HRP20200361T1 - Novi derivati piperidinila, postupak za njihovu pripravu i farmaceutski pripravci koji ih sadrže - Google Patents
Novi derivati piperidinila, postupak za njihovu pripravu i farmaceutski pripravci koji ih sadrže Download PDFInfo
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- HRP20200361T1 HRP20200361T1 HRP20200361TT HRP20200361T HRP20200361T1 HR P20200361 T1 HRP20200361 T1 HR P20200361T1 HR P20200361T T HRP20200361T T HR P20200361TT HR P20200361 T HRP20200361 T HR P20200361T HR P20200361 T1 HRP20200361 T1 HR P20200361T1
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- methyl
- dihydro
- carbonyl
- pyrimidin
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- 238000000034 method Methods 0.000 title claims 3
- 239000008194 pharmaceutical composition Substances 0.000 title 1
- 125000003386 piperidinyl group Chemical group 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims 35
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 10
- 125000005843 halogen group Chemical group 0.000 claims 8
- 239000000825 pharmaceutical preparation Substances 0.000 claims 8
- 125000003118 aryl group Chemical group 0.000 claims 7
- 229910052757 nitrogen Chemical group 0.000 claims 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 6
- 206010028980 Neoplasm Diseases 0.000 claims 5
- 239000002253 acid Substances 0.000 claims 5
- 239000003814 drug Substances 0.000 claims 5
- 229940079593 drug Drugs 0.000 claims 5
- 125000001072 heteroaryl group Chemical group 0.000 claims 5
- 238000004519 manufacturing process Methods 0.000 claims 5
- 150000003839 salts Chemical class 0.000 claims 5
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims 4
- 208000026310 Breast neoplasm Diseases 0.000 claims 4
- 125000000882 C2-C6 alkenyl group Chemical group 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
- 206010041067 Small cell lung cancer Diseases 0.000 claims 4
- 210000004556 brain Anatomy 0.000 claims 4
- 201000011510 cancer Diseases 0.000 claims 4
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims 4
- 208000029742 colonic neoplasm Diseases 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
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims 4
- 208000003174 Brain Neoplasms Diseases 0.000 claims 3
- 206010006187 Breast cancer Diseases 0.000 claims 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 3
- 206010009944 Colon cancer Diseases 0.000 claims 3
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims 3
- 208000002495 Uterine Neoplasms Diseases 0.000 claims 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 3
- 239000002585 base Substances 0.000 claims 3
- 210000000481 breast Anatomy 0.000 claims 3
- 239000003795 chemical substances by application Substances 0.000 claims 3
- 210000001072 colon Anatomy 0.000 claims 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims 3
- 201000004101 esophageal cancer Diseases 0.000 claims 3
- 125000005842 heteroatom Chemical group 0.000 claims 3
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims 3
- 201000007270 liver cancer Diseases 0.000 claims 3
- 229910052760 oxygen Inorganic materials 0.000 claims 3
- 239000001301 oxygen Substances 0.000 claims 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 3
- 210000003932 urinary bladder Anatomy 0.000 claims 3
- 206010046766 uterine cancer Diseases 0.000 claims 3
- -1 4-hydroxy-1-{[(3R,4R)-3-phenylpiperidin-4-yl]carbonyl}piperidin-4-yl Chemical group 0.000 claims 2
- 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
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 2
- 239000003513 alkali Substances 0.000 claims 2
- 230000001028 anti-proliverative effect Effects 0.000 claims 2
- 230000001363 autoimmune Effects 0.000 claims 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 2
- 238000005859 coupling reaction Methods 0.000 claims 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims 2
- 210000003238 esophagus Anatomy 0.000 claims 2
- 208000026278 immune system disease Diseases 0.000 claims 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 2
- 125000004043 oxo group Chemical group O=* 0.000 claims 2
