MXPA98001190A - Inhibitors of prolil endopeptid - Google Patents
Inhibitors of prolil endopeptidInfo
- Publication number
- MXPA98001190A MXPA98001190A MXPA/A/1998/001190A MX9801190A MXPA98001190A MX PA98001190 A MXPA98001190 A MX PA98001190A MX 9801190 A MX9801190 A MX 9801190A MX PA98001190 A MXPA98001190 A MX PA98001190A
- Authority
- MX
- Mexico
- Prior art keywords
- group
- carbon atoms
- alkyl
- atom
- hydrogen atom
- Prior art date
Links
- 230000002401 inhibitory effect Effects 0.000 title claims description 20
- 239000003112 inhibitor Substances 0.000 title description 11
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 184
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 59
- 150000001875 compounds Chemical class 0.000 claims description 58
- 125000000217 alkyl group Chemical group 0.000 claims description 51
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 36
- 239000000126 substance Substances 0.000 claims description 34
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
- 125000003545 alkoxy group Chemical group 0.000 claims description 24
- 125000004430 oxygen atoms Chemical group O* 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 20
- 239000011780 sodium chloride Substances 0.000 claims description 20
- 125000005843 halogen group Chemical group 0.000 claims description 19
- 125000004043 oxo group Chemical group O=* 0.000 claims description 19
- 229910052717 sulfur Inorganic materials 0.000 claims description 19
- 125000004434 sulfur atoms Chemical group 0.000 claims description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 125000003277 amino group Chemical group 0.000 claims description 17
- -1 mercapto, carboxyl group Chemical group 0.000 claims description 16
- 125000002252 acyl group Chemical group 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 230000003287 optical Effects 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 11
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 9
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 9
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 9
- 239000002207 metabolite Substances 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- 239000000651 prodrug Substances 0.000 claims description 9
- 229940002612 prodrugs Drugs 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000005359 phenoxyalkyl group Chemical group 0.000 claims description 8
- 125000004423 acyloxy group Chemical group 0.000 claims description 7
- 125000004414 alkyl thio group Chemical group 0.000 claims description 7
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 7
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 7
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 7
- IQPQWNKOIGAROB-UHFFFAOYSA-N isocyanate group Chemical group [N-]=C=O IQPQWNKOIGAROB-UHFFFAOYSA-N 0.000 claims description 7
- ZBKFYXZXZJPWNQ-UHFFFAOYSA-N isothiocyanate group Chemical group [N-]=C=S ZBKFYXZXZJPWNQ-UHFFFAOYSA-N 0.000 claims description 7
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 7
- 125000004429 atoms Chemical group 0.000 claims description 6
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 claims description 6
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- 239000011541 reaction mixture Substances 0.000 claims description 6
- 108010090225 EC 3.4.21.26 Proteins 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M thiocyanate group Chemical group [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 claims description 5
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 5
- 150000008065 acid anhydrides Chemical class 0.000 claims description 4
- 238000007792 addition Methods 0.000 claims description 4
- 125000005466 alkylenyl group Chemical group 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- 125000005982 diphenylmethyl 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] 0.000 claims description 4
- 125000003700 epoxy group Chemical group 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims description 3
- 150000008064 anhydrides Chemical class 0.000 claims description 3
- 125000005842 heteroatoms Chemical group 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 5
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims 3
- 241000124008 Mammalia Species 0.000 claims 2
- 150000001718 carbodiimides Chemical class 0.000 claims 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 2
- 239000000969 carrier Substances 0.000 claims 2
- 150000004820 halides Chemical class 0.000 claims 2
- 238000005020 pharmaceutical industry Methods 0.000 claims 2
- 125000000858 thiocyanato group Chemical group *SC#N 0.000 claims 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N 2-Pyrrolidone Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims 1
- 125000005741 alkyl alkenyl group Chemical group 0.000 claims 1
- 125000001651 cyanato group Chemical group [*]OC#N 0.000 claims 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 abstract description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 abstract 1
- DTBNBXWJWCWCIK-UHFFFAOYSA-N Phosphoenolpyruvic acid Natural products OC(=O)C(=C)OP(O)(O)=O DTBNBXWJWCWCIK-UHFFFAOYSA-N 0.000 description 34
- 102100019806 PREP Human genes 0.000 description 20
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 14
- 210000004556 Brain Anatomy 0.000 description 10
- 102000004190 Enzymes Human genes 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 206010001897 Alzheimer's disease Diseases 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000005859 coupling reaction Methods 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- 238000005119 centrifugation Methods 0.000 description 4
- 230000001808 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 150000002829 nitrogen Chemical group 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- HDRSLHFTJYMQIL-KRWDZBQOSA-N 4-phenyl-1-[(2S)-2-(pyrrolidine-1-carbonyl)pyrrolidin-1-yl]butan-1-one Chemical compound N1([C@@H](CCC1)C(=O)N1CCCC1)C(=O)CCCC1=CC=CC=C1 HDRSLHFTJYMQIL-KRWDZBQOSA-N 0.000 description 3
- 210000003169 Central Nervous System Anatomy 0.000 description 3
- 230000036499 Half live Effects 0.000 description 3
- 210000004185 Liver Anatomy 0.000 description 3
- 230000032683 aging Effects 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 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
- 239000000203 mixture Substances 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 206010065040 AIDS dementia complex Diseases 0.000 description 2
- 108010059378 Endopeptidases Proteins 0.000 description 2
- 102000005593 Endopeptidases Human genes 0.000 description 2
- 206010021143 Hypoxia Diseases 0.000 description 2
- 206010061255 Ischaemia Diseases 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L MgCl2 Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 210000001853 Microsomes, Liver Anatomy 0.000 description 2
- 206010053643 Neurodegenerative disease Diseases 0.000 description 2
- 206010039966 Senile dementia Diseases 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 230000000875 corresponding Effects 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 230000001146 hypoxic Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 235000015277 pork Nutrition 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 230000000750 progressive Effects 0.000 description 2
- 230000002035 prolonged Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
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- RWRDLPDLKQPQOW-UHFFFAOYSA-N pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
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- 230000001225 therapeutic Effects 0.000 description 2
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ADNPLDHMAVUMIW-CUZNLEPHSA-N (2S)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-N-[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-1-amino-4-methylsulfanyl-1-oxobutan-2-y Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 ADNPLDHMAVUMIW-CUZNLEPHSA-N 0.000 description 1
- CRPTXKKKIGGDBX-UHFFFAOYSA-N (Z)-but-2-ene Chemical group [CH2]C=CC CRPTXKKKIGGDBX-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N 1,4-Butanediol, dimethanesulfonate Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
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- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
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- HMKSXJBFBVGLJJ-UHFFFAOYSA-N 4-(1,3-dioxoisoindol-2-yl)butanoic acid Chemical compound C1=CC=C2C(=O)N(CCCC(=O)O)C(=O)C2=C1 HMKSXJBFBVGLJJ-UHFFFAOYSA-N 0.000 description 1
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- ZKJOXOJMGXFSPF-QYZPTAICSA-N [[(2R,3R,4R,5R)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate;hydrate Chemical compound O.NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 ZKJOXOJMGXFSPF-QYZPTAICSA-N 0.000 description 1
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- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 1
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 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
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([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
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- QXNVGIXVLWOKEQ-UHFFFAOYSA-N disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
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- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
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- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- XNSAINXGIQZQOO-SRVKXCTJSA-N protirelin Chemical compound NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H]1NC(=O)CC1)CC1=CN=CN1 XNSAINXGIQZQOO-SRVKXCTJSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- NFNGYUXIXLYXKH-QRPNPIFTSA-N pyrrolidin-1-yl-[(2S)-pyrrolidin-2-yl]methanone;hydrochloride Chemical compound Cl.C1CCCN1C(=O)[C@@H]1CCCN1 NFNGYUXIXLYXKH-QRPNPIFTSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
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Abstract
The present invention relates to new propyl endopeptidase inhibitors of general formula (
Description
INHIBITORS OF PROLIL ENDOPEPTIDASE
DESCRIPTION OF THE INVENTION The present invention relates to new compounds of the general formula (I), to pharmaceutical compositions containing them, and to the processes for the preparation of these compounds. A further aspect of our present invention is the use of the novel compounds of the general formula (I) for the treatment of CNS diseases, by inhibition of certain enzymes described later on this page. Because of the incidence and social consequences of diseases of the central nervous system, accompanied by amnesia, dementia and the progressive decline of cognitive and intellectual functioning, for example Alzheimer's disease, AIDS dementia, senile dementias of various origins (hypoxia) , ischemia), there are significant demands for new pharmaceutical compounds to treat and prevent the diseases mentioned above. The prolyl endopeptidase PE or PEP is an enzyme that hydrolyzes post-proline (PPCE). It is widespread in mammalian species, and can be found in various organs of the body. The concentration of the enzyme is highest in the brain, testes and skeletal muscle (Yoshimoto ^ T., Ogita, K__, Walter, R. , Koida., M_ and Tsu.ru., O. Biochim, Biophys, Acta, 569, 184-192 (1979).
