MXPA00005846A - Bicyclic derivatives of amino-pyrazinones, process of preparation and pharmaceutical compositions comprising them - Google Patents
Bicyclic derivatives of amino-pyrazinones, process of preparation and pharmaceutical compositions comprising themInfo
- Publication number
- MXPA00005846A MXPA00005846A MXPA/A/2000/005846A MXPA00005846A MXPA00005846A MX PA00005846 A MXPA00005846 A MX PA00005846A MX PA00005846 A MXPA00005846 A MX PA00005846A MX PA00005846 A MXPA00005846 A MX PA00005846A
- Authority
- MX
- Mexico
- Prior art keywords
- methyl
- branched
- pyridyl
- amino
- linear
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 136
- 238000002360 preparation method Methods 0.000 title claims description 127
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 9
- 125000002619 bicyclic group Chemical group 0.000 title claims description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 291
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 28
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 14
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 11
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims abstract description 10
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 8
- 239000011780 sodium chloride Substances 0.000 claims abstract description 8
- 238000007792 addition Methods 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 6
- 239000001301 oxygen Substances 0.000 claims abstract description 5
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims abstract description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000005418 aryl aryl group Chemical group 0.000 claims abstract description 4
- 239000001257 hydrogen Substances 0.000 claims abstract description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract 2
- -1 carboxymethoxy Chemical group 0.000 claims description 245
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 109
- 125000000217 alkyl group Chemical group 0.000 claims description 55
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 34
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- 125000004385 trihaloalkyl group Chemical group 0.000 claims description 11
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 108010022999 Serine Proteases Proteins 0.000 claims description 8
- 102000012479 Serine Proteases Human genes 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- CTSLXHKWHWQRSH-UHFFFAOYSA-N Oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 6
- 125000005842 heteroatoms Chemical group 0.000 claims description 6
- 125000002950 monocyclic group Chemical group 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 229910052786 argon Inorganic materials 0.000 claims description 5
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 4
- 238000010511 deprotection reaction Methods 0.000 claims description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
- 150000002829 nitrogen Chemical group 0.000 claims description 4
- 239000011593 sulfur Substances 0.000 claims description 4
- 150000001204 N-oxides Chemical class 0.000 claims description 3
- 235000010290 biphenyl Nutrition 0.000 claims description 3
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N oxygen atom Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 125000004434 sulfur atoms Chemical group 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 150000002430 hydrocarbons Chemical group 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 230000003000 nontoxic Effects 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000001681 protective Effects 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 230000002829 reduced Effects 0.000 claims description 2
- 239000003638 reducing agent Substances 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 239000003868 thrombin inhibitor Substances 0.000 claims description 2
- 101710006356 ACTI Proteins 0.000 claims 1
- 101700046715 CSTI Proteins 0.000 claims 1
- 101700020566 DEFA4 Proteins 0.000 claims 1
- 101710006353 IP3R Proteins 0.000 claims 1
- 101700035656 ISOTI Proteins 0.000 claims 1
- 101700035039 ITI Proteins 0.000 claims 1
- 101700052013 ITR2 Proteins 0.000 claims 1
- 101700068039 ITRP Proteins 0.000 claims 1
- 101700036939 MTI Proteins 0.000 claims 1
- 101700006801 THBI Proteins 0.000 claims 1
- 101700062451 TI Proteins 0.000 claims 1
- 125000004429 atoms Chemical group 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 claims 1
- 125000006448 cycloalkyl cycloalkyl group Chemical group 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000002753 trypsin inhibitor Substances 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract description 2
- 239000005864 Sulphur Substances 0.000 abstract 1
- 125000000547 substituted alkyl group Chemical group 0.000 abstract 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 abstract 1
- 239000000047 product Substances 0.000 description 140
- IPEHBUMCGVEMRF-UHFFFAOYSA-N Pyrazinamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 description 98
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 28
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 25
- 238000004452 microanalysis Methods 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
- 238000003756 stirring Methods 0.000 description 15
- 125000000579 2,2-diphenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(C1=C([H])C([H])=C([H])C([H])=C1[H])C([H])([H])* 0.000 description 13
- NKCXQMYPWXSLIZ-PSRDDEIFSA-N (2S)-2-[[(2S)-1-[(2S)-5-amino-2-[[2-[[(2S)-6-amino-2-[[2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3R)-2-amino-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-hydroxybutanoyl]amino]propanoyl]amino]-4-oxobutanoyl]amino]-3-m Chemical compound O=C([C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](N)[C@@H](C)O)[C@@H](C)O)C(C)C)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O NKCXQMYPWXSLIZ-PSRDDEIFSA-N 0.000 description 12
- RXMTUVIKZRXSSM-UHFFFAOYSA-N 2,2-diphenylethanamine Chemical compound C=1C=CC=CC=1C(CN)C1=CC=CC=C1 RXMTUVIKZRXSSM-UHFFFAOYSA-N 0.000 description 12
- 108090000190 Thrombin Proteins 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 229960004072 thrombin Drugs 0.000 description 12
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 230000002401 inhibitory effect Effects 0.000 description 10
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 9
- 230000015271 coagulation Effects 0.000 description 8
- 238000005345 coagulation Methods 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- XPQIPUZPSLAZDV-UHFFFAOYSA-N 2-Pyridylethylamine Chemical compound NCCC1=CC=CC=N1 XPQIPUZPSLAZDV-UHFFFAOYSA-N 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- BHHGXPLMPWCGHP-UHFFFAOYSA-N 2-Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 5
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 5
- VKERTPNDMRKZOJ-UHFFFAOYSA-N C1=C2N(CC=N1)C(CC2)C(=O)N Chemical compound C1=C2N(CC=N1)C(CC2)C(=O)N VKERTPNDMRKZOJ-UHFFFAOYSA-N 0.000 description 5
- 230000035492 administration Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- QUSNBJAOOMFDIB-UHFFFAOYSA-N ethyl amine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 5
- 230000000670 limiting Effects 0.000 description 5
- NJGIRBISCGPRPF-KXQOOQHDSA-N (2-aminoethoxy)[(2R)-2-(icosanoyloxy)-3-(pentadecanoyloxy)propoxy]phosphinic acid Chemical class CCCCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP(O)(=O)OCCN)COC(=O)CCCCCCCCCCCCCC NJGIRBISCGPRPF-KXQOOQHDSA-N 0.000 description 4
- UDHUGYDZHFRCQT-UHFFFAOYSA-N 4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrazine-6-carboxamide Chemical compound N1=CC(=O)N2C(C(=O)N)CCC2=C1 UDHUGYDZHFRCQT-UHFFFAOYSA-N 0.000 description 4
- 241000282472 Canis lupus familiaris Species 0.000 description 4
- 210000002381 Plasma Anatomy 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- XINQFOMFQFGGCQ-UHFFFAOYSA-L (2-dodecoxy-2-oxoethyl)-[6-[(2-dodecoxy-2-oxoethyl)-dimethylazaniumyl]hexyl]-dimethylazanium;dichloride Chemical compound [Cl-].[Cl-].CCCCCCCCCCCCOC(=O)C[N+](C)(C)CCCCCC[N+](C)(C)CC(=O)OCCCCCCCCCCCC XINQFOMFQFGGCQ-UHFFFAOYSA-L 0.000 description 3
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 230000020764 fibrinolysis Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000014508 negative regulation of coagulation Effects 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
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- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VVTAUYUSSABNDB-UHFFFAOYSA-N 2,2-bis(4-methoxyphenyl)ethanamine Chemical compound C1=CC(OC)=CC=C1C(CN)C1=CC=C(OC)C=C1 VVTAUYUSSABNDB-UHFFFAOYSA-N 0.000 description 2
- TZQSMONSZJBUQN-UHFFFAOYSA-N 2-[2-(aminomethyl)phenoxy]-N-ethylacetamide Chemical compound CCNC(=O)COC1=CC=CC=C1CN TZQSMONSZJBUQN-UHFFFAOYSA-N 0.000 description 2
- CHZCERSEMVWNHL-UHFFFAOYSA-N 2-hydroxybenzonitrile Chemical compound OC1=CC=CC=C1C#N CHZCERSEMVWNHL-UHFFFAOYSA-N 0.000 description 2
- 206010003178 Arterial thrombosis Diseases 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Carbodicyclohexylimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N Di-tert-butyl dicarbonate Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
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- JFCQEDHGNNZCLN-UHFFFAOYSA-N Glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 229940012957 Plasmin Drugs 0.000 description 2
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- 102000004142 Trypsin Human genes 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- NVKOCDGGRHAHOJ-JTQLQIEISA-N benzyl (2S)-5-oxopyrrolidine-2-carboxylate Chemical compound O=C([C@H]1NC(=O)CC1)OCC1=CC=CC=C1 NVKOCDGGRHAHOJ-JTQLQIEISA-N 0.000 description 2
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- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
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- 238000005259 measurement Methods 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
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- WLKLGOLBAFYVMP-LBPRGKRZSA-N (2R)-2-(2,4-difluorophenyl)-2-(5-methylpyridin-2-yl)ethanamine Chemical compound N1=CC(C)=CC=C1[C@@H](CN)C1=CC=C(F)C=C1F WLKLGOLBAFYVMP-LBPRGKRZSA-N 0.000 description 1
- NBZLAKQOSOGBFJ-HNNXBMFYSA-N (2R)-2-(2,4-dimethylphenyl)-2-(5-ethylpyrimidin-2-yl)ethanamine Chemical compound N1=CC(CC)=CN=C1[C@@H](CN)C1=CC=C(C)C=C1C NBZLAKQOSOGBFJ-HNNXBMFYSA-N 0.000 description 1
- JLSDOWMWXWOBSI-AWEZNQCLSA-N (2R)-2-(2,4-dimethylphenyl)-2-pyridin-2-ylethanamine Chemical compound CC1=CC(C)=CC=C1[C@H](CN)C1=CC=CC=N1 JLSDOWMWXWOBSI-AWEZNQCLSA-N 0.000 description 1
- SSGKYOTYXSUGSK-HNNXBMFYSA-N (2R)-2-(3,4-dimethylphenyl)-2-(5-methoxypyridin-2-yl)ethanamine Chemical compound N1=CC(OC)=CC=C1[C@@H](CN)C1=CC=C(C)C(C)=C1 SSGKYOTYXSUGSK-HNNXBMFYSA-N 0.000 description 1
- RAJYYTMVGFYOET-AWEZNQCLSA-N (2R)-2-(3,4-dimethylphenyl)-2-pyridin-2-ylethanamine Chemical compound C1=C(C)C(C)=CC=C1[C@H](CN)C1=CC=CC=N1 RAJYYTMVGFYOET-AWEZNQCLSA-N 0.000 description 1
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- MNQKINGOWYEPKC-UHFFFAOYSA-N N-methyl-5,10-dihydrobenzo[g]quinolin-10-amine Chemical compound C1=CN=C2C(NC)C3=CC=CC=C3CC2=C1 MNQKINGOWYEPKC-UHFFFAOYSA-N 0.000 description 1
- LQOWTJDHANBMLR-UHFFFAOYSA-N N-methyl-6,11-dihydro-5H-benzo[1,2]cyclohepta[3,4-b]pyridin-11-amine Chemical compound C1CC2=CC=CN=C2C(NC)C2=CC=CC=C21 LQOWTJDHANBMLR-UHFFFAOYSA-N 0.000 description 1
- RVHJBKOGAORLRZ-UHFFFAOYSA-N N-methyl-9,10-dihydroanthracen-9-amine Chemical compound C1=CC=C2C(NC)C3=CC=CC=C3CC2=C1 RVHJBKOGAORLRZ-UHFFFAOYSA-N 0.000 description 1
- VMSWKZSHYGFUPI-UHFFFAOYSA-N N-methyl-9H-fluoren-9-amine Chemical compound C1=CC=C2C(NC)C3=CC=CC=C3C2=C1 VMSWKZSHYGFUPI-UHFFFAOYSA-N 0.000 description 1
- FOEIFDIMFMXWFJ-UHFFFAOYSA-N N-methyl-9H-thioxanthen-9-amine Chemical compound C1=CC=C2C(NC)C3=CC=CC=C3SC2=C1 FOEIFDIMFMXWFJ-UHFFFAOYSA-N 0.000 description 1
- QSNPASFCZRWXNQ-UHFFFAOYSA-N N-methyl-9H-xanthen-9-amine Chemical compound C1=CC=C2C(NC)C3=CC=CC=C3OC2=C1 QSNPASFCZRWXNQ-UHFFFAOYSA-N 0.000 description 1
- VZPARYCEMVNANR-UHFFFAOYSA-N N1=C2C(=CC=C1)C=1C=CC=CC=1C2NC Chemical compound N1=C2C(=CC=C1)C=1C=CC=CC=1C2NC VZPARYCEMVNANR-UHFFFAOYSA-N 0.000 description 1
- BGMLBAAZDMGRCO-LBPRGKRZSA-N O=C([C@H]1NC(=O)CCCC1)OCC1=CC=CC=C1 Chemical compound O=C([C@H]1NC(=O)CCCC1)OCC1=CC=CC=C1 BGMLBAAZDMGRCO-LBPRGKRZSA-N 0.000 description 1
- 229940116315 Oxalic Acid Drugs 0.000 description 1
