HK1113367B - Tetrahydrofurane derivatives for use as inhibitors of matrix metalloproteinases - Google Patents
Tetrahydrofurane derivatives for use as inhibitors of matrix metalloproteinases Download PDFInfo
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Description
The present invention relates to novel bicyclic tetrahydrofurylidene amino acid derivatives, to processes for their preparation and to their use as medicaments.
Joint destruction occurs in diseases such as osteoarthritis and rheumatism, and this destruction is particularly caused by collagenase-induced proteolytic degradation of collagen. Collagenases belong to the Metalloprotease (MP) or Matrix Metalloprotease (MMP) superfamily. MMPs constitute a group of Zn-dependent enzymes involved in the biodegradation of the extracellular matrix (D.YIp et al, Investigational New Drugs17(1999), 387-399 and Michaelides et al, Current Pharmaceutical Design5(1999) 787-819). These MMPs are particularly capable of degrading fibrillar and non-fibrillar collagens and proteoglycans, which are important matrix components. MMPs are involved in wound healing, tumor invasion and translocation of metastases as well as angiogenesis, multiple sclerosis and heart failure (michaels et al, page 788; see above). In particular, they play an important role in the degradation of joint matrix in arthropathy and arthritis, whether osteoarthropathy, osteoarthritis or rheumatoid arthritis.
In addition, MMP activity is essential for many processes that play a role in atherosclerotic plaque formation such as inflammatory cell infiltration and smooth muscle cell migration as well as proliferation and angiogenesis (s.j. george, exp. opin. invest. drugs (2000), 9(5), 993-. In addition, matrix degradation by MMPs can cause any condition ranging from plaque instability to rupture, which can produce signs and symptoms of atherosclerosis, unstable angina, myocardial infarction, or stroke (e.j.m. creemers et al, Circulation res.2001, 89, 201-. In general, the MMP family is generally capable of degrading all components of the vascular extracellular matrix; thus, in normal blood vessels, its activity is largely influenced by regulatory mechanisms. During plaque formation and plaque instability, increased MMP activity results from increased cytokine-and growth factor-stimulated gene transcription, increased zymogen activation, and an imbalance in the MMP/TIMP (tissue inhibitor of metalloproteinases) ratio. It would therefore seem reasonable that inhibition of MMPs or re-attaining MMP-TIMP balance would contribute to the treatment of atherosclerotic disease. In addition, it has also become even more clear that an increase in MMP activity has at least partial effects on other cardiovascular diseases than atherosclerosis, such as restenosis, dilated cardiomyopathy and the aforementioned myocardial infarction. Administration of synthetic inhibitors to experimental animal models of these diseases has been shown to result in significant improvements in, for example, atherosclerotic lesion formation, neointima formation, left ventricular remodeling, pump behavior dysfunction or infarction healing. In various preclinical studies using MMP inhibitors, detailed tissue analysis has shown reduced damage to collagen, improved remodeling of the extracellular matrix, and improved structure and function of the myocardium and blood vessels. Among these processes, the process of matrix remodeling and MMP-mediated fibrosis are particularly considered to be an important part of the progression of cardiac disease (infarction) (Drugs2001, 61, 1239-1252).
Under physiological conditions, MMPs can break down matrix proteins such as collagen, laminin, proteoglycans, elastin or gelatin, and can also treat (i.e., activate or inactivate) many other proteins and enzymes by breaking down, which means that they play an important role throughout the body, which is particularly important in connective tissue and bone.
A number of different MMP inhibitors are known (EP 0606046; WO 94/28889; WO 96/27583; see also reviews such as Current medical Chemistry8, 425-74(2001), Current medical Chemistry11, 2911-. After the first human clinical studies, it has now been found that MMPs can produce side effects. The side effects mainly mentioned are musculoskeletal pain or joint pain. The prior art shows that more selective inhibitors are desired to reduce these side effects (Yip, p 387, see above). The specificity for MMP-1 should be particularly emphasized in this connection, since the extent to which these adverse side effects occur increases markedly when MMP-1 is inhibited.
Thus, a disadvantage of known MMP inhibitors is that they often lack specificity. Most MMP inhibitors inhibit multiple MMPs simultaneously because the catalytic domains of MMPs have similar structures. Thus, inhibitors also adversely affect enzymes with a life function (Massova I et al, The FASEBjournal (1998)12, 1075-.
