CN117343073A - Thiophene ring-containing derivative, preparation method and medical application thereof - Google Patents
Thiophene ring-containing derivative, preparation method and medical application thereof Download PDFInfo
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- CN117343073A CN117343073A CN202210749896.8A CN202210749896A CN117343073A CN 117343073 A CN117343073 A CN 117343073A CN 202210749896 A CN202210749896 A CN 202210749896A CN 117343073 A CN117343073 A CN 117343073A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 239000002464 receptor antagonist Substances 0.000 claims abstract description 11
- 229940044551 receptor antagonist Drugs 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 5
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- 102000008238 LHRH Receptors Human genes 0.000 claims description 13
- 108010021290 LHRH Receptors Proteins 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 125000001188 haloalkyl group Chemical group 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 150000001718 carbodiimides Chemical group 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 238000010930 lactamization Methods 0.000 claims description 2
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 abstract description 8
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 abstract description 8
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 abstract description 6
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 108090000765 processed proteins & peptides Proteins 0.000 description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- 101150110792 GNRHR gene Proteins 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 4
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229940028334 follicle stimulating hormone Drugs 0.000 description 4
- 150000003384 small molecules Chemical class 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
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- 229910002027 silica gel Inorganic materials 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 108700012941 GNRH1 Proteins 0.000 description 2
- NMJREATYWWNIKX-UHFFFAOYSA-N GnRH Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CC(C)C)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 NMJREATYWWNIKX-UHFFFAOYSA-N 0.000 description 2
- 108010000817 Leuprolide Proteins 0.000 description 2
- 102000009151 Luteinizing Hormone Human genes 0.000 description 2
- 108010073521 Luteinizing Hormone Proteins 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 2
- -1 calcium phosphatidylinositol Chemical class 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000002124 endocrine Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000002267 hypothalamic effect Effects 0.000 description 2
- 229960004338 leuprorelin Drugs 0.000 description 2
- 229940040129 luteinizing hormone Drugs 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 230000001817 pituitary effect Effects 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000018 receptor agonist Substances 0.000 description 2
- 229940044601 receptor agonist Drugs 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 238000003650 Calcium Assay Kit Methods 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- OUVXYXNWSVIOSJ-UHFFFAOYSA-N Fluo-4 Chemical compound CC1=CC=C(N(CC(O)=O)CC(O)=O)C(OCCOC=2C(=CC=C(C=2)C2=C3C=C(F)C(=O)C=C3OC3=CC(O)=C(F)C=C32)N(CC(O)=O)CC(O)=O)=C1 OUVXYXNWSVIOSJ-UHFFFAOYSA-N 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 108050000048 Gonadoliberin Proteins 0.000 description 1
- 102000009165 Gonadoliberin Human genes 0.000 description 1
- 102000006771 Gonadotropins Human genes 0.000 description 1
- 108010086677 Gonadotropins Proteins 0.000 description 1
- 101100069055 Homo sapiens GNRHR gene Proteins 0.000 description 1
- 101000996727 Homo sapiens Gonadotropin-releasing hormone receptor Proteins 0.000 description 1
- 101000801643 Homo sapiens Retinal-specific phospholipid-transporting ATPase ABCA4 Proteins 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 102100033617 Retinal-specific phospholipid-transporting ATPase ABCA4 Human genes 0.000 description 1
- 206010046798 Uterine leiomyoma Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 210000004246 corpus luteum Anatomy 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000009982 effect on human Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 101150108262 gnrh1 gene Proteins 0.000 description 1
- 239000002622 gonadotropin Substances 0.000 description 1
- 229940094892 gonadotropins Drugs 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 102000057996 human GNRHR Human genes 0.000 description 1
- 230000004185 hypothalamic-pituitary-gonadal axis Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 201000010260 leiomyoma Diseases 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000000203 mixture Substances 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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000004412 neuroendocrine cell Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 210000003370 receptor cell Anatomy 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 210000004994 reproductive system Anatomy 0.000 description 1
- 208000017443 reproductive system disease Diseases 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000021595 spermatogenesis Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 108010050014 systemin Proteins 0.000 description 1
- HOWHQWFXSLOJEF-MGZLOUMQSA-N systemin Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)OC(=O)[C@@H]1CCCN1C(=O)[C@H]1N(C(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]2N(CCC2)C(=O)[C@H]2N(CCC2)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)N)C(C)C)CCC1 HOWHQWFXSLOJEF-MGZLOUMQSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
-
- 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
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Endocrinology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Diabetes (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a thieno ring-containing derivative, a preparation method and application thereof in medicines. In particular, the present invention relates to a compound represented by the general formula (I) wherein each substituent is as defined in the specification, and pharmaceutically acceptable salts thereof, a process for preparing the same and their use as gonadotropin releasing hormone (GnRh) receptor antagonists.
