HRP20192073T1 - Novi derivati amonija, postupak za njihovu pripravu te farmaceutski pripravci koji ih sadrže - Google Patents
Novi derivati amonija, postupak za njihovu pripravu te farmaceutski pripravci koji ih sadrže Download PDFInfo
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- HRP20192073T1 HRP20192073T1 HRP20192073TT HRP20192073T HRP20192073T1 HR P20192073 T1 HRP20192073 T1 HR P20192073T1 HR P20192073T T HRP20192073T T HR P20192073TT HR P20192073 T HRP20192073 T HR P20192073T HR P20192073 T1 HRP20192073 T1 HR P20192073T1
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- Prior art keywords
- pyrimidin
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- methyl
- ethyl
- thieno
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- 238000000034 method Methods 0.000 title claims 3
- 150000003863 ammonium salts Chemical class 0.000 title 1
- 239000008194 pharmaceutical composition Substances 0.000 title 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 37
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 33
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims 32
- 150000001875 compounds Chemical class 0.000 claims 27
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 12
- -1 (C1-C6) alkyl-S- Chemical group 0.000 claims 12
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 10
- 239000000825 pharmaceutical preparation Substances 0.000 claims 8
- 206010028980 Neoplasm Diseases 0.000 claims 7
- 125000003118 aryl group Chemical group 0.000 claims 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 6
- 238000004519 manufacturing process Methods 0.000 claims 6
- 239000002253 acid Substances 0.000 claims 5
- 201000011510 cancer Diseases 0.000 claims 5
- 239000003814 drug Substances 0.000 claims 5
- 229940079593 drug Drugs 0.000 claims 5
- 150000003839 salts Chemical class 0.000 claims 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 4
- 208000003174 Brain Neoplasms Diseases 0.000 claims 4
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims 4
- 206010025323 Lymphomas Diseases 0.000 claims 4
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims 4
- 206010033128 Ovarian cancer Diseases 0.000 claims 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims 4
- 206010035226 Plasma cell myeloma Diseases 0.000 claims 4
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims 4
- 206010060862 Prostate cancer Diseases 0.000 claims 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims 4
- 208000002495 Uterine Neoplasms Diseases 0.000 claims 4
- 239000002585 base Substances 0.000 claims 4
- 210000004556 brain Anatomy 0.000 claims 4
- 210000000481 breast Anatomy 0.000 claims 4
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims 4
- 210000001072 colon Anatomy 0.000 claims 4
- 208000029742 colonic neoplasm Diseases 0.000 claims 4
- 125000005843 halogen group Chemical group 0.000 claims 4
- 208000014018 liver neoplasm Diseases 0.000 claims 4
- 208000003747 lymphoid leukemia Diseases 0.000 claims 4
- 230000003211 malignant effect Effects 0.000 claims 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims 4
- 201000001441 melanoma Diseases 0.000 claims 4
- 201000000050 myeloid neoplasm Diseases 0.000 claims 4
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims 4
- 201000002528 pancreatic cancer Diseases 0.000 claims 4
- 208000008443 pancreatic carcinoma Diseases 0.000 claims 4
- 208000000587 small cell lung carcinoma Diseases 0.000 claims 4
- 125000006685 (C1-C6) polyhaloalkyl group Chemical group 0.000 claims 3
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims 3
- 206010006187 Breast cancer Diseases 0.000 claims 3
- 208000026310 Breast neoplasm Diseases 0.000 claims 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 3
- 206010009944 Colon cancer Diseases 0.000 claims 3
- 206010041067 Small cell lung cancer Diseases 0.000 claims 3
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims 3
- 125000002619 bicyclic group Chemical group 0.000 claims 3
