WO2021228236A1 - 氘代四氢噻吩并[3,4-d]嘧啶二酮化合物以及包含该化合物的药物组合物 - Google Patents

氘代四氢噻吩并[3,4-d]嘧啶二酮化合物以及包含该化合物的药物组合物 Download PDF

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WO2021228236A1
WO2021228236A1 PCT/CN2021/093882 CN2021093882W WO2021228236A1 WO 2021228236 A1 WO2021228236 A1 WO 2021228236A1 CN 2021093882 W CN2021093882 W CN 2021093882W WO 2021228236 A1 WO2021228236 A1 WO 2021228236A1
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compound
pharmaceutically acceptable
acceptable salt
solvate
hydrate
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French (fr)
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吕彬华
李成伟
杨金庚
宋赠
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苏州泽璟生物制药股份有限公司
上海泽璟医药技术有限公司
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Priority to CN202180030371.2A priority Critical patent/CN115768774A/zh
Publication of WO2021228236A1 publication Critical patent/WO2021228236A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P37/00—Drugs for immunological or allergic disorders
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the invention belongs to the field of medicine. Specifically, the present invention relates to a novel deuterated tetrahydrothieno[3,4-d]pyrimidinedione compound and a pharmaceutical composition containing the compound.
  • GnRH Gonadotropn-releasing hormone
  • Tetrahydrothieno[3,4-d]pyrimidinedione compounds and derivatives are a class of gonadotropin releasing hormone inhibitors.
  • Patent WO2007042392 discloses a series of tetrahydrothieno[3,4-d]pyrimidinedione derivatives.
  • the compound Linzagolix is a selective GnRH inhibitor with a chemical name of 3-(5-((2,3- Difluoro-6-methoxyphenyl) methoxy)-2-fluoro-4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3 ,4-d]pyrimidine-5-carboxylic acid, has the use of treating uterine fibroids, endometriosis and adenomyosis.
  • the compound is in the treatment of endometriosis and adenomyosis ( In the Phase II clinical study of endometriosis and adenomyosis and the Phase III clinical study of uterine fibroids.
  • gonadotropin-releasing hormone is one of the important targets for the research and development of gynecological diseases, in addition to Triptorelin (Triptorelin), Alarelin (Alarelin) and other polypeptide gonadotropin-releasing hormone analogs, Relugolix and Elagolix, etc. Except for a few newly marketed gonadotropin releasing hormone inhibitor drugs, the research progress of GnRH inhibitors is still relatively slow.
  • the purpose of the present invention is to provide a novel compound with gonadotropin releasing hormone inhibitory activity and better pharmacodynamic/pharmacokinetic properties and its use.
  • R 1 , R 2 and R 9 are each independently halogen
  • R 3 , R 4 , R 8 , R 10 , R 11 and R 13 are each independently hydrogen or deuterium;
  • R 5 , R 6 , R 7 and R 12 are each independently selected from: hydrogen, deuterium, C1-C6 alkyl or deuterated C1-C6 alkyl;
  • Additional conditions are: at least one of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 , R 12 or R 13 (such as 1, 2, 3, 4, 5 or 6) Is deuterated alkyl or deuterium.
  • the compound of formula (I) contains at least one deuterium atom, more preferably 2 or more (such as 3, 4, 5 or 6) deuterium atoms.
  • R 1 , R 2 and R 9 are selected from fluorine, chlorine or bromine.
  • R 1 , R 2 and R 9 are fluorine.
  • R 3 and R 4 are hydrogen.
  • R 4 is deuterium
  • R 8 and R 10 are hydrogen.
  • R 8 and R 10 are deuterium.
  • R 10 is deuterium
  • R 11 is selected from: deuterium or hydrogen.
  • R 13 is selected from: deuterium or hydrogen.
  • R 5 and R 12 are selected from: CH 3 , CH 2 D, CHD 2 , CD 3 , CH 2 CH 3 , CD 2 CH 3 , CH 2 CD 3 or CD 2 CD 3 .
  • R 5 and R 12 are selected from: CD 3 or CH 3 .
  • R 5 is CD 3 .
  • R 5 and R 12 are CD 3 .
  • R 12 is CD 3 .
  • R 12 is CH 3 and R 5 is CD 3 .
  • R 12 is CD 3 and R 5 is CH 3 .
  • R 6 and R 7 are selected from deuterium or hydrogen.
  • R 6 and R 7 are both deuterium.
  • R 6 and R 7 are both hydrogen.
  • R 6 is deuterium
  • the compound is a compound selected from the following group or a pharmaceutically acceptable salt thereof:
  • the compound is a compound selected from the following group or a pharmaceutically acceptable salt thereof:
  • the compound is It has the following characteristics: MS calculated value: 513; MS measured value: 514 (M+H) + .
  • the compound is It has the following characteristics: MS calculated value: 513; MS measured value: 514 (M+H) + .
  • the compound is It has the following characteristics: MS calculated value: 511; MS measured value: 512 (M+H) + .
  • the compound is It has the following characteristics: MS calculated value: 514; MS measured value: 515 (M+H) + .
  • the compound is It has the following characteristics: MS calculated value: 516; MS measured value: 517 (M+H) + .
  • the compound is It has the following characteristics: MS calculated value: 510; MS measured value: 511 (M+H) + .
  • the compound is It has the following characteristics: MS calculated value: 511; MS measured value: 512 (M+H) + .
  • the deuterium isotope content of deuterium at the deuterium substitution position is at least greater than the natural deuterium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more It is preferably greater than 95%, more preferably greater than 99%.
  • the compound does not include non-deuterated compounds.
  • the non-deuterated compound is 3-(5-((2,3-difluoro-6-methoxyphenyl)methoxy)-2-fluoro-4-methyl (Oxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid.
  • a method for preparing a pharmaceutical composition which includes the steps of: combining a pharmaceutically acceptable carrier with the compound described in the first aspect of the present invention, or a crystal form, or a pharmaceutically acceptable compound.
  • the accepted salts, hydrates or solvates are mixed to form a pharmaceutical composition.
  • a pharmaceutical composition which contains a pharmaceutically acceptable carrier and the compound described in the first aspect of the present invention, or its crystal form, pharmaceutically acceptable salt, hydrated ⁇ or solvate.
  • the pharmaceutical composition is injection, capsule, tablet, pill, powder or granule.
  • the pharmaceutical composition further contains another therapeutic drug, and the additional therapeutic drug is cancer, cardiovascular disease, inflammation, infection, immune disease, cell proliferative disease, viral disease , Metabolic diseases, or organ transplantation drugs.
  • the additional therapeutic drugs include (but are not limited to): elagolix, Relugolix, Triptorelin, Alarelin, 5-fluorouracil, FOLFOX Avastin TM (avastin, bevacizumab), bexarotene (for bexarotene), bortezomib (bortezomib), calcitriol (calcitriol in), canertinib (canertinib), capecitabine (capecitabine), Gemcitabine, carboplatin, celecoxib, cetuximab, cisplatin, dasatinib, digoxin, enzastaurin , Erlotinib, etoposide, everolimus, fulvestrant, gefitinib, genistein, etoposide Matinib, irinotecan, lapatinib, lenalidomide, letrozole, leucovorin, matuzumab
  • the pharmaceutical composition further contains another therapeutic drug, and the additional therapeutic drug is an anti-pain drug, an anti-anxiety drug, an antidepressant drug, a progestin and the like.
  • the compound described in the first aspect of the present invention or a crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, is provided.
  • the pharmaceutical combination according to the third aspect of the present invention They are used to prepare pharmaceutical compositions for inhibiting gonadotropin releasing hormone.
  • the pharmaceutical composition is used to prepare medicines for the treatment and prevention of the following diseases: pain, prostatic hypertrophy, uterine fibroids, endometriosis, uterine fibroids, amenorrhea, premenstrual synthesis Symptoms and sleep disorders, acne, hair loss, irritable bowel syndrome, lupus erythematosus and other diseases.
  • a method of inhibiting gonadotropin releasing hormone or a method of treating a disease (such as cancer, cell proliferative disease, inflammation, infection, pain, immune disease) is provided, which includes Step: administer the compound described in the first aspect of the present invention, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or administer the drug described in the third aspect of the present invention to a subject in need of treatment combination.
  • a disease such as cancer, cell proliferative disease, inflammation, infection, pain, immune disease
  • Figure 1 is the blood concentration-time curve of the tested drug in Example 8.
  • Figure 2 is the blood concentration-time curve of the tested drug in Example 9.
  • Figure 3 is a blood concentration-time curve of the tested drug in Example 10.
  • Figure 4 is the blood concentration-time curve of the tested drug in Example 11.
  • the inventors unexpectedly discovered that the deuterated tetrahydrothieno[3,4-d]pyrimidinedione compound and pharmaceutically acceptable salt thereof of the present invention have obvious advantages compared with non-deuterated compounds. More excellent pharmacokinetics and/or pharmacodynamic properties, so it is more suitable as a compound that inhibits gonadotropin releasing hormone, and is more suitable for preparing drugs for treating cancer and gonadotropin releasing hormone related diseases.
