SK38599A3 - Derivates of piperidine-ketocarboxylic acid, their preparation and use - Google Patents

Derivates of piperidine-ketocarboxylic acid, their preparation and use Download PDF

Info

Publication number: SK38599A3
Authority: SK; Slovakia
Prior art keywords: alkyl; piperidine; phenyl; general formula; treatment
Prior art date: 1996-10-15

Application number

SK385-99A

Other languages

English (en)

Slovak (sk)

Inventor

Wilfried Lubisch

Achim Moller

Jurgen Delzer

Original Assignee

Basf Ag

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1996-10-15

Filing date

1997-09-23

Publication date

2000-04-10

1997-09-23 Application filed by Basf Ag filed Critical Basf Ag

2000-04-10 Publication of SK38599A3 publication Critical patent/SK38599A3/sk

Links

238000002360 preparation method Methods 0.000 title claims abstract description 11
239000002253 acid Substances 0.000 title claims description 40
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 22
150000001875 compounds Chemical class 0.000 claims abstract description 21
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 13
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 11
239000000825 pharmaceutical preparation Substances 0.000 claims abstract description 5
125000000896 monocarboxylic acid group Chemical group 0.000 claims abstract description 4
150000003839 salts Chemical class 0.000 claims abstract description 4
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 28
239000003112 inhibitor Substances 0.000 claims description 25
108010032088 Calpain Proteins 0.000 claims description 24
102000007590 Calpain Human genes 0.000 claims description 24
-1 CF 3 Inorganic materials 0.000 claims description 14
UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical group C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 12
SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical group N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 12
102000005927 Cysteine Proteases Human genes 0.000 claims description 11
108010005843 Cysteine Proteases Proteins 0.000 claims description 11
YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
201000010099 disease Diseases 0.000 claims description 10
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 9
YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 8
YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 8
150000003254 radicals Chemical class 0.000 claims description 7
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
230000000694 effects Effects 0.000 claims description 6
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
208000028867 ischemia Diseases 0.000 claims description 5
230000004770 neurodegeneration Effects 0.000 claims description 5
208000015122 neurodegenerative disease Diseases 0.000 claims description 5
FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical group C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 4
SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 4
CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 4
230000006378 damage Effects 0.000 claims description 4
208000014674 injury Diseases 0.000 claims description 4
AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical group C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 4
239000000546 pharmaceutical excipient Substances 0.000 claims description 4
XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical group N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims description 4
229930192474 thiophene Chemical group 0.000 claims description 4
230000008733 trauma Effects 0.000 claims description 4
208000024827 Alzheimer disease Diseases 0.000 claims description 3
208000002177 Cataract Diseases 0.000 claims description 3
206010061218 Inflammation Diseases 0.000 claims description 3
230000003683 cardiac damage Effects 0.000 claims description 3
230000004054 inflammatory process Effects 0.000 claims description 3
229940124531 pharmaceutical excipient Drugs 0.000 claims description 3
HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 2
208000023105 Huntington disease Diseases 0.000 claims description 2
102000000589 Interleukin-1 Human genes 0.000 claims description 2
108010002352 Interleukin-1 Proteins 0.000 claims description 2
206010027476 Metastases Diseases 0.000 claims description 2
208000029549 Muscle injury Diseases 0.000 claims description 2
206010028980 Neoplasm Diseases 0.000 claims description 2
ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 2
206010063897 Renal ischaemia Diseases 0.000 claims description 2
208000025747 Rheumatic disease Diseases 0.000 claims description 2
FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 2
206010047163 Vasospasm Diseases 0.000 claims description 2
238000002399 angioplasty Methods 0.000 claims description 2
125000003118 aryl group Chemical group 0.000 claims description 2
RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical group CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 claims description 2
210000004204 blood vessel Anatomy 0.000 claims description 2
125000004432 carbon atom Chemical group C* 0.000 claims description 2
230000004663 cell proliferation Effects 0.000 claims description 2
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
RMBPEFMHABBEKP-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2C3=C[CH]C=CC3=CC2=C1 RMBPEFMHABBEKP-UHFFFAOYSA-N 0.000 claims description 2
PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 2
RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 2
208000001286 intracranial vasospasm Diseases 0.000 claims description 2
ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims description 2
CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 2
125000001624 naphthyl group Chemical group 0.000 claims description 2
NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims description 2
208000037803 restenosis Diseases 0.000 claims description 2
210000002027 skeletal muscle Anatomy 0.000 claims description 2
210000000329 smooth muscle myocyte Anatomy 0.000 claims description 2
150000003852 triazoles Chemical class 0.000 claims description 2
239000003814 drug Substances 0.000 claims 5
230000003961 neuronal insult Effects 0.000 claims 2
206010019196 Head injury Diseases 0.000 claims 1
XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims 1
208000006011 Stroke Diseases 0.000 claims 1
125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
230000000740 bleeding effect Effects 0.000 claims 1
125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims 1
238000007912 intraperitoneal administration Methods 0.000 claims 1
210000003205 muscle Anatomy 0.000 claims 1
208000031225 myocardial ischemia Diseases 0.000 claims 1
UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims 1
125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
229940126534 drug product Drugs 0.000 abstract 1
239000000047 product Substances 0.000 description 42
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 32
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
238000000034 method Methods 0.000 description 24
125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 20
239000000203 mixture Substances 0.000 description 19
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
108010079785 calpain inhibitors Proteins 0.000 description 13
210000004027 cell Anatomy 0.000 description 13
230000002829 reductive effect Effects 0.000 description 13
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
238000006243 chemical reaction Methods 0.000 description 12