PEP has some important role in memory processes, due to the fact that its substrates are biologically active neuropeptides (substance P, hormone that releases thyrotropin, Arg8-Vasopressin). These neuropeptides exert characteristic pharmacological effects on the central nervous system: they are capable of changing the performance of animals and humans in learning and memory tasks (Toide, K., Iwamoto, Z., Fui ara, T., and Abe, H. : J. Pharm, Exp. Therapeutics, 274, 1370-1378 (1995), Riedel, W. and Jolles, J., Drugs &Aging, 8, Z45-274 (.1996)). The neuropeptide substance. P prevents neuronal loss induced by β-amyloid and the expression of Alz-50 proteins in the cerebral cortex
(Kowall, N, Beal, M.F., Busciglio, J., and Duffy, L.K.: Proc.
Nati Acad_e., 88, 724.7-7251 (L991)) .. In brains of patients with Alzheimer's disease, it is well known that the content of cerebral Ach decreases, and brain function suffers severe damage (0'learyy R. and O'Connor, B., J. Neurochep, 65. "953-963 (1595)). An in ihidox of PEP, through an increase in the concentration of TRH, could induce Ach release in the brain, which should result in a better cognitive performance. It can be assumed that a highly specific PEP inhibitor could be useful in the treatment of diseases of the central nervous system in neurodegenerative disorders. The new inhibitor of PEP as a new drug would be:
1. a nootropic drug that has an effect of memory improvement and anti-amnestic, and could be used in the treatment of cognitive decline related to aging;
2. an agent neu apratectnr ,. useful in therapy, of a., acute events (ischemia / hypoxia) b., progressive neurodegenerative disorders: - Alzheimer's disease - AIDS dementia - Huntington's disease. Senile dementia and Alzheimer's disease have become a serious problem and are growing rapidly in the aging population, and a PEP inhibitor may be useful for the general treatment of the serious diseases mentioned above. We set ourselves the task of preparing new PEP inhibitors that exhibited advantageous characteristics that could serve as active ingredients of new drugs. By advantages we mean a strong inhibitory effect of PEP, selectivity, easy transfer through the blood brain barrier, a prolonged half-life, good oral resorption, improved chemical and biological stability, and advantageous therapeutic profile, including lower toxicity and low probability of side effects. During the synthesis and biological examination of numerous new compounds, we find that the new compounds of the formula
(I), wherein A means an organic cyclic group, substituted once several times, or unsubstituted, containing a nitrogen atom with a free valence, and optionally one or more additional heteroatoms selected from a group consisting of nitrogen atom, sulfur atom or oxygen atom, especially a group having the general formula (1), (a), (2), (2a), (3), (3a), (4), (5) ), (6)., (7), (8), (9), (10), (lia), (llb), (12), (12a), (12b), (13), (13a) , (14), (15), (16), (17), (18), (19), (19a), (20), (20a), (21), (22), (23), ( 23a), (23b), (24), (25), (25a), (26), (27), (28), (28a), (28b), (29), (29a), (30) , (31), (32), (32a), (33), (34), (35), (36) - wherein R means a hydrogen atom, an alkyl group of 1-4 carbon atoms, or an aryl or aralkyl group of 6-12 a-tamas. of carbon; R1, R2, R3 and R4 signify, independently of one another, a hydrogen atom, a halogen atom, a hydroxyl group, straight or branched chain alkyl or alkenyl or alkynyl or alkoxy or alkenyloxy or alkynyloxy groups, containing 1 -6 carbon atoms, a nitro group, an amino group, monoalkylamino or onacylamino of 1-12 carbon atoms, a dialkylamino or diacylamino group of 2-24 carbon atoms - wherein the acyl group is one of the alkyl type., aralkyl, cycloalkyl or aryla-, a cyano group, a mercapto group, carboxyl group, esterified carboxyl group of 2-7 carbon atoms, hydroxyalkyl group of 1-6 carbon atoms
carbon, acyl group of 1-7 carbon atoms, acyloxy group of 1-7 carbon atoms, phenyl or benzyl group, anilino group, benzoyl group, phenoxy group, benzyloxy group, isocyanate group, isothiocyanate group, alkylthio group of 1 6 carbon atoms, sulfamino or sulfamollo group, thiocyanate group or cyanate, R5 and R6 mean, independently of one another, hydrogen atom, hydroxyl group, phenyl group or alkyl group of 1-4 carbon atoms, or R5 and R6 together they mean an oxo group; R7 is an alkyl group of 1-6 carbon atoms; R8 means a hydrogen atom or an alkyl group of 1-6 carbon atoms, or an aralkyl group of 7-10 carbon atoms; dotted line means an optional chemical bond; n is zero, 1, 2 or 3; X means a group -CH2-, a group -NH-, a carbon atom, or a hydrogen atom, an oxygen atom or an amino group; or A means a group R '-YN = or a group R'-YN (R9) -, where R' means an alkyl group of 1-6 carbon atoms, an aralkyl group of 7-10 carbon atoms, group diphenylmethyl, alkoxy group, arylalkyloxy group of 7-10 carbon atoms, or a phenyl or phenoxy or phenylalkyl group containing 7-10 carbon atoms, or a phenylalkyloxy group containing 7-10 carbon atoms, optionally
substituted with halogen atoms or alkyl groups of 1-4 carbon atoms, or nitro groups; Y means a chemical bond or an oxo, sulfonyl or sulfinyl group, R9 means a hydrogen atom or an alkyl group of 1-4 carbon atoms; - with the proviso that in the case of formulas (20) and (33) X can not mean a group -CH2-, a group -NH-, an oxygen atom or a sulfur atom, and in the case of formulas (30) and (31), X can not mean a group -CH2-, an oxygen atom or a sulfur atom or an amino group; B means a group - (CH2) m-C (0) -, where m is an integer from 1 to 21; or a group -0- (CH2) P-C (O) -, wherein p is an integer from 1 to 3; or a group
- n where R9, R10, R11, R12, R13 and R14
independently denote one of the other hydrogen, an alkyl or alkoxy group of 1-6 carbon atoms, halogen, an amino group optionally substituted with one or two alkyl groups of 1-6 carbon atoms; or a phenyl, phenoxy, or arylalkyl group of 7-12 carbon atoms, or an arylalkoxy group of 7-12 carbon atoms, each optionally containing 1, 2, or 3 identical or different substituents, identical to R 1, R2, R3 or R4; or
two of R3, R10, Ru, R1¿, R13 and R14 together mean an oxo or epoxy group, or an additional chemical bond, or four of them together signify two additional chemical bonds, and the remaining groups represent hydrogen atoms; or R9, R10, R11, R12, R13 and R14 mean, together with the carbon atoms of the chain, a saturated or unsaturated homocycle, containing 3-8 carbon atoms, or a saturated or unsaturated heterocycle containing 2 or more carbon atoms. -7 carbon atoms and a nitrogen or sulfur atom, to which an aromatic ring of 6-10 carbon atoms is optionally condensed and is zero or 1; C means a prolyl group, or one of the groups of formula (37), (38), (39), £ 40) or (41) - wherein n is zero or 1 or 2, Hlg means a fluorine atom, chlorine, bromine, or iodine; R5 and R6 signify, independently of one another, a hydrogen atom, a hydroxyl group, a phenyl group or an alkyl group of 1-4 carbon atoms, or R5 and R6 together mean an oxo group; R16 means an alkoxy group of 1-4 carbon atoms, or a group -NH-CH2-CN, or a group -NH-CH2-C02R7, wherein R7 is defined above; or the structural unit D or L; or one of the groups of the formula (42) or (43) or (43a) - wherein the dotted line means a chemical bond optionally present-, s is 1, 2 or 3 - or a group of the formula (44 ) - where R15 means an atom of