- 230000000861 pro-apoptotic effect Effects 0.000 claims 2
- 238000000926 separation method Methods 0.000 claims 2
- 239000011593 sulfur Chemical group 0.000 claims 2
- 229910052717 sulfur Inorganic materials 0.000 claims 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims 2
- 210000004291 uterus Anatomy 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
- FBMZEITWVNHWJW-UHFFFAOYSA-N 1,7-dihydropyrrolo[2,3-d]pyrimidin-4-one Chemical compound OC1=NC=NC2=C1C=CN2 FBMZEITWVNHWJW-UHFFFAOYSA-N 0.000 claims 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 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
- 208000017897 Carcinoma of esophagus Diseases 0.000 claims 1
- 239000004593 Epoxy Substances 0.000 claims 1
- 150000001204 N-oxides Chemical class 0.000 claims 1
- 229940079156 Proteasome inhibitor Drugs 0.000 claims 1
- 229910007161 Si(CH3)3 Inorganic materials 0.000 claims 1
- 210000001744 T-lymphocyte Anatomy 0.000 claims 1
- 102000006275 Ubiquitin-Protein Ligases Human genes 0.000 claims 1
- 108010083111 Ubiquitin-Protein Ligases Proteins 0.000 claims 1
- 125000002947 alkylene group Chemical group 0.000 claims 1
- 230000000340 anti-metabolite Effects 0.000 claims 1
- 239000000427 antigen Substances 0.000 claims 1
- 102000036639 antigens Human genes 0.000 claims 1
- 108091007433 antigens Proteins 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
- 239000012752 auxiliary agent Substances 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 125000002837 carbocyclic group Chemical group 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 230000008878 coupling Effects 0.000 claims 1
- 238000010168 coupling process Methods 0.000 claims 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 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
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 239000002955 immunomodulating agent Substances 0.000 claims 1
- 229940121354 immunomodulator Drugs 0.000 claims 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 claims 1
- 239000000543 intermediate Substances 0.000 claims 1
- 229910052740 iodine Inorganic materials 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
- 239000000436 ligase inhibitor Substances 0.000 claims 1
- 210000004185 liver Anatomy 0.000 claims 1
- 230000000394 mitotic effect Effects 0.000 claims 1
- 125000001624 naphthyl group Chemical group 0.000 claims 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 1
- 125000006574 non-aromatic ring group Chemical group 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 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
- 230000006916 protein interaction Effects 0.000 claims 1
- 102000004169 proteins and genes Human genes 0.000 claims 1
- 108090000623 proteins and genes Proteins 0.000 claims 1
- 125000004076 pyridyl group Chemical group 0.000 claims 1
- 238000001959 radiotherapy Methods 0.000 claims 1
- 239000007858 starting material Substances 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 claims 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
Classifications
-
- 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
- C07D471/02—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 two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- 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
- C07D401/14—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 three or more hetero rings
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Claims (26)
1. Spoj formule (I):
[image]
naznačen time, da:
♦ R1 predstavlja arilnu skupinu ili heteroarilnu skupinu,
♦ R2 predstavlja atom vodika ili atom halogena,
♦ R3 predstavlja atom vodika, ravnu ili razgrananu (C1-C6)alkilnu skupinu, ravni ili razgranani halo(C1-C6)alkil, -C(O)-R8 skupinu, -C(O)-OR8 skupinu,
♦ n je cijeli broj jednak 0, 1 ili 2,
♦ W predstavlja skupinu
[image]
u kojoj:
♦ A predstavlja heteroarilni prsten
♦ X predstavlja atom ugljika ili atom dušika,
♦ R4 predstavlja 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, -Y1-NR6R7 skupinu, -Y1-OR6 skupinu, ravnu ili razgrananu halo(C1-C6)alkilnu skupinu, okso skupinu, -Y1-Cy1 skupinu, -Cy1-R7 skupinu, -Cy1-OR7 skupinu ili -Y1-NR6-C(O)-R7 skupinu,