Structurally, most matrix metalloproteinase inhibitors can be divided into sulfonamides and sulfones which carry zinc binding groups. Particular preference is given here to linking to carboxylic acid groups, very particular to linking to hydroxamic acid groups. Their properties are described in detail in, for example, the review articles cited above. The sulfonamide group is characterized in that it is generally based on the use of an aminocarboxylic acid or iminocarboxylic acid basic structure as structural basis. The basic structure of bicyclic imino acids is also used, especially in combination with a benzene ring system. In contrast, only relatively few basic heterobicyclic imino acid structures, in particular furan structures, which are oxygen-containing heteroaromatic rings, have been found in the field of MMP inhibitors. These bicyclic furan systems are described, for example, in EP0803505, EP1065209, EP1217002 or WO99/06410, and similar forms are also disclosed in PCT/US 02/26018.
In an effort to find effective compounds for the treatment of connective tissue diseases, it has now been found that the derivatives employed in the present invention are effective inhibitors of matrix metalloproteinases MMP-2, MMP-3, MMP-8, MMP-9 and MMP-13, while having only a relatively small inhibitory effect on MMP-1, inhibition of MMP-1 may be the cause of side effects.
The present invention therefore relates to compounds of the formula I,
and/or all stereoisomeric forms of the compounds of the formula I and/or mixtures of these forms in any ratio, and/or physiologically tolerable salts of the compounds of the formula I, where
R1 is
A-ring1-B-ring2-D-ring3-E-ring4
A is- (C)0-C4) -an alkylene group,
B. d and E are the same or different and are independently- (C)0-C4) An alkylene group or a group-B1-B2-B3-, wherein
B1 is- (CH)2)v-, where v is an integer 0, 1 or 2,
b3 is- (CH)2)w-, where w is an integer 0, 1 or 2,
provided that the sum of v and w is equal to 0, 1 or 2, and
b2 is
1)-C(O)-
2)-(C2-C4) -an alkenylene group,
3)-S(O)x-, where x is an integer 0, 1 or 2,
4) -N (R6) -, wherein R6 is a hydrogen atom, a methyl group or an ethyl group,
5) -N (R6) -C (Y) -, wherein Y is an oxygen atom or a sulfur atom and R6 is as defined above,
6) -C (Y) -N (R6) -, wherein Y is an oxygen atom or a sulfur atom and R6 is as defined above,
7)-N(R6)-SO2-, where R6 is as defined above,
8)-SO2-N (R6) -, wherein R6 is as defined above,
9)-N(R6)-SO2-N (R6) -, wherein R6 is as defined above,
10) -N (R6) -C (Y) -N (R6) -, wherein Y is an oxygen atom or a sulfur atom and R6 is as defined above,
11)-O-C(O)-N(R6)-，
12)-NH-C(O)-O-，
13)-O-，
14)-C(O)-O-，
15)-O-C(O)-，
16)-O-C(O)-O-，
17)-O-CH2-C(O)-，
18)-O-CH2-C(O)-O-，
19)-O-CH2-C (O) -N (R6) -, wherein R6 is as defined above,
20)-C(O)-CH2-O-，
21)-O-C(O)-CH2-O-，
22)-N(R6)-C(O)-CH2-O-, wherein R6 is as defined above,
23)-O-(CH2)s-O-, wherein s is an integer 2 or 3, or
24)-O-(CH2)t-N (R6) -, wherein t is the integer 2 or 3 and R6 is as defined above,
25)-N(R6)-(CH2)u-O-, wherein u is an integer 2 or 3 and R6 is as defined above,
26) -N (R6) -N (R6) -, wherein R6 is as defined above,
27)-N＝N-，
28) -N (R6) -CH ═ N-, wherein R6 is as defined above,
29) -N-CH-N (R6) -, wherein R6 is as defined above,
30) -N (R6) -C (R7) ═ N-, wherein R6 is as defined above and R7 is-NH-R6,
31) -N ═ C (R7) -N (R6) -, wherein R6 is as defined above, and R7 is-NH-R6, or
32)-(C2-C6) -an alkynylene group,