hydrogen, an alkyl group of 1-6 carbon atoms, a phenyl or naphthyl group; or a group of the formula (45) - wherein Z means a group - NH, an oxygen atom or a sulfur atom; D means a covalent chemical bond, or a prolyl or thioprolyl group, or one of the groups of formula (37) or
(38), (39), (49) or (41); L represents a pyrrolidino or 2-cyanopyrrolidino, thiazolidino or 2-cyano-thiazolidino or piperidino group, optionally substituted with a halogen atom, or geminally with two halogen atoms; or a group of the formula (46) - wherein R17 signifies a hydrogen atom or a cyano group, n is 0, 1 or 2; or a group of formula (47) or (48) or (49); - and the optical, cis-trans, geometric isomers, epimers, tautomers, salts, prodrugs and human and mammalian metabolites thereof that have a significant inhibitory effect of the prolyl endopeptidase, and show one or more advantages mentioned above. Some preferred groups of compounds of the general formula (I) are as defined and claimed in claims 3, 8 and 9. The meaning of "an organic cyclic group substituted once or many times, or unsubstituted, containing an atom of nitrogen with a free valence, and optionally one or more additional heteroatom (s) selected from the group consisting of
of nitrogen atom, sulfur atom or oxygen atom "in the case of A covers all known monocyclic or polycyclic groups that satisfy the definition above In the case of a polycyclic group, the rings may be fused, and / or they may be in a spirocyclic position Some representative examples of the cyclic groups above are represented in formulas (1), (a), (2), (2a), (3), (3a), (4), ( 5), (6), (7), (8), (9), (10), (lia), (llb), (12), (12a), (12b), (13), (13a) , (14), (15), (16), (17), (18), (19), (19a), (20), (20a), (21), (22), (23), ( 23a), (23b), (24), (25), (25a), (26), (27), (28), (28a), (28b), (29), (29a), (30) , (31), (32), (32a), (33), (34), (35), (36) In the definitions of general formula (I), "alkyl group of 1-6 carbon atoms" means a straight or branched chain alkyl group of 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl The "aryl group of 6-10 atoms xle carbon" means, for example, phenyl, tolyl or naphthyl groups. The "aralkyl group of 6-10 carbon atoms" means for example benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl groups. The alkenyl group of 1-6 carbon atoms means a straight or branched chain alkenyl group such as vinyl, allyl, methacryl, crotyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 2-hexenyl, 5-hexenyl. The group
"C 1-6 alkynyl" means a straight or branched chain alkynyl group such as ethynyl, propargyl, 2-butynyl, 3-butynyl, 2-pentynyl, 4-pentynyl, 2-hexynyl, 5-hexynyl, or -methyl-2-hexynyl The cycloalkyl part of the "acyl group of 1-12 carbon atoms" means for example a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group These definitions can be used in the case of groups Alkyloxy, alkenyloxy, alkynyloxy, aryloxy, aralkyloxy, phenylalkyloxy or alkylamino or acylamino We have examined the inhibitory activity of PEP, and the biological stability of the compounds characterized by the formula (I) by applying the following methods: Measurement of PEP activity on rat brain extract After extraction of the cerebellum, whole brain of male rats (Sprague-Dawley, 180-200 g) was homogenized in a double volume of 0.1 M buffer in Tris-HCl, 1 mM EDTA, pH = 7.5 (buffer solution of PEP). The homogenized material was subjected to centrifugation for 30 minutes at 4 ° C to 4000 g, and the supernatant, which contained the enzyme, was collected. The pellet was resuspended in the same volume of buffer, as in the first case, and subjected again to centrifugation under the same conditions. The two supernatants were combined and stored in
aliquots of 1 ml at -70 ° C (for at least 3 months). The supernatant was thawed immediately before the activity measurements, and diluted in a 1:15 ratio with PEP buffer. The activity of the enzyme was measured using the fluorometric method described by JR Atack et al., (Eur. J. Pharmacol., 205, 157-163 (1991) .The reaction of the enzyme was performed at room temperature, for 15 minutes. , in the presence of 62.5 μM Z-glycyl-prolyl-7-amino-4-methyl-coumarin (Bachem Biochem.) as a highly specific synthetic substrate of PEP The inhibitory effect of the compounds was tested under the same conditions, presence of compound at 100 to 0.001 nM The formation of 7-amino-4-methyl-coumarin was detected spectrofluorometrically at an excitation wavelength of 370 nm and emission at 440 nm.The inhibition concentration of 50% of the compounds (IC5o) was calculated by adjusting curves of% inhibition of the enzyme versus inhibitor concentration (M) using the Hill equation.The IC50 values of the compounds of the general formula (I) are in the range of 100. nM - 1 pM Measurement of PEP activity in the brain of pork The prolile endopeptidase from purified pork brain was a kind donation by László Polgár (Enzymology Institute of the Hungarian Acade and of Sciences). The enzyme solution was diluted in the reaction mixture 400,000 times. The measurements were made under the same conditions as in the case of
in vitro measurements of the rat brain preparation. It was demonstrated that the compounds of general formula I are also active on PEP activity in pig brain. In vitro metabolism studies The biological stability of prolyl endopeptidase inhibitors was studied in preparations of mouse, rat and human liver microsomes (preparation of the Central Chemistry Institute of the Hungapan Academy of Sciences). Mouse and rat livers were combined and homogenized in 4 times their volume of Tps-HCl buffer solution (pH 7.4) containing 1.15% KCl and 1 mM EDTA. The homogenized materials were subjected to centrifugation for 30 minutes at 10,000 g, and the supernatants were further subjected to ultracentrifugation for 1 hour at 105,000 g. The pellets were homogenized again, and ultracentrifugation was repeated. The pellets were homogenized again, and diluted with buffer to a final volume of 0.5 g of liver / ml. The sample was frozen in 2 ml aliquots at -80 ° C. The preparations were characterized to determine activities of the cytochrome P450 isoenzyme. The new inhibitors of the general formula (I) were tested under the following conditions: the reaction mixture contained 2 mg of the liver microsomal protein, 0.1 M buffer in Tps-HCl (pH = 7.4), 2 mM in NADP, 20 M in disodium salt of glucose-6-phosphate, 10 mM in MgCl2, 5 U of
