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Last Updated: March 28, 2024

Claims for Patent: 6,207,698


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Summary for Patent: 6,207,698
Title: Sulfonated amino acid derivatives and metalloproteinase inhibitors containing the same
Abstract:Compounds having a metalloproteinase inhibitory activity, represented by the formula (I), its optically active isomers, their pharmaceutically acceptable salts, or hydrates thereof. ##STR1##
Inventor(s): Wantanabe; Fumihiko (Kitakatsuragi-gun, JP), Tsuzuki; Hiroshige (Tsuzuki-gun, JP), Ohtani; Mitsuaki (Nara, JP)
Assignee: Shionogi & Co., Ltd. (Osaka, JP)
Application Number:09/120,197
Patent Claims:1. A pharmaceutical composition comprising a compound of formula I: ##STR627##

wherein R.sup.1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

R.sup.2 is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

R.sup.3 is optionally substituted heteroarylene;

R.sup.4 is a bond, --(CH.sub.2).sub.m --, --CH.dbd.CH--, --C.tbd.C--, --CO--, --CO--NH--, --N.dbd.N--, --N(R.sup.A)--, --NH--CO--NH--, --NH--CO--, --O--, --S--, --SO.sub.2 --NH--, --SO.sub.2 --NH--N.dbd.CH--, or tetrazol-diyl;

R.sup.5 is optionally substituted lower alkyl, optionally substituted C.sub.3 -C.sub.8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group;

R.sup.A is hydrogen or lower alkyl;

Y is --NHOH or --OH; and

m is 1 or 2;

provided R.sup.2 is hydrogen when Y is --NHOH and

R.sup.5 is not lower alkyl when R.sup.4 is --CO--NH-- or --NH--CO--NH--,

its optically active substance, pharmaceutically acceptable salt, or hydrate thereof and a pharmaceutically acceptable carrier.

2. A pharmaceutical composition comprising a compound of formula I: ##STR628##

wherein R.sup.1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

R.sup.2 is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

R.sup.3 is optionally substituted heteroarylene;

R.sup.4 is a bond, --(CH.sub.2).sub.m --, --CH.dbd.CH--, --C.tbd.C--, --CO--, --CO--NH--, --N.dbd.N--, --N(R.sup.A)--, --NH--CO--NH--, --NH--CO--, --S--, --SO.sub.2 NH--, --SO.sub.2 --NH--N.dbd.CH--, or tetrazol-diyl;

R.sup.5 is optionally substituted lower alkyl, optionally substituted C.sub.3 -C.sub.8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group;

R.sup.A is hydrogen or lower alkyl;

Y is --NHOH or --OH; and

m is 1 or 2;

provided R.sup.2 is hydrogen when Y is --NHOH,

R.sup.5 is optionally substituted aryl or optionally substituted heteroaryl when R.sup.4 is --CO--NH--, --NH--CO--, or --NH--CO--NH--; and

R.sup.5 is optionally substituted aryl or optionally substituted heteroaryl when R.sup.4 is tetrazol-diyl; and

its optically active substance, pharmaceutically acceptable salt, or hydrate thereof and a pharmaceutically acceptable carrier.

3. A compound of formula I: ##STR629##

wherein R.sup.1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

R.sup.2 is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

R.sup.3 is optionally substituted heteroarylene;

R.sup.4 is a bond, --(CH.sub.2).sub.m --, --CH.dbd.CH--, --C.tbd.C--, --CO--, --CO--NH--, --N.dbd.N--, --N(R.sup.A)--, --NH--CO--NH--, --NH--CO--, --S--, --SO.sub.2 NH--, --SO.sub.2 --NH--N.dbd.CH--, or tetrazol-diyl;

R.sup.5 is optionally substituted lower alkyl, optionally substituted C.sub.3 -C.sub.8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group;

R.sup.A is hydrogen or lower alkyl;

Y is --NHOH or --OH; and

m is 1 or 2;

provided R.sup.2 is hydrogen when Y is --NHOH,

R.sup.5 is optionally substituted aryl or optionally substituted heteroaryl when R.sup.4 is --CO--NH--, --NH--CO--, or --NH--CO--NH--,

R.sup.5 is lower alkyl, optionally substituted aryl, or optionally substituted heteroaryl when R.sup.4 is tetrazol-diyl; and

its optically active substance, pharmaceutically acceptable salt, or hydrate thereof.

