EP0954526A2 - Substituierte oxadiazol, thiadiazol und triazol serinprotease inhibitore - Google Patents

Substituierte oxadiazol, thiadiazol und triazol serinprotease inhibitore

Info

Publication number
EP0954526A2
EP0954526A2 EP97952232A EP97952232A EP0954526A2 EP 0954526 A2 EP0954526 A2 EP 0954526A2 EP 97952232 A EP97952232 A EP 97952232A EP 97952232 A EP97952232 A EP 97952232A EP 0954526 A2 EP0954526 A2 EP 0954526A2
Authority
EP
European Patent Office
Prior art keywords
compound
alkyl
aryl
carbonyl
oxadiazolyl
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP97952232A
Other languages
English (en)
French (fr)
Inventor
Albert Gyorkos
Lyle W. Spruce
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cortech Inc
Original Assignee
Cortech Inc
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.)
Filing date
Publication date
Priority claimed from US08/761,313 external-priority patent/US5869455A/en
Priority claimed from US08/984,881 external-priority patent/US6015791A/en
Priority claimed from US08/985,056 external-priority patent/US5998379A/en
Priority claimed from US08/984,884 external-priority patent/US6001811A/en
Priority claimed from US08/985,201 external-priority patent/US6150334A/en
Application filed by Cortech Inc filed Critical Cortech Inc
Publication of EP0954526A2 publication Critical patent/EP0954526A2/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06043—Leu-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06052—Val-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06086—Dipeptides with the first amino acid being basic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06104—Dipeptides with the first amino acid being acidic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C07K5/06156—Dipeptides with the first amino acid being heterocyclic and Trp-amino acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/12—Cyclic peptides with only normal peptide bonds in the ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the benzene ring is substituted with an alkyl, such as methyl; with a haloalkyl, such as trifluoromethyl; or with a dialkylamino, preferably dimethylamin ⁇ .
  • R is a fused arylalkyl group such as methylenenaphthyl; or a fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl such as 3, 4-methylenedioxy benzyl.
  • W is O or S; or C or N optionally substituted with H, alkyl or aryl.
  • X is N and Y is O.
  • X is O and Y is N.
  • R 13 is an optionally substituted phenyl or benzyl; pyridyl, piperidinyl, alkyl or H or a fused ring system such as 3,4-methylenedioxybenzyl; R 14 is optionally substituted amino or an arylalkyloxycarboxamide such as benzyloxycarboxamide; and R 15 is H or halo.
  • R 2 is isopropyl and R 3 is H.
  • the present invention additionally provides compounds of the formula (Group V):
  • X is N and Y is O. In another preferred embodiment, X is O and Y is N.
  • the invention further provides compounds of the formula (Group VI):
  • R is alkyl or alkenyl optionally substituted with 1-3 halo or hydroxyl; -alkyl- C(O)OCH 3 ; alkylamino, dialkylamino, alkyldialkylamino; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, (C 5 -C 12 )aryl, (C 5 -C 12 )arylalkyl, (C 5 - C 12 )arylalkenyl, fused (C 5 -C 12 )aryl-cycloalkyl or fused (C 5 -C 12 )aryl-cyclalkylalkyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alk
  • X and Y are independently O, S or N, wherein N is optionally substituted with alkyl or alkenyl optionally substituted with 1-3 halo atoms; (C 5 -C 6 )aryl, arylalkyl or arylalkenyl optionally comprising 1-3 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; and
  • the protecting group [PGR,] is removed from alcohol (D) by reacting the aldehyde of formula (C) with hydrochloric acid in dioxane.
  • the protecting group [PGr t ] may be any suitable group, preferably Boc.
  • R ⁇ , R 12 and E together form a monocyclic or bicyclic ring comprising 5-10
  • Figure 34 shows the activity of certain compounds of Group V.
  • CE-2158 3-(S)-[(Benzyloxycarbonyl)amino-(5,6 phenyl- ⁇ -lactam]-N-[l-(3-[5-
  • CE-2244 2-Oxo-5-methyl-l,4-(l-thiophenodiazepine)-N-[l-(2-[5-(3- methylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
  • CE-2245 2-Oxo-5-methyl- 1 ,4-(2-phenyl- 1 -thiophenodiazepine)-N-[ 1 -(2-[5-(3- methylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
  • CE-2246 4-(R)-(2-Isobutyl)-2,5-imidazolidinedione-N-[l-(2-[5-(3- methylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
  • CE-2247 4-( ⁇
  • ONO-PO-717 2-Oxo-5-(4-chlorophenyl)-l,4-benzodiazepine-N-[l-(2-[5-tert- butyl-l,3 5 4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide
  • ONO-PO-718 2-[5-Amino-6-oxo-2-(4-fluorophenyl)- 1 ,6-dihydro- 1 - pyrimidinyl]-N-[l-(2-[5-(tert-butyl)-l,3,4-oxadiazolyl]carbonyl)-2-(R)- methylpropyl] acetamide
  • Example 10 (CE-2054)(Benzyloxycarbonyl)-I-valyl-N-[l-(3-[5-(3,5- ditrifluoromethylbenzyl)- 1 ,2,4-oxadiazolyl] carbonyl)-2-(S)-methylpropyl]-Z,- prolinamide. Prepared similar to Example 1 of WO 96/16080. FAB MS [M+H] m/z; Calcd: 726, Found: 726.
  • Example 14 (CE-2062)(Benzyloxycarbonyl)-I-valyl-N-[l-(3-[5-(3-phenylbenzyl)- 1,2,4-oxadiazolyl] carbonyl)-2-( ⁇ S)-methylpropyl]-E-prolinamide. Prepared similar to Example 1 of WO 96/16080. FAB MS [M+H] m/z; Calcd: 666, Found: 666.
  • Example 107 2-[5-Amino-6-oxo-2-(3-pyridyl)-l,6-dihydro-l- pyrirnidmyl]-N-[l-(2-[5-( ⁇ , ⁇ -dimethylbenzyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)- methylpropyl]acetamide was prepared in a similar manner to Example 91.
  • Example 110 2-[5-Amino-6-oxo-2-phenyl-l,6-dihydro-l- pyrimidinyl]-N-[l-(2-[5-(l-methylcyclopropyl)-l,3,4-oxadiazolyl]carbonyl)-2-(S)- methylpropyl]acetamide was prepared in a similar manner to Example 91.
  • Optical density (SPECTRA MAX 250, Molecular Devices) at 405 nm due to p-nitroaniline generated by the enzyme reaction was measured at 37°C in order to measure the reaction rate during the period that the production rate of p-nitroaniline remains linear.
  • the rate, mO.D./min. was measured for 10 minutes at 30 second intervals immediately after the addition of the enzyme solution.
  • IC 50 values were determined by log-logit method and converted to K ⁇ values by Dixson plot method. The values are presented in Table 1 below.
  • the inhibitors were dissolved or suspended in polyethylene glycol (PEG), PEG-400 or PEG:H 2 O:EtOH at a concentration of 10 mg/ml.
  • PEG polyethylene glycol
  • PEG-400 PEG:H 2 O:EtOH
  • Rats received 10 mg inhibitor/kg body weight in a volume of 1 ml/kg.
  • the rats were killed with an overdose of urethane (2.5 g/kg; i.p.) and the blood collected in a heparinized tube via cardiac puncture. Red blood cells were separated from the plasma by centrifugation.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Enzymes And Modification Thereof (AREA)
EP97952232A 1996-12-06 1997-12-05 Substituierte oxadiazol, thiadiazol und triazol serinprotease inhibitore Withdrawn EP0954526A2 (de)