glucose-6-phosphate dehydrogenase, and 50 μM in PEP inhibitors in a final volume of 1.5 ml. After the incubation times of 0, 10, 20, and 40 minutes, the reaction was terminated by the addition of acetonitrile. The samples were subjected to centrifugation at 3000 rpm, for 10 minutes. The supernatant was analyzed by CLAR (Supelcosil C18). The amount of substrate that did not change was determined, and the half-life of the compounds was calculated. Some compounds of the general formula I had half-lives in human liver microsomes of more than 7 hours. Such good biological stability is in favor of an effect of prolonged duration in vivo, and is an advantage over other peptide type inhibitors, which are known to be biologically unstable. Published European Patent Application No. 0 232 849 A2 describes numerous PEP inhibitors, including SUAM-1221
(N- [N- (? -phenyl) butyryl-L-prolyl] pyrrolidine). The compounds of the general formula (I) exert a high inhibitory activity on the prolyl endopeptidase, and this is greater than that of the reference compound SUAM-1221 above, measured in our test system described above:
Compounds IC50 (M) in rat brain extract
Example 123 2.78 • 10"10 Example 31 3.60 • 10" 10 Example 171 4.51 • 10"10 SUAM-1221 3.12 • 10" 8 The preparation of the compounds of the general formula (I) was carried out by well-known methods of the literature, or by obvious chemical equivalents thereof, which are related to the synthesis of peptide-type substances. Units A and B of the compounds of the general formula ABCDL (I) - wherein the meanings of A, B, C, D, and L are as described above - are coupled by the reaction of the appropriate acid anhydride or other activated acid derivative and an amine, providing compounds of the general formula (II) - wherein the meanings of A and B are as described above. Coupling of units C and D also occurs by coupling the appropriate activated acid derivative, for example an acid anhydride and an amine. The coupling of the CD and L units to provide compounds of the general formula (III) - wherein the meanings of CD and L are as described above - is carried out by reacting the appropriate mixed anhydride and resp. ester and metallo-organic compound. The starting compounds corresponding to units A, B, C, D, and L are commercially available, or they can be
easily produced by a known transformation of them, as described in Chem. Pharm. Bulletin, 41 (9), 1583-1588 (1993). We have prepared the compounds of general formula (I) by reacting activated derivatives of compounds of general formula (I) with compounds of the general formula (III) under the amide coupling conditions customary in peptide chemistry. The activated derivatives of the compounds having the general formula (II) could be, for example, acid chlorides, which can be synthesized by applying halogenating agents (for example thionyl chloride). The active esters can be produced by 1-hydroxy-benzotriazole, in the presence of N, N '-dicyclohexylcarbodyl ida (Chem. Ber., 103, 788, 1970). The mixed anhydrides can be produced by chloroformic acid ester or pivaloyl chloride (Methoden der Organischen Chemie (Houben-Weyl) Band XV / 2, Synthese von Peptiden, Georg Thieme Verlag, Stuttgart, 1974). The coupling reaction can favorably be carried out preferably in an organic solvent, (at a temperature between -25 ° C and the boiling point of the reaction mixture). The use of agents that take up acid, for example organic amines, is favorable during the reaction. The compounds of the general formula (I) can be purified, if appropriate, by a conventional purification technique, the isomers from which they are separated, if
1
you want, by a conventional separation technique, and are converted, if necessary, to their addition salts with a pharmaceutically acceptable acid. The pharmaceutically acceptable acids may be, for example, hydrochloric, sulfuric, tartaric, fumaric, methanesulfonic, and the like. Another object of the present invention are pharmaceutical compositions containing, as an active ingredient, at least one compound of the general formula (I), or one of its addition salts with a pharmacologically acceptable acid, alone or in combination with one or more excipients or inert and non-toxic vehicles. More particularly, mention may be made, among the pharmaceutical compositions according to the invention, of those which are suitable for oral, parenteral, rectal or nasal administration, as simple or sugar-coated tablets, sublingual tablets, injectable compositions, infusions, concentrates , gelatin capsules, suppositories, creams, ointments, dermal gels, and the like. The dose varies according to the age and weight of the patient, the nature and severity of the disorder, and the route of administration. The latter can be oral, nasal, rectal or parenteral. The unit dose usually varies between 0.1 and 50 mg / kilo of
1
body weight, for a treatment taken 1 to 3 times per 24 hours. The invention will be further clarified by the following tabular, non-limiting examples, in greater detail, and by a detailed description of the process in the case of Example 4. Other embodiments of the invention will be apparent to the person skilled in the art of a consideration of this specification, or the practice of the invention described herein. EXAMPLES Description of the preparation of the compound represented in Example 4 (Table 1) To a solution prepared by dissolving 1.17 g (5.0 mM) of 4-phthalimidobutyric acid and 0.56 g (5.5 mM) of triethylamine in 20 ml of chloroform, they added dropwise 0.61 g (5.0 mM) of pivaloyl chloride at -15 ° C under agitation. The reaction mixture was stirred for 1 hour at the temperature mentioned above, and then a solution prepared by dissolving 1.03 g (5.0 mM) of L-prolyl pyrrolidine hydrochloride salt in a mixture of sodium hydroxide was added thereto dropwise. ml of chloroform and 1.5 ml (1.1 g, 11.0 mM) of triethylamine. The reaction mixture was stirred at room temperature for 4 hours, then washed successively with water, with 30% citric acid solution, with saturated aqueous sodium bicarbonate solution, with water and with saturated sodium chloride solution. The organic phase
dried over calcined magnesium sulfate, and evaporated. Crystallization of the residue from a mixture of 5 ml of chloroform and "10 ml of petroleum ether gave 1.1 g (53%) of N- (4-phthalimido-butanoyl) -L-prolyl-pyrrolidine, which melted at 148 ° C. 149 ° C. The compounds of the general formula I were synthesized by the method described above, starting from the corresponding compounds having the general formula (II) and (III) The structures and physical constants of several new compounds of the Formula general (I) are listed in Table 1.