239000011541 reaction mixture Substances 0.000 description 12
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
238000005160 1H NMR spectroscopy Methods 0.000 description 11
150000002576 ketones Chemical class 0.000 description 11
OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 10
150000001408 amides Chemical class 0.000 description 10
239000011575 calcium Substances 0.000 description 10
229910052791 calcium Inorganic materials 0.000 description 10
239000000543 intermediate Substances 0.000 description 10
239000000243 solution Substances 0.000 description 10
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 9
125000004494 ethyl ester group Chemical group 0.000 description 8
108090000765 processed proteins & peptides Proteins 0.000 description 8
235000019441 ethanol Nutrition 0.000 description 7
239000012074 organic phase Substances 0.000 description 7
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
150000007513 acids Chemical class 0.000 description 6
239000000872 buffer Substances 0.000 description 6
230000030833 cell death Effects 0.000 description 6
235000018102 proteins Nutrition 0.000 description 6
102000004169 proteins and genes Human genes 0.000 description 6
108090000623 proteins and genes Proteins 0.000 description 6
102000004190 Enzymes Human genes 0.000 description 5
108090000790 Enzymes Proteins 0.000 description 5
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
150000001298 alcohols Chemical class 0.000 description 5
150000001299 aldehydes Chemical class 0.000 description 5
238000003776 cleavage reaction Methods 0.000 description 5
229940088598 enzyme Drugs 0.000 description 5
230000007017 scission Effects 0.000 description 5
239000000758 substrate Substances 0.000 description 5
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 4
235000011114 ammonium hydroxide Nutrition 0.000 description 4
238000003556 assay Methods 0.000 description 4
229930195712 glutamate Natural products 0.000 description 4
230000002427 irreversible effect Effects 0.000 description 4
150000004797 ketoamides Chemical class 0.000 description 4
125000000468 ketone group Chemical group 0.000 description 4
229950009215 phenylbutanoic acid Drugs 0.000 description 4
238000005481 NMR spectroscopy Methods 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
DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
230000015572 biosynthetic process Effects 0.000 description 3
239000000460 chlorine Substances 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
230000002401 inhibitory effect Effects 0.000 description 3
230000005764 inhibitory process Effects 0.000 description 3
239000002555 ionophore Substances 0.000 description 3
230000000236 ionophoric effect Effects 0.000 description 3
210000003734 kidney Anatomy 0.000 description 3
230000001404 mediated effect Effects 0.000 description 3
125000005322 morpholin-1-yl group Chemical group 0.000 description 3
238000007254 oxidation reaction Methods 0.000 description 3
239000008194 pharmaceutical composition Substances 0.000 description 3
238000012360 testing method Methods 0.000 description 3
VYMPLPIFKRHAAC-UHFFFAOYSA-N 1,2-ethanedithiol Chemical compound SCCS VYMPLPIFKRHAAC-UHFFFAOYSA-N 0.000 description 2
ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical class OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 description 2
AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 2
LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
XPQIPUZPSLAZDV-UHFFFAOYSA-N 2-pyridylethylamine Chemical compound NCCC1=CC=CC=N1 XPQIPUZPSLAZDV-UHFFFAOYSA-N 0.000 description 2
KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 2
102000004225 Cathepsin B Human genes 0.000 description 2
108090000712 Cathepsin B Proteins 0.000 description 2
102000005600 Cathepsins Human genes 0.000 description 2
108010084457 Cathepsins Proteins 0.000 description 2
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
108010044467 Isoenzymes Proteins 0.000 description 2
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
102000003855 L-lactate dehydrogenase Human genes 0.000 description 2
108700023483 L-lactate dehydrogenases Proteins 0.000 description 2
102000002151 Microfilament Proteins Human genes 0.000 description 2
108010040897 Microfilament Proteins Proteins 0.000 description 2
239000002202 Polyethylene glycol Substances 0.000 description 2
229920002684 Sepharose Polymers 0.000 description 2
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
238000006859 Swern oxidation reaction Methods 0.000 description 2
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
QWCKQJZIFLGMSD-UHFFFAOYSA-N alpha-aminobutyric acid Chemical compound CCC(N)C(O)=O QWCKQJZIFLGMSD-UHFFFAOYSA-N 0.000 description 2
150000001412 amines Chemical class 0.000 description 2
229910001424 calcium ion Inorganic materials 0.000 description 2
HIYAVKIYRIFSCZ-UHFFFAOYSA-N calcium ionophore A23187 Natural products N=1C2=C(C(O)=O)C(NC)=CC=C2OC=1CC(C(CC1)C)OC1(C(CC1C)C)OC1C(C)C(=O)C1=CC=CN1 HIYAVKIYRIFSCZ-UHFFFAOYSA-N 0.000 description 2
150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
239000004359 castor oil Substances 0.000 description 2
235000019438 castor oil Nutrition 0.000 description 2
230000015556 catabolic process Effects 0.000 description 2
238000004113 cell culture Methods 0.000 description 2
210000003169 central nervous system Anatomy 0.000 description 2
238000004587 chromatography analysis Methods 0.000 description 2
210000003618 cortical neuron Anatomy 0.000 description 2
GLNDAGDHSLMOKX-UHFFFAOYSA-N coumarin 120 Chemical compound C1=C(N)C=CC2=C1OC(=O)C=C2C GLNDAGDHSLMOKX-UHFFFAOYSA-N 0.000 description 2
230000001419 dependent effect Effects 0.000 description 2
239000003480 eluent Substances 0.000 description 2
150000002148 esters Chemical class 0.000 description 2
238000002474 experimental method Methods 0.000 description 2
239000000499 gel Substances 0.000 description 2
ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
239000012442 inert solvent Substances 0.000 description 2
238000001802 infusion Methods 0.000 description 2
230000003834 intracellular effect Effects 0.000 description 2
SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 description 2
238000005259 measurement Methods 0.000 description 2
230000011278 mitosis Effects 0.000 description 2
108010068164 mu-calpain Proteins 0.000 description 2
201000006938 muscular dystrophy Diseases 0.000 description 2
239000002674 ointment Substances 0.000 description 2
230000003287 optical effect Effects 0.000 description 2
230000003647 oxidation Effects 0.000 description 2
230000035778 pathophysiological process Effects 0.000 description 2
229920001223 polyethylene glycol Polymers 0.000 description 2
239000000843 powder Substances 0.000 description 2
239000002244 precipitate Substances 0.000 description 2
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
239000011780 sodium chloride Substances 0.000 description 2
238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
239000007921 spray Substances 0.000 description 2
238000003756 stirring Methods 0.000 description 2
238000003786 synthesis reaction Methods 0.000 description 2
230000000699 topical effect Effects 0.000 description 2
WOGITNXCNOTRLK-VOTSOKGWSA-N (e)-3-phenylprop-2-enoyl chloride Chemical compound ClC(=O)\C=C\C1=CC=CC=C1 WOGITNXCNOTRLK-VOTSOKGWSA-N 0.000 description 1
CXWGKAYMVASWDQ-UHFFFAOYSA-N 1,2-dithiane Chemical compound C1CCSSC1 CXWGKAYMVASWDQ-UHFFFAOYSA-N 0.000 description 1
VJOKQRCHYVNKKH-UHFFFAOYSA-N 1-(naphthalene-2-carbonyl)piperidine-4-carboxylic acid Chemical compound C1CC(C(=O)O)CCN1C(=O)C1=CC=C(C=CC=C2)C2=C1 VJOKQRCHYVNKKH-UHFFFAOYSA-N 0.000 description 1
