CN111875614B - Heterocyclyl-substituted thieno [2,3-d ] pyrimidine-2, 4(1H,3H) -diones and their use - Google Patents

Heterocyclyl-substituted thieno [2,3-d ] pyrimidine-2, 4(1H,3H) -diones and their use Download PDF

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CN111875614B
CN111875614B CN202010636105.1A CN202010636105A CN111875614B CN 111875614 B CN111875614 B CN 111875614B CN 202010636105 A CN202010636105 A CN 202010636105A CN 111875614 B CN111875614 B CN 111875614B
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金传飞
钟文和
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Abstract

The invention belongs to the technical field of medicines, and relates to heterocyclic group substituted thieno [2,3-d ] pyrimidine-2, 4(1H,3H) -diketone compounds, application thereof and a pharmaceutical composition containing the compounds, which can be used as gonadotropin releasing hormone receptor antagonists. The invention also relates to methods for preparing such compounds and pharmaceutical compositions, and their use in the prevention or treatment of sex hormone dependent diseases, including but not limited to prostate cancer, endometriosis, uterine fibroids, precocious puberty, and the like.

Description

Heterocyclyl-substituted thieno [2,3-d ] pyrimidine-2, 4(1H,3H) -diones and their use
Technical Field
The invention belongs to the technical field of medicines, and relates to a compound and a pharmaceutical composition for preventing or treating sex hormone-dependent diseases, and a using method and application thereof. In particular, the invention relates to heterocyclic group substituted thieno [2,3-d ] pyrimidine-2, 4(1H,3H) -diones which can be used as gonadotropin releasing hormone receptor antagonists and uses thereof.
Background
The secretion of anterior pituitary hormone is feedback-controlled by peripheral hormones secreted from the target organs of the respective hormones and by secretion-regulating hormones from the hypothalamus, which is the upper central organ of the anterior pituitary (hereinafter, these hormones are collectively referred to as "hypothalamic hormones" in the specification). Currently, it has been confirmed that as hypothalamic hormones, there are nine hormones including, for example, thyrotropin-releasing hormone (TRH) and gonadotropin-releasing hormone (GnRH, sometimes referred to as LH-RH (luteinizing hormone-releasing hormone)). These hypothalamic hormones are thought to exhibit their effects via receptors that are thought to be present in the anterior pituitary; and efforts have been made to find receptor-gene expression specific for these hormones, including in humans. Thus, antagonists or agonists that specifically and selectively act on these receptors should control the action of hypothalamic hormones and the secretion of anterior pituitary hormones. Therefore, such antagonists or agonists are expected to be useful for the prevention or treatment of anterior pituitary hormone-dependent diseases.
Most of the compounds having GnRH antagonistic activity known so far are peptide compounds, for example, GnRH-derived linear peptides (linear peptides) (US 5,140,009 and US 5,171,835), bicyclic peptide derivatives (Journal of Medicinal Chemistry, Vol.36, pp. 3265-3273(1993)), decapeptide compounds modified at position 5 or 6 (WO 9846634A1) and decapeptide compounds modified at position 8 (EP 0277829B 1), and the like.
Peptide compounds present a number of problems to be solved, which are associated with oral absorbability, dosage form, dose volume, drug stability, sustained action, metabolic stability, and the like. Therefore, there is a strong need for an oral GnRH antagonist, particularly an antagonist based on a non-peptide compound, which has an excellent therapeutic effect on sex hormone-dependent diseases such as prostate cancer, endometriosis, precocious puberty and the like, which exhibits not only an instant pituitary-gonadotropic action (acute action) but also excellent oral absorbability.
Disclosure of Invention
The following is a summary of some aspects of the invention only and is not intended to be limiting. These aspects and others are described more fully below. All references in this specification are incorporated herein by reference in their entirety. When the disclosure of the present specification differs from the cited documents, the disclosure of the present specification controls.
The invention relates to a novel heterocyclic group substituted thieno [2,3-d ] pyrimidine-2, 4(1H,3H) -diketone compound, which has unexpected excellent GnRH antagonistic activity and can be used as a gonadotropin releasing hormone receptor antagonist so as to be used for preventing or treating sex hormone dependent diseases, including but not limited to prostate cancer, endometriosis, uterine fibroids, precocious puberty and the like.
The compound has stable property and good safety, and has the advantages of pharmacodynamics and pharmacokinetics, such as good brain/plasma ratio (brain plasma ratio), good bioavailability or good metabolic stability and the like, so the compound has good clinical application prospect.
The invention also provides processes for the preparation of such compounds and pharmaceutical compositions containing them.
In one aspect, the invention relates to a compound that is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt of a compound of formula (I) or a prodrug thereof,
Figure BDA0002568334010000021
wherein R is1、R2a、R2b、R2c、R2d、R3、R4、R5a、R5b、R5c、R5d、R5e、R6a、R6b、R6c、R6dAnd X has the meaning as described in the present invention.
In some embodiments, X is O, S, NR, S (═ O), or S (═ O)2(ii) a Wherein R has the meaning as defined in the description.
In some embodiments, R is H, D, -C (═ O) - (C)1-C6Alkyl group), C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, hydroxy-substitutedC of (A)1-C6Alkyl radical, C3-6Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C6-10Aryl or heteroaryl of 5 to 10 atoms.
In some embodiments, R1Is C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, hydroxy-substituted C1-C6Alkyl, cyano-substituted C1-C6Alkyl, amino substituted C1-C6Alkyl radical, C3-6Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C6-10Aryl or heteroaryl of 5 to 10 atoms.
In some embodiments, each R is2a、R2b、R2c、R2d、R6a、R6b、R6cAnd R6dIndependently H, D, F, Cl, Br, I, -CN, -NO2、-NH2、-OH、-SH、-COOH、-C(＝O)NH2、-C(＝O)NHCH3、-C(＝O)N(CH3)2、-C(＝O)-(C1-C6Alkyl), -C (═ O) - (C)1-C6Alkoxy group), C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkylthio radical, C1-C6Alkylamino, hydroxy-substituted C1-C6Alkyl radical, C3-6Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C6-10Aryl or heteroaryl of 5 to 10 atoms.
In some embodiments, R3And R4Each independently is H, D, -OH, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C3-6Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C6-10Aryl, heteroaryl of 5 to 10 atoms, C3-6Cycloalkyl radical C1-6Alkylene, (heterocyclic group consisting of 3 to 8 atoms) C1-6Alkylene radical, C6-10Aryl radical C1-6Alkylene or (heteroaryl of 5 to 10 atoms) C1-6An alkylene group.
In some embodiments, R5a、R5b、R5c、R5dAnd R5eEach independently is H, D, F, Cl, Br, I, -CN, -NO2、-NH2、 -OH、-SH、-COOH、-C(＝O)NH2、-C(＝O)NHCH3、-C(＝O)N(CH3)2、-C(＝O)-(C1-C6Alkyl), -C (═ O) - (C)1-C6Alkoxy), -NHS (═ O)2C1-C6Alkyl, -N (C)1-6Alkyl) S (═ O)2C1-C6Alkyl, -S (═ O)2C1-C6Alkyl radical, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkylthio radical, C1-C6Alkylamino, hydroxy-substituted C1-C6Alkyl radical, C3-6Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C6-10Aryl or heteroaryl of 5 to 10 atoms.
In some embodiments, R is H, D, -C (═ O) - (C)1-C4Alkyl group), C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Haloalkyl, hydroxy-substituted C1-C4Alkyl radical, C3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C6-10Aryl or heteroaryl of 5 to 6 atoms.
In other embodiments, R is H, D, -C (═ O) -CH3Methyl, ethyl, n-butylPropyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl, 1-methylpropyl, ethenyl, ethynyl, -CHF2、-CF3Hydroxymethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.
In some embodiments, R1Is C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, hydroxy-substituted C1-C4Alkyl, cyano-substituted C1-C4Alkyl, amino substituted C1-C4Alkyl radical, C3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C6-10Aryl or heteroaryl of 5 to 6 atoms.
In other embodiments, R1Is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl, 1-methylpropyl, ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl, -CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CHF2、 -CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, isopropoxy, -OCF3Hydroxymethyl, 2-hydroxyethyl, -CH2CN、-CH2CH2CN、 -CH2CH2CH2CN、-CH2NH2、-CH2CH2NH2、-CH2CH2CH2NH2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, and trisAn azolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl group.
In some embodiments, each R is2a、R2b、R2c、R2d、R6a、R6b、R6cAnd R6dIndependently H, D, F, Cl, Br, I, -CN, -NO2、-NH2、-OH、-SH、-COOH、-C(＝O)NH2、-C(＝O)NHCH3、-C(＝O)N(CH3)2、-C(＝O)-(C1-C4Alkyl), -C (═ O) - (C)1-C4Alkoxy group), C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, C1-C4Alkylthio radical, C1-C4Alkylamino or hydroxy substituted C1-C4An alkyl group.
