WO2020221277A1 - 二氨基嘧啶类化合物治疗子宫内膜异位相关的疼痛的方法 - Google Patents

二氨基嘧啶类化合物治疗子宫内膜异位相关的疼痛的方法 Download PDF

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WO2020221277A1
WO2020221277A1 PCT/CN2020/087689 CN2020087689W WO2020221277A1 WO 2020221277 A1 WO2020221277 A1 WO 2020221277A1 CN 2020087689 W CN2020087689 W CN 2020087689W WO 2020221277 A1 WO2020221277 A1 WO 2020221277A1
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days
group
compound
saturated
alkyl
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PCT/CN2020/087689
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English (en)
French (fr)
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赵焰平
黄淮
王红军
姜媛媛
梁会宁
安然
兰洲
王瑾
周丽莹
刘亚男
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北京泰德制药股份有限公司
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Priority to KR1020217038622A priority Critical patent/KR20220008286A/ko
Priority to MX2021013347A priority patent/MX2021013347A/es
Priority to AU2020266947A priority patent/AU2020266947A1/en
Priority to BR112021021838A priority patent/BR112021021838A8/pt
Priority to CN202080032509.8A priority patent/CN114007620B/zh
Priority to EP20798599.5A priority patent/EP3960178A4/en
Priority to JP2021564186A priority patent/JP2022531570A/ja
Priority to CA3138238A priority patent/CA3138238A1/en
Priority to US17/607,475 priority patent/US20220249478A1/en
Priority to SG11202111960PA priority patent/SG11202111960PA/en
Publication of WO2020221277A1 publication Critical patent/WO2020221277A1/zh

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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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect

Definitions

  • the present invention belongs to the field of biomedicine, and specifically relates to a method for treating, containing or reducing pain associated with endometriosis, which comprises administering a therapeutically effective amount of a diaminopyrimidine compound or a pharmaceutically acceptable compound thereof to an individual in need thereof Salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs of
  • Endometriosis is characterized by the presence of endometrioid tissue outside the uterine cavity, most commonly in the peritoneal cavity. Endometriosis almost only affects premenopausal women, and is a highly common condition that has not yet been fully diagnosed. Endometriosis is the main cause of chronic pelvic pain, dyspareunia, and low fertility. The condition is usually found in women aged 15 to 50 years.
  • analgesics eg, cyclooxygenase-2 inhibitors
  • treatments for endometriosis are currently performed by reducing or suppressing menstruation and estrogen production by the ovaries. This is achieved with danazol, progesterone, oral contraceptive pills, or GnRH agonists.
  • GnRH agonists there are many side effects.
  • the use of GnRH agonists is limited to 6 months due to potential adverse effects on bone mineral density, and the treatment of danazol is also limited due to its androgenic side effects.
  • recurrence of the disease was reported within 5 years of treatment cessation in most patients.
  • the pain associated with endometriosis is the most difficult symptom for most women. For many people, the pain they suffer severely affects their daily lives. It can be continuous or it can be cyclical and consistent with the female cycle.
  • the present invention provides a method of treating, suppressing or reducing pain associated with endometriosis, which comprises administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable Salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs:
  • V 1 is selected from N, And NR;
  • R 1 and R 4 together form -NH-(C 1-6 alkylene)-L-(C 1-6 alkylene)-, preferably -NHCH 2 CH 2 -O-CH 2 CH 2 -:
  • R a and R b are each independently selected from H, -OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, saturated or partially unsaturated C 3- 10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl and C 6-12 aralkyl; or R a and R b, together with which it is The connected atoms together form a 3-12 membered heterocyclic or heteroaromatic ring, and the above groups are further optionally substituted by one or more substituents independently selected from the following: halogen, hydroxyl, oxo, amino, cyano, Nitro, C 1-6 alkyl, -OC 1-6 alkyl, saturated or partially unsaturated C 3-6 cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group, C 6-10 aromatic Group, 5-14 membered heteroaryl and C 6-12 aralkyl.
  • the present invention provides the compound of the above formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound
  • a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound The use of metabolites or prodrugs in the preparation of drugs for treating, suppressing or reducing pain associated with endometriosis.
  • the present invention provides the compound of the above formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound , Metabolites or prodrugs, which are used to treat, contain or reduce pain associated with endometriosis.
  • Figure 1 shows the pass threshold of the endometriosis model rat tested in Example 1.
  • Figure 2 shows the effect of compound 66 on P2X3 mediated current in 1321N1 cells stably transformed with P2X3.
  • Figure 3 shows the concentration-inhibition curve of compound 66 on P2X3 mediated current in 1321N1 cells stably transformed with P2X3.
  • Figure 4 shows the effect of compound 66 on P2X3 mediated current in rat dorsal root ganglion cells.
  • Figure 5 shows the concentration-inhibition curve of compound 66 on P2X3 mediated current in rat dorsal root ganglion cells.
  • alkylene means a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, Propylene or butylene.
  • alkyl is defined as a linear or branched saturated aliphatic hydrocarbon.
  • the alkyl group has 1 to 12, for example 1 to 6 carbon atoms.
  • C 1-6 alkyl refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl Group, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents
  • halogen substitution the group is called "haloalkyl” at this time) (for example, CH 2 F, CHF 2 , CF 3 , CCl 3 , C 2 F 5 , C 2 Cl 5
  • C 1-4 alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Sec-butyl or tert-butyl).
  • alkenyl means a linear or branched monovalent hydrocarbon group that contains one double bond and has 2-6 carbon atoms (“C 2-6 alkenyl”).
  • the alkenyl group is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2 -Hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl.
  • the compound of the present invention contains an alkenyl group, the compound may exist in the form of pure E (enthafen), pure Z (zusammen) or any mixture thereof.
  • alkynyl means a monovalent hydrocarbon group containing one or more triple bonds, which preferably has 2, 3, 4, 5, or 6 carbon atoms, such as ethynyl or propynyl.
  • cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , Cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl Or bicyclo[5.2.0]nonyl, decalinyl, etc.)), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents.
  • monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , Cyclooctyl, cyclon
  • the cycloalkyl group has 3 to 15 carbon atoms.
  • C 3-6 cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclic ring) of 3 to 6 ring carbon atoms Hexyl), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents, such as methyl substituted cyclopropyl.
  • cycloalkylene As used herein, the terms “cycloalkylene”, “cycloalkyl” and “hydrocarbon ring” refer to having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbons Saturated (ie, “cycloalkylene” and “cycloalkyl”) or unsaturated (ie, having one or more double bonds and/or triple bonds in the ring) monocyclic or polycyclic hydrocarbon ring of atoms, which Including but not limited to (ylidene) cyclopropyl (ring), (ylidene) cyclobutyl (ring), (ylidene) cyclopentyl (ring), (ylidene) cyclohexyl (ring), (ylidene) cycloheptyl ( (Cyclo), (ylidene)cyclooctyl (ring), (ylidene)cyclononyl (ring), (ylidene)cyclohexenyl (ring
  • heterocyclyl refers to having, for example, 3-10 (suitably 3-8, more suitably 3-6) Ring atoms, at least one of which is a heteroatom selected from N, O, and S, and the remaining ring atoms are saturated (ie, heterocycloalkyl) or partially unsaturated (ie, have one or more in the ring Double bond and/or triple bond) cyclic group.
  • 3-10 membered (ylidene) heterocycle (yl) has 2-9 (such as 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and is independently selected from N
  • One or more (for example, 1, 2, 3, or 4) heteroatoms of, O, and S are saturated or partially unsaturated (ylidene) heterocycles (groups).
  • heterocyclylene and heterocyclic examples include, but are not limited to: (ethylene) oxirane, (ethylene) aziridinyl, (azetidinyl), (ethylene) oxygen Oxetanyl (oxetanyl), (ylidene)tetrahydrofuranyl, (ylidene)dioxolinyl (dioxolinyl), (ylidene)pyrrolidinyl, (ylidene)pyrrolidonyl, (ylidene)imidazolidinyl, (ylidene) ) Pyrazolidinyl, (ylidene)pyrrolinyl, (ylidene)tetrahydropyranyl, (ylidene)piperidinyl, (ylidene)morpholinyl, (ylidene)dithianyl (dithianyl), (ylidene) Thiomorpholinyl, (ylidene)piperazinyl, or (trithianyl
  • the group also encompasses bicyclic ring systems, including spirocyclic, fused or bridged systems (such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-nitrogen Heterobicyclo[2.2.2]octane etc.).
  • the heterocyclylene and heterocyclic (radical) groups may be optionally substituted with one or more (for example, 1, 2, 3, or 4) suitable substituents.
