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Last Updated: March 28, 2024

Claims for Patent: 6,410,580


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Summary for Patent: 6,410,580
Title: Sulfonylamino derivatives which inhibit matrix-degrading metalloproteinases
Abstract:Compounds of formula (I) wherein W is --OH or --NHOH; X is an optionally substituted heterocycle, NR.sub.1 SO.sub.2 R.sub.2, heterocyclylalkythio, CONR.sub.2 R.sub.3 or NR.sub.1 COR.sub.2 ; Y, Z, R.sub.1 -R.sub.3 and n are as defined in the application. Compounds (I) are inhibitors of matrix-degrading metalloproteinases and are use for the treatment of related conditions. ##STR1##
Inventor(s): Kukkola; Paivi Jaana (Whitehouse Station, NJ), Robinson; Leslie Ann (Del Mar, CA), Sakaki; Junichi (Kawasaki, JP), Nakajima; Motowo (Ashiya, JP)
Assignee: Novartis AG (Basel, CH)
Application Number:09/601,462
Patent Claims:1. A compound of formula I ##STR97##

wherein:

W is --OH or --NHOH;

X is

an unsubstituted or substituted heterocyclic radical, selected from the group consisting of pyrrolidinyl, pyrrolyl, pyrazolyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, oxadiazolyl, 2-oxopyrrolodinyl, 1,3-dioxolane, tetrahydro-1,1-dioxothienyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, indolizinyl, benzofuryl, indazolyl, pyrrolopyridyl, furopyridinyl and dihydrobenzoisothiazolyl;

with the proviso that when X is a nitrogen containing heterocyclic radical, the heterocyclic radical is attached to the (CH.sub.2).sub.m moiety by a ring nitrogen and the proviso that nitrogen and sulfur heteroatoms of the heterocyclic radical may also be oxidized;

Y is oxygen or sulfur;

Z is optionally substituted alkyl; aryl; optionally substituted alkoxy; aryloxy; aralkoxyaryl; aralkoxyheteroaryl; heteroaryl, heterocyclyl, heteroaryloxy, --CONR'.sub.2 R'.sub.3, --NR'.sub.1 COR'.sub.2, --NR'.sub.1 CONR'.sub.2 R'.sub.3, --OCONR'.sub.2 R'.sub.3, --NR'.sub.1 COOR'.sub.4, or --SO.sub.2 R'.sub.2, in which

R'.sub.1 is hydrogen, optionally substituted alkyl, heterocyclylalkyl, aralkyl or heteroarylalkyl and

R'.sub.2 and R'.sub.3 are independently hydrogen, optionally substituted alkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, aryl or heteroaryl; or

R'.sub.2 and R'.sub.3 taken together with the nitrogen atom to which they are attached form a 5- to 7-membered ring, which may optionally contain another heteroatom selected from oxygen, nitrogen and sulfur;

R.sub.4 is optionally substituted alkyl, heterocyclylalkyl, aralkyl, aryl or heteroaryl;

m represents an integer from one to six; and

n represents the integer one;

or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 wherein

W is --OH or --NHOH;

X is an unsubstituted or substituted heterocyclic radical, selected from the group consisting of pyrrolidinyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, oxadiazolyl, 2-oxopyrrolodinyl, 1,3-dioxolane, tetrahydro-1,1-dioxothienyl, indolizinyl, benzofuryl, indazolyl, pyrrolopyridyl, furopyridinyl, and dihydrobenzoisothiazolyl; and

the remaining symbols and radicals have the same meaning as given in claim 1;

or a pharmaceutically acceptable salt thereof.

3. A compound of claim 1 wherein

X is an unsubstituted or substituted heterocyclic radical selected from the group consisting of pyrazolyl, pyrazolinyl, imidazolinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, oxadiazolyl, 1,3-dioxolane, tetrahydro-1,1-dioxothienyl, benzothiazolyl, benzoxazolyl, benzofuryl, indazolyl, pyrrolopyridyl, furopyridinyl, dihydrobenzoisothiazolyl; and

the remaining symbols and radicals have the same meaning as given in claim 1;

or a pharmaceutically acceptable salt thereof.

4. A compound of claim 1 wherein

W is --OH or --NHOH;

X is 3,4,4-trimethyl-2,5-dioxoimidazolinyl, or 1,1,3-trioxo-2,3-dihydrobenzoisothiazolyl;

Z is aryl, aryloxy, heteroaryl or heteroaryloxy;

Y is oxygen or sulfur;

n represents the integer one; and

m represents an integer from two to four;

or a pharmaceutically acceptable salt thereof.

5. A compound of claim 1 wherein

W is --OH; and

the remaining symbols and radicals have the same meaning as given in claim 1;

or a pharmaceutically acceptable salt thereof.

