U.S. patent application number 10/751600 was filed with the patent office on 2005-01-06 for imino acid derivatives as inhibitors of matrix metalloproteinases.
This patent application is currently assigned to AVENTIS PHARMA DEUTSCHLAND GMBH. Invention is credited to Kirsch, Reinhard, Matter, Hans, Ruf, Sven, Schudok, Manfred, Stahl, Petra, Wehner, Volkmar.
Application Number | 20050004166 10/751600 |
Document ID | / |
Family ID | 32519590 |
Filed Date | 2005-01-06 |
United States Patent
Application |
20050004166 |
Kind Code |
A1 |
Schudok, Manfred ; et
al. |
January 6, 2005 |
Imino acid derivatives as inhibitors of matrix
metalloproteinases
Abstract
The invention relates to a bicycloazaheterocyclyl carboxylic
acid sulfonamide derivative of formula I herein, pharmaceutical
preparation comprising it, process for preparing it and method for
its pharmaceutical use.
Inventors: |
Schudok, Manfred;
(Eppstein/Ts, DE) ; Ruf, Sven; (Floersheim,
DE) ; Matter, Hans; (Langenselbold, DE) ;
Wehner, Volkmar; (Sandberg, DE) ; Kirsch,
Reinhard; (Braunschweig, DE) ; Stahl, Petra;
(Frankfurt, DE) |
Correspondence
Address: |
ROSS J. OEHLER
AVENTIS PHARMACEUTICALS INC.
ROUTE 202-206
MAIL CODE: D303A
BRIDGEWATER
NJ
08807
US
|
Assignee: |
AVENTIS PHARMA DEUTSCHLAND
GMBH
Frankfurt am Main
DE
|
Family ID: |
32519590 |
Appl. No.: |
10/751600 |
Filed: |
January 5, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60472572 |
May 22, 2003 |
|
|
|
Current U.S.
Class: |
514/311 ;
514/412; 546/169; 548/452 |
Current CPC
Class: |
A61P 17/02 20180101;
C07D 409/12 20130101; A61P 1/02 20180101; A61P 35/04 20180101; A61P
35/00 20180101; C07D 209/52 20130101; C07D 403/12 20130101; A61P
25/18 20180101; A61P 19/02 20180101; C07D 209/42 20130101; A61P
31/04 20180101; A61P 29/00 20180101; A61P 19/00 20180101; C07D
405/12 20130101; A61P 9/04 20180101; C07D 417/14 20130101; A61P
19/04 20180101; C07D 495/04 20130101; A61P 19/08 20180101; A61P
9/10 20180101 |
Class at
Publication: |
514/311 ;
514/412; 548/452; 546/169 |
International
Class: |
A61K 031/47; A61K
031/403; C07D 209/02 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 3, 2003 |
DE |
10300015.1 |
Claims
What is claimed is:
1. A compound of formula I 81wherein A is
--(C.sub.0-C.sub.4)-alkylene, B, D and E are identical or different
and are, independently of each other, --(C.sub.0-C.sub.4)-alkylene,
--(C.sub.2-C.sub.4)-alkenylene, --S(O).sub.o--, --NH--,
--NH--C(O)--, --C(O)--NH--, --NH--SO.sub.2--, --NH--C(O)--NH--,
--NH--C(S)--, --NH--C(O)--O--, --O--, --O--C(O)--NH--, --C(O)--,
--O--(CH.sub.2).sub.n--O--, or --O--(CH.sub.2).sub.m--NH--, o is
zero, 1 or 2, n is 2 or 3, m is 2 or 3, ring 1, ring 2 or ring 3
are identical or different and are, independently of each other,
covalent bond, --(C.sub.6-C.sub.14)-aryl that is unsubstituted or
substituted, independently of each other, once, twice or three
times, by G, or 5- or 6-membered aromatic heteroaryl ring that is
unsubstituted or substituted, independently of each other, once,
twice or three times, by G, ring 4 is --(C.sub.6-C.sub.14)-aryl
that is unsubstituted or substituted, independently of each other,
once, twice or three times, by G, 5- or 6-membered aromatic
heteroaryl ring that is unsubstituted or substituted, independently
of each other, once, twice or three times, by G. heteroaryl that is
unsubstituted or substituted, independently of each other, once,
twice or three times, by G, or azaheterocyclyl selected from the
group consisting of 82 that are unsubstituted or substituted,
independently of each other, once, twice or three times, by G, G is
hydrogen, halogen, R.sup.4, --O--R.sup.4, --C(O)--R.sup.5,
--S(O).sub.p--R.sup.4, --NO.sub.2, --CN or --NR.sup.3R.sup.4, p is
zero, 1 or 2, X is --OH or --NH--OH, X.sup.1 and X.sup.2 are
identical or different and are, independently of each other,
hydrogen or --(C.sub.1-C.sub.6)-alkyl, or taken together form the
radical .dbd.O, n.sup.1 is --(CH.sub.2).sub.r--, n.sup.2 is
--(CH.sub.2).sub.q--, r is zero, 1, 2 or 3, q is zero, 1, 2 or 3,
R.sup.1 is hydrogen, or --(C.sub.1-C.sub.6)-alkyl that is
unsubstituted or substituted, once or twice, by
--(C.sub.3-C.sub.6)-cyclo- alkyl, --(C.sub.6-C.sub.14)-aryl or
heteroaryl, R2 and R.sup.3 are identical or different and are,
independently of each other, hydrogen or --(C.sub.1-C.sub.6)-alkyl,
R.sup.4 is hydrogen, --(C.sub.1-C.sub.6)-alkyl that is
unsubstituted or substituted, once, twice or three times, by
halogen, --(C.sub.3-C.sub.6)-cycloalkyl, --(C.sub.6-C.sub.14)-aryl
or heteroaryl, --(C.sub.6-C.sub.14)-aryl, heteroaryl,
--C(O)--O--R.sup.5, --C(S)--O--R.sup.5, --C(O)--NH--R.sup.6,
--C(S)--NH--R.sup.6, R.sup.5 is --(C.sub.1-C.sub.6)-alkyl that is
unsubstituted or substituted, once or twice, by
--(C.sub.3-C.sub.6)-cycloalkyl, --(C.sub.6-C.sub.14)-aryl, or
heteroaryl, --(C.sub.6-C.sub.14)-aryl, or heteroaryl, and R.sup.6
is --(C.sub.1-C.sub.6)-alkyl that is unsubstituted or substituted,
once or twice, by --(C.sub.3-C.sub.6)-cycloalkyl,
--(C.sub.6-C.sub.14)-aryl or heteroaryl, or
--(C.sub.6-C.sub.14)-aryl, or heteroaryl, or stereoisomer thereof,
a mixture of stereoisomers thereof in any ratio, or physiologically
tolerable salt thereof.
2. The compound of claim 1, wherein ring 1, ring 2 or ring 3 as
--(C.sub.6-C.sub.14)-aryl is phenyl, naphthyl, 1-naphthyl,
2-naphthyl, biphenylyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl,
anthryl or fluorenyl and is unsubstituted or substituted,
independently of each other, once, twice or three times, by G, or
5- or 6-membered aromatic heteroaryl ring is dihydrofuranyl,
dioxolyl, dioxanyl, furanyl, imidazolidinyl, imidazolinyl,
imidazolyl, isoxazolyl, isoxazolidinyl, 2-isoxazolinyl,
isothiazolyl, isothiazolidinyl, 2-isothiazolinyl, morpholinyl,
oxazolyl, oxothiolanyl, piperazinyl, piperidinyl, pyranyl,
pyrazinyl, pyrazolyl, pyrazolidinyl, pyrazolinyl, pyridazinyl,
pyridinyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, tetrahydrofuranyl,
tetrahydropyridinyl, thiazolyl, thiomorpholinyl, thiophenyl or
thiopyranyl and is unsubstituted or substituted, independently of
each other, once, twice or three times, by G, ring 4 as
--(C.sub.6-C.sub.14)-aryl is phenyl, naphthyl, 1-naphthyl,
2-naphthyl, biphenylyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl,
anthryl or fluorenyl and is unsubstituted or substituted,
independently of each other, once, twice or three times, by G, 5-
or 6-membered aromatic heteroaryl ring is dihydrofuranyl, dioxolyl,
dioxanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl,
isoxazolyl, isoxazolidinyl, 2-isoxazolinyl, isothiazolyl,
isothiazolidinyl, 2-isothiazolinyl, morpholinyl, oxazolyl,
oxothiolanyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl,
pyrazolyl, pyrazolidinyl, pyrazolinyl, pyridazinyl, pyridinyl,
pyrimidinyl, pyrrolyl, pyrrolidinyl, tetrahydrofuranyl,
tetrahydropyridinyl, thiazolyl, thiomorpholinyl, thiophenyl or
thiopyranyl and is unsubstituted or substituted, independently of
each other, once, twice or three times, by G, or heteroaryl is
acridinyl, azetidinyl, benzimidazolyl, benzofuranyl,
benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl,
benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl,
benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl,
chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,
2H,6H-1,5,2-dithiazinyl, dihydrofuran[2,3-b]tetrahyd- rofuran,
fuaranyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,
isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,
isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl,
isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,
oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,
1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl,
oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,
phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,
phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl,
pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl,
pyridazinyl, pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl,
pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,
pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,
4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl,
6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl or xanthenyl, p2
that is unsubstituted or substituted, independently of each other,
once, twice or three times, by G, R.sup.4as
--(C.sub.1-C.sub.6)-alkyl that is unsubstituted or substituted,
once, twice or three times, by halogen,
--(C.sub.3-C.sub.6)-cycloalkyl, phenyl, naphthyl, acridinyl,
azetidinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,
benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl,
benzotetrazolyl, benzisoxazolyl, benzisothiazolyl,
benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl,
chromanyl, chromenyl, cinnolinyl, deca-hydroquinolinyl,
2H,6H-1,5,2-dithiazinyl, dihydrofuran[2,3-b]tetrahydrofuran,
fuaranyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,
isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,
isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl,
isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,
oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,
1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl,
oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,
phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,
phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl,
pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl,
pyridazinyl, pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl,
pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,
pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,
4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-
1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl or xanthenyl,
that is unsubstituted or substituted, independently of each other,
once, twice or three times, by G, --(C.sub.6-C.sub.14)-aryl is
phenyl or naphthyl, or heteroaryl is acridinyl, azetidinyl,
benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl,
benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl,
benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl,
4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,
decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,
dihydrofuran[2,3-b]tetrahyd- rofuran, fuaranyl, furazanyl,
imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl,
indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,
isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl
(benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl,
naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl,
pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,
phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,
piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl,
pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,
pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl,
pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,
pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,
4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl,
6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl or xanthenyl,
that is unsubstituted or substituted, independently of each other,
once, twice or three times, by G, R.sup.5 is
--(C.sub.1-C.sub.6)-alkyl that is unsubstituted or substituted,
once, twice or three times, by --(C.sub.3-C.sub.6)-cycloalkyl,
phenyl, naphthyl, acridinyl, azetidinyl, benzimidazolyl,
benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,
benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl,
benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl,
carbolinyl, chromanyl, chromenyl, cinnolinyl, deca-hydroquinolinyl,
2H,6H-1,5,2-dithiazinyl, dihydrofuran[2,3-b]tetrahydrofuran,
fuaranyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,
isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,
isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl,
isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,
oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,
1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl,
oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,
phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,
phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl,
pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl,
pyridazinyl, pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl,
pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,
pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,
4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl,
6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl or xanthenyl,
that is unsubstituted or substituted, independently of each other,
once, twice or three times, by G, --(C.sub.6-C.sub.14)-aryl is
phenyl or naphthyl, or heteroaryl is acridinyl, azetidinyl,
benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl,
benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl,
benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl,
4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,
decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,
dihydrofuran[2,3-b]tetrahyd- rofuran, fuaranyl, furazanyl,
imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl,
indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,
isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl
(benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl,
naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl,
pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,
phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,
piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl,
pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,
pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl,
pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,
pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,
4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl,
6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl or xanthenyl,
that is unsubstituted or substituted, independently of each other,
once, twice or three times, by G, R.sup.6 as
--(C.sub.1-C.sub.6)-alkyl that is unsubstituted or substituted,
once, twice or three times, by --(C.sub.3-C.sub.6)-cycloalkyl,
phenyl, naphthyl, acridinyl, azetidinyl, benzimidazolyl,
benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,
benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl,
benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl,
carbolinyl, chromanyl, chromenyl, cinnolinyl, deca-hydroquinolinyl,
2H,6H-1,5,2-dithiazinyl, dihydrofuran[2,3-b]tetrahydrofuran,
fuaranyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,
isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,
isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl,
isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,
oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,
1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl,
oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,
phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,
phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl,
pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl,
pyridazinyl, pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl,
pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,
pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,
4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl,
6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl or xanthenyl,
that is unsubstituted or substituted, independently of each other,
once, twice or three times, by G, --(C.sub.6-C.sub.14)-aryl is
phenyl or naphthyl, or heteroaryl is acridinyl, azetidinyl,
benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl,
benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl,
benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl,
4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,
decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,
dihydrofuran[2,3-b]tetrahyd- rofuran, fuaranyl, furazanyl,
imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl,
indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,
isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl
(benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl,
naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl,
pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,
phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,
piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl.
pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,
pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl,
pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,
pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,
4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl,
6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl or xanthenyl,
that is unsubstituted or substituted, independently of each other,
once, twice or three times, by G, and R.sup.1as
--(C.sub.1-C.sub.6)-alkyl that is unsubstituted or substituted,
once, twice or three times, by --(C.sub.3-C.sub.6)-cycloalkyl,
phenyl, naphthyl, acridinyl, azetidinyl, benzimidazolyl,
benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,
benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl,
benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl,
carbolinyl, chromanyl, chromenyl, cinnolinyl, deca-hydroquinolinyl,
2H,6H-1,5,2-dithiazinyl, dihydrofuran[2,3-b]tetrahydrofuran,
fuaranyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,
isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,
isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl,
isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,
oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,
1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl,
oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,
phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,
phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl,
pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl,
pyridazinyl, pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl,
pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,
pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,
4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl,
6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl or xanthenyl,
that is unsubstituted or substituted, independently of each other,
once, twice or three times, by G.
3. The compound of claim 1, wherein B, D and E are identical or
different and are, independently of each other,
--(C.sub.0-C.sub.2)-alkylene, --C.sub.2-alkenylene, --S(O).sub.2--,
--NH--, --NH--C(O)--, --C(O)--NH--, --NH--C(O)--NH--, --O--, or
--C(O)--, ring 1, ring 2 or ring 3 as --(C.sub.6-C.sub.14)-aryl is
phenyl or naphthyl that is unsubstituted or substituted,
independently of each other, once, twice or three times, by G, or
5- or 6-membered aromatic heteroaryl ring that is dihydrofuranyl,
furanyl, morpholinyl, piperazinyl, piperidinyl, pyridinyl,
pyrimidinyl, pyrrolyl, thiazolyl or thiophenyl and are
unsubstituted or substituted, independently of each other, once,
twice or three times, by G, ring 4 as --(C.sub.6-C.sub.14)-aryl is
phenyl or naphthyl and is unsubstituted or substituted,
independently of each other, once, twice or three times, by G, 5-
or 6-membered aromatic heteroaryl ring is dihydrofuranyl, furanyl,
morpholinyl, piperazinyl, piperidinyl, pyridinyl, pyrimidinyl,
pyrrolyl, thiazolyl or thiophenyl and is unsubstituted or
substituted, independently of each other, once, twice or three
times, by G, heteroaryl that is benzofuranyl, benzothiophenyl,
dihydrofuranyl, furanyl, morpholinyl, piperazinyl, piperidinyl,
pyridinyl, pyridothiophenyl, pyrimidinyl, pyrrolyl, thiazolyl or
thiophenyl and are unsubstituted or substituted, independently of
each other, once, twice or three times, by G, or azaheterocyclyl
selected from the group consisting of 83 that is unsubstituted or
substituted, independently of each other, once, twice or three
times, by G, G as halogen is Br, Cl, I or F, and
--S(O).sub.p--R.sup.4 is --S(O).sub.2--R.sup.4, R.sup.4 is
hydrogen, --(C.sub.1-C.sub.4)-alkyl that is unsubstituted or
substituted, once, twice or three times, by Br, Cl, F,
--C.sub.3-cycloalkyl, phenyl, naphthyl, or heteroaryl that is
benzofuranyl, benzothiophenyl, dihydrofuranyl, furanyl,
morpholinyl, piperazinyl, piperidinyl, pyridinyl, pyridothiophenyl,
pyrimidinyl, pyrrolyl, thiazolyl or thiophenyl and are
unsubstituted or substituted, independently of each other, once,
twice or three times, by G, phenyl or naphthyl, heteroaryl that is
benzofuranyl, benzothiophenyl, dihydrofuranyl, furanyl,
morpholinyl, piperazinyl, piperidinyl, pyridinyl, pyridothiophenyl,
pyrimidinyl, pyrrolyl, thiazolyl or thiophenyl and are
unsubstituted or substituted, independently of each other, once,
twice or three times, by G, --C(O)--O--R.sup.5, or
--C(O)--NH--R.sup.6, R.sup.5 is --(C.sub.1 -C.sub.4)-alkyl that is
unsubstituted or substituted, once or twice, by
--C.sub.3-cycloalkyl, phenyl, naphthyl or heteroaryl that is
benzofuranyl, benzothiophenyl, dihydrofuranyl, furanyl,
morpholinyl, piperazinyl, piperidinyl, pyridinyl, pyridothiophenyl,
pyrimidinyl, pyrrolyl, thiazolyl or thiophenyl and are
unsubstituted or substituted, independently of each other, once,
twice or three times, by G, phenyl or naphthyl, or heteroaryl that
is benzofuranyl, benzothiophenyl, dihydrofuranyl, furanyl,
morpholinyl, piperazinyl, piperidinyl, pyridinyl, pyridothiophenyl,
pyrimidinyl, pyrrolyl, thiazolyl or thiophenyl that is substituted,
independently of each other, once, twice or three times, by G,
R.sup.6 is --(C.sub.1-C.sub.4)-alkyl, in which alkyl is
unsubstituted or substituted, once or twice, by
--C.sub.3-cycloalkyl, phenyl, naphthyl or heteroaryl that is
benzofuranyl, benzothiophenyl, dihydrofuranyl, furanyl,
morpholinyl, piperazinyl, piperidinyl, pyridinyl, pyridothiophenyl,
pyrimidinyl, pyrrolyl, thiazolyl or thiophenyl and are
unsubstituted or substituted, independently of each other, once,
twice or three times, by G, phenyl or naphthyl, or heteroaryl that
is benzofuranyl, benzothiophenyl, dihydrofuranyl, furanyl,
morpholinyl, piperazinyl, piperidinyl, pyridinyl, pyridothiophenyl,
pyrimidinyl, pyrrolyl, thiazolyl or thiophenyl that is substituted,
independently of each other, once, twice or three times, by G,
X.sup.1 and X.sup.2 are hydrogen, n.sup.1 and n.sup.2 are
--(CH.sub.2)--, or n.sup.1 is --CH.sub.2).sub.2-- and n.sup.2 is
--(CH.sub.2)--, R.sup.1 is hydrogen, and R2 and R.sup.3 are
hydrogen.
4. A process for preparing the compound of claim 1, comprising
84wherein R.sup.e is a hydrogen or an ester protecting group, with
a compound of formula V,
R.sup.z--SO.sub.2-A-ring.sup.1-B-ring.sup.2-D-ring.sup.3-E-rin-
g.sup.4 (V) in which A, B, D, E and ring.sup.1, ring.sup.2,
ring.sup.3 and ring.sup.4 are defined as in the compound of formula
I, and wherein R.sup.z is chlorine atom, imidazolyl or OH, in the
presence of a base, or after silylation with a suitable silylating
agent, to give a compound of formula VI, 85wherein A, B, D, E,
R.sup.e and ring.sup.1, ring.sup.2, ring.sup.3 and ring.sup.4 are
as defined above, and b) where R.sup.e is the ester protecting
group, reacting a compound of formula VI, which has been prepared
in accordance with step a), with a solution of an alkali such as
NaOH or LiOH, and then treating with acid, to give the carboxylic
acid of formula VII, with modifications in one of the side chains
of ring.sup.1-ring.sup.4 also having previously been carried out,
where appropriate, 86and then converting this compound into the
compound of formula I wherein X is NH--OH, and c) optionally
separating the compound of formula I, which has been prepared in
accordance with steps a) or b) into an individual enantiomer by
means of salt formation with an enantiomerically pure acid or base,
chromatography on a chiral stationary phase or derivatization using
chiral, enantiomerically pure compound, such as an amino acid,
separation of the resulting derivatized diastereomers and
elimination of the chiral auxiliary derivatization group, or d)
optionally isolating the compound of formula I, which has been
prepared in accordance with steps b) or c), in free form or, when
an acidic or basic group is present, converting it into a
corresponding physiologically tolerated salt.
5. A pharmaceutical preparation comprising a pharmaceutically
effective amount of at least one compound according to claim 1 and
a pharmaceutically tolerated carrier.
6. The use of the compound of claim 1 for the prophylaxis or
therapy of a disease such as osteoarthroses, spondyloses, cartilage
loss following joint trauma or a relatively long period of joint
immobilization following meniscus or patella injuries or ligament
rupture.
7. The use of the compound of claim 1 for the prophylaxis or
therapy of a disease s of the connective tissue such as
collagenoses, periodontal disease or wound healing
disturbances.
8. The use of the compound of claim 1 for the prophylaxis or
therapy of a chronic disease of the locomotory apparatus, such as
inflammatory, immunologically-determined or metabolism-determined
acute and chronic arthritide, arthropathy, myalgia and a
disturbance in bone metabolism.
9. The use of the compound of claim 1 for the treatment of
ulceration, atherosclerosis or stenoses.
10. The use of the compound of claim 1 for the treatment of
inflammations, cancer disease, tumor metastasis formation,
cachexia, anorexia, heart failure or septic shock.
11. The use of the compound of claim 1 for the prophylaxis of
myocardial and cerebral infarcts.
Description
FIELD OF THE INVENTION
[0001] The invention relates to a bicycloazaheterocyclyl carboxylic
acid sulfonamide derivative of formula I herein, pharmaceutical
preparation comprising it, process for preparing it and method for
its pharmaceutical use.
BACKGROUND OF THE INVENTION
[0002] In diseases such as osteoarthritis and rheumatism, the joint
is destroyed, with this destruction being due, in particular, to
the proteolytic breakdown of collagen by collagenases. Collagenases
belong to the superfamily of the metalloproteinases (MPs) or matrix
metalloproteinases (MMPs). The MMPs form a group of Zn-dependent
enzymes which are involved in the biological breakdown of the
extracellular matrix (D. Yip et al. in Investigational New Drugs 17
(1999), 387-399 and Michaelides et al. in Current Pharmaceutical
Design 5 (1999) 787-819). These MMPs are able, in particular to
break down fibrillar and nonfibrillar collagen and proteoglycans,
both of which are important matrix constituents. MMPs are involved
in processes of wound healing, tumor invasion, metastasis migration
and in angiogenesis, multiple sclerosis and heart failure
(Michaelides page 788; see above). In particular, they play an
important role in the breakdown of the joint matrix in arthrosis
and arthritis, whether this be osteoarthrosis, osteoarthritis or
rheumatoid arthritis.