Table 1
Secondary Factor Factor Point No. Structural Formula of CO Compound Retention Fusion
and
c
a, b, o, d Assignment of epimeros, can be reversed Abbreviations of eluents: A CM201 Chloroform: methanol = 20: 1 B BM 41 Benzene: methanol = 4: 1 C CM 41 Chloroform: methanol = 4: 1 D DM101 Dichloromethane: methanol = 10: 1 E CM955 Chloroform: methanol = 95: 5 F CM 91 Chloroform: methanol = 9: 1 G DM 91 Dichloromethane: methanol = 9: 1 I HA 21 n-Hexane: acetone = 2: 1 J HA 31 n-Hexane: acetone = 3: 1 K CA 101 Chloroform: acetone = 10: 1
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Having described the invention as above, property is claimed as contained in the following:
Claims (18)
- R14 1 -where R9, R: A R'Y R, R13 and R14 C- C- ¿? independently denote one of the other hydrogen, an alkyl or alkoxy group of 1-6 carbon atoms, halogen, an amino group optionally substituted with one or two alkyl groups of 1-6 carbon atoms; or a phenyl, phenoxy, or arylalkyl group of 7-12 carbon atoms, or an arylalkoxy group of 7-12 carbon atoms, each one of them optionally containing 1, 2 or 3 substituents, identical or different, identical to R1, R2, R3 or R4; or two of R9, R10, R11, R12, R13 and R14 together mean an oxo or epoxy group, or an additional chemical bond, or four of them together signify two additional chemical bonds, and the remaining groups represent hydrogen atoms; or R9, R10, R11, R12, R13 and R14 mean, together with the carbon atoms of the chain, a saturated or unsaturated homocycle, containing 3-8 carbon atoms, or a saturated or unsaturated heterocycle containing 2 or more carbon atoms. -7 carbon atoms and a nitrogen or sulfur atom, to which an aromatic ring of 6-10 carbon atoms is optionally condensed; and w is zero or 1; C means a prolyl group, or one of the groups of formula (37), (38), (39), (40) or (41) - wherein n is zero or 1 or 2, Hlg means a fluorine atom, chlorine, bromine, or iodine; R5 and R6 signify, independently of one another, a hydrogen atom, a hydroxyl group, a phenyl group or an alkyl group of 1-4 carbon atoms, or R5 and R6 together mean an oxo group; R16 means an alkoxy group of 1-4 carbon atoms, or a group -NH-CH2-CN, or a group -NH-CH2-C02R7, wherein R7 is defined above; or the structural unit D or L; or one of the groups in formula (42) or (43) or (43a) - where the dotted line means a optionally present chemical bond -, s is 1, 2 or 3 - or a group of the formula (44) - wherein Rx5 means a hydrogen atom, an alkyl group of 1-6 carbon atoms, a phenyl or naphthyl group; or a group of the formula (45) - wherein Z means a group -NH, an oxygen atom or a sulfur atom; D means a covalent chemical bond, or a prolyl or thioprolyl group, or one of the groups of formula (37) or (38), (39), (49) or (41); L represents a pyrrolidino or 2-cyanopyrrolidino, thiazolidino or 2-cyano-thiazolidino or piperidino group, optionally substituted with a halogen atom, or geminally with two halogen atoms; or a group of the formula (46) - wherein R17 signifies a hydrogen atom or a cyano group, n is 0, 1 or 2; or a group of formula (47) or (48) or (49); - and the optical isomers, cis-trans, geometrical, epimeros, tautomers, salts, prodrugs and human and mammalian metabolites of them.
- 2. Compounds of the general formula (I), - wherein A means one of the groups having the general formula (1), (a), (2), (2a), (3), (3a), (4) , (5), (6), (7), (8), (9), (10), (lia), (llb), (12), (12a), (12b), (13), ( 13a), (14), (15), (16), (17), (18), (19), (19a), (20), (20a), (21), (22), (23) , (23a), (23b), (24), (25), (25a), (26), (27), (28), (28a), (28b), (29), (29a), (30), (31), (32), (32a), (33), (34), (35), (36) - where R means an atom of hydrogen, an alkyl group of 1-4 carbon atoms, or an aryl or aralkyl group of 6-12 carbon atoms; R1, R2, R3 and R4 signify, independently of one another, a hydrogen atom, a halogen atom, a hydroxyl group, straight or branched chain alkyl or alkenyl or alkynyl or alkoxy or alkenyloxy or alkynyloxy groups, containing 1 -6 carbon atoms, a nitro group, an amino, monoalkylamino or monoacylamino group of 1-12 carbon atoms, a dialkylamino or diacylamino group of 2-24 carbon atoms - wherein the acyl group is one of the alkyl, aralkyl type , cycloalkyl or aryl-, a cyano group, a mercapto group, carboxyl group, esterified carboxyl group of 2-7 carbon atoms, hydroxyalkyl group of 1-6 carbon atoms, acyl group of 1-7 carbon atoms, acyloxy group of 1-7 carbon atoms, phenyl or benzyl group, anilino group, benzoyl group, phenoxy group, benzyloxy group, isocyanate group, isothiocyanate group, alkylthio group of 1-6 carbon atoms, sulfa or sulfamoyl group, thiocyanate group or cyanate, R5 and R6 mean, independently of one another, hydrogen atom, hydroxyl group, phenyl group or alkyl group of 1-4 carbon atoms, or R5 and R6 together mean an oxo group; R7 is an alkyl group of 1-6 carbon atoms; Rb means a hydrogen atom or an alkyl group of 1-6 carbon atoms, or an aralkyl group of 7-10 carbon atoms; dotted line means an optional chemical bond; n is zero, 1, 2 or 3; X means a group -CH; -, a group -NH-, a carbon atom, or a hydrogen atom, an oxygen atom or an amino group; or A means a group R '-YN = or a group R'-YN (R9) -, where R' means an alkyl group of 1-6 carbon atoms, an aralkyl group of 7-10 carbon atoms, group diphenylmethyl, alkoxy group, arylalkyloxy group of 7-10 carbon atoms, or a phenyl or phenoxy or phenylalkyl group containing 7-10 carbon atoms, or a phenylalkyloxy group containing 7-10 carbon atoms, optionally substituted with halogen atoms or alkyl groups of 1-4 carbon atoms, or nitro groups; Y means a chemical bond or an oxo, sulfonyl or sulfinyl group, R9 means a hydrogen atom or an alkyl group of 1-4 carbon atoms; - with the proviso that in the case of formulas (20) and (33) X can not mean a group -CH2-, a group -NH-, an oxygen atom or a sulfur atom, and in the case of formulas (30) and (31), X can not mean a group -CH2-, an oxygen atom or a sulfur atom or an amino group; B means a group - (CH2) m-C (0) -, where m is an integer from 1 to 21; or a group -0- (CH2) P-C (0) -, where p is an integer from 1 to 3; or a group independently denote one of the other hydrogen, an alkyl or alkoxy group of 1-6 carbon atoms, halogen, an amino group optionally substituted with one or two alkyl groups of 1-6 carbon atoms; or a phenyl, phenoxy, or arylalkyl group of 7-12 carbon atoms, or an arylalkoxy group of 7-12 carbon atoms, each optionally containing 1, 2 or 3 substituents, identical or different, identical to R 1, R2, R3 or R4; or two of R9, R10, R11, R12, R13 and R14 together mean an oxo or epoxy group, or an additional chemical bond, or four of them together signify two additional chemical bonds, and the remaining groups represent hydrogen atoms; or R9, R10, Ru, R12, R13 and R14 mean, together with the carbon atoms of the chain, a saturated or unsaturated homocycle, containing 3-8 carbon atoms, or a saturated or unsaturated heterocycle containing 2 or -7 carbon atoms and a nitrogen or sulfur atom, to which an aromatic ring of 6-10 carbon atoms is optionally condensed; Y w is zero or 1; C means a prolyl group, or one of the groups of formula (37), (38), (39), (40) or (41) - wherein n is zero or 1 or 2, Hlg means a fluorine atom, chlorine, bromine, or iodine; R5 and R6 signify, independently of one another, a hydrogen atom, a hydroxyl group, a phenyl group or an alkyl group of 1-4 carbon atoms, or R5 and R6 together mean an oxo group; R16 means an alkoxy group of 1-4 carbon atoms, or a group -NH-CH2-CN, or a group -NH-CH2-C02R7, wherein R7 is defined above; or the structural unit D or L; or one of the groups in the formula (42) or (43) or (43a) - wherein the dotted line means an optionally present chemical bond-, s is 1, 2 or 3 - or a group of the formula (44) - wherein R15 signifies an atom of hydrogen, an alkyl group of 1-6 carbon atoms, a phenyl or naphthyl group; or a group of the formula (45) - where Z means a group -NH, an oxygen atom or a sulfur atom; D means a covalent chemical bond, or a prolyl or thioprolyl group, or one of the groups of formula (37) or (38), (39), (49) or (41); L means a pyrrolidino or 2-cyanopyrrolidino, thiazolidino or 2-cyano-thiazolidino or piperidino group, optionally substituted with a halogen atom, or geminally with two halogen atoms; or a group of the formula (46) - wherein R17 signifies a hydrogen atom or a cyano group, n is 0, 1 or 2; or a group of formula (47) or (48) or (49); - and the optical isomers, cis-trans, geometrical, epimeros, tautomers, salts, prodrugs and human and mammalian metabolites of them.