MDJITYWHEVEXJY-UHFFFAOYSA-N 1-naphthalen-2-ylsulfonylpiperidine-4-carboxylic acid Chemical compound C1CC(C(=O)O)CCN1S(=O)(=O)C1=CC=C(C=CC=C2)C2=C1 MDJITYWHEVEXJY-UHFFFAOYSA-N 0.000 description 1
JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 1
GUGQQGROXHPINL-UHFFFAOYSA-N 2-oxobutanoyl chloride Chemical compound CCC(=O)C(Cl)=O GUGQQGROXHPINL-UHFFFAOYSA-N 0.000 description 1
125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
HIYAVKIYRIFSCZ-CYEMHPAKSA-N 5-(methylamino)-2-[[(2S,3R,5R,6S,8R,9R)-3,5,9-trimethyl-2-[(2S)-1-oxo-1-(1H-pyrrol-2-yl)propan-2-yl]-1,7-dioxaspiro[5.5]undecan-8-yl]methyl]-1,3-benzoxazole-4-carboxylic acid Chemical compound O=C([C@@H](C)[C@H]1O[C@@]2([C@@H](C[C@H]1C)C)O[C@@H]([C@@H](CC2)C)CC=1OC2=CC=C(C(=C2N=1)C(O)=O)NC)C1=CC=CN1 HIYAVKIYRIFSCZ-CYEMHPAKSA-N 0.000 description 1
PZASAAIJIFDWSB-CKPDSHCKSA-N 8-[(1S)-1-[8-(trifluoromethyl)-7-[4-(trifluoromethyl)cyclohexyl]oxynaphthalen-2-yl]ethyl]-8-azabicyclo[3.2.1]octane-3-carboxylic acid Chemical compound FC(F)(F)C=1C2=CC([C@@H](N3C4CCC3CC(C4)C(O)=O)C)=CC=C2C=CC=1OC1CCC(C(F)(F)F)CC1 PZASAAIJIFDWSB-CKPDSHCKSA-N 0.000 description 1
GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-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
208000000044 Amnesia Diseases 0.000 description 1
206010006187 Breast cancer Diseases 0.000 description 1
208000026310 Breast neoplasm Diseases 0.000 description 1
239000004255 Butylated hydroxyanisole Substances 0.000 description 1
239000004322 Butylated hydroxytoluene Substances 0.000 description 1
NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
HIYAVKIYRIFSCZ-CVXKHCKVSA-N Calcimycin Chemical compound CC([C@H]1OC2([C@@H](C[C@H]1C)C)O[C@H]([C@H](CC2)C)CC=1OC2=CC=C(C(=C2N=1)C(O)=O)NC)C(=O)C1=CC=CN1 HIYAVKIYRIFSCZ-CVXKHCKVSA-N 0.000 description 1
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
108090000695 Cytokines Proteins 0.000 description 1
102000004127 Cytokines Human genes 0.000 description 1
102000010831 Cytoskeletal Proteins Human genes 0.000 description 1
108010037414 Cytoskeletal Proteins Proteins 0.000 description 1
229920002271 DEAE-Sepharose Polymers 0.000 description 1
238000006021 Dakin-West synthesis reaction Methods 0.000 description 1
206010012289 Dementia Diseases 0.000 description 1
108010016626 Dipeptides Proteins 0.000 description 1
239000004097 EU approved flavor enhancer Substances 0.000 description 1
208000032843 Hemorrhage Diseases 0.000 description 1
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
206010021143 Hypoxia Diseases 0.000 description 1
206010061216 Infarction Diseases 0.000 description 1
AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
239000004166 Lanolin Substances 0.000 description 1
239000002841 Lewis acid Substances 0.000 description 1
208000026139 Memory disease Diseases 0.000 description 1
102100023174 Methionine aminopeptidase 2 Human genes 0.000 description 1
108090000192 Methionyl aminopeptidases Proteins 0.000 description 1
102000008934 Muscle Proteins Human genes 0.000 description 1
108010074084 Muscle Proteins Proteins 0.000 description 1
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
RIYLNECMTVNMSO-GOTSBHOMSA-N N-succinyl-Leu-Tyr-7-amido-4-methylcoumarin Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)CCC(O)=O)CC(C)C)C(=O)NC=1C=C2OC(=O)C=C(C)C2=CC=1)C1=CC=C(O)C=C1 RIYLNECMTVNMSO-GOTSBHOMSA-N 0.000 description 1
208000001738 Nervous System Trauma Diseases 0.000 description 1
108090000189 Neuropeptides Proteins 0.000 description 1
102000003797 Neuropeptides Human genes 0.000 description 1
206010029350 Neurotoxicity Diseases 0.000 description 1
AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
102000035195 Peptidases Human genes 0.000 description 1
108091005804 Peptidases Proteins 0.000 description 1
239000004264 Petrolatum Substances 0.000 description 1
102000003923 Protein Kinase C Human genes 0.000 description 1
108090000315 Protein Kinase C Proteins 0.000 description 1
102000012479 Serine Proteases Human genes 0.000 description 1
108010022999 Serine Proteases Proteins 0.000 description 1
239000005708 Sodium hypochlorite Substances 0.000 description 1
229920002125 Sokalan® Polymers 0.000 description 1
229920002472 Starch Polymers 0.000 description 1
239000012505 Superdex™ Substances 0.000 description 1
102000006463 Talin Human genes 0.000 description 1
108010083809 Talin Proteins 0.000 description 1
206010044221 Toxic encephalopathy Diseases 0.000 description 1
DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
102000004142 Trypsin Human genes 0.000 description 1
108090000631 Trypsin Proteins 0.000 description 1
NGBKFLTYGSREKK-PMACEKPBSA-N Z-Val-Phe-H Chemical compound N([C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C=O)C(=O)OCC1=CC=CC=C1 NGBKFLTYGSREKK-PMACEKPBSA-N 0.000 description 1
238000007171 acid catalysis Methods 0.000 description 1
125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 description 1
230000004913 activation Effects 0.000 description 1
239000004480 active ingredient Substances 0.000 description 1
230000001154 acute effect Effects 0.000 description 1
125000003172 aldehyde group Chemical group 0.000 description 1
239000002168 alkylating agent Substances 0.000 description 1
229940100198 alkylating agent Drugs 0.000 description 1
150000001370 alpha-amino acid derivatives Chemical group 0.000 description 1
JTXJZBMXQMTSQN-UHFFFAOYSA-N amino hydrogen carbonate Chemical class NOC(O)=O JTXJZBMXQMTSQN-UHFFFAOYSA-N 0.000 description 1
239000003963 antioxidant agent Substances 0.000 description 1
230000006907 apoptotic process Effects 0.000 description 1
239000012736 aqueous medium Substances 0.000 description 1
239000007864 aqueous solution Substances 0.000 description 1
230000009286 beneficial effect Effects 0.000 description 1
239000012964 benzotriazole Substances 0.000 description 1
230000037396 body weight Effects 0.000 description 1
235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
229940043253 butylated hydroxyanisole Drugs 0.000 description 1
235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
229940095259 butylated hydroxytoluene Drugs 0.000 description 1
239000003710 calcium ionophore Substances 0.000 description 1
108010007877 calpain inhibitor III Proteins 0.000 description 1
150000001735 carboxylic acids Chemical class 0.000 description 1
230000005779 cell damage Effects 0.000 description 1
208000037887 cell injury Diseases 0.000 description 1
210000000170 cell membrane Anatomy 0.000 description 1
238000002737 cell proliferation kit Methods 0.000 description 1
230000001413 cellular effect Effects 0.000 description 1
238000005119 centrifugation Methods 0.000 description 1
230000002490 cerebral effect Effects 0.000 description 1
238000002512 chemotherapy Methods 0.000 description 1
238000011210 chromatographic step Methods 0.000 description 1
238000007796 conventional method Methods 0.000 description 1
230000001054 cortical effect Effects 0.000 description 1
239000006071 cream Substances 0.000 description 1
239000012043 crude product Substances 0.000 description 1
239000012228 culture supernatant Substances 0.000 description 1
231100000433 cytotoxic Toxicity 0.000 description 1
230000001472 cytotoxic effect Effects 0.000 description 1
GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
238000006731 degradation reaction Methods 0.000 description 1
238000000326 densiometry Methods 0.000 description 1
239000003085 diluting agent Substances 0.000 description 1