[0003] The activity of the MMPs is furthermore essential for many
of the processes which play a role in the formation of
atherosclerotic plaques, such as the infiltration of inflammatory
cells, the migration of smooth muscle cells, and proliferation and
angiogenesis (S. J. George, Exp. Opin. Invest. Drugs (2000), 9 (5),
993-1007). In addition, degradation of the matrix by MMPs can cause
anything from plaque instabilities through to ruptures, with this
being able to lead to the clinical symptoms of atherosclerosis,
unstable angina pectoris, myocardial infarction or stroke (E. J. M.
Creemers et al., Circulation Res. 89, 201-210 (2001)). All in all,
the complete MMP family is able to break down all the components of
the blood vessel extracellular matrix; for this reason, their
activity is to a high degree subject to regulatory mechanisms in
normal blood vessels. The increase in MMP activity during plaque
formation and plaque instability is caused by an increase in
cytokine-stimulated and growth factor-stimulated gene
transcription, an increase in zymogen activation and an imbalance
in the MMP/TIMP (tissue inhibitors of metalloproteases) ratio. It
therefore seems plausible that MMP inhibition or the reattainment
of the MMP/TIMP equilibrium would be of assistance in treating the
atherosclerotic diseases. It is also becoming ever clearer that
aside from atherosclerosis, an increase in MMP activity is also at
least a contributory cause of other cardiovascular diseases such as
restenosis, dilated cardiomyopathy and the already mentioned
myocardial infarction. It has been shown that administering
synthetic inhibitors in experimental animal models can achieve
marked improvements in these diseases as regards, for example,
formation of atherosclerotic lesions, neointima formation,
left-ventricular remodeling, pumping output malfunction or
infarction healing. In a variety of preclinical studies using MMP
inhibitors, detailed tissue analysis indicated a reduction in
collagen damage, an improvement in extracellular matrix remodeling
and an improvement in the structure and function of cardiac muscle
and blood vessels. Of these processes, matrix remodeling processes
and MMP-regulated fibroses are regarded, in particular, as being
important components in the progress of cardiac diseases
(infarction) (Drugs 61, 1239-1252 (2001)).
[0004] MMPs cleave matrix proteins, such as collagen, laminin,
proteoglycans, elastin or gelatin, and also process (i.e., activate
or deactivate), by means of a cleavage, a large number of other
proteins and enzymes under physiological conditions, which means
that they play an important role in the entire organism, with this
role being of particular importance in connective tissue and
bone.
[0005] A large number of different inhibitors of the MMPs are known
(EP0606046; WO94/28889; WO 96/27583; or also overviews such as
Current Medicinal Chemistry 8, 425-74 (2001)). Following the first
clinical studies in humans, it has now been found that MMPs give
rise to side effects. The side effects that are principally
mentioned are musculoskeletal pains or anthralgias. The prior art
states unambiguously that it is expected that more selective
inhibitors will be able to reduce these said side effects (Yip,
page 387, see above). Particular emphasis should be placed in this
case on specificity in respect to MMP-1, as these undesirable side
effects obviously occur to a greater extent with inhibition of
MMP-1.
[0006] The known MMP inhibitors therefore frequently suffer from
the disadvantage of lacking specificity. Most MMP inhibitors
inhibit many MMPs simultaneously because the structure of the
catalytic domain in the MMPs is similar. As a consequence, the
inhibitors have the undesirable property of acting on the enzymes
including those that have a vital function (Massova, I., et al.,
The FASEB Journal (1998) 12, 1075-1095).
[0007] In view of the current situation, it is clear that there is
a need for a compound that is a powerful inhibitor of the matrix
metalloproteinases MMP-2, MMP-3, MMP-8, MMP-9 and MMP-13 whereas it
has only a weak inhibitory effect on MMP-1.
SUMMARY OF THE INVENTION
[0008] The present invention satisfies the above needs by providing
a compound that is a powerful inhibitor of the matrix
metalloproteinases MMP-2, MMP-3, MMP-8, MMP-9 and MMP-13 whereas it
has only a weak inhibitory effect on MMP-1.
[0009] The invention therefore relates to a compound of formula I
1
[0010] wherein
[0011] A is
[0012] --(C.sub.0-C.sub.4)-alkylene,
[0013] B, D and E are identical or different and are, independently
of each other,
[0014] --(C.sub.0-C.sub.4)-alkylene,
[0015] --(C.sub.2-C.sub.4)-alkenylene,
[0016] --S(O).sub.o--,
[0017] --NH--,
[0018] --NH--C(O)--,
[0019] --C(O)--NH--,
[0020] --NH--SO.sub.2--,
[0021] --NH--C(O)--NH--,
[0022] --NH--C(S)--,
[0023] --NH--C(O)--O--,
[0024] --O--,
[0025] --O--C(O)--NH--,
[0026] --C(O)--,
[0027] --O--(CH.sub.2).sub.n--O--, or
[0028] --O--(CH.sub.2).sub.m--NH--,
[0029] o is
[0030] zero, 1 or 2,
[0031] n is
[0032] 2 or3,
[0033] m is
[0034] 2 or 3,
[0035] ring.sup.1, ring.sup.2 or ring.sup.3 are identical or
different and are, independently of each other, covalent bond,
[0036] --(C.sub.6-C.sub.14)-aryl that is unsubstituted or
substituted, independently of each other, once, twice or three
times, by G, or
[0037] 5- or 6-membered aromatic heteroaryl ring that is
unsubstituted or substituted, independently of each other, once,
twice or three times, by G,
[0038] ring.sup.4 is
[0039] --(C.sub.6-C.sub.14)-aryl that is unsubstituted or
substituted, independently of each other, once, twice or three
times, by G,
[0040] 5- or 6-membered aromatic heteroaryl ring that is
unsubstituted or substituted, independently of each other, once,
twice or three times, by G,
[0041] heteroaryl that is unsubstituted or substituted,
independently of each other, once, twice or three times, by G,
or
[0042] azaheterocyclyl selected from the group consisting of 2
[0043] that are unsubstituted or substituted, independently of each
other, once, twice or three times, by G,
[0044] G is
[0045] hydrogen,
[0046] halogen,
[0047] R.sup.4,
[0048] --O--R.sup.4,
[0049] --C(O)--R.sup.5,
[0050] --S(O).sub.p--R.sup.4,
[0051] --NO.sub.2,
[0052] --CN or
[0053] --NR.sup.3R.sup.4,
[0054] p is
[0055] zero, 1 or 2,
[0056] X is
[0057] --OH or --NH--OH,
[0058] X.sup.1 and X.sup.2 are identical or different and are,
independently of each other, hydrogen or --(C.sub.1-C.sub.6)-alkyl,
or taken together form the radical .dbd.O,
[0059] n.sup.1 is
[0060] --(CH.sub.2).sub.r--,
[0061] n.sup.2 is
[0062] --(CH.sub.2).sub.q--,
[0063] r is
[0064] zero, 1, 2 or 3,
[0065] q is
[0066] zero, 1, 2 or 3,
[0067] R.sup.1 is
[0068] hydrogen, or
[0069] --(C.sub.1-C.sub.6)-alkyl that is unsubstituted or
substituted, once or twice, by --(C.sub.3-C.sub.6)-cycloalkyl,
--(C.sub.6-C.sub.14)-ar- yl or heteroaryl,
[0070] R2 and R.sup.3 are identical or different and are,
independently of each other, hydrogen or
--(C.sub.1-C.sub.6)-alkyl,
[0071] R.sup.4is
[0072] hydrogen,
[0073] --(C.sub.1-C.sub.6)-alkyl that is unsubstituted or
substituted, once, twice or three times, by halogen,
--(C.sub.3-C.sub.6)-cycloalkyl, --(C.sub.6-C.sub.14)-aryl or
heteroaryl,
[0074] --(C.sub.6-C.sub.14)-aryl,
[0075] heteroaryl,
[0076] --C(O)--O--R.sup.5,
[0077] --C(S)--O--R.sup.5,
[0078] --C(O)--NH--R.sup.6,
[0079] --C(S)--NH--R.sup.6,
[0080] R.sup.5 is --(C.sub.1-C.sub.6)-alkyl that is unsubstituted
or substituted, once or twice, by --(C.sub.3-C.sub.6)-cycloalkyl,
--(C.sub.6-C.sub.14)-aryl, or heteroaryl,
[0081] --(C.sub.6-C.sub.14)-aryl, or
[0082] heteroaryl, and
[0083] R.sup.6 is
[0084] --(C.sub.1-C.sub.6)-alkyl that is unsubstituted or
substituted, once or twice, by --(C.sub.3-C.sub.6)-cycloalkyl,
--(C.sub.6-C].sub.4)-ar- yl or heteroaryl, or
[0085] --(C.sub.6-C.sub.14)-aryl, or
[0086] heteroaryl, or
[0087] stereoisomer thereof, a mixture of stereoisomers thereof in
any ratio, or physiologically tolerable salt thereof.
[0088] The invention also is directed to a method for preparing the
compound according to the invention, a pharmaceutical preparation
thereof, and its use for inhibiting matrix metalloproteinases
MMP-2, MMP-3, MMP-8, MMP-9 and MMP-13.
DETAILED DESCRIPTION OF THE INVENTION
[0089] Definitions
[0090] As used above, and throughout the description of the
invention, the following terms, unless otherwise indicated, shall
be understood to have the following meanings:
[0091] The term "(C.sub.1-C.sub.6)-alkyl" means hydrocarbon
radicals whose carbon chain is straight or branched and contains
from 1 to 6 carbon atoms, for example methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, tertiary butyl, pentyl, isopentyl,
neopentyl, hexyl, 2,3-dimethylbutane or neohexyl.
[0092] The term "--(C.sub.0-C.sub.4)-alkylene" means hydrocarbon
radicals whose carbon chain is straight or branched and contains
from 1 to 4 carbon atoms, for example methylene, ethylene,
propylene, isopropylene, isobutylene, butylene or tertiary
butylene. "--C.sub.0-alkylene" is a covalent bond.
[0093] The term "--(CH.sub.2).sub.n--, in which n is zero, 1 or 2"
means, for n equal to zero, a covalent bond, for n equal to 1, the
methylene radical and for n equal to 2, the ethylene radical.
[0094] The term "--(C.sub.2-C.sub.4)-alkenylene" means hydrocarbon
radicals whose carbon chain is straight or branched and contains
from 2 to 4 carbon atoms and, depending on the chain length,
possesses one or two double bonds, for example ethenylene,
propenylene, isopropenylene, isobutenylene or butenylene; provided
the possibility exists in principle, the substituents on the double
bond can be arranged in the E configuration or the Z
configuration.
[0095] The term "--(C.sub.2-C.sub.6)-alkynylene" means hydrocarbon
radicals whose carbon chain is straight or branched and contains
from 2 to 6 carbon atoms and, depending on the chain length,
possess 1 or 2 triple bonds, for example ethynylene, propenylene,
isopropynylene, isobuthylynylene, butynylene, pentynylene or
isomers of pentynylene or hexynylene or isomers of hexynylene.
[0096] The term "(C.sub.3-C.sub.6)-cycloalkyl" means a radical that
is derived from 3- to 6-membered monocycles such as cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl.
[0097] The radicals 3
[0098] in the ring of the compound of formula I mean respectively
--(CH.sub.2).sub.r-- and --(CH.sub.2).sub.q-- radicals wherein r
and q are independently zero, 1, 2 or 3, where the variables
n.sup.1 or n.sup.2 in each case indicate the number of the
--CH.sub.2-- radicals in the ring of the formula I. When n.sup.1 or
n.sup.2 has the value zero, a covalent bond is formed resulting in
the ring consisting of a total of 4 ring atoms. When n.sup.1 or
n.sup.2 has the value 1, a --CH.sub.2-- radical is formed resulting
in the ring consisting of 5 ring atoms. When n.sup.1 or n.sup.2 has
the value 2, a --CH.sub.2--CH.sub.2-- radical is formed resulting
in the ring consisting of 6 ring atoms. When n.sup.1 or n.sup.2 has
the value 3, a --CH.sub.2--CH.sub.2--CH.sub.2 radical is formed
resulting in the ring consisting of 7 ring atoms.