- XAPRFLSJBSXESP-UHFFFAOYSA-N Oxycinchophen Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=C(O)C=1C1=CC=CC=C1 XAPRFLSJBSXESP-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- 240000005373 Panax quinquefolius Species 0.000 description 1
- 231100000614 Poison Toxicity 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N Propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
- 229940107700 Pyruvic Acid Drugs 0.000 description 1
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- MNWBNISUBARLIT-UHFFFAOYSA-N Sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- 208000007718 Stable Angina Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 101710029702 TICAM1 Proteins 0.000 description 1
- 101710021425 TRIM69 Proteins 0.000 description 1
- 102100003447 TRIM69 Human genes 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J Tin(IV) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N Trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Vitamin C Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 229940100445 WHEAT STARCH Drugs 0.000 description 1
- 230000002378 acidificating Effects 0.000 description 1
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
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- 230000003042 antagnostic Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
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- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- NVKOCDGGRHAHOJ-SNVBAGLBSA-N benzyl (2R)-5-oxopyrrolidine-2-carboxylate Chemical compound O=C([C@@H]1NC(=O)CC1)OCC1=CC=CC=C1 NVKOCDGGRHAHOJ-SNVBAGLBSA-N 0.000 description 1
- WGLLBHSIXLWVFU-VIFPVBQESA-N benzyl (2S)-4-oxoazetidine-2-carboxylate Chemical compound O=C([C@H]1NC(=O)C1)OCC1=CC=CC=C1 WGLLBHSIXLWVFU-VIFPVBQESA-N 0.000 description 1
- MBFQGSHYJHUUMO-MMFRDWCLSA-N benzyl (2S)-5-cyanopyrrolidine-2-carboxylate;hydrochloride Chemical compound Cl.O=C([C@H]1NC(CC1)C#N)OCC1=CC=CC=C1 MBFQGSHYJHUUMO-MMFRDWCLSA-N 0.000 description 1
- QDFVSYNMKXCEQX-NSHDSACASA-N benzyl (2S)-6-oxopiperidine-2-carboxylate Chemical compound O=C([C@H]1NC(=O)CCC1)OCC1=CC=CC=C1 QDFVSYNMKXCEQX-NSHDSACASA-N 0.000 description 1
- NUXXWEUVZALCOH-UWVGGRQHSA-N benzyl (2S,4S)-4-hydroxy-5-oxopyrrolidine-2-carboxylate Chemical compound N1C(=O)[C@@H](O)C[C@H]1C(=O)OCC1=CC=CC=C1 NUXXWEUVZALCOH-UWVGGRQHSA-N 0.000 description 1
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- 238000005574 benzylation reaction Methods 0.000 description 1
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 1
- 230000000740 bleeding Effects 0.000 description 1
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- 239000008280 blood Substances 0.000 description 1
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- 229960004106 citric acid Drugs 0.000 description 1
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- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CKTNHGVJKUQEBM-UHFFFAOYSA-N ethylazanide Chemical compound CC[NH-] CKTNHGVJKUQEBM-UHFFFAOYSA-N 0.000 description 1
- KONIYTHNVWYBMP-UHFFFAOYSA-N ethylcyclohexane Chemical group [CH2-]C[C+]1CCCCC1 KONIYTHNVWYBMP-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 229940020899 hematological Enzymes Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 239000008079 hexane Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
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- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000000816 peptidomimetic Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 239000001184 potassium carbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004944 pyrazin-3-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- HKSQZEGSMBFHGC-UHFFFAOYSA-N pyrimidine-4-carboxamide Chemical compound NC(=O)C1=CC=NC=N1 HKSQZEGSMBFHGC-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 230000000552 rheumatic Effects 0.000 description 1
- 239000003001 serine protease inhibitor Substances 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
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- 230000002194 synthesizing Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- YQXDVAWQTLDPFF-UHFFFAOYSA-N tert-butyl N-(5-cyano-6-methylpyridin-2-yl)carbamate Chemical compound CC1=NC(NC(=O)OC(C)(C)C)=CC=C1C#N YQXDVAWQTLDPFF-UHFFFAOYSA-N 0.000 description 1
- XCAQIUOFDMREBA-UHFFFAOYSA-N tert-butyl N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate Chemical compound CC(C)(C)OC(=O)NC(=O)OC(C)(C)C XCAQIUOFDMREBA-UHFFFAOYSA-N 0.000 description 1
- KDACTUBHGRNOLL-UHFFFAOYSA-N tert-butyl N-[5-(aminomethyl)-6-ethylpyridin-2-yl]carbamate Chemical compound CCC1=NC(NC(=O)OC(C)(C)C)=CC=C1CN KDACTUBHGRNOLL-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
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Abstract
A compound selected from those of formula (I):wherein:R1 represents hydrogen, optionally substituted alkyl, cycloalkyl or heterocycloalkyl or a group of formula (G):wherein A1 represents single, -CH2-, -CH2-CH2- or -N(CH3)- or oxygen or sulphur, and X1 and X2, which may be identical or different, each represent carbon or nitrogen,R represents hydrogen or linear or branched (C1-C6)alkyl, represents a saturated ring having from 4 to 7 ring members,n represents integer wherein 1<=n<=6,Ar represents aryl or heteroaryl,its isomers, N-oxydes and pharmaceutically-acceptable acid or base addition salts thereof
Description
EUVOS BINYCLIC COMPOUNDS OF AMINOPIRAZINONE, AISA PROCESS ITS PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM DESCRIPTION OF THE INVENTION
The present invention relates to novel bicyclic aminopyrazinone compounds, to a process for their preparation, to pharmaceutical compositions containing them and to their use as inhibitors of serine proteases related to trypsin. One of these serine proteases, thrombin, is a key enzyme for coagulation and plays a central role in the pathology of poisonous and arterial thrombosis, especially in view of its marked ability to cause self-amplification of the coagulation cascade (F. Toti et al., Sang, Thrombosis, Vaisseaux [Blood, Thrombosis Vessels] 1992, 4, 483-494 and TM Really et al., Blood Coagulation and Fibronolysis, 1992, 3, 513-517). The direct and specific inhibition of thrombin is more efficient and has less risk of bleeding than heparin treatment. Direct thrombin inhibitors currently exist but the disadvantages of these peptide substances are that they are not active when administered orally. Peptidomimetic compounds having oral antithrombotic activity have already been described in the literature.
They include, for example, boronic acid compounds described in the patent specifications EP 293 881, EP 471 651, EP 615 978 and EP 792 883 and the compounds described in the patent specifications WO 94 29336 and WO 95 23609. It has been of particular interest to synthesize new serine protease inhibitors in order to increase the effectiveness and selectivity of the compounds already described in the literature. The activity of these new compounds is demonstrated by the increase in various coagulation times. In addition, the compounds are active when administered orally. More specifically, the present invention relates to compounds of formula (I):
wherein: * Rx represents a hydrogen atom or a linear or branched alkyl group (C.-C6) (optionally substituted by one or more identical or different substituents which are selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, carboxy, alkoxycarbonyl ( C ^ Cg) linear or branched and carbamoyl groups), a hydroxy group, a cycloalkyl group, a heterocycloalkyl group or a group of formula (G):
Where Ax represents a single bond, a group -CH-, -CH-CH¿-, or -N (CH3) - or an oxygen or sulfur atom, and X, and X, which may be identical or different, each represents a carbon or nitrogen atom, * R represents a hydrogen atom or a linear or branched alkyl group (Cx-C6), represents a saturated ring having from 4 to 7 members in the ring which may contain, in addition to the nitrogen atom, one or two heteroatoms that select from the groups 0, S or -N (R2) -, R¿ represents a hydrogen atom or a linear or branched (C6-C6) alkyl group, • n represents a whole number where l < n < 6, * Ar represents an aryl or heteroaryl group, their isomers, their N-oxides and addition salts thereof, with a pharmaceutically acceptable acid or base. Among pharmaceutically acceptable acids there can be mentioned by way of non-limiting examples hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid , tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid, camphoric acid, etc. Among the pharmaceutically acceptable bases can be mentioned as non-limiting examples sodium hydroxide, potassium hydroxide, triethylamine, terbutylamine, etc. The term "aryl group" is understood to mean phenyl, biphenyl or naphthyl, each of these groups is optionally substituted by one or more halogen atoms and / or by one or more identical or different groups which are selected from alkyl (Cx- Cg) linear or branched, (optionally substituted by a hydroxy or carboxy group, or by a carbamoyl group (itself optionally substituted by one or two linear or branched alkyl groups (C: -C6)), straight or branched alkoxy (C, -C6) , hydroxy, trihaloalkyl (C? -C6) in which the alkyl portion is linear or branched, trihalogenoalkoxy, in which the alkyl portion is linear or branched, amino (optionally substituted by one or two alkyl groups (C? -C6) linear or branched), a linear or branched alkylcarbonyloxy group, carboxymethoxy and carbamoylmethoxy (optionally N-substituted by one or two linear or branched alkyl groups (C? -C6)). The term "heteroaryl group" is understood to mean a monocyclic or bicyclic aromatic group having from 5 to 12 members in the ring and containing 1, 2 or 3 heteroatoms which are selected from oxygen, nitrogen and sulfur, it being understood that the heteroaryl may to be optionally substituted by one or more halogen atoms and / or by one or more identical or different groups which are selected from alkyl. { C1-CA) linear or branched (optionally substituted by a hydroxy or carboxy group or by a carbamoyl group (itself optionally substituted by one or two linear or branched alkyl groups (Cj-C)), hydroxy, alkoxy (C-) Linear or branched C, trihaloalkyl (C? -Cg) in which the alkyl portion is linear or branched, phenyl, amino (optionally N- substituted by one or more straight or branched alkyl groups (C: -C6), carboxymethoxy and carbamoylmethoxy (optionally substituted by one or two linear or branched (C 1 -C 6) alkyl groups) Among the heteroaryl groups there may be mentioned by way of non-limiting example the thienyl, pyridyl, furyl, pyrrolyl, imidazolyl, ozaxolyl, isozaxolyl groups, thiazolyl, isothiazolyl, pyrimidinyl, pyrazinyl and pyridazinyl The term "cycloalkyl group" is understood to mean a saturated or unsaturated monocyclic or bicyclic hydrocarbon group having from 3 to 12 members in the ring, it being understood that the system of ring optionally can be substituted - by one or more halogen atoms and / or by one or more identical or different groups which are selected from straight or branched alkyl (Cx-Cfi), straight or branched (C? -C6) alkoxy, hydroxy, trihaloalkyl (C, -C6) in which the alkyl portion is linear or branched, amino (optionally substituted by one or more linear or branched (C-C6) alkyl groups), and aryl. Among the cycloalkyl groups there can be mentioned by way of non-limiting example the cyclopentyl, cyclohexyl, indanyl and tetrahydronaphthyl groups. The term "heterocycloalkyl group" is understood to mean a saturated or unsaturated monocyclic or bicyclic group having from 4 to 12 members in the ring and containing 1, 2 or 3 heteroatoms which are selected from oxygen, nitrogen and sulfur, it being understood that the heterocycle may be optionally substituted by one or more halogen atoms and / or by one or more identical or different groups which are selected from straight or branched alkyl (C, -C6), straight or branched (C, -C6) alkoxy, hydroxy , trihaloalkyl (CA-C6) in which the alkyl portion is linear or branched, amino (optionally substituted by one or more linear or branched alkyl groups (C? -Ch)), aryl and diarylmethyl. Among the heterocycloalkyl groups, the azetidinyl, pyrrolidinyl, piperinyl and dihydrocyclopenta [b] pyridyl groups can be mentioned by way of non-limiting example. Preferred compounds of formula (I) are those in which n is 1. The ring as defined for formula (I) is preferably a pyrrolidinyl group.
