Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-12
2003-06-03
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S309000, C546S139000, C546S141000, C546S146000, C546S148000
Reexamination Certificate
active
06573277
ABSTRACT:
The invention relates to cyclic and heterocyclic N-substituted &agr;-iminohydroxamic and -carboxylic acids, to processes for their preparation and to their use as pharmaceuticals.
EP 0 606 046 discloses some arylsulfonamidohydroxamic acid derivatives and their action as matrix metalloproteinase inhibitors.
In the effort to find further efficacious compounds for the treatment of connective tissue disorders, it has now been found that the iminohydroxamic acid derivatives according to the invention are inhibitors of metalloproteinases.
The invention relates to a compound of the formula I
and/or an optionally stereoisomeric form of the compound of the formula I and/or a physiologically tolerable salt of the compound of the formula I, where in the case i)
R
1
is
a) a radical of the formula II
b) a radical of the formula III
c) a radical of the formula IV
where Z is a radical of a heterocycle or a substituted heterocycle such as
1) pyrrole,
2) thiazole,
3) pyrazole,
4) pyridine,
5) imidazole,
6) pyrrolidine,
7) piperidine,
8) thiophene,
9) oxazole,
10) isoxazole,
11) morpholine or
12) piperazine,
d) naphthyl,
e) naphthyl, mono- or trisubstituted by R
2
, or
f) a radical of the formula V
where o is the number 1 or 2 and one of the carbon atoms in the ring may be replaced by —O— or —S—, and
Q as part of the structural formula I
R
2
is
1) phenyl or
2) phenyl which is mono- to trisubstituted by
2.1 hydroxyl,
2.2 —O—R
10
where R
10
1) is (C
1
-C
6
)-alkyl,
2) is (C
3
-C
6
)-cycloalkyl,
3) is benzyl or
4) is phenyl,
2.3 —COOH,
2.4 (C
1
-C
6
)-alkyl,
2.5 (C
3
-C
6
)-cycloalkyl—O—(C
1
-C
4
)-alkyl,
2.6 halogen,
2.7 —CN,
2.8 —NO
2
,
2.9 —CF
3
,
2.10 —O—C(O)—R
10
and R
10
is as defined above,
2.11 —O—C(O)-phenyl, mono- or disubstituted by R
3
,
2.12 —C(O)—O—R
10
and R
10
is as defined above,
2.13 methylenedioxo,
2.14 —C(O)—NR
11
R
12
, where R
11
and R
12
may be identical or different and each is
1) a hydrogen atom,
2) (C
1
-C
4
)-alkyl or
3) benzyl or
4) R
11
and R
12
together with the linking nitrogen atom form a pyrrolidine, piperidine, morpholine or oiperazine radical, or
2.15 NR
13
R
14
, where R
13
is a hydrogen atom or (C
1
-C
4
)-alkyl and
R
14
1) is a hydrogen atom,
2) is (C
1
-C
4
)-alkyl,
3) is benzyl,
4) is —C(O)—R
10
or
5) is —C(O)—O—R
10
,
R
3
and R
4
are identical or different and each is
1) a hydrogen atom,
2) (C
1
-C
5
)-alkyl,
3) (C
1
-C
5
)-alkoxy,
4) halogen,
5) hydroxyl,
6) —O—C(O)—R
10
and R
10
is as defined above, or
7) R
3
and R
4
together form the radical —O—CH
2
—O—,
R
5
is
a) a hydrogen atom,
b) (C
1
-C
5
)-alkyl or
c) benzyl, and
R
6
, R
7
and R
8
are identical or different and each is
a) a hydrogen atom, or
b) has, in the case of i), the meaning of R
2
under items 2.1 to 2.14, and
n is zero, 1 or 2,
m is zero, 1 or 2, the sum of n and m being 1, 2 or 3, or
where in the case ii)
R
1
is
1) phenyl or
2) phenyl, mono- to trisubstituted by R
2
, where R
2
is as defined for the case i) under items 2.1 to 2.15,
Q is the structural moiety X and
R
6
, R
7
and R
8
are identical or different and each is defined as above,
n is 1 and
m is 1, or
where in the case iii)
R
1
, Q, R
6
, R
7
and R
8
are identical or different and each has the meaning mentioned for the case ii),
m and n are zero, 1 or 2 and where the meanings of n and m are not identical, and
X is
a) a covalent bond,
b) —O—,
c) —S—,
d) —S(O)—,
e) —S(O)
2
—,
f) —C(O)— or
g) —C(OH)—, and
Y is
a) —O— or
b) —S—, and
A is HO—NH—C(O)— or HO—C(O)— and
B is
a) —(CH
2
)
q
—, where q is zero, 1, 2, 3 or 4, or
b) is —CH═CH—.