[0099] The term "--(C.sub.6-C.sub.14)-aryl" means aromatic carbon
radicals having from 6 to 14 carbon atoms in the ring.
--(C.sub.6-C.sub.14)-aryl radicals are, for example, phenyl,
naphthyl, for example 1-naphthyl or 2-naphthyl, anthryl or
fluorenyl. Naphthyl radicals and, in particular, phenyl radicals
are preferred aryl radicals.
[0100] The term "5- or 6-membered aromatic heteroaryl ring" means
aromatic ring systems that contain one or two heteroatoms from the
series oxygen, nitrogen and sulfur and can be derived from
dihydrofuran, dioxole, dioxane, furan, imidazolidine, imidazoline,
imidazole, isoxazole, isoxazolidine, 2-isoxazoline, isothiazole,
isothiazolidine, 2-isothiazoline, morpholine, oxazole, oxothiolane,
piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazolidine,
pyrazoline, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine,
tetrahydrofuran, tetrahydropyridine, thiazole, thiomorpholine,
thiophenyl or thiopyran.
[0101] The term "heteroaryl" means a radical such as acridinyl,
azepinyl, azetidinyl, aziridinyl, benzimidazalinyl, benzimidazolyl,
benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,
benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl,
benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl,
chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,
dibenzofuranyl, dibenzothiophenyl,
dihydrofuran[2,3-b]tetrahydrofuranyl, dihydrofuranyl, dioxolyl,
dioxanyl, 2H,6H-1,5,2-dithiazinyl, furanyl, furazanyl,
imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl,
indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,
isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl
(benzimidazolyl), isothiazolidinyl, 2-isothiazolinyl, isothiazolyl,
isoxazolyl, isoxazolidinyl, 2-isoxazolinyl, morpholinyl,
naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl,
oxothiolanyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,
phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,
phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl,
pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl,
pyridazinyl, pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl,
pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,
pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,
4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyridinyl,
6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiomorpholinyl, thiophenyl, triazinyl, 1,2,3-triazolyl,
1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl
and xanthenyl.
[0102] The term azaheterocyclyl 5 or 6 membered carbocyclic ring
wherein one ring carbon thereof is replaced by a nitrogen atom and
has other ring carbon atoms thereof optionally replaced by a
heteroatom such as a nitrogen or oxygen. The azaheterocyclyl is
also partially unsaturated or substituted by one or two oxo.
Particular azaheterocyclyl are selected from the group consisting
of 4
[0103] The term "bicycloazaheterocyclyl carboxylic acid sulfonamide
derivative" pertains to the compound of formula I as defined.
EMBODIMENTS
[0104] Another embodiment of the invention relates to the compound
of formula I wherein
[0105] ring.sup.1, ring.sup.2 or ring.sup.3 as
[0106] --(C.sub.6-C.sub.14)-aryl is phenyl, naphthyl, 1-naphthyl,
2-naphthyl, biphenylyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl,
anthryl or fluorenyl and is unsubstituted or substituted,
independently of each other, once, twice or three times, by G, or
5- or 6-membered aromatic heteroaryl ring is dihydrofuranyl,
dioxolyl, dioxanyl, furanyl, imidazolidinyl, imidazolinyl,
imidazolyl, isoxazolyl, isoxazolidinyl, 2-isoxazolinyl,
isothiazolyl, isothiazolidinyl, 2-isothiazolinyl, morpholinyl,
oxazolyl, oxothiolanyl, piperazinyl, piperidinyl, pyranyl,
pyrazinyl, pyrazolyl, pyrazolidinyl, pyrazolinyl, pyridazinyl,
pyridinyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, tetrahydrofuranyl,
tetrahydropyridinyl, thiazolyl, thiomorpholinyl, thiophenyl or
thiopyranyl and is unsubstituted or substituted, independently of
each other, once, twice or three times, by G,
[0107] ring.sup.4 as
[0108] --(C.sub.6-C.sub.14)-aryl is phenyl, naphthyl, 1-naphthyl,
2-naphthyl, biphenylyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl,
anthryl or fluorenyl and is unsubstituted or substituted,
independently of each other, once, twice or three times, by G, 5-
or 6-membered aromatic heteroaryl ring is dihydrofuranyl, dioxolyl,
dioxanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl,
isoxazolyl, isoxazolidinyl, 2-isoxazolinyl, isothiazolyl,
isothiazolidinyl, 2-isothiazolinyl, morpholinyl, oxazolyl,
oxothiolanyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl,
pyrazolyl, pyrazolidinyl, pyrazolinyl, pyridazinyl, pyridinyl,
pyrimidinyl, pyrrolyl, pyrrolidinyl, tetrahydrofuranyl,
tetrahydropyridinyl, thiazolyl, thiomorpholinyl, thiophenyl or
thiopyranyl and is unsubstituted or substituted, independently of
each other, once, twice or three times, by G, or
[0109] heteroaryl is acridinyl, azetidinyl, benzimidazolyl,
benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,
benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl,
benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl,
carbolinyl, chromanyl, chromenyl, cinnolinyl, deca-hydroquinolinyl,
2H,6H- 1,5,2-dithiazinyl, dihydrofuran[2,3-b]tetrahydrofuran,
fuaranyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,
isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,
isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl,
isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,
oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,
1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl,
oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,
phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,
phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl,
pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl,
pyridazinyl, pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl,
pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,
pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,
4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl,
6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl or xanthenyl,
[0110] that is unsubstituted or substituted, independently of each
other, once, twice or three times, by G,
[0111] R.sup.4 as
[0112] --(C.sub.1-C.sub.6)-alkyl that is unsubstituted or
substituted, once, twice or three times, by halogen,
--(C.sub.3-C.sub.6)-cycloalkyl, phenyl, naphthyl, acridinyl,
azetidinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,
benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl,
benzotetrazolyl, benzisoxazolyl, benzisothiazolyl,
benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl,
chromanyl, chromenyl, cinnolinyl, deca-hydroquinolinyl,
2H,6H-1,5,2-dithiazinyl, dihydrofuran[2,3-b]tetrahydrofuran,
fuaranyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,
isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,
isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl,
isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,
oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,
1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl,
oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,
phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,
phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl,
pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl,
pyridazinyl, pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl,
pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,
pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,
4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl,
6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl or xanthenyl,
[0113] that is unsubstituted or substituted, independently of each
other, once, twice or three times, by G,
[0114] --(C.sub.6-C.sub.14)-aryl is phenyl or naphthyl, or
[0115] heteroaryl is acridinyl, azetidinyl, benzimidazolyl,
benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,
benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl,
benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl,
carbolinyl, chromanyl, chromenyl, cinnolinyl, deca-hydroquinolinyl,
2H,6H-1,5,2-dithiazinyl, dihydrofuran[2,3-b]tetrahydrofuran,
fuaranyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,
isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,
isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl,
isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,
oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,
1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl,
oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,
phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,
phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl,
pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl,
pyridazinyl, pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl,
pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,
pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,
4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl,
6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl or xanthenyl,
[0116] that is unsubstituted or substituted, independently of each
other, once, twice or three times, by G,
[0117] R.sup.5 is
[0118] --(C.sub.1-C.sub.6)-alkyl that is unsubstituted or
substituted, once, twice or three times, by
--(C.sub.3-C.sub.6)-cycloalkyl, phenyl, naphthyl, acridinyl,
azetidinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,
benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl,
benzotetrazolyl, benzisoxazolyl, benzisothiazolyl,
benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl,
chromanyl, chromenyl, cinnolinyl, deca-hydroquinolinyl,
2H,6H-1,5,2-dithiazinyl, dihydrofuran[2,3-b]tetrahydrofuran,
fuaranyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,
isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,
isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl,
isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,
oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,
1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl,
oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,
phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,
phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl,
pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl,
pyridazinyl, pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl,
pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,
pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,
4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl,
6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl or xanthenyl,
[0119] that is unsubstituted or substituted, independently of each
other, once, twice or three times, by G,
[0120] --(C.sub.6-C.sub.14)-aryl is phenyl or naphthyl, or
heteroaryl is acridinyl, azetidinyl, benzimidazolyl, benzofuranyl,
benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl,
benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl,
benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl,
chromanyl, chromenyl, cinnolinyl, deca-hydroquinolinyl,
2H,6H-1,5,2-dithiazinyl, dihydrofuran[2,3-b]tetrahy- drofuran,
fuaranyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,
isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,
isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl,
isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,
oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,
1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl,
oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,
phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,
phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl,
pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl,
pyridazinyl, pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl,
pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,
pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,
4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl,
6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl or xanthenyl,
[0121] that is unsubstituted or substituted, independently of each
other, once, twice or three times, by G,
[0122] R.sup.6 as
[0123] --(C.sub.1-C.sub.6)-alkyl that is unsubstituted or
substituted, once, twice or three times, by
--(C.sub.3-C.sub.6)-cycloalkyl, phenyl, naphthyl, acridinyl,
azetidinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,
benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl,
benzotetrazolyl, benzisoxazolyl, benzisothiazolyl,
benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl,
chromanyl, chromenyl, cinnolinyl, deca-hydroquinolinyl,
2H,6H-1,5,2-dithiazinyl, dihydrofuran[2,3-b]tetrahydrofuran,
fuaranyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,
isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,
isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl,
isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,
oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,
1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl,
oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,
phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,
phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl,
pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl,
pyridazinyl, pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl,
pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,
pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,
4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl,
6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl or xanthenyl,
[0124] that is unsubstituted or substituted, independently of each
other, once, twice or three times, by G,
[0125] --(C.sub.6-C.sub.14)-aryl is phenyl or naphthyl, or
[0126] heteroaryl is acridinyl, azetidinyl, benzimidazolyl,
benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,
benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl,
benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl,
carbolinyl, chromanyl, chromenyl, cinnolinyl, deca-hydroquinolinyl,
2H,6H-1,5,2-dithiazinyl, dihydrofuran[2,3-b]tetrahydrofuran,
fuaranyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,
isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,
isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl,
isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,
oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,
1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl,
oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,
phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,
phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl,
pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl,
pyridazinyl, pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl,
pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,
pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,
4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl,
6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl or xanthenyl,
[0127] that is unsubstituted or substituted, independently of each
other, once, twice or three times, by G, and
[0128] R.sup.1 as
[0129] --(C.sub.1-C.sub.6)-alkyl that is unsubstituted or
substituted, once, twice or three times, by
--(C.sub.3-C.sub.6)-cycloalkyl, phenyl, naphthyl, acridinyl,
azetidinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,
benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl,
benzotetrazolyl, benzisoxazolyl, benzisothiazolyl,
benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl,
chromanyl, chromenyl, cinnolinyl, deca-hydroquinolinyl,
2H,6H-1,5,2-dithiazinyl, dihydrofuran[2,3-b]tetrahydrofuran,
fuaranyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,
isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,
isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl,
isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,
oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,
1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl,
oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,
phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,
phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl,
pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl,
pyridazinyl, pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl,
pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,
pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,
4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl,
6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl or xanthenyl,
[0130] that is unsubstituted or substituted, independently of each
other, once, twice or three times, by G.