208000035475 disorder Diseases 0.000 description 1
150000002019 disulfides Chemical class 0.000 description 1
LOZWAPSEEHRYPG-UHFFFAOYSA-N dithiane Natural products C1CSCCS1 LOZWAPSEEHRYPG-UHFFFAOYSA-N 0.000 description 1
VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
239000003937 drug carrier Substances 0.000 description 1
125000006575 electron-withdrawing group Chemical group 0.000 description 1
210000002257 embryonic structure Anatomy 0.000 description 1
239000003995 emulsifying agent Substances 0.000 description 1
239000000839 emulsion Substances 0.000 description 1
238000005516 engineering process Methods 0.000 description 1
150000002085 enols Chemical class 0.000 description 1
230000002255 enzymatic effect Effects 0.000 description 1
238000001952 enzyme assay Methods 0.000 description 1
210000003743 erythrocyte Anatomy 0.000 description 1
CJAONIOAQZUHPN-KKLWWLSJSA-N ethyl 12-[[2-[(2r,3r)-3-[2-[(12-ethoxy-12-oxododecyl)-methylamino]-2-oxoethoxy]butan-2-yl]oxyacetyl]-methylamino]dodecanoate Chemical compound CCOC(=O)CCCCCCCCCCCN(C)C(=O)CO[C@H](C)[C@@H](C)OCC(=O)N(C)CCCCCCCCCCCC(=O)OCC CJAONIOAQZUHPN-KKLWWLSJSA-N 0.000 description 1
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
150000002191 fatty alcohols Chemical class 0.000 description 1
235000019264 food flavour enhancer Nutrition 0.000 description 1
238000009472 formulation Methods 0.000 description 1
102000034356 gene-regulatory proteins Human genes 0.000 description 1
108091006104 gene-regulatory proteins Proteins 0.000 description 1
229940100242 glycol stearate Drugs 0.000 description 1
208000006454 hepatitis Diseases 0.000 description 1
231100000283 hepatitis Toxicity 0.000 description 1
210000005260 human cell Anatomy 0.000 description 1
229910052739 hydrogen Inorganic materials 0.000 description 1
239000001257 hydrogen Substances 0.000 description 1
230000007062 hydrolysis Effects 0.000 description 1
238000006460 hydrolysis reaction Methods 0.000 description 1
NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
230000007954 hypoxia Effects 0.000 description 1
238000011534 incubation Methods 0.000 description 1
230000006698 induction Effects 0.000 description 1
230000007574 infarction Effects 0.000 description 1
238000002347 injection Methods 0.000 description 1
239000007924 injection Substances 0.000 description 1
QKLFOLOIKNGNCL-UHFFFAOYSA-N isoquinoline;pyridine Chemical group C1=CC=NC=C1.C1=NC=CC2=CC=CC=C21 QKLFOLOIKNGNCL-UHFFFAOYSA-N 0.000 description 1
239000008101 lactose Substances 0.000 description 1
229940039717 lanolin Drugs 0.000 description 1
235000019388 lanolin Nutrition 0.000 description 1
150000007517 lewis acids Chemical class 0.000 description 1
229940057995 liquid paraffin Drugs 0.000 description 1
210000004185 liver Anatomy 0.000 description 1
239000006210 lotion Substances 0.000 description 1
239000000314 lubricant Substances 0.000 description 1
238000002844 melting Methods 0.000 description 1
230000008018 melting Effects 0.000 description 1
230000006984 memory degeneration Effects 0.000 description 1
208000023060 memory loss Diseases 0.000 description 1
230000002503 metabolic effect Effects 0.000 description 1
230000004060 metabolic process Effects 0.000 description 1
KUGLDBMQKZTXPW-JEDNCBNOSA-N methyl (2s)-2-amino-3-methylbutanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)C(C)C KUGLDBMQKZTXPW-JEDNCBNOSA-N 0.000 description 1
150000004702 methyl esters Chemical class 0.000 description 1
GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
238000002156 mixing Methods 0.000 description 1
230000001095 motoneuron effect Effects 0.000 description 1
208000010125 myocardial infarction Diseases 0.000 description 1
RWIVICVCHVMHMU-UHFFFAOYSA-N n-aminoethylmorpholine Chemical compound NCCN1CCOCC1 RWIVICVCHVMHMU-UHFFFAOYSA-N 0.000 description 1
208000028412 nervous system injury Diseases 0.000 description 1
210000004498 neuroglial cell Anatomy 0.000 description 1
230000000926 neurological effect Effects 0.000 description 1
210000002569 neuron Anatomy 0.000 description 1
230000000324 neuroprotective effect Effects 0.000 description 1
230000007135 neurotoxicity Effects 0.000 description 1
231100000228 neurotoxicity Toxicity 0.000 description 1
239000003960 organic solvent Substances 0.000 description 1
229960003104 ornithine Drugs 0.000 description 1
235000006408 oxalic acid Nutrition 0.000 description 1
229910052760 oxygen Inorganic materials 0.000 description 1
239000006072 paste Substances 0.000 description 1
238000005897 peptide coupling reaction Methods 0.000 description 1
230000002688 persistence Effects 0.000 description 1
235000019271 petrolatum Nutrition 0.000 description 1
229940066842 petrolatum Drugs 0.000 description 1
230000004962 physiological condition Effects 0.000 description 1
230000035790 physiological processes and functions Effects 0.000 description 1
230000010118 platelet activation Effects 0.000 description 1
239000002798 polar solvent Substances 0.000 description 1
239000004584 polyacrylic acid Substances 0.000 description 1
229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
239000001267 polyvinylpyrrolidone Substances 0.000 description 1
235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
230000008569 process Effects 0.000 description 1
235000013772 propylene glycol Nutrition 0.000 description 1
230000001681 protective effect Effects 0.000 description 1
230000017854 proteolysis Effects 0.000 description 1
229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
230000009257 reactivity Effects 0.000 description 1
230000010410 reperfusion Effects 0.000 description 1
230000002441 reversible effect Effects 0.000 description 1
230000006965 reversible inhibition Effects 0.000 description 1
206010039073 rheumatoid arthritis Diseases 0.000 description 1
238000012163 sequencing technique Methods 0.000 description 1
235000017557 sodium bicarbonate Nutrition 0.000 description 1
229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
239000001509 sodium citrate Substances 0.000 description 1
NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
239000002904 solvent Substances 0.000 description 1
238000001228 spectrum Methods 0.000 description 1
239000003381 stabilizer Substances 0.000 description 1
239000008107 starch Substances 0.000 description 1
235000019698 starch Nutrition 0.000 description 1
239000000126 substance Substances 0.000 description 1
UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide-pyridine complex Substances O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 description 1
239000000454 talc Substances 0.000 description 1
229910052623 talc Inorganic materials 0.000 description 1
235000012222 talc Nutrition 0.000 description 1
230000001225 therapeutic effect Effects 0.000 description 1
235000010384 tocopherol Nutrition 0.000 description 1
239000011732 tocopherol Substances 0.000 description 1
229960001295 tocopherol Drugs 0.000 description 1
229930003799 tocopherol Natural products 0.000 description 1
231100000331 toxic Toxicity 0.000 description 1
230000002588 toxic effect Effects 0.000 description 1
231100000419 toxicity Toxicity 0.000 description 1
230000001988 toxicity Effects 0.000 description 1
230000009466 transformation Effects 0.000 description 1
238000000844 transformation Methods 0.000 description 1
239000012588 trypsin Substances 0.000 description 1
210000004881 tumor cell Anatomy 0.000 description 1
239000003981 vehicle Substances 0.000 description 1
238000001262 western blot Methods 0.000 description 1
GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Landscapes