4. A compound of the formula IV: ##STR630##

wherein R.sup.1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

R.sup.2 is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

R.sup.7 is optionally substituted aryl or optionally substituted heteroaryl;

R.sup.11 is a bond, --CH.dbd.CH--, or --C.tbd.C--;

X is oxygen atom or sulfur; and

Y is --NHOH or --OH,

its optically active substance, pharmaceutically acceptable salt, or hydrate thereof.

5. A compound of the formula VIII: ##STR631##

wherein R.sup.1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

R.sup.2 is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

R.sup.7 is optionally substituted aryl or optionally substituted heteroaryl; and

R.sup.11 is a bond --CH.dbd.CH-- or --C.tbd.C--,

its optically active substance, pharmaceutically acceptable salt, or hydrate thereof.

6. A compound of the formula XIII: ##STR632##

wherein R.sup.1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

R.sup.7 is optionally substituted aryl or optionally substituted heteroaryl; and

R.sup.11 is a bond --CH.dbd.CH-- or --C.tbd.C--, its optically active substance, pharmaceutically acceptable salt, or hydrate thereof.

7. A method of inhibiting the activity of a metalloproteinase, comprising administering to a subject in need thereof an effective amount of a compound of the formula I: ##STR633##

wherein R.sup.1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

R.sup.2 is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

R.sup.3 is optionally substituted heteroarylene;

R.sup.4 is a bond, --(CH.sub.2).sub.m --, --CH.dbd.CH--, --C.tbd.C--, --CO--, --CO--NH--, --N.dbd.N--, --N(R.sup.A)--, --NH--CO--NH--, --NH--CO--, --S--, --SO.sub.2 NH--, --SO.sub.2 --NH--N.dbd.CH--, or tetrazol-diyl;

R.sup.5 is optionally substituted lower alkyl, optionally substituted C.sub.3 -C.sub.8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group;

R.sup.A is hydrogen or lower alkyl;

Y is --NHOH or --OH; and

m is 1 or 2;

provided R.sup.2 is hydrogen when Y is --NHOH,

R.sup.5 is not lower alkyl when R.sup.4 is --CO--NH-- or --NH--CO--NH--,

its optically active substance, pharmaceutically acceptable salt, or hydrate thereof.

8. A method of inhibiting the activity of a type-IV collagenase, comprising administering to a subject in need thereof an effective amount of a compound of the formula I: ##STR634##

wherein R.sup.1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

R.sup.2 is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

R.sup.3 is optionally substituted heteroarylene;

R.sup.4 is a bond, --(CH.sub.2).sub.m --, --CH.dbd.CH--, --C.tbd.C--, --CO--, --CO--NH--, --N.dbd.N--, --N(R.sup.A)--, --NH--CO--NH--, --NH--CO--, --S--, --SO.sub.2 NH--, --SO.sub.2 --NH--N.dbd.CH--, or tetrazol-diyl;

R.sup.5 is optionally substituted lower alkyl, optionally substituted C.sub.3 -C.sub.8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group;

R.sup.A is hydrogen or lower alkyl;

Y is --NHOH or --OH; and

m is 1 or 2;

provided R.sup.2 is hydrogen when Y is --NHOH--,

R.sup.5 is not lower alkyl when R.sup.4 is --CO--NH-- or --NH--CO--NH--,

its optically active substance, pharmaceutically acceptable salt, or hydrate thereof.

9. The compound of any one of claims 3 to 6, wherein R.sup.1 is i-propyl, benzyl, or (indole-3-yl)methyl.

10. The compound of any one of claims 3 to 6, wherein R.sup.5 and R.sup.7 are phenyl optionally substituted with one or more substituents selected from the group consisting of alkoxy, alkylthio, and alkyl.

11. The compound of any one of claims 3 to 6, wherein a configuration of asymmetric carbon atoms bonding with R.sup.1 is R configuration.

12. The compound of any one of claims 4 to 6, wherein R.sup.11 is --C.tbd.C--.

13. A pharmaceutical composition comprising a compound of any of claims 3-6.

14. The pharmaceutical composition of claim 1, comprising a metalloproteinase inhibitory effective amount of the compound of formula I.

15. The pharmaceutical composition of claim 2, comprising a metalloproteinase inhibitory effective amount of the compound of formula I.

16. The pharmaceutical composition of claim 13, comprising a metalloproteinase inhibitory effective amount of the compound of formula I.

17. The pharmaceutical composition of claim 1, comprising a type-IV collagenase inhibitory effective amount of the compound of formula I.

18. The pharmaceutical composition of claim 2, comprising a type-IV collagenase inhibitory effective amount of the compound of formula I.

19. The pharmaceutical composition of claim 13, comprising a type-IV collagenase inhibitory effective amount of the compound of formula I.

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