OA10639A - C-4' modified adenosine kinase inhibitors - Google Patents

Info

Publication number

OA10639A

OA10639A OA70150A OA70150A OA10639A OA 10639 A OA10639 A OA 10639A OA 70150 A OA70150 A OA 70150A OA 70150 A OA70150 A OA 70150A OA 10639 A OA10639 A OA 10639A

Authority

OA

OAPI

Prior art keywords

compound

phenyl

amino

guanidino

optionally

Prior art date

1995-06-07

Links

• Espacenet
• Global Dossier
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• 239000003121 adenosine kinase inhibitor Substances 0.000 title abstract description 13
• OOXNYFKPOPJIOT-UHFFFAOYSA-N 5-(3-bromophenyl)-7-(6-morpholin-4-ylpyridin-3-yl)pyrido[2,3-d]pyrimidin-4-amine;dihydrochloride Chemical class Cl.Cl.C=12C(N)=NC=NC2=NC(C=2C=NC(=CC=2)N2CCOCC2)=CC=1C1=CC=CC(Br)=C1 OOXNYFKPOPJIOT-UHFFFAOYSA-N 0.000 title description 16
• QUKPALAWEPMWOS-UHFFFAOYSA-N 1h-pyrazolo[3,4-d]pyrimidine Chemical compound C1=NC=C2C=NNC2=N1 QUKPALAWEPMWOS-UHFFFAOYSA-N 0.000 claims abstract description 5
• 150000001875 compounds Chemical class 0.000 claims description 341
• -1 aralkylami.no Chemical group 0.000 claims description 292
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 104
• 125000000217 alkyl group Chemical group 0.000 claims description 69
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 68
• 229910052739 hydrogen Inorganic materials 0.000 claims description 49
• 239000001257 hydrogen Substances 0.000 claims description 49
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 47
• 229910052757 nitrogen Chemical group 0.000 claims description 40
• 125000003118 aryl group Chemical group 0.000 claims description 37
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 32
• 229910052736 halogen Chemical group 0.000 claims description 31
• 150000002367 halogens Chemical group 0.000 claims description 31
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 27
• 125000003545 alkoxy group Chemical group 0.000 claims description 27
• 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 27
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
• 229910052720 vanadium Inorganic materials 0.000 claims description 22
• 125000005518 carboxamido group Chemical group 0.000 claims description 20
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 20
• 125000005842 heteroatom Chemical group 0.000 claims description 19
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
• 125000001769 aryl amino group Chemical group 0.000 claims description 16
• 125000004432 carbon atom Chemical group C* 0.000 claims description 16
• 125000001424 substituent group Chemical group 0.000 claims description 14
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 13
• 229910052760 oxygen Inorganic materials 0.000 claims description 13
• 239000001301 oxygen Substances 0.000 claims description 13
• 125000004122 cyclic group Chemical group 0.000 claims description 11
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
• 125000004429 atom Chemical group 0.000 claims description 10
• 229910052799 carbon Inorganic materials 0.000 claims description 10
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 8
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 8
• 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 8
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 8
• 125000003282 alkyl amino group Chemical group 0.000 claims description 7
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
• 125000003342 alkenyl group Chemical group 0.000 claims description 6
• 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 6
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
• 229910052717 sulfur Inorganic materials 0.000 claims description 6
• 239000011593 sulfur Chemical group 0.000 claims description 6
• 125000002252 acyl group Chemical group 0.000 claims description 4
• 125000002723 alicyclic group Chemical group 0.000 claims description 4
• 125000004414 alkyl thio group Chemical group 0.000 claims description 3
• 125000000304 alkynyl group Chemical group 0.000 claims description 3
• 150000003839 salts Chemical class 0.000 claims description 3
• 125000004659 aryl alkyl thio group Chemical group 0.000 claims description 2
• 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 2
• 125000005110 aryl thio group Chemical group 0.000 claims description 2
• 125000004104 aryloxy group Chemical group 0.000 claims description 2
• 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 2
• 150000005676 cyclic carbonates Chemical class 0.000 claims description 2
• 125000001188 haloalkyl group Chemical group 0.000 claims description 2
• SGPGESCZOCHFCL-UHFFFAOYSA-N Tilisolol hydrochloride Chemical compound [Cl-].C1=CC=C2C(=O)N(C)C=C(OCC(O)C[NH2+]C(C)(C)C)C2=C1 SGPGESCZOCHFCL-UHFFFAOYSA-N 0.000 claims 8
• 150000002431 hydrogen Chemical class 0.000 claims 7
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 5
• ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims 4
• 125000004663 dialkyl amino group Chemical group 0.000 claims 3
• CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims 2
• SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims 2
• QGZKDVFQNNGYKY-OUBTZVSYSA-N Ammonia-15N Chemical compound [15NH3] QGZKDVFQNNGYKY-OUBTZVSYSA-N 0.000 claims 1
• OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 abstract description 55
• 239000002777 nucleoside Substances 0.000 abstract description 36
• 239000002126 C01EB10 - Adenosine Substances 0.000 abstract description 27
• 229960005305 adenosine Drugs 0.000 abstract description 27
• 150000003833 nucleoside derivatives Chemical class 0.000 abstract description 27
• 230000000694 effects Effects 0.000 abstract description 25
• 238000011282 treatment Methods 0.000 abstract description 25
• 239000002718 pyrimidine nucleoside Substances 0.000 abstract description 19
• 230000001965 increasing effect Effects 0.000 abstract description 9
• 238000006467 substitution reaction Methods 0.000 abstract description 8
• 235000000346 sugar Nutrition 0.000 abstract description 6
• 201000010099 disease Diseases 0.000 abstract description 4
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 4
• 230000004054 inflammatory process Effects 0.000 abstract description 4
• 206010061218 Inflammation Diseases 0.000 abstract description 3
• 230000002526 effect on cardiovascular system Effects 0.000 abstract description 3
• 125000003843 furanosyl group Chemical group 0.000 abstract description 3
• 238000002360 preparation method Methods 0.000 abstract description 3
• 208000024172 Cardiovascular disease Diseases 0.000 abstract description 2