  • the present invention has been completed on this basis.
  • halogen refers to F, Cl, Br, and I.
  • C1-C6 alkyl refers to a straight-chain or branched alkyl group including 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl , Tert-butyl, or similar groups.
  • Deuterated C1-C6 alkyl group refers to a group in which one or more hydrogen atoms in the alkyl group are replaced by deuterium atoms.
  • more excellent pharmacokinetic and/or pharmacodynamic performance refers to longer drug half-life (t 1/2 ), or higher drug exposure (AUC), or higher maximum drug Concentration (Cmax), or lower drug clearance rate
  • deuterated refers to the replacement of one or more hydrogens in a compound or group with deuterium. Deuteration can be mono-, di-, poly, or fully-substituted. The terms “one or more deuterated” and “one or more deuterated” are used interchangeably.
  • non-deuterated compound refers to a compound that contains a proportion of deuterium atoms not higher than the natural deuterium isotope content (0.015%).
  • the deuterium isotope content of deuterium at the deuterium substitution position is greater than the natural deuterium isotope content (0.015%), more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, more preferably The content is greater than 97%, more preferably greater than 99%, and even more preferably greater than 99.5%.
  • the compound of formula (I) contains at least one deuterium atom.
  • N is 14 N and/or O is 16 O.
  • the isotope content of 14 N at the position of the nitrogen atom is ⁇ 95%, more preferably ⁇ 99%.
  • the isotopic content of 16 O at the position of the oxygen atom is ⁇ 95%, more preferably ⁇ 99%.
  • F is 19 F and/or S is 32 S.
  • the isotopic content of 19 F at the position of the nitrogen atom is ⁇ 95%, more preferably ⁇ 99%.
  • the isotopic content of 32 S at the position of the oxygen atom is ⁇ 95%.
  • compound of the present invention refers to a compound represented by formula (I).
  • the term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compound of formula (I).
  • the compound of formula (I) of the present invention has the following structure:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are as defined above.
  • R 1 , R 2 and R 9 are fluorine;
  • R 5 and R 12 are each independently selected from: CH 3 , CH 2 D, CHD 2 , CD 3 , CH 2 CH 3 , CD 2 CH 3 , CH 2 CD 3 or CD 2 CD 3 , preferably CH 3 or CD 3 ;
  • R 6 and R 7 are deuterium or hydrogen, preferably R 6 and R 7 are deuterium at the same time.
  • the term "pharmaceutically acceptable salt” refers to a salt formed by the compound of the present invention and an acid or a base suitable for use as a medicine.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • a preferred class of salts are the salts of the compounds of this invention with acids.
  • Acids suitable for salt formation include, but are not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid and other organic acids; and proline, benzene Amino acids such as alanine, aspartic acid and glutamic acid.
  • a base such as alkali metal salt (such as sodium or potassium salt), alkaline earth metal salt (such as magnesium salt or calcium salt), ammonium salt (such as lower alkanolammonium Salt and other pharmaceutically acceptable amine salts), such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butyl Base amine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.
  • alkali metal salt such as sodium or potassium salt
  • alkaline earth metal salt such as magnesium salt or calcium salt
  • ammonium salt such as lower alkanolammonium Salt and other pharmaceutically acceptable amine salts
  • methylamine salt such as sodium or potassium salt
  • alkaline earth metal salt such as magnesium salt or
  • solvate refers to a complex in which the compound of the present invention coordinates with solvent molecules to form a specific ratio.
  • “Hydrate” refers to a complex formed by coordination of the compound of the present invention with water.
  • the compounds of the present invention also include prodrugs of deuterated tetrahydrothieno[3,4-d]pyrimidinedione compounds represented by formula (I).
  • prodrug includes biologically active or inactive itself, and when taken by a proper method, it undergoes metabolism or chemical reaction in the human body to convert it into a class of compounds of formula (I), or A salt or solution composed of a compound of formula (I).
  • the prodrugs include (but are not limited to) carboxylic acid esters, carbonate esters, phosphate esters, nitrate esters, sulfate esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, and azo compounds of the compound , Phosphoramide, glucoside, ether, acetal and other forms.
  • the non-deuterated tetrahydrothieno[3,4-d]pyrimidinedione compounds used in the present invention are known.
  • the corresponding deuterated tetrahydrothieno[3,4-d]pyrimidinedione compound can be prepared by using the corresponding deuterated starting compound as a raw material, and synthesized by the same route.
  • the compound of formula (I) of the present invention can be prepared according to the preparation method described in WO2007042392, except that deuterated raw materials are used in the reaction instead of non-deuterated raw materials.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0°C to 200°C, preferably 0°C to 100°C).
  • the reaction time is usually 0.1 hour to 60 hours, preferably 0.5 to 48 hours.
  • X is selected from F, Cl, Br, I; the definition of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 GR.
  • compound formula II is reacted with alkylating reagents (such as CD 3 X, CH 3 X) under alkaline conditions (such as potassium carbonate) to produce compound formula III; compound III is reduced by metal hydride ion reducing reagent ( (Such as sodium borohydride or sodium borodeuteride) reduction to obtain compound formula IV; formula IV is further halogenated (such as HCl) to form compound formula V; formula V interacts with substituted phenolic compound formula VI to obtain compound formula VII; compound VII is selectively Nitration reaction produces formula VIII; in formula VIII, aromatic nitro groups are subjected to catalytic hydrogenation conditions such as palladium, platinum, Raney nickel to obtain aromatic amine IX; compound IX and compound X are acylated to urea under basic conditions (such as triethylamine), The formula XI is obtained; the intermediate XI is hydrolyzed by lithium hydroxide and acetic acid itself forms a lactam ring to obtain the
  • the above reaction is preferably in an inert solvent such as ethyl acetate, dichloromethane, methyl tert-butyl ether, n-heptane, toluene, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, acetic acid, etc. ,
  • the temperature is 0 ⁇ 200°C.
  • the starting materials can be purchased through commercial channels or synthesized by reported literature.
  • the compound of the present invention Since the compound of the present invention has excellent inhibitory activity on gonadotropin releasing hormone, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and containing the compound of the present invention
  • the pharmaceutical composition which is the main active ingredient can be used to treat, prevent and alleviate diseases mediated by gonadotropin releasing hormone.
  • the compounds of the present invention can be used to treat the following diseases: cancer, cell proliferative diseases, inflammation, infection, immune diseases, pain and the like.
  • the pharmaceutical composition of the present invention contains a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/agent, more preferably, 10-1000 mg of the compound of the present invention/agent.
  • the "one dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid).
  • Magnesium stearate calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as emulsifiers
  • wetting agents such as sodium lauryl sulfate
  • the method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited.
  • Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glycty
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microcapsules with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the dosage form of the compound of the present invention for topical administration includes ointment, powder, patch, propellant and inhalant.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment.
  • the dosage is usually 1 to 2000 mg, preferably 20 to 500 mg.
  • the specific dosage should also consider factors such as the route of administration and the patient's health status, which are all within the skill range of a skilled physician.
  • the compound of the present invention has a series of advantages.
  • the main advantages of the present invention include:
  • the compound of the present invention has excellent inhibitory activity on gonadotropin releasing hormone.
  • the compound of the present invention has better pharmacokinetic parameter characteristics, can change the drug dosage and form a long-acting preparation, and improve applicability.
  • Substituting deuterium for hydrogen atoms in the compound may improve the safety of the compound because some metabolites are inhibited.
  • the compounds of the present invention especially compounds 1 and 21, show unexpectedly excellent pharmacokinetic properties compared to the control compound Linzagolix.
  • compound 6 is prepared from compound 12 through a two-step reaction.
  • compound 10 can be prepared by acylation reaction between compound 15 and phenyl chloroformate (compound 16):
  • methyl iodide is used instead of deuterated methyl iodide (CD 3 I) to prepare the target Compound 17.
  • ESI-MS m/z 514[M+H] + .
  • the difference is: in the steps from formula (V) to formula (VII) according to the synthetic route, 4-fluoro-2-methoxyphenol is substituted for 4-fluoro-2 -(Methoxy-d 3 )phenol, thereby preparing the target compound 18.
  • 1 H NMR (400MHz, DMSO-d 6 ) ⁇ : 14.57 (s, 1H), 11.99 (s, 1H), 7.53-7.48 (m, 1H), 7.38 (s, 1H), 7.26-7.18 (m, 2H) ), 7.14 (d, J 11.6 Hz, 1H), 3.84 (s, 3H); ESI-MS m/z 514 (M+H) + .
  • the difference is: in the steps from formula (III) to formula (IV) according to the synthetic route, NaBH 4 is used instead of NaBD 4 , and at the same time, in formula (V) to formula (VII) In the step, 4-fluoro-2-(methoxy-d 3 )phenol is replaced with 4-fluoro-2-methoxyphenol, so that the target compound 19 is prepared.
