HRP20220852T1 - Postupak za izradu modulatora somatostatina - Google Patents
Postupak za izradu modulatora somatostatina Download PDFInfo
- Publication number
- HRP20220852T1 HRP20220852T1 HRP20220852TT HRP20220852T HRP20220852T1 HR P20220852 T1 HRP20220852 T1 HR P20220852T1 HR P20220852T T HRP20220852T T HR P20220852TT HR P20220852 T HRP20220852 T HR P20220852T HR P20220852 T1 HRP20220852 T1 HR P20220852T1
- Authority
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- Croatia
- Prior art keywords
- compound
- amino
- quinolin
- piperidin
- difluoro
- Prior art date
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- 238000000034 method Methods 0.000 title claims 5
- 102000005157 Somatostatin Human genes 0.000 title 1
- 108010056088 Somatostatin Proteins 0.000 title 1
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 title 1
- 229960000553 somatostatin Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 21
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 18
- 239000002904 solvent Substances 0.000 claims 18
- BPVXAUKYSITSMT-UHFFFAOYSA-N 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-hydroxybenzonitrile hydrochloride Chemical compound Cl.NC1CCN(CC1)c1c(cnc2ccc(cc12)-c1cccc(C#N)c1O)-c1cc(F)cc(F)c1 BPVXAUKYSITSMT-UHFFFAOYSA-N 0.000 claims 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 12
- 239000012453 solvate Substances 0.000 claims 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 9
- 239000008194 pharmaceutical composition Substances 0.000 claims 8
- 230000008878 coupling Effects 0.000 claims 7
- 238000010168 coupling process Methods 0.000 claims 7
- 238000005859 coupling reaction Methods 0.000 claims 7
- 238000000634 powder X-ray diffraction Methods 0.000 claims 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims 6
- 239000003054 catalyst Substances 0.000 claims 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 5
- GVTGYFQUBMBIAE-UHFFFAOYSA-N 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-hydroxybenzonitrile dihydrochloride Chemical compound Cl.Cl.NC1CCN(CC1)c1c(cnc2ccc(cc12)-c1cccc(C#N)c1O)-c1cc(F)cc(F)c1 GVTGYFQUBMBIAE-UHFFFAOYSA-N 0.000 claims 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 4
- 239000012320 chlorinating reagent Substances 0.000 claims 4
- XULIXFLCVXWHRF-UHFFFAOYSA-N 1,2,2,6,6-pentamethylpiperidine Chemical compound CN1C(C)(C)CCCC1(C)C XULIXFLCVXWHRF-UHFFFAOYSA-N 0.000 claims 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims 3
- 238000001914 filtration Methods 0.000 claims 3
- 238000010438 heat treatment Methods 0.000 claims 3
- 239000000203 mixture Substances 0.000 claims 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 3
- 235000015320 potassium carbonate Nutrition 0.000 claims 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 3
- 235000017550 sodium carbonate Nutrition 0.000 claims 3
- 239000007787 solid Substances 0.000 claims 3
- 239000000725 suspension Substances 0.000 claims 3
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims 3
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 claims 2
- GHILNKWBALQPDP-UHFFFAOYSA-N 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-hydroxybenzonitrile Chemical compound NC1CCN(CC1)C1=C(C=NC2=CC=C(C=C12)C=1C(=C(C#N)C=CC=1)O)C1=CC(=CC(=C1)F)F GHILNKWBALQPDP-UHFFFAOYSA-N 0.000 claims 2
- ZKQDCIXGCQPQNV-UHFFFAOYSA-N Calcium hypochlorite Chemical compound [Ca+2].Cl[O-].Cl[O-] ZKQDCIXGCQPQNV-UHFFFAOYSA-N 0.000 claims 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 2
- -1 Compound 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride Chemical class 0.000 claims 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 2
- 239000005708 Sodium hypochlorite Substances 0.000 claims 2