♦ R5 predstavlja atom vodika, atom halogena, ravnu ili razgrananu (C1-C6)alkilnu skupinu, cijano skupinu ili -hidroksi(C1-C6)alkilnu skupinu,
♦ R6 predstavlja atom vodika ili ravnu ili razgrananu (C1-C6)alkilnu skupinu ili -Y2-Si[(C1-C4)alkil]3 skupinu,
♦ R7 predstavlja atom vodika, ravnu ili razgrananu (C1-C6)alkilnu skupinu ili -Y2-Cy2 skupinu,
♦ Y1 i Y2 nevosino jedan o drugome predstavljaju vezu ili ravnu ili razgrananu (C1-C4)alkilensku skupinu,
♦ R8 predstavlja atom vodika ili ravnu ili razgrananu (C1-C6)alkilnu skupinu,
♦ Cy1 i Cy2 neovisno jedan o drugome predstavlja cikloalkilnu skupinu, heterocikloalkilnu skupinu, arilnu skupinu ili heteroarilnu skupinu,
kada se podrazumijeva da:
- "aril" znači fenil, naftil ili indanil skupinu,
- "heteroaril" znači bilo koja mono- ili spojena bi-ciklička skupina sastavljenu od 5 do 10 članova prstena, koja ima najmanje jednu aromatsku skupinu i sadrži 1 do 3 heteroatoma odabrana između kisika, sumpora i dušika,
- "cikloalkil" znači bilo koja mono- ili spojena bi-ciklička nearomatska karbociklička skupina koji sadrži 3 do 7 članova prstena,
- "heterocikloalkil" znači bilo koja nearomatska mono- ili kondenzirana bi-ciklička skupina koji sadrži 3 do 10 članova prstena i koji sadrži 1 do 3 heteroatoma odabrana između kisika, sumpora i dušika, pri čemu je moguće da se tako definirani aril, heteroaril, cikloalkil i heterocikloalkil supstituiraju s 1 do 4 skupine odabrane od ravnog ili razgrananog (C1-C6)alkila, ravnog ili razgrananog (C2-C6)alkenila, ravnog ili razgrananog (C2-C6)alkinila, ravnog ili razgrananog halo(C1-C6)alkila, -Y1-OR', -Y1-NR'R", -Y1-S(O)m-R', okso (ili N-oksida gdje je prikladno), nitro, cijano, -C(O)-R', -C(O)-OR', -O-C(O)-R', -C(O)-NR'R", -Y1-NR'-C(O)-R", -Y1-NR'-C(O)-OR", halogena, ciklopropila i piridinila koji mogu biti supstituirani s ravnom ili razgrananom (C1-C6)alkilnom skupinom,
kada se podrazumijeva da R' i R" neovisno jedan o drugome predstavlja atom vodika, ravnu ili razgrananu (C1-C6)alkilnu skupinu, ravnu ili razgrananu (C2-C6)alkenilnu skupinu, ravnu ili razgrananu (C1-C6)alkoksi skupinu, ravni ili ragranani halo(C1-C6)alkil, ravnu ili razgrananu hidroksi(C1-C6)alkilnu skupinu, ravnu ili razgrananu (C1-C6)alkoksi(C1-C6)alkilnu skupinu, fenilnu skupinu, ciklopropilmetilnu skupinu, tetrahidropiranilnu skupinu ili supstituente para (R', R") koji zajedno s atomom dušika koji ih nosi, tvore ne-aromatski prsten sastavljen od 5 do 7 članova prstena, koji mogu dodatno osim dušika sadržati drugi heteroatom odabran od kisika i dušika,kada je poznato da navedeni dušik može biti supstituiran s 1 do 2 skupine koje predstavljaju atom vodika ili ravnu ili razgrananu (C1-C6)alkilnu skupinu te kada je poznato da m je cijeli broj jednak 0, 1 i 2, njegovi enantiomeri, dijastereoizomeri i njihove adicijske soli s farmaceutski prihvatljivom kiselinom ili lužinom.
2. Spojevi u skladu s patentnim zahtjevom 1, naznačeni time, da W predstavlja skupinu
[image]
u kojoj su R4, R5 i A kako je definirano u patentnom zahtjevu 1.
3. Spojevi u skladu s patentnim zahtjevom 1, naznačeni time, da W predstavlja skupinu
[image]
u kojoj su R4, R5 i A kako je definirano u patentnom zahtjevu 1.
4. Spojevi u skladu s patentnim zahtjevom 1, naznačeni time, da R1 predstavlja fenilnu skupinu.
5. Spojevi u skladu s patentnim zahtjevom 1, naznačeni time, da R2 predstavlja atom vodika.
6. Spojevi u skladu s patentnim zahtjevom 1, naznačeni time, da R3 predstavlja atom vodika, metilnu skupinu, -CH2-CH(CH3)2 skupinu, -CH2-CF3 skupinu, -C(O)-CH3 skupinu, -C(O)-CH(CH3)2 skupinu, -C(O)-CH2-C(CH3)3 skupinu ili -C(O)-OC(CH3)3 skupinu.
7. Spojevi u skladu s patentnim zahtjevom 1, naznačeni time, da R4 predstavlja atom vodika, ravnu ili razgrananu (C1-C6)alkilny skupinu, ravnu ili razgrananu (C2-C6)alkenilnu skupinu, ravnu ili razgrananu (C2-C6)alkinilnu skupinu, -Y1-NR6R7 skupinu, -Y1-OR6 skupinu, ravnu ili razgrananu halo(C1-C6)alkilnu skupinu, -Y1-Cy1 skupinu, -Cy1-R7 skupinu ili -Cy1-OR7 skupinu.
