HRP20221497T1 - Derivati citizina za liječenje ovisnosti - Google Patents
Derivati citizina za liječenje ovisnosti Download PDFInfo
- Publication number
- HRP20221497T1 HRP20221497T1 HRP20221497TT HRP20221497T HRP20221497T1 HR P20221497 T1 HRP20221497 T1 HR P20221497T1 HR P20221497T T HRP20221497T T HR P20221497TT HR P20221497 T HRP20221497 T HR P20221497T HR P20221497 T1 HRP20221497 T1 HR P20221497T1
- Authority
- HR
- Croatia
- Prior art keywords
- optionally substituted
- amino
- formula
- compound
- alkyl
- Prior art date
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- ANJTVLIZGCUXLD-DTWKUNHWSA-N cytisine Chemical class C1NC[C@H]2CN3C(=O)C=CC=C3[C@@H]1C2 ANJTVLIZGCUXLD-DTWKUNHWSA-N 0.000 title claims 4
- 206010012335 Dependence Diseases 0.000 title 1
- -1 phospho, carbonyl Chemical group 0.000 claims 24
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims 21
- 238000000034 method Methods 0.000 claims 19
- 125000001072 heteroaryl group Chemical group 0.000 claims 15
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims 14
- 150000001875 compounds Chemical class 0.000 claims 13
- 125000001424 substituent group Chemical group 0.000 claims 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 8
- 125000003107 substituted aryl group Chemical group 0.000 claims 8
- VUAXHMVRKOTJKP-UHFFFAOYSA-M 2,2-dimethylbutanoate Chemical compound CCC(C)(C)C([O-])=O VUAXHMVRKOTJKP-UHFFFAOYSA-M 0.000 claims 7
- 125000002252 acyl group Chemical group 0.000 claims 7
- 125000003545 alkoxy group Chemical group 0.000 claims 7
- 125000003368 amide group Chemical group 0.000 claims 7
- 125000003435 aroyl group Chemical group 0.000 claims 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims 7
- 239000004202 carbamide Substances 0.000 claims 7
- 125000000392 cycloalkenyl group Chemical group 0.000 claims 7
- 125000001188 haloalkyl group Chemical group 0.000 claims 7
- 125000001475 halogen functional group Chemical group 0.000 claims 7
- 125000004366 heterocycloalkenyl group Chemical group 0.000 claims 7
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims 7
- 239000001257 hydrogen Substances 0.000 claims 7
- 229910052739 hydrogen Inorganic materials 0.000 claims 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 7
- 125000004043 oxo group Chemical group O=* 0.000 claims 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 7
- 125000005017 substituted alkenyl group Chemical group 0.000 claims 7
- 125000000547 substituted alkyl group Chemical group 0.000 claims 7
- 125000004426 substituted alkynyl group Chemical group 0.000 claims 7
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims 7
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 claims 7
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims 7
- 125000003396 thiol group Chemical group [H]S* 0.000 claims 7
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 7
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims 6
- 125000006239 protecting group Chemical group 0.000 claims 5
- 239000002904 solvent Substances 0.000 claims 5
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims 4
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims 4
- 238000006795 borylation reaction Methods 0.000 claims 4
- 239000003795 chemical substances by application Substances 0.000 claims 4
- 238000006243 chemical reaction Methods 0.000 claims 3
- ANJTVLIZGCUXLD-BDAKNGLRSA-N (-)-Cytisine Natural products C1NC[C@@H]2CN3C(=O)C=CC=C3[C@H]1C2 ANJTVLIZGCUXLD-BDAKNGLRSA-N 0.000 claims 2
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 claims 2
- BQHKABBJVFVZNX-UHFFFAOYSA-N 2,3,4,5-tetramethyl-1,10-phenanthroline Chemical compound N1=CC=CC2=CC(C)=C(C(C)=C(C(C)=N3)C)C3=C21 BQHKABBJVFVZNX-UHFFFAOYSA-N 0.000 claims 2