In other embodiments, each R is2a、R2b、R2c、R2d、R6a、R6b、R6cAnd R6dIndependently H, D, F, Cl, Br, I, -CN, -NO2、-NH2、-OH、-SH、-COOH、-C(＝O)NH2、-C(＝O)NHCH3、-C(＝O)N(CH3)2、-C(＝O)-CH3、 -C(＝O)-OCH3Methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, -CHF2、-CF3Methoxy, -OCF3Methylamino, dimethylamino or hydroxymethyl.
In some embodiments, R3And R4Each independently is H, D, -OH, C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, C3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C6-10Aryl, 5-6 atomsSub-constituent heteroaryl, C3-6Cycloalkyl radical C1-4Alkylene, (heterocyclic group consisting of 3 to 6 atoms) C1-4Alkylene radical, C6-10Aryl radical C1-4Alkylene or (heteroaryl of 5 to 6 atoms) C1-4An alkylene group.
In other embodiments, R3And R4Each independently H, D, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, 2-methylpropyl, 1-methylpropyl, ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl, -CHF2、-CF3Methoxy, ethoxy, isopropoxy, -OCF3Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, C3-6Cycloalkyl methylene, C3-6Cycloalkylethylene radical, C3-6Cycloalkylpropylene, (heterocyclyl) methylene of 3-6 atoms, (heterocyclyl) ethylene of 3-6 atoms, phenylmethylene, phenylethylene, phenylpropylene, pyridylmethylene, pyrimidylmethylene, pyrrolylmethylene, pyrazolyl methylene, triazolylmethylene or tetrazolylmethylene.
In some embodiments, R5a、R5b、R5c、R5dAnd R5eEach independently is H, D, F, Cl, Br, I, -CN, -NO2、-NH2、-OH、-SH、-COOH、-C(＝O)NH2、-C(＝O)NHCH3、-C(＝O)N(CH3)2、-C(＝O)-(C1-C4Alkyl), -C (═ O) - (C)1-C4Alkoxy), -S (═ O)2C1-C4Alkyl radical, C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, C1-C4Alkylthio radical, C1-C4Alkylamino or hydroxy substituted C1-C4An alkyl group.
In other embodiments, R5a、R5b、R5c、R5dAnd R5eEach independently is H, D, F, Cl, Br, I, -CN, -NO2、 -NH2、-OH、-SH、-COOH、-C(＝O)NH2、-C(＝O)NHCH3、-C(＝O)N(CH3)2、-C(＝O)-CH3、-C(＝O)-OCH3、 -S(＝O)2CH3Methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, -CHF2、-CF3Methoxy, -OCF3Methylamino, dimethylamino or hydroxymethyl.
In some embodiments, the compound of the present invention, which is a compound of formula (II) or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt of a compound of formula (II), or a prodrug thereof,
Figure BDA0002568334010000041
wherein R is1、R3、R4And X has the meaning as described in the present invention.
In some embodiments, the compound of the present invention is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt of the compound having one of the following structures, or a prodrug thereof:
Figure BDA0002568334010000042
in another aspect, the present invention relates to a pharmaceutical composition comprising a compound disclosed herein.
In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.
In another aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the manufacture of a medicament for the prevention or treatment of a sex hormone dependent disease.
In some embodiments, the sex hormone dependent disorder of the invention is a sex hormone dependent cancer, a bone metastasis of a sex hormone dependent cancer, prostatic hypertrophy, uterine fibroids, endometriosis, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, multiple atrial ovarian syndrome, polycystic ovarian syndrome, acne, alopecia, alzheimer's disease, infertility, irritable bowel syndrome, a benign or malignant tumor that is hormone independent and sensitive to LH-RH (luteinizing hormone releasing hormone), or flushing.
In one aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the manufacture of a medicament useful as a reproduction regulator (reproduction regulator), a contraceptive, an ovulation inducer (ovulation indicator), or for the prevention of postoperative recurrence of sex hormone dependent cancer.
In another aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the manufacture of a medicament for antagonizing gonadotropin releasing hormone (GnRH).
In another aspect, the invention relates to methods for the preparation, isolation and purification of compounds of formula (I) or formula (II).
Biological test results show that the compound has stronger antagonistic activity on gonadotropin releasing hormone (GnRH), so that the compound provided by the invention can be used as a better GnRH antagonist.
Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict.
Detailed description of the invention
Definitions and general terms
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
The following definitions, as used herein, should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.
The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to one or to more than one (i.e., to at least one) of the objects. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.
The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
The term "stereoisomers" refers to compounds having the same chemical structure, but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric (cis/trans) isomers, atropisomers, and the like.
The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization.
"pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.
The term "optionally substituted with … …" is used interchangeably with the term "unsubstituted or substituted with … …", i.e., the structure is unsubstituted or substituted with one or more substituents described herein, including but not limited to D, F, Cl, Br, I, N3， -CN，-NO2，-NH2，-OH，-SH，-COOH，-C(＝O)NH2，-C(＝O)NHCH3，-C(＝O)N(CH3)2-C (═ O) -alkyl, -C (═ O) -alkoxy, -NHS (═ O)2-alkyl, -N (alkyl) S (═ O)2-alkyl, -S (═ O)2Alkyl, alkoxy, alkylthio, alkylamino, alkenyl, alkynyl, haloalkyl, haloalkoxy, hydroxy-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyl-alkylene, heterocyclyl-alkylene, aryl-alkylene, heteroaryl-alkylene and the like.
In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C1-C6Alkyl "means in particular independently disclosed methyl, ethyl, C3Alkyl radical, C4Alkyl radical, C5Alkyl and C6An alkyl group.
In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.
The terms "halogen" and "halo" are used interchangeably herein to refer to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).
The term "alkyl" or "alkyl group" as used herein, denotes a saturated, straight or branched chain, monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. In some embodiments, the alkyl group contains 1 to 6 carbon atoms; in other embodiments, the alkyl group contains 1 to 4 carbon atoms; in still other embodiments, the alkyl group contains 1 to 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)3) Ethyl group (Et, -CH)2CH3) N-propyl (n-Pr, -CH)2CH2CH3) Isopropyl group (i-Pr, -CH (CH)3)2) N-butyl (n-Bu, -CH)2CH2CH2CH3) Isobutyl (i-Bu, -CH)2CH(CH3)2(2-methylpropyl)), sec-butyl (s-Bu, -CH (CH)3)CH2CH3(1-methylpropyl)), tert-butyl (t-Bu, -C (CH)3)3) And so on.
The term "alkylene" refers to a saturated divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a saturated straight or branched chain hydrocarbon. Unless otherwise specified, the alkylene group contains 1 to 10 carbon atoms. In some embodiments, the alkylene group contains 1 to 6 carbon atoms; in other embodiments, the alkylene group contains 1 to 4 carbon atoms; in still other embodiments, the alkylene group contains 1 to 2 carbon atoms. Examples include, but are not limited to, methylene (-CH)2-) ethylene (-CH2CH2-) propylene (-CH)2CH2CH2-) isopropylidene (-CH (CH)3)CH2-) and the like. The alkylene group is optionally substituted with one or more substituents described herein.
The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp2A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH)2) Allyl (-CH)2CH＝CH2) 1-propenyl (i.e., propenyl, -CH ═ CH-CH)3) And so on.
The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp triple bond, wherein the alkynyl radical isMay be optionally substituted with one or more substituents as described herein. In one embodiment, alkynyl groups contain 2-8 carbon atoms; in another embodiment, alkynyl groups contain 2-6 carbon atoms; in yet another embodiment, alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH)2C.ident.CH), 1-propynyl (i.e., propynyl, -C.ident.C-CH)3) And so on.
The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In some embodiments, alkoxy groups contain 1 to 6 carbon atoms; in other embodiments, the alkoxy group contains 1 to 4 carbon atoms; in still other embodiments, alkoxy groups contain 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)3) Ethoxy (EtO, -OCH)2CH3) 1-propoxy (n-propoxy, n-PrO, n-propoxy, -OCH2CH2CH3) 2-propoxy (isopropoxy, i-PrO, i-propoxy, -OCH (CH)3)2) 1-butoxy (n-BuO, n-butoxy, -OCH)2CH2CH2CH3) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)2CH(CH3)2) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)3)CH2CH3) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)3)3) And so on.
The term "alkylthio" means an alkyl group attached to the rest 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 to 12 carbon atoms. In some embodiments, the alkylthio group contains 1 to 6 carbon atoms; in other embodiments, the alkylthio group contains 1 to 4 carbon atoms; in yet another aspectIn some embodiments, the alkylthio group contains 1 to 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, -SCH)3) Ethylthio (EtS, -SCH)2CH3) And so on.
The term "alkylamino" or "alkylamino" denotes an amino group independently substituted with one or two alkyl groups, respectively, including "N-alkylamino" and "N, N-dialkylamino" wherein the alkyl groups have the meaning as described herein. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N-dimethylamino (dimethylamino), N-diethylamino (diethylamino), and the like. The alkylamino group is optionally substituted with one or more substituents described herein.