  • (arylene) and “aromatic ring” refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated ⁇ -electron system.
  • C 6-10 (arylene)” and “C 6-10 aromatic ring” mean aromatic groups containing 6 to 10 carbon atoms, such as (phenylene) (Benzene ring) or ()naphthylene (naphthalene ring).
  • (Arylene) and aromatic ring are optionally substituted by 1 or more (such as 1 to 3) suitable substituents (e.g. halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.) .
  • (arylene) heteroaryl and “heteroaromatic ring” refer to monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and it contains at least one heteroatom which may be the same or different (the heteroatom is for example oxygen, nitrogen Or sulfur), and, in addition, may be benzo-fused in each case.
  • (ylidene)heteroaryl or “heteroaryl ring” is selected from (ylidene)thienyl, (ylidene)furanyl, (ylidene)pyrrolyl, (ylidene)oxazolyl, (ylidene)thiazolyl, (Sub)imidazolyl, (sub)pyrazolyl, (sub)isoxazolyl, (sub)isothiazolyl, (sub)oxadiazolyl, (sub)triazolyl, (sub)thiadiazolyl Etc., and their benzo derivatives; or (ylidene) pyridinyl, (ylidene) pyridazinyl, (ylidene) pyrimidinyl, (ylidene) pyrazinyl, (ylidene) triazinyl, etc., and their benzo derivative.
  • aralkyl preferably denotes an aryl or heteroaryl substituted alkyl group, wherein the aryl, heteroaryl and alkyl are as defined herein.
  • the aryl group may have 6-14 carbon atoms
  • the heteroaryl group may have 5-14 ring atoms
  • the alkyl group may have 1-6 carbon atoms.
  • Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
  • halo or halogen group is defined to include F, Cl, Br, or I.
  • substituted means that one or more (eg, one, two, three, or four) hydrogens on the specified atom are replaced by a selection from the indicated group, provided that no more than the specified atom is present In the case of normal valence and the substitution forms a stable compound. Combinations of substituents and/or variables are only allowed when such combinations form stable compounds.
  • substituent can be (1) unsubstituted or (2) substituted. If the carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, then one or more hydrogens on the carbon (to the extent of any hydrogens present) may be independently and/or together independently Optional substitution of selected substituents. If the nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be independently selected optionally Substituent replacement.
  • each substituent is selected independently of the other. Therefore, each substituent may be the same or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5, or 10 under reasonable conditions.
  • the point of attachment of a substituent can be from any suitable position of the substituent.
  • the present invention also includes all pharmaceutically acceptable isotope-labeled compounds, which are the same as the compounds of the present invention, except that one or more atoms have the same atomic number but the atomic mass or mass number is different from the predominant atomic mass in nature. Or atomic substitution of mass number.
  • isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (such as deuterium ( 2 H), tritium ( 3 H)); isotopes of carbon (such as 11 C, 13 C, and 14 C) ; Isotopes of chlorine (such as 36 Cl); isotopes of fluorine (such as 18 F); isotopes of iodine (such as 123 I and 125 I); isotopes of nitrogen (such as 13 N and 15 N); isotopes of oxygen (such as 15 O , 17 O and 18 O); phosphorus isotopes (such as 32 P); and sulfur isotopes (such as 35 S).
  • isotopes of hydrogen such as deuterium ( 2 H), tritium ( 3 H)
  • isotopes of carbon such as 11 C, 13 C, and 14 C
  • Isotopes of chlorine such as 36 Cl
  • isotopes of fluorine
  • Certain isotope-labeled compounds of the invention can be used in drug and/or substrate tissue distribution studies (such as analysis).
  • the radioisotopes tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because they are easy to incorporate and easy to detect.
  • Substitution with positron emission isotopes (such as 11 C, 18 F, 15 O, and 13 N) can be used to test substrate receptor occupancy in positron emission tomography (PET) studies.
  • the isotopically-labeled compounds of the present invention can be prepared by methods similar to those described in the attached routes and/or examples and preparations by using appropriate isotopically-labeled reagents instead of previously used non-labeled reagents.
  • the pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be replaced by an isotope, for example, D 2 O, acetone-d 6 or DMSO-d 6 .
  • stereoisomer means an isomer due to at least one asymmetric center. In compounds with one or more (for example, one, two, three, or four) asymmetric centers, it can produce racemic mixtures, single enantiomers, diastereomeric mixtures, and individual The diastereomers. Certain individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the present invention may exist in mixtures of two or more structurally different forms (commonly referred to as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait.
  • Solid lines can be used in this article Solid wedge Virtual wedge Depicts the chemical bonds of the compounds of the invention.
  • the use of a solid line to depict the bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom (e.g., specific enantiomers, racemic mixtures, etc.) are included.
  • the use of real or imaginary wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown exist. When present in a racemic mixture, use real and imaginary wedges to define relative stereochemistry, rather than absolute stereochemistry.
  • the compounds of the present invention are intended to be stereoisomers (which include cis and trans isomers, optical isomers (such as R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformational isomers, atropisomers and mixtures thereof) exist in the form of.
  • the compounds of the present invention can exhibit more than one type of isomerism, and are composed of mixtures thereof (for example, racemic mixtures and diastereomeric pairs).
  • the present invention covers all possible crystalline forms or polymorphs of the compounds of the present invention, which can be a single polymorph or a mixture of more than one polymorph in any ratio.
  • compositions of the present invention may exist in free form for treatment, or, when appropriate, in the form of pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, or prodrugs, which can be administered to patients in need thereof. After medication, the compound of the present invention or its metabolites or residues can be directly or indirectly provided. Therefore, when “the compound of the present invention” is referred to herein, it is also intended to cover the above-mentioned various derivative forms of the compound.
  • the pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate , Citrate, cyclamate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate Salt, sea benzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleic acid Salt, malonate, methanesulfonate, methyl sulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmi
  • Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. Examples include aluminum salt, arginine salt, benzathine penicillin salt, calcium salt, choline salt, diethylamine salt, diethanolamine salt, glycinate, lysine salt, magnesium salt, meglumine salt, ethanolamine salt, Potassium, sodium, tromethamine and zinc salts.
  • ester means an ester derived from each of the compounds of the general formula in this application, which includes physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the free acid or alcohol form of the present invention Compound).
  • the compound of the present invention may itself be an ester.
  • the compound of the present invention may exist in the form of a solvate (preferably a hydrate), wherein the compound of the present invention contains a polar solvent as a structural element of the crystal lattice of the compound, particularly, for example, water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, particularly, for example, water, methanol or ethanol.
  • the amount of polar solvent, especially water can be present in a stoichiometric or non-stoichiometric ratio.
  • N-oxides can be formed.
  • Nitrogen-containing heterocycle Those skilled in the art will also recognize that tertiary amines can form N-oxides.
  • metabolites of the compounds of the present invention that is, substances formed in the body when the compounds of the present invention are administered. Such products can be produced by, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Therefore, the present invention includes metabolites of the compounds of the present invention, including compounds prepared by contacting the compound of the present invention with a mammal for a time sufficient to produce its metabolites.
  • the present invention further includes within its scope the prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have less pharmacological activity or no pharmacological activity when administered to or on the body It can be converted into the compound of the present invention having the desired activity by, for example, hydrolytic cleavage.
  • prodrugs will be functional group derivatives of the compound, which are easily converted into the desired therapeutically active compound in vivo.
  • prodrugs please refer to "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella).
  • prodrugs of the present invention can be used, for example, by using certain parts known to those skilled in the art as “pro-moiety (for example, “Design of Prodrugs", described in H. Bundgaard (Elsevier, 1985))" It is prepared by substituting appropriate functional groups present in the compounds of the present invention.
  • the present invention also encompasses compounds of the present invention containing protecting groups.
  • protecting groups In any process of preparing the compounds of the present invention, protection of sensitive groups or reactive groups on any relevant molecule may be necessary and/or desirable, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, such as those described in T.W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, and these references are incorporated herein by reference. Using methods known in the art, the protecting group can be removed at an appropriate subsequent stage.
  • an effective amount refers to the amount of a compound that will relieve one or more symptoms of the condition being treated to a certain extent after being administered.
  • treating means reversing, alleviating, or inhibiting the disease or condition to which such term is applied or the progression of one or more symptoms of such a condition or condition, or Preventing such a disorder or condition or one or more symptoms of such a disorder or condition.
  • “Individual” as used herein includes human or non-human animals.
  • Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from diseases such as the diseases described herein.
  • “non-human animals” include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (such as sheep, dogs). , Cats, cows, pigs, etc.).