The group Ar, as defined for the formula (I), preferably is a phenyl or pyridyl group, each of these groups is optionally substituted by one or more halogen atoms and / or by one or more identical or different groups which select linear or branched alkyl (Cj-C6) (optionally substituted by a hydroxy or carboxy group or by a carbamoyl group (itself optionally substituted by one or two straight or branched alkyl groups (C? -C ,.)), linear or branched (C -C ,,) alkoxy, hydroxy, trihaloalkyl (C? -C6) in which the alkyl portion is linear or branched, amino (optionally substituted by one or two linear (C-, - C6) alkyl groups) or branched), carboxymethoxy and carbamoylmethoxy (optionally N-substituted by one or two linear or branched alkyl groups (C? -Cfe)). The invention also relates to a process for the preparation of compounds of formula (I), characterized in that the compound of formula (II):
Where A is as defined for formula (I), P i represents a protective group of the amino function and B n represents a benzyl group, is reduced using an appropriate reducing agent, to provide a compound of formula (III)
wherein A, P and Bn are as defined above, the hydroxy function of such compound of formula (III) is converted to the methoxy function and then to the cyano function by conventional reactions of organic chemistry to provide, after deprotection of the amino function, a compound of formula (IV):
NC
(IV)
C02Bn wherein A and Bn as defined above, composed of formula (IV) which is reacted with oxalyl chloride to provide a compound of formula
(V):
wherein A and Bn are as defined in the foregoing, compound of formula (V) which is reacted with a compound of formula (VI):
R.-NH2 (VI)
wherein RL is as defined for formula (I), to provide a compound of formula (VII):
wherein A, Bn and Rj are as defined in the above, compound of formula (VII) which is then converted by catalytic hydrogenation to a compound of formula (VIII):
wherein A and R-L are as defined in the foregoing, compound of formula (VIII) which is then converted by catalytic hydrogenation in an alkaline medium to a compound of formula (IX):
where A and R? they are as defined in the above, compound of formula (IX) which is reacted on a compound of formula (X):
where n and Ar are as defined for the formula
(I) to provide, after deprotection where appropriate, a compound of formula (I), compound of formula (I) which is purified, if necessary, according to a conventional purification technique, and separated, if desired, in their isomers according to a conventional separation technique, and converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base The compounds of formula (II) are obtained by benzylation of the Corresponding Acids In addition to the fact that the compounds of the present invention are novel, they have especially useful pharmacological properties, they are potent inhibitors of trypsin-related serine proteases, show significant selectivity with respect to thrombin compared to other serine proteases of coagulation and fibrinolysis These properties make them useful in the treatment of stable or unstable angina, disorders of origin t rheumatic and / or thrombotic complications are generated in the treatment or prevention of myocardial infarction and venous or arterial thrombosis, and in the treatment of complications of cardiovascular vascular diseases, such as atherosclerosis, arteritis, venous disorder and in the treatment of any disorder involving thrombin formation and / or activity. They can also be used in therapeutic association with a thrombolytic agent. The invention also relates to pharmaceutical compositions comprising an active ingredient of a compound of formula (I) together with one or more suitable inert non-toxic excipients. Among the pharmaceutical compositions according to the invention, those which are suitable for oral administration may be more particularly mentioned., parenteral (intravenous or subcutaneous) or nasal, tablets or lozenges, sublingual tablets, gelatin capsules, troches, suppositories, creams, ointments, thermal gels, injectable preparations, ingestible suspensions, etc. The useful dosage can be adapted according to the nature and severity of the disorder, the route of administration and the age and weight of the patient. The dosage varies from 1 to 500 mg per day in one or more administrations. The following examples illustrate the invention but do not limit it in any way. It is understood that a configuration compound (2) or (23) means a compound that is selected from the stereoisomers (2R) and (2S), it being understood that when the compound (2a) represents one of the stereoisomers (2R) or (2S) ), the compound (2ß) represents the other stereoisomer, whose absolute configuration of the carbon atom in position 2 remains undefined. The initial materials used are known or prepared according to known procedures. Preparations A to G present synthesis intermediates, for use in the preparation of the compounds of the invention. The structures of the compounds described in the examples are determined according to the usual spectrophotometric techniques (infrared, NMR, mass spectrometry).
PREPARATION A: 3 -aminome il-6-ter-bu-yloxycarbonylamino-2-mepyridine
Stage A: 6-amino-3-cyano-2-methylpyridine
12 mmoles of copper (I) cyanide are added to 10 mmoles of 6-amino-3-bromo-2-methylpyridine dissolved in dimethylformamide. The mixture is refluxed for 10 hours and then cooled to 80 ° C and poured into a solution of 40 mmoles of sodium cyanide in water. After stirring for 1 hour at room temperature, the mixture is extracted with ethyl acetate. The organic phase is washed, then dried and evaporated to provide the expected product in the form of an ocher solid.
Zt pa B: 6-tert-butyloxycarbonylamino-3-cyano-2-methylpyridine
A solution of sodium hydroxide IN (11 mmol) and tert-butyl dicarbonate (11 mmol) is added to 10 mmol of the compound described in the preceding step dissolved in terbutanol. After stirring for 1 hour, the solvents are removed by evaporation, the residue is taken up in ethyl acetate, and the organic phase is washed, dried and evaporated to provide the expected product.
Step c: 6-tert-Butyloxycarbonylamino-3-aminomethyl lo-2-methylpyridine
A solution of the compound described in the preceding step (10 mmol) in ethanol is placed under hydrogen overnight in the presence of Raney nickel. After removal of the catalyst by filtration, the solvent is removed by evaporation to provide the expected product.
PREPARATION B: 3-aminomethyl-6-tert-butyloxycarbonylamino-2-, 5- dimethylpyridine
The expected product is obtained according to the process described in Preparation A from 6-amino-3-bromo-2,5-dimethylpyridine.
PREPARATION C: 3-aminomethyl-6-ter-b-tyloxycarbonylamino-2,4-dimethylpyridine
The expected product is obtained according to the process described in Preparation A from 6-amino-3-bromo-2,4-dimethylpyridine.
PREPARATION D: 3-aminomethyl-6-tert-butyloxycarbonylamino-2-ethylpyridine
The expected product is obtained according to the process described in Preparation A from 6-amino-3-bromo-2-ethylpyridine.
PREPARATION E: 2- [2- (aminomethyl) phenoxy] -N-ethylacetamide
Step A - 2- (2-Cyanophenoxy) ethyl acetate 30 mmoles of potassium carbonate and 11 mmoles of ethyl acetate are added to a solution of 10 mmoles of 2-hydroxybenzonitrile in acetonitrile. After stirring overnight, the solution is filtered and evaporated, the residue is taken up in ethyl acetate and the organic phase is washed, dried and then evaporated to provide the expected product.
Stage: 2- [2-cyanophenoxy] acetic acid
11 mmol of sodium hydroxide IN is added to a solution, at 0 ° C, of the compound obtained in the preceding step (10 mmol) in tetrahydrofuran. After stirring overnight, the mixture is evaporated and the residue is taken up in water. The organic phase is washed with ethyl acetate and acidified by 4N hydrochloric acid. The resulting precipitate is filtered and dried.
Stage C: 2- [2-cyanophenoxy] -N-ethylacetamide
11 mmol of N-hydroxysuccinimide and 11 mmol of N, N '-dicyclohexylcarbodiimide are added to a solution of the compound described in the preceding step (10 mmol) in dimethylformamide. After stirring for 2 hours at room temperature, 11 mmoles of ethylamine are added. After stirring overnight, the mixture is evaporated, filtered and taken up in ethyl acetate. The organic phase is washed with water and dried. The expected product is obtained after evaporation.
Step D: 2- [2- (aminomethyl) phenoxy] -N-ethylacetamide
The expected product is obtained according to the process described in step C of preparation A from a compound obtained in the preceding step.
PREPARATION F: 2- [2- (aminomethyl) -4-chlorophenoxy] -N-ethylacetamide
The expected product is obtained according to the process described in Preparation E, substituting 2-hydroxybenzonitrile for 5-chloro-2-hydroxybenzonitrile.
PREPARATION G: 3-aminomethyl-ß-tert-butyloxycarbonylamino-2-hydroxymethylpyridine
The expected product is obtained according to the process described in Preparation A, substituting 6-amino-3-bromo-2-hydroxymethylpyridine.
EXAMPLE 1: (6S) -N- Dichlorohydrate? (6-Amino-2-methyl-3-pyridi-D-methyl-4-oxo-3- (2-phenethylamino) -4,6,7,8-tetrahydropyrrolo TI, 2-al pyrazin-6-carboxamide Stage A: (2S) -N benzyl-tert-butoxycarbonyl-5-oxoprolinate
11 mmol of dimethylaminopyridine and 11 mmol of di-tert-butyl dicarbonate are added at 10 [deg.] C. to 10 mmol of benzyl (2S) -5-oxoprolinate (the preparation process of which is described by E. Campaigne et al., ( J. Heterocycl, Chem. 1975, 12, 391)) dissolved in dichloromethane. After stirring for 24 hours at room temperature, the reaction mixture is washed and then dried and evaporated to provide the expected product in the form of a viscous oil.
Stage B: (2S) -N-tert-butoxycarbonyl-5-hydroxyprolinate benzyl
18 mmol of an IM solution of diisobutylaluminum hydride in hexane are added, under argon at -78 ° C, to 10 mmol of the compound obtained in the preceding step dissolved in tetrahydrofuran. After stirring for 20 minutes at -78 ° C, a saturated aqueous solution of ammonium chloride is added and then an aqueous solution of 10% sodium carbonate. After stirring overnight at room temperature, the reaction mixture is filtered, and the filtrate is evaporated and taken up in dichloromethane. The organic phase is washed, dried and then evaporated. The residue is purified by chromatography on silica gel using a dichloromethane / ethyl acetate 95/5 mixture, as eluent. The expected product is obtained in the form of a yellow oil.
Stage C: benzyl (2S) -N-tert-butoxycarbonyl-5-methoxyproline
A solution of 0.1% paratoluenesulfonic acid in 88 ml of anhydrous methanol is added to 10 mmol of the compound obtained in the preceding step. After stirring for an hour, an aqueous solution of 10% sodium carbonate is added and the product is extracted with dichloromethane. The expected product is obtained in the form of a slightly yellow oil.
Stage D: Benzyl (2S) -5-cyanoprolinate hydrochloride
A solution of tin tetrachloride in 7.1 ml of anhydrous dichloromethane in 5% v / v is added and then 20.6 mmole of trimethylsilyl cyanide is added, at -40 ° C under argon, to 10 mmole of the compound obtained in the preceding step. After stirring for 2 hours at -40 ° C, an aqueous solution of 10% sodium carbonate is added, the aqueous phase is extracted with dichloromethane, and the organic phase is washed, dried and then evaporated. The resulting residue is purified by chromatography on silica gel using a dichloromethane / ethyl acetate 95/5 mixture as eluent. The resulting yellow oil is dissolved in ethyl acetate and then a gaseous hydrogen chloride stream is passed therethrough, at 0 ° C, for 30 minutes. After stirring overnight at room temperature, the precipitate that forms is filtered, rinsed with ethyl acetate and dried in vacuo using a desiccator.
Stage E: (6S) -1, 3-dichloro-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxylic acid benzyl ester
40 mmoles of oxalyl chloride are added to 10 mmoles of the compound obtained in the preceding step, dissolved in ortho-dichlorobenzene. After stirring for 15 hours at 100 ° C, the mixture is returned to room temperature and the solvents are removed by evaporation. The resulting residue is purified by chromatography on silica gel using a dichloromethane / ethyl acetate 95/5 mixture as eluent. The expected product is obtained in the form of a beige solid.
Step F: (6S) -1-chloro-oxo-3- (2-phenethylamine) -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxylic acid benzyl 30 mmoles are added 2-phenethylamine at 10 mmol of the compound obtained in the preceding step dissolved in ethyl acetate. After stirring for 2 hours at reflux, the reaction mixture is returned to room temperature and ethyl acetate is added. The organic phase is washed, dried and then evaporated. The resulting residue is purified by chromatography on silica gel using a dichloromethane / ethyl acetate mixture as the eluent. The resulting product is obtained in the form of a white solid.
Step G: (6S) -l-Chloro-4-oxo-3- (2-phenethylamino) -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxylic acid
42 mg of 10% Pd / C are added to 10 mmol of the compound obtained in the preceding step dissolved in dioxane. The mixture is placed under hydrogen for 5 hours under pressure and at room temperature. After removal of the catalyst by filtration, the solvent is removed by evaporation to provide the expected product as a white solid.
Step H: _ (6S) -4-Oxo-3- (2-phenethylamino) -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxylic acid
mmol of a solution of sodium hydroxide IN is added to 10 mmol of the compound obtained in the preceding stage dissolved in dioxane. The mixture is placed under nitrogen overnight under pressure and room temperature in the presence of 10% Pd / C (42 mg). After removal of the catalyst by filtration, the solvent is removed by evaporation and the residue is taken up in water and then acidic with KHS04. The precipitate is separated by filtration and dried in vacuo using the desiccator in the presence of P20s. The expected product is obtained in the form of a white solid.
Step I: (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- (2-phenethylamine) -4,6,7,8-tetrahydropyrrholehydrochloride 1,2-a] pyrazine-6-carboxamide
11 mmol of 0- (lH-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate and 11 mmol of diisopropylethylamine are added to 10 mmol of the compound obtained in the preceding step and 11 mmol of the compound described in preparation A dissolved in dimethylformamide. After stirring overnight at room temperature, the solvent is removed by evaporation. The resulting residue is taken up in ethyl acetate. The organic phase is washed, dried and then evaporated.
The resulting residue is dissolved in ethyl acetate and then a gaseous hydrogen chloride stream is passed through it at 0 ° C for 30 minutes. After stirring overnight at room temperature, the precipitate that forms is filtered off, rinsed with ethyl acetate and dried in vacuo using a desiccator.