ring 1, ring 2 and ring 3, which are identical or different, independently of one another are
1) A covalent bond is formed between the first and second substrate,
2)-(C6-C14) -an aryl group,wherein aryl is unsubstituted or substituted once, twice or three times, independently of one another, by G, or
3) A 4-to 15-membered Het ring, wherein the Het ring is unsubstituted or substituted once, twice or three times independently of one another by G,
ring 4 is
1)-(C6-C14) Aryl, where aryl is unsubstituted or substituted once, twice or three times, independently of one another, by G,
2) a 4-to 15-membered Het ring, wherein the Het ring is unsubstituted or substituted once, twice or three times independently of one another by G, or
3) Is one of the following radicals, and these radicals are unsubstituted or substituted, independently of one another, once, twice or three times by G,
g is 1) a hydrogen atom,
2) the halogen(s) are selected from the group consisting of,
3)＝O，
4)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or substituted by halogen, - (C)3-C6) -cycloalkyl, - (C)2-C6) -alkynyl, - (C)6-C14) -aryl or Het ring substitution once, twice or three times,
5)-(C6-C14) -an aryl group,
6) the ring (Het) of the ring (Het),
7) -C (O) -O-R10 wherein R10 is
a)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or is- (C)3-C6) -cycloalkyl, - (C)2-C6) -alkynyl, - (C)6-C14) -aryl or Het ring takeThe generation is carried out once or twice,
b)-(C6-C14) -aryl or
c) The ring (Het) of the ring (Het),
8) -C (S) -O-R10, wherein R10 is as defined above,
9) -C (O) -NH-R11, wherein R11 is
a)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or is- (C)3-C6) -cycloalkyl, - (C)2-C6) -alkynyl, - (C)6-C14) Aryl or Het ring substituted once or twice, or
b)-(C6-C14) -aryl or
c) The ring (Het) of the ring (Het),
10) -C (S) -NH-R11, wherein R11 is as defined above,
11) -O-R12 wherein R12 is
a) A hydrogen atom, and a nitrogen atom,
b)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or substituted by halogen, - (C)3-C6) -cycloalkyl, - (C)2-C6) -alkynyl, - (C)6-C14) -aryl or Het ring substitution once, twice or three times,
c)-(C6-C14) -an aryl group,
d) the ring (Het) of the ring (Het),
e) -C (O) -O-R13 wherein R13 is
e)1)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or is- (C)3-C6) -cycloalkyl, - (C)2-C6) -alkynyl, - (C)6-C14) Aryl or Het ring substituted once or twice, or
e)2)-(C6-C14) -aryl or
e)3) a Het ring of the general formula (I),
f) -C (S) -O-R13, wherein R13 is as defined above,
g) -C (O) -NH-R14, wherein R14 is
g)1)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or is- (C)3-C6) -cycloalkyl, - (C)2-C6) -alkynyl, - (C)6-C14) Aryl or Het ring substituted once or twice, or
g)2)-(C6-C14) -aryl or
g)3) Het ring, or
h) -C (S) -NH-R14, wherein R14 is as defined above,
12) -C (O) -R10, wherein R10 is as defined above,
13)-S(O)p-R12, wherein R12 is as defined above and p is an integer 0, 1 or 2,
14)-NO2，
15) -CN, or
16) -N (R15) -R12, wherein R15 is
a) A hydrogen atom, and a nitrogen atom,
b)-(C1-C6) -alkyl, or
c)-SO2-(C1-C6) -alkyl, wherein alkyl is unsubstituted or is- (C)3-C6) -cycloalkyl, - (C)2-C6) -alkynyl, - (C)6-C14) -aryl or Het ring is substituted once or twice, and R12 is as defined above, or
17)-SO2-N (R12) -R16, wherein R12 is as defined above and R16 is as defined below,
x is-OH or-NH-OH,
m is an integer of 0, 1 or 2,
n is an integer 0, 1 or 2, with the proviso that the sum of m and n is equal to 2,
o is an integer of 1 or 2,