  • mice Male SD rats, weighing about 180g, were fasted overnight and divided into 3 groups, 4 rats in each group, and were administered by gavage.
  • the first group was given 3 mg/kg of the control compound Linzagolix and 3 mg/kg of compound 1 at the same time by gavage, and the second group was given 3 mg/kg of the control compound Linzagolix and 3 mg/kg of compound 21 by gavage at the same time.
  • the third group was given the control compound Linzagolix at 3 mg/kg and the compound 22 at 3 mg/kg at the same time.
  • the solvent of each group was 0.5% CMC: 0.1% Tween80 aqueous solution.
  • blood was collected at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12 and 24 hours after administration, and the concentration of each component in plasma was determined by LC/MS/MS.
  • mice Male SD rats, weighing about 180 g, were fasted overnight, and were divided into 3 groups, 4 rats in each group, and they were administered separately in parallel.
  • the first group was given 3 mg/kg of the control compound Linzagolix by gavage
  • the second group was given 3 mg/kg of compound 21 by gavage
  • the third group was given 3 mg/kg of compound 20 by gavage.
  • the solvent of each group was 0.5% CMC: 0.1% Tween80 aqueous solution.
  • blood was collected at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12 and 24 hours after administration, and the concentration of each component in plasma was determined by LC/MS/MS.
  • Example 8 and Example 9 show that: compared with the control compound Linzagolix, the compound of the present invention has better pharmacokinetic properties, especially the compounds 1 and 21 of the present invention have more excellent AUC and Cmax, and therefore have Better bioavailability and efficacy.
  • the compound 21 of the present invention exhibits better pharmacokinetic properties in beagle dogs.
  • the plasma exposure AUC and maximum blood concentration (Cmax) of the compound of the present invention are greatly increased, and AUC and Cmax are increased by 115.0% and 107.3%, respectively.
  • Examples 10 and 11 show that: compared with the control compound Linzagolix, the compound of the present invention has better pharmacokinetic properties, especially the compound 21 of the present invention has more excellent AUC and Cmax, and therefore has better biological properties. Utilization and efficacy.
  • any compound of formula I (especially compound 1 or 21) prepared in Examples 1-7 was used to prepare a pharmaceutical composition according to the following formula.
  • the above-mentioned materials are mixed uniformly and then filled into ordinary gelatin capsules to obtain 1000 capsules.

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Abstract

提供式(I)所示的氘代的四氢噻吩并[3,4-d]嘧啶二酮化合物以及含有该化合物、或其晶型、药学上可接受的盐、水合物或溶剂合物的药物组合物，所述化合物可用于治疗和/或预防促性腺素释放激素(GnRH)依赖性相关性疾病，例如子宫肌瘤、子宫内膜异位、子宫纤维瘤、闭经、经前期综合征等。

Description

氘代四氢噻吩并[3,4-d]嘧啶二酮化合物以及包含该化合物的药物组合物 技术领域
本发明属于医药领域。具体地，本发明涉及新型的氘代四氢噻吩并[3,4-d]嘧啶二酮化合物以及含该化合物的药物组合物。
背景技术
促性腺素释放激素(Gonadotropn-releasing hormone,GnRH)是一类由下丘脑分泌，刺激或抑制垂体促性腺激素的分泌，对脊椎动物生殖的调控起重要作用。
四氢噻吩并[3,4-d]嘧啶二酮化合物及衍生物是一类促性腺素释放激素的抑制剂。在专利WO2007042392中公开了系列四氢噻吩并[3,4-d]嘧啶二酮衍生物，其中，化合物Linzagolix是选择性的GnRH抑制剂，化学名为3-(5-((2,3-二氟-6-甲氧基苯基)甲氧基)-2-氟-4-甲氧基苯基)-2,4-二氧-1,2,3,4-四氢噻吩并[3,4-d]嘧啶-5-羧酸，具有治疗子宫纤维瘤、子宫内膜异位症和子宫腺肌病的用途，目前该化合物正处于治疗子宫内膜异位症和子宫腺肌病(endometriosis and adenomyosis)的临床II期研究和子宫纤维瘤(uterine fibroids)的临床III期研究中。
虽然促性腺素释放激素是妇科疾病药物研发的重要靶点之一，然而除了曲普瑞林(Triptorelin)、丙氨瑞林(Alarelin)等多肽类促性腺素释放激素类似物及Relugolix和Elagolix等少数新近上市的促性腺素释放激素抑制剂药物外，GnRH抑制剂研究进展仍相对缓慢。
因此，本领域仍需要开发具有对促性腺素释放激素具有很好抑制活性或更好药效学/药代动力学性能的化合物。
发明内容
本发明的目的是提供一种新型的具有促性腺素释放激素抑制活性和更好药效学/药代动力学性能的化合物及其用途。
在本发明的第一方面中，提供了一种式(I)所示的氘代的四氢噻吩并[3,4-d]嘧啶二酮化合物、或其晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2021093882-appb-000001
Figure PCTCN2021093882-appb-000002
式中：
R 1、R 2和R 9各自独立地为卤素；
R 3、R 4、R 8、R 10、R 11和R 13各自独立地为氢或氘；
R 5、R 6、R 7和R 12各自独立地选自：氢、氘、C1-C6烷基或氘代C1-C6烷基；
附加条件是：R 3、R 4、R 5、R 6、R 7、R 8、R 10、R 11、R 12或R 13中至少一个(如1、2、3、4、5或6)是氘代烷基或氘。
在另一优选例中，式(I)化合物至少含有1个氘原子，更佳地2个或2个以上(如3、4、5或6)氘原子。
在另一优选例中，R 1、R 2和R 9选自氟、氯或溴。
在另一优选例中，R 1、R 2和R 9为氟。
在另一优选例中，R 3和R 4为氢。
在另一优选例中，R 4为氘。
在另一优选例中，R 8和R 10为氢。