My elementary scandal:
% C% H% N% C1 Calculated: 56.22 5.74 17.10 14.43 Found: 56.93 5.73 17.34 14.60
Example 2: (6R) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- (2-phenethylamino) -4,6,7,8-tetrahydropyrrholehydrochloride 1,2-a] pyrazine-6-carboxamide
The expected product is obtained from benzyl (2R) -5-oxoprolinate, according to the process described in example 1.
Example 3: N- [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- (2-phenethylamino) -4,6,7,8-tetrahydropyrrolo [1, 2-dihydrochloride] a] pyrazine-6-carboxamide
The expected product is obtained from benzyl (±) -5-oxoprolinate, according to the process described in example 1.
Example 4 (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- (2-phenethylamino) -6,7,8,9-tetrahydro-4H-dihydrochloride -py [1, 2-a] pyrazine-6-carboxamide
The expected product is obtained from benzyl (2S) -6-oxo-2-piperidinecarboxylate, according to the process described in example 1.
Example 5: (3S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -5-oxo-6- (2-enenethylamino) -2,3-dihydro-5H-dihydrochloride - [l, 3] thiazolo [3,2-a] pyrazine-3-carboxamide
The expected product is obtained according to the process described in example 1 from (4R) -2-oxo-l, 3-thiazolidin-4-carboxylic acid benzyl ester.
Example 6: (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -3 - [(2, 2-diphenylethyl) amino] -4-oxo-4,6,7-dihydrochloride , 8- tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, 2,2-diphenylethylamine and the compound described in preparation A.
Elemental microanalysis:
% C% H% N% C1 Calculated: 61.38 5.68 14.81 12.49 Found: 61.97 5.76 15.10 12.41
Example 7: (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -3 - [(3,4-dimethoxyphenethyl) amino] -4-oxo-4,6,7,7,7,9-dihydrochloride , 8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide monohydrate
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, 3,4-dimethoxyphenethylamine and the compound described in preparation A.
Elemental micro-analysis:
% C% H% N% C1 Calculated: 52.73 6.02 14.76 12.45 Found: 53.39 6.26 14.70 13.00 Example 8 (6S) -N- [(6-amino-2-methyl-3-pyridyl) methyl] -4 -oxo trichlorohydrate -3- [(2- (4-pi ridi l) e ti l) amino] -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, 4- (2-aminoethyl) pyridine and the compound described in preparation A .
Example 9: (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -3 - [(2-cyclohexylethyl) amino] -4-oxo-4,6,7,8-dihydrochloride -tetrahydropyrrolo [1, 2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, 2-cyclohexylethylamine and the compound described in preparation A.
Example 10: (2R) -N- [(6S) -6- Hydrochloride. { 5 [(((6-amino-2-methyl-3-pyridyl) methyl) amino] -carbonyl.} -4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazin-3 -yl] -phenylalanine The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, (2R) -phenylalanine terbutyl ester and the compound described in Preparation A.
EXAMPLE 11 (3S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -5-oxo-6- (2-enethyl-amino) -2,3-dihydro-5H- [(6-amino-2-methyl) dihydrochloride] 1, 3] oxazolo [3, 2-a] pyrazine-3-carboxamide
The expected product is obtained according to the process described in Example 1, starting from (4R) -2-oxo-l, 3-oxazolidin-4-carboxylic acid benzyl, which preparation is described in Tet. Lett. 1995, 3_6_ (37), 6595-6598.
Example 12: (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -3-benzylamino-4-oxo-4,6,7,8-tetrahydropyrrolo [1, 2-dihydrochloride] a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, benzylamine and the compound described in preparation A.
Elemental microanalysis
% c% H% N% C1 Calculated: 55.35 5.49 17.60 14.85 Found: 55.97 5.33 17.62 14.47
Example 13 (6S) -N - [(6-amino-2-methyl-3-pyridyl) ethyl] -4-oxo-3- (3-phenylpropylamino) -4,6,7,8-tetrahydropyrrolo dihydrochloride [1 , 2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, 3-phenylpropylamine and the compound described in preparation A.
Elemental microanalysis:
% c% H% N% C1 Calculated: 57.03 5.98 16.63 14.03 Found: 57.23 5.94 16.45 14.32
Example 14: (6S) -N- [(6-amino-2-methyl-3-pyridyl) methyl] -3-diphenyl-methylamino-4-oxo-4,6,7,8-tetrahydropyrrolo [1, 2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, diphenylethylamine and the compound described in preparation A.
Elemental microanalysis:
% c% H% N% C1 Calculated: 60.76 5.46 15. 18 12.81 Found: 60.59 5.53 15. 11 13.62
Example 15: (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [2- (2-pyridyl) -ethylamino] -4,6 trichlorohydrate, 7, 8- tetrahydropyrrolo [1,2- a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, 2- (2-pyridyl) ethylamine and the compound described in preparation A .
Elemental microanalysis:
% C% H% N C1 Calculated: 49. 96 5.34 18., 54 20.11 Found: 50. 27 5.23 18. 46 20.08
Example 16: (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [2- (3-pyridyl) -ethylamino] -4,6 trichlorohydrate, 7, 8- te rahidropirrolo [1,2- a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, 2- (3-pyridyl) -ethylamine and the compound described in the preparation TO.
Elemental microanalysis:
% C% H% N% C1 Calculated: 49.96 5.34 18. .54 20.11 Found: 49.13 5.32 18. 08 20.00 Example 17 (6S) -N- [(6-amino-2-methyl-3-pyridyl) methyl) hydrochloride ] -3- (indan-2-yl-methylamino) -4-oxo-4,6,7,8-tetrahydropyrrolo [1,2- a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, 2-indan-2-ylmethylamine and the compound described in preparation A.
Elemental microanalysis:
% c% H% N% C1 Calculated: 58.03 5.84 16.24 13.70 Found: 57.90 5.69 16.20 13.05
Example 18 (6S) -N - [(6-amino-2-methyl-3-pyridyl) ethyl] -3- [(1,1'-biphenyl) -4-ylmethylamino] -4-oxo- (6S) -hydrochloride 4, 6,7, 8-tetrahydropyrrolo [1, 2- a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (1,1 '-diphenyl) -4-yl-methylamine and the compound described in preparation A.
Example 19: (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -3- (2-methyl-2-f nyl-propylamino) -oxo-4,6-dihydrochloride 7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, 2-methyl-2-phenylpropylamine and the compound described in preparation A.
Elemental microanalysis:% c% H% N% C1 Calculated: 57.80 6.21 16.18 13.65 Found: 57.29 6.49 15.93 14.22
Example 20: (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [(2) -2- (2-pyridyl) -2- f trichlorohydrate enetylamino] -4,6,7,8-tetrahydropyrrolo [1,2- a] pyrazine-6-carboxamide
Stage A: (2) -2- (2-pyridyl) -2-f-eethylamine
The expected product is obtained by separation of (±) -2- (2-pyridyl) -2-phenethylamine (described in J. Am. Chem. Soc. 1971, 3, 5542) using D-dibenzoyltartaric acid.
Step B: (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4 -oxo-3- [(2) -2- (2-pyridyl) -2-phenethylamino trichlorohydrate ] -4, 6, 7, 8-tetrahydropyrrolo [1, 2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, the compound obtained in the preceding step and the compound described in preparation A.
Elemental microanalysis:
% C% H% N% C1 Calculated: 55., 59 5.33 16., 21 17.58 Found; 54., 83 5.46 15., 83 18.41
Example 21 (6S) -N- [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- ([(2β) -2- (2-pyridyl) -2-phenethylamino] trichlorohydrate ] -4,6,7,8-tetrahydropyrrolo [1,2- a] pyrazine-6-carboxamide The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in Step E of Example 1, (2β) -2- (2-pyridyl) -2-phenethylamine and the compound described in Preparation A.
Example 22 (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -3- [2, 2-di- (2-pyridyl) ethylamino] -4-OXO-, 6-tetrahydrochloride , 7, 8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of Example 1, 2, 2-di- (2-pyridyl) ethylamine and the compound described in preparation A.
Elemental microanalysis:
% C% H% N% C1 Calculated: 50.48 5.02 17.44 22.07 Found: 50.73 5.18 17.28 22.56
Example 23: (6S) -N- [(6-amino-2-methyl-3-pyridyl) methyl] -3- [2, 2-bis- (4-methoxyphenyl) ethylamino] -4-oxohydrochloride -4, 6, 7, 8 - tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of Example 1, 2, 2-bis- (4-methoxyphenyl) ethylamine and the compound described in preparation A.
Example 24 (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -3- [2, 2-bis- (4-hydroxy-phenyl) -ethylamino] -4-oxo- (6S) -hydrochloride 4, 6, 7, 8 - tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of Example 1, 2, 2-bis- (4-hydroxyphenyl) ethylamine and the compound described In the preparation
TO.
Example 25: (6S) -N- [(6-amino-2-methyl-3-pyridyl) methyl] -3- [2, 2-bis- (4-chlorophenyl) ethylamino] -4-oxohydrochloride -4, 6, 7, 8 - tetrahydropyrrolo [1, 2-a] pyrazine-6-carboxy ida
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of Example 1, 2, 2-bis- (4-chlorophenyl) ethylamine and the compound described in preparation A.
Example 26 (6S) -N - [(6-amino-2-methyl-3-pyridyl) ethyl] -3- [2, 2-di- (p-tolyl) ethylamino] -4-oxo-4 dihydrochloride, 6,7, 8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of Example 1, 2, 2-di- (p-tolyl) ethylamine and the compound described in preparation A.
EXAMPLE 27 (6S) -N- [(6-amino-2-methyl-3-pyridinyl) methyl] -3- [2, 2-bis- (4-fluorophenyl) ethylamino] -4- hydrochloride. oxo-4, 6, 7, 8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in Step E of Example 1, 2, 2-bis- (4-fluorophenyl) ethylamine and the compound described in Preparation A. Example 28: (6S) -N- [(6-amino-2-methyl-3-hydrochloride - pyridyl) methyl] -3- [2, 2-dicyclohexyl-ethylamino] -4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, 2,2-dicyclohexylethylamine and the compound described in preparation A.
Elemental microanalysis:
% c% H% N% C1 Calculated: 60. , 10 7. 65 14.39 12.23 Found: 60. , 27 7. 67 14.50 12.29
Example 29: (6S) -N- [(6-amino-2-methyl-3-pyridyl) l-thiol] -3- [2, 2-bi s - (2, 4-difluorophenyl) ethylamide ] -4-oxo-4,6,7,8-tetrahydropyolo [1,2-a] pyrazin-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of Example 1, 2, 2-bis- (2,4-difluorophenyl) ethylamine and the compound described in preparation A.
Example 30 (6S) -N- [(6-amino-2-methyl-3-pyridyl) 1-methyl] -3- [2, 2-bi s - (2,6-dimethylphenyl) ethylamino] -4-dihydrochloride -oxo-4, 6, 7, 8 - tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of Example 1, 2, 2-bis- (2,6-dimethylphenyl) ethylamine and the compound described in the preparation
TO.
Example 31: (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -3- [2, 2-bis- (6-ethyl-2-pyridyl) ethylamino] -4-tetrahydrochloride -oxo-4, 6, 7, 8 - tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, 2, 2-bis- (6-ethyl-2-pyridyl) ethylamine and the compound described in preparation A.
Example 32: (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [(2R) -2- (1-naphyl) -2- trichlorohydrate (2-pyridyl) ethylamino] -4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (2R) -2- (l-naphthyl) -2- (2 -pyridyl) ethylamine and the compound described in preparation A.
Example 33 (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [(2S) -2- (1-naphyl) -2- trichlorohydrate (2-pyridyl) ethylamino] -4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, (2S) -2- (l-naphthyl) -2- (2-pyridyl) ethylamine and the compound described in preparation A.
Example 34 (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [(2R) -2- (2-naphthyl) -2- (2-naphthyl) trichlorohydrate - pyridyl) ethylamino] -4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (2R) -2- (2-naphthyl) -2- (2 -pyridyl) ethylamine and the compound described in preparation A.
Example 35 (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [(2S) -2- (2-naphthyl) -2- (2-naphthyl) trichlorohydrate - pyridyl) ethylamino] -4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (2S) -2- (2-naphthyl) -2- (2 -pyridyl) ethylamine and the compound described in preparation A.
Example 36: (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [(2R) -2- (2-pyridyl) -2-phenylbutylamino trichlorohydrate ] -4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (2R) -2- (2-pyridyl) -2-phenylbutylamine and the compound described in preparation A.
Example 37: (6S) -N- [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [(2S) -2- (2-pyridyl) -2-phenylbutylamino trichlorohydrate ] -4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (2S) -2- (2-pyridyl) -2-phenylbutylamine and the compound described in preparation A.
Example 38: (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -3 - [(9H-fluoren-9-yl) -methylamino] -4-oxo-4-dihydrochloride, 6,7, 8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (9H-fluoren-9-yl) methylamine and the compound described in Preparation A.