y1 and Y2 are the same or different and are each independently
1) A hydrogen atom, and a nitrogen atom,
2) the halogen(s) are selected from the group consisting of,
3)-CN，
4)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or substituted by halogen, - (C)3-C6) -cycloalkyl, - (C)2-C6) -alkynyl, - (C)6-C14) -aryl or Het ring substitution once, twice or three times,
5)-(C6-C14) -an aryl group,
6) the ring (Het) of the ring (Het),
7) -C (O) -O-R10, wherein R10 is as defined above,
8) -C (S) -O-R10, wherein R10 is as defined above,
9) -C (O) -NH-R11, wherein R11 is as defined above,
10) -C (S) -NH-R11, wherein R11 is as defined above,
11) -O-R12, wherein R12 is as defined above,
12) -O-C (O) -R10, wherein R10 is as defined above,
13) -C (O) -R10, wherein R10 is as defined above,
14)-S(O)w-R12, wherein R12 is as defined above and w is an integer 0, 1 or 2,
15) -N (R15) -R12, wherein R15 is as defined above, or
16)-SO2-N (R12) -R16, wherein R12 is as defined above, and
r16 is a) a hydrogen atom,
b)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or is- (C)3-C6) -cycloalkyl, - (C)2-C6) -alkynyl, - (C)6-C14) -aryl or Het ring substitution once or twice,
c) -C (O) -O-R8, wherein R8 has the following meanings,
d) -O-R8, wherein R8 has the following meaning, or
e)-(C3-C6) -cycloalkyl, or
Y1 and Y2 together form
a)＝O，
b)＝S，
c) N-R17 wherein R17 is
c)1)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or is- (C)3-C6) -cycloalkyl, - (C)2-C6) -alkynyl, - (C)6-C14) Aryl or Het ring substituted once or twice, or
c)2)-(C6-C14) -an aryl group,
c)3) a hydrogen atom or
c)4) Het ring, or
d) N-O-R17, wherein R17 is as defined above, or
Y1 and Y2 form- (C) together with the carbon atom to which they are bonded3-C7) Cycloalkyl, wherein cycloalkyl is unsubstituted or substituted by- (C)1-C6) Alkyl, - (C)2-C6) -alkynyl, - (C)3-C6) -cycloalkyl, - (C)6-C14) Aryl or halogen substituted once or twice, or
Y1 and Y2 together with the carbon atom to which they are bonded form part of the structure of the compound of formula I
OrWherein
q and r are each independently of the other an integer 2, 3 or 4, and- (CH)2)q-or- (CH)2)rIs unsubstituted or is- (C)1-C6) Alkyl, - (C)2-C6) -alkynyl, - (C3-C)6) -cycloalkyl, - (C)6-C14) Aryl or halogen substituted once or twice,
r2 is a hydrogen atom, a methyl group or an ethyl group,
r3 and R4 are the same or different and are each independently
1) A hydrogen atom, and a nitrogen atom,
2)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or is- (C)3-C6) -cycloalkyl, - (C)2-C6) -alkynyl, - (C)6-C14) -aryl or Het ring substitution once or twice,
3) -C (O) -O-R8 wherein R8 is
a) A hydrogen atom, and a nitrogen atom,
b)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or is- (C)3-C6) -cycloalkyl, - (C)2-C6) -alkynyl, - (C)6-C14) -aryl or Het ring substituted once or twice or once to five times by fluorine,
c)(C6-C14) -aryl or
d) The ring (Het) of the ring (Het),
4) -O-R8, wherein R8 has the meaning given above,
5)-(C3-C6) -a cycloalkyl group,
6) -a halogen, in the form of a halogen,
7)-NO2，
8) -CN, or
9) R3 and R4 form- (C) together with the carbon atom to which they are bonded6-C14) An aryl ring, wherein the ring is unsubstituted or substituted once or twice by G,
10) r3 and R4 form- (C) together with the carbon atom to which they are bonded5-C7) -a cycloalkyl ring, or
11) R3 and R4, taken together with the carbon atom to which they are bonded, form a 5, 6 or 7 membered Het ring wherein the ring is unsubstituted or substituted once by G.
