutical compositions of the invention can also be used particularly advantageously in combination with at least one selected from the group consisting of steroidal or non-steroidal anti-androgens or anti-estrogens, chemical Therapeutic agent, GnRH antagonist peptide (antagonistic peptide), alpha-reductase inhibitor, alpha-receptor inhibitor, aromatase inhibitor, 17beta-hydroxysteroid dehydrogenase inhibitor, adrenal androgen production inhibitor, kinase inhibitor , hormone therapy drugs and drugs that inhibit cell growth factors or their receptors.
  • chemotherapeutic agents include ifosfamide, doxorubicin, peplomycin, cisplatin, cyclophosphamide, 5-FU, UFT, Methotrexate (methotrexate), mitomycin C (mitomycin C), mitoxantrone (mitoxantrone), etc.
  • GnRH antagonistic peptide includes parenteral GnRH antagonistic peptides such as cetrorelix, ganirelix, abarrelix and the like.
  • the compounds and pharmaceutical compositions of the present invention may also be used in veterinary treatment of mammals in pets, introduced species and farm animals. Examples of other animals include horses, dogs and cats.
  • the compounds of the present invention include pharmaceutically acceptable derivatives thereof.
  • a compound of the present disclosure or a pharmaceutical composition comprising a compound of the present disclosure may be administered at one time, or several times at different time intervals over a specified period of time, depending on the dosing regimen.
  • the disclosed compounds may be administered concurrently with, prior to or subsequent to one or more other therapeutic agents.
  • the compounds of the present invention can be administered separately with other therapeutic agents by the same or different route of administration, or in the same pharmaceutical composition.
  • the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, wherein the substituents are as defined in formula (I), formula (II) or formula (III).
  • the following reaction schemes and examples serve to further illustrate the content of the present invention.
  • Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether were obtained by refluxing and drying with metallic sodium.
  • Anhydrous dichloromethane and chloroform were obtained by refluxing with calcium hydride.
  • Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.
  • reaction flasks are plugged with suitable rubber stoppers, and the substrate is injected through a syringe. Glassware is dry.
  • the chromatographic column is a silica gel column.
  • Silica gel 300-400 mesh was purchased from Qingdao Ocean Chemical Factory.
  • the measurement conditions for low-resolution mass spectrometry (MS) data are: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1 ⁇ 30 mm, 3.5 microns, 6 min, flow rate 0.6 mL/min.
  • Mobile phase 5 %-95% ( CH3CN with 0.1% formic acid) in ( H2O with 0.1% formic acid) using electrospray ionization (ESI) at 210 nm/254 nm with UV detection.
  • ESI electrospray ionization
  • the intermediate compound represented by the formula ( 11 ) can be prepared by the following process: the compound represented by the formula ( 1 ) reacts with the ethyl cyanoacetate represented by the formula ( 2 ) to obtain the compound represented by the formula ( 3 ); Then the compound represented by formula ( 3 ) is ring-closed under the action of sulfur powder to obtain the compound represented by formula ( 4 ). The compound represented by the formula ( 4 ) is reacted with ethyl chloroformate to obtain the compound represented by the formula ( 5 ).
  • the compound represented by the formula ( 5 ) reacts with the compound represented by the formula ( 6 ) to obtain the compound represented by the formula ( 7 ); the compound represented by the formula ( 7 ) is brominated to obtain the compound represented by the formula ( 8 ).
  • the compound represented by the formula ( 8 ) is reacted with the compound represented by the formula ( 9 ) to obtain the compound represented by the formula ( 10 ).
  • the compound represented by formula ( 10 ) is subjected to ester hydrolysis to obtain the intermediate compound represented by formula ( 11 ).
  • the compound represented by the formula ( 17 ) can be prepared by the following process: the compound represented by the formula ( 11 ) reacts with the compound represented by the formula ( 12 ) to obtain the compound represented by the formula ( 13 ); represented by the formula ( 13 ) The compound represented by the formula ( 14 ) is obtained by ring closure of the compound; the nitro group of the compound represented by the formula ( 14 ) is reduced to obtain the compound represented by the formula ( 15 ); the compound represented by the formula ( 15 ) and the formula ( 16 ) The indicated compound was reacted to obtain the target product indicated by ( 17 ).
  • the compound represented by formula ( 17' ) can be prepared by the following process: the compound represented by formula ( 11 ) reacts with the compound represented by formula ( 12' ) to obtain the compound represented by formula ( 13' ); formula ( 13 ) The compound represented by ' ) is closed to obtain the compound represented by the formula ( 14' ); the nitro group of the compound represented by the formula ( 14' ) is reduced to obtain the compound represented by the formula ( 15' ); the compound represented by the formula ( 15' ) The compound is reacted with the compound represented by formula ( 16 ) to obtain the target product represented by ( 17' ).
  • Ethyl 2-amino-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate (12 g, 39.2 mmol), pyridine (11 mL, 140 mmol) and dichloromethane were combined at 25 °C (100mL) was added to a 250mL single-neck round bottom flask, ethyl chloroformate (6.7mL, 70mmol) was added, and the reaction was continued to stir for 2 hours; the reaction was stopped, water (50mL) was added, the liquid was separated, the organic phase was collected, and anhydrous sulfuric acid was added.
  • the title compound in this step was prepared according to the method described in Example 1, Step 8, namely 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methane yl)-5-(4-nitrophenyl)thiophene-3-carboxylic acid (3.6 g, 6.93 mmol), N-(5-amino-2-pyridyl)-N-methyl-methanesulfonamide (1.67 g g, 8.3 mmol), N,N-diisopropylethylamine (4.02 mL, 23.0 mmol) and a solution of 1-propylphosphoric anhydride in ethyl acetate (8.25 mL, 13.9 mmol, 50%) in DMF (35 mL) The reaction was prepared, and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)
  • Step 2) N-(5-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-nitrophenyl)-2,4- Dioxo-1,2-dihydrothieno[2,3-d]pyrimidine Synthesis of pyridin-3(4H)-yl)pyridin-2-yl)-N-methylmethanesulfonamide
  • Step 2) N-(6-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-nitrophenyl)-2,4- Dioxo-1,2-dihydrothieno[2,3-d]pyrimidine Synthesis of Perid-3(4H)-yl)pyridazin-3-yl)-N-methylmethanesulfonamide
  • Step 2) N-(6-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-nitrophenyl)-2,4- Dioxo-1,2-dihydrothieno[2,3-d]pyrimidine Synthesis of pyridin-3(4H)-yl)pyridin-2-yl)-N-methylmethanesulfonamide
  • the antagonism effect of the compounds of the present invention on the transfected humanized GnRH receptor in RBL-1 cells was evaluated by fluorescence method to detect cytoplasmic calcium flux.
  • Example number IC50 (nM) Example 1 2.887 Example 2 1.435 Example 3 5.584 Example 4 0.9104
  • Example B Pharmacokinetic evaluation of the compounds of the present invention after intravenous or gavage quantification in rats and dogs
  • the present invention evaluates the pharmacokinetic studies of the compounds of the present invention in rats and/or dogs, and the animal information is shown in Table B.
  • the compounds of the present invention were administered to test animals in the form of 10% DMSO+10% Kolliphor HS15+78% Saline+2% (2% HCl) solution or 78% Saline+2% (2% HCl)+20% PEG400 solution. Before administration, animals were fasted for 12 hours and had free access to water.
  • the dose was 1 mg/kg (rats) or 0.5 mg/kg (dogs), and blood was collected at the following time points after administration (about 0.2 mL of blood): 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24h (dog) or 0.083, 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24h (rat), EDTA-K 2 was pre-added in the blood collection tube as an anticoagulant.
  • the administration dose was 5 mg/kg (rats) or 2.5 mg/kg (dogs), and intravenous blood was collected at the following time points after administration (about 0.2 mL of blood): 0.25, 0.5 , 1.0, 2.0, 4.0, 6.0, 8.0 and 24h (dog) or 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24h (rat), EDTA-K 2 was pre-added into the blood collection tube as an anticoagulant. Blood samples were centrifuged at 12,000 rpm for 2 minutes, and plasma was collected and stored at -20°C or -70°C. .
  • the analysis results show that the compounds of the present invention have good pharmacokinetic properties in rats and/or dogs. It shows that the compound of the present invention has good drug-forming property and good clinical application prospect.