- 239000003795 chemical substances by application Substances 0.000 claims 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims 3
- 201000004101 esophageal cancer Diseases 0.000 claims 3
- 210000003238 esophagus Anatomy 0.000 claims 3
- 125000001072 heteroaryl group Chemical group 0.000 claims 3
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims 3
- 201000007270 liver cancer Diseases 0.000 claims 3
- 125000002950 monocyclic group Chemical group 0.000 claims 3
- 125000001424 substituent group Chemical group 0.000 claims 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims 3
- 210000003932 urinary bladder Anatomy 0.000 claims 3
- 206010046766 uterine cancer Diseases 0.000 claims 3
- 208000023275 Autoimmune disease Diseases 0.000 claims 2
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims 2
- 206010005003 Bladder cancer Diseases 0.000 claims 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 2
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims 2
- 125000003342 alkenyl group Chemical group 0.000 claims 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 2
- 125000002837 carbocyclic group Chemical group 0.000 claims 2
- 150000001732 carboxylic acid derivatives Chemical group 0.000 claims 2
- 238000006243 chemical reaction Methods 0.000 claims 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- 125000005842 heteroatom Chemical group 0.000 claims 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 2
- 229910052757 nitrogen Chemical group 0.000 claims 2
- 229910052760 oxygen Inorganic materials 0.000 claims 2
- 239000001301 oxygen Substances 0.000 claims 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 2
- 230000000861 pro-apoptotic effect Effects 0.000 claims 2
- 238000000926 separation method Methods 0.000 claims 2
- 229910052717 sulfur Inorganic materials 0.000 claims 2
- 239000011593 sulfur Chemical group 0.000 claims 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims 1
- 150000001204 N-oxides Chemical class 0.000 claims 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims 1
- 229940079156 Proteasome inhibitor Drugs 0.000 claims 1
- 230000002378 acidificating effect Effects 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 125000000304 alkynyl group Chemical group 0.000 claims 1
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 claims 1
- 125000000129 anionic group Chemical group 0.000 claims 1
- 230000000340 anti-metabolite Effects 0.000 claims 1
- 229940100197 antimetabolite Drugs 0.000 claims 1
- 239000002256 antimetabolite Substances 0.000 claims 1
- 239000002246 antineoplastic agent Substances 0.000 claims 1
- 125000003710 aryl alkyl group Chemical group 0.000 claims 1
- 230000001363 autoimmune Effects 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- 230000008878 coupling Effects 0.000 claims 1
- 238000010168 coupling process Methods 0.000 claims 1
- 238000005859 coupling reaction Methods 0.000 claims 1
- 201000010099 disease Diseases 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
- 231100000024 genotoxic Toxicity 0.000 claims 1
- 230000001738 genotoxic effect Effects 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- GLUUGHFHXGJENI-UHFFFAOYSA-O hydron piperazine Chemical compound [H+].C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-O 0.000 claims 1
- 210000000987 immune system Anatomy 0.000 claims 1
- 208000026278 immune system disease Diseases 0.000 claims 1
- 239000000543 intermediate Substances 0.000 claims 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 229940043355 kinase inhibitor Drugs 0.000 claims 1
- 230000000394 mitotic effect Effects 0.000 claims 1
- 125000001624 naphthyl group Chemical group 0.000 claims 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims 1
- 239000002574 poison Substances 0.000 claims 1
- 231100000614 poison Toxicity 0.000 claims 1
- 239000003207 proteasome inhibitor Substances 0.000 claims 1
- 125000006239 protecting group Chemical group 0.000 claims 1
- 238000001959 radiotherapy Methods 0.000 claims 1