The term "hydroxy-substituted alkyl" means that the alkyl group is substituted with one or more hydroxy groups (-OH), wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the hydroxy-substituted alkyl group contains 1 to 12 carbon atoms. In some embodiments, the hydroxy-substituted alkyl group contains 1 to 6 carbon atoms, e.g., hydroxy-substituted C1-C6An alkyl group; in other embodiments, the hydroxy-substituted alkyl group contains 1 to 4 carbon atoms, e.g., hydroxy-substituted C1-C4An alkyl group; in still other embodiments, the hydroxy-substituted alkyl group contains 1 to 3 carbon atoms, e.g., hydroxy-substituted C1-C3An alkyl group. Examples include, but are not limited to, hydroxymethyl, hydroxyethyl (e.g., 2-hydroxyethyl), 2-hydroxy-1-propyl, 3-hydroxy-1-propyl, 2, 3-dihydroxypropyl, and the like.
The term "cyano-substituted alkyl" denotes an alkyl group substituted with one or more cyano (-CN) groups, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the cyano-substituted alkyl group contains 1 to 12 carbon atoms. In some embodiments, cyano-substituted alkanesThe radical containing 1 to 6 carbon atoms, e.g. cyano-substituted C1-C6An alkyl group; in other embodiments, the cyano-substituted alkyl group contains 1 to 4 carbon atoms, e.g., cyano-substituted C1-C4An alkyl group; in still other embodiments, the cyano-substituted alkyl group contains 1 to 3 carbon atoms, e.g., cyano-substituted C1-C3An alkyl group. Examples include, but are not limited to, cyanomethyl (-CH)2CN), cyanoethyl (e.g. 2-cyanoethyl, -CH)2CH2CN), 2-cyano-1-propyl (-CH)2CH(CN)CH3) 3-cyano-1-propyl (-CH)2CH2CH2CN), 2, 3-dicyanopropyl group (-CH)2CH(CN)CH2CN), and the like.
The term "amino-substituted alkyl" denotes an alkyl group substituted with one or more amino groups (-NH)2) Wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the amino-substituted alkyl group contains 1 to 12 carbon atoms. In some embodiments, the amino-substituted alkyl group contains 1 to 6 carbon atoms, e.g., amino-substituted C1-C6An alkyl group; in other embodiments, the amino-substituted alkyl group contains 1 to 4 carbon atoms, e.g., amino-substituted C1-C4An alkyl group; in still other embodiments, the amino-substituted alkyl group contains 1 to 3 carbon atoms, e.g., amino-substituted C1-C3An alkyl group. Examples include, but are not limited to, aminomethyl (-CH)2NH2) Aminoethyl (e.g. 2-aminoethyl, -CH)2CH2NH2) 2-amino-1-propyl (-CH)2CH(NH2)CH3) 3-amino-1-propyl (-CH)2CH2CH2NH2) 2, 3-diaminopropyl (-CH)2CH(NH2)CH2NH2) And so on.
The term "haloalkyl" or "haloalkoxy" denotes an alkyl or alkoxy group substituted with one or more halogen atoms, wherein the alkyl and alkoxy groups have the meaning as described herein, whichLike examples include, but are not limited to, -CHF2、-CF3、-CHFCH2F、-CF2CHF2、 -CH2CHF2、-CH2CF3、-CH2CF2CHF2、-OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CHF2、-OCH2CF3、 -OCH2CF2CHF2And the like. In some embodiments, C1-C6The haloalkyl group containing a fluorine-substituted C1-C6An alkyl group; in other embodiments, C1-C4The haloalkyl group containing a fluorine-substituted C1-C4An alkyl group; in still other embodiments, C1-C2The haloalkyl group containing a fluorine-substituted C1-C2An alkyl group.
The term "cycloalkyl" denotes a saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 ring carbon atoms. In some embodiments, cycloalkyl groups contain 3 to 10 ring carbon atoms, e.g., C3-10A cycloalkyl group; in other embodiments, cycloalkyl groups contain 3 to 8 ring carbon atoms, e.g., C3-8A cycloalkyl group; in still other embodiments, cycloalkyl groups contain 3-6 ring carbon atoms, e.g., C3-6A cycloalkyl group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Wherein, as described in the present invention, C3-8Cycloalkyl radicals including C3-6A cycloalkyl group; said C3-6Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl group may be optionally substituted with one or more substituents described herein.
The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms; wherein the heterocyclic group is non-aromatic and does not contain any aromatic ring. Unless otherwise specified, heterocyclyl may be carbon-or nitrogen-based, and-CH2The radical-may optionally be replaced by-C (═ O) -groupAnd (4) generation. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atoms of the ring may optionally be oxidized to the N-oxide. The term "heterocyclyl" may be used interchangeably with the term "heterocycle". As described herein, the heterocyclyl group may consist of 3 to 8 atoms or 3 to 6 atoms, optionally selected from C, N, O or S and at least one atom being N, O or S; wherein the heterocyclic group consisting of 3 to 8 atoms includes a heterocyclic group consisting of 3 to 6 atoms; the heterocyclic group consisting of 3 to 6 atoms includes a heterocyclic group consisting of 3 to 5 atoms. Specifically, the heterocyclic group consisting of 3 to 6 atoms includes, but is not limited to, ethylene oxide, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, and the like. The heterocyclyl group may be optionally substituted with one or more substituents described herein.
The term "aryl" denotes a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring is aromatic and has one or more attachment points to the rest of the molecule. The term "aryl" may be used interchangeably with the terms "aromatic ring" or "aromatic ring". Examples of the aryl group may include phenyl, indenyl, 2, 3-dihydro-1H-indenyl, naphthyl and anthryl. The aryl group may be optionally substituted with one or more substituents described herein. Unless otherwise stated, the group "C6-10Aryl "represents an aryl group containing from 6 to 10 ring carbon atoms.
The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 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 wherein the heteroaryl has one or more attachment points to the rest of the molecule. when-CH is present in the heteroaryl group2When it is a group, -CH2-the group may optionally be replaced by-C (═ O) -. Unless otherwise statedThe heteroaryl group may be attached to the rest of the molecule (e.g. the main structure in the general formula) via any reasonable site which may be C or N. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". The heteroaryl group may be optionally substituted with one or more substituents described herein. In some embodiments, heteroaryl is 5-10 atom consisting of heteroaryl, meaning that heteroaryl contains 1-9 ring carbon atoms and 1,2,3, or 4 ring heteroatoms selected from O, S and N; in other embodiments, heteroaryl is 5-6 atom heteroaryl, meaning that heteroaryl contains 1-5 ring carbon atoms and 1,2,3, or 4 ring heteroatoms selected from O, S and N; examples of heteroaryl groups consisting of 5 to 6 atoms include, but are not limited to, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, triazolyl, tetrazolyl, and the like.
The term "j-k atoms" means that the cyclic group consists of j-k ring atoms including carbon atoms and/or heteroatoms such as O, N, S, P; j and k are each independently any non-zero natural number, and k > j; the term "j-k" includes j, k and any natural number therebetween. For example, "3-8 atoms", "3-6 atoms", "5-10 atoms", or "5-6 atoms" means that the cyclic group consists of 3-8, 3-6, 5-10, or 5-6 ring atoms, including carbon atoms and/or heteroatoms such as O, N, S, P.
The terms "cycloalkylalkylene", "heterocyclylalkylene", "arylalkylene", "heteroarylalkylene" mean that the cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each independently attached to the rest of the molecule through an alkylene group, wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl and alkylene groups all have the meaning described herein. For example, 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.
The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I) or formula (II). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent.
"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, 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.
As used herein, "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 are: berge et al, description of the scientific 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 such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate,succinate, malonate, or by other methods described in the literature, such as ion exchange. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-C8Sulfonates and aromatic sulfonates.
"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term "hydrate" refers to an association of solvent molecules that is water.
When the solvent is water, the term "hydrate" may be used. In one embodiment, a molecule of a compound of the present invention may be associated with a 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 the 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 biological effectiveness of the compound in its non-hydrated form.
The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.
The term "prevent" or "prevention" refers to a reduction in the risk of acquiring a disease or disorder (i.e., arresting the development of at least one clinical symptom of a disease in a subject that may be facing or predisposed to facing such a disease, but who has not yet experienced or exhibited symptoms of the disease).
The term "therapeutically effective amount" means an amount of a compound that, when administered to a subject to treat a disease, is sufficient to effect treatment of the disease. The "therapeutically effective amount" may vary with the compound, the disease and the severity, as well as the condition, age, weight, sex, etc., of the subject to be treated.
Unless otherwise indicated, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, pharmaceutically acceptable salts and prodrugs thereof, of the compounds of the present invention are encompassed within the scope of the present invention.
In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated as within this invention and are included as disclosed compounds in this invention. When stereochemistry is indicated by a solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of the structure are so well-defined and defined.
Nitroxides of the compounds of the present invention are also included within the scope of the present invention. The nitroxides of the compounds of the present invention may be prepared by oxidation of the corresponding nitrogen-containing basic species using a common oxidizing agent (e.g. hydrogen peroxide) in the presence of an acid such as acetic acid at elevated temperature, or by reaction with a peracid in a suitable solvent, for example peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or 3-chloroperoxybenzoic acid in chloroform or dichloromethane.