在另一优选例中，R 8和R 10为氘。
在另一优选例中，R 10为氘。
在另一优选例中，R 11选自：氘或氢。
在另一优选例中，R 13选自：氘或氢。
在另一优选例中，R 5、R 12选自：CH 3、CH 2D、CHD 2、CD 3、CH 2CH 3、CD 2CH 3、CH 2CD 3或CD 2CD 3。
在另一优选例中，R 5、R 12选自：CD 3或CH 3。
在另一优选例中，R 5为CD 3。
在另一优选例中，R 5和R 12为CD 3。
在另一优选例中，R 12为CD 3。
在另一优选例中，R 12为CH 3，R 5为CD 3。
在另一优选例中，R 12为CD 3，R 5为CH 3。
在另一优选例中，R 6、R 7选自：氘或氢。
在另一优选例中，R 6和R 7同时为氘。
在另一优选例中，R 6和R 7同时为氢。
在另一优选例中，R 6为氘。
在另一优选例中，所述化合物是选自下组的化合物或其药学上可接受的盐：
Figure PCTCN2021093882-appb-000003
Figure PCTCN2021093882-appb-000004
在另一优选例中，所述化合物是选自下组的化合物或其药学上可接受的盐：
3-(5-((2,3-二氟-6-甲氧基苯基)甲氧基-d 2)-2-氟-4-(甲氧基-d 3)苯基)-2,4-二氧-1,2,3,4-四氢噻吩并[3,4-d]嘧啶-5-羧酸；
Figure PCTCN2021093882-appb-000005
3-(5-((2,3-二氟-6-(甲氧基-d 3)苯基)甲氧基-d 2)-2-氟-4-甲氧基苯基)-2,4-二氧-1,2,3,4-四氢噻吩并[3,4-d]嘧啶-5-羧酸；
Figure PCTCN2021093882-appb-000006
3-(5-((2,3-二氟-6-(甲氧基-d 3)苄基)氧基)-2-氟-4-甲氧基苯基)-2,4-二氧-1,2,3,4-四氢噻吩并[3,4-d]嘧啶-5-羧酸；
Figure PCTCN2021093882-appb-000007
3-(5-((2,3-二氟-6-(甲氧基-d 3)苄基)氧基)-2-氟-4-(甲氧基-d 3)苯基)-2,4-二氧-1,2,3,4-四氢噻吩并[3,4-d]嘧啶-5-羧酸；
Figure PCTCN2021093882-appb-000008
3-(5-((2,3-二氟-6-(甲氧基-d 3)苯基)甲氧基-d 2)-2-氟-4-(甲氧基-d 3)苯基)-2,4-二氧-1,2,3,4-四氢噻吩并[3,4-d]嘧啶-5-羧酸；
Figure PCTCN2021093882-appb-000009
3-(5-(((2,3-二氟-6-甲氧基苯基)甲氧基-d 2)-2-氟-4-甲氧基苯基)-2,4-二氧-1,2,3,4-四氢噻吩并[3,4-d]嘧啶-5-羧酸；
Figure PCTCN2021093882-appb-000010
3-(5-((2,3-二氟-6-甲氧基苄基)氧基)-2-氟-4-(甲氧基-d 3)苯基)-2,4-二氧-1,2,3,4-四氢噻吩并[3,4-d]嘧啶-5-羧酸；
Figure PCTCN2021093882-appb-000011
3-(5-((2,3-二氟-6-甲氧基苯基)甲氧基-d)-2-氟-4-甲氧基苯基)-2,4-二氧-1,2,3,4-四氢噻吩并[3,4-d]嘧啶-5-羧酸；
Figure PCTCN2021093882-appb-000012
3-(5-((2,3-二氟-6-甲氧基苯基)甲氧基-d)-2-氟-4-(甲氧基-d 3)苯基)-2,4-二氧-1,2,3,4-四氢噻吩并[3,4-d]嘧啶-5-羧酸；
Figure PCTCN2021093882-appb-000013
3-(5-((2,3-二氟-6-(甲氧基-d 3)苯基)甲氧基-d)-2-氟-4-甲氧基苯基)-2,4-二氧-1,2,3,4-四氢噻吩并[3,4-d]嘧啶-5-羧酸；
Figure PCTCN2021093882-appb-000014
3-(5-((2,3-二氟-6-(甲氧基-d 3)苯基)甲氧基-d)-2-氟-4-(甲氧基-d 3)苯基)-2,4-二氧-1,2,3,4-四氢噻吩并[3,4-d]嘧啶-5-羧酸
Figure PCTCN2021093882-appb-000015
在另一优选例中，所述的化合物为
Figure PCTCN2021093882-appb-000016
其具有如下特征：MS计算值:513；MS测量值:514(M+H) +。
在另一优选例中，所述的化合物为
Figure PCTCN2021093882-appb-000017
其具有如下特征：MS计算值:513；MS测量值:514(M+H) +。
在另一优选例中，所述的化合物为
Figure PCTCN2021093882-appb-000018
其具有如下特征：MS计算值:511；MS测量值:512(M+H) +。
在另一优选例中，所述的化合物为
Figure PCTCN2021093882-appb-000019
其具有如下特征：MS计算值:514；MS测量值:515(M+H) +。
在另一优选例中，所述的化合物为
Figure PCTCN2021093882-appb-000020
其具有如下特征：MS计算值:516；MS测量值:517(M+H) +。
在另一优选例中，所述的化合物为
Figure PCTCN2021093882-appb-000021
其具有如下特征：MS计算值:510；MS测量值:511(M+H) +。
在另一优选例中，所述的化合物为
Figure PCTCN2021093882-appb-000022
其具有如下特征：MS计算值:511；MS测量值:512(M+H) +。
在另一优选例中，氘在氘取代位置的氘同位素含量至少是大于天然氘同位素含量(0.015％)，较佳地大于30％，更佳地大于50％，更佳地大于75％，更佳地大于95％，更佳地大于99％。
在另一优选例中，所述的化合物不包括非氘代的化合物。
在另一优选例中，所述的非氘代的化合物为3-(5-((2,3-二氟-6-甲氧基苯基)甲氧基)-2-氟-4-甲氧基苯基)-2,4-二氧-1,2,3,4-四氢噻吩并[3,4-d]嘧啶-5-羧酸。
在本发明的第二方面中，提供了一种制备药物组合物的方法，包括步骤：将药学上可接受的载体与本发明第一方面中所述的化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物进行混合，从而形成药物组合物。
在本发明的第三方面中，提供了一种药物组合物，它含有药学上可接受的载体和本发明第一方面中所述的化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物。
在另一优选例中，所述的药物组合物为注射剂、囊剂、片剂、丸剂、散剂或颗粒剂。
在另一优选例中，所述的药物组合物还含有另外的治疗药物，所述的另外的治疗药物为癌症、心血管疾病、炎症、感染、免疫性疾病、细胞增殖性疾病、病毒性疾病、代谢性疾病、或器官移植的药物。
更佳地，所述的另外的治疗药物包括(但并不限于)：恶拉戈利(elagolix)、Relugolix、曲普瑞林(Triptorelin)、丙氨瑞林(Alarelin)、5-氟尿嘧啶、FOLFOX、阿瓦斯丁 TM(avastin，bevacizumab)、贝沙罗汀(bexarotene)、硼替佐米(bortezomib)、骨化三醇(calcitriol)、卡奈替尼(canertinib)、卡培他滨(capecitabine)、吉西他滨(gemcitabine)、碳铂(carboplatin)、塞来考昔(celecoxib)、西妥昔单抗(cetuximab)、顺铂(cisplatin)、达沙替尼(dasatinib)、地高辛(digoxin)、enzastaurin、埃罗替尼(Erlotinib)、依托泊甙(etoposide)、依维莫司(everolimus)、氟维司群(fulvestrant)、吉非替尼(gefitinib)、金雀异黄素(genistein)、伊马替尼(imatinib)、依立替康(irinotecan)、拉帕替尼(lapatinib)、来那度胺(lenalidomide)、来曲唑(letrozole)、亚叶酸(leucovorin)、马妥珠单抗(matuzumab)、奥沙利铂(oxaliplatin)、紫杉醇(paclitaxel)、多西他赛(doxetaxel)、帕尼单抗(panitumumab)、PEG化的粒细胞集落刺激因子(pegfilgrastin)、PEG化的α-干扰素(peglated alfa-interferon)、培美曲塞(pemetrexed)、
Figure PCTCN2021093882-appb-000023
E、沙铂(satraplatin)、西罗莫司(sirolimus)、舒尼替尼(sutent，sunitinib)、舒林酸(sulindac)、泰索帝(taxotere)、替莫唑胺(temodar、temozomolomide)、驮瑞塞尔(Torisel)、替西罗莫司(temsirolimus)、替吡法尼(tipifarnib)、曲妥单抗(trastuzumab)、丙戊酸(valproic acid)、长春氟宁(vinflunine)、Volociximab、Vorinostat、索拉非尼(Sorafenib)、克唑替尼(Crizotinib)、埃克替尼(Lcotinib)、拉帕替尼(Lapatinib)、托法替尼(Tofacitinib)、PD-0332991(Palbociclib)、安贝生坦(ambrisentan)、多柔比星、甲氨蝶呤、泼尼松、利妥昔单抗(rituximab)、CD40和/或CD154特异性抗体、融合蛋白、NF-kB抑制剂、非甾体抗炎药、凝血因子FXa抑制剂(如利伐沙班等)、抗-TNF抗体、抗生素药物如刺孢霉素(calicheamicin)、放线菌素(actinomycin)、阿霉素(doxorubicin)、肿瘤免疫治疗药物如抗PD-1抗体、抗PD-L1抗体等。