[0131] Another embodiment of the invention relates to the compound
of formula I wherein
[0132] B, D and E are identical or different and are, independently
of each other,
[0133] --(C.sub.0-C.sub.2)-alkylene,
[0134] --C.sub.2-alkenylene,
[0135] --S(O).sub.2--,
[0136] --NH--,
[0137] --NH--C(O)--,
[0138] --C(O)--NH--,
[0139] --NH--C(O)--NH--,
[0140] --O--, or
[0141] --C(O)--,
[0142] ring.sup.1, ring.sup.2 or ring.sup.3 as
[0143] --(C.sub.6-C.sub.14)-aryl is phenyl or naphthyl that is
unsubstituted or substituted, independently of each other, once,
twice or three times, by G, or 5- or 6-membered aromatic heteroaryl
ring that is dihydrofuranyl, furanyl, morpholinyl, piperazinyl,
piperidinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl or
thiophenyl and are unsubstituted or substituted, independently of
each other, once, twice or three times, by G,
[0144] ring.sup.4 as
[0145] --(C.sub.6-C.sub.14)-aryl is phenyl or naphthyl and is
unsubstituted or substituted, independently of each other, once,
twice or three times, by G,
[0146] 5- or 6-membered aromatic heteroaryl ring is dihydrofuranyl,
furanyl, morpholinyl, piperazinyl, piperidinyl, pyridinyl,
pyrimidinyl, pyrrolyl, thiazolyl or thiophenyl and is unsubstituted
or substituted, independently of each other, once, twice or three
times, by G,
[0147] heteroaryl that is benzofuranyl, benzothiophenyl,
dihydrofuranyl, furanyl, morpholinyl, piperazinyl, piperidinyl,
pyridinyl, pyridothiophenyl, pyrimidinyl, pyrrolyl, thiazolyl or
thiophenyl and are unsubstituted or substituted, independently of
each other, once, twice or three times, by G, or azaheterocyclyl
selected from the group consisting of 5
[0148] that is unsubstituted or substituted, independently of each
other, once, twice or three times, by G,
[0149] G as
[0150] halogen is Br, Cl, I or F, and
[0151] --S(O).sub.p--R.sup.4 is --S(O).sub.2--R.sup.4,
[0152] R.sup.4 is
[0153] hydrogen,
[0154] --(C.sub.2-C.sub.4)-alkyl that is unsubstituted or
substituted, once, twice or three times, by Br, Cl, F,
--C.sub.3-cycloalkyl, phenyl, naphthyl, or heteroaryl that is
benzofuranyl, benzothiophenyl, dihydrofuranyl, furanyl,
morpholinyl, piperazinyl, piperidinyl, pyridinyl, pyridothiophenyl,
pyrimidinyl, pyrrolyl, thiazolyl or thiophenyl and are
unsubstituted or substituted, independently of each other, once,
twice or three times, by G,
[0155] phenyl or naphthyl,
[0156] heteroaryl that is benzofuranyl, benzothiophenyl,
dihydrofuranyl, furanyl, morpholinyl, piperazinyl, piperidinyl,
pyridinyl, pyridothiophenyl, pyrimidinyl, pyrrolyl, thiazolyl or
thiophenyl and are unsubstituted or substituted, independently of
each other, once, twice or three times, by G,
[0157] --C(O)--O--R.sup.5, or
[0158] --C(O)--NH--R.sup.6,
[0159] R.sup.5 is
[0160] --(C.sub.2-C.sub.4)-alkyl that is unsubstituted or
substituted, once or twice, by --C.sub.3-cycloalkyl, phenyl,
naphthyl or heteroaryl that is benzofuranyl, benzothiophenyl,
dihydrofuranyl, furanyl, morpholinyl, piperazinyl, piperidinyl,
pyridinyl, pyridothiophenyl, pyrimidinyl, pyrrolyl, thiazolyl or
thiophenyl and are unsubstituted or substituted, independently of
each other, once, twice or three times, by G,
[0161] phenyl or naphthyl, or
[0162] heteroaryl that is benzofuranyl, benzothiophenyl,
dihydrofuranyl, furanyl, morpholinyl, piperazinyl, piperidinyl,
pyridinyl, pyridothiophenyl, pyrimidinyl, pyrrolyl, thiazolyl or
thiophenyl that is substituted, independently of each other, once,
twice or three times, by G,
[0163] R.sup.6 is
[0164] --(C.sub.1-C.sub.4)-alkyl, in which alkyl is unsubstituted
or substituted, once or twice, by --C.sub.3-cycloalkyl, phenyl,
naphthyl or heteroaryl that is benzofuranyl, benzothiophenyl,
dihydrofuranyl, furanyl, morpholinyl, piperazinyl, piperidinyl,
pyridinyl, pyridothiophenyl, pyrimidinyl, pyrrolyl, thiazolyl or
thiophenyl and are unsubstituted or substituted, independently of
each other, once, twice or three times, by G,
[0165] phenyl or naphthyl, or
[0166] heteroaryl that is benzofuranyl, benzothiophenyl,
dihydrofuranyl, furanyl, morpholinyl, piperazinyl, piperidinyl,
pyridinyl, pyridothiophenyl, pyrimidinyl, pyrrolyl, thiazolyl or
thiophenyl that is substituted, independently of each other, once,
twice or three times, by G,
[0167] X.sup.1 and X.sup.2 are
[0168] hydrogen,
[0169] n.sup.1 and n.sup.2 are
[0170] --CH.sub.2)--, or n.sup.1 is --(CH.sub.2).sub.2-- and n is
--(CH.sub.2)--,
[0171] R.sup.1 is
[0172] hydrogen, and
[0173] R2 and R.sup.3 are
[0174] hydrogen.
[0175] Preference is given to pyridyl; such as 2-pyridyl, 3-pyridyl
or 4-pyridyl; pyrrolyl; such as 2-pyrrolyl and 3-pyrrolyl; furyl;
such as 2-furyl and 3-furyl; thiophenyl, thienyl; such as 2-thienyl
and 3-thienyl; imidazolyl, pyrazolyl, oxazolyl, isoxazolyl,
thiazolyl, isothiazolyl, tetrazolyl, pyridazinyl, pyrazinyl,
pyrimidinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl,
1,3-benzodioxolyl, indazolyl, benzimidazolyl, benzoxazolyl,
benzothiazolyl, quinolinyl, isoquinolinyl, chromanyl, isochromanyl,
cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,
pyridoimidazolyl, pyridopyridinyl, pyridopyrimidinyl, purinyl and
pteridinyl.
[0176] Another particular embodiment of the invention is a process
for the preparation of the compound according to formula I,
comprising
[0177] a) reacting a compound of formula IV, 6
[0178] wherein R.sup.e is a hydrogen or an ester protecting group,
with a compound of formula V,
R.sup.z--SO.sub.2-A-ring.sup.1-B-ring.sup.2-D-ring.sup.3-E-ring.sup.4
(V)
[0179] in which A, B, D, E and ring.sup.1, ring.sup.2, ring.sup.3
and ring.sup.4 are defined as in the compound of formula I, and
wherein R.sup.2 is chlorine atom, imidazolyl or OH, in the presence
of a base, or after silylation with a suitable silylating agent, to
give a compound of formula VI, 7
[0180] wherein A, B, D, E, R.sup.e and ring.sup.1, ring.sup.2,
ring.sup.3 and ring.sup.4 are as defined above, and
[0181] b) where R.sup.e is the ester protecting group, reacting a
compound of formula VI, which has been prepared in accordance with
step a), with a solution of an alkali such as NaOH or LiOH, and
then treating with acid, to give the carboxylic acid of formula
VII, with modifications in one of the side chains of
ring.sup.1-ring.sup.4 also having previously been carried out,
where appropriate, 8
[0182] and then converting this compound into the compound of
formula I wherein X is NH--OH, and
[0183] c) optionally separating the compound of formula I, which
has been prepared in accordance with steps a) or b) into an
individual enantiomer by means of salt formation with an
enantiomerically pure acid or base, chromatography on a chiral
stationary phase or derivatization using chiral, enantiomerically
pure compound, such as an amino acid, separation of the resulting
derivatized diastereomers and elimination of the chiral auxiliary
derivatization group, or
[0184] d) optionally isolating the compound of formula I, which has
been prepared in accordance with steps b) or c), in free form or,
when an acidic or basic group is present, converting it into a
corresponding physiologically tolerated salt.
[0185] Compounds such as those of formulae IV to VII are only
exemplary compounds; in accordance with formula I it is also
possible to configure four-ring, six-ring and seven-ring compounds
instead of the five-ring compound.
[0186] The groups that are used in Protective Groups in Organic
Synthesis, T. H. Greene, P. G. M. Wuts, Wiley-Interscience, 1991,
as groups for protecting esters can be employed as the ester
protecting group R.sup.e. Examples of preferred ester protecting
groups are methyl, ethyl, isopropyl, tert-butyl or benzyl.
[0187] The starting compounds and reagents that are used can either
be prepared using known methods or are commercially available.
[0188] The reactions take place as depicted, for example, in WO
97/18194. The reaction in accordance with process step a) takes
place in the presence of a base such as KOH, NaOH, LiOH,
N,O-bis(trimethylsilyl)acetam- ide (BSA), N-methylmorpholine (NMM),
N-ethylmorpholine (NEM), triethylamine (TEA), diisopropylethylamine
(DIPEA), pyridine, collidine, imidazole or sodium carbonate in
solvents such as tetrahydrofuran (THF), dimethylformamide (DMF),
dimethylacetamide, dioxane, acetonitrile, toluene, chloroform or
methylene chloride, or else in the presence of water.
[0189] Modifications in the side chain F means that, for example, a
nitro group is hydrogenated using the metal catalyst Pd/C or
reacted with SnCl.sub.2 or Zn under standard conditions and the
resulting amino group can then be subjected to further
modification, for example by reacting it with carbonyl chlorides,
sulfonyl chlorides, chloroformic esters, isocyanates,
isothiocyanates, or other reactive or activatable reagents, in
order to arrive at the precursors of the novel compounds of formula
I. For this case, it is frequently advantageous if R.sup.e is an
ester in compound VI since side reactions are to be expected when
the carboxylic acid is unprotected.
[0190] Provided it arises as a mixture of diastereomers or
enantiomers, or accrues in the chosen synthesis as their mixtures,
the compound of formula I is separated, in process step c), into
the pure stereoisomers either by means of chromatography on an
optionally chiral support material or, provided the racemic
compound of formula I is capable of salt formation, by means of
fractional crystallization of the diastereomeric salts which have
been formed using an optically active base or acid as auxiliary
substance. Examples of suitable chiral stationary phases for the
thin-layer or column chromatographic separation of enantiomers are
modified silica gel supports (what are termed Pirkle phases) and
also high molecular weight carbohydrates, such as triacetyl
cellulose. Following appropriate derivatization, which is known to
the skilled person, gas-chromatographic methods on chiral
stationary phases can also be used for analytical purposes. In
order to separate the enantiomers of the racemic carboxylic acids,
the diastereomeric salts, which differ in solubility, are formed
using an optically active, as a rule commercially available, base
such as (-)-nicotine, (+)- and (-)-phenylethylamine, quinine bases,
L-lysine or L- and D-arginine, the more sparingly soluble component
is isolated as a solid, the more readily soluble diastereomer is
separated out from the mother liquor, and the pure enantiomers are
isolated from the diastereomer salts which have been obtained in
this way. The racemic compounds of the formula I which contain a
basic group, such as amino group, can, in what is in principle the
same manner, be converted into the pure enantiomers using optically
active acids, such as (+)-camphor-10-sulfonic acid, D- and
L-tartaric acid, D- and L-lactic acid and (+) and (-)-mandelic
acid. Chiral compounds which contain alcohol or amine functions can
also be converted into the corresponding esters or amides using
appropriately activated or optionally N-protected enantiomerically
pure amino acids or, conversely, chiral carboxylic acids can be
converted into the amides using carboxyl-protected enantiomerically
pure amino acids or into the corresponding chiral esters using
enantiomerically pure hydroxyl carboxylic acids such as lactic
acid. The chirality of the amino acid or alcohol radical which has
been introduced in enantiomerically pure form can then be used for
separating the isomers by the diastereomers, which are now present,
being separated by means of crystallization or chromatography on
suitable stationary phases and, after that, using suitable methods
to once again eliminate the entrained chiral molecule moiety.
