CZ20032502A3 - Inhibitory metalloproteinasy - Google Patents
Inhibitory metalloproteinasy Download PDFInfo
- Publication number
- CZ20032502A3 CZ20032502A3 CZ20032502A CZ20032502A CZ20032502A3 CZ 20032502 A3 CZ20032502 A3 CZ 20032502A3 CZ 20032502 A CZ20032502 A CZ 20032502A CZ 20032502 A CZ20032502 A CZ 20032502A CZ 20032502 A3 CZ20032502 A3 CZ 20032502A3
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- CZ
- Czechia
- Prior art keywords
- group
- alkyl
- apci
- carbon atoms
- formula
- Prior art date
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- 239000003475 metalloproteinase inhibitor Substances 0.000 title claims description 47
- 150000001875 compounds Chemical class 0.000 claims abstract description 319
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 73
- 201000010099 disease Diseases 0.000 claims abstract description 66
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 66
- 230000001404 mediated effect Effects 0.000 claims abstract description 43
- 102000005741 Metalloproteases Human genes 0.000 claims abstract description 41
- 108010006035 Metalloproteases Proteins 0.000 claims abstract description 41
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 40
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 33
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 33
- 238000011282 treatment Methods 0.000 claims abstract description 26
- 230000027455 binding Effects 0.000 claims abstract description 23
- 238000009739 binding Methods 0.000 claims abstract description 23
- 229910052751 metal Inorganic materials 0.000 claims abstract description 20
- 239000002184 metal Substances 0.000 claims abstract description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 439
- -1 arylheteroalkyl Chemical group 0.000 claims description 155
- 238000000034 method Methods 0.000 claims description 90
- 125000004432 carbon atom Chemical group C* 0.000 claims description 66
- 229910052757 nitrogen Inorganic materials 0.000 claims description 50
- 239000001257 hydrogen Substances 0.000 claims description 43
- 101710170181 Metalloproteinase inhibitor Proteins 0.000 claims description 41
- 229940126170 metalloproteinase inhibitor Drugs 0.000 claims description 41
- 150000003839 salts Chemical class 0.000 claims description 39
- 150000002148 esters Chemical class 0.000 claims description 37
- 102000002274 Matrix Metalloproteinases Human genes 0.000 claims description 34
- 108010000684 Matrix Metalloproteinases Proteins 0.000 claims description 34
- 238000002360 preparation method Methods 0.000 claims description 32
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 30
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 claims description 30
- 238000001727 in vivo Methods 0.000 claims description 30
- 102100027998 Macrophage metalloelastase Human genes 0.000 claims description 27
- 229910005965 SO 2 Inorganic materials 0.000 claims description 27
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 24
- 102000004190 Enzymes Human genes 0.000 claims description 23
- 108090000790 Enzymes Proteins 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 23
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 23
- 125000004429 atom Chemical group 0.000 claims description 22
- 125000001072 heteroaryl group Chemical group 0.000 claims description 20
- 239000001301 oxygen Chemical group 0.000 claims description 20
- 102100027995 Collagenase 3 Human genes 0.000 claims description 19
- 125000005842 heteroatom Chemical group 0.000 claims description 19
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 17
- 239000011593 sulfur Chemical group 0.000 claims description 17
- 102100030416 Stromelysin-1 Human genes 0.000 claims description 16
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 16
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 16
- 125000000524 functional group Chemical group 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- UZFMOKQJFYMBGY-UHFFFAOYSA-N 4-hydroxy-TEMPO Chemical group CC1(C)CC(O)CC(C)(C)N1[O] UZFMOKQJFYMBGY-UHFFFAOYSA-N 0.000 claims description 14
- 102100030411 Neutrophil collagenase Human genes 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
- 150000003573 thiols Chemical group 0.000 claims description 14
- 241001465754 Metazoa Species 0.000 claims description 13
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 13
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 12
- 125000004434 sulfur atom Chemical group 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 150000001356 alkyl thiols Chemical group 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 10
- 125000003368 amide group Chemical group 0.000 claims description 9