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  • Pulmonology (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte au domaine technique des produits pharmaceutiques et concerne un composé hétéroaryl-pyrimidinedione substitué par un sulfonamide et son utilisation, et une composition pharmaceutique contenant ledit composé, qui peut jouer le rôle d'antagonistes du récepteur de l'hormone de libération des gonadotropines. L'invention concerne également un procédé de préparation d'un tel composé et d'une telle composition pharmaceutique, et leur rôle dans la prévention ou le traitement de maladies dépendant des hormones sexuelles, notamment, sans caractère limitatif, des utilisations dans des maladies telles que le cancer de la prostate, l'endométriose, les fibromes utérins et la puberté précoce.
PCT/CN2020/119044 2020-09-29 2020-09-29 Composé hétéroaryl-pyrimidinedione substitué par un sulfonamide et son utilisation WO2022067573A1 (fr)

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CN202080103757.7A CN116438181A (zh) 2020-09-29 2020-09-29 磺酰胺基取代的杂芳基嘧啶二酮类化合物及其用途

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1173868A (zh) * 1995-02-08 1998-02-18 武田药品工业株式会社 噻吩并嘧啶衍生物,其制备和应用
EP1479684A1 (fr) * 2002-01-30 2004-11-24 Takeda Chemical Industries, Ltd. Thienopyrimidines, procedes de fabrication et d'utilisation correspondants
CN101272806A (zh) * 2005-07-22 2008-09-24 武田药品工业株式会社 过早排卵抑制剂
WO2019020102A1 (fr) * 2017-07-28 2019-01-31 江苏恒瑞医药股份有限公司 Procédé de préparation d'un dérivé de pyrimidone hétéroaryle et intermédiaire d'un dérivé de pyrimidone hétéroaryle
CN111574534A (zh) * 2020-05-25 2020-08-25 东莞市东阳光新药研发有限公司 苯基取代的噻吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮类化合物及其用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1173868A (zh) * 1995-02-08 1998-02-18 武田药品工业株式会社 噻吩并嘧啶衍生物,其制备和应用
EP1479684A1 (fr) * 2002-01-30 2004-11-24 Takeda Chemical Industries, Ltd. Thienopyrimidines, procedes de fabrication et d'utilisation correspondants
CN101272806A (zh) * 2005-07-22 2008-09-24 武田药品工业株式会社 过早排卵抑制剂
WO2019020102A1 (fr) * 2017-07-28 2019-01-31 江苏恒瑞医药股份有限公司 Procédé de préparation d'un dérivé de pyrimidone hétéroaryle et intermédiaire d'un dérivé de pyrimidone hétéroaryle
CN111574534A (zh) * 2020-05-25 2020-08-25 东莞市东阳光新药研发有限公司 苯基取代的噻吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮类化合物及其用途

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