UA68383C2

UA68383C2 - Phthalazine derivatives and pharmaceutical compositions

Phthalazine derivatives and pharmaceutical compositions Download PDF

Info

Publication number: UA68383C2
Authority: UA; Ukraine
Prior art keywords: methoxy; mmol; compound; methyl; dichloropyridin
Prior art date: 1998-07-21

Application number

UA2001010439A

Other languages

English (en)

Ukrainian (uk)

Original Assignee

Zambon Spa

Priority date

1998-07-21

Filing date

1999-07-13

Publication date

2004-08-16

1999-07-13 Application filed by Zambon Spa filed Critical Zambon Spa

2004-08-16 Publication of UA68383C2 publication Critical patent/UA68383C2/uk

Links

239000008194 pharmaceutical composition Substances 0.000 title claims description 8
LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical class C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 title description 10
150000001875 compounds Chemical class 0.000 claims abstract description 281
-1 nitro, carboxy groups Chemical group 0.000 claims abstract description 47
125000000623 heterocyclic group Chemical group 0.000 claims abstract description 34
239000001257 hydrogen Substances 0.000 claims abstract description 34
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 34
125000003118 aryl group Chemical group 0.000 claims abstract description 22
125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 16
125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 14
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 12
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims abstract description 11
150000003839 salts Chemical class 0.000 claims abstract description 10
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 9
125000001424 substituent group Chemical group 0.000 claims abstract description 9
125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 8
125000005843 halogen group Chemical group 0.000 claims abstract description 7
125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 6
125000005842 heteroatom Chemical group 0.000 claims abstract description 6
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 6
125000003282 alkyl amino group Chemical group 0.000 claims abstract description 5
125000003368 amide group Chemical group 0.000 claims abstract description 5
125000001769 aryl amino group Chemical group 0.000 claims abstract description 5
125000004104 aryloxy group Chemical group 0.000 claims abstract description 5
125000004043 oxo group Chemical group O=* 0.000 claims abstract description 5
125000003107 substituted aryl group Chemical group 0.000 claims abstract description 5
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 4
125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 4
125000005844 heterocyclyloxy group Chemical group 0.000 claims abstract description 4
125000000217 alkyl group Chemical group 0.000 claims description 28
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
125000003545 alkoxy group Chemical group 0.000 claims description 12
125000002947 alkylene group Chemical group 0.000 claims description 10
238000011282 treatment Methods 0.000 claims description 10
125000003342 alkenyl group Chemical group 0.000 claims description 8
125000000304 alkynyl group Chemical group 0.000 claims description 8
230000000172 allergic effect Effects 0.000 claims description 6
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
229910052740 iodine Inorganic materials 0.000 claims description 5
208000027866 inflammatory disease Diseases 0.000 claims description 3
208000023504 respiratory system disease Diseases 0.000 claims description 3
HMTGPYRFOCPERJ-UHFFFAOYSA-N 1-[(3,5-dichloropyridin-4-yl)methyl]-6-methoxy-4-phenylphthalazine Chemical compound N=1N=C(C=2C=CC=CC=2)C2=CC(OC)=CC=C2C=1CC1=C(Cl)C=NC=C1Cl HMTGPYRFOCPERJ-UHFFFAOYSA-N 0.000 claims description 2
RQKYYWBMXHYBAP-UHFFFAOYSA-N 4-(chloromethyl)-2,2-dimethyl-1,3,2-dioxasilolane Chemical group C[Si]1(C)OCC(CCl)O1 RQKYYWBMXHYBAP-UHFFFAOYSA-N 0.000 claims description 2
125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
208000026935 allergic disease Diseases 0.000 claims description 2
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
125000004076 pyridyl group Chemical group 0.000 claims description 2
NBNCEZNBWYPDFB-UHFFFAOYSA-N 4-[4-[(3,5-dichloropyridin-4-yl)methyl]-7-methoxyphthalazin-1-yl]morpholine Chemical compound N=1N=C(N2CCOCC2)C2=CC(OC)=CC=C2C=1CC1=C(Cl)C=NC=C1Cl NBNCEZNBWYPDFB-UHFFFAOYSA-N 0.000 claims 1
101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 claims 1
125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 claims 1
150000004702 methyl esters Chemical class 0.000 claims 1
238000012876 topography Methods 0.000 claims 1
125000003277 amino group Chemical group 0.000 abstract description 3
125000004209 (C1-C8) alkyl group Chemical group 0.000 abstract description 2
239000002587 phosphodiesterase IV inhibitor Substances 0.000 abstract description 2
125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 2
125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 2
125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 2
125000004649 C2-C8 alkynyl group Chemical group 0.000 abstract 2
125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 abstract 1
125000004648 C2-C8 alkenyl group Chemical group 0.000 abstract 1