- 125000002619 bicyclic group Chemical group 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 230000002401 inhibitory effect Effects 0.000 claims description 8
- 125000006168 tricyclic group Chemical group 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 7
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 6
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 6
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 6
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000006413 ring segment Chemical group 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- 101000577887 Homo sapiens Collagenase 3 Proteins 0.000 claims description 5
- 125000005157 alkyl carboxy group Chemical group 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 125000002950 monocyclic group Chemical group 0.000 claims description 5
- 125000005599 alkyl carboxylate group Chemical group 0.000 claims description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 150000007942 carboxylates Chemical class 0.000 claims description 4
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 125000004001 thioalkyl group Chemical group 0.000 claims description 4
- LBYVZRFDLNAPRC-UHFFFAOYSA-N 2-sulfanylguanidine Chemical compound NC(=N)NS LBYVZRFDLNAPRC-UHFFFAOYSA-N 0.000 claims description 3
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 3
- 125000005418 aryl aryl group Chemical group 0.000 claims description 3
- 150000001504 aryl thiols Chemical group 0.000 claims description 3
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 3
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 claims description 3
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 3
- 125000004441 haloalkylsulfonyl group Chemical group 0.000 claims description 3
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 claims description 3
- 101000577881 Homo sapiens Macrophage metalloelastase Proteins 0.000 claims description 2
- 101000990902 Homo sapiens Matrix metalloproteinase-9 Proteins 0.000 claims description 2
- 101000990908 Homo sapiens Neutrophil collagenase Proteins 0.000 claims description 2
- 101000990915 Homo sapiens Stromelysin-1 Proteins 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
- 125000005120 alkyl cycloalkyl alkyl group Chemical group 0.000 claims description 2
- 150000001409 amidines Chemical class 0.000 claims description 2
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 2
- 125000005362 aryl sulfone group Chemical group 0.000 claims description 2
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 2
- 125000004994 halo alkoxy alkyl group Chemical group 0.000 claims description 2
- HDCXQTPVTAIPNZ-UHFFFAOYSA-N n-({[4-(aminosulfonyl)phenyl]amino}carbonyl)-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NC1=CC=C(S(N)(=O)=O)C=C1 HDCXQTPVTAIPNZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 2
- 125000001174 sulfone group Chemical group 0.000 claims description 2
- 150000003457 sulfones Chemical class 0.000 claims description 2
- RPMXALUWKZHYOV-UHFFFAOYSA-N nitroethene Chemical compound [O-][N+](=O)C=C RPMXALUWKZHYOV-UHFFFAOYSA-N 0.000 claims 2
- 125000005422 alkyl sulfonamido group Chemical group 0.000 claims 1
- 125000004350 aryl cycloalkyl group Chemical group 0.000 claims 1
- 150000001721 carbon Chemical group 0.000 claims 1
- ZMUADARPXLFDHP-UHFFFAOYSA-N nitrocarbamic acid Chemical compound OC(=O)N[N+]([O-])=O ZMUADARPXLFDHP-UHFFFAOYSA-N 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 abstract description 20
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 417
- 238000005481 NMR spectroscopy Methods 0.000 description 296
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 222
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 214
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 174
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 143
- 239000000243 solution Substances 0.000 description 123
- 239000000047 product Substances 0.000 description 120
- 239000000203 mixture Substances 0.000 description 117
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 114
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 106
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 99
- 229910001868 water Inorganic materials 0.000 description 98
- 239000011541 reaction mixture Substances 0.000 description 80
- 238000006243 chemical reaction Methods 0.000 description 76
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 63
- 238000000668 atmospheric pressure chemical ionisation mass spectrometry Methods 0.000 description 62
- 235000019439 ethyl acetate Nutrition 0.000 description 59
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 55