- KPQCKFFSPXOBQZ-UHFFFAOYSA-N 3,4-ditert-butyl-2-pyridin-2-ylpyridine Chemical group CC(C)(C)C1=CC=NC(C=2N=CC=CC=2)=C1C(C)(C)C KPQCKFFSPXOBQZ-UHFFFAOYSA-N 0.000 claims 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 2
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims 2
- 150000001413 amino acids Chemical class 0.000 claims 2
- 239000003849 aromatic solvent Substances 0.000 claims 2
- 229940027564 cytisine Drugs 0.000 claims 2
- 229930017327 cytisine Natural products 0.000 claims 2
- 238000010511 deprotection reaction Methods 0.000 claims 2
- WLTBZOGEOMUMMY-UHFFFAOYSA-N ditert-butyl-[2-(2-ditert-butylphosphanylphenoxy)phenyl]phosphane Chemical compound CC(C)(C)P(C(C)(C)C)C1=CC=CC=C1OC1=CC=CC=C1P(C(C)(C)C)C(C)(C)C WLTBZOGEOMUMMY-UHFFFAOYSA-N 0.000 claims 2
- ANJTVLIZGCUXLD-UHFFFAOYSA-N ent-cytisine Natural products C1NCC2CN3C(=O)C=CC=C3C1C2 ANJTVLIZGCUXLD-UHFFFAOYSA-N 0.000 claims 2
- 150000002148 esters Chemical class 0.000 claims 2
- YUWFEBAXEOLKSG-UHFFFAOYSA-N hexamethylbenzene Chemical compound CC1=C(C)C(C)=C(C)C(C)=C1C YUWFEBAXEOLKSG-UHFFFAOYSA-N 0.000 claims 2
- 239000000203 mixture Substances 0.000 claims 2
- 239000007858 starting material Substances 0.000 claims 2
- ZKWQSBFSGZJNFP-UHFFFAOYSA-N 1,2-bis(dimethylphosphino)ethane Chemical compound CP(C)CCP(C)C ZKWQSBFSGZJNFP-UHFFFAOYSA-N 0.000 claims 1
- BEHYHCBDZZQSBV-UHFFFAOYSA-N 2,3-dimethyl-1,10-phenanthroline Chemical compound C1=CC=NC2=C(N=C(C(C)=C3)C)C3=CC=C21 BEHYHCBDZZQSBV-UHFFFAOYSA-N 0.000 claims 1
- GWCJKCRIXOCARP-UHFFFAOYSA-N 3,4-dimethoxy-2-pyridin-2-ylpyridine Chemical group COC1=CC=NC(C=2N=CC=CC=2)=C1OC GWCJKCRIXOCARP-UHFFFAOYSA-N 0.000 claims 1
- DHDHJYNTEFLIHY-UHFFFAOYSA-N 4,7-diphenyl-1,10-phenanthroline Chemical compound C1=CC=CC=C1C1=CC=NC2=C1C=CC1=C(C=3C=CC=CC=3)C=CN=C21 DHDHJYNTEFLIHY-UHFFFAOYSA-N 0.000 claims 1
- IMEVSAIFJKKDAP-UHFFFAOYSA-N 4-methoxy-2-(4-methoxypyridin-2-yl)pyridine Chemical compound COC1=CC=NC(C=2N=CC=C(OC)C=2)=C1 IMEVSAIFJKKDAP-UHFFFAOYSA-N 0.000 claims 1
- CGOKJLAKJSTSDO-UHFFFAOYSA-N 5-bromo-4-chloro-3-iodo-2-phenylmethoxypyridine Chemical group BrC=1C(=C(C(=NC=1)OCC1=CC=CC=C1)I)Cl CGOKJLAKJSTSDO-UHFFFAOYSA-N 0.000 claims 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 claims 1
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 claims 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims 1
- 150000001263 acyl chlorides Chemical class 0.000 claims 1
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 125000001931 aliphatic group Chemical group 0.000 claims 1
- 125000003342 alkenyl group Chemical group 0.000 claims 1
- 125000005907 alkyl ester group Chemical group 0.000 claims 1
- 125000000304 alkynyl group Chemical group 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 claims 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims 1
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 claims 1
- 239000003054 catalyst Substances 0.000 claims 1
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 229910052741 iridium Inorganic materials 0.000 claims 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- 239000003446 ligand Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 150000004702 methyl esters Chemical class 0.000 claims 1
- IYRGXJIJGHOCFS-UHFFFAOYSA-N neocuproine Chemical compound C1=C(C)N=C2C3=NC(C)=CC=C3C=CC2=C1 IYRGXJIJGHOCFS-UHFFFAOYSA-N 0.000 claims 1
- 229910052759 nickel Inorganic materials 0.000 claims 1
- 229910052763 palladium Inorganic materials 0.000 claims 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims 1
- 238000002360 preparation method Methods 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- 229910052703 rhodium Inorganic materials 0.000 claims 1