- 239000000908 ammonium hydroxide Substances 0.000 claims 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims 2
- 125000005620 boronic acid group Chemical group 0.000 claims 2
- 238000006243 chemical reaction Methods 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- 239000000460 chlorine Substances 0.000 claims 2
- 229910052801 chlorine Inorganic materials 0.000 claims 2
- 229940125904 compound 1 Drugs 0.000 claims 2
- 238000000113 differential scanning calorimetry Methods 0.000 claims 2
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 claims 2
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 claims 2
- 229910052763 palladium Inorganic materials 0.000 claims 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims 2
- 230000005855 radiation Effects 0.000 claims 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims 2
- 238000001228 spectrum Methods 0.000 claims 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims 2
- 229950009390 symclosene Drugs 0.000 claims 2
- CKXZPVPIDOJLLM-UHFFFAOYSA-N tert-butyl n-piperidin-4-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCNCC1 CKXZPVPIDOJLLM-UHFFFAOYSA-N 0.000 claims 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims 2
- 238000001757 thermogravimetry curve Methods 0.000 claims 2
- PBIMIGNDTBRRPI-UHFFFAOYSA-N trifluoro borate Chemical group FOB(OF)OF PBIMIGNDTBRRPI-UHFFFAOYSA-N 0.000 claims 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims 2
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims 2
- 235000019798 tripotassium phosphate Nutrition 0.000 claims 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims 2
- 229910000406 trisodium phosphate Inorganic materials 0.000 claims 2
- 235000019801 trisodium phosphate Nutrition 0.000 claims 2
- QWQBQRYFWNIDOC-UHFFFAOYSA-N (3,5-difluorophenyl)boronic acid Chemical compound OB(O)C1=CC(F)=CC(F)=C1 QWQBQRYFWNIDOC-UHFFFAOYSA-N 0.000 claims 1
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 claims 1
- BBLJNWQYENOWPH-UHFFFAOYSA-N 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dien-1-one Chemical compound ClC1=C(Cl)C(=O)C(Cl)(Cl)C(Cl)=C1Cl BBLJNWQYENOWPH-UHFFFAOYSA-N 0.000 claims 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims 1
- KJILYZMXTLCPDQ-UHFFFAOYSA-N 6-bromo-4-chloroquinoline Chemical compound C1=C(Br)C=C2C(Cl)=CC=NC2=C1 KJILYZMXTLCPDQ-UHFFFAOYSA-N 0.000 claims 1
- 206010000599 Acromegaly Diseases 0.000 claims 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- 241000124008 Mammalia Species 0.000 claims 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims 1
- 206010052399 Neuroendocrine tumour Diseases 0.000 claims 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 230000031709 bromination Effects 0.000 claims 1
- 238000005893 bromination reaction Methods 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 239000002775 capsule Substances 0.000 claims 1
- 238000005660 chlorination reaction Methods 0.000 claims 1
- OCXGTPDKNBIOTF-UHFFFAOYSA-N dibromo(triphenyl)-$l^{5}-phosphane Chemical compound C=1C=CC=CC=1P(Br)(C=1C=CC=CC=1)(Br)C1=CC=CC=C1 OCXGTPDKNBIOTF-UHFFFAOYSA-N 0.000 claims 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims 1
- 229940011051 isopropyl acetate Drugs 0.000 claims 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims 1
- 208000016065 neuroendocrine neoplasm Diseases 0.000 claims 1
- 201000011519 neuroendocrine tumor Diseases 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 claims 1
- 239000006187 pill Substances 0.000 claims 1
- 239000002002 slurry Substances 0.000 claims 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 1
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 claims 1
- 239000003826 tablet Substances 0.000 claims 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
