Multicatalytic protease inhibitors

• US 5,614,649 A
• Filed: 11/03/1995
• Issued: 03/25/1997
• 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:
  US08/552,794
• Time in Patent Office: 508 Days
• Field of Search: 554/56, 554/54, 554/55, 554/53, 540/452, 549/213, 549/399, 514/183, 514/452, 514/463, 514/519, 514/590, 514/616
• US Class Current: 554/56
• 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 31/277 having a ring, e.g. verapamil
• 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: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 inhibitors 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 of formula:

##STR49## 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 three 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)--Q;

Q is selected from the group consisting of --CH--R₈, --C(=O)CH₃, --C(=O)CH₂ Cl, --C(=O)CH₂ Br, --C(=O)CH₂ F, --C(=O)CHF₂, --C(=O)CF₃, --C(=O)C(=O)R₇, --C(=O)C(=O)NH--R₇, --C(=O)CO₂ --R₇, --C(=O)CO₂ H, --B(OH)₂, ##STR50## where p and q, independently, are 2 or 3;

W is cycloalkyl;

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

R₆ is --(CH₂)_m --NH--C(=NH)--NH--;

R₇ is selected from the group consisting of phenyl, and alkyl having from one to eight carbons, said alkyl group being optionally substituted with one or more halogen atoms, aryl, or heteroaryl groups;

R₈ is selected from the group consisting of =O, =N--NHC(=O)--NH₂, =N--OH, =N--OCH₃, =N--O--CH₂ --C₆ H₅, =NNH--C(=S)--NH₂ and =N--NH--J;

R₉ is selected from the group consisting of hydrogen, and alkyl having from one to six carbons, said alkyl group being optionally substituted with one or more halogen atoms, aryl or heteroaryl groups;

J is a protecting group;

n is an integer from 3 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 Q is --CH--R₈.

8. The compound of claim 1 wherein Q is selected from the group consisting of --C(=O)CH₃, --C(=O)CH₂ C, --C (=O)CH₂ Br, --C(=O) CH₂ F, --C (=O) CHF₂, --C(=O)CF₃, --C (=O)C(=O) R₇, --C(=O)C(=O)NH--R₇, --C(=O)CO₂ --R₇, --C(=O)CO₂ H, --B(OH)₂, ##STR51##

9. The compound of claim 7 wherein Q is selected from the group consisting of --CH--R₈, --B(OH)₂, --C(=O)C(=O)NH--R₇, ##STR52##

10. The compound of claim 7 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.

11. 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 ;

Q is --CH--R₈ ;

R₇ is --CH(CH₃)₂ ; and

R₈ is =O.

12. The compound of claim 1 wherein R₁ is --C=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 ;

Q is --CH--R₈ ;

R₇ is --CH(CH₃)₂ ; and

R₈ is =O.

13. 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 ;

Q is selected from the group consisting of --B(OH)₂, --C(=O)C(=O)NH--R₇, ##STR53## and R₇ is selected from the group consisting of --CH(CH₃)₂ and --CH₂ --CH₃.

14. 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 ;

Q is --CH--R₈ ;

R₇ is --CH(CH₃)₂ ; and

R₈ is selected from the group consisting of =N--NHC(=O)--NH₂, =N--OH, =N--OCH₃, and =N--O--CH₂ --C₆ H₅.