- 239000010948 rhodium Substances 0.000 claims 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 239000012453 solvate Substances 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims 1
- 150000003462 sulfoxides Chemical class 0.000 claims 1
- 229910052723 transition metal Inorganic materials 0.000 claims 1
- 150000003624 transition metals Chemical class 0.000 claims 1
- USLYUBIQUAPPLX-UHFFFAOYSA-N triazol-1-ylmethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCN1C=CN=N1 USLYUBIQUAPPLX-UHFFFAOYSA-N 0.000 claims 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 claims 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims 1
- 229920002554 vinyl polymer Polymers 0.000 claims 1
- 229910052725 zinc Inorganic materials 0.000 claims 1
- 239000011701 zinc Substances 0.000 claims 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- 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
- A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
-
- 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
- A61K31/69—Boron compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/34—Tobacco-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/18—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
- B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
- B01J31/1815—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
- B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
- B01J31/1825—Ligands comprising condensed ring systems, e.g. acridine, carbazole
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
- B01J31/2409—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Addiction (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Psychiatry (AREA)
- Epidemiology (AREA)
- Toxicology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyridine Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Claims (17)
1. Postupak za pripremu 4-supstituiranog analoga citizina formule (I):
[image]
ili njegove farmaceutski prihvatljive soli, solvata i/ili estera, naznačen time, što:
R1 je
• hidroksil;
• halogen;
• opcionalno supstituirani alifatik;
• opcionalno supstituirani cikloalifatik;
• opcionalno supstituirani heterocikloalifatik;
• opcionalno supstituirani aril;
• opcionalno supstituirani heteroaril;
• -(CH2)m-NR6R7R8, gdje
◦ svaki od R6 i R7 je nezavisno odabran iz grupe koja se sastoji od vodika, halo, hidroksi, okso, amino, amido, nitro, cijano, alkoksi, N-alkil amino, N,N-dialkil amino, fosfo, karbonila, karboksi, sulfoksi, sulfinila, sulfonila, sulfanila, sulfamida, sulfo, merkapto, karbamoila, metil pivalata, trimetilsilila, uree, tiouree, opcionalno supstituiranog arila, opcionalno supstituiranog heteroarila, opcionalno supstituiranog alkila, opcionalno supstituiranog cikloalifatika, opcionalno supstituiranog heterocikloalifatika, opcionalno supstituiranog heteroarila, opcionalno supstituiranog haloalkila, opcionalno supstituiranog aroila, opcionalno supstituiranog heteroaroila, opcionalno supstituiranog acila, opcionalno supstituiranog alkenila, opcionalno supstituiranog alkinila, opcionalno supstituiranog aralkila, opcionalno supstituiranog cikloalkila, opcionalno supstituiranog cikloalkenila, opcionalno supstituiranog heterocikloalkila ili opcionalno supstituiranog heterocikloalkenila ili
◦ jedan od R6 ili R7 je -CO-R9, a drugi od R6 ili R7 je kao što je gore definirano,
◦ R8 je odabran iz grupe koja se sastoji od vodika, halo, hidroksi, okso, amino, amido, nitro, cijano, alkoksi, N-alkil amino, N,N-dialkil amino, fosfo, karbonila, karboksi, sulfoksi, sulfinila, sulfonila, sulfanila, sulfamida, sulfo, merkapto, karbamoila, metil pivalata, trimetilsilila, uree, tiouree, opcionalno supstituiranog arila, opcionalno supstituiranog heteroarila, opcionalno supstituiranog alkila, opcionalno supstituiranog cikloalifatika, opcionalno supstituiranog heterocikloalifatika, opcionalno supstituiranog heteroarila, opcionalno supstituiranog haloalkila, opcionalno supstituiranog aroila, opcionalno supstituiranog heteroaroila, opcionalno supstituiranog acila, opcionalno supstituiranog alkenila, opcionalno supstituiranog alkinila, opcionalno supstituiranog aralkila, opcionalno supstituiranog cikloalkila, opcionalno supstituiranog cikloalkenila, opcionalno supstituiranog heterocikloalkila ili opcionalno supstituiranog heterocikloalkenila, ili je odsutan,