  • the present invention provides a method of treating, suppressing or reducing pain associated with endometriosis, which comprises administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable Salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs of:
  • V 1 is selected from N, And NR;
  • R 1 and R 4 together form -NH-(C 1-6 alkylene)-L-(C 1-6 alkylene)-, preferably -NHCH 2 CH 2 -O-CH 2 CH 2 -;
  • R a and R b are each independently selected from H, -OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, saturated or partially unsaturated C 3- 10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl and C 6-12 aralkyl; or R a and R b, together with which it is The connected atoms together form a 3-12 membered heterocyclic or heteroaromatic ring, and the above groups are further optionally substituted by one or more substituents independently selected from the following: halogen, hydroxyl, oxo, amino, cyano, Nitro, C 1-6 alkyl, -OC 1-6 alkyl, saturated or partially unsaturated C 3-6 cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group, C 6-10 aromatic Group, 5-14 membered heteroaryl and C 6-12 aralkyl.
  • the present invention provides the compound of the above formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope labeled Use of the compound, metabolite or prodrug in the preparation of a medicament for the treatment, suppression or alleviation of pain associated with endometriosis.
  • the present invention provides the compound of the above formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope labeled A compound, metabolite, or prodrug used to treat, contain, or reduce pain associated with endometriosis.
  • L is selected from CH 2, O, S and NH.
  • V 1 is selected from N, And NCH 3 .
  • each occurrence of R a and R b is independently selected from H, -OH, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, benzyl, methoxy and ethoxy; or R a and R b, together with the atom to which they are attached together form a 5-8 membered heterocyclyl or heteroaryl ring.
  • the compound of formula (I) has a structure of any of the following formulas:
  • the compound of formula (I) has a structure of any of the following formulas:
  • R 1 is selected from F, Cl, Br, I and C 2-6 alkynyl, preferably Br or ethynyl;
  • R 3 is C 1-6 alkyl, preferably isopropyl.
  • the present invention covers technical solutions obtained by arbitrarily combining various embodiments.
  • the compound of formula (I) has the following structure:
  • the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound is in an amount of about 0.005 mg/day to about 5000 mg/day, for example, about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350 , 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500 or 5000 mg/day.
  • the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound is administered in an amount of about 1 ng/kg to about 200 mg/kg, about 1 ⁇ g/kg to about 100 mg/kg, or about 1 mg/kg to about 50 mg/kg per day, for example, about 1 ⁇ g/kg per unit dose.
  • the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound The daily dose of metabolites or prodrugs is given at one time or in two, three or four doses.
  • the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, Metabolites or prodrugs are administered continuously for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 Days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, At least 30 days, at least 35 days, at least 40 days, at least 45 days, at least 50 days, at least half a year, at least 1 year, at least 2 years, at least 3 years, at least 4 years, at least 5 years or more.
  • the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound One or more (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) courses of metabolites or prodrugs, wherein each course lasts for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days , At least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days; and the interval between every two courses of treatment is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, two weeks, three
  • the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, Metabolites or prodrugs are administered by injection (such as intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including drip) or transdermal; or by oral, buccal, transnasal, transmucosal, topical, or It can be administered in the form of ophthalmic preparations or by inhalation.
  • the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound is selected from tablets, capsules, lozenges, hard candy, powders, sprays, emulsions, creams, ointments, suppositories, gels, pastes, lotions, injections, nano formulations , Patches, aqueous suspensions, injectable solutions, elixirs and syrups.
  • the pain associated with endometriosis is selected from the group consisting of chronic pelvic pain caused by endometriosis, menstrual pain, intercourse pain, waist pain, abdominal pain, vagina pain, internal organ pain, and menstrual period One or more of stool pain and/or urination pain.
  • reagents used in the following examples were purchased from Aladdin, Shanghai Shaoyuan, Alfa Aesar, Sinopharm Chemical Reagent Co., Ltd. and other companies.
  • Surgical modeling The rats were fasted and watered the night before the operation. The operation was performed under aseptic conditions under anesthesia with ketamine hydrochloride (73mg/kg) and xylazine (8.8mg/kg). Cut the midline of the rat's abdomen to expose the uterus. Cut about 1cm of tissue from the left uterine horn and the connected fat tissue, and ligate the broken end. Soak this 1cm uterine horn in a sterile lactic acid solution, expand the uterine horn longitudinally, and cut each uterine horn into 4 parts (each about 2.5mm X 2.5mm).
  • a piece of peeled uterine tissue was sutured to the inferior peritoneum with 6/0 braided silk thread, so that the inner membrane surface was close to the peritoneum.
  • one was sutured to the mesentery the other was sutured to the bifurcation of the uterus, and one was sutured near the right ovary.
  • Hot plate experiment 4 weeks after the operation, the rats were randomly divided into three groups, and each group was given vehicle (0.5% CMC-Na), 120 mg/kg compound 66, and 60 mg/kg positive control cloth. Lofen. A hot plate experiment was performed within 1-2 hours after the administration to determine the pain threshold, and the time for the rat to lift or lick the hindfoot for the first time was recorded. A total of four times were recorded, and the average value was taken as the pain threshold of a rat.
  • Autopsy cut the abdomen along the original suture to check the health of the transplanted tissue and abdominal organs.
  • the criteria for successful model construction are as follows: the graft shows cystic growth and enlargement visible to the naked eye; fresh blood vessels and a little connective tissue are formed on the wall of the cyst, and there is cool or yellow liquid in the vesicle; the graft is made into paraffin sections, and histopathology after HE staining Proved to be rat endometrial tissue.
  • I 1 is the control current
  • I 2 is the current after compound 66 is administered.
  • the tested concentrations of compound 66 included 4, 12, 37, 110, and 330 nM, and at least 3 cells were tested at each concentration (n ⁇ 3).
  • the membrane current was recorded using HEKA EPC-10 patch clamp amplifier and PATCHMASTER acquisition system.
  • Whole-cell recording mode was used to record the P2X3-mediated current of a single cell. After the cell is sealed and ruptured, clamp it at -60mV.
  • I 1 is the control current
  • I 2 is the current after compound 66 is administered.
  • the tested concentrations of compound 66 included 4, 12, 37, 110, and 330 nM, and at least 3 cells were tested at each concentration (n ⁇ 3).