- 239000007858 starting material Substances 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 claims 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 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
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Cephalosporin Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Claims (31)
1. Spoj formule (I):
naznačen time, da
• Y predstavlja -NH- skupinu ili atom kisika,
• R1 predstavlja ravnu ili razgrananu (C1-C6)alkilnu skupinu, ravnu ili razgrananu (C2-C6)alkenilnu skupinu, ravnu ili razgrananu (C2-C6)alkinilnu skupinu, ravnu ili razgrananu (C1-C6)alkoksi skupinu, -S-(C1-C6)alkilnu skupinu, ravnu ili razgrananu (C1-C6)polihaloalkilnu skupinu, hidroksi skupinu, hidroksi(C1-C6)alkilnu skupinu, cijano skupinu, -NR9R9', -Cy1 ili atom halogena,
• R2, R3 i R4 neovisno jedan o drugome predstavljaju atom vodika, atom halogena, ravnu ili razgrananu (C1-C6)alkilnu skupinu, ravnu ili razgrananu (C2-C6)alkenilnu skupinu, ravnu ili razgrananu (C2- C6)alkinilnu skupinu, ravnu ili razgrananu (C1-C6)polihaloalkil, hidroksi skupinu, hidroksi(C1- C6)alkilnu skupinu, ravnu ili razgrananu (C1-C6)alkoksi skupinu, -S-(C1-C6)alkilnu skupinu, cijano skupinu, nitro skupinu, -alkil(C0-C6)-NR9R9', -O-alkil(C1-C6)-NR9R9', -C(O)-OR9, -O-C(O)-R9, -C(O)- NR9R9', -NR9-C(O)-R9', -NR9-C(O)-OR9',-alkil(C1-C6)-NR9-C(O)-R9', -SO2-NR9R9', -SO2-alkil(C1-C6),
• R5 predstavlja vodikov atom,
• R6 predstavlja skupinu
• R7 predstavlja vodikov atom ili ravnu ili razgrananu (C1-C6)alkilnu skupinu,
• R8 predstavlja -O-P(O)(O-)(O-) skupinu, -O-P(O)(O-)(OR10) skupinu, -O-P(O)(OR10)(OR10') skupinu, -O-SO2-O- skupinu, -O-SO2-OR10 skupinu, -Cy2, -O-C(O)-R9 skupinu, -O-C(O)-OR9 skupinu ili -O- C(O)-NR9R9' skupinu;
• R9 i R9' neovisno jedan o drugom predstavljaju atom vodika, ravnu ili razgrananu (C1-C6)alkilnu skupinu ili ravnu ili razgrananu amino(C1-C6)alkilnu skupinu,
• R10 i R10' neovisno jedan o drugom predstavljaju atom vodika, ravnu ili razgrananu (C1-C6)alkilnu skupinu ili arilalkil(C1-C6) skupinu,
• Cy1 i Cy2 neovisno jedan o drugom, predstavljaju cikloalkilnu skupinu, heterocikloalkilnu skupinu, arilnu skupinu ili heteroarilnu skupinu,
kada je moguće da tako definiran amonij postoji kao zwitterionski oblik ili da ima jednovalentni anionski oblik protu-iona,
pri čemu se podrazumijeva da:
- "aril" znači fenil ili naftilnu skupinu,
- "heteroaril" znači bilo koju mono- ili bicikličku skupinu sastavljenu od 5 do 10 članova prstena, koji imaju najmanje jednu aromatsku polovicu koja sadrži 1 do 3 heteroatoma odabrana između kisika, sumpora i dušika,
- "cikloalkil" znači bilo koju mono- ili bicikličku nearomatsku karbocikličku skupinu koja sadrži 3 do 10 članova prstena,
- "heterocikloalkil" znači bilo koju mono- ili bicikličku nearomatsku karbocikličku skupinu koja sadrži 3 do 10 članova prstena, a sadrže od 1 do 3 heteroatoma odabranih između kisika, sumpora i dušika, koji mogu uključuti spojene, premoštene ili spiro prstenaste sustave,
Pri čemu su moguće tako definirane arilne, heteroarilne, cikloalkilne i heterocikloalkilne skupine te alkil, alkenil, alkinil, alkoksi skupine koje treba supstituirati s 1 do 4 skupine odabrane od ravnog ili razgrananog (C1-C6) alkila, ravne ili razgranane (C2-C6)alkenilne skupine, ravne ili razgranane (C2-C6) alkinilne skupine, ravnog ili razgrananog (C1-C6) alkoksi, (C1-C6) alkil-S-, hidroksi, okso (ili N-oksid prema potrebi), nitro, cijano, -C(O)-OR', -O-C(O)-R', -C(O)-NR'R”, -NR'R'', -(C=NR')-OR'', ravnog ili razgrananog (C1-C6) polihaloalkila, trifluorometoksi ili halogena, podrazumijeva se da R' i R'' međusobno neovisno predstavljaju atom vodika ili ravnu ili razgrananu (C1-C6) alkilnu skupinu i podrazumijeva se da jedan ili više ugljikovih atoma prethodnih mogućih supstituenata mogu biti deuterirani, njihovi enantiomeri, dijastereoizomeri i atropisomeri i njihove adicijske soli s farmaceutski prihvatljivom kiselinom ili lužinom.