-
- 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
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Crystals, And After-Treatments Of Crystals (AREA)
- Eye Examination Apparatus (AREA)
- Optical Communication System (AREA)
- Peptides Or Proteins (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Claims (17)
1. Spoj 3-[4-(4-amino-piperidin-1-il)-3-(3,5-difluoro-fenil)-hinolin-6-il]-2-hidroksi-benzonitril monohidroklorid, ili njegov solvat, koje ima sljedeću strukturu:
[image]
2. Spoj prema patentnom zahtjevu 1, naznačeno time što je spoj kristalni 3-[4-(4-amino-piperidin-1-il)-3-(3,5-difluoro-fenil)-hinolin-6-il]-2-hidroksi-benzonitril monohidroklorid, ili njegov solvat, koji ima sljedeću strukturu:
[image]
3. Kristalni 3-[4-(4-amino-piperidin-1-il)-3-(3,5-difluoro-fenil)-hinolin-6-il]-2-hidroksi-benzonitril monohidroklorid, ili njegov solvat, prema patentnom zahtjevu 2, koji ima:
- obrazac rendgenske difrakcije praha (XRPD) sa maksimumima na 4.5° 2-teta, 9.1° 2-teta, 10.2° 2-teta, 16.3° 2-teta, 18.4° 2-teta, i 19.1° 2-teta, mjereno pomoću Cu Kα1 zračenja;
- termogram diferencijalne skenirajuće kalorimetrije (DSC) sa endotermom koja ima početak na 207 °C i maksimum na 220 °C, mjereno sa stopom zagrijavanja od 10.0 °C/min;
- infracrveni (IR) spektar sa maksimumima na 2223 cm-1, 1620 cm-1, 1595 cm-1, 1457 cm-1, 1238 cm-1, 1220 cm-1, i 1117 cm-1;
- nepromijenjen XRPD kada se zagrijava do 200° C, nakon izlaganja 90% relativnoj vlažnosti tokom 24 sata, ili nakon izlaganja 75% RH i 40 °C tokom jednog tjedna, ili kombinacijama ovoga;
ili
- kombinacije ovoga.
4. Kristalni 3-[4-(4-amino-piperidin-1-il)-3-(3,5-difluoro-fenil)-hinolin-6-il]-2-hidroksi-benzonitril monohidroklorid, ili njegov solvat, prema patentnom zahtjevu 2 ili patentnom zahtjevu 3, koji ima obrazac rendgenske difrakcije praha (XRPD) sa maksimumima na 4.5° 2-teta, 9.1° 2-teta, 10.2° 2-teta, 16.3° 2-teta, 18.4° 2-teta, i 19.1° 2-teta, mjereno pomoću Cu Kα1 zračenja.
5. Kristalni 3-[4-(4-amino-piperidin-1-il)-3-(3,5-difluoro-fenil)-hinolin-6-il]-2-hidroksi-benzonitril monohidroklorid, ili njegov solvat, prema bilo kojem od patentnih zahtjeva 2-4 – 4 koji ima termogram diferencijalne skenirajuće kalorimetrije (DSC) sa endotermom koja ima početak na 207 °C i maksimum na 220 °C, mjereno sa stopom zagrijavanja od 10.0 °C/min.
6. Kristalni 3-[4-(4-amino-piperidin-1-il)-3-(3,5-difluoro-fenil)-hinolin-6-il]-2-hidroksi-benzonitril monohidroklorid, ili njegov solvat, prema bilo kojem od patentnih zahtjeva 2-5, koji ima nepromijenjen XRPD kada se zagrijava do najviše 200° C.
7. Kristalni 3-[4-(4-amino-piperidin-1-il)-3-(3,5-difluoro-fenil)-hinolin-6-il]-2-hidroksi-benzonitril monohidroklorid, ili njegov solvat, prema bilo kojem od patentnih zahtjeva 2-6, koji ima nepromijenjen XRPD nakon izlaganja relativnoj vlažnosti većoj od 90% tokom 24 sata i nakon izlaganja 75% RH i 40 °C tokom jednog tjedna.
8. Kristalni 3-[4-(4-amino-piperidin-1-il)-3-(3,5-difluoro-fenil)-hinolin-6-il]-2-hidroksi-benzonitril monohidroklorid, ili njegov solvat, prema bilo kojem od patentnih zahtjeva 2-7, koji ima infracrveni (IR) spektar sa karakterističnim maksimumima na 2223 cm-1, 1620 cm-1, 1595 cm-1, 1457 cm-1, 1238 cm-1, 1220 cm-1 i 1117 cm-1.
9. Spoj prema patentnom zahtjevu 1, naznačeno time što je spoj amorfni 3-[4-(4-amino-piperidin-1-il)-3-(3,5-difluoro-fenil)-hinolin-6-il]-2-hidroksi-benzonitril monohidroklorid, koji ima sljedeću strukturu:
[image]
10. Farmaceutska kompozicija koja sadrži spoj prema bilo kojem od patentnih zahtjeva 1-9 i najmanje jedan farmaceutski prihvatljiv ekscipijens;
pri čemu je izborno farmaceutska kompozicija formulirana za primjenu kod sisavaca putem oralne primjene.