在另一优选例中，所述的药物组合物还含有另外的治疗药物，所述的另外的治疗 药物为抗疼痛药物、抗焦虑药物、抗抑郁药物、孕激素等。
在本发明的第四方面中，提供了本发明第一方面中所述的化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物本发明第三方面所述的药物组合物的用途，它们被用于制备抑制促性腺素释放激素的药物组合物。
在另一优选例中，所述的药物组合物用于制备用于治疗和预防以下疾病的药物：疼痛、前列腺肥大、子宫肌瘤、子宫内膜异位、子宫纤维瘤、闭经、经前期综合征以及睡眠障碍、痤疮、脱发、肠激综合征、红斑狼疮等疾病。
在本发明的第五方面中，提供了一种抑制促性腺素释放激素的方法或一种疾病(如癌症、细胞增殖性疾病、炎症、感染、疼痛、免疫性疾病)的治疗方法，它包括步骤：给需要治疗的对象施用本发明第一方面中所述的化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物，或施用本发明第三方面中所述的药物组合物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1为实施例8中测试药物的血药浓度-时间曲线。
图2为实施例9中测试药物的血药浓度-时间曲线。
图3为实施例10中测试药物的血药浓度-时间曲线。
图4为实施例11中测试药物的血药浓度-时间曲线。
具体实施方式
本发明人经过研究，意外地发现，本发明的氘代的四氢噻吩并[3,4-d]嘧啶二酮化合物及其药学上可接受的盐与未氘代的化合物相比，具有明显更优异的药物动力学和/或药效学性能，因此更适合作为抑制促性腺素释放激素的化合物，进而更适用制备治疗癌症以及促性腺素释放激素相关疾病的药物。在此基础上完成了本发明。
定义
如本文所用，“卤素”指F、Cl、Br、和I。
如本文所用，“C1-C6烷基”是指包括1-6个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、或类似基团。“氘代C1-C6烷基”是指烷基中的一个或多个氢原子被氘原子取代的基团。
如本文所用，“更优异的药物动力学和/或药效学性能”是指更长的药物半衰期(t 1/2)，或者更高的药物暴露量(AUC)，或者更高的最大药物浓度(Cmax)，或者更低的 药物清除率
如本文所用，“氘代”指化合物或基团中的一个或多个氢被氘所取代。氘代可以是一取代、二取代、多取代或全取代。术语“一个或多个氘代的”与“一次或多次氘代”可互换使用。
如本文所用，“非氘代的化合物”是指含氘原子比例不高于天然氘同位素含量(0.015％)的化合物。
在另一优选例中，氘在氘取代位置的氘同位素含量是大于天然氘同位素含量(0.015％)，更佳地大于50％，更佳地大于75％，更佳地大于95％，更佳地大于97％，更佳地大于99％，更佳地大于99.5％。
在另一优选例中，式(I)化合物至少含有1个氘原子。
优选地，式(I)化合物中，N为 14N和/或O为 16O。
在另一优选例中，所述化合物中， 14N在氮原子所在位置的同位素含量≥95％，更佳地≥99％。
在另一优选例中，所述化合物中， 16O在氧原子所在位置的同位素含量≥95％，更佳地≥99％。
优选地，式(I)化合物中，F为 19F和/或S为 32S。
在另一优选例中，所述化合物中， 19F在氮原子所在位置的同位素含量≥95％，更佳地≥99％。
在另一优选例中，所述化合物中， 32S在氧原子所在位置的同位素含量≥95％。
活性成分
如本文所用，术语“本发明化合物”指式(I)所示的化合物。该术语还包括及式(I)化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物。
本发明所述式(I)化合物具有如下结构：
Figure PCTCN2021093882-appb-000024
式中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12和R 13的定义如上所述。
优选地，R 1、R 2和R 9为氟；
R 5、R 12各自独立地选自：CH 3、CH 2D、CHD 2、CD 3、CH 2CH 3、CD 2CH 3、CH 2CD 3或CD 2CD 3，优选为CH 3或CD 3；
R 6、R 7为氘或氢，优选为R 6和R 7同时为氘。
其中，术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸；甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、乙磺酸、甲苯磺酸、苯磺酸、萘磺酸等有机酸；以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。另一类优选的盐是本发明化合物与碱形成的盐，例如碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐)，例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐，以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
术语“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。“水合物”是指本发明化合物与水进行配位形成的配合物。
此外，本发明化合物还包括式(I)所示的氘代四氢噻吩并[3,4-d]嘧啶二酮化合物的前药。术语“前药”包括其本身可以是具有生物学活性的或非活性的，当用适当的方法服用后，其在人体内进行代谢或化学反应而转变成式(I)的一类化合物，或式(I)的一个化合物所组成的盐或溶液。所述的前药包括(但不局限于)所述化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、砜酯、亚砜酯、氨基化合物、氨基甲酸盐、偶氮化合物、磷酰胺、葡萄糖苷、醚、乙缩醛等形式。
制备方法
下面更具体地描述本发明式(I)结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。
本发明使用的未氘代的四氢噻吩并[3,4-d]嘧啶二酮化合物是已知的。对应氘代的四氢噻吩并[3,4-d]嘧啶二酮化合物的制备可以用相应的氘代起始化合物为原料，用同样的路线合成。例如，本发明式(I)化合物可按WO2007042392中所述的制备方法制备，不同点在于在反应中用氘代的原料代替非氘代的原料。
通常，在制备流程中，各反应通常在惰性溶剂中，在室温至回流温度(如0℃～200℃，优选0℃～100℃)下进行。反应时间通常为0.1小时-60小时，较佳地为0.5-48小时。
下面的通用制备路线可以用于合成本发明式(I)结构的化合物。
Figure PCTCN2021093882-appb-000025
合成路线一
其中：X选自F、Cl、Br、I；R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12的定义同前。
如合成路线一所示，化合物式II经烷基化试剂(如CD 3X、CH 3X)在碱性(如碳酸钾)条件下反应生产化合物式III；化合物III经金属氢负离子还原试剂(如硼氢化钠或硼氘化钠)还原得到化合物式IV；式IV进一步卤化(如HCl)，形成化合物式V；式V与取代酚类化合物式VI作用得到化合物式VII；化合物VII经选择性硝化反应得到式VIII；式VIII中芳硝基经如钯、铂、雷尼镍等催化氢化条件得到芳胺IX；化合物IX与化合物X在碱性(如三乙胺)条件下酰化成脲，得到式XI；该中间体XI经氢氧化锂水解和醋酸自身成内酰胺环得到本发明化合物式I。上述反应优选在惰性溶剂，如乙酸乙酯，二氯甲烷、甲基叔丁基醚、正庚烷、甲苯、四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、乙酸等中，温度0～200℃下进行。
起始原料可通过商业途径购买或通过以报道文献合成。
化合物VI的制备方法如下面合成路线二所示：
Figure PCTCN2021093882-appb-000026
合成路线二
在惰性溶剂(如二氯甲烷)中，式XII化合物和间氯过氧苯甲酸经拜耳-维利格氧化重排反应后，进一步水解，得到化合物VI；其中，R 8、R 9、R 10、R 12的定义同前。
化合物X的制备方法如下面合成路线三所示：
Figure PCTCN2021093882-appb-000027
合成路线三
由式XIII化合物经酰化作用形成活泼酰胺酯式X；其中，R 11的定义同前。
药物组合物和施用方法
由于本发明化合物具有优异的对促性腺素释放激素的抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解由对促性腺素释放激素介导的疾病。根据现有技术，本发明化合物可用于治疗以下疾病：癌症、细胞增殖性疾病、炎症、感染、免疫性疾病、疼痛等。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-1000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure PCTCN2021093882-appb-000028