8. Spoj u skladu s patentnim zahtjevom 1, naznačen time, da R5 predstavlja atom vodika, atom joda, atom klora, metilnu skupinu ili -CH2-OH skupinu.
9. Spojevi u skladu s patentnim zahtjevom 1, naznačeni time, da R6 predstavlja atom vodika, metilnu skupinu ili -(CH2)2-Si(CH3)3 skupinu.
10. Spojevi u skladu s patentnim zahtjevom 1, naznačeni time, da R7 predstavlja atom vodika, metilnu skupinu ili -CH2-Cy2 skupinu.
11. Spojevi u skladu s patentnim zahtjevom 1, naznačeni time, da su:
- terc-butil (3S,4S)-4-({4-hidroksi-4-[(4-oksotieno[2,3-d]pirimidin-3(4H)-il)metil]piperidin-1-il}karbonil)- 3-fenilpiperidin-1-karboksilat;
- terc-butil (3R,4R)-4-[(4-hidroksi-4-{[4-okso-7-(piridin-2-il)-4,7-dihidro-3H-pirolo[2,3-d]pirimidin- 3-il]metil}piperidin-1-il)karbonil]-3-fenilpiperidin-1-karboksilat;
- terc-butil (3R,4R)-4-[(4-hidroksi-4-{[7-(4-metoksifenil)-4-okso-4,7-dihidro-3H-pirolo[2,3-d]pirimidin-3- il]metil}piperidin-1-il)karbonil]-3-fenilpiperidin-1-karboksilat;
- terc-butil (3R,4R)-4-[(4-hidroksi-4-{[1-(4-metoksifenil)-4-okso-1,4-dihidro-5H-pirazolo[3,4-d]pirimidin- 5-il]metil}piperidin-1-il)karbonil]-3-fenilpiperidin-1-karboksilat;
- terc-butil (3R,4R)-4-[(4-{[7-(4-fluoro-3-metoksifenil)-4-okso-4,7-dihidro-3H-pirolo[2,3-d]pirimidin- 3-il]metil}-4-hidroksipiperidin-1-il)karbonil]-3-fenilpiperidin-1-karboksilat;
- terc-butil (3R,4R)-4-[(4-{[1-(2,3-dihidro-1,4-benzodioksin-6-il)-4-okso-1,4-dihidro-5H-pirazolo[3,4-d] pirimidin-5-il]metil}-4-hidroksipiperidin-1-il)karbonil]-3-fenilpiperidin-1-karboksilat;
- 3-[(4-hidroksi-1-{[(3R,4R)-3-fenilpiperidin-4-il]karbonil}piperidin-4-il)metil]-7-fenil- 3,7-dihidro-4Hpirolo[2,3-d]pirimidin-4-on;
- 5-[(4-hidroksi-1-{[(3R,4R)-3-fenilpiperidin-4-il]karbonil}piperidin-4-il)metil]-1-fenil-1,5- dihidro-4Hpirazolo[3,4-d]pirimidin-4-on;
- 3-[(4-hidroksi-1-{[(3R,4R)-3-fenilpiperidin-4-il]karbonil}piperidin-4-il)metil]-7-(piridin-2-il)- 3,7-dihidro-4H-pirolo[2,3-d]pirimidin-4-on;
- 3-[(4-hidroksi-1-{[(3R,4R)-3-fenil-1-(2,2,2-trifluoroetil)piperidin-4-il]karbonil}piperidin-4-il)metil]-3,7- dihidro-4H-pirolo[2,3-d]pirimidin-4-on;
- 3-[(4-hidroksi-1-{[(3R,4R)-1-metil-3-fenilpiperidin-4-il]karbonil}piperidin-4-il)metil]-7-fenil-3,7-dihidro- 4H-pirolo[2,3-d]pirimidin-4-on;
- 7-(4-fluorofenil)-3-[(4-hidroksi-1-{[(3R,4R)-3-fenilpiperidin-4-il]karbonil}piperidin-4-il)metil]-3,7- dihidro-4H-pirolo[2,3-d]pirimidin-4-on;
- 3-[(4-hidroksi-1-{[(3R,4R)-3-fenilpiperidin-4-il]karbonil}piperidin-4-il)metil]-7-(4metoksifenil)-3,7- dihidro-4H-pirolo[2,3-d]pirimidin-4-on;
- 3-[(4-hidroksi-1-{[(3R,4R)-3-fenilpiperidin-4-il]karbonil}piperidin-4-il)metil]-7-(3metoksifenil)-3,7- dihidro-4H-pirolo[2,3-d]pirimidin-4-on;
- 7-(4-fluorofenil)-3-[(4-hidroksi-1-{[(3R,4R)-1-metil-3-fenilpiperidin-4-il]karbonil}piperidin-4-il)metil]- 3,7-dihidro-4H-pirolo[2,3-d]pirimidin-4-on;
