Multicatalytic protease inhibitors

• US 5,550,262 A
• Filed: 11/14/1994
• Issued: 08/27/1996
• Est. Priority Date: 11/14/1994
• Status: Expired due to Term

• Current Assignee: Cephalon Incorporated (Teva Pharmaceutical Industries Limited)
• Original Assignee: Cephalon Incorporated (Teva Pharmaceutical Industries Limited)
• Inventors: Diebold, James L., Chatterjee, Sankar, Iqbal, Mohamed, Siman, Robert, Kauer, James C.
• Primary Examiner(s): Nucker, Christine M.
• Assistant Examiner(s): Prickril, Benet
• Application Number:
  US08/337,795
• Time in Patent Office: 652 Days
• Field of Search: 514/19, 564/123, 554/57, 554/54, 554/51, 554/36, 554/42, 558/432
• US Class Current: 554/57
• CPC Class Codes: A61K 31/18 Sulfonamides compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 31/22 of acyclic acids, e.g. pravastatin
• CPC Class Codes: A61K 31/353 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• CPC Class Codes: A61K 31/4035 Isoindoles, e.g. phthalimide
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 279/36 Substituted N-nitroguanidines
• CPC Class Codes: C07C 311/09 the carbon skeleton being further substituted by at least two halogen atoms
• CPC Class Codes: C07C 311/47 Y being a hetero atom
• CPC Class Codes: C07C 311/64 X and Y being nitrogen atoms, e.g. N-sulfonylguanidine
• CPC Class Codes: C07C 337/08 the other nitrogen atom being further doubly-bound to a carbon atom, e.g. thiosemicarbazones
• CPC Class Codes: C07D 209/48 with oxygen atoms in positions 1 and 3, e.g. phthalimide
• CPC Class Codes: C07D 311/70 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C07K 5/0207 containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids
• CPC Class Codes: C07K 5/06095 Arg-amino acid

Abstract

Disclosed herein are inbibitors of the multicatalytic protease enzyme which are represented by the general formula: ##STR1## Constituent members and preferred constituent members are disclosed herein. Methodologies for making and using the disclosed compounds are also set forth herein.

Claims

1. A compound represented by the formula:

##STR44## wherein;

R₁ is selected from the group consisting of --C.tbd.N, --C(O)OR₉, phthalimido, --NH--SO₂ R₉, and --NH--J;

R₂ is selected from the group consisting of H, hydroxyl, alkyl having from one to ten carbons, and cycloalkyl having from five to seven carbons;

R₃ is selected from the group consisting of --(CH₂)_m --NH--C (═

N--R₅)--NH₂, --R₆ --NO₂, --R₆ --J and --R₆ --CN;

R₄ is --CH (CH₂ --R₇)--CH--R₈ ;

R₅ is selected from the group consisting of --NO₂, --CN, --J; and

R₆ is --(CH₂)_m --NH--C (═

NH) --NH--;

R₇ is alkyl having from one to eight carbons, said alkyl group being optionally substituted with one or more phenyl groups, or C₆ H₅ ; and

R₈ is selected from the group consisting of ═

O ═

N--NHC(O)--NH₂, ═

N--OH, ═

N--OCH₃, ═

N--O--CH₂ --C₆ H₅, ═

NNHC--C(S)--NH₂ and ═

N--NH--J;

R₉ is alkyl having from one to six carbons, said alkyl group being optionally substitued with one or more halogen atoms, aryl, or heteroaryl groups;

J is a protecting group;

n is an integer from 5 to 10; and

m is an integer from 2 to 5.

2. The compound of claim 1 wherein R₁ is selected from the group consisting of --C.tbd.N, --C (O)OCH₃, phthalimido and --NH--SO₂ CF₃.

3. The compound of claim 1 wherein R₂ is selected from the group consisting of H and cyclopentyl.

4. The compound of claim 1 wherein R₃ is --(CH₂)₃ --NH--C (═

N--R₅)--NH₂.

5. The compound of claim 4 wherein R₅ is selected from the group consisting of --NO₂, CN, --PMC, --MTR, --MTS, and TOS.

6. The compound of claim 1 wherein R₇ is selected from the group consisting of --CH(CH₃)₂, --(CH₂)₂ --CH₃ and --C₆ H₅.

7. The compound of claim 1 wherein R₈ is selected from the group consisting of ═

O ═

N--NHC(O)--NH₂, ═

N--OH, ═

N--OCH₃, ═

N--O--CH₂ --C₆ H₅, and ═

NNH--C(S)--NH₂.

8. The compound of claim 1 wherein R₁ is selected from the group consisting of --C(O)OCH₃, phthalimido and --NHSO₂ CF₃ ;

R₂ is cyclopentyl;

R₃ is --(CH₂)₃ --NH--C(═

N--NO₂)--NH₂ ;

R₇ is --CH(CH₃)₂ ; and

R₈ is ═

O.

9. The compound of claim 1 wherein R₁ is --C.tbd.N;

R₂ is cyclopentyl;

R₃ is selected from the group consisting of --(CH₂)₃ --NH--C (═

N--NO₂)--NH₂ and --(CH₂)₃ --NH--C(═

N--J)--NH₂ ;

R₇ is --CH(CH₃)_2;

and R₈ is ═

O.

10. The compound of claim 1 wherein R₁ is --C.tbd.N;

R₂ is cyclopentyl;

R₃ is selected from the group consisting of --(CH₂)₃ --NH--C(═

N--NO₂)--NH₂ and --(CH₂)₃ --NH--C(═

N--J)--NH₂ ;

R₇ is --CH(CH₃)₂ ; and

R₈ is selected from the group consisting of ═

N--NHC(O)--NH₂, ═

N--OH, ═

N--OCH₃, and ═

N--)--CH₂ --C₆ H₅.