Example 39 (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -3- [(9,10-dihydro-9-anthryl) -methylamino] -4-oxo-4-hydrochloride , 6,7, 8-tetrahydropyrrolo [1, 2- a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (9,10-dihydro-9-anthryl) methylamine and the compound described in preparation A.
Example 40 (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -3- [(10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) hydrochloride ) methylamino] -4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide The expected product is obtained according to the process described in steps F to I of example 1, from the compound described in step E of example 1, (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl)) methylamine and the compound described in preparation A.
Elemental microanalysis:
% C% H% N% C1 Calculated: 62.73 5.77 14.16 11.95 Found: 63.02 5.83 14.09 11.49
Example 41 (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [(9H-xanthen-9-l) methylamino] -4,6 hydrochloride] 7, 8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (9H-xanthen-9-yl) methylamine and the compound described in Preparation A.
Example 42: (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [(9H-thioxanthen-9-yl) methylamino] -4,6-dihydrochloride] , 7, 8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (9H-thioxanthen-9-yl) methylamine and the compound described in Preparation A.
EXAMPLE 43 (6S) -N- [(6-amino-2-methyl-3-pyridyl) methyl] -3- [(10-methyl-9,10-dihydro-9-ac di-di-nyl) -di-dihydrochloride] l ami no] - 4, 6, 7, 8 - tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (10-methyl-9,10-dihydro-9-acridinyl) methylamine and the compound described in preparation A.
Example 44 (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -3- [(9H-indeno- [2, 1-b] pyridin-9-yl) methylamino] trichlorohydrate] -4,6,7,8-tetrahydropyrrolo [1,2- a] pyrazine-6-carboxamide The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in Step E of Example 1, (9H-indeno- [2, 1-b] pyridin-9-yl) methylamine and the compound described in Preparation A.
Example 45 (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -3- [(5,10-dihydrobenzo [g] quinolin-10-yl) methylamino] trichlorohydrate] 4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (5,10-dihydrobenzo [g] quinolin-10-yl) methylamine and the compound described in Preparation A.
Example 46: (6S) -N- [(6-amino-2-methyl-3-pyridyl) methyl] -3- [(6,11-dihydro-5H-benzo [5,6] cyclohepta [1], dihydrochloride] 2-b] pyridin-1-yl) methylamino] -4,6,7,8-tetrahydropyrrolo [1,2- a] pyrazin-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (6,11-dihydro-5H-benzo [5,6] cyclohepta [1, 2-b] pyridin-11-yl) methylamine and the compound described in preparation A.
EXAMPLE 47 (6S) -N- [(6-amino-2-methyl-3-pyridyl) methyl] -3- [(10,11-dihydro-4,6-diaza-5H-dibenzo [a, d]] dhydrochloride ] cyclohepten-5-yl) methylamino] -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, (10,11-dihydro-4,6-diaza-5H-dibenzo). [a, d] cyclohepten-5-yl) methylamine and the compound described in Preparation A.
EXAMPLE 48 (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [2- (5-phenyl-2-pyridyl) methyl amino] -hydrochloride] 4, 6, 7, 8 - tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, 2- (5-phenyl-2-pyridyl) methylamine and the compound described in Preparation A.
Example 49: (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [2- (5-byl-2-pyridyl) trichlorohydrate lamino] - 4, 6, 7, 8 - tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, 2- (5-butyl-2-pyridyl) methylamine and the compound described in preparation A.
Example 50: (6S) -N- [(6-amino-2-methyl-3-pyridyl) ethyl] -3- [2- (1-naphthyl) ethylamino] -4-oxo-4,6,7-dihydrochloride , 8- etrahydropyrrolo [1, 2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, 2- (l-naphthyl) ethylamine and the compound described in preparation A .
Elemental microanalysis:
% C% H% N% C1 Calculated: 59.89 5.58 15.52 13.09 Found: 60.47 5.84 15.57 12.76 Example 51: (6S) -N- [(6-amino-2-methyl-3-pyridyl) methyl] -3- hydrochloride [2- (2-naphthyl) methylamino] -4-oxo-4,6,7,8-tetrahydropyrrolo [1,2- a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, 2- (2-naphthyl) ethylamine and the compound described in preparation A .
Elemental microanalysis:% c% H% N% C1 Calculated: 59., 89 5.58 15.52 13.09 Found; 60. 66 5.71 15.65 12.58
EXAMPLE 52 (6S) -N- [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [2- (5-ethoxy-6-methyl-2- pyridyl) dihydrochloride ) ethyl ami no] - 4, 6, 7, 8 - tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, 2- (5-ethoxy-6-methyl-2-pyridyl) ethylamine and the compound described in preparation A.
Elemental microanalysis:
% c% H% N% C1 Calculated: 54.55 6.04 17.81 12.8 Found: 55.70 6.13 17.71 13.1
Example 53: (6S) -N- [(6-amino-2-methyl-3-pyridyl) methyl] -4 -oxo-3- [2- (6,7-dihydro-5H-cyclopenta [b]] trichlorohydrate pyridin-2-yl) ethylamino] -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, 2- (6,7-dihydro-5H-cyclopenta [b] pyridine) -2-yl) ethylamine and the compound described in preparation A.
Example 54: (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -3- [1,3-di- (2-pyridyl) -2- p ropanami] - tetrahydrochloride] 4-oxo-4, 6, 7, 8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, 1,3-di- (2-pyridyl) -2-propanamine and the compound described in preparation A.
Example 55 (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -3- [1,3-diphenyl-2-propanamino] -4-oxo-4,6,7,7,5,5-dihydrochloride. , 8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of Example 1, 1,3-diphenyl-2-propanamine and the compound described in the preparation TO.
Example 56 (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -3- [(2) -3,3,3-trifluoro-2-phenyl-1-propanamide] dihydrochloride - 4 -oxo-4, 6, 7, 8 - tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (2) -3,3,3-trifluoro-2-phenyl- 1-Propanamine and the compound described in Preparation A.
Example 57: (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -3- [(2ß) -3,3,3-trifluoro-2-phenyl-1-proppamine ] - 4 -oxo-4, 6, 7, 8 - tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (2β) -3,3,3-trifluoro-2-phenyl- 1-Propanamine and the compound described in Preparation A.
Example 58 (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -3- [(2R) -3,3,3-trifluoro-2-cyclohexyl-1-proppamine ] -4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (2R) -3,3,3-trif luoro-2-cyclohexyl -l-propanamine and the compound described in preparation A.
Example 59: (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -3- [(2S) -3,3,3-trifluoro-2-cyclohexyl-1-proppamine ] -4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (2S) -3,3,3-trifluoro-2-cyclohexyl- l-propanamine and the compound described in preparation A.
Example 60: (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -3- (2-indanamino) -4-oxo-4,6,7,8-tetrahydropyrrolohydrochloride 1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, 2-indanamino and the compound described in preparation A.
Elemental microanalysis:
% C% H% N% C1 Calculated: 57.26 5.61 16.69 14.08 Found: 57.75 5.54 16.72 14.07 Example 61: (6S) -N- [(6-amino-2-methyl-3-pyridyl) methyl] -3- hydrochloride (1-phenyl-3-azetidinamino) -4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, l-phenyl-3-azetidinamine and the compound described in preparation A.
Example 62 (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -3- (l-benzhydryl-3-azetidiamino) -4-oxo-4,6,7,8-hydrochloride -tetrahydropyrrolo [1, 2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, l-benzhydryl-3-azithylamine and the compound described in preparation A.
Example 63: (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -3- (1- (2-naphyl) -3-azetidylamino) -4-OXO-4-dihydrochloride , 6,7, 8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, 1- (2-naphthyl) -3-azetidinamine and the compound described in Preparation A.
Example 64 (6S) -N - [(6-amino-2-methyl-3-pyridyl) ethyl] -3- (4,4-di-enyl-cyclohexylamino) -4-OXO-4,6,7-dihydrochloride 8-tetrahydropyrrolo [1, 2-a] pyrazin-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, 4,4-diphenylcyclohexylamine and the compound described in the preparation
TO.
Example 65 (6S) -N - [(6-amino-2,5-dimethyl-3-pyridyl) methyl] -3- (2, 2-diphenyl-ethylamino) -4-oxo-4,6,7 dihydrochloride , 8- tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, 2,2-diphenylethylamine and the compound described in preparation B.
Example 66: (6S) -N - [(6-amino-2,4-dimethyl-3-pyridyl) methyl] -3- (2, 2-diphenyl-ethylamino) -4-oxo-4,6-dihydrochloride 7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, 2,2-diphenylethylamine and the compound described in preparation C.
Example 67 (6S) -N - [(6-amino-2-ethyl-3-pyridyl) methyl] -3- (2, 2-diphenylethylamino) -4-oxo-4,6,7-dihydrochloride 8 - tetrahydropyrrolo [1, 2-a] pyraz-6-carboxamide The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, 2,2-diphenylethylamine and the compound described in preparation D.
Example 68: (6S) -N - [(6-amino-2,5-dimethyl-3-pyridyl) methyl] -3- [2- (2-pyridyl) -ethylamino) -4-oxo-4 trichlorohydrate, 6,7, 8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, 2- (2-pyridyl) -ethylamine and the compound described in the preparation B.
Elemental microanalysis:
% c% H% N% C1 Calculated: 49.88 5.53 17., 71 21.12 Found 50.07 5.65 17., 68 20.99
Example 69 (6S) -N - [(6-amino-2,4-dimethyl-3-pyridyl) methyl] -3- [2- (2-pyridyl) -ethylamino) -4-oxo-4,6-trichlorohydrate , 7, 8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of the example 1, 2- (2-pyridyl) -ethylamine and the compound described in preparation C.
EXAMPLE 70 (6S) -N- [(6-amino-2-ethyl-3-pyridyl) methyl] -3- [2- (2-pyridyl) -ethylamino) -4-oxo-4,6,8,7 trichlorohydrate , 8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, 2- (2-pyridyl) -ethylamine and the compound described in the preparation D.
Example 71 (6S) -N- [(2-ethylcarbonylmethoxy) benzyl] -4-oxo-3- (2-phenethyl-amino) -4,6,7,8-tetrahydropyrrolo [1,2- a] pyrazin-6 -carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, 2-phenethylamine and the compound described in preparation E.
Elemental microanalysis
% C% H% N Calculated: 66.24 6.38 14. .30 Found: 65.52 6.33 14., 18
Example 72 (6S) -N- [3- (1H-imidazol-4-yl) propyl] -4-oxo-3- (2, 2-diphenyl-ethylamino) -4,6,7,8-tetrahydropyrrhohydrochloride [1, 2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, 2,2-diphenylethylamine and 3- (1H-imidazole-4) -yl) propylamine described in Liebigs
Ann. Chem. 1992, 317-323.
Elemental microanalysis:
% C% H% N% C1 Calculated: 61. .34 5.86 15., 33 11.64 Found: 61., 43 5.83 14. 91 11.97
Example 73 (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -3- [2, 2-bis- (2-fluoro-4-methoxyphenyl) ethylamino] 4-hydrochloride. oxo-4, 6, 7, 8 - tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, 2, 2-bis- (2-fluoro-4-methoxy-enyl) ethylamine and the compound described in preparation A.
Example 74: (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -3- [2, 2-bis- (4-fluoro-2-methoxyphenyl) ethylamino] -4-hydrochloride -oxo-4, 6, 7, 8 - tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, 2, 2-bis- (4-fluoro-2-methoxyphenyl) ethylamine and the compound described in preparation A.
Example 75: (6S) -N- [(6-amino-2-methyl-3-pyridyl) methyl] -3- [2, 2-bis- (2-fluoro-p-toli l) eti lamino] dihydrochloride] - 4 -oxo-4, 6, 7, 8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide The expected product is obtained according to the process described in steps F to I of Example 1, starting from compound described in step E of example 1, 2, 2-bis- (2-fluoro-p-tolyl) ethylamine and the compound described in preparation A.
Example 7 (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4 -oxo-3- [(2R) -2- (5-methyl-2-pyridyl) trichlorohydrate - 2- (4-methoxyphenyl) ethylamino] -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (2R) -2- (5-methyl-2-pyridyl) - 2- (4-methoxyphenyl) ethylamine and the compound described in Preparation A.
Example 77 (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [(2S) -2- (5-methyl-2-pyridyl) trichlorohydrate] 2- (4-methoxyphenyl) ethylamino] -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (2S) -2- (5-methyl-2-pyridyl) - 2- (4-methoxyphenyl) ethylamine and the compound described in Preparation A.
Example 78 (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [(2R) -2- (2-pyridyl) -2- (3-amino-3-pyridyl) trichlorohydrate , 4-dimethylphenyl) ethylamino] -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (2R) -2- (2-pyridyl) -2- (3 , 4-dimethylphenyl) ethylamine and the compound described in Preparation A.