2. Spoj formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da Y predstavlja atom kisika.
3. Spoj formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da najmanje jedna od skupina odabranih od R2, R3 i R4 ne predstavlja atom vodika.
4. Spoj formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da R1 predstavlja ravnu ili razgrananu (C1-C6)alkilnu skupinu ili atom halogena.
5. Spoj formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da R2 predstavlja atom halogena, hidroksi skupinu, ravnu ili razgrananu (C1-C6)alkoksi skupinu.
6. Spoj formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da R3 i R4 predstavljaju atom vodika.
7. Spoj formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da su supstituenti para (R1, R4) i supstituenti para (R2, R3) istovjetni.
8. Spoj formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da R6 predstavlja skupinu
pri čemu su R7 i R8 kako je definirano u patentnom zahtjevu 1.
9. Spoj formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da R6 predstavlja skupinu
pri čemu su R7 i R8 kako je definirano u patentnom zahtjevu 1.
10. Spoj formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da R7 predstavlja metilnu skupinu ili atom vodika.
11. Spoj formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da R8 predstavlja -O- P(O)(O-)(OR10) skupinu u kojoj R10 predstavlja atom vodika, benzilnu skupinu ili metilnu skupinu.
12. Spoj formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da R8 predstavlja 5-metil-2-okso-1,3-dioksol-4-ilnu skupinu; -O-C(O)-CH3 skupinu; -O-C(O)-tBu skupinu; -O-C(O)-CH2-NH2 skupinu; -O-C(O)-CH[CH(CH3)2]-NH2 skupinu; -O-C(O)-O-CH2CH3 skupinu; ili -O-C(O)-N(CH2CH3)2 skupinu.
13. Spoj u skladu s patentnim zahtjevom 1, naznačen time, da je:
- {4-[2-(4-{(5Sa)-4-[(1R)-1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4-il]metoksi}fenil)etoksi]-6- (4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-kloro-3-metilfenoksi)etil]-1-metilpiperazin-1-ium-1-il}metil hidrogenfosfat;
- benzil {4-[2-(4-{(5Sa)-4-[1R)-1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4-il]metoksi}fenil)etoksi]-6-(4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-kloro-3-metilfenoksi)etil]-1- metilpiperazin-1-ium-1-il}metil fosfat;
- {4-[2-(4-{(5Sa)-4-[(1R)-1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4-il]metoksi}fenil)etoksi]-6- (4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-kloro-3-metilfenoksi)etil]-1-metilpiperazin-1-ium-1- il}metil metil fosfat;
- {4-[2-(4-{(5Sa)-4-[(1R)-1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4-il]metoksi}fenil)etoksi]-6- (4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-kloro-3-etilfenoksi)etil]-1-metilpiperazin-1-ium-1-il}metil hidrogenfosfat;
- {4-[2-(3-bromo-4-{(5Sa)-4-[(1R)-1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4- il]metoksi}fenil)etoksi]-6-(4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-klorofenoksi)etil]-1- metilpiperazin-1-ium-1-il}metil hidrogenfosfat;
- benzil {4-[2-(3-bromo-4-{(5Sa)-4-[(1R)-1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4- il]metoksi}fenil)etoksi]-6-(4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-klorofenoksi)etil]-1- metilpiperazin-1-ium-1-il}metil fosfat;
- {4-[2-(3-bromo-4-{(5Sa)-4-[(1R)-1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4- il]metoksi}fenil)etoksi]-6-(4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-klorofenoksi)etil]-1- metilpiperazin-1-ium-1-il}metil metilfosfat;