The compounds of formula (I) or formula (II) may be present in the form of a salt. In some embodiments, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith. In other embodiments, the salt need not be a pharmaceutically acceptable salt, and may be an intermediate useful in the preparation and/or purification of a compound of formula (I) or formula (II) and/or in the isolation of an enantiomer of a compound of formula (I) or formula (II).
Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H、3H、11C、13C、14C、15N、17O、18O、18F、31P、32P、35S、36Cl and125I。
in another aspect, the invention relates to intermediates for the preparation of compounds of formula (I) or formula (II).
Pharmaceutical compositions, formulations and administration of the compounds of the invention
The invention provides a pharmaceutical composition, which comprises a compound shown as a formula (I) or a formula (II) or an individual stereoisomer, a racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of the invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant or vehicle, 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, for example, in Ansel h.c.et al, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, philidelphia; 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.
It will also be appreciated that certain compounds of the invention may be present in free form or, if appropriate, in the form of a pharmaceutically acceptable derivative thereof, when used in therapy. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any additional adduct or derivative that upon administration to a patient in need thereof provides, directly or indirectly, a compound of the present invention or a metabolite or residue thereof.
Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, pharmaceutically acceptable excipients may be selected for their specific 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, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function, and provide alternative functions, depending on how many such excipients are present in the formulation and which other excipients are present in the formulation.
The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. Some commonly used methods in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
Thus, in another aspect, the invention relates to a process for preparing a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof, which process comprises admixing the ingredients. Pharmaceutical compositions comprising the disclosed compounds may be prepared by mixing, for example, at ambient temperature and atmospheric pressure.
The compounds disclosed herein are generally formulated in a dosage form suitable for administration to a patient by a desired route. For example, 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, e.g., 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.
In some embodiments, the compounds disclosed herein can be formulated in oral dosage forms. In other embodiments, the compounds disclosed herein may be formulated in an inhalation dosage form. In other embodiments, the compounds disclosed herein can be formulated for nasal administration. In still other embodiments, the compounds disclosed herein can be formulated for transdermal administration. In still other embodiments, the compounds disclosed herein may be formulated for topical administration.
The pharmaceutical compositions provided by the present invention may be provided as compressed tablets, milled tablets, chewable lozenges, fast-dissolving tablets, double-compressed tablets, enteric-coated tablets, sugar-coated or film-coated tablets.
The pharmaceutical composition provided by the present invention may be provided in soft or hard capsules, which may be prepared from gelatin, methylcellulose, starch or calcium alginate.
The pharmaceutical compositions provided by the present invention may be administered parenterally by injection, infusion or implantation for local or systemic administration. Parenteral administration as used herein includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.
The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and solid forms suitable for solution or suspension in a liquid prior to injection. Such dosage forms may be prepared according to conventional methods known to those skilled in The art of pharmaceutical Science (see Remington: The Science and Practice of Pharmacy, supra).
In another aspect, the disclosed pharmaceutical compositions may be formulated in any dosage form suitable for administration to a patient by inhalation, such as a dry powder, aerosol, suspension, or solution composition.
Pharmaceutical compositions suitable for transdermal administration may be prepared as discrete patches intended to remain in intimate contact with the epidermis of the patient for an extended period of time. For example, the active ingredient may be delivered from a patch agent by iontophoresis, as generally described in Pharmaceutical Research,3(6),318 (1986).
Pharmaceutical compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
Use of the Compounds and pharmaceutical compositions of the invention
The compounds and pharmaceutical compositions provided by the present invention have excellent GnRH antagonistic activity and low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxin, drug interactions and carcinogenicity). Also, the compound or the pharmaceutical composition is excellent in oral absorbability, action sustainability, stability and pharmacokinetics. Furthermore, the compounds or pharmaceutical compositions are less affected by plasma components. Therefore, the compound or the pharmaceutical composition of the present invention can be safely used in mammals (e.g., human, monkey, cow, horse, dog, cat, rabbit, rat, mouse, etc.) to prevent and/or treat diseases depending on male or female hormones, diseases caused by excess of these hormones, etc. by controlling plasma sex hormone concentration using GnRH receptor antagonism to inhibit gonadotropin secretion.
Specifically, the compound or the pharmaceutical composition of the present invention is suitable for the prevention and/or treatment of sex hormone-dependent cancer (e.g., prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.), bone metastasis of sex hormone-dependent cancer, prostatic hypertrophy, uterine myoma, endometriosis, uterine fibroid, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, multiple atrial ovarian syndrome (multilocular ovarian syndrome), polycystic ovarian syndrome, acne, alopecia, alzheimer's disease (alzheimer's disease, senile dementia of the alzheimer's type and a mixed type thereof), and the like. The compounds of the invention are also useful for regulating male and female reproduction (e.g., pregnancy regulators, menstrual cycle regulators, and the like). The compounds or pharmaceutical compositions of the invention may also be used as male or female contraceptives or as female ovulation inducers. Based on the rebound effect after drug withdrawal, the compound or the pharmaceutical composition of the invention can be used for treating infertility. Furthermore, 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. Furthermore, the compound or the 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 sex hormone-dependent cancer (an agent for preventing postoperative recurrence of prostate cancer; an agent for preventing postoperative recurrence of breast cancer or ovarian cancer before or after menopause; particularly an agent for preventing postoperative recurrence of breast cancer or ovarian cancer before menopause).
Furthermore, the compounds or pharmaceutical compositions of the invention are suitable for regulating the estrus of animals, improving the quality of meat and promoting the growth of animals in animal husbandry. The compounds of the present invention are also suitable for fish spawning promoters (fisher spawning promoters).
The compounds or pharmaceutical compositions of the present invention may also be used to inhibit transient increases in plasma testosterone concentrations (flare phenomena) observed when administering GnRH superagonists such as acremolin acetate. The compound of the present invention can be used in combination with a super-agonist such as leuprolide acetate, gonadorelin (gonadorelin), buserelin (buserelin), triptorelin (triptorelin), goserelin (goserelin), nalfrelin (nafarelin), histrelin (histrelin), deslorelin (deslorelin), mirerelin (meterelin) and goserelin (lecirelin). Especially preferred is leuprolide acetate.
It may also be particularly advantageous to use the compounds or pharmaceutical compositions of the invention in combination with at least one substance selected from the group consisting of steroidal or non-steroidal antiandrogenic agents or antiestrogenic agents, chemotherapeutic agents, GnRH antagonist peptides, alpha-reductase inhibitors, alpha-receptor inhibitors, aromatase inhibitors, 17 beta-hydroxysteroid dehydrogenase inhibitors, adrenoandrogen production inhibitors, kinase inhibitors, hormone therapy agents and agents inhibiting cell growth factors or their receptors.
The above-mentioned "chemotherapeutic agent" includes ifosfamide (ifosfamide), doxorubicin (adriamycin), pellomycin (polyplomycin), cisplatin (cissplatin), cyclophosphamide (cyclophosphamide), 5-FU, UFT, methotrexate (methotrexate), mitomycin C (mitomycin C), mitoxantrone (mitoxantrone), and the like. The above-mentioned "GnRH antagonistic peptide" includes non-oral GnRH antagonistic peptides such as cetrorelix (cetrorelix), ganirelix (ganirelix), abarelix (abarelix), and the like.
In addition to being beneficial for human therapy, the compounds and pharmaceutical compositions of the present invention may also find application in veterinary therapy for pets, animals of the introduced species and mammals in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compound of the present invention includes pharmaceutically acceptable derivatives thereof.
In some embodiments, a disclosed compound or a pharmaceutical composition comprising a disclosed compound may be administered once or several times at different time intervals over a specified period of time according to a dosing regimen. The compounds disclosed herein may be administered simultaneously, or before or after, one or more other therapeutic agents. The compounds of the invention may be administered separately from the other therapeutic agents, by the same or different routes of administration, or in the same pharmaceutical composition.
General synthetic procedure
To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.
In general, the compounds of the invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I) or formula (II), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.
The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin Haojian Yunyu chemical Co., Ltd, Tianjin Shucheng chemical reagent factory, Wuhan Xin Huayuan scientific and technological development Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaolingyi factory.
The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.
The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.
The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants.
1H NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer.1H NMR Spectrum in CDC13、DMSO-d6、 CD3OD or acetone-d6TMS (0ppm) or chloroform (7.26ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (singlets, singlet), d (doublets ), t (triplets, triplet), q (quatets, quartets), m (multiplets ), br (broadended, broad), brs (broadended singlets, broad singlet), dd (doublets ), ddd (doublets, doublets), ddles of doublets), ddt (doublets of doublets, doublets), dt (doublets ), dq (doublets of doublets, doublets), td (triplets of doublets, triplet), tt (triplet of triplets). Coupling constant J, expressed in Hertz (Hz).
The conditions for determining low resolution Mass Spectrometry (MS) data were: agilent 6120 four-stage rod HPLC-M (column model: Zorbax SB-C18, 2.1X 30mm,3.5 micron, 6min, flow rate 0.6 mL/min. mobile phase 5% -95% (CH with 0.1% formic acid)3CN) in (H containing 0.1% formic acid)2O) by electrospray ionization (ESI) at 210nm/254nm, with UV detection.
