WO2021098810A1 - 用作选择性雄激素受体调节剂的化合物 - Google Patents
用作选择性雄激素受体调节剂的化合物 Download PDFInfo
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- WO2021098810A1 WO2021098810A1 PCT/CN2020/130314 CN2020130314W WO2021098810A1 WO 2021098810 A1 WO2021098810 A1 WO 2021098810A1 CN 2020130314 W CN2020130314 W CN 2020130314W WO 2021098810 A1 WO2021098810 A1 WO 2021098810A1
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- pharmaceutically acceptable
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- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 230000037257 muscle growth Effects 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- 210000001087 myotubule Anatomy 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005484 neopentoxy group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 108091008581 nuclear androgen receptors Proteins 0.000 description 1
- 102000006255 nuclear receptors Human genes 0.000 description 1
- 108020004017 nuclear receptors Proteins 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical class [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000022558 protein metabolic process Effects 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 102000005969 steroid hormone receptors Human genes 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 1
- 239000012414 tert-butyl nitrite Substances 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Classifications
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/402—1-aryl substituted, e.g. piretanide
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/26—Androgens
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids
Definitions
- the present invention relates to a class of compounds as non-steroidal-selective androgen receptor modulators, and their application in the preparation of drugs for the treatment of related diseases mediated by androgen receptors. Specifically, it relates to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
- Androgen receptor also known as NR3C4
- NR3C4 belongs to the steroid receptor in the nuclear receptor superfamily. By binding to androgen, it can stimulate protein synthesis and metabolism, strengthen muscles and bones, and maintain hormone balance in the body. Androgens play an important physiological role as an intermediary substance. With age, the production of androgens in the human body decreases, and age-related diseases occur, such as muscle atrophy, cachexia, osteoporosis, fractures, fatigue and weakness, hypogonadism, and other muscular and skeletal disorders.
- Non-steroidal-selective androgen receptor modulators SARMs
- SARMs as partial agonists of androgen receptors, can selectively stimulate the anabolic pathways of androgen receptors in muscles and bones, increase the number and thickness of muscle fibers, and strengthen Bone density and bone strength accelerate the recovery of fractures, thereby effectively treating various age-related diseases such as muscle atrophy and fractures, avoiding serious side effects, and having a high therapeutic index.
- the non-steroidal-selective androgen receptor modulator VK5211 (WO2009082437) developed by Viking Therapeutics is in clinical phase II.
- the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
- T 1 is independently selected from N, CH and CR 5 ;
- T 2 is independently selected from N, CH and CR 6 ;
- R 1 is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1- 3 alkoxy optionally substituted with 1, 2 or 3 R a;
- R 2 and R 3 are each independently selected from F, Cl, Br, I, OH and NH 2 ;
- R 2 , R 3 and the atoms to which they are connected together form a C 3-5 cycloalkyl group, and the C 3-5 cycloalkyl group is optionally substituted with 1, 2 or 3 R b ;
- R 4 is independently selected from F, Cl, Br, I, OH, C 1-6 alkyl and C 1-6 alkoxy, the C 1-6 alkyl and C 1-6 alkoxy are optionally selected by 1, 2 or 3 R c substitutions;
- R 5 is independently selected from F, Cl, Br, I, CN, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy are optionally 1, 2 or 3 R d substitutions;
- R 6 is independently selected from F, Cl, Br, I, OH, NH 2 and CN;
- R a , R b and R d are each independently selected from F, Cl, Br, I and OH;
- R c is independently selected from F, Cl, Br, I, OH, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy are optionally selected by 1, 2 or 3 R substitutions;
- R is independently selected from F, Cl, Br and I.
- R 1 is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CH 2 CH 3 , C(CH 3 ) 2 and OCH 3 , so said CH 3, CH 2 CH 3, C (CH 3) 2 OCH 3, and optionally substituted with 1,2 or 3 substituents R a, the other variables are as defined in the present invention.
- R 1 is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , C (CH 3 ) 2 and OCH 3 , and other variables are as defined in the present invention.
- the above-mentioned R 2 , R 3 and the atoms to which they are connected together form a cyclopropyl, cyclobutyl and cyclopentyl group
- the cyclopropyl, cyclobutyl and cyclopentyl groups are optionally selected by 1, 2 or 3 R b substitutions, and other variables are as defined in the present invention.