- N-[(5Sa)-5-{3-kloro-4-[2-(4-{[(hidroksifosfinato)oksi]metil}-4-metilpiperazin-4-ium-1-il)etoksi]-2- metilfenil}-6-(4-fluorofenil)tieno[2,3-d]pirimidin-4-il]-2-{[2-(2-metoksifenil)pirimidin-4-il]metoksi}- D-fenilalanin;
- {4-[2-(4-{4-[(1R)-1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4-il]metoksi}fenil)etoksi]-6-(4- fluorofenil)tieno[2,3-d]pirimidin-5-il}-2,6-dikloro-3,5-dimetilfenoksi)etil]-1-metilpiperazin-1-ium-1-il}metil hidrogenfosfat;
- {4-[2-(4-{4-[(1R)-1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4-il]metoksi}fenil)etoksi]-6-(4- fluorofenil)tieno[2,3-d]pirimidin-5-il}-3,5-dimetilfenoksi)etil]-1-metilpiperazin-1-ium-1-il}metil hidrogenfosfat;
- {[2-(4-{(5Sa)-4-[(1R)-1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4-il]metoksi}fenil)etoksi]-6-(4- fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-kloro-3-metilfenoksi)etil](dimetil)amonij}metil hidrogenfosfat;
- 1-{4-[2-(4-{(5Sa)-4-[(1R)-1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4-il]metoksi}fenil)etoksi]- 6-(4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-kloro-3-metilfenoksi)etil]-1-metilpiperazin-1-ium-1-il}etil hidrogenfosfat;
- 1-{4-[2-(3-bromo-4-{(5Sa)-4-[(1R)-1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4- il]metoksi}fenil)etoksi]-6-(4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-klorofenoksi)etil]-1- metilpiperazin-1-ium-1-il}etil hidrogenfosfat;
- {1-[2-(4-{(5Sa)-4-[(1R)-1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4 il]metoksi}fenil)etoksi]-6- (4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-kloro-3-metilfenoksi)etil]-4-metilpiperazin-1-ium-1-il}metil hidrogenfosfat;
- {1-[2-(3-bromo-4-{(5Sa)-4-[(1R)-1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4- il]metoksi}fenil)etoksi]-6-(4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-klorofenoksi)etil]-4- metilpiperazin-1-ium-1-il}metil hidrogenfosfat;
- {4-[2-(4-{(5Sa)-4-[(1R)-1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4-il]metoksi}fenil)etoksi]-6- (4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-kloro-3-metilfenoksi)etil]-1-metilpiperazin-1-ium-1- il}metil sulfat;
- 1-[(acetiloksi)metil]-4-[2-(4-{(5Sa)-4-[(1R)-1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4- il]metoksi}fenil)etoksi]-6-(4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-kloro-3-metilfenoksi)etil]-1- metilpiperazin-1-ium;
- 4-[2-(4-{(5Sa)-4-[(1R)-1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4-il]metoksi}fenil)etoksi]-6- (4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-kloro-3-metilfenoksi)etil]-1- {[(etoksikarbonil)oksi]metil}-1-metilpiperazin-1-ium;
- 4-[2-(4-{(5Sa)-4-[(1R)-1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4il]metoksi}fenil)etoksi]-6- (4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-kloro-3-metilfenoksi)etil]-1- {[(dietilkarbamoil)oksi]metil}-1-metilpiperazin-1-ium;
- 4-[2-(4-{(5Sa)-4-[(1R)-1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4-il]metoksi}fenil)etoksi]-6- (4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-kloro-3-metilfenoksi)etil]-1-[(gliciloksi)metil]-1- metilpiperazin-1-ium;
- 4-[2-(4-{(5Sa)-4-[(1R)-1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4-il]metoksi}fenil)etoksi]-6- (4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-kloro-3-metilfenoksi)etil]-1-{1- [(dietilkarbamoil)oksi]etil}-1-metilpiperazin-1-ium;