Pure compounds were detected by UV at 210nm/254nm using Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (column model: NOVASEP 50/80 mm DAC).
The following acronyms are used throughout the invention:
mmol of DMF N, N-dimethylformamide
CDC13Deuterated chloroform nM, nmol/L nanomole per liter
DMSO dimethyl sulfoxide M, mol/L, mol per liter
DMSO-d6Deuterated dimethyl sulfoxide mg
G of AIBN azobisisobutyronitrile
Kg of NBS N-bromosuccinimide
EA Ethyl acetate mL, mL
DCM Dichloromethane μ L, μ L microliter
Saline normal Saline Pd/C palladium/carbon
min PEG400 polyethylene glycol 400
h hour EDTA-K2Ethylenediaminetetraacetic acid dipotassium salt
Py pyridine RT, RT Room temperature
The following synthetic schemes describe the procedures for preparing the presently disclosed compounds, wherein X and R are as follows, unless otherwise indicated1Having the definitions set out in the present invention.
Synthesis scheme 1
Formula (A), (B) and15) The compound shown can be prepared by the following steps: formula (A), (B) and1) A compound of the formula2) Reacting the cyanoacetic acid ethyl ester to obtain a compound of formula (I)3) A compound shown in the specification; then formula (A), (B), (C)3) The compound is subjected to ring closing under the action of sulfur powder to obtain a compound of the formula (I)4) The compounds shown. Formula (II)(4) Reacting the compound with phenyl chloroformate to obtain a compound of formula (I)5) The compounds shown. Formula (A), (B) and5) A compound of the formula6) The compound shown in the formula (I) is reacted to obtain7) A compound shown in the specification; formula (A), (B) and7) The compound is subjected to ring closure reaction to obtain a compound of the formula (I)8) The compounds shown. Formula (A), (B) and8) A compound of the formula9) Reacting the compound shown in the formula (A) to obtain a compound shown in the formula (B)10) The compounds shown. Formula (A), (B) and10) Brominating the compound shown to obtain a compound shown as a formula (I)11) A compound shown in the specification; formula (II)(11) The compound shown is reacted with dimethylamine hydrochloride to obtain a compound shown as a formula (I)12) A compound shown in the specification; formula (A), (B) and12) Reduction of the nitro group of the compound to give a compound of the formula13) A compound shown in the specification; formula (A), (B) and13) A compound of the formula14) Or formula (A)14’) The compound shown in the formula (I) is reacted to obtain15) The target product shown.
Figure BDA0002568334010000141
The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further illustrated below in connection with the examples.
Examples
Example Synthesis of 4- (1- (2, 6-difluorobenzyl) -5- ((dimethylamino) methyl) -2, 4-dioxo-3- (tetrahydro-2H-pyran-4-yl) -1,2,3, 4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -3-methoxyurea
Figure BDA0002568334010000142
Step 1) Synthesis of (E/Z) -2-cyano-3-methyl-4- (4-nitrophenyl) butyl-2-enoic acid ethyl ester
Figure BDA0002568334010000151
P-nitroacetophenone (5.3g,29.6mmol) and ethyl cyanoacetate (9.64mL,88.8mmol) were added to a 250mL single-neck round-bottom flask, followed by the addition of n-heptanoic acid (4.37mL,29.6mmol), benzylamine (3.6mL,32mmol) and toluene (50mL), followed by reaction for 12 hours at 130 ℃ over a water separator; after completion of the reaction, it was cooled to room temperature, spin-dried under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 18/1) to give the title compound as a pale yellow oil (7.24g, 89.2%).
MS(ESI,neg.ion)m/z:273.3[M-H]-.
Step 2) Ethyl 2-amino-4-methyl-5- (4-nitrophenyl)) Synthesis of thiophene-3-carboxylic acid esters
Figure BDA0002568334010000152
(E/Z) -2-cyano-3-methyl-4- (4-nitrophenyl) butyl-2-enoic acid ethyl ester (7.2g,26.2mmol), sulfur powder (1.68g,52.4mmol) and ethanol (80mL) were added to a 250mL single-neck round-bottom flask, diethylamine (6.8mL,65mmol) was added, the reaction was stirred for 15 minutes, and then transferred to 65 ℃ for further reaction for 3 hours; the reaction was stopped, cooled to room temperature, spin-dried under reduced pressure, and purified by column chromatography (petroleum ether/dichloromethane (v/v) ═ 5/1) to give the title compound as a red-brown solid (5.23g, 65.1%).
MS(ESI,pos.ion)m/z:307.1[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm)8.22(d,J＝8.9Hz,2H),7.48(d,J＝8.9Hz,2H),6.27(s,2H),4.33(q,J＝ 7.1Hz,2H),2.40(s,3H),1.38(t,J＝7.1Hz,3H).
Step 3) Synthesis of Ethyl 4-methyl-5- (4-nitrophenyl) -2- ((phenoxycarbonylacyl) amino) thiophene-3-carboxylate Become into
Figure BDA0002568334010000153
Ethyl 2-amino-4-methyl-5- (4-nitrophenyl) thiophene-3-carboxylate (10.5g,34.3mmol), pyridine (9.7mL,120 mmol), and methylene chloride (100mL) were added to a 250mL single-neck round-bottom flask at 25 deg.C, phenyl chloroformate (5.2mL,41mmol) was added, and the reaction was allowed to continue stirring for 2 hours; the reaction was stopped, water (50mL) was added, anhydrous sodium sulfate (1.5g) was added, dried, filtered, the filtrate was spin-dried under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 30/1) to give the title compound as a yellow solid (12.25g, 83.8%).
MS(ESI,pos.ion)m/z:427.1[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm)11.04(s,1H),8.27(d,J＝8.8Hz,2H),7.55(d,J＝8.8Hz,2H),7.41(d,J＝ 8.3Hz,2H),7.29–7.27(m,1H),7.23(d,J＝8.6Hz,2H),4.43(q,J＝7.1Hz,2H),2.44(s,3H),1.45(t,J＝7.1 Hz,3H).
Step 4) Ethyl 4-methyl-5- (4-nitrophenyl) -2- (3- (tetrahydro-2H-pyran-4-yl) ureido) thiophene-3- Synthesis of carboxylic acid esters
Figure BDA0002568334010000154
Ethyl 4-methyl-5- (4-nitrophenyl) -2- ((phenoxycarbonylacyl) amino) thiophene-3-carboxylate (0.64g,1.5mmol) and tetrahydrofuran (25mL) were added to a 100mL single-neck round bottom flask, followed by triethylamine (0.45g,4.4mmol) and tetrahydropyran-4-amine (450mg, 4.4mmol), and the reaction was stirred for an additional 3 hours at 70 deg.C in an oil bath; the reaction was stopped, cooled to room temperature, quenched by addition of water (30mL), extracted with ethyl acetate (40mL), and the organic phase was collected and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a yellow solid (0.58g, 89.1%).
MS(ESI,pos.ion)m/z:434.4[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm)8.27(d,J＝8.6Hz,2H),7.57(d,J＝8.6Hz,2H),4.39(q,J＝7.1Hz,2H), 4.01(d,J＝11.7Hz,2H),3.95(dd,J＝7.4,3.8Hz,1H),3.52(t,J＝11.0Hz,2H),2.43(s,3H),2.01(d,J＝10.7 Hz,2H),1.56(qd,J＝11.8,4.4Hz,2H),1.43(t,J＝7.1Hz,3H).
Step 5) 5-methyl-6- (4-nitrophenyl) -3- (tetrahydro-2H-pyran-4-yl) thieno [2,3-d]A pyrimidine-2-containing compound having a structure represented by, synthesis of 4(1H,3H) -dione
Figure BDA0002568334010000161
Ethyl 4-methyl-5- (4-nitrophenyl) -2- (3- (tetrahydro-2H-pyran-4-yl) ureido) thiophene-3-carboxylate (3.8g,8.8mmol) and methanol (50mL) were added to a 100mL single neck round bottom flask, followed by sodium methoxide (1.2g,22mmol) and the reaction stirred for an additional 5 hours at 70 ℃ in an oil bath; the reaction was stopped, cooled to room temperature, the solvent was removed by rotary drying under reduced pressure, then water (20mL) was added, stirred for 10 min and filtered, and the filter cake was dried at 60 ℃ to give the title compound as a yellow solid (3.1g, 91.2%).
Step 6)1- (2, 6-difluorobenzyl) -5-methyl-6- (4-nitrophenyl) -3- (tetrahydro-2H-pyran-4-yl) thia-ne Thieno [2,3-d ]]Synthesis of pyrimidine-2, 4(1H,3H) -diones
Figure BDA0002568334010000162
5-methyl-6- (4-nitrophenyl) -3- (tetrahydro-2H-pyran-4-yl) thieno [2,3-d ] pyrimidine-2, 4(1H,3H) -dione (2.1g, 5.4mmol), potassium iodide (1.7g,10.2mmol), potassium carbonate (1.4g,10.1mmol), and DMF (30mL) were added to a 100mL single-neck round bottom flask at 25 deg.C, followed by 2, 6-difluorobenzyl chloride (1.7g,10mmol), and the reaction was continued for 4 hours; the reaction was stopped, quenched by addition of water (100mL), filtered, and the filter cake solid collected and dried at 60 ℃ to give the title compound as a yellow solid (2.4g, 85.7%).