- R c is independently selected from F, Cl, Br, I, OH, CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , C(CH 3 ) 2 and OCH 3.
- Other variables are as defined in the present invention.
- R 4 is independently selected from F, Cl, Br, I, OH, C 1-3 alkyl group and a C 1-3 alkoxy group, a C 1- 3 alkyl group and a C 1 -3 Alkoxy is optionally substituted with 1, 2 or 3 R c , and other variables are as defined in the present invention.
- R 4 is independently selected from F, Cl, Br, I, OH, CH 3 , CH 2 CH 3 and OCH 3 , and the CH 3 , CH 2 CH 3 and OCH 3 are optionally selected from Replace with 1, 2 or 3 R c , and other variables are as defined in the present invention.
- R 4 is independently selected from F, Cl, Br, I, OH, CH 3 , CF 3 , CH 2 CH 3 , OCH 3 and Other variables are as defined in the present invention.
- R 4 is independently selected from Other variables are as defined in the present invention.
- R 5 is independently selected from F, Cl, Br, I, CN, CH 3 and OCH 3 , and other variables are as defined in the present invention.
- R 5 is independently selected from F, Cl, Br, I, CN, CH 3 and OCH 3 , and other variables are as defined in the present invention.
- the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from:
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in the present invention.
- the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from:
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in the present invention.
- the present invention also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof,
- the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from:
- the above-mentioned compound or a pharmaceutically acceptable salt thereof is used in the preparation of a medicament for the treatment of androgen receptor-mediated related diseases.
- the above application is characterized in that the drug is a non-steroidal-selective androgen receptor modulator drug.
- the above application is characterized in that the drug is used for various senile diseases such as muscle atrophy, fracture, osteoporosis, and so on.
- the compounds of the invention have selective androgen receptor modulating activity.
- the compound of the present invention has certain oral exposure and oral bioavailability, and has good oral PK properties.
- pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues. , Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which is prepared from the compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
- a base addition salt can be obtained by contacting the compound with a sufficient amount of base in a pure solution or a suitable inert solvent.
- Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salt or similar salts.
- the acid addition salt can be obtained by contacting the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent.
- Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, the organic acid includes, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and
- the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or organic solvent or a mixture of both.
- the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
- the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the invention.
- Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
- enantiomer or “optical isomer” refers to stereoisomers that are mirror images of each other.
- cis-trans isomer or “geometric isomer” is caused by the inability to freely rotate the double bond or the single bond of the ring-forming carbon atom.
- diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the relationship between the molecules is non-mirror mirror image.
- wedge-shaped solid line keys And wedge-shaped dashed key Represents the absolute configuration of a solid center, with a straight solid line key And straight dashed key Indicates the relative configuration of the three-dimensional center, using wavy lines Represents a wedge-shaped solid line key Or wedge-shaped dashed key Or use wavy lines Represents a straight solid line key Or straight dashed key
- the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in enantiomers” refer to one of the isomers or pairs of
- the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater than or equal 99.9%.
- the term “isomer excess” or “enantiomeric excess” refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90%, and the content of the other isomer or enantiomer is 10%, the isomer or enantiomer excess (ee value) is 80% .
- optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
- the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with an appropriate optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered.
- the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which uses a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
- the compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
- compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
- deuterium can be substituted for hydrogen to form deuterated drugs.
- the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
- deuterated drugs can reduce toxic side effects and increase drug stability. , Enhance the efficacy, prolong the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
- substituted means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
- oxygen it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.
- optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
- any variable such as R
- its definition in each case is independent.
- the group can optionally be substituted with up to two Rs, and R has independent options in each case.
- combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
- linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
- the substituent can be bonded to any atom on the ring, for example, a structural unit It means that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene.
- substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom.
- a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group.
- the middle linking group L is -MW-, at this time -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right It can also be formed by connecting ring A and ring B in the direction opposite to the reading order from left to right Combinations of the linking groups, substituents, and/or variants thereof are only permitted if such combinations result in stable compounds.
- any one or more sites of the group can be connected to other groups through chemical bonds.
- the connection method of the chemical bond is not positioned, and there is a H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will correspondingly decrease with the number of chemical bonds connected to become the corresponding valence number ⁇ The group.
- the chemical bond between the site and other groups can be a straight solid bond Straight dashed key Or wavy line Said.