- 7-(3-klorofenil)-3-[(4-hidroksi-1-{[(3R,4R)-3-fenilpiperidin-4-il]karbonil}piperidin-4-il)metil]-3,7- dihidro-4H-pirolo[2,3-d]pirimidin-4-on;
- 7-(4-klorofenil)-3-[(4-hidroksi-1-{[(3R,4R)-3-fenilpiperidin-4-il]karbonil}piperidin-4-il)metil]-3,7- dihidro-4H-pirolo[2,3-d]pirimidin-4-on;
- 3-[(1-{[(3R,4R)-1-acetil-3-fenilpiperidin-4-il]karbonil}-4-hidroksipiperidin-4-il)metil]-7-fenil-3,7- dihidro-4H-pirolo[2,3-d]pirimidin-4-on;
- 3-[(4-hidroksi-1-{[(3R,4R)-1-metil-3-fenilpiperidin-4-il]karbonil}piperidin-4-il)metil]-7-(4-metoksifenil)- 3,7-dihidro-4H-pirolo[2,3-d]pirimidin-4-on;
- 7-(3-klorofenil)-3-[(4-hidroksi-1-{[(3R,4R)-1-metil-3-fenilpiperidin-4-il]karbonil}piperidin-4-il)metil]- 3,7-dihidro-4H-pirolo[2,3-d]pirimidin-4-on;
- 7-(4-klorofenil)-3-[(4-hidroksi-1-{[(3R,4R)-1-metil-3-fenilpiperidin-4-il]karbonil}piperidin-4-il)metil]- 3,7-dihidro-4H-pirolo[2,3-d]pirimidin-4-on;
- 7-(4-fluoro-3-metoksifenil)-3-[(4-hidroksi-1-{[(3R,4R)-3-fenilpiperidin-4-il]karbonil}piperidin-4-il)metil] -3,7-dihidro-4H-pirolo[2,3-d]pirimidin-4-on;
- 3-[(4-hidroksi-1-{[(3R,4R)-1-(2-metilpropil)-3-fenilpiperidin-4-il]karbonil}piperidin-4-il)metil]-7-fenil- 3,7-dihidro-4H-pirolo[2,3-d]pirimidin-4-on;
- 1-(2,3-dihidro-1,4-benzodioksin-6-il)-5-[(4-hidroksi-1-{[(3R,4R)-3-fenilpiperidin-4-il]karbonil}piperidin- 4-il)metil]-1,5-dihidro-4H-pirazolo[3,4-d]pirimidin-4-on;
- 3-[(1-{[(3R,4R)-1-acetil-3-fenilpiperidin-4-il]karbonil}-4-hidroksipiperidin-4-il)metil]-7-(4-fluorofenil)- 3,7-dihidro-4H-pirolo[2,3-d]pirimidin-4-on;
- (3R,4R)-4-[(4-hidroksi-4-{[1-(4-metoksifenil)-4-okso-1,4-dihidro-5H-pirazolo[3,4-d]pirimidin-5-il]metil} piperidin-1-il)karbonil]-1,1-dimetil-3-fenilpiperidinij;
- 3-[(4-hidroksi-1-{[(3R,4R)-1-(2-metilpropanoil)-3-fenilpiperidin-4-il]karbonil}piperidin-4-il)metil]-7- fenil-3,7-dihidro-4H-pirolo[2,3-d]pirimidin-4-on;
- 3-[(1-{[(3R,4R)-1-acetil-3-fenilpiperidin-4-il]karbonil}-4-hidroksipiperidin-4-il)metil]-7-(4-metoksifenil)- 3,7-dihidro-4H-pirolo[2,3-d]pirimidin-4-on;
- 3-[(1-{[(3R,4R)-1-acetil-3-fenilpiperidin-4-il]karbonil}-4-hidroksipiperidin-4-il)metil]-7-(3-metoksifenil)- 3,7-dihidro-4H-pirolo[2,3-d]pirimidin-4-on;
- 3-[(1-{[(3R,4R)-1-acetil-3-fenilpiperidin-4-il]karbonil}-4-hidroksipiperidin-4-il)metil]-7-(3-klorofenil)- 3,7-dihidro-4H-pirolo[2,3-d]pirimidin-4-on;
- 3-[(1-{[(3R,4R)-1-acetil-3-fenilpiperidin-4-il]karbonil}-4-hidroksipiperidin-4-il)metil]-7-(4-klorofenil)- 3,7-dihidro-4H-pirolo[2,3-d]pirimidin-4-on;
- 3-[(1-{[(3R,4R)-1-(2,2-dimetilpropanoil)-3-fenilpiperidin-4-il]karbonil}-4-hidroksipiperidin-4-il)metil]-7 -fenil-3,7-dihidro-4H-pirolo[2,3-d]pirimidin-4-on;
- 3-[(1-{[(3R,4R)-1-(3,3-dimetilbutanoil)-3-fenilpiperidin-4-il]karbonil}-4-hidroksipiperidin-4-il)metil]-7- fenil-3,7-dihidro-4H-pirolo[2,3-d]pirimidin-4-on.