- 3. Compounds according to claim 2, characterized in that A means a group of the general formula (20a) or (23a) - wherein R means a hydrogen atom, an alkyl group of 1-4 carbon atoms, or an aryl group or aralkyl of 6-12 carbon atoms; R1, R2, R3 and R4 signify, independently of one another, a hydrogen atom, a halogen atom, a hydroxyl group, straight or branched chain alkyl or alkenyl or alkynyl or alkoxy or alkenyloxy or alkynyloxy groups, containing 1 -6 carbon atoms, a nitro group, an amino, monoalkylamino or monoacylamino group of 1-12 carbon atoms, a dialkylamino or diacylamino group of 2-24 carbon atoms - wherein the acyl group is one of the alkyl, aralkyl type , cycloalkyl or aryl-, a cyano group, a mercapto group, carboxyl group, esterified carboxyl group of 2-7 carbon atoms, hydroxyalkyl group of 1-6 carbon atoms, acyl group of 1-7 carbon atoms, acyloxy group from 1-7 carbon atoms, phenyl or benzyl group, anilino group, benzoyl group, phenoxy group, benzyloxy group, isocyanate group, isothiocyanate group, alkylthio group of 1-6 carbon atoms, sulfamino or sulfamollo group, thiocyanate group or cyanate, R5 and Rb signify, independently of one another, hydrogen atom, hydroxyl group, phenyl group or alkyl group of 1-4 carbon atoms, or Rb and R ° together mean an oxo group; R7 is an alkyl group of 1-6 carbon atoms; R8 means a hydrogen atom or an alkyl group of 1-6 carbon atoms, or an aralkyl group of 7-10 carbon atoms; dotted line means an optional chemical bond; n is zero, 1, 2 or 3; X means a group -CH2-, a group -NH-, a carbon atom, or a hydrogen atom, an oxygen atom or an amino group; B means a group - (CH2) m-C (O) -, where m is 2 or 3; C means a prolyl group, or a group of general formula (38) or (41) - wherein n is 1 or 2; D means a covalent chemical bond; L means a pyrrolidino or thiazolidino group - and the optical isomers, cis-trans, geometrical, epi-eros, tautomers, salts, prodrugs and human and mammalian metabolites thereof.
- 4. Pharmaceutical composition characterized in that it contains one or more compounds of the general formula (I) - wherein the meanings of A, B, C, D, and L are as given in claims 1 and 2 - and / or the optical isomers, cis-trans, geometrical, epimeros, tautomers, salts, prodrugs and human and mammalian metabolites thereof, alone or together with carriers and / or usual auxiliary materials applied in the pharmaceutical industry.
- 5. A process for the preparation of compounds of the general formula (I) - wherein the meanings of A, B, C, D, and L are as given in claims 1 and 2 - and / or the optical isomers, cis- trans, geometrical, epimerous, tautomeric, and their salts, characterized in that a racemic or optically active carboxylic acid of the general formula (II) - wherein the meanings of A and B are as given in claims 1 and 2 - is transformed to an acid halide, or an active ester, or a mixed acid anhydride, or a carbodiimide, and the resulting compound is reacted with a racemic or optically active compound, or its salt of the general formula (III), - in where the meanings of C, D and L are as given in claim 1 - and the resulting compound of the general formula (I) - wherein the meanings of A, B, C, D, and L are as given in Claims 1 and 2 - optionally separated into its optical isomers, cis-trans, or geometries, epimers or tautomers, or a salt is formed of the compounds of general formula (I), or the compounds of the general formula (I) are liberated from their salts.
- 6. Use of the compounds of the general formula (I) according to claim 1 or 2, characterized in that it is for the inhibition of the prolyl-endopeptidase enzyme in mammals, including man.
- 7. Compounds of the general formula (I), characterized in that A means, one of the groups having the general formula (1), (2), (2a), (3) and (3a), (4), (5) , (6), (7), (8), (9), (10), (lia), (llb), (12), (12a), (13), (13a), (14), ( 15), (16), (17), (18), (19), (20), (21), (22), (23), (24), (25), (25a), (26) , (27), (28), (28a), (29), (30), (31), (32), (32a), (33), (34), (35), (36) - en where R means a hydrogen atom, an alkyl group of 1-4 carbon atoms, or an aryl or aralkyl group of 6-10 carbon atoms; R1, R2, R3 and R4 signify, independently of one another, a hydrogen atom, a halogen atom, a hydroxyl group, straight or branched chain alkyl or alkenyl or alkynyl or alkoxy or alkenyloxy or alkynyloxy groups, containing 1 -6 carbon atoms, a nitro group, an amino, monoalkylamino or monoacylamino group of 1-12 carbon atoms, a dialkylamino or diacylamino group of 2-24 carbon atoms carbon - wherein the acyl group is one of the alkyl, aralkyl, cycloalkyl or aryl type -, a cyano group, a mercapto group, carboxyl group, esterified carboxyl group of 2-7 carbon atoms, hydroxyalkyl group of 1-6 carbon atoms carbon, acyl group of 1-7 carbon atoms, acyloxy group of 1-7 carbon atoms, phenyl or benzyl group, anilino group, benzoyl group, phenoxy group, benzyloxy group, isocyanate group, isothiocyanate group, alkylthio group of 1 6 carbon atoms, sulfamino or sulfamoyl group, thiocyanato group or cyanate, R5 and Rb signify, independently of one another, hydrogen atom, hydroxyl group, phenyl group or alkyl group of 1-4 carbon atoms, or R5 and R6 together they mean an oxo group; R 'means an alkyl group of 1-6 carbon atoms; R8 means a hydrogen atom or an alkyl group of 1-6 carbon atoms, or an aralkyl group of 7-10 carbon atoms; dotted line means an optional chemical bond; n is zero, 1, 2 or 3; X means a group -CH2-, a group -NH-, a carbon atom ^ or a hydrogen atom, an oxygen atom or an amino group; or A means a group R '-Y-N = or a group R'-Y-N (R9) -, where R' means an alkyl group of 1-6 carbon atoms, an aralkyl group of 7-10 carbon atoms, group diphenylmethyl, alkoxy group, arylalkyloxy group of 7-10 carbon atoms, or a phenyl or phenoxy or phenylalkyl group containing 7-10 carbon atoms, or a phenylalkyloxy group containing 7-10 carbon atoms, optionally substituted with halogen atoms or alkyl groups of 1-4 carbon atoms, or nitro groups; Y means a chemical bond or an oxo, sulfonyl or sulfinyl group, R9 means a hydrogen atom or an alkyl group of 1-4 carbon atoms; - with the proviso that in the case of formulas (20) and (33) X can not mean a group -CH2-, a group -NH-, an oxygen atom or a sulfur atom, and in the case of formulas (30) and (31), X can not mean a group -CH2-, an oxygen atom or a sulfur atom or an amino group; B means a group - (CH2) m-C (O) -, where m is an integer from 1 to 21; or a group -O- (CH_2) P-C (O) -, wherein p is an integer from 1 to 3; or a group -where R9, R10, Rn, R12, R13 and R14 independently denote one of the other hydrogen, an alkyl or alkoxy group of 1-6 carbon atoms, halogen, an amino group optionally substituted with one or two alkyl groups of 1-6 carbon atoms; or a phenyl, phenoxy, or arylalkyl group of 7-12 carbon atoms, or an arylalkoxy group of 7-12 carbon atoms, each ring thereof optionally containing 1, 2 or 3 substituents, identical or different, identical to R1, R2 , R3 or R4; or two of R9, R10, R11, R12, R13 and R14 together mean an oxo or epoxy group, or an additional chemical bond, or four of them together signify two additional chemical bonds, and the remaining groups represent hydrogen atoms; or R9, R10, R11, R12, R13 and R14 mean, together with the carbon atoms of the chain, a saturated or unsaturated homocycle, containing 3-8 carbon atoms, or a saturated or unsaturated heterocycle containing 2 or more carbon atoms. -7 carbon atoms and a nitrogen or sulfur atom, to which an aromatic ring of 6-10 carbon atoms is optionally condensed; and w is zero or 1; C means a prolyl group, or one of the groups of formula (37), (38), (39), (40) or (41) - wherein n is zero or 1 or 2, Hlg means a fluorine atom, chlorine, bromine, or iodine; R5 and R6 signify, independently of one another, a hydrogen atom, a hydroxyl group, a phenyl group or an alkyl group of 1-4 carbon atoms, or R5 and R6 together mean an oxo group; Rld means an alkoxy group of 1-4 carbon atoms, or a group -NH-CH2-CN, or a group -NH-CH2-C02R7, wherein R7 is defined above; or the structural unit D or L; or one of the groups of the formula (42) or (43) - wherein the dotted line means an optionally present chemical bond, or a group of the formula (44) -. wherein R 5 represents a hydrogen atom, alkyl group of 1-6 carbon atoms, a phenyl or naphthyl group; or a group of the formula (45) - wherein Z means a group -NH, an oxygen atom or a sulfur atom; D means a covalent chemical bond, or a prolyl or thioprolyl group, or one of the groups of formula (37) or (38), (39), (49) or (41); L represents a pyrrolidino or 2-cyanopyrrolidino, thiazolidino or 2-cyano-thiazolidino or piperidino group, optionally substituted with a halogen atom, or geminally with two halogen atoms; or a group of the formula (46) - wherein R17 signifies a hydrogen atom or a cyano group, n is 0, 1 or 2; or a group of the formula (47) or (48); and the optical, cis-trans, geometric isomers, epimers, tautomers, salts, prodrugs and human and mammalian metabolites thereof. (priority: August 1, 1995)