- the straight solid bond in -OCH 3 means that it is connected to other groups through the oxygen atom in the group;
- the straight dashed bond in indicates that the two ends of the nitrogen atom in the group are connected to other groups;
- the wavy line in represents the connection to other groups through the 1 and 2 carbon atoms in the phenyl group;
- the number of atoms in a ring is generally defined as the number of ring members.
- “5-7 membered ring” refers to a “ring” in which 5-7 atoms are arranged around.
- C 1-6 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 6 carbon atoms.
- the C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups, etc.; it may Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
- C 1-6 alkyl examples include but are not limited to methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl) , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
- C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms.
- the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
- Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
- C 1-6 alkoxy refers to those alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule through an oxygen atom.
- the C 1-6 alkoxy group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 and C 3 alkoxy, etc. .
- C 1-6 alkoxy examples include but are not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy) Oxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexyloxy and the like.
- C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through an oxygen atom.
- the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
- Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy) and the like.
- C 3-5 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 5 carbon atoms, which is a monocyclic ring system, and the C 3-5 cycloalkyl includes C 3 -4 and C 4-5 cycloalkyl, etc.; it can be monovalent, divalent or multivalent.
- Examples of C 3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and the like.
- protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
- amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
- Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethyloxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl group, such as trimethylsilyl (TMS) and tert-butyldi
- hydroxyl protecting group refers to a protecting group suitable for preventing side reactions of the hydroxyl group.
- Representative hydroxy protecting groups include but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl groups (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
- alkyl groups such as methyl, ethyl, and tert-butyl
- acyl groups such as alkanoyl groups (such as acetyl)
- arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (
- the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
- the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
- the single crystal X-ray diffraction method uses the Bruker D8 venture diffractometer to collect the diffraction intensity data of the cultured single crystal.
- the light source is CuK ⁇ radiation
- the scanning method After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure to confirm the absolute configuration.
- the solvent used in the present invention is commercially available.
- aq stands for water; eq stands for equivalent or equivalent; DCM stands for dichloromethane; PE stands for petroleum ether; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate; EtOH stands for ethanol; MeOH stands for Methanol; Cbz represents benzyloxycarbonyl, which is an amine protecting group; BOC represents tert-butoxycarbonyl is an amine protecting group; rt represents room temperature; O/N represents overnight; THF represents tetrahydrofuran; Boc 2 O represents di-tert Butyl dicarbonate; TFA stands for trifluoroacetic acid; DIPEA stands for diisopropylethylamine; iPrOH stands for 2-propanol; mp stands for melting point.
- reaction solution was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (10mL*3), the organic phases were combined, and the organic phases were washed with saturated brine (10mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate Concentrate under reduced pressure to obtain a crude product, which is purified by column chromatography to obtain compound 8-2.
- reaction solution was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (10mL*3), the organic phases were combined, and the organic phases were washed with saturated brine (10mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate Concentrate under reduced pressure to obtain the crude product, which is purified by column chromatography to obtain compound 9-2.
- the crude product was prepared Purification by high performance liquid chromatography (basic system) to obtain compound 10A.
- SFC detection ee: 90.48%), column: Chiralpak AS-3 150x4.6mm ID, 3 ⁇ m; mobile phase: A: supercritical carbon dioxide, B: 0.05% isopropylamine methanol solution; gradient: B initial 10% hold for 0.5 minutes , In 2.0 minutes from 10% to 40%, 40% hold for 2.0 minutes, return to 10% in 0.7 minutes, 10% balance for 0.8 minutes; flow rate: 2.5mL/min; column temperature: 35°C; wavelength: 220nm, Retention time: 1.63min.
- Compound 12-2 (1.00g, 3.93mmol), zinc cyanide (230mg, 1.96mmol, 124.72 ⁇ L), tris(dibenzylideneacetone)dipalladium (359mg, 393.00 ⁇ mol), 1, 1'-bis(diphenylphosphine)ferrocene (217mg, 393.00 ⁇ mol), N,N-dimethylformamide (10mL) was replaced with nitrogen three times, and reacted at 120°C for 16 hours.
- reaction solution was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by preparative high performance liquid chromatography (basic system) and separated by supercritical fluid chromatography (basic system) to obtain compound 13A.