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Abstract

一种生物医药领域治疗、遏制或减轻子宫内膜异位相关的疼痛的方法，其包括向需要其的个体给药治疗有效量的式（I）的二氨基嘧啶类化合物或其药学上可接受的盐、酯、立体异构体、多晶型、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药。

Description

二氨基嘧啶类化合物治疗子宫内膜异位相关的疼痛的方法 发明领域
本发明属于生物医药领域，并具体涉及治疗、遏制或减轻子宫内膜异位相关的疼痛的方法，其包括向需要其的个体给药治疗有效量的二氨基嘧啶类化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药。
发明背景
子宫内膜异位症的特征在于子宫腔外存在子宫内膜样组织，最常见是在腹膜腔中。子宫内膜异位症几乎只影响绝经前的女性，并且是高度普遍和尚未得到全面诊断的病症。子宫内膜异位症是慢性骨盆疼痛、性交困难和低生育力的主要原因。该病症通常在15至50岁年龄的女性中发现。
当止痛药(如，环加氧酶-2抑制剂)无效时，用于子宫内膜异位症的治疗目前通过卵巢减少或抑制月经和雌激素产生来进行。这通过达那唑、孕酮、口服避孕丸或GnRH激动剂来实现。然而，存在许多副作用，例如，因为对骨矿物质密度潜在的不利作用，GnRH激动剂的使用限于6个月，而由于其产雄激素副作用，达那唑的治疗也是受限的。此外，在应答使用GnRH激动剂治疗的病人中，报道了在大部分病人中在治疗停止5年内病症复发。
子宫内膜异位症相关的疼痛是大部分女性最难克服的症状。对许多人而言，她们遭受的疼痛严重影响了日常生活。其可以是持续的或可以是周期性的并与女性周期一致。
发明概述
在一个方面中，本发明提供治疗、遏制或减轻子宫内膜异位相关的疼痛的方法，其包括向需要其的个体给药治疗有效量的式(I)的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
Figure PCTCN2020087689-appb-000001
其中：
L选自C(＝O)、CRR’、NR、O、S、S＝O和S(＝O) 2；
V 1选自N、
Figure PCTCN2020087689-appb-000002
和NR；
V 2选自CR 6和C(＝O)；
Figure PCTCN2020087689-appb-000003
表示单键或双键，条件是当
Figure PCTCN2020087689-appb-000004
为单键时，V 1为NR并且V 2为C(＝O)；
R和R’各自独立地选自H、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、饱和或部分不饱和的C 3-10环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基，所述环烃基和杂环基中至多2个环成员为C(＝O)；
R 1、R 2、R 3和R 6各自独立地选自H、卤素、-CN、-NO 2、-NH 2、-OH、-SH、-Se-R、 -Si(R) 3、C 1-6烷基、C 2-6烯基、C 2-6炔基、饱和或部分不饱和的C 3-10环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、卤代C 1-6烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-S(＝O)(＝NR)R a、-NR aR b、-C(＝O)NR aR b、-C(＝S)NR aR b、-C(＝NR)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-NR aR b、-C 1-6亚烷基-OR a、-C 1-6亚烷基-C(＝O)R、-C 1-6亚烯基-OR a、-O-C 1-6亚烷基-NR aR b和-P(＝O)R aR b；
R 4和R 5各自独立地选自H、-C(＝O)OR a、-NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-C 1-6亚烷基-NR aR b、-C 1-6亚烷基-OR a、-C 1-6亚烷基-O-C 1-6亚烷基-OR a、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、饱和或部分不饱和的C 3-10环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；
或者R 1与R 4共同构成-NH-(C 1-6亚烷基)-L-(C 1-6亚烷基)-，优选为-NHCH 2CH 2-O-CH 2CH 2-：
上述烷基、亚烷基、烯基、炔基、环烃基、杂环基、芳基、杂芳基和芳烷基在每次出现时各自任选地被一个或多个独立地选自下列的取代基取代：卤素、羟基、氧代、氨基、氰基、硝基、-Si(R) 3、C 1-6烷基、饱和或部分不饱和的C 3-6环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-NR aR b、-C 1-6亚烷基-OR a、-C 1-6亚烯基-OR a和-O-C 1-6亚烷基-NR aR b，所述烷基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、羟基、氧代、氨基、氰基、硝基、-NR aR b、C 1-6烷基、-O-C 1-6烷基、饱和或部分不饱和的C 3-6环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；并且
R a和R b在每次出现时各自独立地选自H、-OH、C 1-6烷基、C 2-6烯基、C 2-6炔基、饱和或部分不饱和的C 3-10环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；或者R a和R b连同其所连接的原子共同构成3-12元杂环或杂芳环，上述基团进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、羟基、氧代、氨基、氰基、硝基、C 1-6烷基、-O-C 1-6烷基、饱和或部分不饱和的C 3-6环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基。
在另一方面中，本发明提供上述式(I)的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药在制备用于治疗、遏制或减轻子宫内膜异位相关的疼痛的药物中的用途。
在另一方面中，本发明提供上述式(I)的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其用于治疗、遏制或减轻子宫内膜异位相关的疼痛。
附图简要说明
图1显示实施例1中测试的子宫内膜异位模型大鼠的通阈值。
图2显示在稳转P2X3的1321N1细胞中施用化合物66对P2X3介导电流的作用。
图3显示在稳转P2X3的1321N1细胞中化合物66对P2X3介导电流的浓度-抑制曲线。
图4显示在大鼠背根神经节细胞中施用化合物66对P2X3介导电流的作用。
图5显示在大鼠背根神经节细胞中化合物66对P2X3介导电流的浓度-抑制曲线。
发明详细描述
定义
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。
术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。
如本文中所使用，术语“亚烷基”表示饱和二价烃基，优选表示具有1、2、3、4、5或6个碳原子的饱和二价烃基，例如亚甲基、亚乙基、亚丙基或亚丁基。
如本文中所使用，术语“烷基”定义为线性或支化饱和脂肪族烃。在一些实施方案中，烷基具有1至12个，例如1至6个碳原子。例如，如本文中所使用，术语“C 1-6烷基”指1至6个碳原子的线性或支化的基团(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基或正己基)，其任选地被1或多个(诸如1至3个)适合的取代基如卤素取代(此时该基团被称作“卤代烷基”)(例如CH 2F、CHF 2、CF 3、CCl 3、C 2F 5、C 2Cl 5、CH 2CF 3、CH 2Cl或-CH 2CH 2CF 3等)。术语“C 1-4烷基”指1至4个碳原子的线性或支化的脂肪族烃链(即甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)。
如本文中所使用，术语“烯基”意指线性的或支化的单价烃基，其包含一个双键，且具有2-6个碳原子(“C 2-6烯基”)。所述烯基为例如乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基和4-甲基-3-戊烯基。当本发明的化合物含有烯基时，所述化合物可以纯E(异侧(entgegen))形式、纯Z(同侧(zusammen))形式或其任意混合物形式存在。
如本文中所使用，术语“炔基”表示包含一个或多个三键的单价烃基，其优选具有2、3、4、5或6个碳原子，例如乙炔基或丙炔基。
如本文中所使用，术语“环烷基”指饱和的单环或多环(诸如双环)烃环(例如单环，诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基，或双环，包括螺环、稠合或桥连系统(诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基或双环[5.2.0]壬基、十氢化萘基等))，其任选地被1或多个(诸如1至3个)适合的取代基取代。所述环烷基具有3至15个碳原子。例如，术语“C 3-6环烷基”指3至6个成环碳原子的饱和的单环或多环(诸如双环)烃环(例如环丙基、环丁基、环戊基或环己基)，其任选地被1或多个(诸如1至3个)适合的取代基取代，例如甲基取代的环丙基。
如本文中所使用，术语“亚环烃基”、“环烃基”和“烃环”是指具有例如3-10个(适合地具有3-8个，更适合地具有3-6个)环碳原子的饱和(即，“亚环烷基”和“环烷基”)或不饱和的(即在环内具有一个或多个双键和/或三键)单环或多环烃环，其包括但不限于(亚)环丙基(环)、(亚)环丁基(环)、(亚)环戊基(环)、(亚)环己基(环)、(亚)环庚基(环)、(亚)环辛基(环)、(亚)环壬基(环)、(亚)环己烯基(环)等。