Example 79: (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [(2S) -2- (2-pyridyl) -2- trichlorohydrate 3,4-dimethylphenyl) ethylamino] -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (2S) -2- (2-pyridyl) -2- (3 , 4-dimethylphenyl) ethylamine and the compound described in Preparation A.
Example 80: (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [(2R) -2- (2-pyridyl) -2- trichlorohydrate 2,4-dimethylphenyl) ethylamino] -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (2R) -2- (2-pyridyl) -2- (2 , 4-dimethylphenyl) ethylamine and the compound described in Preparation A.
Example 81 (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [(2S) -2- (2-pyridyl) -2- (2-pyridyl) trichlorohydrate , 4-dimethylphenyl) ethylamino] -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (2S) -2- (2-pyridyl) -2- (2 , 4-dimethylphenyl) ethylamine and the compound described in Preparation A.
Example 82: (6S) -N- [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [(2R) -2- (2-pyridyl) -2- trichlorohydrate 4- ethylphenyl) ethylamino] -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (2R) -2- (2-pyridyl) -2- (4 -ethylphenyl) ethylamine and the compound described in Preparation A.
Example 83 (6S) -N - [(6-amino-2-methyl-3-pyridyl) ethyl] -4-oxo-3- [(2S) -2- (2-pyridyl) -2- (4-amino-3-pyridyl) trichlorohydrate ethylphenyl) ethylamino] -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (2S) -2- (2-pyridyl) -2- (4 -ethylphenyl) ethylamine and the compound described in Preparation A.
Example 84: (6S) -N- [(6-amino-2-methyl-3-pyridyl) methyl] -3- [2, 2-bis- (2-fluoro-4-hydroxyphenyl) ethylamino] -4-hydrochloride -oxo-4, 6, 7, 8 - tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, 2, 2-bis- (2-fluoro-4-hydroxy-enyl) ethylamine and the compound described in preparation A.
EXAMPLE 85 (6S) - N - [(6-amino-2-methyl-3-pyridyl) methyl] -3- [2, 2-bi s - (2,4-di ethoxyphenyl) ethylamino] - hydrochloride 4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, 2, 2-bis- (2, -dimethoxyphenyl) ethylamine and the compound described in preparation A.
Example 86 (6S) -N - [(2-ethylcarbamoylmethoxy) -benzyl] -4-oxo-3- [2- (2-pyridyl) -ethylamino] -4,6,7,8-tetrahydropyrrolo [l,] -hydrochloride 2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, 2- (2-pyridyl) -ethylamine and the compound described in the preparation AND.
Example 87 (6S) -N- [(5-Chloro-2-ethylcarbamoylmethoxy) -benzyl] -4-oxo-3- [2- (2-pyridyl) -ethylamino] -4,6,7,8-hydrochloride tetrahydropyrrolo [1, -a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, 2- (2-pyridyl) -ethylamine and the compound described in the preparation F.
Example 88: (6S) -N- (2, 5-dichlorobenzyl) -4-oxo-3- [2- (2-pyridyl) -ethylamino] -4,6,7,8-tetrahydropyrrolohydrochloride [1, 2] -a] pyrazine-6-carboxamide The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, 2- (2-pyridyl) - ethylamine and 2,5-dichlorobenzylamine.
Example 89: (6S, 8R) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -3- [(2,2-di-enylethyl) amino] -8-hydroxy-4- hydrochloride oxo-4, 6,7, 8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
Stage A: (2S, 4R) -4-hydroxy-5-oxo-2-pyrrolidinecarboxylate benzyl
The expected product is obtained according to the process described in J. Org. Chem. 1996, .61 (14), 4838-41.
EtaOA B: (6S, 8R) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -3 - [(2, 2-diphenylethyl) amino] -8-hydroxy-4-oxohydrochloride -4, 6, 7, 8-tetrahydropyroid [1, 2- a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in Example 1, from the compound described in the preceding step, 2,2-diphenylethylamine and the compound described in Preparation A.
Example 90: (6S, 8S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -3 - [(2, 2-diphenylethyl) amino] -8-hydroxy-4-hydrochloride oxo-4, 6,7, 8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
Stage A; (2S, S) benzyl-4-hydroxy-5-oxo-2-pyrrolidinecarboxylate
The expected product is obtained according to the process described in J. Org. Chem. 1996, £ 1 (14), 4838-41.
Step B: (6S, 8S) -N- [(6-amino-2-methyl-3-pyridyl) methyl] -3 - [(2, 2-diphenylethyl) amino] -8-hydroxy-4-oxohydrochloride -4, 6, 7, 8 -tetrahydropyrrolo [1, 2- a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in Example 1, from the compound described in the preceding step, 2,2-diphenylethylamine and the compound described in Preparation A.
EXAMPLE 91 (6S, 8R) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -3 - [(2, 2-diphenylethyl) amino] -8-methoxy-4-oxo- (6S, 8R) -hydrochloride 4, 6,7, 8-tetrahydropyrrolo [1,2-a] pyrazin-6-sarboxamide Stage A: (2S, 4R) -4-methoxy-5-oxo-2-pyrrolidinecarboxylate benzyl
The expected product is obtained according to the process described in J. Chem. (B) 1996, 35 (11), 1221-24 from the compound described in step A of example 89.
Et ffü B; (6S, 8R) -N- [(6-amino-2-methyl-3-pyridyl) methyl] -3 - [(2, 2-diphenylethyl) amino] -8-methoxy-4-oxo-4-dihydrochloride, 6, 7, 8-tetrahydropyrrolo [1, 2- a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in Example 1, from the compound described in the preceding step, 2,2-diphenylethylamine and the compound described in Preparation A.
EXAMPLE 92 (6S, 8S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -3 - [(2, 2-diphenylethyl) amino] -8-methoxy-4-oxo- (6S, 8S) dihydrochloride 4, 6.7, 8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
Stage A. (2S, S) -4-methoxy-5-oxo-2-pyrrolidinecarboxylate benzyl The expected product is obtained according to the process described in Indian. J. Chem. (B) 1996, 3_5 (11), 1221-24 from the compound described in step A of example 90.
Step B: (6S, 8S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -3 - [(2, 2-diphenylethyl) amino] -8-methoxy-4 -oxohydrochloride -4, 6, 7, 8-tetrahydropyrrolo [1, 2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in Example 1, from the compound described in the preceding step, 2,2-diphenylethylamine and the compound described in Preparation A.
EXAMPLE 93 (6S) -N - [(6-amino-2-hydroxymethyl-3-pyridyl) methyl] -3- [(2, 2-diphenylethyl) amino) -4 -oxo-4,6,7-dihydrochloride , 8 - tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, 2,2-diphenylethylamine and the compound described in preparation G.
Example 94 (3R) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -6 - [(2, 2-diphenylethyl) amino] -1-methyl-5-oxo-l, hydrochloride 2,3,5-tetrahydroimidazo [1,2- a] pyrazine-3-carboxamide
Stage A: benzyl (4R) -l-methyl-2-oxo-4-imidazolidincarboxylate
The expected product is obtained according to the process described in Synth. Commun. 1996, 2 £ (11) 2165-75.
Step B. (3R) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -6 - [(2, 2-diphenylethyl) amino] -1-met il-5 -oxo- dihydrochloride 1, 2, 3, 5-tetrahydroimidazo [1,2-a] pyrazine-3-carboxamide
The expected product is obtained according to the process described in Example 1, from the compound described in the preceding step, 2,2-diphenylethylamine and the compound described in Preparation A.
Example 95 (8S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -2 -oxo-3- (2-enedylamino) -1,4-diazabicyclo [4.2.0] octahydrochloride 3,5-Dien-8-carboxamide The expected product is obtained according to the process described in Example 1, starting from benzyl (2S) -4-oxo-2-azetidinecarboxylate, 2-phenethylamine and the compound described in preparation A.
Example 96: (6S) -N- [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- (2 -phene ti lami) dichlorohydrate - 4,6,7,8 , 9, 10-hexahydropyrazino [1,2-a] azepine-6-carboxamide
The expected product is obtained according to the process described in example 1, starting from benzyl (2S) -7-oxo-2-azepanecarboxylate, 2-phenethylamine and the compound described in preparation A.
EXAMPLE 97 (6R) -N- (6-Amino-2-methyl-3-pyridyl) methyl] -3- [2, 2-bis- (4-methoxyphenyl) -ethylamino] -4-oxo-4-dihydrochloride , 6,7, 8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in Example 1, starting from (2R) -5-benzyl oxoprolinate, 2,2-bis- (-methoxyphenyl) -ethylamine and the compound described in Preparation A.
Example 98: N- [(6-amino-2-methyl-3-pyridyl) methyl] -3- [2, 2-bis- (4-methoxyphenyl) -ethylamino] -4-oxo-4,6-dihydrochloride 7,8-tetrahydropyrrolo [1, 2- a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in Example 1, starting from (±) -5-benzyl oxoprolinate, 2,2-bis- (4-methoxyphenyl) -ethylamine and the compound described in preparation A .
Elemental microanalysis:
% C% H% N% C1 Calculated: 59.33 5.78 13., 39 11.30 Found: 60.19 5.70 13., 50 11.61
Example 99: (6S) -N- [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [(2R) -2- (5-methyl-2-pyridyl) trichlorohydrate) -2- (2,4-difluorophenyl) -ethylamino] -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (2R) -2 (5-methyl-2-pyridyl) -2 - (2,4-difluorophenyl) -ethylamine and the compound described in Preparation A.
Example 100 (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [(2S) -2- (5-methyl-2-pyridyl) trichlorohydrate - 2- (2,4-difluorophenyl) -ethylamino] -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (2S) -2 (5-methyl-2-pyridyl) -2 - (2,4-difluorophenyl) -ethylamine and the compound described in Preparation A.
Example 101: (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3-amino-4,6,7,8-tetrahydropyrrolo [1, 2-trichlorohydrate] a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, di- (tert-butyl) imidodicarbonate and the compound described in preparation A.
Example 102: (4S) -N- [(6-amino-2-methyl-3-pyridyl) methyl] -l-methyl-6-oxo-7- (2-phenethylamino) -1,3,4-dihydrochloride 6- ehydrohydro-2H-pyrazino [1,2-a] pyrimidine-4-carboxamide
The expected product is obtained according to the process described in example 1, starting from (4S) -l-methyl-2-oxo-hexahydro-4-pyrimidinecarboxylate, 2-phenethylamine and the compound described in preparation A.
Example 103 (6S) -N- [(2-ethylcarbamoylmethoxy) -benzyl] -4-oxo-3- (2, 2-diphenyl) -ethylamino) -4,6,7,8-tetrahydropyrrolohydrochloride [1,2] -a] pyrazin-6-sarboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, 2-diphenylethylamine and the compound described in preparation E.
Elemental microanalysis:
% c% H% N% C1 Calculated: 65.83 6.03 11.63 5.89 Found: 65.82 6.00 11.57 5.64 Example 104: (6S) -N- [(6-amino-2-methyl-3-pyridyl) methyl] dihydrochloride] oxo-3- [(2-phenyl-cyclopropyl) amino] -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, from the compound described in step E of example 1, (2-phenyl-cyclopropyl) amine and the compound described in preparation A .
Example 105 (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [(2,2-diphenyl-cyclic op r op il) ami no] dihydrochloride] - 4, 6, 7, 8 - tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (2, 2-diphenyl-cyclopropyl) amine and the compound described in Preparation A.
Example 106: (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [(2R) -2- (2,4-dimethylphenyl) -2-trichlorohydrate - (5-ethyl-2-pi rimidini l) e ti lamino] - 4, 6, 7, 8 - tetrahydropyrrolo [1,2-a] pyrazin-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (2R) -2- (2,4-dimethylphenyl) -2 - (5-ethyl-2-pyrimidinyl) ethylamine and the compound described in preparation A.
Example 107 (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [(2S) -2- (2,4-dimethylphenyl) -2 - trichlorohydrate. (5-ethyl-2-pyrimidini l) e ti lamino] -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (2S) -2- (2,4-dimethylphenyl) -2 - (5-ethyl-2-pyrimidinyl) ethylamine and the compound described in preparation A.
Example 108: (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [(2R) -2- (5-methyl-2-pyridyl) trichlorohydrate) -2- (p-tolyl) ethylamino] -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (2R) -2- (5-methyl-2-pyridyl) - 2- (p-tolyl) -ethylamine and the compound described in preparation A.
Example 109: (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [(2S) -2- (5-methyl-2-pyridyl) trichlorohydrate ) -2- (p-tolyl) ethylamino] -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (2S) -2- (5-methyl-2-pyridyl) - 2- (p-tolyl) -ethylamine and the compound described in preparation A.
Example 110: (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [(2R) -2- (5-methoxy-2-pyridyl) trichlorohydrate -2- (4-methoxyphenyl) -ethylamino] -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (2R) -2- (5-methoxy-2-pyridyl) - 2- (4-methoxyphenyl) -ethylamine and the compound described in Preparation A.