[0191] Acidic or basic products of the compound of the formula I
may be present in the form of their salts or in free form.
Preference is given to pharmacologically tolerated salts, e.g.
alkali metal salts or alkaline earth metal salts or hydrochlorides,
hydrobromides, sulfates, hemisulfates, all possible phosphates and
also salts of the amino acids, natural bases or carboxylic
acids.
[0192] Physiologically tolerated salts are prepared according to
process step d) in a manner known per se from compounds of the
formula I, including their stereoisomeric forms, which are capable
of salt formation. The compounds of formula I form stable alkali
metal salts, alkaline earth metal salts or optionally substituted
ammonium salts with basic reagents such as hydroxides, carbonates,
hydrogen carbonates, alkoxides and ammonia or organic bases, for
example trimethylamine or triethylamine, ethanolamine,
diethanolamine or triethanolamine, trometamol or else basic amino
acids, for example lysine, ornithine or arginine. Insofar as the
compounds of formula I possess basic groups, stable acid addition
salts can also be prepared using strong acids. Both inorganic and
organic acids, such as hydrochloric acid, hydrobromic acid,
sulfuric acid, phosphoric acid, methanesulfonic acid,
benzenesulfonic acid, p-toluenesulfonic acid,
4-bromobenzenesulfonic acid, cyclohexylamidosulfonic acid,
trifluoromethylsulfonic acid, acetic acid, oxalic acid, tartaric
acid, succinic acid glycerol phosphoric acid, lactic acid, malic
acid, adipic acid, citric acid, fumaric acid, maleic acid, gluconic
acid, glucuronic acid and trifluoroacetic acid are suitable for
this purpose.
[0193] The invention also relates to a pharmaceutical preparation
comprising a pharmaceutically effective amount of at least one
compound of formula I and/or of a physiologically tolerated salt of
the compound of formula I and/or an optionally stereoisomeric form
of the compound of formula I, together with a pharmaceutically
suitable and physiologically tolerated carrier substance, additive
and/or other active compounds and auxiliary substances.
[0194] On account of their pharmacological properties, compounds
according to the invention are suitable for the selective
prophylaxis and therapy of all those diseases whose course involves
an increase in the activity of the metalloproteinases. These
diseases include degenerative joint diseases, such as
osteoarthroses, spondyloses, cartilage loss following joint trauma
or a relatively long period of joint immobilization following
meniscus injuries or patella injuries or ligament rupture. They
also include diseases of the connective tissue such as
collagenoses, periodontal diseases, wound healing disturbances and
chronic diseases of the locomotory apparatus, such as inflammatory,
immunologically-determine- d or metabolism-determined acute and
chronic arthritides, arthropathies, myalgias and disturbances in
bone metabolism. In addition, the compound of formula I is suitable
for treating ulceration, atherosclerosis and stenoses. The compound
of formula I is furthermore suitable for treating inflammations,
cancer diseases, tumor metastasis formation, cachexia, anorexia,
heart failure and septic shock. The compound is also suitable for
the prophylaxis of myocardial and cerebral infarcts.
[0195] The pharmaceutical according to the invention can be
administered by means of oral, inhalative, rectal or transdermal
administration or by means of subcutaneous, intraarticular,
intraperitoneal or intravenous injection. Oral administration is
preferred.
[0196] The invention also relates to a process for producing a
pharmaceutical, in which process at least one compound of formula I
is brought, together with a pharmaceutically suitable and
physiologically tolerated excipient and, where appropriate, other
suitable active compounds, additives or auxiliary substances, into
a suitable form for administration.
[0197] Examples of suitable solid or galenic preparation forms are
granules, powders, sugar-coated tablets, tablets, (micro)capsules,
suppositories, syrups, juices, suspensions, emulsions, drops or
injectable solutions, and also preparations involving a protracted
release of active compound, in the production of which customary
adjuvants such as carrier substances, disintegrants, binders,
coating agents, swelling agents, glidants, lubricants, flavorings,
sweeteners and solubilizers are used. Frequently employed auxiliary
substances which may be mentioned are magnesium carbonate, titanium
dioxide, lactose, mannitol and other sugars, talc, milk protein,
gelatin, starch, cellulose and its derivatives, animal and
vegetable oils, such as cod liver oil, sunflower oil, peanut oil or
sesame oil, polyethylene glycol and solvents, such as sterile water
and monohydric or polyhydric alcohols such as glycerol.
[0198] The pharmaceutical preparations are preferably produced and
administered in dosage units, with each unit containing, as the
active constituent, a defined dose of the novel compound of formula
I. In the case of solid dose units, such as tablets, capsules,
sugar-coated tablets or suppositories, this dose can be up to about
1,000 mg, preferably, however, from about 50 to 300 mg, while it
can be up to about 300 mg, preferably, however, from about 10 to
100 mg, in the case of injection solutions in ampoule form.
[0199] Depending on the activity of the compound of formula I,
daily doses of from about 20 mg to 1,000 mg of active compound,
preferably of from about 100 mg to 500 mg, are indicated for
treating an adult patient of about 70 kg in weight. However, higher
or lower daily doses may also possibly be appropriate. The daily
dose may be administered either by means of a once-only
administration in the form of a single dosage unit or of several
smaller dosage units or else by means of the multiple
administration of subdivided doses at defined intervals.
[0200] The starting materials and intermediates may be prepared by
the application or adaptation of known methods, or their obvious
chemical equivalents.
[0201] The compounds of the invention, their methods or preparation
and their biological activity will appear more clearly from the
examination of the following examples which are presented as an
illustration only and are not to be considered as limiting the
invention in its scope.
EXAMPLES
[0202] As a rule, end products are determined by means of
mass-spectroscopic methods (FAB MS, ESI MS) and .sup.1H NMR (400
MHz, in DMSO-D6); the main peak or the two main peaks is/are given
in each case. Temperatures are given in degrees centigrade; RT
denotes room temperature (from 22.degree. C. to 26.degree. C.).
Abbreviations that are used are either explained or conform to the
customary conventions.
[0203] The invention is explained in more detail below with the aid
of examples.
1-Arylsulfonyloctahydrocyclopenta[b]pyrrole-2-carboxylic acid
[0204] General Directions 1:
[0205] The carboxylic acid (6.45 mmol) is dissolved in 20 ml of
dimethylformamide (DMF), after which 3 equivalents of a 3N solution
of NaOH (6.45 ml) are added at 0.degree. C. After 10 min, a
solution of the arylsulfonyl chloride (1.1 equivalents, 7.1 mmol)
in from 10 to 15 ml of DMF was slowly added dropwise; after the
mixture had reached room temperature, it was stirred for at most a
further 12 hours (h) at temperatures of between 20.degree. C. and
80.degree. C. and the solvent was removed under reduced pressure.
The crude product was purified chromatographically.
EXAMPLES
Compound No.4:
1-[4-(1,1-Dimethylpropyl)benzenesulfonyl]octahydrocyclopent-
a[b]pyrrole-2-carboxylic acid
[0206] 1 g of octahydrocyclopenta[b]pyrrole-2-carboxylic acid (6.45
mmol) was dissolved in 20 ml of DMF, after which 3 equivalents of a
3 N solution of NaOH (6.45 ml) were added at 0.degree. C. After 10
minutes (min), a solution of 1.75 g of
4-(1,1-dimethylpropylbenzenesulfonyl chloride (1.1 equivalents, 7.1
mmol) in 12 ml of DMF was slowly added dropwise; after it had
reached room temperature (RT), the mixture was stirred at
40.degree. C. for a further 6 h and, after that, the solvent was
removed under reduced pressure. The crude product was purified
chromatographically.
Compound No. 20:
1-(4-Acetylbenzenesulfonyl)octahydrocyclopenta[b]pyrrole--
2-carboxylic acid
[0207] 1 g of octahydrocyclopenta[b]pyrrole-2-carboxylic acid (6.45
mmol) was dissolved in 20 ml of DMF, after which 3 equivalents of a
3N solution of NaOH (6.45 ml) were added at 0.degree. C. After 10
min, a solution of 1.55 g of 4-acetylbenzenesulfonyl chloride (1.1
equivalents, 7.1 mmol) in 8 ml of DMF was slowly added dropwise;
after it had reached RT, the mixture was stirred at 40.degree. C.
for a further 6 h and, after that, the solvent was removed under
reduced pressure. The crude product was purified
chromatographically.
1-Arylsulfonyloctahydrocyclopenta[b]pyrrole-2-carboxylic acid
hydroxyamide
[0208] General Directions 2:
[0209] The sulfonated carboxylic acid was dissolved in 10 ml of
DMF, after which 1.1 equivalents of ethyl chloroformate, 2.2
equivalents of N-ethylmorpholine and 3 equivalents of
trimethylsilylhydroxylamine were added. After the mixture had been
heated at 80.degree. C. for at least 4 h, the solvent was removed
under reduced pressure and the crude product was purified using
chromatographic methods.
EXAMPLES
Compound No. 50:
1-(Naphthaline-1-sulfonyl)octahydrocyclopenta[b]pyrrole-2-
-carboxylic acid hydroxyamide
[0210] 200 mg (0.56 mmol) of
1-(naphthaline-1-sulfonyl)octahydrocyclopenta-
[b]pyrrole-2-carboxylic acid were dissolved in 10 ml of DMF, after
which 0.61 mmol of ethyl chloroformate, 1.23 mmol of
N-ethylmorpholine and 1.68 mmol of trimethylsilylhydroxylamine were
added. After the mixture had been heated at 80.degree. C. for 6 h,
the solvent was removed under reduced pressure and the crude
product was purified using chromatographic methods.
Compound No. 52:
1-(4-Methanesulfonylbenzenesulfonyl)octahydrocyclopenta[b-
]pyrrole-2-carboxylic acid hydroxyamide
[0211] 200 mg (0.55 mmol) of
1-(4-methanesulfonylbenzenesulfonyl)octahydro-
cyclopenta-[b]pyrrole-2-carboxylic acid were dissolved in 10 ml of
DMF, after which 0.60 mmol of ethyl chloroformate, 1.22 mmol of
N-ethylmorpholine and 1.67 mmol of trimethylsilylhydroxylamine were
added. After the mixture had been heated at 80.degree. C. for 4 h,
the solvent was removed under reduced pressure and the crude
product was purified using chromatographic methods.
[0212] Special Directions:
Compound No. 27:
1-(4'-Aminobiphenyl4-sulfonyl)octahydrocyclopenta[b]pyrro-
le-2-carboxylic acid
[0213] 1 g of
1-(4'-nitrobiphenyl4-sulfonyl)octahydrocyclopenta[b]pyrrole--
2-carboxylic acid (27) was dissolved in 15 ml of DMF, after which
0.1 g of hydrogenation catalyst (10% Pd on active charcoal) was
added and the starting compound was quantitatively hydrogenated
within 2 h. After the solvent had been removed, the crude product
was purified chromatographically.
Compound No. 37:
1-(4-Aminobenzenesulfonyl)octahydrocyclopenta[b]pyrrole-2-
-carboxylic acid
[0214] 1 g of
1-(4-nitrobenzenesulfonyl)octahydrocyclopenta[b]pyrrole-2-ca-
rboxylic acid (14) was dissolved in 15 ml of DMF, after which 0.1 g
of hydrogenation catalyst (10% Pd on active charcoal) was added and
the starting compound was quantitatively hydrogenated within 2 h.
After the solvent had been removed, the crude product was purified
chromatographically.