如本文中所使用，术语“杂环基”、“亚杂环基”和“杂环”是指具有例如3-10个(适合地具有3-8个，更适合地具有3-6个)环原子、其中至少一个环原子是选自N、O和S的杂原子且其余环原子是C的饱和(即，杂环烷基)或部分不饱和的(即在环内具有一个或多个双键和/或三键)环状基团。例如，“3-10元(亚)杂环(基)”是具有2-9个(如2、3、4、5、6、7、8或9个)环碳原子和独立地选自N、O和S的一个或多个(例如1个、2个、3个或4个)杂原子的饱和或部分不饱和(亚)杂环(基)。亚杂环基和杂环(基)的实例包括但不限于：(亚)环氧乙烷基、(亚)氮丙啶基、(亚)氮杂环丁基(azetidinyl)、(亚)氧杂环丁基(oxetanyl)、(亚)四氢呋喃基、(亚)二氧杂环戊烯基(dioxolinyl)、(亚)吡咯烷基、(亚)吡咯烷酮基、(亚)咪唑烷基、(亚)吡唑烷基、(亚)吡咯啉基、(亚)四氢吡喃基、(亚)哌啶基、(亚)吗啉基、(亚) 二噻烷基(dithianyl)、(亚)硫吗啉基、(亚)哌嗪基或(亚)三噻烷基(trithianyl)。所述基团也涵盖双环系统，包括螺环、稠合或桥连系统(诸如8-氮杂螺[4.5]癸烷、3，9-二氮杂螺[5.5]十一烷、2-氮杂双环[2.2.2]辛烷等)。亚杂环基和杂环(基)可任选地被一个或多个(例如1个、2个、3个或4个)适合的取代基取代。
如本文中所使用，术语“(亚)芳基”和“芳环”指具有共轭π电子系统的全碳单环或稠合环多环芳族基团。例如，如本文中所使用，术语“C 6-10(亚)芳基”和“C 6-10芳环”意指含有6至10个碳原子的芳族基团，诸如(亚)苯基(苯环)或(亚)萘基(萘环)。(亚)芳基和芳环任选地被1或多个(诸如1至3个)适合的取代基(例如卤素、-OH、-CN、-NO 2、C 1-6烷基等)取代。
如本文中所使用，术语“(亚)杂芳基”和“杂芳环”指单环、双环或三环芳族环系，其具有5、6、8、9、10、11、12、13或14个环原子，特别是1或2或3或4或5或6或9或10个碳原子，且其包含至少一个可以相同或不同的杂原子(所述杂原子是例如氧、氮或硫)，并且，另外在每一种情况下可为苯并稠合的。特别地，“(亚)杂芳基”或“杂芳环”选自(亚)噻吩基、(亚)呋喃基、(亚)吡咯基、(亚)噁唑基、(亚)噻唑基、(亚)咪唑基、(亚)吡唑基、(亚)异噁唑基、(亚)异噻唑基、(亚)噁二唑基、(亚)三唑基、(亚)噻二唑基等，以及它们的苯并衍生物；或(亚)吡啶基、(亚)哒嗪基、(亚)嘧啶基、(亚)吡嗪基、(亚)三嗪基等，以及它们的苯并衍生物。
如本文中所使用，术语“芳烷基”优选表示芳基或杂芳基取代的烷基，其中所述芳基、杂芳基和烷基如本文中所定义。通常，所述芳基可具有6-14个碳原子，所述杂芳基可具有5-14个环原子，并且所述烷基可具有1-6个碳原子。示例性芳烷基包括但不限于苄基、苯基乙基、苯基丙基、苯基丁基。
如本文中所使用，术语“卤代”或“卤素”基团定义为包括F、Cl、Br或I。
如本文中所使用，术语“含氮杂环”指饱和或不饱和的单环或双环基团，其在环中具有2、3、4、5、6、7、8、9、10、11、12或13个碳原子和至少一个氮原子，其还可任选地包含一个或多个(例如一个、两个、三个或四个)选自N、O、C＝O、S、S＝O和S(＝O) 2的环成员，其通过所述含氮杂环中的氮原子以及任一其余环原子与分子的其余部分连接，所述含氮杂环任选地为苯并稠合的，并且优选通过所述含氮杂环中的氮原子以及所稠合的苯环中的任一碳原子与分子的其余部分连接。
术语“取代”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。
如果取代基被描述为“任选地被取代”，则取代基可(1)未被取代或(2)被取代。如果取代基的碳被描述为任选地被取代基列表中的一个或多个取代，则碳上的一个或多个氢(至存在的任何氢的程度)可单独和/或一起被独立地选择的任选的取代基替代。如果取代基的氮被描述为任选地被取代基列表中的一个或多个取代，则氮上的一个或多个氢(至存在的任何氢的程度)可各自被独立地选择的任选的取代基替代。
如果取代基被描述为“独立地选自”一组，则各取代基独立于另一者被选择。因此，各取代基可与另一(其他)取代基相同或不同。
如本文中所使用，术语“一个或多个”意指在合理条件下的1个或超过1个，例如2个、3个、4个、5个或10个。
除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。
当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代的环中的任一成环原子。
本发明还包括所有药学上可接受的同位素标记的化合物，其与本发明的化合物相同，除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占 优势的原子质量或质量数的原子替代。适合包含入本发明的化合物中的同位素的实例包括(但不限于)氢的同位素(例如氘( 2H)、氚( 3H))；碳的同位素(例如 11C、 13C及 14C)；氯的同位素(例如 36Cl)；氟的同位素(例如 18F)；碘的同位素(例如 123I及 125I)；氮的同位素(例如 13N及 15N)；氧的同位素(例如 15O、 17O及 18O)；磷的同位素(例如 32P)；及硫的同位素(例如 35S)。某些同位素标记的本发明的化合物(例如掺入放射性同位素的那些)可用于药物和/或底物组织分布研究(例如分析)中。放射性同位素氚(即 3H)及碳-14(即 14C)因易于掺入且容易检测而特别可用于该目的。用正电子发射同位素(例如 11C、 18F、 15O及 13N)进行取代可在正电子发射断层显像术(PET)研究中用于检验底物受体占据情况。被同位素标记的本发明的化合物可通过与描述于随附路线和/或实施例及制备中的那些类似的方法通过使用适当的被同位素标记的试剂代替之前采用的非标记的试剂来制备。本发明的药学上可接受的溶剂合物包括其中结晶溶剂可被同位素取代的那些，例如，D 2O、丙酮-d 6或DMSO-d 6。
术语“立体异构体”表示由于至少一个不对称中心形成的异构体。在具有一个或多个(例如一个、两个、三个或四个)不对称中心的化合物中，其可产生外消旋混合物、单一对映异构体、非对映异构体混合物和单独的非对映异构体。特定个别分子也可以几何异构体(顺式/反式)存在。类似地，本发明的化合物可以两种或更多种处于快速平衡的结构不同的形式的混合物(通常称作互变异构体)存在。互变异构体的代表性实例包括酮-烯醇互变异构体、苯酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体等。要理解，本申请的范围涵盖所有这样的以任意比例(例如60％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％、99％)的异构体或其混合物。
本文中可使用实线
Figure PCTCN2020087689-appb-000005
实楔形
Figure PCTCN2020087689-appb-000006
或虚楔形
Figure PCTCN2020087689-appb-000007
描绘本发明的化合物的化学键。使用实线以描绘键连至不对称碳原子的键欲表明，包括该碳原子处的所有可能的立体异构体(例如，特定的对映异构体、外消旋混合物等)。使用实或虚楔形以描绘键连至不对称碳原子的键欲表明，存在所示的立体异构体。当存在于外消旋混合物中时，使用实及虚楔形以定义相对立体化学，而非绝对立体化学。除非另外指明，否则本发明的化合物意欲可以立体异构体(其包括顺式及反式异构体、光学异构体(例如R及S对映异构体)、非对映异构体、几何异构体、旋转异构体、构象异构体、阻转异构体及其混合物)的形式存在。本发明的化合物可表现一种以上类型的异构现象，且由其混合物(例如外消旋混合物及非对映异构体对)组成。
本发明涵盖本发明的化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。
还应当理解，本发明的某些化合物可以游离形式存在用于治疗，或适当时，以其药学上可接受的衍生物形式存在。在本发明中，药学上可接受的衍生物包括但不限于，药学上可接受的盐、酯、溶剂合物、N-氧化物、代谢物或前药，在将它们向需要其的患者给药后，能够直接或间接提供本发明的化合物或其代谢物或残余物。因此，当在本文中提及“本发明的化合物”时，也意在涵盖化合物的上述各种衍生物形式。
本发明的化合物的药学上可接受的盐包括其酸加成盐及碱加成盐。
适合的酸加成盐由形成药学可接受盐的酸来形成。实例包括乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环己氨磺酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、海苯酸盐、盐酸盐/氯化物、氢溴酸盐/溴化物、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐(naphthylate)、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸盐、糖二酸盐、硬脂酸盐、丁二酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐 及昔萘酸盐(xinofoate)。
适合的碱加成盐由形成药学可接受盐的碱来形成。实例包括铝盐、精氨酸盐、苄星青霉素盐、钙盐、胆碱盐、二乙胺盐、二乙醇胺盐、甘氨酸盐、赖氨酸盐、镁盐、葡甲胺盐、乙醇胺盐、钾盐、钠盐、氨丁三醇盐及锌盐。
适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts：Properties，Selection，and Use”(Wiley-VCH，2002)。用于制备本发明的化合物的药学上可接受的盐的方法为本领域技术人员已知的。
如本文中所使用，术语“酯”意指衍生自本申请中各个通式化合物的酯，其包括生理上可水解的酯(可在生理条件下水解以释放游离酸或醇形式的本发明的化合物)。本发明的化合物本身也可以是酯。
本发明的化合物可以溶剂合物(优选水合物)的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
本领域技术人员会理解，由于氮需要可用的孤对电子来氧化成氧化物，因此并非所有的含氮杂环都能够形成N-氧化物；本领域技术人员会识别能够形成N-氧化物的含氮杂环。本领域技术人员还会认识到叔胺能够形成N-氧化物。用于制备杂环和叔胺的N-氧化物的合成方法是本领域技术人员熟知的，包括用过氧酸如过氧乙酸和间氯过氧苯甲酸(MCPBA)、过氧化氢、烷基过氧化氢如叔丁基过氧化氢、过硼酸钠和双环氧乙烷(dioxirane)如二甲基双环氧乙烷来氧化杂环和叔胺。这些用于制备N-氧化物的方法已在文献中得到广泛描述和综述，参见例如：T.L.Gilchrist，Comprehensive Organic Synthesis，vol.7，pp 748-750；A.R.Katritzky和A.J.Boulton，Eds.，Academic Press；以及G.W.H.Cheeseman和E.S.G.Werstiuk，Advances in Heterocyclic Chemistry，vol.22，pp 390-392，A.R.Katritzky和A.J.Boulton，Eds.，Academic Press。
在本发明的范围内还包括本发明的化合物的代谢物，即在给药本发明的化合物时体内形成的物质。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、酶解等产生。因此，本发明包括本发明的化合物的代谢物，包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。