- 4-[2-(4-{(5Sa)-4-[(1R)-1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4-il]metoksi}fenil)etoksi]-6- (4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-kloro-3-metilfenoksi)etil]-1-metil-1-[(5-metil-2-okso-1,3- dioksol-4-il)metil]piperazin-1-ium;
- 4-[2-(4-{(5Sa)-4-[(1R)-1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4-il]metoksi}fenil)etoksi]-6- (4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-kloro-3-metilfenoksi)etil]-1-metil-1-[(L- valiloksi)metil]piperazin-1-ium;
- 4-[2-(4-{(5Sa)-4-[(1R)-1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4-il]metoksi}fenil)etoksi]-6- (4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-kloro-3-metilfenoksi)etil]-1-{[(2,2- dimetilpropanoil)oksi]metil}-1-metilpiperazin-1-ium;
- 1-[(acetiloksi)metil]-4-[2-(3-bromo-4-{(5Sa)-4-[(1R)-1-karboksi-2-(2-{[2-(2 metoksifenil)pirimidin- 4-il]metoksi}fenil)etoksi]-6-(4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-klorofenoksi)etil]-1- metilpiperazin-1-ium;
- 4-[2-(3-bromo-4-{(5Sa)-4-[(1R)-1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4- il]metoksi}fenil)etoksi]-6-(4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-klorofenoksi)etil]-1- {[(etoksikarbonil)oksi]metil}-1-metilpiperazin-1-ium;
- 4-[2-(3-bromo-4-{(5Sa)-4-[(1R)-1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4- il]metoksi}fenil)etoksi]-6-(4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-klorofenoksi)etil]-1- {[(dietilkarbamoil)oksi]metil}-1-metilpiperazin-1-ium;
- 4-[2-(3-bromo-4-{(5Sa)-4-[(1R)-1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4- il]metoksi}fenil)etoksi]-6-(4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-klorofenoksi)etil]-1- [(gliciloksi)metil]-1-metilpiperazin-1-ium;
- 4-[2-(3-bromo-4-{(5Sa)-4-[(1R)-1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4- il]metoksi}fenil)etoksi]-6-(4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-klorofenoksi)etil]-1-{1- [(dietilkarbamoil)oksi]etil}-1-metilpiperazin-1-ium;
- 4-[2-(3-bromo-4-{(5Sa)-4-[(1R)-1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4- il]metoksi}fenil)etoksi]-6-(4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-klorofenoksi)etil]-1-metil-1- [(5-metil-2-okso-1,3-dioksol-4-il)metil]piperazin-1-ium;
- 4-[2-(3-bromo-4-{(5Sa)-4-[(1R)-1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4- il]metoksi}fenil)etoksi]-6-(4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-klorofenoksi)etil]-1-metil-1- [(L-valiloksi)metil]piperazin-1-ium;
- 4-[2-(3-bromo-4-{(5Sa)-4-[(1R)-1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4- il]metoksi}fenil)etoksi]-6-(4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-klorofenoksi)etil]-1-{[(2,2- dimetilpropanoil)oksi]metil}-1-metilpiperazin-1-ium.
14. Spoj u skladu s patentnim zahtjevom 1, naznačen time, da je {4-[2-(4-{(5Sa)-4-[(1R)-1- karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4-il]metoksi}fenil)etoksi]-6-(4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-kloro-3-metilfenoksi)etil]-1-metilpiperazin-1-ium-1-il}metil hidrogenfosfat.
15. Spoj u skladu s patentnim zahtjevom 1, naznačen time, da je {4-[2-(3-bromo-4-{(5Sa)-4-[(1R)- 1-karboksi-2-(2-{[2-(2-metoksifenil)pirimidin-4-il]metoksi}fenil)etoksi]-6-(4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-klorofenoksi)etil]-1-metilpiperazin-1-ium-1-il}metil hidrogenfosfat.