Description
Technical Field
The invention belongs to the field of medicines, and relates to a thieno ring-containing derivative and pharmaceutically acceptable salts thereof, a preparation method thereof, a pharmaceutical composition containing the derivative and application of the derivative serving as a gonadotropin releasing hormone (GnRh) receptor antagonist.
Background
Gonadotropin releasing hormone (Gonadoliberin; gonadotropin releasing hormone; gnRH), also known as Luteinizing Hormone Releasing Hormone (LHRH), is a decapeptide hormone (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH) synthesized by hypothalamic neuroendocrine cells 2 ) Is a central regulator in the endocrine reproductive system. It is delivered to the lobe by the hypothalamic pituitary portal circulatory systemIn vivo, binding to GnRH receptor cells of the anterior pituitary, secretion and release of gonadotropins such as luteinizing hormone (Luteinizing Hormone, LH) and Follicle Stimulating Hormone (FSH), regulate normal development of the ovary and corpus luteum, playing an important role in the hypothalamic-pituitary-gonadal axis. GnRH receptors exert their regulatory effects by coupling to G proteins that activate the calcium phosphatidylinositol second messenger system, while LH regulates the production of sex steroids and FSH regulates the development of male spermatogenesis and female follicles.
LH and FSH are released into the circulation and bind to receptors on specific cells of the ovary or testis, stimulating the production of steroids. In the presence of sex steroids, the conditions such as endometriosis, uterine fibroids and prostate cancer are aggravated, and long-acting peptide GnRH receptor agonists and antagonists are required to be administered for treatment and control.
Peptide GnRH receptor antagonists include GnRH-derived linear peptides (US 5,171,835), cyclic hexapeptide derivatives (US 2002/0065309), bicyclic peptide derivatives (Journal of Medicinal Chemistry,1993; 36:3265-73), and the like; and peptide GnRH receptor agonists include Leuprorelin (Leuprorelin, pGlu-His-Trp-Ser-Tyr-d-Leu-Leu-Arg-Pro-NHEt). However, peptide compounds have a number of problems to be solved including oral absorbability, dosage form, dosage volume, drug stability, sustained action, and metabolic stability. The main reason why the small molecule GnRH receptor antagonist is superior to the existing peptide-based therapeutic methods is that the small molecule GnRH receptor antagonist can be directly administered orally, thereby being convenient and quick.
A series of small molecule GnRH receptor antagonists presently disclosed include WO2006096785, WO2010026993, WO2011076687, WO2012175514, and the like.
Although significant research has been conducted in this field, there is still a need to continue to develop more effective small molecule GnRH receptor antagonists, and the present invention provides a novel structure of GnRH receptor antagonist, and it is found that compounds having such structure have good activity, and can effectively treat endocrine reproductive system diseases.
Disclosure of Invention
The invention provides a compound shown in a general formula (I) and pharmaceutically acceptable salts thereof:
wherein:
X 1 and X 2 Each independently selected from halogen or C 1-3 A haloalkyl group; preferably fluorine, chlorine or trifluoromethyl;
n is selected from 1, 2 or 3.
In a preferred embodiment of the invention, the compound is selected from:
the invention also provides a method for preparing the compound shown in the general formula (I) and the pharmaceutically acceptable salt thereof, which comprises the following steps:
in the presence of condensing agent, the compound shown in the general formula (II) undergoes molecular lactamization reaction in a solvent to obtain the compound shown in the general formula (I);
X 1 and X 2 Each independently selected from halogen or C 1-3 A haloalkyl group; preferably fluorine, chlorine or trifluoromethyl;
n is selected from 1, 2 or 3;
the condensing agent is selected from carbodiimide condensing agents; DCC, DIC or EDCI are preferred.