◦ R9 je odabran iz grupe koja se sastoji od vodika, halo, hidroksi, okso, amino, amido, nitro, cijano, alkoksi, N-alkil amino, N,N-dialkil amino, fosfo, karbonila, karboksi, sulfoksi, sulfinila, sulfonila, sulfanila, sulfamida, sulfo, merkapto, karbamoila, metil pivalata, trimetilsilila, uree, tiouree, opcionalno supstituiranog arila, opcionalno supstituiranog heteroarila, opcionalno supstituiranog alkila, opcionalno supstituiranog cikloalifatika, opcionalno supstituiranog heterocikloalifatika, opcionalno supstituiranog heteroarila, opcionalno supstituiranog haloalkila, opcionalno supstituiranog aroila, opcionalno supstituiranog heteroaroila, opcionalno supstituiranog acila, opcionalno supstituiranog alkenila, opcionalno supstituiranog alkinila, opcionalno supstituiranog aralkila, opcionalno supstituiranog cikloalkila, opcionalno supstituiranog cikloalkenila, opcionalno supstituiranog heterocikloalkila ili opcionalno supstituiranog heterocikloalkenila,
◦ i m je 0, 1, 2, 3, 4 ili 5,
• -(CH2)m-O-(CH2)n-R10, gdje
◦ R10 je odabran iz grupe koja se sastoji od vodika, halo, hidroksi, okso, amino, amido, nitro, cijano, alkoksi, N-alkil amino, N,N-dialkil amino, fosfo, karbonila, karboksi, sulfoksi, sulfinila, sulfonila, sulfanila, sulfamida, sulfo, merkapto, karbamoila, metil pivalata, trimetilsilila, uree, tiouree, opcionalno supstituiranog arila, opcionalno supstituiranog heteroarila, opcionalno supstituiranog alkila, opcionalno supstituiranog cikloalifatika, opcionalno supstituiranog heterocikloalifatika, opcionalno supstituiranog heteroarila, opcionalno supstituiranog haloalkila, opcionalno supstituiranog aroila, opcionalno supstituiranog heteroaroila, opcionalno supstituiranog acila, opcionalno supstituiranog alkenila, opcionalno supstituiranog alkinila, opcionalno supstituiranog aralkila, opcionalno supstituiranog cikloalkila, opcionalno supstituiranog cikloalkenila, opcionalno supstituiranog heterocikloalkila ili opcionalno supstituiranog heterocikloalkenila, i
◦ m i n su svaki nezavisno 0, 1, 2, 3, 4 ili 5,
• -CN
• -COOR12, gdje je R12 odabran iz grupe koja se sastoji od vodika, halo, hidroksi, okso, amino, amido, nitro, cijano, alkoksi, N-alkil amino, N,N-dialkil amino, fosfo, karbonila, karboksi, sulfoksi, sulfinila, sulfonila, sulfanila, sulfamida, sulfo, merkapto, karbamoila, metil pivalata, trimetilsilila, uree, tiouree, opcionalno supstituiranog arila, opcionalno supstituiranog heteroarila, opcionalno supstituiranog alkila, opcionalno supstituiranog cikloalifatika, opcionalno supstituiranog heterocikloalifatika, opcionalno supstituiranog heteroarila, opcionalno supstituiranog haloalkila, opcionalno supstituiranog aroila, opcionalno supstituiranog heteroaroila, opcionalno supstituiranog acila, opcionalno supstituiranog alkenila, opcionalno supstituiranog alkinila, opcionalno supstituiranog aralkila, opcionalno supstituiranog cikloalkila, opcionalno supstituiranog cikloalkenila, opcionalno supstituiranog heterocikloalkila ili opcionalno supstituiranog heterocikloalkenila,
• -(CH2)o-CO-(CH2)p-R13, gdje