6. A compound of claim 1 which is:

(2R)-(4-Benzenesulfonylthiophene-2-sulfonylamino]-5-(1,1,3-trioxo-2,3-dihyd robenzoisothiazol-2-yl)pentanoic acid;

(2R)-(5-Benzenesulfonylthiophene-2-sulfonylamino]-5-(1,1,3-trioxo-2,3-dihyd robenzoisothiazol-2-yl)pentanoic acid;

(2R)-[5-(5-Trifluoromethylpyridine-2-sulfonyl)thiophene-2-sulfonylamino]-5- (1,1,3-trioxo-2-dihydrobenzoisothiazol-2-yl)pentanoic acid;

(2R)-(4-Benzenesulfonylthiophene-2-sulfonyl-amino]-5-(1,1,3-trioxo-2,3-dihy drobenzoisothiazol-2-yl)pentanoic acid hydroxyamide;

(2R)-(5-Benzenesulfonylthiophene-2-sulfonylamino]-5-(1,1,3-trioxo-2,3-dihyd robenzoisothiazol-2-yl)pentanoic acid hydroxyamide;

(2R)-[5-(5-Trifluoromethylpyridine-2-sulfony1)thiophene-2-sulfonylamino]-5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl)pentanoic acid hydroxyamide;

or a pharmaceutically acceptable salt of any said compound.

7. A pharmaceutical composition comprising an effective matrix-degrading metalloproteinase inhibiting amount of a compound of the formula I according to claim 1 in combination with one or more pharmaceutically acceptable carriers.

8. A pharmaceutical composition for treatment of tumours in warm-blooded animals, including humans, comprising an antitumourally effective dose of a compound of the formula I according to claim 1 or a pharmaceutically acceptable salt of such a compound together with a pharmaceutical carrier.

9. A method of inhibiting matrix-degrading metalloproteinase activity in mammals which comprises administering to a mammal in need thereof an effective matrix-degrading metalloproteinase inhibiting amount of a compound of the formula I according to claim 1.

10. A method of inhibiting stromelysin or collagenase activity in mammals which comprises administering to a mammal in need thereof an effective stromelysin or collagenase inhibiting amount of a compound of the formula I according to claim 1.

11. A method of treating matrix-degrading metalloproteinase dependent conditions in mammals which comprises administering to a mammal in need thereof an effective matrix-degrading metalloproteinase inhibiting amount of a compound of the formula I according to claim 1.

12. A method of treating a warm blooded animal suffering from a tumor disease, by administering an antitumorally effective amount of compound of formula I according to claim 1 or a pharmaceutically acceptable salt of such a compound.

13. A process for the preparation of a sulfonylamino acid or sulfonylamino hydroxamic acid of formula I ##STR98##

wherein

W is --OH or --NHOH;

X is

an unsubstituted or substituted heterocyclic radical, selected from the group consisting of pyrrolidinyl, pyrrolyl, pyrazolyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, oxadiazolyl, 2-oxopyrrolodinyl, 1,3-dioxolane, tetrahydro-1,1-dioxothienyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, indolizinyl, benzofuryl, indazolyl, pyrrolopyridyl, furopyridinyl and dihydrobenzoisothiazolyl;

with the proviso that when X is a nitrogen containing heterocyclic radical, the heterocyclic radical is attached to the (CH.sub.2).sub.m moiety by a ring nitrogen and the proviso that nitrogen and sulfur heteroatoms of the heterocyclic radical may also be oxidized;

Y is oxygen or sulfur;

Z is optionally substituted alkyl, aryl, optionally substituted alkoxy, aryloxy, aralkoxyaryl, aralkoxyheteroaryl, heteroaryl, heterocyclyl, heteroaryloxy, --CONR'.sub.2 R'.sub.3, --NR'.sub.1 COR'.sub.2, --NR'.sub.1 CONR'.sub.2 R'.sub.3, --OCONR'.sub.2 R'.sub.3, --NR'.sub.1 COOR'.sub.4, or --SO.sub.2 R'.sub.2, in which

R'.sub.1 is hydrogen, optionally substituted alkyl, heterocyclylalkyl, aralkyl or heteroarylalkyl and

R'.sub.2 and R'.sub.3 are independently hydrogen, optionally substituted alkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, aryl or heteroaryl; or

R'.sub.2 and R'.sub.3 taken together with the nitrogen atom to which they are attached form a 5- to 7-membered ring, which may optionally contain another heteroatom selected from oxygen, nitrogen and sulfur;

R.sub.4 is optionally substituted alkyl, heterocyclylalkyl, aralkyl, aryl or heteroaryl;

m represents an integer from one to six; and

n represents the integer one;

or a salt thereof, which comprises

reacting a compound of formula IV ##STR99##

in which X is as defined above for compounds of the formula I with a sulfonyl chloride of formula V ##STR100##

to form a compound of formula VI, ##STR101##

and optionally, after treating a compound of formula VI with anhydrous acid to form a compound of formula I where W is a hydroxyl, reacting the compound of formula I where W is hydroxyl with a protected hydroxylamine and removing the protecting group to form a compound of formula I where W is hydroxylamino.

14. A method of treating according to claim 12 wherein said warm-blooded animal is a human.

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