In a preferred embodiment of the present invention, the condensing agent of the above preparation method is selected from DCC or EDCI.
In a further preferred embodiment of the invention, the solvent of the above preparation method is selected from DMF or DMA.
In a further preferred embodiment of the invention, the molar ratio of the condensing agent of the above preparation to the compound of general formula (II) is 1:1 to 3:1.
in a further preferred embodiment of the present invention, the reaction temperature of the above preparation method is 40 to 100 ℃; preferably 60 to 80 ℃.
The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the above compound and pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
The invention also relates to application of the compound and pharmaceutically acceptable salts thereof or the pharmaceutical composition in preparing medicines of GnRH receptor antagonists.
Detailed Description
Unless stated to the contrary. The following terms used in the specification and claims have the following meanings.
"alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms. Preferably an alkyl group having 1 to 10 carbon atoms, more preferably an alkyl group having 1 to 6 carbon atoms, most preferably an alkyl group having 1 to 3 carbon atoms, most preferably a methyl group. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl.
"haloalkyl" means an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above.
"halogen" means fluorine, chlorine, bromine or iodine.
"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
"DCC" refers to dicyclohexylcarbodiimide;
"DIC" refers to diisopropylcarbodiimide;
"EDCI" refers to 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide;
"DMF" refers to N, N-dimethylformamide;
"DMA" means N, N-dimethylacetamide;
"DMAP" refers to 4-dimethylaminopyridine.
Detailed Description
The present invention will be explained in more detail with reference to the following examples, which are only for illustrating the technical aspects of the present invention and do not limit the spirit and scope of the present invention.
The experimental methods of the present invention, in which specific conditions are not specified, are generally performed according to conventional conditions or according to conditions suggested by the manufacturer of the raw materials or goods. The reagents of specific origin are not noted and are commercially available conventional reagents.
Compound 1-1 of the present invention was prepared by the method disclosed with reference to CN 104703992B.
Examples
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR chemical shifts (6) are given in units of 10-6 (ppm). NMR was performed using a Varian INOVA-400 NMR apparatus with deuterated chloroform (CDCl) 3 ) The internal standard is Tetramethylsilane (TMS).
MS was measured using an ACQUITY UPLC (ESI) mass spectrometer, test conditions: ESI source, negative ion mode.
HPLC was performed using Agilent 1200DAD high pressure liquid chromatography (Sunfire C18X 4.6mm column) and Waters 2695-2996 high pressure liquid chromatography (Gimini C18X 4.6mm column).
The average inhibition rate of kinase and IC50 value were measured by NovoStar microplate reader (BMG, germany).
The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The known starting materials of the present invention can be synthesized using or according to methods known in the art or can be purchased from the companies ABCR GmbH & Co.KG, acros Organics, aldrich Chemical Company, shaog chemical technology (Accela ChemBio Inc), dary chemicals, and the like.
Example 1
Preparation of Compound 1
DMAP (40 mg, EDCI (440 mg,2.312 mmol) and compound 1-1 (1 g,1.926 mmol) are added into a 100ml three-mouth bottle, the three-mouth bottle is vacuumized to replace nitrogen, then the three-mouth bottle is dissolved in 25ml DMF, the temperature is raised to 60-80 ℃ and stirred for 6-8 hours, the color of the reaction liquid is gradually deepened, the reaction is monitored to be finished by HPLC, and if the residual raw materials can be supplemented with EDCI until the raw materials are completely reacted; cooling to 0-15 ℃, slowly adding 50ml of water into the reaction liquid under stirring, precipitating a large amount of solids, further cooling to-5-0 ℃, stirring for 1-2h, filtering and collecting a target product, washing a filter cake with water, and drying to obtain 0.86g of the compound of the example 1, wherein the yield is as follows: 91% purity 97.4% (HPLC).