本发明在其范围内进一步包括本发明的化合物的前药，其为自身可具有较小药理学活性或无药理学活性的本发明的化合物的某些衍生物当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的本发明的化合物。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其他信息可参见“Pro-drugs as Novel Delivery Systems”，第14卷，ACS Symposium Series(T.Higuchi及V.Stella)。本发明的前药可例如通过用本领域技术人员已知作为“前-部分(pro-moiety)(例如“Design of Prodrugs”，H.Bundgaard(Elsevier，1985)中所述)”的某些部分替代本发明的化合物中存在的适当官能团来制备。
本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现，例如，在T.W.Greene&P.G.M.Wuts，Protective Groups in Organic Synthesis，John Wiley&Sons，1991中所述的那些保护基，这些参考文献通过援引加入本文。使用本领域已知的方法，在适当的后续阶段可以移除保护基。
术语“约”是指在所述数值的±10％范围内，优选±5％范围内，更优选±2％范围内。
如本文中所使用的术语“有效量”指被给药后会在一定程度上缓解所治疗病症的一或多种症状的化合物的量。
除非另外说明，否则如本文中所使用，术语“治疗(treating)”意指逆转、减轻、抑制 这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状的进展，或预防这样的病症或病况或者这样的病症或病况的一或多种症状。
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
具体实施方式
在一些实施方案中，本发明提供治疗、遏制或减轻子宫内膜异位相关的疼痛的方法，其包括向需要其的个体给药治疗有效量的式(I)的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
Figure PCTCN2020087689-appb-000008
其中：
L选自C(＝O)、CRR’、NR、O、S、S＝O和S(＝O) 2；
V 1选自N、
Figure PCTCN2020087689-appb-000009
和NR；
V 2选自CR 6和C(＝O)；
Figure PCTCN2020087689-appb-000010
表示单键或双键，条件是当
Figure PCTCN2020087689-appb-000011
为单键时，V 1为NR并且V 2为C(＝O)；
R和R’各自独立地选自H、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、饱和或部分不饱和的C 3-10环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基，所述环烃基和杂环基中至多2个环成员为C(＝O)；
R 1、R 2、R 3和R 6各自独立地选自H、卤素、-CN、-NO 2、-NH 2、-OH、-SH、-Se-R、-Si(R) 3、C 1-6烷基、C 2-6烯基、C 2-6炔基、饱和或部分不饱和的C 3-10环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、卤代C 1-6烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-S(＝O)(＝NR)R a、-NR aR b、-C(＝O)NR aR b、-C(＝S)NR aR b、-C(＝NR)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-NR aR b、-C 1-6亚烷基-OR a、-C 1-6亚烷基-C(＝O)R、-C 1-6亚烯基-OR a、-O-C 1-6亚烷基-NR aR b和-P(＝O)R aR b；
R 4和R 5各自独立地选自H、-C(＝O)OR a、-NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-C 1-6亚烷基-NR aR b、-C 1-6亚烷基-OR a、-C 1-6亚烷基-O-C 1-6亚烷基-OR a、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、饱和或部分不饱和的C 3-10环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；
或者R 1与R 4共同构成-NH-(C 1-6亚烷基)-L-(C 1-6亚烷基)-，优选为-NHCH 2CH 2-O-CH 2CH 2-；
上述烷基、亚烷基、烯基、炔基、环烃基、杂环基、芳基、杂芳基和芳烷基在每次出现时各自任选地被一个或多个独立地选自下列的取代基取代：卤素、羟基、氧代、氨基、氰基、硝基、-Si(R) 3、C 1-6烷基、饱和或部分不饱和的C 3-6环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-NR aR b、 -C 1-6亚烷基-OR a、-C 1-6亚烯基-OR a和-O-C 1-6亚烷基-NR aR b，所述烷基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、羟基、氧代、氨基、氰基、硝基、-NR aR b、C 1-6烷基、-O-C 1-6烷基、饱和或部分不饱和的C 3-6环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；并且
R a和R b在每次出现时各自独立地选自H、-OH、C 1-6烷基、C 2-6烯基、C 2-6炔基、饱和或部分不饱和的C 3-10环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；或者R a和R b连同其所连接的原子共同构成3-12元杂环或杂芳环，上述基团进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、羟基、氧代、氨基、氰基、硝基、C 1-6烷基、-O-C 1-6烷基、饱和或部分不饱和的C 3-6环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基。
在另一些实施方案中，本发明提供上述式(I)的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药在制备用于治疗、遏制或减轻子宫内膜异位相关的疼痛的药物中的用途。
在另一些实施方案中，本发明提供上述式(I)的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其用于治疗、遏制或减轻子宫内膜异位相关的疼痛。
在优选的实施方案中，L选自CH 2、O、S和NH。
在优选的实施方案中，V 1选自N、
Figure PCTCN2020087689-appb-000012
和NCH 3。
在优选的实施方案中，V 2选自CH、C-NHCH 3、C-OCH 3、C-F、和C(＝O)。
在优选实施方案中，R a和R b在每次出现时各自独立地选自H、-OH、甲基、乙基、正丙基、异丙基、环丙基、苯基、苄基、甲氧基和乙氧基；或者R a和R b连同其所连接的原子共同构成5-8元杂环或杂芳环。
在优选实施方案中，R 1、R 2、R 3和R 6各自独立地选自H、F、Cl、Br、I、-CN、-NH 2、-OH、-SH、-Se-CH 3、-Si(CH 3) 3、-CH 2NH 2、-CH 2NHCH 3、-CH 2N(CH 3) 2、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、环丙基、环丁基、环戊基、环己基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、三氟甲基、乙酰基、-C(＝O)OH、-C(＝O)NH 2、-C(＝S)NH 2、-C(＝NH)NH 2、-NHCH 3、-NHCH 2CH 3、-NHCH 2CF 3、-N(CH 3) 2、-N(CH 3)(C 2H 5)、-N(C 2H 5) 2、-NHCH 2CH 2OH、-NH-C(＝O)CH 3、-NH-C(＝O)CH＝CH 2、甲氧基、乙氧基、丙氧基、苯基、-NH-C(＝O)-NH 2、-NH-C(＝O)OCH 3、-SCH 3、-SCH 2CH 3、-SC(CH 3) 3、-SBn、-S(＝O)CH 3、-S(＝O)Bn、-S(＝O) 2CH 3、-S(＝O) 2Bn、-S(＝O) 2NH 2、-S(＝O) 2NHCH 3、-S(＝O) 2N(CH 3) 2、-S(＝O)(＝NH)CH 3、-P(＝O)(CH 3) 2、-P(＝O)(C 2H 5) 2、
Figure PCTCN2020087689-appb-000013
Figure PCTCN2020087689-appb-000014
Figure PCTCN2020087689-appb-000015
在优选实施方案中，R 4和R 5各自独立地选自H、-C(＝O)OC(CH 3) 3、-NH 2、-NHCH 3、-NHPh、-NHC(＝O)CH 3、-NHBoc、甲基、乙基、-CH 2CF 3、正丙基、异丙基、正丁基、异丁基、叔丁基、环丙基、环丁基、环戊基、环己基、苯基、苄基、
Figure PCTCN2020087689-appb-000016
Figure PCTCN2020087689-appb-000017
在优选实施方案中，所述式(I)的化合物具有任意下式的结构：
Figure PCTCN2020087689-appb-000018
优选具有任意下式的结构：
Figure PCTCN2020087689-appb-000019
更优选地，所述式(I)的化合物具有任意下式的结构：
Figure PCTCN2020087689-appb-000020
其中：
R 1选自F、Cl、Br、I和C 2-6炔基，优选为Br或乙炔基；并且
R 3为C 1-6烷基，优选为异丙基。
本发明涵盖对各个实施方案进行任意组合所得的技术方案。
在优选实施方案中，所述式(I)的化合物具有以下结构：
Figure PCTCN2020087689-appb-000021
Figure PCTCN2020087689-appb-000022
Figure PCTCN2020087689-appb-000023
Figure PCTCN2020087689-appb-000024
Figure PCTCN2020087689-appb-000025
Figure PCTCN2020087689-appb-000026