• 208000026106 cerebrovascular disease Diseases 0.000 abstract description 2
• 150000004943 pyrrolo[2,3-d]pyrimidines Chemical class 0.000 abstract description 2
• 230000001105 regulatory effect Effects 0.000 abstract description 2
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 258
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 162
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 152
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 148
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 122
• 238000000034 method Methods 0.000 description 90
• 229940093499 ethyl acetate Drugs 0.000 description 86
• 235000019439 ethyl acetate Nutrition 0.000 description 86
• 239000000741 silica gel Substances 0.000 description 61
• 229910002027 silica gel Inorganic materials 0.000 description 61
• 229960001866 silicon dioxide Drugs 0.000 description 61
• 239000000243 solution Substances 0.000 description 57
• 239000000203 mixture Substances 0.000 description 53
• 230000015572 biosynthetic process Effects 0.000 description 43
• 239000000377 silicon dioxide Substances 0.000 description 41
• 238000003786 synthesis reaction Methods 0.000 description 41
• 230000002829 reductive effect Effects 0.000 description 40
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
• 239000011541 reaction mixture Substances 0.000 description 29
• CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 28
• 229920006395 saturated elastomer Polymers 0.000 description 28
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 27
• 238000003818 flash chromatography Methods 0.000 description 25
• JJTNLWSCFYERCK-UHFFFAOYSA-N 7h-pyrrolo[2,3-d]pyrimidine Chemical compound N1=CN=C2NC=CC2=C1 JJTNLWSCFYERCK-UHFFFAOYSA-N 0.000 description 23
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 23
• 230000005764 inhibitory process Effects 0.000 description 23
• 238000003756 stirring Methods 0.000 description 23
• 150000001720 carbohydrates Chemical class 0.000 description 22
• 235000014633 carbohydrates Nutrition 0.000 description 22
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
• 238000007912 intraperitoneal administration Methods 0.000 description 21
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
• 229960003010 sodium sulfate Drugs 0.000 description 20
• 229910052938 sodium sulfate Inorganic materials 0.000 description 20
• 235000011152 sodium sulphate Nutrition 0.000 description 20
• 241000700159 Rattus Species 0.000 description 19
• 238000005859 coupling reaction Methods 0.000 description 19
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
• 230000008878 coupling Effects 0.000 description 18
• 238000010168 coupling process Methods 0.000 description 18
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 17
• 238000010511 deprotection reaction Methods 0.000 description 17
• 235000002639 sodium chloride Nutrition 0.000 description 17
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
• 210000002683 foot Anatomy 0.000 description 16
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
• 108010076278 Adenosine kinase Proteins 0.000 description 15
• 102100032534 Adenosine kinase Human genes 0.000 description 15
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 15
• 239000011780 sodium chloride Substances 0.000 description 15
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 14
• 239000012044 organic layer Substances 0.000 description 14
• 125000000623 heterocyclic group Chemical group 0.000 description 13
• 206010010904 Convulsion Diseases 0.000 description 12
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
• 238000006243 chemical reaction Methods 0.000 description 12
• 239000003112 inhibitor Substances 0.000 description 12
• 229960002668 sodium chloride Drugs 0.000 description 12
• 239000000725 suspension Substances 0.000 description 11
• 239000002253 acid Substances 0.000 description 10
• 150000001412 amines Chemical class 0.000 description 10
• 239000002585 base Substances 0.000 description 10
• 239000003795 chemical substances by application Substances 0.000 description 10
• 238000002347 injection Methods 0.000 description 10
• 239000007924 injection Substances 0.000 description 10
• 239000003921 oil Substances 0.000 description 10
• 239000003981 vehicle Substances 0.000 description 10
• WHSIXKUPQCKWBY-IOSLPCCCSA-N 5-iodotubercidin Chemical compound C1=C(I)C=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O WHSIXKUPQCKWBY-IOSLPCCCSA-N 0.000 description 9
• 208000002193 Pain Diseases 0.000 description 9
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
• 210000004027 cell Anatomy 0.000 description 9
• 238000009472 formulation Methods 0.000 description 9
• 229940043355 kinase inhibitor Drugs 0.000 description 9
• 235000019198 oils Nutrition 0.000 description 9
• 239000003757 phosphotransferase inhibitor Substances 0.000 description 9
• 125000006239 protecting group Chemical group 0.000 description 9
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
• 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 8
• 229960001040 ammonium chloride Drugs 0.000 description 8
• 235000019270 ammonium chloride Nutrition 0.000 description 8
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 8
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• 150000004944 pyrrolopyrimidines Chemical group 0.000 description 8
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• 229910052708 sodium Inorganic materials 0.000 description 8
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• HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 6
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• 210000003169 central nervous system Anatomy 0.000 description 6
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• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
• UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 6
• XGLVDUUYFKXKPL-UHFFFAOYSA-N 2-(2-methoxyethoxy)-n,n-bis[2-(2-methoxyethoxy)ethyl]ethanamine Chemical compound COCCOCCN(CCOCCOC)CCOCCOC XGLVDUUYFKXKPL-UHFFFAOYSA-N 0.000 description 5
• 101710169336 5'-deoxyadenosine deaminase Proteins 0.000 description 5
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• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
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• VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 5
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• VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
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• 239000007864 aqueous solution Substances 0.000 description 4
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