12. Postupak za dobivanje spoja formule (I) u skladu s patentnim zahtjevom 1, naznačen time, što se kao početni materijal koristi spoj formule (II):
[image]
pri čemu su R2 i n kako je definirano za formulu (I), koji je podvrgnut vezivanju sa spojem formule (III):
[image]
pri čemu je R1 kako je definirano za formulu (I), a R3' predstavlja -C(O)-OR8 skupinu u kojoj je R8 definiran za formulu (I), kako bi se dobio spoj formule (IV):
[image]
pri čemu su R1, R2, R3' i n kako je ranije gore definirano, spoj formule (IV) koji se dalje pretvara u epoksidni spoj formule (V):
[image]
pri čemu su R1, R2, R3' i n kako je ranije gore definirano,
spoj formule (V) koji je dalje podvrgnut vezivanju sa spojem formule (VI):
[image]
pri čemu je W definiran kao formula (I),
kako bi se dobio spoj formule (I-a), poseban slučaj spojeva formule (I):
[image]
pri čemu su R1, R2, R3', n i W kako je ranije gore definirano,
koji spoj formule (I / a) može tada biti podvrgnut reakciji uklanjanja R3' skupine, kako bi se dobio spoj formule (I-b), poseban slučaj spojeva formule (I):
[image]
pri čemu su R1, R2, n i W kako je ranije gore definirano, koji spoj formule (I / b) tada može biti podvrgnut reakciji spajanja sa spojem formule R3"-Cl gdje R3" predstavlja ravnu ili razgrananu (C1-C6) alkilnu skupinu, linearnu ili razgrananu halo (C1-C6) alkil ili -C(0)-R8 skupinu u kojoj je R8 kao što je definirano za formulu (I), kako bi se dobio spoj formule (I-c), poseban slučaj spojeva formule (I):
[image]
pri čemu su R1, R2, R3", n i W kako je ranije gore definirano,
koji spojevi formule (I / a) do (I / c), koji čine ukupnost spojeva formule (I), se mogu potom pročistiti uobičajenom tehnikom razdvajanja, koja se po želji pretvara u njezin dodatak soli s farmaceutski prihvatljivom kiselinom ili lužinom i koje se po izboru mogu odvojiti od njegovih izomera uobičajenom tehnikom razdvajanja, pri čemu se podrazumijeva da se u bilo kojem trenutku tijekom postupka koji je gore opisan smatra određenim, nekim skupinama (hidroksi, amino ... ) početnih reagensa ili sintetskih intermedijara može se zaštititi, nakon toga ukloniti zaštitom i funkcionalizirati, kako zahtijeva sinteza.
13. Farmaceutski pripravak, naznačen time, da sadrži spoj formule (I) u skladu s bilo kojim od patentnih zahtjeva 1 do 11 ili njegovu adicijsku sol s farmaceutski prihvatljivom kiselinom ili bazom u kombinaciji s jednim ili više farmaceutski prihvatljivih pomoćnih sredstava.
14. Farmaceutski pripravak u skladu s patentnim zahtjevom 13, naznačen time, da se koristi kao pro- apoptotička i / ili anti-proliferacijska sredstva.