Figure PCTCN2020087689-appb-000027
Figure PCTCN2020087689-appb-000028
Figure PCTCN2020087689-appb-000029
在一些实施方案中，将所述式(I)的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药以约0.005mg/日至约5000mg/日的量，例如约0.005、0.05、0.5、5、10、20、30、40、50、100、150、200、250、300、350、400、450、500、550、600、650、700、750、800、850、900、950、1000、1500、2000、2500、3000、3500、4000、4500或5000mg/日的量给药。
在一些实施方案中，将所述式(I)的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药以每日约1ng/kg至约200mg/kg、约1μg/kg至约100mg/kg或者约1mg/kg至约50mg/kg的量给药，例如以每单位剂量约1μg/kg、约10μg/kg、约25μg/kg、约50μg/kg、约75μg/kg、约100μg/kg、约125μg/kg、约150μg/kg、约175μg/kg、约200μg/kg、约225μg/kg、约250μg/kg、约275μg/kg、约300μg/kg、约325μg/kg、约350μg/kg、约375μg/kg、约400μg/kg、约425μg/kg、约450μg/kg、约475μg/kg、约500μg/kg、约525μg/kg、约550μg/kg、约575μg/kg、约600μg/kg、约625μg/kg、约650μg/kg、约675μg/kg、约700μg/kg、约725μg/kg、约750μg/kg、约775μg/kg、约800μg/kg、约825μg/kg、约850μg/kg、约875μg/kg、约900μg/kg、约925μg/kg、约950μg/kg、约975μg/kg、约1mg/kg、约5mg/kg、约10mg/kg、约15mg/kg、约20mg/kg、约25mg/kg、约30mg/kg、约35mg/kg、约40mg/kg、约45mg/kg、约50mg/kg、约60mg/kg、约70mg/kg、约80mg/kg、约90mg/kg、约100mg/kg、约125mg/kg、约150mg/kg、约175mg/kg、约200mg/kg体重的量给药。
在一些实施方案中，将所述式(I)的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药的每日剂量一次性给予或分两次、三次或四次给予。
在一些实施方案中，将所述式(I)的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药连续给药至少3天、至少4天、至少5天、至少6天、至少7天、至少8天、至少9天、至少10天、至少11天、至少12天、至少13天、至少14天、至少15天、至少16天、至少17天、至少18天、至少19天、至少20天、至少21天、至少22天、至少23天、至少24天、至少25天、至少30天、至少35天、至少40天、至少45天、至少50天、至少半年、 至少1年、至少2年、至少3年、至少4年、至少5年或更多年。
在一些实施方案中，将所述式(I)的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药给药一个或多个(例如1、2、3、4、5、6、7、8、9或10个)疗程，其中每个疗程持续至少3天、至少4天、至少5天、至少6天、至少7天、至少8天、至少9天、至少10天、至少11天、至少12天、至少13天、至少14天、至少15天、至少16天、至少17天、至少18天、至少19天、至少20天、至少21天、至少22天、至少23天、至少24天、至少25天、至少30天、至少35天、至少40天、至少45天或至少50天；并且每两个疗程之间间隔0、1、2、3、4、5、6、7、8、9、10天、两周、三周或四周。
在一些实施方案中，将所述式(I)的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药通过注射(如静脉内、动脉内、皮下、腹膜内、肌内注射，包括滴注)或经皮给药；或通过口服、含服、经鼻、透粘膜、局部、以眼用制剂的形式或通过吸入给药。
在一些实施方案中，将所述式(I)的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药以选自片剂、胶囊剂、锭剂、硬糖剂、散剂、喷雾剂、乳剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、注射剂、纳米制剂、贴剂、水性混悬剂、可注射溶液剂、酏剂和糖浆剂的剂型给药。
在一些实施方案中，所述子宫内膜异位相关的疼痛选自子宫内膜异位引发的慢性盆腔痛、经期痛、性交疼痛、腰部疼痛、腹部疼痛、阴道疼痛、内脏器官疼痛以及月经期间大便疼痛和/或小便疼痛中的一种或多种。
实施例
为了使本发明的目的和技术方案更加清楚，以下结合具体实施例进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。并且，下列实施例中未提及的具体实验方法，均按照常规实验方法进行。
如无其它说明，以下实施例中使用的试剂购自阿拉丁、上海韶远、Alfa Aesar、国药集团化学试剂有限公司等公司。
本申请化合物66根据PCT/CN2018/112829(将其以其整体援引加入本文)中描述的方法制备。
实施例1
自体移植诱发型子宫内膜异位症模型大鼠的热板实验
动物：由北京维通利华实验动物技术有限公司购得约8-12周性成熟未交配雌性SPF级Sprague-Dawley大鼠(200-220g)。经阴道涂片检查选择动情期大鼠。
饲养：在12/12小时光暗循环下饲养。
手术造模：手术前夜大鼠禁食，不禁水。手术在盐酸氯胺酮(73mg/kg)与赛拉嗪(8.8mg/kg)麻醉，无菌条件下进行。将大鼠腹部中线切开，暴露子宫。在左侧子宫角以及相连的脂肪组织处截取约1cm的组织，断端结扎。将此1cm的子宫角浸泡在无菌的乳酸溶液中，将子宫角纵向展开，每个子宫角切成4个部分(每个约2.5mm X 2.5mm)。用6/0的编织丝线将1块剥离的子宫组织缝合于腹膜下壁，使内膜面紧贴腹膜。其余3块剥离的子宫组织中，1块缝合于肠系膜，另1块缝合于子宫分叉处，1块缝合于右卵巢附近。缝合切口，同时留取内膜组织送病理检查以确认为子宫内膜。
热板实验：手术4周后，将大鼠随机分为三组，向各组通过口服方式分别给予溶媒(0.5％CMC-Na)、120mg/kg的化合物66，以及60mg/kg的阳性对照布洛芬。在给药后 1-2小时内分别进行热板实验测定痛阈值，记录大鼠首次抬后足或舔后足的时间，共记录四次，取平均值作为一只大鼠的痛阈值。
尸检：沿原缝合处切开腹部，检查移植组织以及腹腔器官的健康状况。模型构建成功标准如下：肉眼可见移植物呈囊性生长增大；囊壁有新鲜血管和少许结缔组织生成，囊泡内有清凉或黄色液体；移植物制成石蜡切片，HE染色后病理组织学证明为大鼠子宫内膜组织。
将造模成功的大鼠计入统计学组(溶媒组12只动物，测试组11只动物，并且对照组13只动物)。结果使用Graphpad Prism软件进行one-way ANONA Dunnett’s多重比较法分析，**表示p＜0.01，***表示p＜0.001)。结果如图1中所示。
结果表明测试组的大鼠的痛阈值显著高于溶媒组和对照组大鼠的痛阈值，表明本发明的化合物遏制并减轻了子宫内膜异位相关的疼痛。
实施例2.对稳转P2X3的1321N1细胞系的P2X3介导电流的抑制
采用HEKA EPC-10膜片钳放大器和PATCHMASTER采集系统记录膜电流。将1321N1 P2X3稳转细胞转移到一个嵌于倒置显微镜平台的约1ml的浴槽中，采用重力灌流系统灌流细胞外液(2mM CaCl 2，1mM MgCl 2，5mM KCl，155mM NaCl，12mM葡萄糖以及10mM HEPES(pH＝7.4))。采用全细胞记录模式记录单个细胞的P2X3介导的电流。当细胞封接破膜后，钳制在-60mV。灌流10μM的Na2ATP 5s，将此时诱发的P2X3介导电流作为对照电流。然后用一定浓度的化合物66的溶液(用细胞外液配制)处理细胞5min，随后同时施用该浓度的化合物66的溶液和10μM的Na2ATP来诱发细胞电流(化合物对电流的作用参见图2)，通过以下公式计算其相对于对照电流的抑制率：
相对于对照电流的抑制率＝(1-I 2/I 1)*100％
其中I 1为对照电流，I 2为施用化合物66后的电流。所测试的化合物66的浓度包括4、12、37、110和330nM，每个浓度至少测试3个细胞(n≥3)。
以化合物66的浓度为横坐标，以对照电流的抑制率为纵坐标作图(参见图3)，并将数据用Hill方程拟合得到化合物66对于将10μM的Na2ATP诱发的P2X3电流抑制50％所需的浓度(IC 50)为26.16nM。
实施例3.对离体培养的大鼠背根神经节(DRG)的P2X3介导的电流的抑制
采用HEKA EPC-10膜片钳放大器和PATCHMASTER采集系统记录膜电流。将大鼠原代背根神经节细胞转移到一个嵌于倒置显微镜平台的约1ml的浴槽中，采用重力灌流系统灌流细胞外液(2mM CaCl 2，1mM MgCl 2，5mM KCl，155mM NaCl，12mM葡萄糖以及10mM HEPES(pH＝7.4))。采用全细胞记录模式记录单个细胞的P2X3介导的电流。当细胞封接破膜后，钳制在-60mV。灌流30μM a，b-Me ATP(也称作“α，β-meATP”)5s，将此时诱发的P2X3介导的电流作为对照电流，然后用一定浓度的化合物66的溶液(用细胞外液配制)处理细胞5min，随后同时施用该浓度的化合物66的溶液和30μM的a，b-Me ATP来诱发细胞电流(化合物对电流的作用参见图4)，通过以下公式计算其相对于对照电流的抑制率：
相对于对照电流的抑制率＝(1-I 2/I 1)*100％
其中I 1为对照电流，I 2为施用化合物66后的电流。所测试的化合物66的浓度包括4、12、37、110和330nM，每个浓度至少测试3个细胞(n≥3)。
以化合物66的浓度为横坐标，以对照电流的抑制率为纵坐标作图(参见图5)，并将数据用Hill方程拟合得到化合物66对于将30μM a，b-Me ATP诱发的P2X3电流抑制50％所需的浓度(IC 50)为28.30nM。
除本文中描述的那些外，根据前述描述，本发明的各种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。

Claims (11)

  1. 治疗、遏制或减轻子宫内膜异位相关的疼痛的方法，其包括向需要其的个体给药治疗有效量的式(I)的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
    Figure PCTCN2020087689-appb-100001
    其中：
    L选自C(＝O)、CRR’、NR、O、S、S＝O和S(＝O) 2；