16. Spoj u skladu s patentnim zahtjevom 1, naznačen time, da je {[2-(4-{(5Sa)-4-[(1R)-1-karboksi- 2-(2-{[2-(2-metoksifenil)pirimidin-4-il]metoksi}fenil)etoksi]-6-(4-fluorofenil)tieno[2,3-d]pirimidin-5-il}-2-kloro-3-metilfenoksi)etil](dimetil)amonij}metil hidrogenfosfat.
17. Postupak priprave spoja formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da se kao početni material za postupak koristio spoj formule (II):
gdje su R1, R2, R3, R4, R5 i Y definirani kao za formulu (I), a R6' predstavlja -N(CH3)2 skupinu ili 4- metilpiperazinil skupinu, koji je izložen reakciji koja štiti funkciju karboksilne kiseline da bi se dobio spoj formule (III):
gdje su R1, R2, R3, R4, R6' i Y kako je gore definirano i T predstavlja zaštitnu skupinu za karboksilnu skupinu kisele funkcije kao što je, na primjer, para-metoksibenzil skupina, koja je izložena povezivanju sa spojem formule (IV):
gdje su R7 i R8 definirani kao za formulu (I), kako bi se dobio spoj formule (V):
gdje su R1, R2, R3, R4, T i Y kako je gore definirano, a R6 je kako je definirao u patentnom zahtjevu 1, koji se potom izlaže reakciji koja uklanja zaštitnu funkciju karboksilne kiseline, kako bi se dobio spoj formule (I), koji se može pročistiti u skladu s uobičajenom tehnikom separacije, koji, ako je to poželjno, se pretvara u njegove adicijske soli s farmaceutski prihvatljivom kiselinom ili lužinom, a po izboru u njegove izomere uobičajenom tehnikom separacije, kada se podrazumijeva da se u bilo kojem trenutku tijekom gore opisanog postupka, kada je to prikladno, neke skupine (hidroksi, amino ...) polaznih reagensa ili sintetskih intermedijara mogu zaštititi, nakon toga im se može skinuti zaštita i funkcionalizirati, prema zahtjevu sinteze.
18. Farmaceutski pripravak, naznačen time, da sadrži spoj formule (I), u skladu s bilo kojim od patentnih zahtjeva 1 do 16 ili njegovu adicijsku sol s farmaceutski prihvatljivom kiselinom ili lužinom u kombinaciji s jednim ili dva farmaceutski prihvatljiva ekscipijensa.
19. Farmaceutski pripravak u skladu s patentnim zahtjevom 18, naznačen time, da se koristi kao pro-apoptotičko sredstvo.
20. Farmaceutski pripravak u skladu s patentnim zahtjevom 19, naznačen time, da se koristi za liječenje karcinoma te auto-imunih bolesti i bolesti imunološkog sustava.
21. Farmaceutski pripravak za uporabu u liječenju karcinoma u skladu s patentnim zahtjevom 20, naznačen time, da su karcinomi karcinom mokraćnog mjehura, mozga, dojke i maternice, kroničnih limfoidnih leukemija, karcinoma debelog crijeva, jednjaka i jetre, limfoblastičnih leukemija, akutnih mijeloidnih leukemija, limfoma, melanoma, zloćudne hemopatije, mijeloma, karcinoma jajnika, carcinoma pluća ne-malih stanica, karcinoma prostate, karcinoma gušterače i karcinoma pluća malih stanica.
22. Uporaba farmaceutskog pripravka u skladu s patentnim zahtjevom 18, naznačena time, što se koristi u proizvodnji lijekova za upotrebu kao proapoptotička sredstva.
23. Uporaba farmaceutskog pripravka u skladu s patentnim zahtjevom 18, naznačena time, što se koristi u proizvodnji lijekova za upotrebu u liječenju karcinoma i bolesti autoimunog i imunološkog sustava.