- 8. Compounds in accordance with the claim 7, characterized in that A means a group of the general formula (1) or (9) u (lia) u (llb) or (13) or (22) - wherein R means a hydrogen atom, an alkyl group of 1-4 carbon atoms, or an aryl or aralkyl group of 6-10 carbon atoms; R1, R2, R3 and R4 mean, independently of each other, a hydrogen atom, a halogen atom, a hydroxyl group, alkyl or alkenyl or alkynyl or alkoxy or alkenyloxy or straight or branched chain alkynyloxy groups, containing 1-6 carbon atoms, a nitro group, an amino group , monoalkylamino or monoacylamino of 1-12 carbon atoms, a dialkylamino or diacylamino group of 2-24 carbon atoms - where the acyl group is one of the alkyl, aralkyl, cycloalkyl or aryl type -, a cyano group, a group mercapto, carboxyl group, esterified carboxyl group of 2-7 carbon atoms, hydroxyalkyl group of 1-6 carbon atoms, acyl group of 1-7 carbon atoms, acyloxy group of 1-7 carbon atoms, phenyl or benzyl group , anilino group, benzoyl group, phenoxy group, benzyloxy group, isocyanate group, isothiocyanate group, alkylthio group of 1-6 carbon atoms, sulfamino or sulphamoyl group, thiocyanate group or cyanate, R5 and R6 mean, independently of each other, atom of hydrogen, gr ux hydroxyl, phenyl group or alkyl group of 1-4 carbon atoms, or R5 and R6 together mean an oxo group; R7 is an alkyl group of 1-6 carbon atoms; Rd means a hydrogen atom or an alkyl group of 1-6 carbon atoms, or an aralkyl group of 7-10 carbon atoms; dotted line means an optional chemical bond; n is zero, 1, 2 or 3; X means a group -CH2-, a group -NH-, a carbon atom, or a hydrogen atom, an oxygen atom or an amino group; B means a group - (CH2) m-C (O) -, where m is 2 or 3; C means a prolyl group, or a group of the general formula (38) or (41) - wherein n is zero or 1 or 2; D means a covalent chemical bond; means a pyrrolidino group - and the optical, cis-trans, geometric isomers, epimers, tautomers, salts, prodrugs and human and mammalian metabolites thereof. (Priority: August 17, 1995)
- 9. Compounds according to claim 7, characterized in that: A means a group of the general formula (1) or (4) or (9) u (Ha) u (llb) - wherein R means a hydrogen atom., A alkyl group of 1-4 carbon atoms, or an aryl or aralkyl group of 6-10 carbon atoms, * R1, R2, R3 and R4 signify, independently of one another, a hydrogen atom, a halogen atom, an hydroxyl group, alkyl or alkenyl or alkynyl or alkoxy groups or straight or branched chain alkenyloxy or alkynyloxy, containing from 1-6 carbon atoms, a nitro group, an amino, monoalkylamino or monoacylamino group of 1-12 carbon atoms, a dialkylamino or diacyla ino group of 2-24 carbon atoms carbon - wherein the acyl group is one of the alkyl, aralkyl, cycloalkyl or aryl type -, a cyano group, a mercapto group, carboxyl group, esterified carboxyl group of 2-7 carbon atoms, hydroxyalkyl group of 1-6 carbon atoms carbon, acyl group of 1-7 carbon atoms, acyloxy group of 1-7 carbon atoms, phenyl or benzyl group, anilino group, benzoyl group, phenoxy group, benzyloxy group, isocyanate group, isothiocyanate group, alkylthio group of 1- 6 carbon atoms, sulfamino or sulphamoyl group, thiocyanate group or cyanate, R5 and R6 mean, independently of one another, hydrogen atom, hydroxyl group, phenyl group or alkyl group of 1-4 carbon atoms, or R5 and R6 together they mean an oxo group; R7 is an alkyl group of 1-6 carbon atoms; R8 means a hydrogen atom or an alkyl group of 1-6 carbon atoms, or an aralkyl group of 7-10 carbon atoms; dotted line means an optional chemical bond; n is zero, 1, 2 or 3; X means a group -CH2-, a group -NH-, a carbon atom, or a hydrogen atom, an oxygen atom or an amino group; B means a group - (CH mC (0) -, where m is 2 or 3, C means a prolyl group, or a group of the general formula (38) or (41) - where n is zero or 1 or 2; D means a covalent chemical bond; L means a pyrrolidone or thiazolidino group - and the optical, cis-trans, geometric, epimer, tautomer, salt, prodrug, and human and mammalian metabolites thereof (Priority: August 17 of 1995)
- 10. Pharmaceutical composition characterized in that it contains one or more compounds of the general formula (I) - wherein the meanings of A, B, C, D, and L are as given in claim 7 - and / or the optical isomers, cis- trans, geometrical, epimeros, tautomers, salts, prodrugs and human and mammalian metabolites thereof, alone or together with carriers and / or usual auxiliary materials applied in the pharmaceutical industry. (Priority: August 17, 1995)
- 11. A process for the preparation of compounds of the general formula (I) - wherein the meanings of A, B, C, D, and L are as given in claim 7 - and the optical, cis-trans, geometric isomers, epimers, tautomers, and their salts, characterized in that a racemic or optically active carboxylic acid of the general formula (II) - wherein the meanings of A and B are as given in claim 7 - is transformed to an acid halide, or an active ester, or a mixed acid anhydride, or a carbodiimide, and the resulting compound is reacted with a racemic or optically active compound, or its salt of the general formula (III), - wherein the meanings of C, D and L are as given in claim 7. - and the resulting compound of the general formula (I) - wherein the meanings of A, B, C, D, and L are as given in claim 7 - optionally separated into their optical isomers, cis-trans, or geometries, epimers or tautomers, or a salt is formed of the compounds of general formula (I), or the compounds of the general formula (I) are liberated from their salts. (Priority: August 17, 1995)
- 12. A process according to claim 11, characterized in that an acid addition salt of the compound of general formula (III) is used. (Priority: August 17, 1995)
- 13. A process according to claim 11, characterized in that a reactive mixed anhydride is formed by starting from a compound of the general formula (II), and applying pivaloyl chloride. (Priority: August 17, 1995)
- 14. A process according to claim 11, characterized in that the reaction is carried out in an organic solvent. (.Priority: August 17, 1995)
- 15. A process according to claim 11, characterized in that the reaction is carried out at a temperature between -25 ° C and the boiling point of the reaction mixture. (Priority: August 17, 1995)
- 16. A process according to claim 11, characterized in that the reaction is carried out in the presence of an agent that captures acid. (Priority: August 17, 1995)
- 17. Use of the compounds of the general formula (I) according to claim 6, characterized in that it is for the inhibition of the prolyl-endopeptidase enzyme in mammals, including man. (Priority: August 17, 1995)
- 18. Compounds according to claim 1 or claim 7, characterized in that they are substantially as described above.