    V 1选自N、
    Figure PCTCN2020087689-appb-100002
    和NR；
    V 2选自CR 6和C(＝O)；
    Figure PCTCN2020087689-appb-100003
    表示单键或双键，条件是当
    Figure PCTCN2020087689-appb-100004
    为单键时，V 1为NR并且V 2为C(＝O)；
    R和R’各自独立地选自H、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、饱和或部分不饱和的C 3-10环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基，所述环烃基和杂环基中至多2个环成员为C(＝O)；
    R 1、R 2、R 3和R 6各自独立地选自H、卤素、-CN、-NO 2、-NH 2、-OH、-SH、-Se-R、-Si(R) 3、C 1-6烷基、C 2-6烯基、C 2-6炔基、饱和或部分不饱和的C 3-10环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、卤代C 1-6烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-S(＝O)(＝NR)R a、-NR aR b、-C(＝O)NR aR b、-C(＝S)NR aR b、-C(＝NR)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-NR aR b、-C 1-6亚烷基-OR a、-C 1-6亚烷基-C(＝O)R、-C 1-6亚烯基-OR a、-O-C 1-6亚烷基-NR aR b和-P(＝O)R aR b；
    R 4和R 5各自独立地选自H、-C(＝O)OR a、-NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-C 1-6亚烷基-NR aR b、-C 1-6亚烷基-OR a、-C 1-6亚烷基-O-C 1-6亚烷基-OR a、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、饱和或部分不饱和的C 3-10环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；
    或者R 1与R 4共同构成-NH-(C 1-6亚烷基)-L-(C 1-6亚烷基)-，优选为-NHCH 2CH 2-O-CH 2CH 2-；
    上述烷基、亚烷基、烯基、炔基、环烃基、杂环基、芳基、杂芳基和芳烷基在每次出现时各自任选地被一个或多个独立地选自下列的取代基取代：卤素、羟基、氧代、氨基、氰基、硝基、-Si(R) 3、C 1-6烷基、饱和或部分不饱和的C 3-6环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-NR aR b、-C 1-6亚烷基-OR a、-C 1-6亚烯基-OR a和-O-C 1-6亚烷基-NR aR b，所述烷基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、羟基、氧代、氨基、氰基、硝基、-NR aR b、C 1-6烷基、-O-C 1-6烷基、饱和或部分不饱和的C 3-6环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；并且
    R a和R b在每次出现时各自独立地选自H、-OH、C 1-6烷基、C 2-6烯基、C 2-6炔基、饱和或部分不饱和的C 3-10环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；或者R a和R b连同其所连接的原子共同构成3-12元杂环或杂芳环，上述基团进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、羟基、氧代、氨基、氰基、硝基、C 1-6烷基、-O-C 1-6烷基、饱和或部分不饱和的C 3-6环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基。
  2. 权利要求1的方法，其中所述化合物具有任意下式的结构：
    Figure PCTCN2020087689-appb-100005
    优选具有任意下式的结构：
    Figure PCTCN2020087689-appb-100006
    Figure PCTCN2020087689-appb-100007
    更优选地，所述式(I)的化合物具有任意下式的结构：
    Figure PCTCN2020087689-appb-100008
    其中：
    R 1选自F、Cl、Br、I和C 2-6炔基，优选为Br或乙炔基；并且
    R 3为C 1-6烷基，优选为异丙基。
  3. 权利要求1或2的方法，其中所述化合物具有以下结构：
    Figure PCTCN2020087689-appb-100009
    Figure PCTCN2020087689-appb-100010
    Figure PCTCN2020087689-appb-100011
    Figure PCTCN2020087689-appb-100012
    Figure PCTCN2020087689-appb-100013
    Figure PCTCN2020087689-appb-100014
    Figure PCTCN2020087689-appb-100015
    Figure PCTCN2020087689-appb-100016
    Figure PCTCN2020087689-appb-100017
  4. 权利要求1-3中任一项的方法，其中将所述式(I)的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药以约0.005mg/日至约5000mg/日的量，例如约0.005、0.05、0.5、5、10、20、30、40、50、100、150、200、250、300、350、400、450、500、550、600、650、700、750、800、850、900、950、1000、1500、2000、2500、3000、3500、4000、4500或5000mg/日的量给药。
  5. 权利要求1-3中任一项的方法，其中将所述式(I)的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药以每日约1ng/kg至约200mg/kg、约1μg/kg至约100mg/kg或者约1mg/kg至约50mg/kg的量给药，例如以每单位剂量约1μg/kg、约10μg/kg、约25μg/kg、约50μg/kg、约75μg/kg、约100μg/kg、约125μg/kg、约150μg/kg、约175μg/kg、约200μg/kg、约225μg/kg、约250μg/kg、约275μg/kg、约300μg/kg、约325μg/kg、约350μg/kg、约375μg/kg、约400μg/kg、约425μg/kg、约450μg/kg、约475μg/kg、约500μg/kg、约525μg/kg、约550μg/kg、约575μg/kg、约600μg/kg、约625μg/kg、约650μg/kg、约675μg/kg、约700μg/kg、约725μg/kg、约750μg/kg、约775μg/kg、约800μg/kg、约825μg/kg、约850μg/kg、约875μg/kg、约900μg/kg、约925μg/kg、约950μg/kg、约975μg/kg、约1mg/kg、约5mg/kg、约10mg/kg、约15mg/kg、约20mg/kg、约25mg/kg、约30mg/kg、约35mg/kg、约40mg/kg、约45mg/kg、约50mg/kg、约60mg/kg、约70mg/kg、约80mg/kg、约90mg/kg、约100mg/kg、约125mg/kg、约150mg/kg、约175mg/kg、约200mg/kg体重的量给药。
  6. 权利要求1-5中任一项的方法，其中将所述式(I)的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药的每日剂量一次性给予或分两次、三次或四次给予。
  7. 权利要求1-6中任一项的方法，其中将所述式(I)的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药连续给药至少3天、至少4天、至少5天、至少6天、至少7天、至少8天、至少9天、至少10天、至少11天、至少12天、至少13天、至少14天、至少15天、至少16天、至少17天、至少18天、至少19天、至少20天、至少21天、至少22天、至少23天、至少24天、至少25天、至少30天、至少35天、至少40天、至少45天、至少50天、至少半年、至少1年、至少2年、至少3年、至少4年或至少5年。
  8. 权利要求1-7中任一项的方法，其中将所述式(I)的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药给药一个或多个(例如1、2、3、4、5、6、7、8、9或10个)疗程，其中每个疗程持续至少3天、至少4天、至少5天、至少6天、至少7天、至少8天、至少9天、至少10天、至少11天、至少12天、至少13天、至少14天、至少15天、至少16天、至少17天、至少18天、至少19天、至少20天、至少21天、至少22天、至少23天、至少24天、至少25天、至少30天、至少35天、至少40天、至少45天或至少50天；并且每两个疗程之间间隔0、1、2、3、4、5、6、7、8、9、10天、两周、三周或四周。
  9. 权利要求1-8中任一项的方法，其中将所述式(I)的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药通过注射(如静脉内、动脉内、皮下、腹膜内、肌内注射，包括滴注)或经皮给药；或通过口服、含服、经鼻、透粘膜、局部、以眼用制剂的形式或通过吸入给药。
  10. 权利要求1-9中任一项的方法，其中将所述式(I)的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药以选自片剂、胶囊剂、锭剂、硬糖剂、散剂、喷雾剂、乳剂、乳膏剂、软膏剂、 栓剂、凝胶剂、糊剂、洗剂、注射剂、纳米制剂、贴剂、水性混悬剂、溶液剂、酏剂和糖浆剂的剂型给药。
  11. 权利要求1-10中任一项的方法，其中所述子宫内膜异位相关的疼痛选自子宫内膜异位引发的慢性盆腔痛、经期痛、性交疼痛、腰部疼痛、腹部疼痛、阴道疼痛、内脏器官疼痛以及月经期间大便疼痛和/或小便疼痛中的一种或多种。
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