Applications Claiming Priority (21)

Application Number Priority Date Filing Date Title
US771317 1985-08-30
US760916 1991-09-17
US761190 1991-09-18
US761313 1996-12-06
US762381 1996-12-06
US08/761,313 US5869455A (en) 1994-11-21 1996-12-06 Serine protease inhibitors-N-substituted derivatives
US08/761,190 US5807829A (en) 1994-11-21 1996-12-06 Serine protease inhibitor--tripeptoid analogs
US08/771,317 US5801148A (en) 1994-11-21 1996-12-06 Serine protease inhibitors-proline analogs
US08/760,916 US5861380A (en) 1994-11-21 1996-12-06 Serine protease inhibitors-keto and di-keto containing ring systems
US08/762,381 US5891852A (en) 1994-11-21 1996-12-06 Serine protease inhibitors-cycloheptane derivatives
US98529897A 1997-12-04 1997-12-04
US985056 1997-12-04
US08/984,881 US6015791A (en) 1994-11-21 1997-12-04 Serine protease inhibitors-cycloheptane derivatives
US985201 1997-12-04
US08/985,056 US5998379A (en) 1994-11-21 1997-12-04 Serine protease inhibitors-proline analogs
US984881 1997-12-04
US985298 1997-12-04
US08/984,884 US6001811A (en) 1994-11-21 1997-12-04 Serine protease inhibitors--N-substituted derivatives
US984884 1997-12-04
US08/985,201 US6150334A (en) 1994-11-21 1997-12-04 Serine protease inhibitors-tripeptoid analogs
PCT/US1997/021636 WO1998024806A2 (en) 1996-12-06 1997-12-05 Substituted oxadiazole, thiadiazole and triazole serine protease inhibitors

Publications (1)

Publication Number Publication Date
EP0954526A2 true EP0954526A2 (de) 1999-11-10

Family

ID=27581319

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97952232A Withdrawn EP0954526A2 (de) 1996-12-06 1997-12-05 Substituierte oxadiazol, thiadiazol und triazol serinprotease inhibitore

Country Status (11)

Country Link
EP (1) EP0954526A2 (de)
JP (1) JP3220169B2 (de)
CN (1) CN1247542A (de)
AU (1) AU734615B2 (de)
CA (1) CA2272548A1 (de)
HU (1) HUP0100669A3 (de)
NO (1) NO992734L (de)
NZ (1) NZ336046A (de)
RU (1) RU2217436C2 (de)
TR (2) TR199901681T2 (de)
WO (1) WO1998024806A2 (de)

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JP3220169B2 (ja) 2001-10-22
AU734615B2 (en) 2001-06-21
HUP0100669A3 (en) 2001-12-28
AU5589498A (en) 1998-06-29
NO992734D0 (no) 1999-06-04
RU2217436C2 (ru) 2003-11-27
NZ336046A (en) 2000-10-27
WO1998024806A3 (en) 1998-10-15
JP2001507679A (ja) 2001-06-12
WO1998024806B1 (en) 1999-05-20
TR200103270T2 (tr) 2003-03-21
CN1247542A (zh) 2000-03-15
WO1998024806A2 (en) 1998-06-11
HUP0100669A2 (hu) 2001-08-28
CA2272548A1 (en) 1998-06-11
NO992734L (no) 1999-08-02
TR199901681T2 (xx) 2000-03-21

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