Sulfonylaminophosphinic and sulfonylaminophosphonic acid...

Details Sulfonylaminophosphinic and sulfonylaminophosphonic acid... Sulfonylaminophosphinic and sulfonylaminophosphonic acid...

2001-03-20

2002-12-31

Rao, Deepak R. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

C514S086000, C514S089000, C514S090000, C514S091000, C514S092000, C514S094000, C514S095000, C514S099000, C544S055000, C544S096000, C544S243000, C546S022000, C548S112000, C548S113000, C548S119000, C549S006000, C549S218000, C549S222000

Reexamination Certificate

active

06500811

ABSTRACT:

The invention relates to novel sulfonylaminophosphinic and sulphonylaminophosphonic acid derivatives, processes for their preparation and use thereof as pharmaceuticals.
The present application claims priority under 35 U.S.C. § 119 to German applications No. 19831980.0 filed Jul. 16, 1998, and No. 19921680.0 filed May 12, 1999. Both priority applications are entirely incorporated herein by reference.
The applications EP 0 606 046, WO 95/35276 and WO 96/27583 describe arylsulfonamidohydroxamic acids and their action as matrix metalloproteinase inhibitors. Specific arylsulfonamidocarboxylic acids are used as intermediates for the preparation of thrombin inhibitors (EP 0 468 231) and aldose reductase inhibitors (EP 0 305 947). The application EP 0 757 037 also describes the action of sulfonylaminocarboxylic acid derivatives as metalloproteinase inhibitors. The arylsulfonyl group has furthermore proved to be an effective protective group of the amino function of &agr;-aminocarboxylic acids. R. Roemmele, H. Rapoport, 53 J. ORG. CHEM. 2367 (1988).
In the attempt to find efficacious compounds for the treatment of connective tissue disorders, it has now been found that the sulfonylaminophosphinic and -phosphonic acid derivatives according to the invention are strong inhibitors of metalloproteinases. Particular value is placed here on the inhibition of stromelysin (matrix metalloproteinase 3, “MMP-3”), of neutrophil collagenase (“MMP-8”) and of aggrecanase, since these enzymes are involved to a considerable extent in the degradation of proteoglycans, as important constituents of the cartilaginous tissue. A. J. Fosang et al., 98 J. CLIN. INVEST. 2292 (1996).
The pathological loss of aggrecan, the main proteoglycan of the cartilage, includes proteolytic cleavages in its interglobular domain. Amino acid sequence analyses of proteoglycan metabolites, isolated from the synovial fluid of patients who are suffering from injury to a joint, from osteoarthrosis or from an inflammatory joint condition, showed that a proteolytic cleavage preferably takes place between the amino acids Glu
373
and Ala
374
in the interglobular domain of human aggrecan. Lohmander et al., 36 ARTHRITIS RHEUM. 1214 (1993). Until now, it was not yet possible to identify the proteolytic activity which is responsible for this cleavage. It is designated as “aggrecanase” and can be included in the metalloproteinases family.
The detection of the expression of MT1-MMP in human cartilaginous tissue for the first time (Büttner et al., 40 ARTHRITIS RHEUM. 704 (1997)), combined with the proof that the catalytic domain of this enzyme cleaves at the “aggrecanase” cleavage site in the recombinant aggrecan fusion protein rAgg1
mut
(Büttner et al., 333 BIOCHEM. J. 159 (1998)), led to the testing of the strong matrix metalloproteinase inhibitors described here with respect to their action against an “aggrecanase” activity. It was possible here to show using various assay systems that the sulfonylaminophosphinic and -phosphonic acid derivatives are also strong inhibitors for the “aggrecanase” activity.
The invention therefore relates to the compounds of the formula I
stereoisomeric forms thereof, and physiologically tolerable salts thereof, where
(A.) R
1
is
1. phenyl;
2. phenyl, which is mono- or disubstituted by
2.1. (C
1
-C
6
)-alkyl,
2.2. hydroxyl,
2.3. (C
1
-C
6
)-alkyl-C(O)—O—,
2.4. (C
1
-C
6
)-alkyl-O—,
2.5. (C
1
-C
6
)-alkyl-O—(C
1
-C
4
)-alkyl-O—,
2.6. halogen,
2.7. —CF
3
,
2.8. —CN,
2.9. —NO
2
,
2.10. HO—C(O)—,
2.11. (C
1
-C
6
)-alkyl-O—C(O)—,
2.12. methylenedioxo,
2.13. R
4
—(R
5
)N—C(O)—,
2.14. R
4
—(R
5
)N—, or
2.15 a heteroaromatic described under A.3.1 to A.3.16;
3. a heteroaromatic described under A.3.1 to A.3.16, which is unsubstituted or substituted by one or more radicals described under A.2.1 to A.2.15,