Organic Chemistry (AREA)
Chemical & Material Sciences (AREA)
Health & Medical Sciences (AREA)
Bioinformatics & Cheminformatics (AREA)
Engineering & Computer Science (AREA)
Pharmacology & Pharmacy (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Medicinal Chemistry (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
General Chemical & Material Sciences (AREA)
Chemical Kinetics & Catalysis (AREA)
Neurology (AREA)
Biomedical Technology (AREA)
Neurosurgery (AREA)
Vascular Medicine (AREA)
Cardiology (AREA)
Heart & Thoracic Surgery (AREA)
Psychology (AREA)
Urology & Nephrology (AREA)
Hospice & Palliative Care (AREA)
Psychiatry (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Hydrogenated Pyridines (AREA)
Plural Heterocyclic Compounds (AREA)

SK385-99A 1996-10-15 1997-09-23 Derivates of piperidine-ketocarboxylic acid, their preparation and use SK38599A3 (en)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
DE19642591A DE19642591A1 (de)	1996-10-15	1996-10-15	Neue Piperidin-Ketocarbonsäure-Derivate, deren Herstellung und Anwendung
PCT/EP1997/005202 WO1998016512A1 (de)	1996-10-15	1997-09-23	Neue piperidin-ketocarbonsäure-derivate, deren herstellung und anwendung