◦ R13 je odabran iz grupe koja se sastoji od vodika, halo, hidroksi, okso, amino, amido, nitro, cijano, alkoksi, N-alkil amino, N,N-dialkil amino, fosfo, karbonil, karboksi, sulfoksi, sulfinila, sulfonila, sulfanila, sulfamida, sulfo, merkapto, karbamoila, metil pivalata, trimetilsilila, uree, tiouree, opcionalno supstituiranog arila, opcionalno supstituiranog heteroarila, opcionalno supstituiranog alkila, opcionalno supstituiranog cikloalifatika, opcionalno supstituiranog heterocikloalifatika, opcionalno supstituiranog heteroarila, opcionalno supstituiranog haloalkila, opcionalno supstituiranog aroila, opcionalno supstituiranog heteroaroila, opcionalno supstituiranog acila, opcionalno supstituiranog alkenila, opcionalno supstituiranog alkinila, opcionalno supstituiranog aralkila, opcionalno supstituiranog cikloalkila, opcionalno supstituiranog cikloalkenila, opcionalno supstituiranog heterocikloalkila ili opcionalno supstituiranog heterocikloalkenila, i
◦ o i p su svaki nezavisno 0, 1, 2, 3, 4 ili 5,
• aminokiselina ili njen ester,
• acil-klorid,
• zaštitna grupa, ili
• citizinil,
svaki od R2, R3 i R4 je nezavisno odabran iz grupe koja se sastoji od vodika, halo, hidroksi, okso, amino, amido, nitro, cijano, alkoksi, N-alkil amino, N,N-dialkil amino, fosfo, karbonila, karboksi, sulfoksi, sulfinila, sulfonila, sulfanila, sulfamida, sulfo, merkapto, karbamoil, metil pivalata, trimetilsilila, uree, tiouree, opcionalno supstituiranog arila, opcionalno supstituiranog heteroarila, opcionalno supstituiranog alkila, opcionalno supstituiranog cikloalifatika, opcionalno supstituiranog heterocikloalifatika, opcionalno supstituiranog heteroarila, opcionalno supstituiranog haloalkila, opcionalno supstituiranog aroila, opcionalno supstituiranog heteroaroila, opcionalno supstituiranog acila, opcionalno supstituiranog alkenila, opcionalno supstituiranog alkinila, opcionalno supstituiranog aralkila, opcionalno supstituiranog cikloalkila, opcionalno supstituiranog cikloalkenila, opcionalno supstituiranog heterocikloalkila ili opcionalno supstituiranog heterocikloalkenila, aminokiseline ili citizina, ili R4 može biti zaštitna grupa, ili grupa koja ima strukturu -(CH2)v-FORMULA 1, gdje v predstavlja 0, 1, 2, 3, 4, 5 ili 6, a FORMULA 1 je spoj formule (I) kao što je ovdje opisano,
gdje postupak obuhvaća:
i) pružanje spoja formule IIa
[image]
gdje su R2, R3 i R4 kao što je gore definirano;
ii) proizvodnju spoja formule IIb
[image]
gdje su R2, R3 i R4 kao što je gore definirano, a BComp je borilirani kompleks, dovođenjem u kontakt spoja formule IIa s agensom za borilaciju;
iii) zamjenu BComp sa R1 kako bi se proizvelo spoj formule I:
[image]
2. Postupak prema zahtjevu 1, naznačen time, što spoj formule IIa pružen u koraku i) sadrži atom vodika na poziciji R4, pri čemu taj korak dalje obuhvaća supstituciju atoma vodika na poziciji R4 zaštitnom grupom.
3. Postupak prema zahtjevu 2, naznačen time, što je zaštitna grupa Boc.
4. Postupak prema zahtjevu 2 ili zahtjevu 3, naznačen time, što je spoj formule IIa citizin.
5. Postupak prema bilo kojem od zahtjeva 1 do 4, naznačen time, što je agens za borilaciju odabran od:
agensa formule (RO)2-B-B-(OR)2 ili HB(OR)2; i
B2Pin2 ili B2Cat2.
6. Postupak prema bilo kojem od zahtjeva 1 do 5, naznačen time, što je molarni odnos agens za borilaciju : polazni materijal formule IIa najmanje oko 0.5 : 1, najmanje oko 0.75 : 1, najmanje oko 1 : 1, najmanje oko 1.5 : 1 ili najmanje oko 2 : 1.
7. Postupak prema bilo kojem od zahtjeva 1 do 6, naznačen time, što se reakcija u koraku ii) izvodi u prisustvu katalizatora na bazi prijelaznog metala koji sadrži iridij, paladij, cink, nikl i/ili rodij.
8. Postupak prema bilo kojem od zahtjeva 1 do 7, naznačen time, što se reakcija u koraku ii) izvodi u otapalu odabranom od esterskog otapala, etarskog otapala, ketonskog otapala, sulfoksidnog otapala, aromatičnog otapala, fluoriranog aromatičnog otapala, alkanskog otapala ili njihovih smjesa.