Compound No. 22:
1-(4'-Isopropoxycarbonylaminobiphenyl4-sulfonyl)octahydro-
cyclopenta[b]pyrrole-2-carboxylic acid
[0215] 500 mg (1.30 mmol) of
1-(4'-aminobiphenyl4-sulfonyl)octahydrocyclop-
enta[b]pyrrole-2-carboxylic acid were dissolved in 3 ml of DMF,
after which the solution was cooled down to 0.degree. C. in an ice
bath and 2.6 mmol of pyridine were added. After the mixture had
been stirred at 0.degree. C. for 15 min, 2 mmol of isopropyl
chloroformate in 3 ml of DMF were added. The reaction solution was
then stirred at RT for a further 2 h. The crude product was
purified using chromatographic methods.
Compound No. 32:
1-(4'-Cyclopropylmethoxycarbonylaminobiphenyl4-sulfonyl)--
octahydrocyclopenta[b]pyrrole-2-carboxylic acid
[0216] 500 mg (1.30 mmol) of
1-(4'-aminobiphenyl4-sulfonyl)octahydrocyclop-
enta[b]pyrrole-2-carboxylic acid were dissolved in 3 ml of DMF,
after which the solution was cooled down to 0.degree. C. in an ice
bath and 2.6 mmol of pyridine were added. After the mixture had
been stirred at 0.degree. C. for 15 min, 2 mmol of
cyclopropylmethyl chloroformate in 3 ml of DMF were added. The
reaction solution was then stirred at RT for a further 6 h. The
crude product was purified using chromatographic methods.
Compound No.23:
1-(4'-Methanesulfonylaminobiphenyl4-sulfonyl)octahydrocycl-
openta[b]pyrrole-2-carboxylic acid
[0217] 500 mg (1.30 mmol) of
1-(4'-aminobiphenyl-4-sulfonyl)octahydrocyclo-
penta[b]pyrrole-2-carboxylic acid were dissolved in 3 ml of DMF,
after which the solution was cooled down to 0.degree. C. in an ice
bath and 2.6 mmol of pyridine were added. After the mixture had
been stirred at 0.degree. C. for 15 min, 1.40 mmol of
methanesulfonyl chloride in 3 ml of DMF were added. The reaction
solution was then stirred at room temperature for a further 6 h.
The crude product was purified using chromatographic methods.
Compound No. 25:
1-(4'-Benzenesulfonylaminobiphenyl-4-sulfonyl)octahydrocy-
clopenta[b]pyrrole-2-carboxylic acid
[0218] 500 mg (1.30 mmol) of
1-(4'-aminobiphenyl-4-sulfonyl)octahydrocyclo-
penta[b]pyrrole-2-carboxylic acid were dissolved in 3 ml of DMF,
after which the solution was cooled down to 0.degree. C. in an ice
bath and 2.6 mmol of pyridine were added. After the mixture had
been stirred at 0.degree. C. for 15 min, 1.5 mmol of
benzenesulfonyl chloride in 6 ml of DMF were added. The reaction
solution was then stirred at RT for a further 12 h. The crude
product was purified using chromatographic methods.
Compound No. 24:
1-(4'-Benzoylaminobiphenyl-4-sulfonyl)octahydrocyclopenta-
[b]pyrrole-2-carboxylic acid
[0219] 500 mg (1.30 mmol) of
1-(4'-aminobiphenyl-4-sulfonyl)octahydrocyclo-
penta[b]pyrrole-2-carboxylic acid were dissolved in 3 ml of DMF,
after which the solution was cooled down to 0.degree. C. in an ice
bath and 2.6 mmol of pyridine were added. After the mixture had
been stirred at 0.degree. C. for 15 min, 1.8 mmol of benzoyl
chloride in 3 ml of DMF were added. The reaction solution was then
stirred at RT for a further 20 h. The crude product was purified
using chromatographic methods.
Compound No. 26:
1-[4'-(3-Phenylureido)biphenyl-4-sulfonyl]octahydrocyclop-
enta[b]pyrrole-2-carboxylic acid
[0220] 500 mg (1.30 mmol) of
14'-aminobiphenyl4-sulfonyl)octahydrocyclopen-
ta[b]pyrrole-2-carboxylic acid were dissolved in 3 ml of DMF, after
which the solution was cooled down to 0.degree. C. in an ice bath
and 1.4 mmol of phenylisocyanate were added. The reaction solution
was then stirred at RT for a further 4 h. The crude product was
purified using chromatographic methods.
Preparation Examples
[0221]
1 No. Structure MS (ESI+) NMR 1 9 399.92 400.10 1.4-1.85:m,6H;
1.9:m,1H; 2.35:m,1H; 2.55:m,1H; 2.7:s,3H; 4.0:m,1H; 4.2:m,1H;
7.6:d,1H; (.1:m,2H; 12.1,bs,1H 2 10 373.45 374.08 1.3-1.9:m,8H;
2.15:m,1H; 3.95:m,1H; 3.3:s,3H; 4.2:m,1H; 8.1:d,2H; 8.2:d,2H;
12.5:bs,1H 3 11 374.26 374.06 1.4-1.9:m,7H; 2.15:m,1H; 2.45:m,1H;
3.9:m,1H; 4.1:m,1H; 7.75:d,2H; 7.85:d,2H 13.0:bs,1H 4 12 365.9
366.19 0.6:t,3H; 1.3:s,6H; 1.35-1.8:m,8H; 1.9:m,1H; 2.1:m,1H;
2.4:m,1H; 3.85:m,1H; 4.0:m,1H; 7.55:d,2H; 7.75:d,2H; 12.8:bs,1H 5
13 351.47 352.15 1.45:s,9H; 1.5-1.8:m,6H; 1.9:m,1H; 2.15:m,1H;
2.45:m,1H; 3.85:m,1H; 4.05:m,1H; 7.6:d,2H; 7.85:d,2H; 12.5:s,1H 6
14 309.39 310.22 1.35:m,2H; 1.7:m,5H; 2.3:m,1H; 2.65:m,1H;
4.15:m,2H; 4.5:m,2H; 7.4:m,5H 7 15 441.55 442.11 1.3-1.9:m,7H;
2.2:m,1H; 2.55:m,1H; 4.0:m,1H; 4.2:m,1H; 7.6:m,2H; 7.8:m,2H;
7.95:m,1H; 8.05:m,2H; 13.0:bs,1H 8 16 352.01 353.14 1.3-1.8:m,611;
1.9:m,1H; 2.1:s,3H; 2.15:m,1H; 2.45:1H; 3.85:1H; 4.0:1H; 7.8:m,4H;
10.9:s,1H 9 17 345.42 346.10 1.3-1.8:m,6H; 1.9:m,1H; 2.1:m,1H;
2.4:m,1H; 3.95:m,1H; 4.2:m,1H; 7.7:m,2H; 7.9:d,1H; 8.05:d,1H;
8.15:d,1H; 8.2:d,1H; 8.5:s,1H; 12.8:bs,1H 10 18 446.91 447.11
1.3-1.8:m,6H; 1.9:m,1H; 2.15:m,1H; 2.45:m,1H; 3.9:m,1H; 4.1:m,1H;
7.2:d,1H; 7.4:d,2H; 7.6:d,1H; 7.75:m,2H; 7.9:d,2H 11 19 398.52
399.02 1.3-1.8:m,6H; 1.95:m,1H; 2.2:m,1H; 2.5:m,1H; 2.7:s,3H;
3.95:m,1H; 4.05:m,1H; 7.65:s,2H; 8.1:s,1H 12 20 388.28 388.04
1.3-1.8:m,6H; 1.9:m,1H; 2.1:m,1H; 2.45:m,1H; 3.9:m,1H; 4.1:m,1H;
4.4:s,2H; 7.7:d,2H; 7.85:d,2H 13 21 478.41 480.04 1.3-1.9:m,711;
2.4:m,1H; 2.7:m,1H; 3.05:t,2H; 3.45:m,2H; 4.25:m,1H; 4.35:m,1H;
7.35:m,2H; 7.65:m,6H 14 22 340.36 341.04 1.3-1.9:m,7H; 2.1:m,1H;
2.45:m,1H; 3.9:m,1H; 4.2:m,1H; 8.1:d,2H; 8.4:d,2H 15 23 421.26
421.97 1.3-1.8:m,6H; 1.9:m,1H; 2.1:m,1H; 2.45:m,1H; 3.8:m,1H;
4.05:m,1H; 7.55:d,1H; 8.05:d,1H 16 24 320.37 321.10 1.3-1.9:m,7H;
2.2:m,1H; 2.45:m,1H; 3.95:m,1H; 4.2:m,1H; 8.0:d,2H; 8.1:d,2H;
12.8:s,1H 17 25 321.39 322.02 1.35-1.8:m,6H; 1.95:m,1H; 2.4:m,1H;
2.65:m,1H; 4.05:m,1H; 4.2:m,1H; 7.4:s,2H; 7.45:m,3H; 7.7:m,2H 18 26
379.36 379.97 1.3-1.9:m,711; 2.15:m,1H; 2.5:m,1H; 3.9:m,1H;
4.1:m,1H; 7.6:d,2H; 8.0:d,2H; 12.8:s,1H 19 27 363.36 364.00
1.3-1.9:m,711; 2.2:m,1H; 2.5:m,1H; 4.0:m,1H; 4.2:m,1H; 8.1:d,2H;
8.15:d,2H; 12.95:s,1H 20 28 337.39 338.05 1.3-1.8:m,6H; 1.9:m,1H;
2.15:m,1H; 2.45:m,1H; 2.65:s,3H; 3.9:m,1H; 4.15:m,1H; 7.95:d,2H;
8.15:d,2H; 12.8:s,1H 21 29 440.56 441.09 1.3-1.8:m,6H; 1.9:m,1H;
2.0:m,4H; 2.15:m,1H; 2.45:m,1H; 3.3:m,4H; 3.9:m,1H; 4.05:m,1H;
6.6:d,2H; 7.6:d,2H; 7.8:m,4H 22 30 472.56 473.16 11.3-1.8:m,6H;
1.35:d,6H; 1.9:m,1H; 2.2:m,1H; 2.45:m,1H; 3.9:s,1H; 4.0:s,1H;
4.9:s,1H; 7.6:d,2H; 7.8:d,2H; 7.8:m,4H; 10.0:s,1H 23 31 464.56
465.20 1.3-1.9:m,711; 2.1:m,1H; 2.4:m,1H; 3.0:s,3H; 3.9:s,1H;
4.05:s,1H; 7.35:d,2H; 7.8:d,2H; 7.9:m,4H; 9.9:s,1H 24 32 490.58
491.34 1.3-1.9:m,7H; 2.1:m,1H; 2.4:m,1H; 3.95:m,1H; 4.1:m,1H;