Publications (1)

Publication Number	Publication Date
SK38599A3 true SK38599A3 (en)	2000-04-10

Family

ID=7808858

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
SK385-99A SK38599A3 (en)	1996-10-15	1997-09-23	Derivates of piperidine-ketocarboxylic acid, their preparation and use

Country Status (24)

Country	Link
US (1)	US6380220B1 (pt)
EP (1)	EP0934273A1 (pt)
JP (1)	JP2001501955A (pt)
KR (1)	KR20000049130A (pt)
CN (1)	CN1239950A (pt)
AR (1)	AR009379A1 (pt)
AU (1)	AU736754B2 (pt)
BG (1)	BG103338A (pt)
BR (1)	BR9711908A (pt)
CA (1)	CA2268917A1 (pt)
CO (1)	CO4930264A1 (pt)
CZ (1)	CZ126899A3 (pt)
DE (1)	DE19642591A1 (pt)
HR (1)	HRP970549A2 (pt)
HU (1)	HUP9904104A3 (pt)
IL (1)	IL129089A0 (pt)
NO (1)	NO991761L (pt)
NZ (1)	NZ334979A (pt)
PL (1)	PL332720A1 (pt)
RU (1)	RU2189974C2 (pt)
SK (1)	SK38599A3 (pt)
TR (1)	TR199900819T2 (pt)
WO (1)	WO1998016512A1 (pt)
ZA (1)	ZA979175B (pt)