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h) 吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选20～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的化合物与现有技术中已知的非氘代化合物相比，具有一系列优点。本发明的主要优点包括：
(1)本发明化合物对促性腺素释放激素具有优异的抑制活性。
(2)本发明化合物具有更好的药代动力学参数特性，可以改变药物剂量并形成长效制剂，改善适用性。
(3)用氘取代化合物中的氢原子，由于其氘同位素效应，能够提高化合物在动物 体内的药物浓度，以提高药物疗效。
(4)用氘取代化合物中的氢原子,由于某些代谢产物被抑制，可能提高化合物的安全性。
(5)本发明化合物，尤其是化合物1和21相对于对照化合物Linzagolix表现出意想不到的优异药代动力学特性。
下面结合具体实施例，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。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则份数和百分比为重量份和重量百分比。
实施例1 制备3-(5-((2,3-二氟-6-(甲氧基-d 3)苯基)甲氧基-d 2)-2-氟-4-(甲氧基-d 3)苯基)-2,4-二氧-1,2,3,4-四氢噻吩并[3,4-d]嘧啶-5-羧酸(化合物1)
Figure PCTCN2021093882-appb-000029
1、制备2,3-二氟-6-(甲氧基-d 3)苯甲酸甲酯(化合物3)
室温下，向反应瓶中加入化合物2,3-二氟-6-羟基苯甲酸(5.0g)和N,N-二甲基甲酰胺(30ml)，搅拌溶解，反应液澄清；加入碳酸钾(12.2g)，搅拌30min，缓慢滴加氘代碘甲烷(10.0g)，滴加结束后升温至40℃，搅拌15-20h，薄层色谱检测；反应结束后，加入水(60ml)，乙酸乙酯(60ml)，搅拌30min，萃取2次，合并有机相，饱和食盐水洗，硫酸镁干燥，减压浓缩得油状物，向油状物中加入石油醚(12ml)，溶解，降温0℃，逐渐析出固体，搅拌3h，抽滤，干燥得到标题化合物4.8g。 1H NMR(400MHz,DMSO-d 6)δ:7.70-7.75(m,1H),7.31-7.36(m,1H)；ESI-MS m/z 209[M+H] +。
2、制备(2,3-二氟-6-(甲氧基-d 3)苯基)甲烷-d 2-醇(化合物4)
室温下，向反应瓶中加入化合物3(4.2g)、四氢呋喃(20ml)，降温至-10～-5℃，加入硼氘化钠(2.54g)，搅拌下将碘(5.1g)，四氢呋喃(10ml)配成溶液；控温-10℃左右滴入上述反应液搅拌2h，然后升温至40℃，反应48h。反应结束后，将反应液倒入冰水中，加入甲苯萃取，水洗，脱溶，得到标题化合物3.8g。ESI-MS m/z 162[M+H-H 2O]+。
3、制备2-(氯甲基-d 2)-3,4-二氟-1-(甲氧基-d 3)苯(化合物5)
向反应瓶瓶中加入化合物4(3.8g)、甲苯(30ml)、浓盐酸(30ml),升温至40℃，反应24h。反应结束后，降温，停止搅拌，静置，分液，水层加入甲苯萃取，水洗，脱溶，得到标题化合物3.6g。
4、制备1,2-二氟-3-((4-氟-2-(甲氧基-d 3)苯氧基)甲基-d 2)-4-(甲氧基-d 3)苯(化合物7)
向反应瓶中加入化合物5(3.6g)、4-氟-2-(甲氧基-d 3)苯酚(3.0g)、四氢呋喃(30ml)，加入25％NaOH水溶液(3.5g)，升温至60℃，反应20h。薄层色谱检测，反应结束后，降温，加入水，搅拌30min，静置，分液，水层加入甲苯萃取，水洗，脱溶，得到粗品6g。经过异丙醇/水结晶纯化，得到目标化合物(5.0g)。 1H NMR(400MHz,DMSO-d 6)δ:7.46-7.41(m,1H),7.22-7.17(m,1H),7.01-6.97(m,1H),6.93-6.89(m,1H),6.69-6.64(m,1H).ESI-MS m/z 305[M-H] -。
5、制备1,2-二氟-3-((4-氟-2-(甲氧基-d 3)-5-硝基苯氧基)甲基-d 2)-4-(甲氧基-d 3)苯(化合物8)
向反应瓶加入化合物7(3.0g)、乙酸(24ml)、硝酸(1.4g)，升温至60℃反应8h。反应结束后，降温至室温，加入水，搅拌2h，抽滤，晾干，得到目标化合物(2.8g)。 1H NMR(400MHz,DMSO-d 6)δ:7.78-7.76(d,J＝7.6Hz,1H),7.54-7.49(m,1H),7.31-7.24(m,2H).ESI-MS m/z 350[M-H] -。
6、制备5-((2,3-二氟-6-(甲氧基-d 3)苯基)甲氧基-d 2)-2-氟-4-(甲氧基-d 3)苯胺(化合物9)
向反应瓶加入化合物8(2.0g)、乙酸乙酯，氢气置换2次，加入10％钯碳催化剂(0.2g)，再次用氢气置换，通入氢气，室温搅拌20h，薄层色谱检测，反应结束；反应液用硅藻土过滤，乙酸乙酯淋洗，减压移除溶剂，得到粗品；固体用甲醇和水结晶纯化，得到目标化合物1.5g。 1H NMR(400MHz,DMSO-d 6)δ:7.43-7.38(m,1H),7.23-7.18(m,1H),6.77(d,J＝12.4Hz,1H),6.51(d,J＝8.8Hz,1H),4.64(s,2H)。ESI-MS m/z 322[M+H] +,320[M-H] -。
7、制备二甲基4-(3-(5-((2,3-二氟-6-(甲氧基-d3)苯基)甲氧基-d 2)-2-氟-4-(甲氧基-d3)苯基)脲基噻吩-2,3-二羧酸盐(化合物11)
向反应瓶加入化合物9(1.5g)、4-((苯氧羰基)氨基)噻吩-2,3-二羧酸二甲酯(化合物10，1.6g)、四氢呋喃(15ml)，搅拌，加入三乙胺(0.2g)，升温至30℃，搅拌24h，薄层色谱检测，反应结束，将反应液减压移除溶剂，得粗品，加入乙酸乙酯和甲醇打浆得到标题化合物2.0g。 1H NMR(400MHz,DMSO-d 6)δ:8.95(s,1H),8.83(s,1H),7.94(s,1H),7.73(d,J＝8.0Hz,1H),7.47-7.42(m,1H),7.23-7.18(m,1H),7.01(d,J＝12.8Hz,1H 1H),3.89(s,3H),3.83(s,3H)。ESI-MS m/z 563[M+H] +。
8、制备3-(5-((2,3-二氟-6-(甲氧基-d 3)苯基)甲氧基-d 2)-2-氟-4-(甲氧基-d 3)苯基)-2,4-二氧-1,2,3,4-四氢噻吩并[3,4-d]嘧啶-5-羧酸(化合物1)
向反应瓶加入化合物11(2.0g)、四氢呋喃(6ml)、甲醇(6ml)和水(6ml)搅拌固体不溶；将氢氧化锂一水合物配成7.3％的水溶液，室温下加入反应瓶中，搅拌3h，升温至30℃，搅拌24h，反应液固体消失，溶液澄清，薄层色谱检测，反应结束。向反应液中加入醋酸，30℃搅拌3-5h，薄层色谱检测，反应结束。加入水，降温至0-10℃，搅拌2-3h，抽滤，得到目标化合物1.7g。 1H NMR(400MHz,DMSO-d 6)δ:14.57(s,1H),12.0(s,1H),7.53-7.48(m,1H),7.39(s,1H),7.27-7.12(m,3H)。ESI-MS m/z 517[M+H] +。
其中，化合物6由化合物12经两步反应制备。
Figure PCTCN2021093882-appb-000030
(i)制备1-(4-氟-2-(甲氧基-d 3)苯基)乙-1-酮(化合物14)
向反应瓶加入1-(4-氟-2-羟苯基)乙-1-酮(20g)、N,N-二甲基甲酰胺(60ml)，和无水碳酸钾，搅拌，滴加对甲苯磺酸氘代甲酯(化合物13，32g)，搅拌，逐渐析出固体，升温至30℃，搅拌约20h，薄层色谱检测，反应结束；将反应液倒入水中，析出固体，搅拌3h，抽滤，滤饼用水淋洗，抽干，滤饼晾干，得到标题化合物21.5g。 1H NMR(400MHz,DMSO-d 6)δ:7.71-7.67(m,1H),7.10-7.07(m,1H),6.88-6.83(m,1H),2.51(s,3H)。ESI-MS m/z 172[M+H] +。
(ii)制备4-氟-2-(甲氧基-d 3)苯酚(化合物6)
向反应瓶加入1-(4-氟-2-(甲氧基-d 3)苯基)乙-1-酮(20g)、二氯甲烷(120ml)，搅拌，加入间氯过氧苯甲酸(44g)，升温至回流24h，析出固体；反应结束，降温至室温，抽滤，减压移除溶剂，得到粗品；将粗品中加入乙醇(60ml)、水(60ml)、氢氧化钠(14.4g)，搅拌24h，向反应液中，加入浓盐酸，调节pH＝7，加入二氯甲烷萃取，有机层用水，饱和食盐水洗，有机层加入硫酸钠干燥，抽滤，减压移除溶剂得混合物，加入乙酸乙酯和石油醚搅拌打浆，抽滤，滤液减压移除溶剂，得到黑色油状物，油状物经过柱层析纯化(乙酸乙酯:石油醚＝10:1),得到标题化合物12.3g。 1H NMR(400MHz,DMSO-d 6)δ:8.87(m,1H),6.84-6.81(m,1H),6.77-6.74(m,1H)，659-6.54(m,1H)。
此外，化合物10可由化合物15与氯甲酸苯酯(化合物16)经酰化反应制备：
制备4-((苯氧羰基)氨基)噻吩-2,3-二羧酸二甲酯(化合物10)
Figure PCTCN2021093882-appb-000031