MS(ESI,pos.ion)m/z:514.2[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm)8.29(d,J＝8.7Hz,2H),7.55(d,J＝8.7Hz,2H),7.37–7.30(m,1H),6.94 (t,J＝8.1Hz,2H),5.34(s,2H),5.18(ddd,J＝12.1,8.3,4.0Hz,1H),4.11(dd,J＝11.3,4.1Hz,2H),2.90(qd,J ＝12.4,4.6Hz,2H),2.60(s,3H),1.60(d,J＝12.7Hz,4H).
Step 7)5- (bromomethyl) -1- (2, 6-difluorobenzyl) -6- (4-nitrophenyl) -3- (tetrahydro-2H-pyran-4- Yl) thieno [2,3-d]Synthesis of pyrimidine-2, 4(1H,3H) -diones
Figure BDA0002568334010000171
1- (2, 6-difluorobenzyl) -5-methyl-6- (4-nitrophenyl) -3- (tetrahydro-2H-pyran-4-yl) thieno [2,3-d ] pyrimidine-2, 4(1H,3H) -dione (2.4g,4.7mmol), azobisisobutyronitrile (110mg,0.67mmol), N-bromosuccinimide (1.2g, 6.7mmol), and chlorobenzene (50mL) were added to a 100mL single-necked round bottom flask and reacted in an oil bath at 80 ℃ for 7 hours under nitrogen; the reaction was stopped, cooled to room temperature, and a saturated sodium bicarbonate solution (20mL) was added, followed by liquid separation and drying of the organic phase over anhydrous sodium sulfate (1 g); filtration and spin-drying of the filtrate under reduced pressure gave the title compound as a pale yellow solid (2.6g, 95%).
Step 8)1- (2, 6-difluorobenzyl) -5- ((dimethylamino) methyl) -6- (4-nitrophenyl) -3- (tetrahydro- 2H-pyran-4-yl) thieno [2,3-d]Synthesis of pyrimidine-2, 4(1H,3H) -diones
Figure BDA0002568334010000172
5- (bromomethyl) -1- (2, 6-difluorobenzyl) -6- (4-nitrophenyl) -3- (tetrahydro-2H-pyran-4-yl) thieno [2,3-d ] pyrimidine-2, 4(1H,3H) -dione (340mg,0.57mmol), dimethylamine hydrochloride (0.1g,1.2mmol), and DMF (10mL) were added to a 100mL single neck round bottom flask at 25 deg.C, followed by triethylamine (0.3mL,2.14mmol) and the reaction was allowed to stir for an additional 16 hours; the reaction was stopped, water (30mL) was added, ethyl acetate was extracted (40mL), the organic phase was separated, the organic phase was collected, dried under reduced pressure, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a yellow solid (0.25g, 78.3%).
MS(ESI,pos.ion)m/z:557.1[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm)8.27(d,J＝8.6Hz,2H),7.83(d,J＝8.7Hz,2H),7.33(dt,J＝13.8,6.9Hz, 1H),6.94(t,J＝8.1Hz,2H),5.35(s,2H),4.13(dd,J＝14.3,7.2Hz,4H),4.08(d,J＝4.1Hz,1H),3.78(s,2H), 2.23(s,6H),1.89(brs,2H),1.59(d,J＝10.1Hz,2H).
Step 9)6- (4-aminophenyl) -1- (2, 6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (tetrahydro- 2H-pyran-4-yl) thieno [2,3-d]Synthesis of pyrimidine-2, 4(1H,3H) -diones
Figure BDA0002568334010000173
1- (2, 6-difluorobenzyl) -5- ((dimethylamino) methyl) -6- (4-nitrophenyl) -3- (tetrahydro-2H-pyran-4-yl) thieno [2,3-d ] pyrimidine-2, 4(1H,3H) -dione (2.0g,3.6mmol), ethyl hydrogen chloride acetate solution (4mL,2M), and methanol (60mL) were added to a 250mL single neck round bottom flask at 25 ℃ followed by Pd/C (0.6g), and reacted under a hydrogen balloon for 3 hours; the reaction was stopped, the bulk of the solvent was removed by rotary drying under reduced pressure, methanol (10mL) was added, followed by addition of a solid sodium bicarbonate to adjust the pH to 8, and the sample was stirred directly on silica gel and purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound as an off-white solid (1.6g, 84.2%).
MS(ESI,pos.ion)m/z:527.2[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm)8.22(d,J＝8.8Hz,2H),7.78(d,J＝8.8Hz,2H),7.56(d,J＝7.9Hz,1H), 7.45(dd,J＝13.1,7.9Hz,1H),7.26–7.19(m,1H),5.50(s,2H),5.17(tt,J＝12.0,3.8Hz,1H),4.06(dd,J＝ 11.3,4.1Hz,2H),3.75(s,2H),3.50(t,J＝11.4Hz,2H),2.89(d,J＝2.7Hz,2H),2.21(s,6H),1.57(d,J＝10.1 Hz,2H).
Step 10)1- (4- (1- (2, 6-difluorobenzyl) -5- ((dimethylamino) methyl) -2, 4-dioxo-3- (tetra-amino) hydro-2H-pyran-4-yl) -1,2,3, 4-tetrahydrothieno [2,3-d]Synthesis of pyrimidin-6-yl) phenyl) -3-methoxyurea
Figure BDA0002568334010000181
6- (4-aminophenyl) -1- (2, 6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (tetrahydro-2H-pyran-4-yl) thieno [2,3-d ] pyrimidine-2, 4(1H,3H) -dione (0.3g,0.57mmol), phenyl N-methoxycarbamate (0.4g,2.4mmol), and tetrahydrofuran (10mL) were added to a 100mL single neck round bottom flask, followed by triethylamine (0.3mL,2.14mmol), and reacted in an oil bath at 80 ℃ for 6 hours; the reaction was stopped, cooled to room temperature, and then water (50mL) was added, followed by extraction with dichloromethane (70mL), liquid separation, organic phase collection, spin-drying under reduced pressure, and column chromatography purification (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound as a white solid (0.23g, 67.3%).
MS(ESI,pos.ion)m/z:600.3[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm)7.68(s,1H),7.62(s,1H),7.56(d,J＝8.5Hz,2H),7.45(d,J＝8.5Hz,2H), 7.31(d,J＝6.6Hz,1H),6.91(t,J＝8.1Hz,2H),5.32(d,J＝5.1Hz,2H),5.21(ddd,J＝12.0,8.4,4.0Hz,1H), 4.08(dd,J＝11.1,3.9Hz,2H),3.82(s,3H),3.74(s,2H),3.52(t,J＝11.4Hz,2H),2.89(qd,J＝12.3,4.4Hz, 2H),2.18(s,6H),1.60(d,J＝10.3Hz,2H).
Example Synthesis of 21- (4- (1- (2, 6-difluorobenzyl) -5- ((dimethylamino) methyl) -2, 4-dioxo-3- (tetrahydro-2H-pyran-4-yl) -1,2,3, 4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -3-ethylurea
Figure BDA0002568334010000182
The title compound was prepared as described in example 1, step 10 by reacting 6- (4-aminophenyl) -1- (2, 6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (tetrahydro-2H-pyran-4-yl) thieno [2,3-d ] pyrimidine-2, 4(1H,3H) -dione (0.3g,0.57mmol), ethyl isocyanate (0.2g,2.8mmol), triethylamine (0.4mL,2.9mmol) in tetrahydrofuran (10mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound as a white solid (257mg, 75.5%).
MS(ESI,pos.ion)m/z:598.2[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm)7.45(s,1H),7.43(s,2H),7.35(d,J＝8.4Hz,2H),6.89(t,J＝8.1Hz,2H), 5.30(d,J＝8.3Hz,2H),5.20(t,J＝11.8Hz,1H),4.12–4.02(m,2H),3.73(s,2H),3.47(t,J＝11.5Hz,2H), 3.31–3.21(m,2H),2.88(tt,J＝12.2,6.1Hz,2H),2.17(s,6H),1.58(d,J＝11.0Hz,2H),1.11(t,J＝7.2Hz, 3H).
