UA82497C2

UA82497C2 - Тієнопіримідиндіони і їх використання у модуляції аутоімунних хвороб

Тієнопіримідиндіони і їх використання у модуляції аутоімунних хвороб Download PDF

Info

Publication number: UA82497C2
Authority: UA; Ukraine
Prior art keywords: formula; compound; group; alkyl; methyl
Prior art date: 2003-01-17

Application number

UAA200506373A

Other languages

English (en)

Russian (ru)

Ukrainian (uk)

Inventor

Саймон Дейвид Гил

Энтони Говард Инголл

Original Assignee

Astrazeneca Ab

Priority date

2003-01-17

Filing date

2004-01-15

Publication date

2008-04-25

2004-01-15 Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab

2004-01-15 Priority claimed from PCT/SE2004/000053 external-priority patent/WO2004065395A1/en

2008-04-25 Publication of UA82497C2 publication Critical patent/UA82497C2/uk

Links

150000001875 compounds Chemical class 0.000 claims abstract description 105
238000000034 method Methods 0.000 claims abstract description 14
125000003118 aryl group Chemical group 0.000 claims abstract description 12
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
238000002560 therapeutic procedure Methods 0.000 claims abstract description 9
150000003839 salts Chemical class 0.000 claims description 38
-1 Sodalkanoyl Chemical group 0.000 claims description 33
125000000217 alkyl group Chemical group 0.000 claims description 24
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
229910052757 nitrogen Inorganic materials 0.000 claims description 21
238000006243 chemical reaction Methods 0.000 claims description 20
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 18
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
201000010099 disease Diseases 0.000 claims description 16
229910052736 halogen Inorganic materials 0.000 claims description 13
125000004982 dihaloalkyl group Chemical group 0.000 claims description 11
150000002367 halogens Chemical class 0.000 claims description 11
125000005842 heteroatom Chemical group 0.000 claims description 10
229910052739 hydrogen Inorganic materials 0.000 claims description 10
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
125000004385 trihaloalkyl group Chemical group 0.000 claims description 10
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
125000004093 cyano group Chemical group *C#N 0.000 claims description 8
125000001188 haloalkyl group Chemical group 0.000 claims description 8
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 8
125000004043 oxo group Chemical group O=* 0.000 claims description 8
229910052760 oxygen Inorganic materials 0.000 claims description 8
239000001301 oxygen Chemical group 0.000 claims description 8
229910052709 silver Inorganic materials 0.000 claims description 8
229910052717 sulfur Chemical group 0.000 claims description 8
239000011593 sulfur Chemical group 0.000 claims description 8
125000000464 thioxo group Chemical group S=* 0.000 claims description 8
239000001257 hydrogen Substances 0.000 claims description 7
125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 7
125000001424 substituent group Chemical group 0.000 claims description 7
125000004122 cyclic group Chemical class 0.000 claims description 6
125000006413 ring segment Chemical group 0.000 claims description 6
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
229910052799 carbon Inorganic materials 0.000 claims description 5
125000004432 carbon atom Chemical group C* 0.000 claims description 5
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
239000011737 fluorine Substances 0.000 claims description 5
229910052731 fluorine Inorganic materials 0.000 claims description 5
125000000623 heterocyclic group Chemical group 0.000 claims description 5
125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
125000006239 protecting group Chemical group 0.000 claims description 5
239000012453 solvate Substances 0.000 claims description 5
125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
230000015572 biosynthetic process Effects 0.000 claims description 4
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
206010062016 Immunosuppression Diseases 0.000 claims description 3
125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 3
125000001589 carboacyl group Chemical group 0.000 claims description 3
230000001506 immunosuppresive effect Effects 0.000 claims description 3
125000004076 pyridyl group Chemical group 0.000 claims description 3
125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
208000018569 Respiratory Tract disease Diseases 0.000 claims description 2
125000005843 halogen group Chemical group 0.000 claims description 2
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
125000000335 thiazolyl group Chemical group 0.000 claims description 2
230000003993 interaction Effects 0.000 claims 4
125000004453 alkoxycarbonyl group Chemical group 0.000 claims 1
239000003937 drug carrier Substances 0.000 claims 1
238000012876 topography Methods 0.000 claims 1
238000002360 preparation method Methods 0.000 abstract description 4
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 49
239000000243 solution Substances 0.000 description 20
235000019439 ethyl acetate Nutrition 0.000 description 17
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
239000000203 mixture Substances 0.000 description 15
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 12
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
238000004949 mass spectrometry Methods 0.000 description 11
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206010039083 rhinitis Diseases 0.000 description 10
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 9
239000012442 inert solvent Substances 0.000 description 9
230000002829 reductive effect Effects 0.000 description 9