向反应瓶加入碳酸钾(1.1g)、水(12ml)，搅拌溶解，降温至5-10℃，加入四氢呋 喃(12ml)，缓慢加入4-氨基噻吩-2,3-二羧酸二甲酯盐酸盐(化合物15，2.0g)，搅拌，加入氯甲酸苯酯(化合物16，1.3g)，搅拌20h，薄层色谱检测；反应结束，静置，分液，水层加入甲基叔丁基醚萃取，有机层用饱和食盐水洗，减压移除溶剂，得到淡黄色液体。向残留物中，加入甲基叔丁基醚和庚烷结晶得到标题化合物1.9g。 1H NMR(400MHz,DMSO-d 6)δ:10.23(m,1H),7.80(s,1H),7.45-7.41(m,2H),7.28-7.25(m,1H),7.21-7.19(m,2H),3.82(s,6H)；ESI-MS m/z 336[M+H] +。ESI-MS.m/z 336[M+H] +。
实施例2 制备3-(5-((2,3-二氟-6-甲氧基苯基)甲氧基-d 2)-2-氟-4-(甲氧基-d 3)苯基)-2,4-二氧-1,2,3,4-四氢噻吩并[3,4-d]嘧啶-5-羧酸(化合物17)
Figure PCTCN2021093882-appb-000032
按实施例1中所述的方法，不同点在于：在按合成路线一由式(II)到式(III)步骤中，用碘甲烷代替氘代碘甲烷(CD 3I)，从而制得目标化合物17。 1H NMR(400MHz,DMSO-d 6)δ:14.55(s,1H),12.02(s,1H),7.51-7.44(m,1H),7.40(s,1H),7.26(d,J＝7.2Hz,1H),7.13(d,J＝11.6Hz,1H),6.93-6.90(m,1H),3.81(s,3H)。ESI-MS m/z 514[M+H] +。
实施例3 制备3-(5-((2,3-二氟-6-(甲氧基-d 3)苯基)甲氧基-d 2)-2-氟-4-甲氧基苯基)-2,4-二氧-1,2,3,4-四氢噻吩并[3,4-d]嘧啶-5-羧酸(化合物18)
Figure PCTCN2021093882-appb-000033
按实施例1中所述的方法，不同点在于：在按合成路线一由在式(V)到式(VII)步骤中，用4-氟-2-甲氧基苯酚替换4-氟-2-(甲氧基-d 3)苯酚，从而制得目标化合物18。 1H NMR(400MHz,DMSO-d 6)δ:14.57(s,1H),11.99(s,1H),7.53-7.48(m,1H),7.38(s,1H),7.26-7.18(m,2H),7.14(d,J＝11.6Hz,1H),3.84(s,3H)；ESI-MS m/z 514(M+H) +。
实施例4 制备3-(5-((2,3-二氟-6-(甲氧基-d 3)苄基)氧基)-2-氟-4-甲氧基苯基)-2,4- 二氧-1,2,3,4-四氢噻吩并[3,4-d]嘧啶-5-羧酸(化合物19)
Figure PCTCN2021093882-appb-000034
按实施例1中所述的方法，不同点在于：在按合成路线一由式(III)到式(IV)步骤中，用NaBH 4代替NaBD 4，同时在式(V)到式(VII)步骤中，用4-氟-2-甲氧基苯酚替换4-氟-2-(甲氧基-d 3)苯酚，从而制得目标化合物19。 1H NMR(400MHz,DMSO-d 6)δ:14.57(s,1H),12.00(s,1H),7.53-7.48(m,1H),7.39(s,1H),7.26(d,J＝7.2Hz,1H),7.23-7.19(m,1H),7.14(d,J＝11.6Hz,1H),4.90(s,2H),3.84(s,3H)。ESI-MS m/z 512(M+H) +。
实施例5 制备3-(5-((2,3-二氟-6-(甲氧基-d 3)苄基)氧基)-2-氟-4-(甲氧基-d 3)苯基)-2,4-二氧-1,2,3,4-四氢噻吩并[3,4-d]嘧啶-5-羧酸(化合物20)
Figure PCTCN2021093882-appb-000035
按实施例1中所述的方法，不同点在于：在按合成路线一由式(III)到式(IV)步骤中，用NaBH 4代替NaBD 4，从而制得目标化合物20。 1H NMR(400MHz,DMSO-d 6)δ:14.57(s,1H),12.00(s,1H),7.53-7.48(m,1H),7.39(s,1H),7.25(d,J＝7.2Hz,1H),7.23-7.19(m,1H),7.13(d,J＝11.6Hz,1H),4.90(s,2H)。ESI-MS m/z 515(M+H) +。
实施例6 制备3-(5-(((2,3-二氟-6-甲氧基苯基)甲氧基-d 2)-2-氟-4-甲氧基苯基)-2,4-二氧-1,2,3,4-四氢噻吩并[3,4-d]嘧啶-5-羧酸(化合物21)
Figure PCTCN2021093882-appb-000036
1、制备(2,3-二氟-6-甲氧基苯基)甲烷-d 2-醇(化合物24)
室温下，向反应瓶中加入化合物23(2.0g)、四氢呋喃(15ml)，降温至-10～-5℃，加入硼氘化钠(1.3g)，搅拌下将碘(2.7g)、四氢呋喃(6ml)配成溶液；控温-10℃左右滴入上述反应液，搅拌2h，然后升温至40℃，反应48h。反应结束后，将反应液倒入冰水中，加入甲苯萃取，水洗，脱溶，得到标题化合物1.4g。ESI-MS m/z 159[M+H-H 2O] +。
2、制备2-(氯甲基-d 2)-3,4-二氟-1-甲氧基苯(化合物25)
向反应瓶瓶中加入化合物24(1.4g)、甲苯(15ml)、浓盐酸(15ml),升温至40℃，反应24h。反应结束后，降温，停止搅拌，静置，分液，水层加入甲苯萃取，水洗，脱溶，得到标题化合物1.2g。
3、制备1,2-二氟-3-((4-氟-2-甲氧基苯氧基)甲基-d 2)-4-甲氧基苯(化合物27)
向反应瓶中加入化合物25(1.2g)、4-氟-2-甲氧基苯酚(化合物26，0.9g)、四氢呋喃(12ml)，加入25％NaOH水溶液(1.4g)，升温至60℃，反应20h。薄层色谱板检测，反应结束后，降温，加入水，搅拌30min，静置，分液，水层加入甲苯萃取，水洗，脱溶，得到粗品2g。固体经过异丙醇/水结晶纯化，得到标题化合物1.0g。 1H NMR(400MHz,DMSO-d 6)δ:7.50-7.42(m,1H),7.05-7.01(m,1H),6.92-6.88(m,2H),6.70-6.65(m,1H),3.80(s,3H),3.74(s,3H)；ESI-MS m/z 299[M-H] -。
4、制备1,2-二氟-3-((4-氟-2-甲氧基-5-硝基苯氧基)甲基-d 2)-4-甲氧基苯(化合物28)
向反应瓶加入化合物27(1.0g)、乙酸(8ml)、硝酸(0.5g)，升温至60℃反应8h。反应结束后，降温至室温，加入水，搅拌2h，抽滤，晾干，得到标题化合物0.8g。 1H NMR(400MHz,DMSO-d 6)δ:7.85(d,J＝7.6Hz,1H),7.53-7.46(m,1H),7.26(d,J＝13.2Hz,1H),6.95-6.91(m,1H),3.88(s,3H),3.84(s,3H)；ESI-MS m/z 344[M-H] -。
5、制备5-((2,3-二氟-6-(甲氧基-d 3)苯基)甲氧基-d 2)-2-氟-4-(甲氧基-d 3)苯胺(化合物29)
向反应瓶加入化合物28(0.8g)、乙酸乙酯，氢气置换2次，加入10％钯碳催化剂(0.1 g)，再次用氢气置换，通入氢气，室温搅拌20h，薄层色谱板检测，反应结束；反应液用硅藻土过滤，乙酸乙酯淋洗，减压移除溶剂，得到粗品；固体用甲醇和水结晶纯化，得到标题化合物0.5g。 1H NMR(400MHz,DMSO-d 6)δ:7.48-7.41(m,1H),6.91-6.88(m,1H),6.76(d,J＝12.4Hz,1H),6.54(d,J＝8.8Hz,1H),4.64(s,2H),3.81(s,3H),3.61(s,3H)；ESI-MS m/z 316[M+H] +。
6、制备二甲基4-(3-(5-((2,3-二氟-6-甲氧基苯基)甲氧基-d 2)-2-氟-4-甲氧基苯基)脲基噻吩-2,3-二羧酸盐(化合物30)
向反应瓶加入化合物29(0.5g)、4-((苯氧羰基)氨基)噻吩-2,3-二羧酸二甲酯(化合物10，0.6g)、四氢呋喃(5ml)，搅拌，加入三乙胺(0.1g)，升温至30℃，搅拌24h，薄层色谱板检测，反应结束，将反应液减压移除溶剂，得粗品，加入乙酸乙酯、甲醇打浆得到标题化合物0.5g。 1H NMR(400MHz,DMSO-d 6)δ:8.95(s,1H),8.82(s,1H),7.94(s,1H),7.74(d,J＝8.0Hz,1H),7.49-7.42(m,1H),7.00(d,J＝12.8Hz,1H),6.91-6.89(m,1H),3.89(s,3H),3.83(s,3H),3.82(s,3H),3.71(s,3H)；ESI-MS m/z 557[M+H] +。
7、制备3-(5-((2,3-二氟-6-甲氧基苯基)甲氧基-d 2)-2-氟-4-甲氧基苯基)-2,4-二氧-1,2,3,4-四氢噻吩并[3,4-d]嘧啶-5-羧酸(化合物21)
向反应瓶加入化合物30(0.5g)、四氢呋喃(1.5ml)、甲醇(1.5ml)和水(1.5ml)搅拌固体不溶；将氢氧化锂一水合物配成7.3％的水溶液，室温下加入反应瓶中，搅拌3h，升温至30℃，搅拌24h，反应液固体消失，溶液澄清，薄层色谱板检测，反应结束。向反应液中加入醋酸，30℃搅拌3-5h，薄层色谱检测，反应结束。加入水，降温至0-10℃，搅拌2-3h，抽滤，得到目标化合物0.46g。 1H NMR(400MHz,DMSO-d 6)δ:14.56(s,1H),12.03(s,1H),7.52-7.45(m,1H),7.40(s,1H),7.27(d,J＝7.6Hz,1H),7.14(d,J＝11.6Hz,1H),6.92-6.90(m,1H),3.81(s,6H)；ESI-MS m/z 511[M+H] +。