- 239000007787 solid Substances 0.000 description 51
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 49
- 239000002904 solvent Substances 0.000 description 49
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 47
- 238000004458 analytical method Methods 0.000 description 47
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 42
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical group O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 42
- 238000005882 aldol condensation reaction Methods 0.000 description 40
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 38
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 38
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 33
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 32
- 239000007858 starting material Substances 0.000 description 32
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
- 239000000725 suspension Substances 0.000 description 31
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 30
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 description 30
- VMAQYKGITHDWKL-UHFFFAOYSA-N 5-methylimidazolidine-2,4-dione Chemical compound CC1NC(=O)NC1=O VMAQYKGITHDWKL-UHFFFAOYSA-N 0.000 description 29
- 239000012043 crude product Substances 0.000 description 29
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- 239000000741 silica gel Substances 0.000 description 26
- 229910002027 silica gel Inorganic materials 0.000 description 26
- 101710187853 Macrophage metalloelastase Proteins 0.000 description 24
- 238000001704 evaporation Methods 0.000 description 24
- 230000008020 evaporation Effects 0.000 description 24
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 23
- 238000003786 synthesis reaction Methods 0.000 description 23
- 230000015572 biosynthetic process Effects 0.000 description 22
- 229940088598 enzyme Drugs 0.000 description 22
- 150000002431 hydrogen Chemical class 0.000 description 22
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 22
- 239000000543 intermediate Substances 0.000 description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 20
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 20
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 20
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
- 239000001099 ammonium carbonate Substances 0.000 description 20
- 235000012501 ammonium carbonate Nutrition 0.000 description 20
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 20
- 150000001412 amines Chemical class 0.000 description 19
- 239000003921 oil Substances 0.000 description 19
- 235000019198 oils Nutrition 0.000 description 19
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
- 238000012360 testing method Methods 0.000 description 19
- 239000012267 brine Substances 0.000 description 18
- 230000000694 effects Effects 0.000 description 18
- 239000012074 organic phase Substances 0.000 description 17
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 16
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
- 238000004587 chromatography analysis Methods 0.000 description 16
- 150000002576 ketones Chemical class 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 16
- 239000002253 acid Substances 0.000 description 15
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- 108050005238 Collagenase 3 Proteins 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 14
- 239000002585 base Substances 0.000 description 14
- 229940091173 hydantoin Drugs 0.000 description 14
- 238000002953 preparative HPLC Methods 0.000 description 14
- 229920006395 saturated elastomer Polymers 0.000 description 14
- VKUYLANQOAKALN-UHFFFAOYSA-N 2-[benzyl-(4-methoxyphenyl)sulfonylamino]-n-hydroxy-4-methylpentanamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N(C(CC(C)C)C(=O)NO)CC1=CC=CC=C1 VKUYLANQOAKALN-UHFFFAOYSA-N 0.000 description 13
- 101710108790 Stromelysin-1 Proteins 0.000 description 13
- 101710118230 Neutrophil collagenase Proteins 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 12
- 150000001299 aldehydes Chemical class 0.000 description 12
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 12
- 239000003480 eluent Substances 0.000 description 12
- 150000001469 hydantoins Chemical class 0.000 description 12
- 230000005764 inhibitory process Effects 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 230000008569 process Effects 0.000 description 12
- 238000000746 purification Methods 0.000 description 12
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 12
- 150000001413 amino acids Chemical class 0.000 description 11
- 239000008346 aqueous phase Substances 0.000 description 11