- SFC detection ee:99.78%), column: Chiralpak AS-3 150x4.6mm ID, 3 ⁇ m; mobile phase: A: supercritical carbon dioxide, B: 0.05% isopropylamine methanol solution; gradient: B initial 10% hold for 0.5 minutes , In 2.0 minutes from 10% to 40%, 40% hold for 2.0 minutes, return to 10% in 0.7 minutes, 10% balance for 0.8 minutes; flow rate: 2.5mL/min; column temperature: 35°C; wavelength: 220nm, Retention time: 1.75min.
- reaction solution was concentrated under reduced pressure to obtain a crude product, and the crude product was separated by preparative high performance liquid chromatography (neutral system) to obtain compound 16A.
- SFC detection ee: 95.6%
- column Chiralpak AD-3 150x4.6mm ID, 3 ⁇ m
- mobile phase A: supercritical carbon dioxide
- B 0.05% isopropylamine methanol solution
- gradient B initial 10% hold for 0.5 minutes , In 2.0 minutes from 10% to 40%, 40% hold for 2.0 minutes, return to 10% in 0.7 minutes, 10% balance for 0.8 minutes
- flow rate 2.5mL/min
- column temperature 35°C
- wavelength 220nm
- Retention time 2.06min.
- 1.1 Compound preparation Dilute the test compound to working concentration, use Echo to dilute each compound in a 4-fold ratio with 10 concentration gradients, and add the compound to the 384-well cell plate according to the microplate layout, 200nL per well;
- 1.2AR cell detection medium 87% Opti-MEM (reduced serum medium), 10% Dialyzed FBS (dialysis fetal bovine serum), 1% NEAA (non-essential amino acids), 1% sodium pyruvate and 1% penicillin-chain Mycin
- the culture medium, trypsin and Dulbecco's phosphate buffer are placed in a 37°C water bath to preheat;
- pancreatin 1.5 Add 3.5 mL of pancreatin to the cell culture flask and shake it gently to make the pancreatin fully contact with the cells and then remove the pancreatin. After aspirating the pancreatin, place the culture flask in a 37°C incubator containing 5% CO 2 for about 1 minute ;
- the compound of the present invention has significant agonistic activity on androgen receptor (AR).
- the LC-MS/MS method was used to determine the drug concentration in plasma at different times after intravenous and intragastric administration of Compound 1A, Compound 3A and Compound 14A. Study the pharmacokinetic behavior of the compound in rats and evaluate its pharmacokinetic characteristics.
- the LC-MS/MS method was used to determine the content of the test compound in the rat's plasma after intravenous and intragastric administration.
- the linear range of the method is 2.00 ⁇ 6000nmol/L; plasma samples are analyzed after acetonitrile-precipitated protein treatment.
- the pharmacokinetic test results of compound 1A, compound 3A and compound 14A are shown in Table 2 below.
- the compound of the present invention is well absorbed orally, and has a certain oral exposure and oral bioavailability.
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Abstract
Description
细胞 | 细胞代数 | 细胞活力 | 细胞密度(个/mL) |
AR | 20 | 95.1% | 1.53×10 6 |
化合物编号 | EC 50(nM) | 化合物编号 | EC 50(nM) |
化合物1A | 2.04 | 化合物9A | 1.66 |
化合物2A | 2.57 | 化合物10A | 0.27 |
化合物3A | 0.24 | 化合物11A | 2.36 |
化合物4A | 0.72 | 化合物12A | 19.22 |
化合物5A | 5.61 | 化合物13A | 10.14 |
化合物6A | 9.68 | 化合物14A | 7.08 |