实施例7 制备3-(5-((2,3-二氟-6-甲氧基苄基)氧基)-2-氟-4-(甲氧基-d3)苯基)-2,4-二氧-1,2,3,4-四氢噻吩并[3,4-d]嘧啶-5-羧酸(化合物22)
Figure PCTCN2021093882-appb-000037
按实施例1中所述的方法，不同点在于：在式(II)到式(III)步骤中，用CH 3I代替CD 3I，同时在式(III)到式(IV)步骤中，用NaBH 4代替NaBD 4，从而制得目标化合物22。 1H NMR(400MHz,DMSO-d 6)δ:14.55(s,1H),12.02(s,1H),7.52-7.45(m,1H),7.40(s, 1H),7.26(d,J＝7.2Hz,1H),7.13(d,J＝11.2Hz,1H),6.93-6.90(m,1H),4.96(s,2H),3.81(s,3H)。ESI-MS m/z 512(M+H) +。
实施例8：大鼠中的药代动力学评价
8.1药代动力学测试评价
雄性SD大鼠，体重180g左右，禁食过夜后，平均分成3组，每组4只大鼠，采用灌胃给药方式给药。第一组同时灌胃给予3mg/kg的对照化合物林扎戈利(Linzagolix)和3mg/kg化合物1等量混合物，第二组同时灌胃给予3mg/kg的对照化合物Linzagolix和3mg/kg化合物21等量混合物，第三组同时灌胃给予3mg/kg的对照化合物Linzagolix和3mg/kg化合物22等量混合物。各组溶媒为0.5％CMC:0.1％Tween80水溶液。每组分别在给药后0.5，1.0，2.0，4.0，6.0，8.0，12和24h采血，用LC/MS/MS测定血浆中各组分浓度。
8.2测试结果
各组药物组合的血药浓度-时间曲线如图1所示，药代动力学参数如表1所示：
表1 实施例8药代动力学参数总结(n＝4，均值)
Figure PCTCN2021093882-appb-000038
如表1所示，在相同大鼠中，同时灌胃给药本发明化合物和对照化合物Linzagolix的等量混合物时，与对照化合物相比，本发明化合物在大鼠体内均体现出更好的药代动力学性质。其中，化合物1、化合物21和化合物22的血浆暴露量AUC和最大血药浓度(Cmax)均有一定提高，其中，化合物1和化合物21的提高幅度最为显著(AUC分别增加22.2％、53.7％；Cmax分别增加65.98％、60.8％)。
实施例9：大鼠中的药代动力学评价
9.1药代动力学测试评价
雄性SD大鼠，体重180g左右，禁食过夜后，平均分成3组，每组4只大鼠，采用单独平行给药方式给药。第一组灌胃给予3mg/kg的对照化合物Linzagolix，第二组灌胃 给予3mg/kg的化合物21，第三组灌胃给予3mg/kg的化合物20。各组溶媒为0.5％CMC:0.1％Tween80水溶液。每组分别在给药后0.5，1.0，2.0，4.0，6.0，8.0，12和24h采血，用LC/MS/MS测定血浆中各组分浓度。
9.2测试结果
各组药物组合的血药浓度-时间曲线如图2所示，药代动力学参数如表2所示：
表2 实施例9药代动力学参数总结：(n＝4，均值)
Figure PCTCN2021093882-appb-000039
如表2所示，在相同的给药剂量情况下，相对于对照化合物Linzagolix，化合物21与化合物20的最大血药浓度(Cmax)均显著提升，分别增加38.6％和41.3％。另外，化合物21的血浆暴露量AUC也显著增加(28.1％)，而化合物20的血浆暴露量AUC与对照化合物相当。
实施例8和实施例9的结果表明：与对照化合物Linzagolix相比，本发明化合物有更好的药代动力学性质，尤其是本发明化合物1和21具有更为优异的AUC和Cmax，因而具有更好的生物利用度和药效。
实施例10：比格犬中的药代动力学评价
1.药代动力学测试评价
雄性比格犬，4条，体重7-10kg，禁食过夜后采用灌胃方式给药。每条犬同时灌胃给予5mg/kg的对照化合物Linzagolix和5mg/kg化合物21等量混合物。溶媒为0.5％CMC:0.1％Tween80水溶液。分别在给药后0.25，0.5，1.0，2.0，4.0，6.0，8.0，12和24h采血，用LC/MS/MS测定血浆中各组分浓度。
2.测试结果
药物的血药浓度-时间曲线如图3所示，药代动力学参数如表3所示：
表3 实施例10药代动力学参数总结：(n＝4，均值)
Figure PCTCN2021093882-appb-000040
如表3所示，在比格犬中，同时灌胃给药本发明化合物21和对照化合物Linzagolix的等量混合物时，与对照化合物相比，本发明化合物在比格犬体内体现出更好的药代动力学性质。与对照化合物Linzagolix相比，本发明化合物21的血浆暴露量AUC和最大血药浓度(Cmax)均有大幅提高，其AUC、Cmax分别增加191.1％、208.3％。
实施例11：比格犬中的药代动力学评价
1.药代动力学测试评价
雄性比格犬，4条，体重7-10kg，禁食过夜后采用交叉设计方法(2*2交叉)灌胃给药，两轮给药间隔1周。各组分别灌胃给予5mg/kg的对照化合物Linzagolix或给予5mg/kg的化合物21。溶媒为0.5％CMC:0.1％Tween80水溶液。分别在给药后0.25，0.5，1.0，2.0，4.0，6.0，8.0，12和24h采血，用LC/MS/MS测定血浆中各组分浓度。
2.测试结果
药物的血药浓度-时间曲线如图4所示，药代动力学参数如表4所示：
表4 实施例11药代动力学参数总结：(n＝4，均值)
Figure PCTCN2021093882-appb-000041
如表4所示，在相同给药剂量情况下，通过2*2交叉给药，相对于对照化合物Linzagolix，本发明化合物21在比格犬体内体现出更好的药代动力学性质。其中，与对照化合物Linzagolix相比，本发明化合物的血浆暴露量AUC和最大血药浓度(Cmax)均有大幅提高，AUC、Cmax分别增加115.0％、107.3％。
实施例10和11的结果表明：与对照化合物Linzagolix相比，本发明化合物有更好的药代动力学性质，尤其是本发明化合物21具有更为优异的AUC和Cmax，因而具有更好的生物利用度和药效。
实施例12药物组合物
在本实施例中，取实施例1-7中制备的任一式I化合物(尤其是化合物1或21)，按以下配方制备药物组合物。
式I化合物(如化合物1或21) 100g
无水乳糖 130g
微晶纤维素 70g
按常规方法，将上述物质混合均匀后，装入普通明胶胶囊，得到1000颗胶囊。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种式(I)所示的氘代的四氢噻吩并[3,4-d]嘧啶二酮化合物、或其晶型、药学上可接受的盐、水合物或溶剂合物：
    Figure PCTCN2021093882-appb-100001
    其中：
    R 1、R 2和R 9各自独立地为卤素；
    R 3、R 4、R 8、R 10、R 11和R 13各自独立地为氢或氘；
    R 5、R 6、R 7和R 12各自独立地选自：氢、氘、C1-C6烷基或氘代C1-C6烷基；
    附加条件是：R 3、R 4、R 5、R 6、R 7、R 8、R 10、R 11、R 12或R 13中至少一个是氘代烷基或氘。
  2. 如权利要求1所述的化合物、或其晶型、药学上可接受的盐、水合物或溶剂合物，其特征在于，R 1、R 2和R 9为氟。
  3. 如权利要求1所述的化合物、或其晶型、药学上可接受的盐、水合物或溶剂合物，其特征在于，R 5、R 12各自独立地选自：CH 3、CH 2D、CHD 2、CD 3、CH 2CH 3、CD 2CH 3、CH 2CD 3或CD 2CD 3，特别优选为CH 3或CD 3。
  4. 如权利要求1所述的化合物、或其晶型、药学上可接受的盐、水合物或溶剂合物，其特征在于，R 5为CD 3。
  5. 如权利要求1中所述的化合物、或其晶型、药学上可接受的盐、水合物或溶剂合物，其特征在于，R 6、R 7为氘或氢。
  6. 如权利要求1中所述的化合物、或其晶型、药学上可接受的盐、水合物或溶剂合物，其特征在于，R 6、R 7为氘。
  7. 如权利要求1所述的化合物、或其晶型、药学上可接受的盐、水合物或溶剂合物，其特征在于，所述化合物是选自下组的化合物或其药学上可接受的盐：
    Figure PCTCN2021093882-appb-100002
    Figure PCTCN2021093882-appb-100003
  8. 一种药物组合物，其特征在于，包含权利要求1所述的化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物；和药学上可接受的载体。
  9. 如权利要求8所述的药物组合物，其特征在于，所述药物组合物还包含另外的治疗药物，所述的另外的治疗药物为治疗癌症、细胞增殖性疾病、心血管疾病、炎症、感染、免疫性疾病、病毒性疾病、镇痛或代谢性疾病的药物。
  10. 一种权利要求1所述的化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物或如权利要求8所述的药物组合物的用途，其特征在于，用于制备抑制促性腺素释放激素(GnRH)的药物组合物。
PCT/CN2021/093882 2020-05-15 2021-05-14 氘代四氢噻吩并[3,4-d]嘧啶二酮化合物以及包含该化合物的药物组合物 WO2021228236A1 (zh)

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