11. Farmaceutska kompozicija prema patentnom zahtjevu 10, naznačena time što je farmaceutska kompozicija u obliku farmaceutske kompozicije u čvrstom obliku.
12. Farmaceutska kompozicija prema patentnom zahtjevu 10 ili patentnom zahtjevu 11, naznačena time što je farmaceutska kompozicija u obliku tablete, pilule ili kapsule.
13. Spoj prema bilo kojem od patentnih zahtjeva 1 do 9, ili farmaceutska kompozicija prema bilo kojem od patentnih zahtjeva 10-12, za uporabu u liječenju akromegalije ili neuroendokrinog tumora, ili njihovih kombinacija.
14. Postupak za pravljenje kristalnog 3-[4-(4-amino-piperidin-1-il)-3-(3,5-difluoro-fenil)-hinolin-6-il]-2-hidroksi-benzonitril monohidroklorida, ili njegovog solvata, koji obuhvaća korake:
(a) izrade suspenzije od 3-[4-(4-amino-piperidin-1-il)-3-(3,5-difluoro-fenil)-hinolin-6-il]-2-hidroksi-benzonitril dihidro-klorida u 5 zapremina mješavine izopropanol:voda (1:1);
(i) zagrijavanja suspenzije (a) do 45° C;
(ii) dodavanja 0.5 do 1.2 ekvivalenata otopine amonij hidroksida, otopine natrij bikarbonata ili otopine natrij hidroksida u zagrijanu suspenziju iz koraka (a)(i) kako bi se dobio pH od 4.0-6.0;
(iii) dodavanja vode tokom 2 sata u mješavinu iz koraka (a)(ii); i
(iv) filtriranja suspenzije iz koraka (a)(iii) kako bi se dobio 3-[4-(4-amino-piperidin-1-il)-3-(3,5-difluoro-fenil)-hinolin-6-il]-2-hidroksi-benzonitril monohidroklorid, ili njegov solvat;
ili
(b) dodavanja pogodnog otapala u 3-[4-(4-amino-piperidin-1-il)-3-(3,5-difluoro-fenil)-hinolin-6-il]-2-hidroksi-benzonitril;
(i) dodavanja 1 ekvivalenta klorovodične kiseline u mješavinu otapala i 3-[4-(4-amino-piperidin-1-il)-3-(3,5-difluoro-fenil)-hinolin-6-il]-2-hidroksi-benzonitrila iz (b); i
(ii) filtriranja čvrstih materija koje se dobivaju u koraku (b)(ii) kako bi se dobio 3-[4-(4-amino-piperidin-1-il)-3-(3,5-difluoro-fenil)-hinolin-6-il]-2-hidroksi-benzonitril monohidroklorid, ili njegov solvat;
ili
(c) miješanja 3-[4-(4-amino-piperidin-1-il)-3-(3,5-difluoro-fenil)-hinolin-6-il]-2-hidroksi-benzonitril dihidro-klorida u 20 zapremina do 50 zapremina vode; i
(i) filtriranja čvrstih materija iz koraka (c) kako bi se dobio 3-[4-(4-amino-piperidin-1-il)-3-(3,5-difluoro-fenil)-hinolin-6-il]-2-hidroksi-benzonitril monohidroklorid, ili njegov solvat;
pri čemu, izborno:
otopina amonij hidroksida se koristi u (a)(ii); i
pogodno otapalo u (b) je metanol, etanol, izopropil alkohol, aceton, metil acetat, etil acetat, tetrahidrofuran, tetrahidropiran, voda, ili njihove kombinacije.