9. Postupak prema bilo kojem od zahtjeva 1 do 8, naznačen time, što se korak ii) izvodi u prisustvu liganda odabranog od:
tetrametil-1,10-fenantrolina (Me4phen), di-terc-butil-2,2’-bipiridila (dtbpy), 2,2’-bipiridina (bpy), 1,1’-bis(difenilfosfino)ferocena (dppf), bis(2-di-terc-butilfosfinofenil)etra, 1,3-bis(difenilfosfino)propana, (dppp) 1,2-bis(difenilfosfino)etana (dppe), heksametilbenzena (C6Me6), ksantfosa ili 1,2- bis(dimetilfosfino)etana (dmpe); i
fenantrolina (phen), dimetilfenantrolina (me2phen) tetrametil-1,10-fenantrolina (me4phen), batofenantrolina (batofen), di-terc-butil-2,2’-bipiridila (dtbpy), 2,2’-bipiridina (bpy), dimetoksi-2,2’-bipiridila (MeO-bpy), 1,1’-bis(difenilfosfino)ferocena (dppf), bis(2-di-terc-butilfosfinofenil)etera, 1,3-bis(difenilfosfino)propana (dppp), 1,2-bis(difenilfosfino)etana (dppe), heksametilbenzena (C6Me6), neokuproina, ksantfosa, 1,2-is(dimetilfosfino)etana (dmpe), ili jednog od:
[image]
[image]
[image]
[image]
10. Postupak prema zahtjevu 9, naznačen time, što je molarni odnos borilacija : polazni materijal formule IIa manji od oko 2 : 1, manji od oko 1.5 : 1, manji od oko 1 : 1, manji od oko 0.75 : 1, manji od oko 0.5 : 1, manji od oko 0.1 : 1, manji od oko 0.05 : 1, do najmanje oko 0.001 : 1.
11. Postupak prema bilo kojem od zahtjeva 1 do 10, naznačen time, što se borilacija u koraku ii) izvodi na temperaturi od oko 50°C do oko 100°C.
12. Postupak prema bilo kojem od zahtjeva 1 do 11, naznačen time, što prije početka koraka iii) spoj formule IIb nije izoliran iz smjese proizvoda formirane u koraku ii) i/ili između koraka ii) i iii) se ne izvodi korak pročišćavanja.
13. Postupak prema bilo kojem od zahtjeva 1 do 12, naznačen time, što korak iii) počinje u istoj reakcijskoj zoni u kojoj je izveden korak ii).
14. Postupak prema bilo kojem od zahtjeva 1 do 13, naznačen time, što se, u koraku iii) BComp zamjenjuje prvim intermedijarnim supstituentom R1.
15. Postupak prema zahtjevu 14, naznačen time, što se prvi intermedijarni supstituent zamjenjuje drugim intermedijarnim supstituentom R1, ili supstituentom R1 da bi se dobilo spoj formule I;
ili se prvi intermedijarni supstituent zamjenjuje drugim intermedijarnim supstituentom R1 i drugi intermedijarni supstituent se zamjenjuje trećim intermedijarnim supstituentom R1, ili supstituentom R1 da bi se dobilo spoj formule I.
16. Postupak prema bilo kojem od zahtjeva 13 do 15, naznačen time, što su prvi, drugi ili treći intermedijarni supstituenti R1 nezavisno odabrani od bromo, kloro, jodo, benziloksipiridina, alkil estera npr. metil estera, alkenila npr. vinila, alkinila npr. acetilenila, trimetilsililacetilena, 1,2,3-triazol-1-ilmetil pivalata, cijano, aminometila, N-Boc-aminometila i (benziloksi)karbonil)piperazin-1-ila.
17. Postupak prema bilo kojem od zahtjeva 1 do 16, naznačen time, što spoj formule IIb ili formule I sadrži zaštitnu grupu na poziciji R4, gdje postupak dalje obuhvaća deprotekciju R4 grupe spoja formule IIb ili formule I, i deprotekcija R4 grupe spoja formule IIb ili formule I se odvija po završetku koraka ii), prije početka koraka iii), tijekom koraka iii) ili po završetku koraka iii).