101100134922 Gallus gallus COR5 gene Proteins 0.000 abstract 1
229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 abstract 1
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 243
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 180
239000000203 mixture Substances 0.000 description 175
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 141
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 138
239000000243 solution Substances 0.000 description 112
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 84
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 78
239000007787 solid Substances 0.000 description 73
238000002844 melting Methods 0.000 description 70
230000008018 melting Effects 0.000 description 70
239000012074 organic phase Substances 0.000 description 66
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 65
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 54
239000003480 eluent Substances 0.000 description 50
238000010992 reflux Methods 0.000 description 48
238000004809 thin layer chromatography Methods 0.000 description 47
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 44
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 42
239000000725 suspension Substances 0.000 description 41
238000003756 stirring Methods 0.000 description 32
239000004264 Petrolatum Substances 0.000 description 25
235000019271 petrolatum Nutrition 0.000 description 25
229940066842 petrolatum Drugs 0.000 description 25
IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 24
229960000583 acetic acid Drugs 0.000 description 23
238000000034 method Methods 0.000 description 20
239000003921 oil Substances 0.000 description 20
229910052700 potassium Inorganic materials 0.000 description 20
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
239000003610 charcoal Substances 0.000 description 18
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
239000000126 substance Substances 0.000 description 16
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 15
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
238000002156 mixing Methods 0.000 description 15
239000002244 precipitate Substances 0.000 description 15
239000000047 product Substances 0.000 description 15
INJOULQGSUBQJR-UHFFFAOYSA-N 4-[(3,5-dichloropyridin-4-yl)methyl]-7-methoxy-1,2-dihydrophthalazine Chemical compound N=1NCC2=CC(OC)=CC=C2C=1CC1=C(Cl)C=NC=C1Cl INJOULQGSUBQJR-UHFFFAOYSA-N 0.000 description 14
238000006243 chemical reaction Methods 0.000 description 13
102000004190 Enzymes Human genes 0.000 description 12
108090000790 Enzymes Proteins 0.000 description 12
YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 12
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
150000002431 hydrogen Chemical class 0.000 description 12
210000004027 cell Anatomy 0.000 description 11
MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 11
YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 11
OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 10
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
239000008346 aqueous phase Substances 0.000 description 10
238000004821 distillation Methods 0.000 description 10
LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 9
239000012359 Methanesulfonyl chloride Substances 0.000 description 9
239000002253 acid Substances 0.000 description 9
230000000694 effects Effects 0.000 description 9
QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 9
210000001616 monocyte Anatomy 0.000 description 9
239000012071 phase Substances 0.000 description 9
239000000843 powder Substances 0.000 description 9
FZNLULCNCVCWKJ-UHFFFAOYSA-N 1-[(3,5-dichloropyridin-4-yl)methyl]-4-ethyl-6-methoxyphthalazine Chemical compound C12=CC=C(OC)C=C2C(CC)=NN=C1CC1=C(Cl)C=NC=C1Cl FZNLULCNCVCWKJ-UHFFFAOYSA-N 0.000 description 8
YBHYECGRNFZJPC-UHFFFAOYSA-N 3,5-dichloro-4-methylpyridine Chemical compound CC1=C(Cl)C=NC=C1Cl YBHYECGRNFZJPC-UHFFFAOYSA-N 0.000 description 8
101100237844 Mus musculus Mmp19 gene Proteins 0.000 description 8
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
238000000354 decomposition reaction Methods 0.000 description 8
XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
239000011734 sodium Substances 0.000 description 8
RPQKQQJAHJDVOD-UHFFFAOYSA-N 4-chloro-1-[(3,5-dichloropyridin-4-yl)methyl]-6-methoxyphthalazine Chemical compound N=1N=C(Cl)C2=CC(OC)=CC=C2C=1CC1=C(Cl)C=NC=C1Cl RPQKQQJAHJDVOD-UHFFFAOYSA-N 0.000 description 7
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
239000003054 catalyst Substances 0.000 description 7
HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 7
239000003112 inhibitor Substances 0.000 description 7
230000005764 inhibitory process Effects 0.000 description 7
230000008569 process Effects 0.000 description 7
239000002994 raw material Substances 0.000 description 7
ZYKKSNKZEXNOLS-UHFFFAOYSA-N 4-[(3,5-dichloropyridin-4-yl)methyl]-7-methoxy-2h-phthalazin-1-one Chemical compound N=1NC(=O)C2=CC(OC)=CC=C2C=1CC1=C(Cl)C=NC=C1Cl ZYKKSNKZEXNOLS-UHFFFAOYSA-N 0.000 description 6
LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
101000939500 Homo sapiens UBX domain-containing protein 11 Proteins 0.000 description 6
WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 6
XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 6
102100029645 UBX domain-containing protein 11 Human genes 0.000 description 6
208000006673 asthma Diseases 0.000 description 6
230000003197 catalytic effect Effects 0.000 description 6
CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 6
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
238000011534 incubation Methods 0.000 description 6
238000001953 recrystallisation Methods 0.000 description 6
230000002829 reductive effect Effects 0.000 description 6
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
HGSCIJVKEUKATE-UHFFFAOYSA-M (5-methoxy-3-oxo-1h-2-benzofuran-1-yl)-triphenylphosphanium;bromide Chemical compound [Br-].O1C(=O)C2=CC(OC)=CC=C2C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 HGSCIJVKEUKATE-UHFFFAOYSA-M 0.000 description 5
HQVCWVGSZXODRW-UHFFFAOYSA-N 2-(4-methoxyphenyl)-4,4-dimethyl-5h-1,3-oxazole Chemical compound C1=CC(OC)=CC=C1C1=NC(C)(C)CO1 HQVCWVGSZXODRW-UHFFFAOYSA-N 0.000 description 5
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 5
102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 5
108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 5
238000004458 analytical method Methods 0.000 description 5
230000015572 biosynthetic process Effects 0.000 description 5
239000000872 buffer Substances 0.000 description 5
229910052799 carbon Inorganic materials 0.000 description 5
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 5
238000001035 drying Methods 0.000 description 5
OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 5
230000007170 pathology Effects 0.000 description 5
229920006395 saturated elastomer Polymers 0.000 description 5
229910052708 sodium Inorganic materials 0.000 description 5
239000011780 sodium chloride Substances 0.000 description 5
RXNZFHIEDZEUQM-UHFFFAOYSA-N 2-bromo-1,3-thiazole Chemical compound BrC1=NC=CS1 RXNZFHIEDZEUQM-UHFFFAOYSA-N 0.000 description 4
ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 4
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
229910020163 SiOCl Inorganic materials 0.000 description 4
239000007983 Tris buffer Substances 0.000 description 4
125000003710 aryl alkyl group Chemical group 0.000 description 4
208000010668 atopic eczema Diseases 0.000 description 4
239000000969 carrier Substances 0.000 description 4
238000004587 chromatography analysis Methods 0.000 description 4
238000010438 heat treatment Methods 0.000 description 4
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
210000004493 neutrocyte Anatomy 0.000 description 4
229910052763 palladium Inorganic materials 0.000 description 4
YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 4
UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
238000003786 synthesis reaction Methods 0.000 description 4
ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 4
WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 4
LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 description 3
VVCMGAUPZIKYTH-VGHSCWAPSA-N 2-acetyloxybenzoic acid;[(2s,3r)-4-(dimethylamino)-3-methyl-1,2-diphenylbutan-2-yl] propanoate;1,3,7-trimethylpurine-2,6-dione Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O.CN1C(=O)N(C)C(=O)C2=C1N=CN2C.C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 VVCMGAUPZIKYTH-VGHSCWAPSA-N 0.000 description 3
108010044467 Isoenzymes Proteins 0.000 description 3
AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 3
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
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CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
WMKHZHSMSFKWAQ-UHFFFAOYSA-M [5-(difluoromethoxy)-3-oxo-1h-2-benzofuran-1-yl]-triphenylphosphanium;bromide Chemical compound [Br-].O1C(=O)C2=CC(OC(F)F)=CC=C2C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 WMKHZHSMSFKWAQ-UHFFFAOYSA-M 0.000 description 3
230000004913 activation Effects 0.000 description 3
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
150000001721 carbon Chemical group 0.000 description 3
238000005119 centrifugation Methods 0.000 description 3
239000003795 chemical substances by application Substances 0.000 description 3
238000004090 dissolution Methods 0.000 description 3
239000003814 drug Substances 0.000 description 3
150000002148 esters Chemical class 0.000 description 3
239000000284 extract Substances 0.000 description 3
230000003311 flocculating effect Effects 0.000 description 3
125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
239000008187 granular material Substances 0.000 description 3
229910052736 halogen Inorganic materials 0.000 description 3
150000002367 halogens Chemical group 0.000 description 3
125000001072 heteroaryl group Chemical group 0.000 description 3
238000005984 hydrogenation reaction Methods 0.000 description 3
230000002401 inhibitory effect Effects 0.000 description 3
229940072033 potash Drugs 0.000 description 3
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
235000015320 potassium carbonate Nutrition 0.000 description 3
239000011541 reaction mixture Substances 0.000 description 3
239000001632 sodium acetate Substances 0.000 description 3
235000017281 sodium acetate Nutrition 0.000 description 3
239000002904 solvent Substances 0.000 description 3
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