15. Farmaceutski pripravak u skladu s patentnim zahtjevom 14, naznačen time, da se koristi za liječenje karcinoma i bolesti autoimunog i imunološkog sustava.
16. Farmaceutski pripravak u skladu s patentnim zahtjevom 15, naznačen time, da se koristi za liječenje karcinoma mokraćnog mjehura, mozga, dojke i maternice, kronične limfne leukemije, raka debelog crijeva, jednjaka i jetre, limfoblastične leukemije, akutne mijeloidne leukemije, limfoma, melanoma, zloćudne hemopatije, mijeloma, karcinoma jajnika, karcinoma pluća ne-malih stanica, raka prostate, raka gušterače i raka pluća malih stanica.
17. Uporaba farmaceutskog pripravka u skladu s patentnim zahtjevom 13, naznačena time, što se koristi u proizvodnji lijekova za uporabu kao proapoptotička i / ili antiproliferacijska sredstva.
18. Uporaba farmaceutskog pripravka u skladu s patentnim zahtjevom 13, naznačena time, što se koristi u proizvodnji lijekova za uporabu u liječenju karcinoma i bolesti autoimunog i imunološkog sustava.
19. Uporaba farmaceutskog pripravka u skladu s patentnim zahtjevom 13, naznačena time, što je namijenjena proizvodnji lijekova za uporabu u liječenju karcinoma mokraćnog mjehura, mozga, dojke i maternice, kronične limfne leukemije, raka debelog crijeva, jednjaka i jetre, limfoblastične leukemije, akutne mijeloidne leukemije, limfoma, melanoma, zloćudne hemopatije, mijeloma, raka jajnika, raka pluća ne-malih stanica, raka prostate, karcinoma gušterače i raka pluća malih stanica.
20. Spoj formule (I) u skladu s bilo kojim od patentnih zahtjeva 1 do 11 ili njegova adicijska sol s farmaceutski prihvatljivom kiselinom ili bazom, naznačen time, da je za uporabu u liječenju karcinoma mokraćnog mjehura, mozga, dojke i maternice, kronične limfoidne leukemije, karcinoma debelog crijeva, jednjaka i jetre, limfoblastične leukemija, akutne mijeloične leukemije, limfoma, melanoma, zloćudne hemopatije, mijeloma, karcinoma jajnika, raka pluća ne-malih stanica, raka prostate, raka gušterače i raka pluća malih stanica.
21. Uporaba spoja formule (I) u skladu s bilo kojim od patentnih zahtjeva 1 do 11 ili njegove adicijske soli s farmaceutski prihvatljivom kiselinom ili bazom, naznačena time, da se koristi u proizvodnji lijekova za upotrebu u liječenju karcinoma mokraćnog mjehura, mozga, dojke i maternice, kronične limfoidne leukemije, raka debelog crijeva, jednjaka i jetre, limfoblastičnih leukemija, akutne mijeloidne leukemije, limfoma, melanoma, zloćudne hemopatije, mijeloma, raka jajnika, karcinoma pluća nemalih stanica, raka prostate, karcinom gušterače i raka pluća malih stanica.
22. Kombinacija spoja formule (I) u skladu s bilo kojim od patentnih zahtjeva 1 do 11, naznačena time, da je sa sredstvima protiv karcinoma odabranim između genotoksičnih sredstava, mitotskih otrova, anti-metabolita, inhibitora proteasoma, inhibitora kinaze, inhibitora interakcije proteina i proteina, imunomodulatora, E3 inhibitora ligaze, terapije himernim antigenom za T-stanice i protutijela.
23. Farmaceutski pripravak, koji sadrži kombinaciju u skladu s patentnim zahtjevom 22, naznačen time, da je u kombinaciji s jednim ili više farmaceutski prihvatljivih pomoćnih sredstava.
24. Kombinacija u skladu s patentnim zahtjevom 22, naznačena time, da se koristi za liječenje karcinoma.
25. Upotreba kombinacije u skladu s patentnim zahtjevom 22, naznačena time, što je za proizvodnju lijekova za upotrebu u liječenju karcinoma.
26. Spoj formule (I) u skladu s bilo kojim od patentnih zahtjeva 1 do 11, naznačen time, da se koristi za liječenje karcinoma koji zahtijevaju radioterapiju.