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| GBGB1614235.8A GB201614235D0 (en) | 2016-08-19 | 2016-08-19 | Compounds |
| GBGB1709642.1A GB201709642D0 (en) | 2017-06-16 | 2017-06-16 | Compounds |
| PCT/GB2017/052438 WO2018033742A2 (en) | 2016-08-19 | 2017-08-17 | Compounds |
| EP17771833.5A EP3500572B1 (en) | 2016-08-19 | 2017-08-17 | Cytisine derivatives for the treatment of addiction |
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| US5304121A (en) | 1990-12-28 | 1994-04-19 | Boston Scientific Corporation | Drug delivery system making use of a hydrogel polymer coating |
| US5242916A (en) * | 1992-07-07 | 1993-09-07 | R. J. Reynolds Tobacco Company | Method for treatment of neurodegenerative diseases |
| US5994341A (en) | 1993-07-19 | 1999-11-30 | Angiogenesis Technologies, Inc. | Anti-angiogenic Compositions and methods for the treatment of arthritis |
| US6099562A (en) | 1996-06-13 | 2000-08-08 | Schneider (Usa) Inc. | Drug coating with topcoat |
| ES2264169T3 (es) | 1996-10-30 | 2006-12-16 | Pfizer Inc. | Derivados azabiciclicos de piridona fusionada o de citisina, su preparacion y su uso en la terapia de adiccion. |
| US8030300B2 (en) * | 2003-06-10 | 2011-10-04 | Georgetown University | Ligands for nicotinic acetylcholine receptors, and methods of making and using them |
| BG65536B1 (bg) | 2004-04-16 | 2008-11-28 | "Софарма" Ад | Лекарствена форма, съдържаща цитизин |
| US20090318491A1 (en) | 2006-01-27 | 2009-12-24 | Yale Univeristy | Cytisine and Acetylcholine Analogs and Methods of Treating Mood Disorders |
| WO2007115092A2 (en) * | 2006-03-29 | 2007-10-11 | Georgetown University | 10-substituted cytisine derivatives and methods of use thereof |
| US8642612B2 (en) * | 2006-07-18 | 2014-02-04 | Potomac Pharmaceuticals, Inc. | Nicotinic desensitizers and methods of selecting, testing, and using them |
| JO3078B1 (ar) | 2009-11-27 | 2017-03-15 | Janssen Pharmaceutica Nv | مورفولينوثيازولات بصفتها منظمات الوستيرية نوع الفا 7 موجبة |
| TWI567061B (zh) * | 2011-07-01 | 2017-01-21 | 吉李德科學股份有限公司 | 用於治療成癮之化合物 |
| CN103509021B (zh) | 2012-06-21 | 2016-08-17 | 天津药明康德新药开发有限公司 | 金雀花碱衍生物及其制备方法和抗癌作用研究 |
| FR2992315B1 (fr) | 2012-06-25 | 2014-08-08 | Pf Medicament | Derives utiles dans le traitement de maladies du systeme nerveux central |
| JP6324964B2 (ja) | 2013-08-23 | 2018-05-16 | 久光製薬株式会社 | 貼付剤 |
| AU2017313390A1 (en) * | 2016-08-19 | 2019-03-07 | The University Of Bristol | Cytisine derivatives for the treatment of addiction |
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| GB201713217D0 (en) | 2017-10-04 |
| RS63872B1 (sr) | 2023-02-28 |
| LT3500572T (lt) | 2023-02-10 |
| JP2019528286A (ja) | 2019-10-10 |
| EP3500572A2 (en) | 2019-06-26 |
| JP7178538B2 (ja) | 2022-11-28 |
| EP4112620A1 (en) | 2023-01-04 |
| CN110088106A (zh) | 2019-08-02 |
| GB2558700A (en) | 2018-07-18 |
| WO2018033742A3 (en) | 2018-05-17 |
| PL3500572T3 (pl) | 2023-02-06 |
| EP3500572B1 (en) | 2022-10-26 |
| US20230203038A1 (en) | 2023-06-29 |
| CA3032899A1 (en) | 2018-02-22 |
| WO2018033742A2 (en) | 2018-02-22 |
| US11667638B2 (en) | 2023-06-06 |
| DK3500572T3 (da) | 2022-12-19 |
| HUE061016T2 (hu) | 2023-05-28 |
| AU2021261840B2 (en) | 2023-08-03 |
| US11905287B2 (en) | 2024-02-20 |
| JP2022159381A (ja) | 2022-10-17 |
| AU2021261840A1 (en) | 2021-12-02 |
| AU2017313390A1 (en) | 2019-03-07 |
| ES2935204T3 (es) | 2023-03-02 |
| AU2023248084A1 (en) | 2023-11-02 |
| US20240287073A1 (en) | 2024-08-29 |
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| GB2558700B (en) | 2022-07-27 |
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