Families Citing this family (27)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
WO1999054310A2 (de)	1998-04-20	1999-10-28	Basf Aktiengesellschaft	Neue substituierte amide, deren herstellung und anwendung
WO1999054320A1 (de) *	1998-04-20	1999-10-28	Basf Aktiengesellschaft	Neue heterocyclisch substituierte amide mit cystein-protease hemmender wirkung
WO1999054305A1 (de)	1998-04-20	1999-10-28	Basf Aktiengesellschaft	Heterocyclisch substituierte amide als calpainhemmer
DE19817459A1 (de) *	1998-04-20	1999-10-21	Basf Ag	Neue heterozyklische substituierte Amide, Herstellung und Anwendung
US6117870A (en) *	1998-11-12	2000-09-12	Fujirebio Kabushiki Kaisha	Cyclic amide derivatives
AU6936500A (en) *	1999-08-24	2001-03-19	Regents Of The University Of California, The	Non-quinoline inhibitors of malaria parasites
CZ20011872A3 (cs)	1999-09-29	2002-03-13	Ortho-Mcneil Pharmaceutical, Inc.	Isonipekotamidy pro léčbu onemocnění zprostředkovaných integriny
AU2001267886A1 (en)	2000-06-30	2002-01-14	Seikagaku Corporation	Epoxycarboxylic acid amides, azides and amino alcohols and processes for preparation of alpha-keto amides by using them
DE10114762A1 (de) *	2001-03-26	2002-10-02	Knoll Gmbh	Verwendung von Cysteinprotease-Inhibitoren
EP1389205B1 (en)	2001-04-09	2005-12-21	Ortho-McNeil Pharmaceutical Research Inc.	Quinazoline and quinazoline-like compounds for the treatment of integrin-mediated disorders
EP1539744A4 (en)	2002-07-11	2007-06-06	Vicuron Pharm Inc	N-HYDROXYAMIDE DERIVATIVES WITH ANTIBACTERIAL EFFECT
WO2005019177A1 (en) *	2003-08-14	2005-03-03	Icos Corporation	Aminopiperidine amide derivatives as vla-1 integrin antagonists and uses thereof
EP1682524A1 (en) *	2003-10-24	2006-07-26	Aventis Pharmaceuticals, Inc.	Novel keto-oxadiazole derivatives as cathepsin inhibitors
AR064693A1 (es)	2006-12-29	2009-04-22	Abbott Gmbh & Co Kg	Compuestos carboxamidas y su utilizacion en la elaboracion de un medicamento para el tratamiento de enfermedades asociadas a alta actividad de calpaina.
TWI453019B (zh) *	2007-12-28	2014-09-21	Abbvie Deutschland	甲醯胺化合物
TWI519530B (zh)	2009-02-20	2016-02-01	艾伯維德國有限及兩合公司	羰醯胺化合物及其作為鈣蛋白酶（ｃａｌｐａｉｎ）抑制劑之用途
US8236798B2 (en)	2009-05-07	2012-08-07	Abbott Gmbh & Co. Kg	Carboxamide compounds and their use as calpain inhibitors
US9051304B2 (en)	2009-12-22	2015-06-09	AbbVie Deutschland GmbH & Co. KG	Carboxamide compounds and their use as calpain inhibitors V
US8598211B2 (en)	2009-12-22	2013-12-03	Abbvie Inc.	Carboxamide compounds and their use as calpain inhibitors IV
JP2013544866A (ja)	2010-12-09	2013-12-19	アッヴィ・ドイチュラント・ゲー・エム・ベー・ハー・ウント・コー・カー・ゲー	カルボキサミド化合物及びカルパイン阻害剤ｖとしてのその使用
SG11201406345XA (en)	2012-04-03	2014-11-27	Abbvie Deutschland	Carboxamide compounds and their use as calpain inhibitors v
EP3426674A4 (en)	2016-03-09	2019-08-14	Blade Therapeutics, Inc.	CYCLIC KETO AMID COMPOUNDS AS CALPAIN MODULATORS AND METHOD FOR THE PRODUCTION AND USE THEREOF
AU2017292646A1 (en)	2016-07-05	2019-02-07	Blade Therapeutics, Inc.	Calpain modulators and therapeutic uses thereof
WO2018064119A1 (en)	2016-09-28	2018-04-05	Blade Therapeutics, Inc.	Calpain modulators and therapeutic uses thereof
KR20200010220A (ko)	2017-06-01	2020-01-30	에자이 알앤드디 매니지먼트 가부시키가이샤	피라졸로퀴놀린 유도체를 함유하는 루이소체 질병 치료제
KR20200010211A (ko)	2017-06-01	2020-01-30	에자이 알앤드디 매니지먼트 가부시키가이샤	Pde9 저해제를 포함하는 약제학적 조성물
RU2020130022A (ru) *	2018-03-28	2022-05-04	Блэйд Терапьютикс, Инк.	Модуляторы кальпаина и их терапевтическое применение

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
SE8904298D0 (sv) *	1989-12-21	1989-12-21	Astra Ab	New compounds
CA2098609A1 (en) *	1990-12-28	1992-06-29	Raymond T. Bartus	Use of calpain inhibitors in the inhibition and treatment of neurodegeneration
WO1992012140A1 (en)	1990-12-28	1992-07-23	Georgia Tech Research Corporation	Peptides ketoamides, ketoacids, and ketoesters
CA2071621C (en)	1991-06-19	1996-08-06	Ahihiko Hosoda	Aldehyde derivatives
EP0650368A1 (en) *	1992-06-24	1995-05-03	Cortex Pharmaceuticals, Inc.	Use of calpain inhibitors in the inhibition and treatment of medical conditions associated with increased calpain activity
US5541290A (en) *	1993-06-24	1996-07-30	Harbeson; Scott L.	Optically pure calpain inhibitor compounds