3.1. pyrrole,
3.2. pyrazole,
3.3. imidazole,
3.4. triazole,
3.5. thiophene,
3.6. thiazole,
3.7. oxazole,
3.8. isoxazole,
3.9. pyridine,
3.10. pyrimidine,
3.11. pyrrolidine,
3.12. indole,
3.13. benzothiophene,
3.14. benzimidazole,
3.15. benzoxazole, or
3.16. benzothiazole; or
4. —O—(C
1
-C
6
)-alkyl;
(B.) R
2
, R
4
and R
5
independently of one another are identical or different and are
1. a hydrogen atom;
2. (C
1
-C
6
)-alkyl-;
3. HO—C(O)—(C
1
-C
6
)-alkyl-;
4. phenyl- (CH
2
)n—, in which phenyl is unsubstituted or mono- or disubstituted with radicals described under A.2.1 to A.2.15, or is substituted by —NH—C(O)—(C
1
-C
3
)-alkyl, and n is the integer zero, 1, or 2;
5. picolyl; or
6. R
4
and R
5
, together with the nitrogen to which they are bonded, form a 4- to 7-membered ring, and the ring is unsubstituted, or a carbon atom in the ring is replaced by —O—, —S—, or —NH—, or two adjacent carbon atoms of the 4- to 7-membered ring are part of a benzyl radical;
(C.) R and R
3
are identical or different and are
1. a hydrogen atom;
2. (C
1
-C
10
)-alkyl-, in which alkyl is unsubstituted or monosubstituted by —OH;
3. (C
2
-C
10
)-alkenyl-, in which alkenyl is linear or branched;
4. R
2
—O—(C
1
-C
6
)-alkyl-;
5. R
2
—S(O)
n
—(C
1
-C
6
)-alkyl-, where n is the integer zero, 1, or 2;
6. R
2
—S(O)(═NH)—(C
1
-C
6
)-alkyl-;
7. a radical of formula IIo
in which n is the integer zero, 1, or 2, and W is a nitrogen, oxygen, or sulfur atom;
8. phenyl-(CH
2
)
m
—, in which m is the integer zero, 1, 2, 3, 4, 5, or 6, wherein the —(CH
2
)
m
— chain is unsubstituted or monosubstituted by —OH, and wherein phenyl is unsubstituted or mono- or disubstituted by
8.1 radicals described under A.2.1 to A.2.15,
8.2 —O—(CH
2
)
m
-phenyl, in which phenyl is unsubstituted or mono- or disubstituted with radicals described under A.2.1 to A.2.15, and m is the integer zero, 1, 2, 3, 4, 5, or 6,
8.3 —C(O)—(CH
2
)
m
-phenyl, in which phenyl is defined under C.8.2;
9. heteroaryl-(CH
2
)
m
—, in which heteroaryl is defined under A.3.1 to A.3.16, m is defined under C.8, the —(CH
2
)
m
— chain is unsubstituted or monosubstituted by —OH, and heteroaryl is unsubstituted or mono- or disubstituted by
9.1 radicals described under A.2.1 to A.2.15,
9.2 —CH(O),
9.3 —SO
2
-phenyl, in which phenyl is unsubstituted or substituted as defined under C.8.2 or C.8.3,
9.4 —O—(CH
2
)
m
-phenyl;
10. —(CH
2
)
m
—P(O)(OH)—(C
1
-C
3
)-alkyl, in which m is defined under C.8;
11. a characteristic radical of an amino acid;
12. R
6
—C(O)—(C
0
C
6
)-alkyl- in which R
6
is
12.1. a hydrogen atom,
12.2. (C
1
-C
6
)-alkyl-,
12.3. phenyl, which is unsubstituted or substituted with one or more radicals described under A.2.1 to A.2.15,
12.4. heteroaryl, which is defined under A.3.1 to A.3.16, and is unsubstituted or substituted with one or more radicals described under A.2.1 to A.2.15, or is substituted by —(C
1
-C
4
)-alkyl-COOH,
12.5. —OH,
12.6. —OR
2
, in which R
2
has the meaning described under B.1 to B.6,
12.7. —NR
4
—(R
5
), in which R
4
and R
5
are defined under B.1 to B.6,
12.8. heteroaryl-(CH
2
)
m
—NH—, in which heteroaryl is defined under A.3.1 to A.3.16, and is unsubstituted or substituted with one or more radicals described under A.2.1 to A.2.15, and m is defined under C.8,
12.9. R
4
—(R
5
)N—NH—, in which R
4
and R
5
are defined under B.1 to B.6,
12.10. HO—C(O)—CH(R
3
)—NH—, in which R
3
is defined under C.1 to C.11;
13. —(CH
2
)
p
—N(R
9
)(R
10
), in which p is an integer zero, 1, 2, 3, or 4, in which R
9
and R
10
are identical or different and are
13.1. a hydrogen atom,
13.2. phenyl-(CH
2
)
m
—, in which phenyl is unsubstituted or mono- or disubstituted with radicals described under A.2.1 to A.2.15, and m is the integer zero, 1, 2, or 3,
13.3. R
x
—C(O)—, in which R
x
is
3.1 (C
1
-C
6
)-alkyl-,
3.2 (C
2
-C
6
)-alkenyl-,
3.3 phenyl-(CH
2
)
m
—, in which phenyl is unsubstituted or mono- or disubstituted with radicals described under A.2.1 to A.2.15, and m is the integer zero, 1, 2, or 3, or
3.4 heteroaryl-(CH
2
)
m
—, in which heteroaryl is defined under A.3.1 to A.3.16,
13.4. R
x
—O—C(O)—, in which R
x
is defined under C.13.3,
13.5. R
x
—CH(NH
2
)—C(O)—, in which R
x
is defined under C.13.3,
13.6. R
8
—N(R
7
)—C(O)—, in which R
8
is
6.1 a hydrogen atom

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