15. Postupak sinteze 3-[4-(4-amino-piperidin-1-il)-3-(3,5-difluoro-fenil)-hinolin-6-il]-2-hidroksi-benzonitril monohidroklorida:
[image]
koji obuhvaća korake:
(1) obrade spoja A-VI:
[image]
Spoj A-VI
klorovodičnom kiselinom u pogodnom otapalu kako bi se dobio 3-[4-(4-amino-piperidin-1-il)-3-(3,5-difluoro-fenil)-hinolin-6-il]-2-hidroksi-benzonitril dihidroklorid; i (2) obrade 3-[4-(4-amino-piperidin-1-il)-3-(3,5-difluoro-fenil)-hinolin-6-il]-2-hidroksi-benzonitril dihidroklorida vodenim amonijakom kako bi se dobio 3-[4-(4-amino-piperidin-1-il)-3-(3,5-difluoro-fenil)-hinolin-6-il]-2-hidroksi-benzonitril monohidroklorid;
izborno, pri čemu je pogodno otapalo izopropil alkohol, etil acetat ili izopropil acetat.
16. Postupak prema patentnom zahtjevu 15, naznačen time što se Spoj A-VI priprema:
(1) reakcijom spoja A-IV:
[image]
Spoj A-IV
sa spojem 1:
[image]
Spoj 1
pri čemu,
B je boronska kiselina, boronat ester ili trifluoroborat;
u prisustvu katalizatora spajanja, pogodne baze, i u pogodnom otapalu, kako bi bilo osiguran spoj A-V:
[image]
spoj A-V
i
(2) reakcijom spoja A-V sa 3,5-difluorofenilboronskom kiselinom:
[image]
u prisustvu katalizatora spajanja, pogodne baze, i u pogodnom otapalu, kako
bi bilo osiguran spoj A-VI;
izborno, pri čemu:
B je boronska kiselina ili trifluoroborat;
katalizator spajanja iz koraka (1) je paladijski katalizator;
pogodna baza iz koraka (1) je trietilamin, diizopropiletilamin, 1,2,2,6,6-pentametilpiperidin, tributilamin, natrij bikarbonat, Na2CO3, K2CO3, Cs2CO3, NaOAc, KOAc, Ba(OH)2, Na3PO4 ili K3PO4;
pogodno otapalo iz koraka (1) je acetonitril, dimetilformamid, etanol, tetrahidrofuran, izopropil alkohol, 1,4-dioksan, voda, ili njihove kombinacije.
katalizator spajanja iz koraka (2) je paladijski katalizator;
pogodna baza iz koraka (2) je trietilamin, diizopropiletilamin, 1,2,2,6,6-pentametilpiperidin, tributilamin, natrij bikarbonat, Na2CO3, K2CO3, Cs2CO3, NaOAc, KOAc, Ba(OH)2, Na3PO4 ili K3PO4; i
pogodno otapalo iz koraka (2) je acetonitril, dimetilformamid, etanol, tetrahidrofuran, izopropil alkohol, 1,4-dioksan, voda, ili njihove kombinacije.
17. Postupak prema patentnom zahtjevu 16, naznačen time što se Spoj A-IV priprema:
(1) kloriranjem spoja A-I
[image]
Spoj A-I;
pomoću pogodnog sredstva za kloriranje u pogodnom otapalu, kako bi se dobio spoj A-II
[image]
Spoja A-II;
(2) bromiranjem spoja A-II pomoću pogodnog sredstva za bromiranje u pogodnom otapalu, kako bi se dobilo spoj A-III:
[image]
Spoja A-III;
i
(3) spajanjem 4-(N-Boc amino)piperidina sa spojem A-III u prisustvu pogodne baze i u pogodnom otapalu, kako bi se dobio spoj A-IV;
ili
(i) spajanjem 4-(N-Boc amino)piperidina sa 6-bromo-4-kloro-hinolinom u prisustvu pogodne baze i u pogodnom otapalu kako bi se dobio spoj 4;
[image]
Spoj 4;
i
(ii) kloriranjem spoja 4 pomoću pogodnog sredstva za kloriranje u pogodnom otapalu, kako bi se dobio spoj A-IV;
izborno, pri čemu:
sredstvo za kloriranje iz koraka (1) je N-klorosukcinimid, trikloroizocijanmokraćna kiselina, sulfuril klorid, klor, natrij hipoklorit, kalcij hipoklorit, hipoklorna kiselina, ili 2,3,4,5,6,6-heksakloro-2,4-cikloheksadien-1-on; i
pogodno otapalo iz koraka (1) je octena kiselina, voda, etanol, metanol, toluen, diklorometan, tetrahidrofuran, dioksan ili N,N-dimetilformamid.