1996
- 1996-10-15 DE DE19642591A patent/DE19642591A1/de not_active Withdrawn
1997
- 1997-09-23 NZ NZ334979A patent/NZ334979A/en unknown
- 1997-09-23 RU RU99109969/04A patent/RU2189974C2/ru active
- 1997-09-23 JP JP10517955A patent/JP2001501955A/ja active Pending
- 1997-09-23 AU AU47770/97A patent/AU736754B2/en not_active Ceased
- 1997-09-23 WO PCT/EP1997/005202 patent/WO1998016512A1/de not_active Ceased
- 1997-09-23 HU HU9904104A patent/HUP9904104A3/hu unknown
- 1997-09-23 IL IL12908997A patent/IL129089A0/xx unknown
- 1997-09-23 SK SK385-99A patent/SK38599A3/sk unknown
- 1997-09-23 US US09/284,543 patent/US6380220B1/en not_active Expired - Fee Related
- 1997-09-23 CN CN97180507A patent/CN1239950A/zh active Pending
- 1997-09-23 PL PL97332720A patent/PL332720A1/xx unknown
- 1997-09-23 CZ CZ991268A patent/CZ126899A3/cs unknown
- 1997-09-23 KR KR1019990703216A patent/KR20000049130A/ko not_active Withdrawn
- 1997-09-23 CA CA002268917A patent/CA2268917A1/en not_active Abandoned
- 1997-09-23 EP EP97910332A patent/EP0934273A1/de not_active Withdrawn
- 1997-09-23 BR BR9711908A patent/BR9711908A/pt unknown
- 1997-09-23 TR TR1999/00819T patent/TR199900819T2/xx unknown
- 1997-10-14 CO CO97060053A patent/CO4930264A1/es unknown
- 1997-10-14 ZA ZA979175A patent/ZA979175B/xx unknown
- 1997-10-14 HR HR19642591,3A patent/HRP970549A2/hr not_active Application Discontinuation
- 1997-10-14 AR ARP970104718A patent/AR009379A1/es not_active Application Discontinuation
1999
- 1999-04-14 NO NO991761A patent/NO991761L/no not_active Application Discontinuation
- 1999-04-15 BG BG103338A patent/BG103338A/bg unknown

Also Published As

Publication number	Publication date
JP2001501955A (ja)	2001-02-13
CO4930264A1 (es)	2000-06-27
CA2268917A1 (en)	1998-04-23
AU4777097A (en)	1998-05-11
HUP9904104A3 (en)	2001-01-29
BG103338A (bg)	2000-01-31
AU736754B2 (en)	2001-08-02
US6380220B1 (en)	2002-04-30
BR9711908A (pt)	1999-08-24
CN1239950A (zh)	1999-12-29
IL129089A0 (en)	2000-02-17
RU2189974C2 (ru)	2002-09-27
PL332720A1 (en)	1999-10-11
KR20000049130A (ko)	2000-07-25
NO991761D0 (no)	1999-04-14
EP0934273A1 (de)	1999-08-11
HUP9904104A2 (hu)	2000-05-28
DE19642591A1 (de)	1998-04-16
ZA979175B (en)	1999-04-14
NO991761L (no)	1999-04-14
NZ334979A (en)	2001-02-23
TR199900819T2 (xx)	1999-06-21
HRP970549A2 (en)	1998-08-31
AR009379A1 (es)	2000-04-12
CZ126899A3 (cs)	1999-07-14
WO1998016512A1 (de)	1998-04-23

Publication	Publication Date	Title
US6380220B1 (en)	2002-04-30	Derivatives from piperidine-keto acid, their preparation and use
JP4621351B2 (ja)	2011-01-26	カルパインインヒビターとしての複素環式的に置換されたアミド
JP4621350B2 (ja)	2011-01-26	複素環置換アミド、その製造および使用
US6448254B1 (en)	2002-09-10	Substituted amides, their production and their use
SK282680B6 (sk)	2002-11-06	Ketobenzamidy, farmaceutické prípravky s ich obsahom a ich použitie na potlačenie chorôb
US6753327B1 (en)	2004-06-22	Substituted amides, their preparation and use
SK14122000A3 (sk)	2001-05-10	Substituované benzamidy, ich príprava a použitie
BG103433A (bg)	2000-02-29	Бензамидоалдехиди и тяхното използване като инхибитори на цистеинпротеаза
KR20010042839A (ko)	2001-05-25	시스테인 프로테아제를 억제하는 효과를 나타내고헤테로시클릭 치환체가 있는 신규 아미드
CN1303372A (zh)	2001-07-11	新的杂环取代酰胺、其制备以及应用
MXPA00009969A (en)	2002-03-26	New substituted amides, their production and their use
HK1032045A (en)	2001-07-06	New derivatives from piperidine-keto acid, their preparation and use
HK1037359A (en)	2002-02-08	New substituted amides, their production and their use
HK1037371A (en)	2002-02-08	Novel heterocyclically substituted amides with cysteine protease-inhibiting effect
MXPA00009755A (en)	2001-07-09	New substituted amides, their production and their use
MXPA00010145A (en)	2001-07-31	Heterocyclically substituted amides, their production and their use
MXPA00010149A (en)	2001-07-31	Substituted benzamides, their production and their use as cysteine protease inhibitors
HK1037189A (en)	2002-02-01	New heterocyclically substituted amides, their production and their use