Preference is given to a compound of the formula I and/or a physiologically tolerable salt of the compound of the formula I and/or an optionally stereoisomeric form of the compound of the formula I, where
R
1
in the case i) is a radical of the formula II or III and Q is the structural moiety VI, VII, VIII or X,
R
1
in the case ii) is phenyl or phenyl, mono- to trisubstituted by methoxy, and Q is the structural moiety X, or
R
1
in the case iii) is phenyl, Q is the structural moiety X, n is zero and m is 2, and
A is HO—NH—C(O)— or HO—C(O)—,
B is a covalent bond,
X is an oxygen atom or a covalent bond, and
R
2
is phenyl or phenyl substituted by
a) hydroxyl,
b) —O—R
10
, where R
10
is (C
1
-C
3
)-alkyl or benzyl,
c) (C
1
-C
2
)-alkyl,
d) fluorine or chlorine,
e) —CN,
f) —CF
3
or
g) NR
13
R
14
, where R
13
and R
14
are each (C
1
-C
3
)-alkyl,
R
3
, R
4
, R
5
, R
6
, R
7
and R
8
are identical or different and each is
a) a hydrogen atom,
b) methoxy,
c) methylenedioxo,
d) amino or
e) hydroxyl.
Particular preference is given to the compounds
R-2-(biphenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamic acid,
R-2-(4-chlorobiphenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamic acid,
R-2-(4-chlorobiphenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,
R-2-(4-phenoxybenzenesulfonyl)1,2,3,4-tetrahydroisoquinoline-3-hydroxamic acid,
R-2-(4-phenoxybenzenesulfonyl)1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,
R-2-(4-(4-dimethylaminophenoxy)benzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamic acid,
R-2-(4-dimethylaminobiphenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,
R-2-(4-benzoylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamic acid,
R-2-(4-methoxybenzenesulfonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-hydroxamic acid,
R-2-(4-methoxybenzenesulfonyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline-3-hydroxamic acid,
2-(4-methoxybenzenesulfonyl)-6,7-propylene-1,2,3,4-tetrahydroisoquinoline-1-hydroxamic acid,
R-5-(4-methoxybenzenesulfonyl)4,5,6,7-tetrahydro-1 H-imidazo-(4,5-c)-pyridine-6-hydroxamic acid,
R-2-(4-methoxybenzenesulfonyl)-1,2,3,4-tetrahydro-9H-pyrido-(3,4-c)-indole-3-hydroxamic acid,
R-2-(4-phenoxybenzenesulfonyl)-1,2,3,4-tetrahydro-9H-pyrido-(3,4-c)-indole-3-hydroxamic acid.
Furthermore, particular emphasis is given to those compounds of the formula I where the central carbon atom between amino and acid group is present as R enantiomer.
The term halogen is understood as meaning fluorine, chlorine, bromine or iodine. The term alkyl or alkoxy is understood as meaning radicals whose carbon chain may be straight-chain, branched or cyclic. Cyclic alkyl radicals are, for example, 3- to 6-membered monocycles such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The “heterocycles of the formula V” include, for example, thiomorpholine, piperidine, morpholine or piperazine.
Suitable physiologically tolerable salts of the compound of the formula I are, for example, alkali metal, alkaline earth metal and ammonium salts including those of organic ammonium bases or basic amino acids.
The invention also provides a process for preparing the compound of the formula I and/or a physiologically tolerable salt of the compound of the formula I and/or an optionally stereoisomeric form of the compound of the formula I which comprises
a) reacting an imino acid of the formula XI
where the radical Q and n and m are as defined in the formula I with a (C
1
-C
4
)-alcohol or a benzyl alcohol to give the compound of the formula XII
where R
x
is (C
1
-C
4
)-alkyl or benzyl, or
b) reacting a compound of the formula XII prepared according to process a) with the compound of the formula XIII
where R
1
is as defined in formula I and R
Z
is a chlorine atom, imidazolyl or —OH, in the presence of a base or, if appropriate, a dehydrating agent to give a compound of the formula XIV
where Q, R
1
, n and m are as defined in formula I and R
x
is as defined in formula XII, or
c) reacting a compound of the formula XII prepared according to process a) with a base and subsequently with a compound of the formula XIII to give a compound of the formula XIV, or
d) reacting a compound of the formula XI with a compound of the formula XIII to give a compound of the formula XV
where Q, R
1
, n and m are as defined in formula I, or
e) reacting a compound of the formula XIV to give a compound of the formula XV, or
f) reacting a compound of the formula XIV prepared according to process b) or c) with the hydroxylamine
Bartnik Eckart
Haase Burkhard
Schudok Manfred
Schwab Wilfried
Thorwart Werner
Desai Rita
Rotman Alan L.
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