Example Synthesis of 31- (4- (1- (2, 6-difluorobenzyl) -5- ((dimethylamino) methyl) -2, 4-dioxo-3- (tetrahydro-2H-pyran-4-yl) -1,2,3, 4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -3-cyclopropylurea
Figure BDA0002568334010000191
This step the title compound was prepared as described in example 1, step 10, i.e. 6- (4-aminophenyl) -1- (2, 6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (tetrahydro-2H-pyran-4-yl) thieno [2,3-d]Pyrimidine-2, 4(1H,3H) -dione (0.3g,0.57mmol), phenyl N-cyclopropylcarbamate (0.2g,1.12mmol), triethylamine (0.4mL,2.9mmol) were reacted in tetrahydrofuran (10mL), and the crude product was isolated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 15/1) to give the title compound as a white solid (0.14g, 40.3%). MS (ESI, pos.ion) M/z 610.1[ M + H ]]+；
1H NMR(400MHz,CDCl3)δ(ppm)7.87(s,1H),7.52(d,J＝8.4Hz,2H),7.32(d,J＝8.3Hz,2H),6.90(t,J＝ 8.1Hz,2H),5.30(s,2H),5.19(t,J＝12.0Hz,1H),4.06(dd,J＝10.9,3.5Hz,2H),3.84(s,2H),3.48(dd,J＝ 13.1,9.7Hz,2H),3.04(dd,J＝14.5,7.3Hz,1H),2.84(dd,J＝12.2,4.1Hz,2H),2.25(s,6H),1.59(d,J＝10.8 Hz,2H),0.76(d,J＝5.6Hz,2H),0.57(brs,2H).
Example Synthesis of 4- (1- (2, 6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (1, 1-dioxotetrahydro-2H-thiopyran-4-yl) -2, 4-dioxo-1, 2,3, 4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -3-methoxyurea
Figure BDA0002568334010000192
Step 1) Ethyl 2- (3- (1, 1-dioxotetrahydro-2H-thiopyran-4-yl) ureido) -4-methyl-5- (4-nitro-n-oxide Synthesis of phenyl) thiophene-3-carboxylic acid esters
Figure BDA0002568334010000193
This step was prepared by the method described in example 1, step 4, reacting ethyl 4-methyl-5- (4-nitrophenyl) -2- ((phenoxycarbonyl) amino) thiophene-3-carboxylate (0.85g,1.99mmol), 4-aminotetrahydro-2H-thiopyran 1, 1-dioxide (0.45g,2.99mmol), triethylamine (0.83mL,5.98mmol) in DMF (10mL) and drying to give the title compound as a pale yellow solid (0.8g, 83.3%).
MS(ESI,pos.ion)m/z:480.4[M-H]-；
1H NMR(400MHz,CDCl3)δ(ppm)10.87(s,1H),8.28(d,J＝8.6Hz,2H),7.56(d,J＝8.6Hz,2H),5.47(d,J＝ 7.4Hz,1H),4.39(q,J＝7.1Hz,2H),4.10–4.01(m,1H),3.18(d,J＝4.6Hz,4H),2.43(s,5H),2.28–2.17(m, 2H),1.44(t,J＝7.1Hz,3H).
Step 2)3- (1, 1-dioxotetrahydro-2H-thiopyran-4-yl) -5-methyl-6- (4-nitrophenyl) thieno [2,3-d]Synthesis of pyrimidine-2, 4(1H,3H) -diones
Figure BDA0002568334010000201
This step was prepared by the method described in reference to example 1, step 5, i.e., ethyl 2- (3- (1, 1-dioxotetrahydro-2H-thiopyran-4-yl) ureido) -4-methyl-5- (4-nitrophenyl) thiophene-3-carboxylate (1.0g,2.08mmol) and sodium methoxide (0.35g,6.23 mmol) were reacted in methanol (20mL) and dried to give the title compound as a pale yellow solid (0.86g, 95.1%).
MS(ESI,pos.ion)m/z:435.9[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm)12.34(s,1H),8.30(d,J＝8.7Hz,2H),7.74(d,J＝8.7Hz,2H),5.11(s, 1H),3.08(d,J＝12.1Hz,4H),2.52(d,J＝2.8Hz,3H),2.44(s,2H),1.92(d,J＝11.9Hz,2H).
Step 3)1- (2, 6-difluorobenzyl) -3- (1, 1-dioxotetrahydro-2H-thiopyran-4-yl) -5-carbaRadical-6- (4-Nitrophenyl) thieno [2,3-d]Synthesis of pyrimidine-2, 4(1H,3H) -diones
Figure BDA0002568334010000202
This title compound was prepared as described in example 1, step 6 by reacting 3- (1, 1-dioxotetrahydro-2H-thiopyran-4-yl) -5-methyl-6- (4-nitrophenyl) thieno [2,3-d ] pyrimidine-2, 4(1H,3H) -dione (0.85g,1.95mmol), potassium iodide (0.65g,3.9 mmol), potassium carbonate (0.54g,3.9mmol) and 2, 6-difluorobenzyl chloride (0.63g,3.9mmol) in DMF (8mL) and drying to give the title compound as a pale yellow solid (1.01g, 91.8%).
1H NMR(400MHz,CDCl3)δ(ppm)8.30(d,J＝8.7Hz,2H),7.54(d,J＝8.7Hz,2H),7.34(dd,J＝14.8,8.2Hz, 1H),6.95(t,J＝8.1Hz,2H),5.35(s,2H),5.19(t,J＝12.0Hz,1H),3.54–3.41(m,2H),3.20(d,J＝7.6Hz,4H), 2.58(s,3H),2.07–2.01(m,2H).
Step 4)5- (bromomethyl) -1- (2, 6-difluorobenzyl) -3- (1, 1-dioxotetrahydro-2H-thiopyran-4-one- 6- (4-nitrophenyl) thieno-6-yl b2,3-d]Synthesis of pyrimidine-2, 4(1H,3H) -diones
Figure BDA0002568334010000211
This title compound was prepared as described in example 1, step 7 by reacting 1- (2, 6-difluorobenzyl) -3- (1, 1-dioxotetrahydro-2H-thiopyran-4-yl) -5-methyl-6- (4-nitrophenyl) thieno [2,3-d ] pyrimidine-2, 4(1H,3H) -dione (2.89g,5.15mmol), azobisisobutyronitrile (0.22g,1.29mmol), and N-bromosuccinimide (1.76g,9.79mmol) in chlorobenzene (30mL) to give the title compound as a pale yellow solid (3.26g, 98.8%).
Step 5)1- (2, 6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (1, 1-dioxotetrahydro-2H-thioxo Pyran-4-yl) -6- (4-nitrophenyl) thieno [2,3-d]Synthesis of pyrimidine-2, 4(1H,3H) -diones
Figure BDA0002568334010000212
The title compound was prepared as described in example 1, step 8 by reacting 5- (bromomethyl) -1- (2, 6-difluorobenzyl) -3- (1, 1-dioxotetrahydro-2H-thiopyran-4-yl) -6- (4-nitrophenyl) thieno [2,3-d ] pyrimidine-2, 4(1H,3H) -dione (0.57g,0.89 mmol), dimethylamine hydrochloride (0.18g,2.21mmol) and triethylamine (0.37mL,2.67mmol) in DMF (6mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) 40/1) to give the title compound as a pale yellow solid (0.41g, 75.9%).
MS(ESI,pos.ion)m/z:605.1[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm)8.29(d,J＝8.7Hz,2H),7.80(d,J＝8.7Hz,2H),7.35(dt,J＝14.7,7.2Hz, 1H),6.95(t,J＝8.2Hz,2H),5.34(d,J＝14.8Hz,2H),5.20(t,J＝11.9Hz,1H),3.76(d,J＝5.1Hz,2H),3.27– 3.11(m,4H),2.27(s,2H),2.05(d,J＝13.3Hz,2H),1.64(s,6H).
Step 6)6- (4-aminophenyl) -1- (2, 6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (1, 1-bis Oxotetrahydro-2H-thiopyran-4-yl) thieno [2,3-d]Synthesis of pyrimidine-2, 4(1H,3H) -diones
Figure BDA0002568334010000213
The title compound was prepared as described in example 1, step 9 by reacting 1- (2, 6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (1, 1-dioxotetrahydro-2H-thiopyran-4-yl) -6- (4-nitrophenyl) thieno [2,3-d ] pyrimidine-2, 4(1H,3H) -dione (0.4g, 0.66mmol), Pd/C (0.15g) and ethyl acetate hydrogen chloride solution (1.0mL,2M) were reacted in methanol (5mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a white solid (0.26g, 68.4%).
MS(ESI,pos.ion)m/z:575.3[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm)7.35–7.29(m,1H),7.22(d,J＝8.3Hz,2H),6.91(t,J＝8.1Hz,2H),6.71 (d,J＝8.3Hz,2H),5.32(s,2H),5.22(t,J＝11.9Hz,1H),3.85(s,2H),3.71(brs,2H),3.45(dd,J＝25.0,12.3Hz, 2H),3.24–3.13(m,4H),2.18(s,6H).
Step 7)1- (4- (1- (2, 6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (1, 1-dioxotetrahydro- 2H-Thiopyran-4-yl) -2, 4-dioxo-1, 2,3, 4-tetrahydrothieno [2,3-d]Pyrimidin-6-yl) phenyl) -3-methoxy Synthesis of ureides
Figure BDA0002568334010000221
The title compound was prepared as described in example 1, step 10 by reacting 6- (4-aminophenyl) -1- (2, 6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (1, 1-dioxotetrahydro-2H-thiopyran-4-yl) thieno [2,3-d ] pyrimidine-2, 4(1H,3H) -dione (0.3g, 0.52mmol), phenyl N-methoxycarbamate (0.44g,2.61mmol), triethylamine (0.36mL,2.61mmol) in DMF (5mL), and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound as a white solid (0.15g, 44.3%).