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
102100026933 Myelin-associated neurite-outgrowth inhibitor Human genes 0.000 description 7
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
239000002253 acid Substances 0.000 description 7
239000002585 base Substances 0.000 description 7
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
238000004440 column chromatography Methods 0.000 description 6
239000003480 eluent Substances 0.000 description 6
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
239000000377 silicon dioxide Substances 0.000 description 6
239000007787 solid Substances 0.000 description 6
239000002904 solvent Substances 0.000 description 6
210000002345 respiratory system Anatomy 0.000 description 5
238000011282 treatment Methods 0.000 description 5
102100033891 Arylsulfatase I Human genes 0.000 description 4
208000023275 Autoimmune disease Diseases 0.000 description 4
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
101000925544 Homo sapiens Arylsulfatase I Proteins 0.000 description 4
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
208000010668 atopic eczema Diseases 0.000 description 4
210000004027 cell Anatomy 0.000 description 4
FDLDWKIEWAWOSL-UHFFFAOYSA-N ethyl acetate;2-methylpentane Chemical compound CCCC(C)C.CCOC(C)=O FDLDWKIEWAWOSL-UHFFFAOYSA-N 0.000 description 4
238000001704 evaporation Methods 0.000 description 4
230000008020 evaporation Effects 0.000 description 4
239000000284 extract Substances 0.000 description 4
CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
239000000725 suspension Substances 0.000 description 4
WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 3
241000282414 Homo sapiens Species 0.000 description 3
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
230000001684 chronic effect Effects 0.000 description 3
239000003085 diluting agent Substances 0.000 description 3
238000001035 drying Methods 0.000 description 3
210000004072 lung Anatomy 0.000 description 3
229910000027 potassium carbonate Inorganic materials 0.000 description 3
230000035755 proliferation Effects 0.000 description 3
238000011321 prophylaxis Methods 0.000 description 3
229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
235000017557 sodium bicarbonate Nutrition 0.000 description 3
208000011580 syndromic disease Diseases 0.000 description 3
210000001519 tissue Anatomy 0.000 description 3
AQOSPGCCTHGZFL-UHFFFAOYSA-N 1-(3a-hydroxy-7-methoxy-1,2,4,8b-tetrahydropyrrolo[2,3-b]indol-3-yl)ethanone Chemical compound COC1=CC=C2NC3(O)N(C(C)=O)CCC3C2=C1 AQOSPGCCTHGZFL-UHFFFAOYSA-N 0.000 description 2
HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 2
NOIXNOMHHWGUTG-UHFFFAOYSA-N 2-[[4-[4-pyridin-4-yl-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]phenoxy]methyl]quinoline Chemical group C=1C=C(OCC=2N=C3C=CC=CC3=CC=2)C=CC=1C1=NN(CC(F)(F)F)C=C1C1=CC=NC=C1 NOIXNOMHHWGUTG-UHFFFAOYSA-N 0.000 description 2
VHBFEIBMZHEWSX-UHFFFAOYSA-N 2-isothiocyanatopropane Chemical compound CC(C)N=C=S VHBFEIBMZHEWSX-UHFFFAOYSA-N 0.000 description 2
208000030507 AIDS Diseases 0.000 description 2
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CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
201000004624 Dermatitis Diseases 0.000 description 2
ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
101000985278 Escherichia coli 5-carboxymethyl-2-hydroxymuconate Delta-isomerase Proteins 0.000 description 2
CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
102100040448 Leukocyte cell-derived chemotaxin 1 Human genes 0.000 description 2
BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
229910019142 PO4 Inorganic materials 0.000 description 2
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
241000721454 Pemphigus Species 0.000 description 2
GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
210000001744 T-lymphocyte Anatomy 0.000 description 2
230000002378 acidificating effect Effects 0.000 description 2
239000004480 active ingredient Substances 0.000 description 2
230000001154 acute effect Effects 0.000 description 2
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229910052783 alkali metal Inorganic materials 0.000 description 2
230000000172 allergic effect Effects 0.000 description 2
208000006673 asthma Diseases 0.000 description 2
239000012298 atmosphere Substances 0.000 description 2
HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 2
239000012267 brine Substances 0.000 description 2
150000001732 carboxylic acid derivatives Chemical group 0.000 description 2
230000003197 catalytic effect Effects 0.000 description 2
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
238000010790 dilution Methods 0.000 description 2
239000012895 dilution Substances 0.000 description 2
150000002148 esters Chemical class 0.000 description 2
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
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230000007062 hydrolysis Effects 0.000 description 2
238000006460 hydrolysis reaction Methods 0.000 description 2
150000007529 inorganic bases Chemical class 0.000 description 2
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
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229910052708 sodium Inorganic materials 0.000 description 2
239000011734 sodium Substances 0.000 description 2
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239000000126 substance Substances 0.000 description 2
238000012360 testing method Methods 0.000 description 2
238000004809 thin layer chromatography Methods 0.000 description 2
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
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GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
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