CZ20031010A3 - Léčivo pro léčení rheumatoidní arthritis a způsob identifikace činidla, které selektivně inhibuje aktivitu EP4 - Google Patents
Léčivo pro léčení rheumatoidní arthritis a způsob identifikace činidla, které selektivně inhibuje aktivitu EP4 Download PDFInfo
- Publication number
- CZ20031010A3 CZ20031010A3 CZ20031010A CZ20031010A CZ20031010A3 CZ 20031010 A3 CZ20031010 A3 CZ 20031010A3 CZ 20031010 A CZ20031010 A CZ 20031010A CZ 20031010 A CZ20031010 A CZ 20031010A CZ 20031010 A3 CZ20031010 A3 CZ 20031010A3
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- CZ
- Czechia
- Prior art keywords
- alkyl
- ethyl
- amino
- phenyl
- imidazo
- Prior art date
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- 239000003795 chemical substances by application Substances 0.000 title claims description 31
- 230000000694 effects Effects 0.000 title claims description 24
- 206010039073 rheumatoid arthritis Diseases 0.000 title claims description 15
- 239000003814 drug Substances 0.000 title claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 172
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 139
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 26
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 21
- 238000011282 treatment Methods 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 229910052799 carbon Inorganic materials 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims description 459
- -1 imidazole compound Chemical class 0.000 claims description 424
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 119
- 125000003118 aryl group Chemical group 0.000 claims description 79
- 125000002950 monocyclic group Chemical group 0.000 claims description 71
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 56
- 229910052736 halogen Inorganic materials 0.000 claims description 51
- 229910052757 nitrogen Inorganic materials 0.000 claims description 51
- 229910052717 sulfur Chemical group 0.000 claims description 51
- 239000001257 hydrogen Substances 0.000 claims description 46
- 150000002367 halogens Chemical class 0.000 claims description 45
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 40
- 125000005842 heteroatom Chemical group 0.000 claims description 38
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 34
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 33
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 32
- 125000002619 bicyclic group Chemical group 0.000 claims description 32
- 239000011593 sulfur Chemical group 0.000 claims description 32
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 27
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- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 20
- 125000005843 halogen group Chemical group 0.000 claims description 19
- 125000000304 alkynyl group Chemical group 0.000 claims description 18
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 17
- 239000001301 oxygen Substances 0.000 claims description 17
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 15
- 102000054727 Serum Amyloid A Human genes 0.000 claims description 14
- 108700028909 Serum Amyloid A Proteins 0.000 claims description 14
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 14
- 241001465754 Metazoa Species 0.000 claims description 12
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- 150000002431 hydrogen Chemical class 0.000 claims description 12
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 claims description 12
- 125000005936 piperidyl group Chemical group 0.000 claims description 11
- 125000004760 (C1-C4) alkylsulfonylamino group Chemical group 0.000 claims description 10
- 125000004043 oxo group Chemical group O=* 0.000 claims description 10
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- 102000015696 Interleukins Human genes 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
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- 241000124008 Mammalia Species 0.000 claims description 8
- 102100024450 Prostaglandin E2 receptor EP4 subtype Human genes 0.000 claims description 8
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 8
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 7
- 208000018937 joint inflammation Diseases 0.000 claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 238000001727 in vivo Methods 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
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- 206010020718 hyperplasia Diseases 0.000 claims description 4
- XTFIVUDBNACUBN-UHFFFAOYSA-N 1,3,5-trinitro-1,3,5-triazinane Chemical compound [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)C1 XTFIVUDBNACUBN-UHFFFAOYSA-N 0.000 claims description 3
- 125000006590 (C2-C6) alkenylene group Chemical group 0.000 claims description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
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- 238000004519 manufacturing process Methods 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 619
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 144
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 240
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- UXFYIGKLRGDWJQ-UHFFFAOYSA-N phenyl n-[2-[4-[(4,6-dimethyl-3-nitropyridin-2-yl)amino]phenyl]ethyl]carbamate Chemical compound CC1=CC(C)=C([N+]([O-])=O)C(NC=2C=CC(CCNC(=O)OC=3C=CC=CC=3)=CC=2)=N1 UXFYIGKLRGDWJQ-UHFFFAOYSA-N 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- OAHKWDDSKCRNFE-UHFFFAOYSA-N phenylmethanesulfonyl chloride Chemical compound ClS(=O)(=O)CC1=CC=CC=C1 OAHKWDDSKCRNFE-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
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- LZMJNVRJMFMYQS-UHFFFAOYSA-N poseltinib Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC(OC=2C=C(NC(=O)C=C)C=CC=2)=C(OC=C2)C2=N1 LZMJNVRJMFMYQS-UHFFFAOYSA-N 0.000 description 1
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- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 1
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridine hydrochloride Substances [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 1
- NKFLEFWUYAUDJV-UHFFFAOYSA-N pyridine-3-sulfonamide Chemical compound NS(=O)(=O)C1=CC=CN=C1 NKFLEFWUYAUDJV-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000007781 signaling event Effects 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
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- 239000000758 substrate Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- BUXTXUBQAKIQKS-UHFFFAOYSA-N sulfuryl diisocyanate Chemical compound O=C=NS(=O)(=O)N=C=O BUXTXUBQAKIQKS-UHFFFAOYSA-N 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- WQCXYFJSMDPLIH-UHFFFAOYSA-N tert-butyl [2-[4-(5,6-dichloro-2-ethylbenzimidazol-1-yl)phenyl]ethyl-[(2-methylpropan-2-yl)oxycarbonyl]amino] carbonate Chemical compound CCC1=NC2=CC(Cl)=C(Cl)C=C2N1C1=CC=C(CCN(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C=C1 WQCXYFJSMDPLIH-UHFFFAOYSA-N 0.000 description 1
- 125000006318 tert-butyl amino group Chemical group [H]N(*)C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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