MS(ESI,pos.ion)m/z:648.2[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm)7.65(s,1H),7.57(d,J＝8.5Hz,2H),7.43(d,J＝8.4Hz,2H),7.34–7.29 (m,1H),7.22(s,1H),6.93(t,J＝8.1Hz,2H),5.33(d,J＝4.9Hz,2H),5.22(t,J＝11.8Hz,1H),3.84(s,3H), 3.45(d,J＝12.2Hz,2H),3.19(d,J＝10.6Hz,4H),2.19(s,6H),2.06(d,J＝12.0Hz,2H),1.64–1.56(m,2H).
Example Synthesis of 51- (4- (1- (2, 6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (1, 1-dioxotetrahydro-2H-thiopyran-4-yl) -2, 4-dioxo-1, 2,3, 4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -3-ethylurea
Figure BDA0002568334010000222
This step titled compound was prepared by the method described in reference to example 1, step 10, namely 6- (4-aminophenyl) -1- (2, 6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (1, 1-dioxotetrahydro-2H-thiopyran-4-yl) thieno [2,3-d ]]Pyrimidine-2, 4(1H,3H) -dione (0.4g, 0.7mmol), ethyl isocyanate (0.15g,2.09mmol), pyridine (0.17mL,2.09mmol) were reacted in tetrahydrofuran (10mL), and the crude product was isolated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound as a white solid (0.26g, 57.9%). MS (ESI, pos. ion) M/z 646.3[ M + H ]]+；
1H NMR(400MHz,CDCl3)δ(ppm)7.49(d,J＝8.5Hz,2H),7.35–7.29(m,3H),6.92(t,J＝8.2Hz,2H),5.32 (d,J＝3.4Hz,2H),5.22(d,J＝11.9Hz,1H),3.94(s,2H),3.43(d,J＝12.8Hz,2H),3.23–3.11(m,4H),2.34(s, 6H),2.09(d,J＝12.4Hz,2H),1.44–1.36(m,2H),1.18(t,J＝7.2Hz,3H).
Example Synthesis of 61- (4- (1- (2, 6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (1, 1-dioxotetrahydro-2H-thiopyran-4-yl) -2, 4-dioxo-1, 2,3, 4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -3-cyclopropylurea
Figure BDA0002568334010000231
The title compound was prepared as described in example 1, step 10 by reacting 6- (4-aminophenyl) -1- (2, 6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (1, 1-dioxotetrahydro-2H-thiopyran-4-yl) thieno [2,3-d ] pyrimidine-2, 4(1H,3H) -dione (0.25g, 0.44mmol), phenyl N-cyclopropylcarbamate (0.23g,1.3mmol), triethylamine (0.18mL,1.3mmol) in DMF (5mL), and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 15/1) to give the title compound as a white solid (0.24 g, 82.8%).
MS(ESI,pos.ion)m/z:658.2[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm)7.52(d,J＝8.5Hz,2H),7.40(d,J＝8.4Hz,2H),7.09(s,1H),6.92(t,J＝ 8.1Hz,2H),5.32(d,J＝3.0Hz,2H),5.22(t,J＝12.0Hz,1H),3.71(s,2H),3.45(d,J＝12.5Hz,2H),3.17(brs, 4H),2.92(brs,1H),2.17(s,6H),2.05(d,J＝13.1Hz,2H),0.89(d,J＝6.2Hz,4H).
Biological assay
Example A: antagonism of humanized GnRH receptors by Compounds of the invention
Purpose of experiment
The antagonism of the compounds of the present invention against the transfected humanized GnRH receptor in RBL-1 cells (rat basophilic leukemia cells) was evaluated by fluorescence detection of cytosolic calcium flux.
Experimental procedure
The cells were suspended in HBSS buffer (Invitrogen ), 20mM HEPES buffer (Invitrogen ), and then diluted at 1.186X 104The density of cells/well is averaged into the microwell reaction plate. After mixing the fluorescent probe (Fluo8Direct, AAT biosquest) with HBSS buffer (20 mM HEPES buffer, PH 7.4 was added), each well was added, and the cells were incubated at 30 ℃ for 60 min. Then the reaction plate is placed in a microplate reader (FlipR Tetra, Molecular Device) for testing, a compound to be tested or HBSS buffer solution (blank control) is added, 8nM LH-RH is added after 5min, and the change of fluorescence intensity which is in direct proportion to the calcium ion concentration in cytoplasm is measured. The inhibition ratio of the compound was calculated with the fluorescence intensity of the blank control group to which no compound was added being 100% (inhibition ratio being 0%). Measuring the inhibition rate of the compound at different concentrations, and calculating the IC50The value is obtained. The results of the experiment are shown in table a below.
TABLE A antagonistic Effect of the Compounds of the invention on humanized GnRH receptors
Example No. 2 IC50(nM)
Example 1 138.7
Example 2 110.1
Example 3 101.8
Example 6 98.19
The experimental result shows that the compound has good antagonistic action on the humanized GnRH receptor.
Example B pharmacokinetic evaluation of the Compounds of the invention after intravenous injection or gavage in rats and dogs
The present invention evaluates the pharmacokinetic studies of the compounds of the invention in rats and/or dogs for details in the animal information given in table B.
Table B information sheet of the subject animals of the present invention
Figure BDA0002568334010000241
Test method
The compounds of the invention were administered to the test animals as 10% DMSO + 10% Kolliphor HS15+ 78% Saline + 2% (2% HCl) solution or 78% Saline + 2% (2% HCl) + 20% PEG400 solutionThe administration is carried out, and animals are fasted for 12h before administration and have free water. For the group administered by intravenous injection, the dose was 1mg/kg (rat) or 0.5mg/kg (dog), and blood was taken intravenously (blood volume taken was about 0.2mL) at the following time points after administration: 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 is added into the blood sampling tube in advance2Can be used as anticoagulant. For the gavage group, 5mg/kg (rat) or 2.5mg/kg (dog) was administered, and intravenous blood sampling (blood volume taken about 0.2mL) was performed at the following time points after administration: 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 is added into the blood sampling tube in advance2Can be used as anticoagulant. Blood samples were centrifuged at 12,000rpm for 2 minutes, plasma was collected and stored at-20 ℃ or-70 ℃. .
The plasma samples collected above were processed (frozen plasma was thawed at room temperature, vortexed for 15s, 10-20. mu.L of plasma was taken, 120-150. mu.L of acetonitrile solution containing the internal standard was added, vortexed for 5min, centrifuged at 4,000rpm for 5min, 100. mu.L of supernatant was taken, and 120-150. mu.L of methanol/water (v/v. 1/1) was added and mixed) and then the concentration of the compounds in the plasma was analyzed by LC/MS/MS.
The analysis result shows that the compound of the invention has better pharmacokinetic property in rats and/or dogs. The compound of the invention has good drug property and good clinical application prospect.
In the description herein, references to the description of the term "one embodiment," "an embodiment," "some embodiments," "an example," "a specific example" or "some examples" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment, or example is included in at least one embodiment, or example of the invention. In this specification, a schematic representation of the above terms does not necessarily refer to the same embodiment, implementation, or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments, implementations, or examples. Furthermore, the various examples, embodiments, or examples described in this specification, as well as features of various examples, embodiments, or examples, may be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (5)

1. A compound which is a compound represented by formula (I) or a tautomer or a pharmaceutically acceptable salt of the compound represented by formula (I),
Figure FDA0003403548300000011
wherein:
x is O, S, S (═ O) or S (═ O)2；
R1Is cyclopropyl;
each R2a、R2b、R2c、R2d、R6a、R6b、R6cAnd R6dIndependently is H or D;
R3and R4Each independently is H, D or C1-C4An alkyl group;
R5b、R5cand R5dEach independently is H or D;
R5aand R5eEach independently is F.
2. The compound of claim 1, wherein R3And R4Each independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl or 1-methylpropyl.
3. The compound of claim 1, which is a compound having one of the following structures or a tautomer or a pharmaceutically acceptable salt of a compound having one of the following structures:
Figure FDA0003403548300000012
4. a pharmaceutical composition comprising a compound of any one of claims 1-3; and
the pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.
5. Use of a compound according to any one of claims 1 to 3 or a pharmaceutical composition according to claim 4 for the manufacture of a medicament for the prevention or treatment of a sex hormone dependent disease;
wherein the sex hormone dependent disease is a sex hormone dependent cancer, bone metastasis of a sex hormone dependent cancer, prostatic hypertrophy, hysteromyoma, endometriosis, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, multi-atrial ovarian syndrome, polycystic ovarian syndrome, acne, alopecia, infertility or irritable bowel syndrome.
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Patentee before: Dongguan dongyangguang new drug R & D Co.,Ltd.

Patentee before: SUNSHINE LAKE PHARMA Co.,Ltd.

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