1H NMR(400MHz,CDCl 3 )δ7.21-7.23(m，2H),7.27-7.4923(m，2H),7.17-7.21(m，1H),7.21-7.23(t，2H),5.68(br,2H)，4.47(s,2H),4.21-4.26(q,2H)，4.47(s,3H),1.23-1.27(t,3H)。
MS m/s(ESI)：488.2[M+1] +
Examples 2-6 were synthesized by the synthesis method of example 1. The data are as follows:
biological evaluation
Test example 1 determination of in vitro protein Activity of the inventive Compounds against human GnRHr (GnRH receptor)
The purpose of the experiment is as follows: the method is used for determining the inhibition effect of the compound on the activity of the human GnRHR protein expressed in human GnRHR/CHO stable transgenic plant cells.
Experimental materials and instruments:
1、Fluo-4NW Calcium Assay Kits(F36206，invitrogen)；
2、DMEM/F12(SH30023.01B，thermo)；
3、G418(11811-031，invitrogen)；
4. FlexStation3 microplate reader.
Experimental protocol:
transferring a mammalian expression vector containing a human GnRHR gene into CHO cells by using an LTX reagent containing PlusTM; antibiotic selection was started every other day, and monoclonal cell lines were selected.
Human GnRhr/CHO stable cells were seeded into 96 well plates at a density of 25000 cells/well. Every other day, the medium was removed, 100. Mu.L of Fluo-4 dye-containing loading buffer was added to each well, and incubated at 37℃for 30 minutes. After the time, the plates were moved to room temperature for 10 minutes for equilibration. Each compound was prepared at 7 concentrations of 100. Mu.M, 10. Mu.M, 1. Mu.M, 0.1. Mu.M, 0.01. Mu.M, 0.001. Mu.M, 0.0001. Mu.M, etc. in DMSO, 1. Mu.L was added to each well and incubated at room temperature for 10 minutes. Detection was performed using a flexstation3 microplate reader, and 50. Mu.L of GnRH polypeptide stimulus was automatically added by the machine, and the values were read immediately at 494/516 nM. IC of compound 50 The value can be obtained by adopting fluorescence values corresponding to different concentrations through software calculation.
The inhibitory activity of the compound of the present invention against human GnRHr was measured by the above test, and the measured IC 50 The values are shown in Table 1.
TABLE 1
| Examples numbering | IC 50 (nM) |
| 1 | 0.9 |
| 6 | 10.2 |
Conclusion:
the compound has obvious inhibition effect on human GnRHR activity.
Claims (9)
1. A compound of formula (I) and pharmaceutically acceptable salts thereof:
wherein:
X 1 and X 2 Each independently selected from halogen or C 1-3 A haloalkyl group; preferably fluorine, chlorine or trifluoromethyl;
n is selected from 1, 2 or 3.
2. The compound of formula (I) according to claim 1, wherein said compound is selected from the group consisting of:
3. a process for preparing a compound of formula (I) as defined in claim 1 and pharmaceutically acceptable salts thereof, which comprises:
in the presence of condensing agent, the compound shown in the general formula (II) undergoes molecular lactamization reaction in a solvent to obtain the compound shown in the general formula (I);
X 1 and X 2 Each independently selected from halogen or C 1-3 A haloalkyl group; preferably fluorine, chlorine or trifluoromethyl;
n is selected from 1, 2 or 3;
the condensing agent is selected from carbodiimide condensing agents; DCC, DIC or EDCI are preferred.
4. A method of preparation according to claim 3, wherein the condensing agent is selected from DCC or EDCI.
5. The method of claim 3 or 4, wherein the solvent is selected from DMF or DMA.
6. The process according to any one of claims 3 to 5, wherein the molar ratio of condensing agent to compound of formula (II) is 1:1 to 3:1.
7. the method according to any one of claims 3 to 6, wherein the temperature of the reaction is 40 to 100 ℃; preferably 60 to 80 ℃.
8. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or 2, and pharmaceutically acceptable salts thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
9. Use of a compound according to claim 1 or 2, and pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to claim 8, for the manufacture of a medicament for a GnRH receptor antagonist.
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