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 11
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- ISDBWOPVZKNQDW-UHFFFAOYSA-N 4-phenylbenzaldehyde Chemical compound C1=CC(C=O)=CC=C1C1=CC=CC=C1 ISDBWOPVZKNQDW-UHFFFAOYSA-N 0.000 description 8
- 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 description 8
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 8
- 241000700159 Rattus Species 0.000 description 8
- 238000003818 flash chromatography Methods 0.000 description 8
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 8
- 230000014759 maintenance of location Effects 0.000 description 8
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 8
- 238000000926 separation method Methods 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 8
- GCTFDMFLLBCLPF-UHFFFAOYSA-N 2,5-dichloropyridine Chemical compound ClC1=CC=C(Cl)N=C1 GCTFDMFLLBCLPF-UHFFFAOYSA-N 0.000 description 7
- NXKTUUPSINAQEA-UHFFFAOYSA-N 4-(4-fluorophenyl)-1-methylsulfonylpiperidine Chemical compound C1CN(S(=O)(=O)C)CCC1C1=CC=C(F)C=C1 NXKTUUPSINAQEA-UHFFFAOYSA-N 0.000 description 7
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 7
- 230000005526 G1 to G0 transition Effects 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 7
- 235000001014 amino acid Nutrition 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
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- 238000006731 degradation reaction Methods 0.000 description 7
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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| SE0100902A SE0100902D0 (sv) | 2001-03-15 | 2001-03-15 | Compounds |
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| US6890915B2 (en) | 2001-05-25 | 2005-05-10 | Bristol-Myers Squibb Pharma Company | Hydantoins and related heterocycles as inhibitors of matrix metalloproteinases and/or TNF-α converting enzyme (TACE) |
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| US20050119251A1 (en) * | 2001-12-21 | 2005-06-02 | Jian-Min Fu | Nicotinamide derivatives and their use as therapeutic agents |
| JP4485941B2 (ja) * | 2002-06-05 | 2010-06-23 | 株式会社カネカ | 光学活性α−メチルシステイン誘導体の製造方法 |
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| JP4866610B2 (ja) * | 2003-08-18 | 2012-02-01 | 富士フイルムファインケミカルズ株式会社 | ピリジルテトラヒドロピリジン類およびピリジルピペリジン類 |
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| US7648992B2 (en) | 2004-07-05 | 2010-01-19 | Astrazeneca Ab | Hydantoin derivatives for the treatment of obstructive airway diseases |
| SE0401763D0 (sv) * | 2004-07-05 | 2004-07-05 | Astrazeneca Ab | Compounds |
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-
2002
- 2002-03-13 JP JP2002573759A patent/JP2004527511A/ja not_active Withdrawn
- 2002-03-13 BR BR0208105-9A patent/BR0208105A/pt not_active IP Right Cessation
- 2002-03-13 MX MXPA03008180A patent/MXPA03008180A/es unknown
- 2002-03-13 EP EP02704034A patent/EP1370536A1/en not_active Withdrawn
- 2002-03-13 RU RU2003127732/04A patent/RU2003127732A/ru not_active Application Discontinuation
- 2002-03-13 HU HU0400206A patent/HUP0400206A3/hu unknown
- 2002-03-13 CZ CZ20032502A patent/CZ20032502A3/cs unknown
- 2002-03-13 PL PL02364714A patent/PL364714A1/xx not_active Application Discontinuation
- 2002-03-13 WO PCT/SE2002/000475 patent/WO2002074750A1/en not_active Ceased
- 2002-03-13 EE EEP200300439A patent/EE200300439A/xx unknown
- 2002-03-13 CA CA002440632A patent/CA2440632A1/en not_active Abandoned
- 2002-03-13 IL IL15757002A patent/IL157570A0/xx unknown
- 2002-03-13 CN CNA028100417A patent/CN1509275A/zh active Pending
- 2002-03-13 KR KR10-2003-7011989A patent/KR20030082990A/ko not_active Withdrawn
- 2002-03-13 SK SK1093-2003A patent/SK10932003A3/sk not_active Application Discontinuation
- 2002-03-13 US US10/471,808 patent/US20040147573A1/en not_active Abandoned
-
2003
- 2003-09-10 IS IS6944A patent/IS6944A/is unknown
- 2003-09-11 NO NO20034025A patent/NO20034025L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| JP2004527511A (ja) | 2004-09-09 |
| HUP0400206A2 (hu) | 2004-08-30 |
| HUP0400206A3 (en) | 2004-10-28 |
| MXPA03008180A (es) | 2003-12-12 |
| RU2003127732A (ru) | 2005-03-20 |
| EE200300439A (et) | 2003-12-15 |
| WO2002074750A1 (en) | 2002-09-26 |
| CA2440632A1 (en) | 2002-09-26 |
| IS6944A (is) | 2003-09-10 |
| US20040147573A1 (en) | 2004-07-29 |
| PL364714A1 (en) | 2004-12-13 |
| EP1370536A1 (en) | 2003-12-17 |
| KR20030082990A (ko) | 2003-10-23 |
| BR0208105A (pt) | 2004-03-09 |
| NO20034025L (no) | 2003-11-13 |
| IL157570A0 (en) | 2004-03-28 |
| NO20034025D0 (no) | 2003-09-11 |
| CN1509275A (zh) | 2004-06-30 |
| SK10932003A3 (sk) | 2004-04-06 |
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