sredstvo za bromiranje iz koraka (2) je fosfor tribromid, fosfor oksibromid, hidrobromna kiselina, brom, ili dibromotrifenilfosforan;
pogodno otapalo iz koraka (2) je acetonitril, voda, etanol, izopropanol, diklorometan, toluen, N,N-dimetilformamid, octena kiselina ili aceton.
pogodna baza iz koraka (3) je trietilamin, diizopropiletilamin, 1,8-diazabicikloundek-7-en, 1,2,2,6,6-pentametilpiperidin, tributilamin, natrij bikarbonat, Na2CO3, K2CO3, ili Cs2CO3; i
pogodno otapalo iz koraka (3) je N,N-dimetilformamid, N,N-dimetilacetamid, dimetilsulfoksid, diklormetan, kloroform, ugljik tetraklorid, dioksan, tetrahidrofuran, toluen, acetonitril, etanol ili izopropanol; i/ili
sredstvo za kloriranje iz koraka (ii) je N-klorosukcinimid, trikloroizocijanmokraćna kiselina, sulfuril klorid, klor, natrij hipoklorit, kalcij hipoklorit, hipoklorna kiselina ili 2,3,4,5,6,6-heksakloro-2,4-cikloheksadien-1-on; i
pogodno otapalo iz koraka (ii) je octena kiselina, voda, etanol, metanol, toluen, diklorometan, tetrahidrofuran, dioksan ili N,N-dimetilformamid.
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| PCT/US2019/013844 WO2019143718A1 (en) | 2018-01-17 | 2019-01-16 | Process of making somatostatin modulators |
| EP19740733.1A EP3740475B1 (en) | 2018-01-17 | 2019-01-16 | Process of making somatostatin modulators |
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| US11028068B2 (en) | 2017-07-25 | 2021-06-08 | Crinetics Pharmaceuticals, Inc. | Somatostatin modulators and uses thereof |
| AU2019209469B2 (en) | 2018-01-17 | 2022-09-08 | Crinetics Pharmaceuticals, Inc. | Process of making somatostatin modulators |
| JP2023540137A (ja) * | 2020-09-09 | 2023-09-21 | クリネティックス ファーマシューティカルズ，インク． | ソマトスタチン調節因子の製剤 |
| CN113214050B (zh) * | 2021-05-15 | 2022-07-19 | 宁夏忠同生物科技有限公司 | 一种合成2,3,5,6-四氟苯酚的方法 |
| AU2023207068A1 (en) * | 2022-01-11 | 2024-07-11 | Crinetics Pharmaceuticals, Inc. | Uses of a somatostatin modulator for the treatment of carcinoid syndrome |
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| FR2802206B1 (fr) | 1999-12-14 | 2005-04-22 | Sod Conseils Rech Applic | Derives de 4-aminopiperidine et leur utilisation en tant que medicament |
| WO2003045920A1 (en) | 2001-11-27 | 2003-06-05 | Merck & Co., Inc. | 4-aminoquinoline compounds |
| WO2003066055A1 (en) | 2002-02-04 | 2003-08-14 | F. Hoffmann-La Roche Ag | Quinoline derivatives as npy antagonists |
| WO2005024416A1 (en) | 2003-09-05 | 2005-03-17 | Binghe Wang | Water soluble boronic acid fluorescent reporter compounds and methods of use thereof |
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| WO2008051272A2 (en) | 2006-03-13 | 2008-05-02 | Merck & Co., Inc. | Somatostatin agonists |
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| KR20140041583A (ko) | 2011-05-23 | 2014-04-04 | 엘란 파마슈티컬스, 엘엘씨 | Ｌｒｒｋ2 키나제 활성의 억제제 |
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| WO2016049568A1 (en) | 2014-09-25 | 2016-03-31 | Araxes Pharma Llc | Methods and compositions for inhibition of ras |
| WO2017003723A1 (en) | 2015-07-01 | 2017-01-05 | Crinetics Pharmaceuticals, Inc. | Somatostatin modulators and uses thereof |
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