Example 111 (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [(2S) -2- (5-methoxy-2-pyridyl) trichlorohydrate 2- (4-methoxyphenyl) -ethylamino] -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (2S) -2- (5-methoxy-2-pyridyl) - 2- (4-methoxyphenyl) -ethylamine and the compound described in Preparation A.
Example 112 (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [(2R) -2- (5-methoxy-2-pyridyl) trichlorohydrate 2- (3,4-Dimethylphenyl) -ethylamino] -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (2R) -2- (5-methoxy-2-pyridyl) - 2- (3,4-Dimethylphenyl) -ethylamine and the compound described in Preparation A.
Example 113 (6S) -N - [(6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- [(2S) -2- (5-methoxy-2-pyridyl) trichlorohydrate 2- (3,4-Dimethylphenyl) -ethylamino] -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
The expected product is obtained according to the process described in steps F to I of Example 1, starting from the compound described in step E of example 1, (2S) -2- (5-methoxy-2-pyridyl) - 2- (3,4-Dimethylphenyl) -ethylamine and the compound described in Preparation A.
The following examples are prepared according to the processes described in example 1 using the corresponding initial materials.
Example 114: N- [(6-amino-2-methyl-3-pyridyl) -methyl] -3 - [(2, 2-diphenylethyl) amino] -4-oxo-4,6,7,8- dihydrochloride tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
Elemental microanalysis:
% C% H% N% C1 Calculated: 61.38 5.68 14.81 12.49 Found: 61.97 5.76 15.10 12.41
EXAMPLE 115: (6R) -N - [(6-Amino-2-methyl-3-pyridyl) -methyl-3- [(2, 2-dif-phenylethyl) amino] -4-oxo-4,6-dihydrochloride, 7, 8- te rahidropirrolo [1, 2-a] pyrazin-6-carboxamide
EXAMPLE 116 (6S) -N- [(6-Amino-2-methyl-3-pyridyl) -methyl-4-oxo-3- [(2R) -2- (2-pyridyl) -2- (4-pyridyl) trichlorohydrate - trif luorom oxy nyl) - and ylamino] - 4, 6, 7, 8 - tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide EXAMPLE 117 (6S) -N- [(6-Amino-2-) trichlorohydrate] methyl-3-pyridyl) -methyl-4-oxo-3- [(2S) -2- (2-pyridyl) -2- (4-trifluoromethoxyphenyl) -ethylamino] -4,6,7,8-tetrahydropyrrolo [1 , 2-a] pyrazine-6-carboxamide
EXAMPLE 9; (6S) -N- [(6-Amino-2-methyl-3-pyridyl) -methyl-4-oxo-3- [(2R) -2- (4,6-dimethyl-2-pyridyl) trichlorohydrate - 2- (4-methoxyphenyl) -ethylamino] -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
EXAMPLE 119 (6S) -N - [(6-Amino-2-methyl-3-pyridyl) -p? And yl-4-oxo-3- [(2S) -2- (4,6-dimethyl) trichlorohydrate] 2- pyridyl) -2- (4-methoxyphenyl) -ethylamino] -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
EXAMPLE 120: (6S) -N- [(6-Amino-2-methyl-3-pyridyl) -methyl-4-oxo-3- [(2R) -2- (5-methyl-2-pyridyl) trichlorohydrate) -2- (2-fluoro-4-methoxyphenyl) -ethylamino] -4,6,7,8-tetrahydropyrole [1,2- a] pyrazine-6-carboxamide
EXAMPLE 121 (6S) -N- [(6-Amino-2-methyl-3-pyridyl) -methyl-4-oxo-3- [(2S) -2- (5-methyl-2-pyridyl) trichlorohydrate] 2- (2-f-luoro-4-methoxyphenyl) -ethylamino] -4,6,7,8-tetrahydropyrrolo [1,2- a] pyrazine-6-carboxamide
EXAMPLE 122 (6S) -N - [(6-Amino-2-methyl-3-pyridyl) -methyl-4-oxo-3- [(2R) -2- (5-methoxy-2-pyridyl) trichlorohydrate] 2- (2,6-dimethyl-4-methoxyphenyl) -ethylamino] -4,6,7,8-tetrahydropyrrolo [1,2- a] pyrazin-6-sarboxamide
EXAMPLE 123 (6S) -N - [(6-Amino-2-methyl-3-pyridyl) -methyl-4-oxo-3- [(2S) -2- (5-methoxy-2-pyridyl) trichlorohydrate] 2- (2,6-dimethyl-4-methoxyphenyl) -ethylamino] -4,6,7,8-tetrahydropyrrolo [1,2- a] pyrazin-6-sarboxamide
EXAMPLE 124 (6S) -N- [(6-Amino-2-methyl-3-pyridyl) -methyl-4-oxo-3- [(2R) -2- (4,6-dimethyl-2-pyridyl) trichlorohydrate] ) -2- (4-methyl-2-methoxyphenyl) -ethylamino] -4,6,7,8-tetrahydropyrrolo [1,2- a] pyrazine-6-carboxamide EXAMPLE 12 (6S) -N- [( 6-Amino-2-methyl-3-pyridyl) -methyl-4-oxo-3- [(2S) -2- (4,6-dimethyl-2-pyridyl) -2- (4-methyl-2-methoxyphenyl) ) -ethylamino] - 4,6,7,8-tetrahydropyrrolo [1,2- a] pyrazine-6-carboxamide
EXAMPLE O 126: (6S) -N - [(6-Amino-2-methyl-3-pyridyl) -methyl-3- [2, 2-bis- (4-dimethylamino-phenyl) -ethylamino] -4-tetrahydrochloride -oxo-4,6,7,8-tetrahydro-pyrrolo [1,2-a] pyrazine-6-carboxamide
PLO AXIS 127 (6S) -N- [(6-Amino-2-methyl-3-pyridyl) -methyl-3- [2,2-bis- (2-fluorophenyl) -ethoxylamino] -4-oxo- 4, 6,7, 8-tetrahydropyrrolo [1, 2- a] pyrazine-6-carboxamide
EXAMPLE 128 (6S) -N- [(6-Amino-2-methyl-3-pyridyl) -methyl-3- [2, 2-bis- (2-methoxy-phenyl) -ethylamino] -4-oxohydrochloride -4, 6.7, 8-tetrahydropyrrolo [1,2- a] pyrazine-6-carboxamide
EXAMPLE 129: (6S) -N- [(6-Amino-2-methyl-3-pyridyl) -methyl-3- [2, 2-bis- (2-chloro-phenyl) -ethylamino] -4- hydrochloride oxo-4, 6,7, 8-tetrahydropyrrolo [1, 2-a] pyrazine-6-carboxamide EXAMPLE 130 (6S) -N- [(6-Amino-2-methyl-3-pyridyl) methyl) hydrochloride 3- [2, 2-bis- (2-hydroxy-phenyl) -ethylamino] -4-oxo-4,6,7,8-tetrahydropyrrolo [1,2- a] pyrazine-6-carboxamide
EXAMPLE 131 (6S) -N- [(6-Amino-2-methyl-3-pyridyl) -methyl-3- [2, 2-bis- (3-methoxy-phenyl) -ethylamino] -4-oxohydrochloride -4, 6.7, 8-tetrahydropyrrolo [1,2-a] pxrazin-6-sarboxamide
EXAMPLE 132 (6S) -N - [(6-Amino-2-methyl-3-pyridyl) -methyl-3- [2, 2-bis- (3-fluoro-phenyl) -ethylamino] -4-oxohydrochloride -4, 6.7, 8-tetrahydropyrrolo [1,2- a] pyrazine-6-carboxamide
EXAMPLE 133 (6S) -N- [(6-Amino-2-methyl-3-pyridyl) -methyl-3- [2, 2-bis- (3-sloro-phenyl) -ethylamino] -4-oxohydrochloride -4, 6.7, 8-tetrahydropyrrolo [1,2-a] pyrazin-6-sarboxamide
EXAMPLE 134 (6S) -N- [(6-Amino-2-methyl-3-pyridyl) -methyl-3- [2, 2-bis- (3-hydroxy-phenyl) -ethylamino] -4-oxohydrochloride -4, 6.7, 8-tet ahydropyrrolo [1, 2-a] pxrazin-6-sarboxamide EXAMPLE 135 (6S) -N- [(6-Amino-2-methyl-3-pyridyl) -methyl) -hydrochloride 4-oxo-3- [(2R) -2- (4-methoxy-phenyl) 2- (2-benz or [c] pyridyl) -ethylamino] -4,6,7,8-tetrahydropyrrolo [1, 2 - a] pyrazine-6-carboxamide
EXAMPLE 136: (6S) -N- [(6-Amino-2-methyl-3-pyxdxl) -methyl-4-oxo-3- [(2S) -2- (4-methoxy-phenyl) -2-trislorohydrate - (2-benzo [c] pyridyl) -ethylamino] -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
EXAMPLE 137 (6S) -N- [(6-Amino-2-methyl-3-pyridyl) -methyl] -3- [2, 2-bis- (2-thienyl) -ethylamino] -4-oxo- (6S) -hydrochloride 4, 6,7, 8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
EXAMPLE O, 138; (6S) -N- [(6-Amino-2-methyl-3-pyridyl) -methyl-4-oxo-3- [(2R) -2-phenyl-2-enenellamino] -4-hydrochloride, 6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
EXAMPLE 139 (6S) -N- [(6-Amino-2-methyl-3-pyridyl) -methyl-4-oxo-3- ((2S) -2-phenyl-2-enene] lamino] dihydrochloride] -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazox-6-carboxamide EXAMPLE 140 (6S) -N- [(6-Amino-2-methyl-3-pyridyl) -methyl-4-dihydrochloride] -oxo-3- [(2R) -2-hydroxy-2-phenyl-2-phenethylamino] -4,6,7,8-tetrahydropyrrolo [1,2- a] pyrazine-6-carboxamide
EXAMPLE 141 (6S) -N- [(6-Amino-2-methyl-3-pyridyl) -methyl-4-oxo-3- [(2S) -2-hydroxy-2-phenyl-2-phenethylamino] dihydrochloride] -4,6,7, 8-tetrahydropyrrolo [1,2- a] pyrazin-6-sarboxamide
EXAMPLE 142 (6S) -N - [(6-Amino-2-methyl-3-pyridyl) -methyl-4-oxo-3- [N-methyl-2-phenyl-2-phenethylamino] -4-6-hydrochloride , 7, 8-tetrahydropyrrolo [1,2-a] pyrazin-6-sarboxamide
EXAMPLE 143: (6S) -N- [(6-Amino-2-methyl-3-pyridyl) -methyl-4-oxo-3- [N-methyl-2- (2-pyridyl) -2-phenethylamino] trislorohydrate ] -4,6,7,8-tetrahydropyrolo [1,2-a] pyrazine-6-carboxamide
EXAMPLE 144 (6S) -N - [(6-Amino-2-methyl-3-pyridyloxy) -methyl-3- [(2, 2-diphenylethyl) amino] -4-OXO-4,6,7, dihydrochloride 8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide EXAMPLE 145: (6S) -N- [(4,6-Dimethyl-2-etholaminocarbonylmethoxy-3-pyridyl) methyl-3- [(2, 2- diphenylethyl) amino] -4 -oxo-4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
EXAMPLE 146 (6 S) - N - [(2-Etxlsarbamoylmethoxy) -bensil-4-oxo-3- [(2R) -2- (5-methyl-2-pyridyl) -2- (p-tolyl) dihydrochloride] ethylamino] -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazin-6-sarboxamide
EXAMPLE 147 (6 S) - N - [(2-Ethylcarbamoylmethoxy) -benzyl-4-oxo-3- [(2S) -2- (5-methyl-2-pyridyl) -2- (p-tolyl) -hydrochloride ethylamino] -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
EXAMPLE 148 (6S) -N- [(6-Amino-2, 5-dimethyl-3-pyridyl) -methyl-3- [(2R) -2- (5-methyl-2-pyridyl) -2- trislorohydrate (p-tolyl) -ethylamino] -4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
EXAMPLE 149 (6S) ~ N- [(6-.Amino-2, S-dimethyl-S-pyridyl) -methyl-3- [(2S) -2- (5-metxl-2-pyridyl) -2-trichlorohydrate - (p-tolyl) -ethylamino] -4-oxo-4, 6, 7, 8- tetrahxdropirrolo [1, 2-a] pyrazine-6-carboxamide EXAMPLE 150 (6S) -N- [(6-Amino) trichlorohydrate -2-methyl-3-pyridyl) -methyl-4-oxo-3- [(2R) -2- (5-methyl-2-pyridyl) -2- (4-methyl-2-methoxyphenyl) -ethylamino] - 4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
EXAMPLE 151 (6S) -N - [(6-Amino-2-methyl-3-pyridyl) -methyl-4-oxo-3- [(2S) -2- (5-methyl-2-pyridyl) trichlorohydrate - 2- (4-methyl-2-methoxyphenyl) -ethylamino] -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazin-6-sarboxamide
EXAMPLE 152 (6S) -N- [(6-Amino-2-methyl-3-pyridyl) -methyl] -4-oxo-3- [(2R) -2- (4,6-dimethyl-2-tris-hydrochloride. pyrid 1) -2- (2,4-dimethoxy-enyl) -ethylamino] -4,6,7,8-etrahydropyrrolo [1,2-a] pyrazine-6-carboxamide
EXAMPLE 153 (6S) -N- [(6-Amino-2-methyl-3-pyridyl) -methyl-4-oxo-3- [(2S) -2- (4,6-dimethyl-2-pyridyl) trishydrochloride ) -2- (2,4-dimethyl phenyl) -ethylamino] -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide PHARMACOLOGICAL STUDY OF COMPOUNDS OF THE INVENTION
EXAMPLE 154: Anticoagulant activity, measurement of thrombin time and activated cephalin time in humans
In order to evaluate the anticoagulant activity of the compounds of the invention, the thrombin time (TT), and activated cephalin time (ACT) for human plasma samples were determined. A ST4 coagulometer (Diagnostica Stago, France) was used. Plasma is taken, deficient in platelets and lyophilized (Stago) in distilled water. The TT is obtained using the Prest Thrombin reagent and ACT using the PTT Automate Cephalin reagent. Inhibitor is added as a solvent (10 μl) to plasma (90 μl), and the incubation is carried out for 2 minutes at 37 ° C. 100 μl of Prest Thrombin (TT) or PTT Automate Cephalin (ACT) are added and a stopwatch is started at the same time. Under these conditions, the TT is of the order of 18 seconds and the ACT is of 12 seconds. The activity of an antagonist was evaluated by its ability to prolong the TT and the ACT in relation to the control. The effect of the inhibitors is expressed by the concentration in μM that doubles the coagulation time (Ctt2).