Applications Claiming Priority (3)
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| HUP9502426 | 1995-08-17 | ||
| HU9502426A HUT76640A (en) | 1995-08-17 | 1995-08-17 | Compounds of pharmaceutical activity cyclic amide derivatives, pharmaceutical compositions containing them, process for producing them and their use |
| PCT/HU1996/000041 WO1997007116A1 (en) | 1995-08-17 | 1996-07-26 | Prolylendopeptidase inhibitors |
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| BR9815786A (en) | 1998-03-31 | 2000-11-21 | Warner Lambert Co | Quinolones as serine protease inhibitors |
| BR9815785A (en) | 1998-03-31 | 2000-12-05 | Warner Lambert Co | Quinoxalinones as serine protease inhibitors such as factor xa and thrombin |
| US8642051B2 (en) | 2000-03-21 | 2014-02-04 | Suzanne Jaffe Stillman | Method of hydration; infusion packet system(s), support member(s), delivery system(s), and method(s); with business model(s) and Method(s) |
| WO2005019188A1 (en) * | 2003-08-22 | 2005-03-03 | Takeda Pharmaceutical Company Limited | Fused pyrimidine derivative and use thereof |
| US7320992B2 (en) * | 2003-08-25 | 2008-01-22 | Amgen Inc. | Substituted 2,3-dihydro-1h-isoindol-1-one derivatives and methods of use |
| WO2005030217A1 (en) * | 2003-09-23 | 2005-04-07 | Merck & Co., Inc. | Quinazoline potassium channel inhibitors |
| WO2006058720A2 (en) | 2003-11-03 | 2006-06-08 | Probiodrug Ag | Novel compounds for the treatment of neurological disorders |
| WO2006116157A2 (en) * | 2005-04-22 | 2006-11-02 | Alantos Pharmaceuticals Holding, Inc. | Dipeptidyl peptidase-iv inhibitors |
| EP2730571A1 (en) * | 2012-11-12 | 2014-05-14 | Universitat De Barcelona | 1-[1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives |
| US9392814B2 (en) | 2014-06-06 | 2016-07-19 | Nicholas J. Singer | Delivery system for drinks |
| USD773313S1 (en) | 2015-06-23 | 2016-12-06 | Nicholas J. Singer | Package |
| JOP20170113B1 (en) * | 2016-05-09 | 2023-03-28 | Bayer Pharma AG | Substituted 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-3(2H)-ones and 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-ones and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1320734C (en) | 1986-02-04 | 1993-07-27 | Suntory Limited | Pyrrolidineamide derivative of acylamino acid and pharmaceutical composition containing the same |
| CA2004028C (en) * | 1988-12-08 | 1998-09-22 | Motoki Torizuka | Condensed benzene derivative |
| EP0419683A4 (en) * | 1989-04-13 | 1992-03-11 | Japan Tobacco Inc. | New amino acid derivatives having prolylendopeptidase inhibitor activity |
| EP0468469A2 (en) * | 1990-07-27 | 1992-01-29 | Japan Tobacco Inc. | Proline derivatives |
-
1995
- 1995-08-17 HU HU9502426A patent/HUT76640A/en unknown
-
1996
- 1996-07-26 EE EE9800044A patent/EE9800044A/en unknown
- 1996-07-26 AT AT96925926T patent/ATE252096T1/en not_active IP Right Cessation
- 1996-07-26 TR TR1998/00243T patent/TR199800243T1/en unknown
- 1996-07-26 PL PL96325013A patent/PL325013A1/en unknown
- 1996-07-26 IL IL12326896A patent/IL123268A0/en unknown
- 1996-07-26 JP JP9509080A patent/JPH11514970A/en not_active Ceased
- 1996-07-26 CZ CZ98457A patent/CZ45798A3/en unknown
- 1996-07-26 WO PCT/HU1996/000041 patent/WO1997007116A1/en not_active Application Discontinuation
- 1996-07-26 NZ NZ313751A patent/NZ313751A/en unknown
- 1996-07-26 US US09/011,703 patent/US6191161B1/en not_active Expired - Fee Related
- 1996-07-26 AU AU66279/96A patent/AU725429B2/en not_active Ceased
- 1996-07-26 CN CN96197030A patent/CN1092193C/en not_active Expired - Fee Related
- 1996-07-26 DE DE69630391T patent/DE69630391T2/en not_active Expired - Fee Related
- 1996-07-26 KR KR1019980701148A patent/KR19990037669A/en not_active Application Discontinuation
- 1996-07-26 EA EA199800200A patent/EA001399B1/en not_active IP Right Cessation
- 1996-07-26 MX MX9801190A patent/MX9801190A/en unknown
- 1996-07-26 BR BR9610075A patent/BR9610075A/en unknown
- 1996-07-26 SK SK189-98A patent/SK18998A3/en unknown
- 1996-07-26 EP EP96925926A patent/EP0861246B1/en not_active Expired - Lifetime
- 1996-07-26 CA CA002235677A patent/CA2235677A1/en not_active Abandoned
- 1996-08-01 ZA ZA9606554A patent/ZA966554B/en unknown
- 1996-08-13 HR HR960375A patent/HRP960375B1/en not_active IP Right Cessation
- 1996-08-15 TW TW085109928A patent/TW486476B/en active
- 1996-08-15 YU YU47096A patent/YU47096A/en unknown
- 1996-08-16 AR ARP960104018A patent/AR009225A1/en unknown
-
1998
- 1998-02-16 NO NO980643A patent/NO980643L/en not_active Application Discontinuation
- 1998-02-16 IS IS4668A patent/IS4668A/en unknown
- 1998-03-12 BG BG102323A patent/BG102323A/en unknown
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