24. Uporaba farmaceutskog pripravka u skladu s patentnim zahtjevom 18, naznačena time, što se koristi u proizvodnji lijekova za uporabu u liječenju karcinoma mokraćnog mjehura, mozga, dojke i maternice, kroničnih limfnih leukemija, karcinoma debelog crijeva, jednjaka i jetre, limfoblastičnih leukemija, akutnih mijeloidnih leukemija, limfomi, melanomi, zloćudne hemopatije, mijelomi, karcinoma jajnika, carcinoma pluća ne-malih stanica, karcinoma prostate, karcinoma gušterače I carcinoma pluća malih stanica.
25. Spoj formule (I), u skladu s bilo kojim od patentnih zahtjeva 1 do 16, ili njegova adicijska sol s farmaceutski prihvatljivom kiselinom ili bazom, naznačen time, da se koristi za liječenje karcinoma mokraćnog mjehura, mozga, dojke i maternice, kroničnih limfnih leukemija, karcinoma debelog crijeva, jednjaka i jetre, limfoblastične leukemije, akutne mijeloidne leukemije, limfoma, melanoma, zloćudne hemopatije, mijeloma, karcinoma jajnika, karcinoma pluća ne-malih stanica, karcinoma prostate, karcinoma gušterače i carcinoma pluća malih stanica.
26. Uporaba spoja formule (I) prema bilo kojem od zahtjeva 1 do 16, ili njegove adicijske soli s farmaceutski prihvatljivom kiselinom ili bazom, naznačena time, da se koristi za proizvodnju lijekova za liječenje karcinoma mokraćnog mjehura, mozga dojke i maternice, kronične limfoidne leukemije, karcinoma debelog crijeva, jednjaka i jetre, limfoblastične leukemije, akutne mijeloidne leukemije, limfoma, melanoma, zloćudne hemopatije, mijeloma, karcinoma jajnika, karcinom pluća ne-malih stanica, karcinoma prostate, karcinoma gušterače i karcinom pluća malih stanica.
27. Kombinacija spoja formule (I) u skladu s bilo kojim od patentnih zahtjeva 1 do 16, naznačen time, da je ista s antikancerogenim sredstvom odabranim od genotoksičnih agensa, mitotskih otrova, antimetabolita, inhibitora proteasoma, inhibitora kinaze i antitijela.
28. Farmaceutski pripravak, naznačen time, da sadrži kombinaciju u skladu s patentnim zahtjevom 27, u kombinaciji s jednim ili više farmaceutski prihvatljivih pomoćnih sredstava.
29. Kombinacija u skladu s patentnim zahtjevom 27, naznačena time, da se koristi za liječenje karcinoma.
30. Uporaba kombinacije u skladu s patentnim zahtjevom 27, naznačena time, što se koristi u proizvodnji lijekova za uporabu liječenja karcinoma.
31. Spoj formule (I), u skladu s bilo kojim od patentnih zahtjeva 1 do 16, naznačen time, da je namijenjen upotrebi u liječenju karcinoma koji zahtijevaju radioterapiju.
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| PCT/EP2016/081688 WO2017125224A1 (en) | 2016-01-19 | 2016-12-19 | New ammonium derivatives, a process for their preparation and pharmaceutical compositions containing them |
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| AU2018205735B2 (en) * | 2017-01-06 | 2024-02-01 | Les Laboratoires Servier | Combination of a MCL-1 inhibitor and a taxane compound, uses and pharmaceutical compositions thereof |
| BR112019026959A2 (pt) | 2017-06-22 | 2020-07-07 | Les Laboratoires Servier | combinação de um inibidor de mcl-1 e um tratamento com padrão de atendimento para cânceres hematológicos, seus usos e composições farmacêuticas |
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| BR112020003163A2 (pt) * | 2017-08-15 | 2020-09-15 | AbbVie Deutschland GmbH & Co. KG | inibidores macrocíclicos de mcl-1 e métodos de uso |
| CA3073112A1 (en) | 2017-08-15 | 2019-02-21 | Abbvie Inc. | Macrocyclic mcl-1 inhibitors and methods of use |
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| CA3119395A1 (en) | 2018-11-14 | 2020-05-22 | Les Laboratoires Servier | Combination of a mcl-1 inhibitor and midostaurin, uses and pharmaceutical compositions thereof |
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