The compounds of the invention cause a very significant prolongation of the coagulation times and of Ctt2 are given in Table 1 below, by way of example:
Table 1
EXAMPLE 155: Inhibition of thrombin and serine proteases of f brinólxsis
For an in vitro evaluation of the inhibitory activity of the products of the invention in human thrombin (Sigma, specific activity 3230 UNIH / mg), purified human fibrinogen (4 mM, Stago) (Fg) is added to a given amount of thrombin (0.7 nM) that has previously been incubated with or without the inhibitor to be tested (20 ° C, 10 minutes). For an in vitro evaluation of the selectivity of the products with respect to plasmin, the same protocol is applied to purified human plasmin (2 nM, Stago) using as substrate a peptide containing paranitroanilide: <Glu-Phe-Lys-pNA (0.50 mM, S 2403, Kabi). The inhibitors, enzymes and substrates are diluted in the same buffer (0.01 mM phosphate buffer, PH), 7.4 containing 0.12 M sodium chloride and 0.05% bovine serum albumin) and then distributed in a polystyrene microtiter plate in a volume of 50 μl. Fibrin formed by thrombin or by paranitroanilide released by the action of serine protease is measured using a spectrophotometer at 405 nm after 15 to 30 minutes of reaction at 20 ° C. Table 2 below provides in nM, the concentration of the compounds that inhibit 50% of the enzymatic activity (IC50) of the thrombin compared to the control if product. The results obtained show that the compounds of the invention are potent inhibitors of human thrombin with respect to human fibrinogen.
Table 2
Table 3 below provides in nM the concentration of the compounds that inhibit 50% of the enzymatic activity (IC50) of professed fibrinolysis. The results obtained show that the compounds of the invention have a very significant selectivity towards the serine proteases of fibrinolysis.
Tafo to 3
EXAMPLE 156; Anticoagulant activity after administration per os to dogs
Male or female dogs weighing 11 to 28 kg are treated orally with the products of the invention (5 or 10 mg / kg). The coagulation times (TT, ACT) are determined from dog plasma samples 10 minutes before and 30 minutes, 1 hour, 2 hours, 4 hours and 6 hours after the administration of the products. The measurements of the coagulation times are carried out as described in Example 114. Under the conditions of our experiments, the TT is of the order of 19 seconds and the ACT is of the order of 18 seconds. The substances of the invention significantly increase TT and ACT in animals. Table 4 summarizes the results obtained. The results show that the maximum increase in TT and ACT obtained after p.o. of the dogs. The values show the number of times in which the initial time has increased.
Table 4 Maximum increments of TT and ACT (number of times the initial time has increased)
EXAMPLE 157 Pharmaceutical composition
Formulation for the preparation of 1000 tablets, each with a dose of 10 mg: Compound of example 1 10 g Hydroxypropyl cellulose 2 g Wheat starch 10 g Lactose 100 g Magnesium stearate 3 g Talc - 3 g
Claims (10)
1. A compound of formula (I) wherein: * Rx represents a hydrogen atom or a linear or branched (C? -C6) alkyl group (optionally substituted by one or more identical or different substituents which are selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, carboxy, alkoxycarbonyl ( C? -C6) linear or branched and carbamoyl groups), a hydroxy group, a cycloalkyl group, a heterocycloalkyl group or a group of formula (G): Where A? represents a simple link, a group -CH2-, -CH2-CH2-, or -N (CH3) - or an oxygen or sulfur atom, and X, and X2, which may be identical or different, each represents a carbon or nitrogen atom, * R represents a hydrogen atom or a linear or branched (C? -C6) alkyl group, represents a saturated ring having from 4 to 7 members in the ring which may contain, in addition to the nitrogen atom, one or two heteroatoms which select from the groups O, S or -N (R2) -, R2 represents a hydrogen atom or a straight or branched alkyl group (C? -C6),? n represents an integer where l < n < 6, * -Ar represents an aryl or heteroaryl group, their isomers, their N-oxides and addition salts thereof, with a pharmaceutically acceptable acid or base. The term "aryl group" is understood to mean phenyl, biphenyl or naphthyl, each of these groups is optionally substituted by one or more halogen atoms and / or by one or more identical or different groups which are selected from alkyl (C? -C6) linear or branched, (optionally substituted by a hydroxy or carboxy group, or by a carbamoyl group (itself optionally substituted by one or two linear or branched alkyl groups (C? -C6)), alkoxy (C? -C6) linear or branched, hydroxy, trihaloalkyl (C? -C6) in which the alkyl portion is linear or branched, trihalogenoalkoxy, in which the alkyl portion is linear or branched, amino (optionally substituted by one or two alkyl groups) (C? -C6) linear or branched), a linear or branched alkylcarbonyl-xi group, carboxymethoxy and carbamoylmethoxy (optionally N-substituted by one or two linear or branched alkyl groups (C, -C6)). The term "heteroaryl group" is understood to mean a monocyclic or bicyclic aromatic group having from 5 to 12 members in the ring and containing 1, 2 or 3 heteroatoms which are selected from oxygen, nitrogen and sulfur, it being understood that the heteroaryl may optionally being substituted by one or more halogen atoms and / or by one or more identical or different groups which are selected from straight or branched (C-C6) alkyl (optionally substituted by a hydroxy or carboxy group or by a carbamoyl group (in itself optionally substituted by one or two linear or branched (C, -C ,,) alkyl groups), hydroxy, straight or branched (C? -C6) alkoxy, trihaloalkyl (C? -C6) in which the alkyl portion is linear or branched, phenyl, amino (optionally N-substituted by one or more linear or branched alkyl (C? -C6) groups), carboxymethoxy and carbamoylmethoxy (optionally substituted by one or two linear (C? -C6) alkyl groups or branched). The term "cycloalkyl group" is understood to mean a saturated or unsaturated monocyclic or bicyclic hydrocarbon group having from 3 to 12 members in the ring, it being understood that the ring system may optionally be substituted by one or more halogen atoms and / or by one or more identical or different groups which are selected from linear or branched alkyl (C? ~ C6), straight or branched (C? -C6) alkoxy, hydroxy, trihaloalkyl (C? -C6) in which the alkyl portion is linear or branched, amino (optionally substituted by one or more linear or branched alkyl groups (C? -C6)), and aryl. The term "heterocycloalkyl group" is understood to mean a saturated or unsaturated monocyclic or bicyclic group having from 4 to 12 members in the ring and containing 1, 2 or 3 heteroatoms that are selected from oxygen, nitrogen and sulfur, it being understood that the heterocycle may be optionally substituted by one or more halogen atoms and / or by one or more identical or different groups which are selected from straight or branched alkyl (C? -C6), alkoxy (C-), Cg) linear or branched, hydroxy, trihaloalkyl (C, -C in which the alkyl portion is linear or branched, amino (optionally substituted by one or more linear or branched alkyl (C? -C6) groups), aryl and diarylmethyl.
2. The compound of formula I) as defined in claim 1, wherein n is 1.
3. The compound of formula I) as defined in claim 1, wherein represents a pyrrolidinyl group.
4. The compound of formula (I) as defined in any of claims 1 to 3, wherein Ar represents a phenyl or pyridyl group, each of these groups is optionally substituted by one or more halogen atoms and / or by one or more more identical or different groups which select from straight or branched alkyl (C? -C6) (optionally substituted by a hydroxy or carboxy group or by a carbamoyl group (itself optionally substituted by one or two linear alkyl groups (Cj-C6)) or branched)), linear or branched (C-C6) alkoxy, hydroxy, trihaloalkyl (C? -C6) in which the alkyl portion is linear or branched, amino (optionally substituted by one or two alkyl groups (C? C6) linear or branched), carboxymethoxy and carbamoylmethoxy (optionally N-substituted by one or two linear or branched alkyl groups (C? -C6)).
5. The compound of formula (I) as defined in claim 4, wherein Ar represents a pyridyl group optionally substituted by one or more halogen atoms and / or by one or more identical or different groups which select from alkyl (C? - C6) linear or branched (optionally substituted by a hydroxy or carboxy group or by a carbamoyl group (itself optionally substituted by one or two linear or branched alkyl groups (C¿-C6)), (C? -C6) alkoxy linear or branched, hydroxy, trihaloalkyl (C? -C6) in which the alkyl portion is linear or branched, amino (optionally substituted by one or two linear or branched alkyl groups (Cj-Cg)), carboxymethoxy and carbamoylmethoxy (optionally N) -substituted by one or two linear or branched alkyl groups (C? -C6).
6. The compound of formula (I) as defined in claim 1, which is (6S) -N- f (6-amino-2-methyl-3-pyridyl) methyl] -4-oxo-3- (2- phenethylamino) -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide, their isomers and their addition salts with a pharmaceutically acceptable acid.
7. A process for the preparation of the compounds of formula (I) as defined in claim 1, characterized in that a compound of formula (II): wherein A is as defined for formula (I), Pj represents a protective group of the amino function and Bn represents a benzyl group, is reduced using an appropriate reducing agent, to provide a compound of formula (III): wherein A, Px and Bn are as defined above, the hydroxy function of such compound of formula (III) is converted to the methoxy function and then to the cyano function by conventional reactions of organic chemistry to provide, after deprotection of the amino function, a compound of formula (IV): NC (IV) C02Bn wherein A and Bn as defined in the foregoing, compound of formula (IV) which is reacted on oxalyl chloride to provide a compound of formula (V): wherein A and Bn are as defined in the foregoing, compound of formula (V) which is reacted with a compound of formula (VI): R.-NH, (VI) wherein Rx is as defined for formula (I), to provide a compound of formula (VII): wherein A, Bn and Rx are as defined in the above, compound of formula (VII) which is then converted by catalytic hydrogenation to a compound of formula (VIII): wherein A, and Rx are as defined in the above, compound of formula (VIII) which is then converted by catalytic hydrogenation in a compound to an alkaline medium of formula (IX): wherein A and Rx are as defined in the above, compound of formula (IX) which is reacted with a compound of formula (X): where n and Ar are as defined for the formula : D to provide, after deprotection where appropriate, a compound of formula (I), compound of formula (I) which is purified, if necessary, according to a conventional purification technique, and separated, if is desired, in its isomers according to a conventional separation technique, and converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base.
8. The pharmaceutical composition comprising as active ingredient a compound as defined in any of claims 1 to 6 in combination with one or more inert, non-toxic, pharmaceutically acceptable carriers.
9. The pharmaceutical composition as defined in claim 8, for use as a trypsin inhibitor related to serine protease.
10. The pharmaceutical composition as defined in claim 9, for use as a thrombin inhibitor. SUMMARY OF THE INVENTION The compound of formula (I): where: hydrogen, an alkyl group - Rx represents a substituted atom, cycloalkyl, or heterocycloalkyl, or optionally a group of formula (G): (G) , represents a single bond, a group N (CH3) - or an oxygen or sulfur atom, and Xx den be identical or different, represent carbon or nitrogen, sit a hydrogen atom or a group I or branched, represents a saturated ring that has 4 to 7 members, enter an integer where l < n < 6, an aryl or heteroaryl group, os, their N-oxides and pharmaceutically acceptable base addition salts. os.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR99.07538 | 1999-06-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA00005846A true MXPA00005846A (en) | 2002-07-25 |
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