化合物7A | 8.98 | 化合物16A | 0.43 |
化合物8A | 0.67 | 化合物17A | 5.08 |
Claims (20)
- 式(I)所示化合物或其药学上可接受的盐,其中,T 1独立地选自N、CH和CR 5;T 2独立地选自N、CH和CR 6;R 1独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基,所述C 1-3烷基和C 1- 3烷氧基任选被1、2或3个R a取代;R 2和R 3分别独立地选自F、Cl、Br、I、OH和NH 2;或者,R 2、R 3和它们相连的原子共同构成C 3-5环烷基,所述C 3-5环烷基任选被1、2或3个R b取代;R 4独立地选自F、Cl、Br、I、OH、C 1-6烷基和C 1-6烷氧基,所述C 1-6烷基和C 1-6烷氧基任选被1、2或3个R c取代;R 5独立地选自F、Cl、Br、I、CN、C 1-3烷基和C 1-3烷氧基,所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R d取代;R 6独立地选自F、Cl、Br、I、OH、NH 2和CN;R a、R b和R d分别独立地选自F、Cl、Br、I和OH;R c独立地选自F、Cl、Br、I、OH、C 1-3烷基和C 1-3烷氧基,所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R取代;R独立地选自F、Cl、Br和I。
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,R 1独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2CH 3、C(CH 3) 2和OCH 3,所述CH 3、CH 2CH 3、C(CH 3) 2和OCH 3任选被1、2或3个R a取代。
- 根据权利要求2所述化合物或其药学上可接受的盐,其中,R 1独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2F、CHF 2、CF 3、CH 2CH 3、C(CH 3) 2和OCH 3。
- 根据权利要求1~3任意一项所述化合物或其药学上可接受的盐,其中,R 2、R 3和它们相连的原子共同构成环丙基、环丁基和环戊基,所述环丙基、环丁基和环戊基任选被1、2或3个R b取代。
- 根据权利要求1~3任意一项所述化合物或其药学上可接受的盐,其中,R c独立地选自F、Cl、Br、I、OH、CH 3、CH 2F、CHF 2、CF 3、CH 2CH 3、C(CH 3) 2和OCH 3。
- 根据权利要求6所述化合物或其药学上可接受的盐,其中,R 4独立地选自F、Cl、Br、I、OH、C 1-3烷基和C 1-3烷氧基,所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R c取代。
- 根据权利要求7所述化合物或其药学上可接受的盐,其中,R 4独立地选自F、Cl、Br、I、OH、CH 3、CH 2CH 3和OCH 3,所述CH 3、CH 2CH 3和OCH 3任选被1、2或3个R c取代。
- 根据权利要求1~3任意一项所述化合物或其药学上可接受的盐,其中,R 5独立地选自F、Cl、Br、I、CN、CH 3和OCH 3,所述CH 3和OCH 3任选被1、2或3个R d取代。
- 根据权利要求11所述化合物或其药学上可接受的盐,其中,R 5独立地选自F、Cl、Br、I、CN、CH 3和OCH 3。
- 根据权利要求1~18任意一项所述的化合物或其药学上可接受的盐在制备治疗雄激素受体介导的相关疾病的药物中的应用。
- 根据权利要求19所述的应用,其特征在于,所述药物是用于肌肉萎缩、骨折、骨质疏松症等多种老年性疾病的药物。
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WO2005086735A2 (en) * | 2004-03-04 | 2005-09-22 | Bristol-Myers Squibb Company | Novel bicyclic compounds as modulators of androgen receptor function and method |
WO2005090282A1 (en) * | 2004-03-12 | 2005-09-29 | Ligand Pharmaceuticals Incorporated | Androgen receptor modulator compounds and methods |
EP1911743A1 (en) * | 2005-08-01 | 2008-04-16 | Takeda Pharmaceutical Company Limited | Cyclic amine compound |
CN101175747A (zh) * | 2005-05-13 | 2008-05-07 | 伊莱利利公司 | 作为选择性雄激素受体调节剂的取代的n-芳基吡咯烷化合物 |
CN101945853A (zh) * | 2007-12-21 | 2011-01-12 | 配体药物公司 | 选择性雄激素受体调节剂(sarm)及其应用 |
WO2012047617A1 (en) * | 2010-09-28 | 2012-04-12 | Radius Health, Inc. | Selective androgen receptor modulators |
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WO2005086735A2 (en) * | 2004-03-04 | 2005-09-22 | Bristol-Myers Squibb Company | Novel bicyclic compounds as modulators of androgen receptor function and method |
WO2005090282A1 (en) * | 2004-03-12 | 2005-09-29 | Ligand Pharmaceuticals Incorporated | Androgen receptor modulator compounds and methods |
CN101175747A (zh) * | 2005-05-13 | 2008-05-07 | 伊莱利利公司 | 作为选择性雄激素受体调节剂的取代的n-芳基吡咯烷化合物 |
EP1911743A1 (en) * | 2005-08-01 | 2008-04-16 | Takeda Pharmaceutical Company Limited | Cyclic amine compound |
CN101945853A (zh) * | 2007-12-21 | 2011-01-12 | 配体药物公司 | 选择性雄激素受体调节剂(sarm)及其应用 |
WO2012047617A1 (en) * | 2010-09-28 | 2012-04-12 | Radius Health, Inc. | Selective androgen receptor modulators |
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