7.55:m,2H; 7.8-8.1:m,8H; 8.4:m,2H 25 33 526.63 527.12 1.3-1.8:m,6H;
1.8:m,1H; 2.0:m,1H; 2.1:m,1H; 3.85:m,1H; 4.05:m,1H; 7.2:m,1H;
7.6:m,6H; 7.9:m,6H 26 34 505.59 506.28 1.3-1.8:m,6H; 1.9:m,1H;
2.15:m,1H; 2.45:m,1H; 3.9:m,1H; 4.1:m,1H; 7.0-8.5:m,13H; 12.8:s,1H
27 35 386.47 387.14 1.3-1.8:m,6H; 1.85:m,1H; 2.1:m,1H; 2.4:m,1H;
3.85:m,1H; 4.1:m,1H; 8.1:d,2H; 8.3:d,2H 28 36 416.46 417.23
1.3-1.8:m,6H; 1.9:m,1H; 2.15:m,1H; 2.45:m,1H; 3.95:m,1H; 4.10:m,1H;
8.0:m,4H; 8.1:d,2H; 8.3:d,2H 29 37 549.67 550.37 1.3-1.8:m,6H;
1.9:m,1H; 2.15:m,1H; 2.45:m,1H; 3.25:m,4H; 3.4:m,4H; 3.9:m,1H;
4.05:m,1H; 7.1:m,6H; 7.7:d,H; 7.9:m,4H; 30 38 405.90 406.21
1.3-1.8:m,6H; 1.9:m,1H; 2.2:m,1H; 2.45:m,1H; 3.9:m,1H; 4.1:m,1H;
7.6:d,2H; 7.8:d,2H; 7.95:m,4H 31 39 371.46 372.16 1.3-1.8:m,6H;
1.9:m,1H; 2.2:m,1H; 2.45:m,1H; 3.9:m,1H; 4.1:m,1H; 7.5:m,3H;
7.75:m,2H; 7.95:m,4H 32 40 484.58 485.12 0.35:m,2H; 0.55:m,2H;
1.3-1.8:m,8H; 1.95:m,1H; 2.3:m,1H; 3.95:1H; 4.2:m,1H; 7.6:m,3H;
7.85:m,3H; 8.05:m,2H 33 41 301.39 302.06 1.3-1.8:m,6H; 1.9:m,1H;
2.2:m,1H; 2.4:m,1H; 3.9:m,1H; 4.05:m,1H; 7.3:m,1H; 7.7:m,1H;
8.0:m,1H 34 42 335.83 336.01 1.3-1.8:m,6H; 1.9:m,1H; 2.15:m,1H;
2.5:m,1H; 3.95:m,1H; 4,:m,1H; 7.35:m,1H; 7.35:d,1H; 7.65:d,1H 35 43
428.51 429.24 1.3-1.7:m,6H; 1.9:m,1H; 2.1:m,1H; 2.4:m,1H; 3.8:m,1H;
4.0:m,1H; 7.3:m,5H; 7.8:d,2H; 7.85:d,2H,10.8:s,1H 36 44 470.57
471.22 1.3-1.7:m,6H; 1.85:m,1H; 2.1:m,1H; 2.45:m,1H; 3.9:m,1H;
4.1:m,1H; 7.5:m,2H; 7.9:d,2H; 8.05:m,4H; 8.45:s,1H; 10.9:s,1H 37 45
310.09 311.13 1.3-1.7:m,6H; 1.85:m,1H; 2.1:m,1H; 2.4:m,1H;
3.8:m,1H; 3.9:m,1H; 6.6:d,2H; 7.45:d,2H; 38 46 386.88 387.14
1.3-2.0:m,711; 2.2:m,1H; 2.55:m,1H; 4.2:m,1H; 4.25:m,1H; 7.65:d,1H;
8.2:s,1H; 8.7:d,2H 39 47 529.02 529.25 1.3-1.8:m,6H; 1.8:m,1H;
2.1:m,1H; 2.4:m,1H; 3.95:m,1H; 4.2:m,1H; 5.2:s,2H; 7.4:m,5H;
8.0:m,2H; 8.2:d,1H; 8.4:d,1H; 8.55:s,1H 40 48 558.69 559.32
1.2:s,9H; 1.3-1.7:m,6H; 1.9:m,1H; 2.25:m,1H; 2.45:m,1H; 2.85:m,2H;
3.5:m,2H; 3.65:m,1H; 3.8:s,3H; 3.9:s,3H; 4.5:m,1H; 7.0:d,1H;
7.2:d,1H; 7.45:m,2H; 7.7:m,2H; 8.15:m,1H 41 49 474.56 475.21
1.3-1.8:m,6H; 2.0:m,1H; 2.3:m,1H; 2.6:m,1H; 2.9:m,4H; 3.6:m,4H;
3.8:m,1H; 4.1:s,3H; 4.5:m,1H; 7.5:d,1H; 7.95:d,1H; 8.05:d,1H 42 50
404.45 405.22 1.3-1.8:m,6H; 1.85:m,1H; 2.1:m,1H; 2.45:m,1H;
3.9:m,1H; 4.05:m,1H; 6.7:d,1H; 7.4:d,1H; 7.8:d,2H; 8.0:m,3H;
10.4:s,1H 43 51 432.47 433.23 1.3-1.7:m,6H; 1.85:m,1H; 2.1:m,1H;
2.45:m,1H; 3.9:m,1H; 4.05:m,1H; 7.4:m,2H; 7.8:m,2H; 8.05:m,4H;
10.6:s,1H 44 52 483.37 483.19 1.3-1.8:m,6H; 1.85:m,1H; 2.15:m,1H;
2.45:m,1H; 3.9:m,1H; 4.05:m,1H; 7.5:d,1H; 7.65:d,1H; 7.75:s,1H;
7.8:d,2H; 7.9:d,2H; 10.9:s,1H 45 53 503.96 504.25 1.3-1.85:m,6H;
2.05:m,1H; 2.4:m,1H; 2.65:m,1H; 3.95:s,3H; 4.0:m,1H; 4.6:m,1H;
7.2:d,2H; 7.3:m,1H; 7.4:d,1H; 7.85:s,1H; 7.9:d,1H; 8.2:d,1H;
8.45:s,1H 46 54 350.85 351.14 1.4-2.0:m,811; 2.4:m,1H; 3.8:m,1H;
3.95:m,1H; 7.35:d,1H; 7.65:d,1H; 10.4:s,1H; 47 55 316.40 317.17
1.8-2.4:m,811; 2.85:m,1H; 3.8:m,1H; 3.9:m,1H; 7.25:m,1H; 7.8:m,1H;
8.05:m,1H; 10.4:s,1H 48 56 366.48 367.22 1.35:s,9H; 1.4-1.95:m,8H;
2.35:m,1H; 3.8-4.0:m,2H; 7.6:d,2H; 7.8:d,2H; 10.55:s,1H 49 57
367.43 368.19 1.4-1.95:m,811; 2.1:s,3H; 2.35:m,1H,3.8-4.0:m,2H;
7.8:m,4H; 10.4:s,1H; 10.6:s,1H 50 58 360.44 361.77 1.4-2.0:m,811;
2.35:m,1H; 3.841:m,2H; 7.65:m,2H; 7.95:d,1H; 8.10:d,1H; 8.15:m,2H;
8.5:s,1H, 10.6:s,1H 51 59 414.93 415.12 1.4-1.9:m,7H;
1.95-2.2:m,2H; 2.7:s,3H; 4.1:m,2H; 7.6:m,1H; 8.1:m,2H; 10.6:s,1H 52
60 388.46 389.14 1.4-1.8:m,8H; 1.90:m,1H; 3.4:s,3H; 3.9:m,2H;
8.15:m,4H; 10.6:s,1H 53 61 389.27 389.07 1.4-2.0:m,8H; 2.40:m,1H;
3.9:m,2H; 7.8:m,4H; 10.6:s,1H 54 62 413.54 414.05 N.A. 55 63 461.93
462.07 1.4-2.1:m,811; 2.4:m,1H; 3.95:m,2H; 7.65:d,1H; 7.40:d,1H;
7.50:d,1H; 7.60 d,1H; 7.75:m,1H; 7.95:d,2H; 10.6:s,1H 56 64 335.38
336.14 1.4-2.1:m,8H; 2.4:m,1H; 2.4:m,1H; 3.95:m,2H; 8.0:d,2H;
8.1:2H; 10.6:1H; 57 65 336.41 337.11 1.4-1.8:m,6H; 2.0:m,1H;
2.2:m,1H; 2.6:m,1H; 3.95:m,1H; 4.05:m,1H; 7.9:m,4H; 7.7:m,2H;
10.5:s,1H 58 66 499.59 500.09 0.35:m,2H; 0.55:m,2H; 1.1-1.85:m,9H;
1.95:m,2H; 2.35:m,1H; 3.85:m,1H; 3.95:m,1H; 7.60:d,2H; 7.7:d,2H;
7.9:m,4H; 9.8:s,1H; 10.6:s,1H 59 67 378.38 379.02 1.4-2.1:m,8H;
2.4:m,1H; 3.9:m,2H; 8.0:d,2H; 8.1:d,2H; 10.65:s,1H 60 68 487.58
488.36 1.26:d,6H; 1.4-2.0:m,8H; 2.35:m,1H; 3.85:m,2H; 4.95:1H;
7.6:d,2H; 7.7:2H; 7.85:m,4H; 9.8:s,1H; 10.6:s,1H 61 69 431.12
432.01 1.4-1.8:m,811; 2.45:m,1H; 3.9:m,2H; 8.05:m,6H; 8.35:m,2H;
10.65:s,1H 62 70 420.92 421.24 1.4-1.8:m,6H; 2.0:m,2H; 2.4:m,1H;
3.95:m,2H; 7.6:d,2H; 7.8:d,2H; 8.0:m,4H; 10.6:s,1H 63 71 564.68
565.39 1.4-2.05:m,811; 2.35:m,1H; 3.35:m,4H; 3.40:m,4H; 3.9:m,2H;
7.1:m,6H; 7.6:d,2H; 7.9:m,4H; 10.6:s,1H 64 72 386.47 387.19
1.4-2.0:811; 2.45:1H; 3.95:m,2H; 7.45:m,3H; 7.75:m,2H; 7.95:m,4H;
10.6:s,1H 65 73 435.99 437.02 1.4-20:m,811; 2.35:m,1H; 3.85:m,2H;
7.6:d,2H; 8.0:d,2H; 10.6:s,1H 66 74 355.08 356.09 1.4-2.0:m,811;
2.35:m,1H; 3.95:m,2H; 8.15:d,2H; 8.4:d,2H; 10.6:s,1H 67 75 493.42
493.10 1.4-1.95:m,8H; 2.35:m,1H; 2.70:m,2H; 3.0:m,2H; 4.1:m,1H;
4.3:m,1H; 7.4:m,2H; 7.6:m,6H; 10.6:s,1H 68 76 520.61 521.16
1.4-1.9:m,8H; 2.4:m,1H; 3.85:m,2H; 7.0-8.0:m,12H; 8.6:s,1H;
8.8:s,1H; 10.6:s,1H 69 77 435.52 436.19 1.4-1.85:m,6H; 1.9:m,2H;
2.4:m,1H; 3.95:m,2H; 7.25:m,1H; 7.8-8.1:m,6H; 8.9:s,1H; 10.5:s,1H
70 78 498.39 498.17 1.4-1.85:m,6H; 1.9:m,2H; 2.4:m,1H; 3.85:m,2H;
7.6-7.9:m,711; 8.95:s,1H; 11.0:s,1H 71 79 419.59 420.21
1.4-1.85:m,6H; 1.95:m,2H; 2.3:m,1H; 3.95:m,2H; 3.85:m,2H; 6.7:m,1H;
7.4:m,1H; 7.8:m,2H; 8.0:m,3H; 8.9:s,1H; 10.8:s,1H 72 80 573.71
574.38 1.25:s
[0222] The IC.sub.50, i.e., the inhibitor concentration that is
required for 50% inhibition of the enzyme activity, is determined
graphically by plotting the percentage inhibitions at different
inhibitor concentrations.
[0223] The buffer solution contains 0.05% Brij (Sigma, Deisenhofen,
Germany) and also 0.1 mol of Tris/HCl/l, 0.1 mol of NaCl/l and 0.01
mol of CaCl.sub.2/l (pH=7.5).
[0224] The enzyme solution contains 1.67 .mu.g/ml of the enzyme
domain.
[0225] The substrate solution contains 0.75 mmol of the fluorogenic
substrate (7-methoxycoumarin4-yl)acetyl-Pro-Leu-Gly-Leu-3-(2',
4'-dinitrophenyl)-L-2,3-diaminopropionyl-Ala-Arg-NH.sub.2/l
(Bachem, Heidelberg, Germany).
[0226] The following table 2 shows the results.
2 TABLE 2 Example MMP-3 MMP-8 MMP-13 No. IC.sub.50 (nM) IC.sub.50
(nM) IC.sub.50 (nM) 13 200 200 700 21 160 4 100 29 >10,000
10,000 260 57 330 320 200 61 22 3 2 63 200 3,700 4.2 64 100 20 3 65
300 100 220
[0227] The present invention may be embodied in other specific
forms without departing from the spirit or essential attributes
thereof.
* * * * *