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| FR1655392A FR3052452B1 (fr) | 2016-06-10 | 2016-06-10 | Nouveaux derives de piperidinyle, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| EP17727927.0A EP3468974B1 (en) | 2016-06-10 | 2017-06-09 | New piperidinyl derivatives, a process for their preparation and pharmaceutical compositions containing them |
| PCT/EP2017/064067 WO2017212012A1 (en) | 2016-06-10 | 2017-06-09 | New piperidinyl derivatives, a process for their preparation and pharmaceutical compositions containing them |
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| WO2017155844A1 (en) | 2016-03-07 | 2017-09-14 | Enanta Pharmaceuticals, Inc. | Hepatitis b antiviral agents |
| AU2018254577A1 (en) | 2017-04-21 | 2019-12-05 | Epizyme, Inc. | Combination therapies with EHMT2 inhibitors |
| KR102556744B1 (ko) | 2017-08-28 | 2023-07-18 | 이난타 파마슈티칼스, 인코포레이티드 | B형 간염 항바이러스제 |
| CA3083320C (en) | 2017-11-29 | 2022-08-16 | Les Laboratoires Servier | Piperidinyl derivatives as inhibitors of ubiquitin specific protease 7 |
| GB201801562D0 (en) | 2018-01-31 | 2018-03-14 | Almac Diagnostics Ltd | Pharmaceutical compounds |
| UY38291A (es) * | 2018-07-05 | 2020-06-30 | Servier Lab | Nuevos derivados de amino-pirimidonilo un proceso para su preparación y composiciones farmacéuticas |
| US10865211B2 (en) | 2018-09-21 | 2020-12-15 | Enanta Pharmaceuticals, Inc. | Functionalized heterocycles as antiviral agents |
| UY38423A (es) * | 2018-10-19 | 2021-02-26 | Servier Lab | Nuevos derivados amino-pirimidonil-piperidinilo, un proceso para su preparación y composiciones farmacéuticas que los contienen |
| WO2020106816A1 (en) | 2018-11-21 | 2020-05-28 | Enanta Pharmaceuticals, Inc. | Functionalized heterocycles as antiviral agents |
| KR20210102285A (ko) * | 2018-12-06 | 2021-08-19 | 알막 디스커버리 리미티드 | 약학적 화합물 및 유비퀴틴 특이적 단백질분해효소 19 (usp19)의 억제제로서의 사용 |
| WO2020247444A1 (en) | 2019-06-03 | 2020-12-10 | Enanta Pharmaceuticals, Inc, | Hepatitis b antiviral agents |
| US11760755B2 (en) | 2019-06-04 | 2023-09-19 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
| WO2020247575A1 (en) | 2019-06-04 | 2020-12-10 | Enanta Pharmaceuticals, Inc. | Hepatitis b antiviral agents |
| US11738019B2 (en) | 2019-07-11 | 2023-08-29 | Enanta Pharmaceuticals, Inc. | Substituted heterocycles as antiviral agents |
| WO2021055425A2 (en) | 2019-09-17 | 2021-03-25 | Enanta Pharmaceuticals, Inc. | Functionalized heterocycles as antiviral agents |
| CN113087718B (zh) * | 2020-01-09 | 2024-02-09 | 四川科伦博泰生物医药股份有限公司 | 噻吩并嘧啶酮类化合物及其医药应用 |
| CN112608320B (zh) * | 2020-01-16 | 2023-03-17 | 中国药科大学 | 哌啶类化合物及其制备方法和医药用途 |
| GB202001980D0 (en) | 2020-02-13 | 2020-04-01 | Almac Discovery Ltd | Therapeutic mentods |
| WO2021188414A1 (en) | 2020-03-16 | 2021-09-23 | Enanta Pharmaceuticals, Inc. | Functionalized heterocyclic compounds as antiviral agents |
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| CN101674831A (zh) * | 2007-03-02 | 2010-03-17 | 先灵公司 | 用于治疗糖尿病或疼痛的哌啶基哌啶和哌嗪基哌啶 |
| EP2565186A1 (en) * | 2011-09-02 | 2013-03-06 | Hybrigenics S.A. | Selective and reversible inhibitors of ubiquitin specific protease 7 |
| TWI698436B (zh) * | 2014-12-30 | 2020-07-11 | 美商佛瑪治療公司 | 作為泛素特異性蛋白酶７抑制劑之吡咯并及吡唑并嘧啶 |
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- 2018-12-04 EC ECSENADI201890144A patent/ECSP18090144A/es unknown
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- 2018-12-06 CO CONC2018/0013210A patent/CO2018013210A2/es unknown
- 2018-12-07 NI NI201800132A patent/NI201800132A/es unknown
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2020
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