HRP970549A2 - Novel piperidineketocarboxylic acid derivatives, their preparation and use - Google Patents

Novel piperidineketocarboxylic acid derivatives, their preparation and use

Info

Publication number: HRP970549A2
Authority: HR; Croatia
Prior art keywords: alkyl; formula; phenyl; acid derivatives; piperidineketocarboxylic
Prior art date: 1996-10-15

Application number

HR19642591,3A

Other languages

English (en)

Croatian (hr)

Inventor

Juergen DELZER

Original Assignee

Juergen Delzer

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

1997-10-14

Publication date

1998-08-31

1997-10-14 Application filed by Juergen Delzer filed Critical Juergen Delzer

1998-08-31 Publication of HRP970549A2 publication Critical patent/HRP970549A2/hr

Links

239000002253 acid Substances 0.000 title claims description 25
238000002360 preparation method Methods 0.000 title description 5
108010032088 Calpain Proteins 0.000 claims description 30
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239000003112 inhibitor Substances 0.000 claims description 24
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 22
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 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
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical group COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 11
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
201000010099 disease Diseases 0.000 claims description 9
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 9
SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical group N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 8
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 7
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208000014674 injury Diseases 0.000 claims description 7
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RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
230000000694 effects Effects 0.000 claims description 6
238000004519 manufacturing process Methods 0.000 claims description 6
239000000825 pharmaceutical preparation Substances 0.000 claims description 6
150000003254 radicals Chemical class 0.000 claims description 6
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FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical group C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 4
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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
YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
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239000001257 hydrogen Substances 0.000 claims description 4
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AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical group C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 4
230000004770 neurodegeneration Effects 0.000 claims description 4
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XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical group N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims description 4
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125000004432 carbon atom Chemical group C* 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
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150000002431 hydrogen Chemical group 0.000 claims description 2
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238000007912 intraperitoneal administration Methods 0.000 claims 1
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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
239000000047 product Substances 0.000 description 42
238000000034 method Methods 0.000 description 32
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YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 20
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
150000001875 compounds Chemical class 0.000 description 18
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
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239000000543 intermediate Substances 0.000 description 14
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150000002576 ketones Chemical class 0.000 description 11
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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
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- 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
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- 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
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- 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

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Organic Chemistry (AREA)
Chemical & Material Sciences (AREA)
Health & Medical Sciences (AREA)
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Hospice & Palliative Care (AREA)
Psychiatry (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Hydrogenated Pyridines (AREA)
Plural Heterocyclic Compounds (AREA)

HR19642591,3A 1996-10-15 1997-10-14 Novel piperidineketocarboxylic acid derivatives, their preparation and use HRP970549A2 (en)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
DE19642591A DE19642591A1 (de)	1996-10-15	1996-10-15	Neue Piperidin-Ketocarbonsäure-Derivate, deren Herstellung und Anwendung

Publications (1)

Publication Number	Publication Date
HRP970549A2 true HRP970549A2 (en)	1998-08-31

Family

ID=7808858

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
HR19642591,3A HRP970549A2 (en)	1996-10-15	1997-10-14	Novel piperidineketocarboxylic acid derivatives, their preparation and use

Country Status (24)

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

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
SK38599A3 (en)	2000-04-10
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
AR009379A1 (es)	2000-04-12
CZ126899A3 (cs)	1999-07-14
WO1998016512A1 (de)	1998-04-23

Legal Events

Date	Code	Title
1998-08-31	A1OB	Publication of a patent application
1999-02-27	AIPI	Request for the grant of a patent on the basis of a substantive examination of a patent application
2004-09-30	ODBC	Application rejected

Publication	Publication Date	Title
AU736754B2 (en)	2001-08-02	Novel piperidineketocarboxylic acid derivatives, 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
US6448254B1 (en)	2002-09-10	Substituted amides, their production and their use
US6630493B1 (en)	2003-10-07	Heterocyclically substituted amides, their preparation and use
HRP970680A2 (en)	1998-10-31	New ketobenzamides and their use
HRP20000777A2 (en)	2001-06-30	New substituted benzamides, their production and use
JP2011063604A (ja)	2011-03-31	新規の複素環式の置換されたアミド、その製造および使用
HRP20000788A2 (en)	2001-06-30	Novel heterocyclically substituted amides with cysteine protease-inhibiting effect
KR20010042840A (ko)	2001-05-25	신규한 치환된 아미드, 그의 제조 및 그의 용도
HK1037371A (en)	2002-02-08	Novel heterocyclically substituted amides with cysteine protease-inhibiting effect
MXPA00009969A (en)	2002-03-26	New substituted amides, their production and their use
MXPA00010274A (en)	2001-07-31	Novel heterocyclically substituted amides with cysteine protease-inhibiting effect
MXPA00010145A (en)	2001-07-31	Heterocyclically substituted amides, their production and their use