The invention also relates to compounds of the formula I, in which
A is- (C)0-C4) -an alkylene group,
B. d and E are the same or different and are independently- (C)0-C4) An alkylene group or a group-B1-B2-B3-, wherein
B1 is- (CH)2)v-, where v is an integer 0, 1 or 2,
b3 is- (CH)2)w-, where w is an integer 0, 1 or 2,
provided that the sum of v and w is equal to 0, 1 or 2, and
b2 is
1)-C(O)-
2)-(C2-C4) -an alkenylene group,
3)-S(O)x-, where x is an integer 0, 1 or 2,
4) -N (R6) -, wherein R6 is a hydrogen atom, a methyl group or an ethyl group,
5) -N (R6) -C (Y) -, wherein Y is an oxygen atom or a sulfur atom and R6 is as defined above,
6) -C (Y) -N (R6) -, wherein Y is an oxygen atom or a sulfur atom and R6 is as defined above,
7)-N(R6)-SO2-, where R6 is as defined above,
8)-SO2-N (R6) -, wherein R6 is as defined above,
9)-N(R6)-SO2-N (R6) -, wherein R6 is as defined above,
10) -N (R6) -C (Y) -N (R6) -, wherein Y is an oxygen atom or a sulfur atom and R6 is as defined above,
11)-O-C(O)-N(R6)-，
12)-NH-C(O)-O-，
13)-O-，
14)-C(O)-O-，
15)-O-C(O)-，
16)-O-C(O)-O-，
17)-O-CH2-C(O)-，
18)-O-CH2-C(O)-O-，
19)-O-CH2-C (O) -N (R6) -, wherein R6 is as defined above,
20)-C(O)-CH2-O-，
21)-O-C(O)-CH2-O-，
22)-N(R6)-C(O)-CH2-O-, wherein R6 is as defined above,
23)-O-(CH2)s-O-, wherein s is an integer 2 or 3, or
24)-O-(CH2)t-N (R6) -, wherein t is the integer 2 or 3 and R6 is as defined above,
25)-N(R6)-(CH2)u-O-, wherein u is an integer 2 or 3 and R6 is as defined above,
26) -N (R6) -N (R6) -, wherein R6 is as defined above,
27)-N＝N-，
28) -N (R6) -CH ═ N-, wherein R6 is as defined above,
29) -N-CH-N (R6) -, wherein R6 is as defined above,
30) -N (R6) -C (R7) ═ N-, wherein R6 is as defined above and R7 is-NH-R6,
31) -N ═ C (R7) -N (R6) -, wherein R6 is as defined above, and R7 is-NH-R6, or
32)-(C2-C6) -an alkynylene group,
ring 1, ring 2 and ring 3, which are identical or different, independently of one another are
1) A covalent bond is formed between the first and second substrate,
2)-(C6-C14) Aryl, where aryl is selected from the series phenyl, naphthyl, 1-naphthyl, 2-naphthyl, anthracenyl or fluorenyl, is unsubstituted or substituted once, twice or three times, independently of one another, by G, or
3) A 4-to 15-membered Het ring, wherein Het ring is a group selected from the following series: acridinyl, azaA group, an azetidinyl group, an aziridinyl group, a benzimidazolyl group, a benzofuranyl group, a benzothienyl group, a benzothiophenyl group, a benzoxazolyl group, a benzothiazolyl group, a benzotriazolyl group, a benzotetrazolyl group, a benzisoxazolyl group, a benzisothiazolyl group, a carbazolyl group, a 4 aH-carbazolyl group, a carbolinyl group, a quinazolinyl group, a quinolyl group, a 4H-quinolizinyl group, a quinoxalinyl group, a quinuclidinyl group, a chromanyl group, a chromenyl group, a cinnolinyl group, a decahydroquinolyl group, a dibenzofuranyl group, a dibenzothiophenyl group, a dihydrofuran [2]Tetrahydrofuranyl, dihydrofuranyl, dioxolyl,Dioxacyclohexyl, 2H, 6H-1, 5, 2-dithiazinyl, furyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuryl, isochromanyl, isoindolyl, isoindolinyl, isoindolyl (benzimidazolyl), isothiazolidinyl, 2-isothiazolinyl, isothiazolyl, isoxazolyl, isoxazolidinyl, 2-isoxazolinyl, morpholinyl, naphthyridinyl, octahydroisoquinolyl, oxadiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, oxathiolanyl (oxothiolanyl), phenanthridinyl, furazanyl, imidazolidinyl, imidazolinyl, isoquinolinyl (benzimidazolyl), isothiazolinyl, isothiazolidinyl, indazolyl, isothiazolidinyl, and the like, Phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridothienyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyridinyl, 6H-1, 2, 5-thiadiazinyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, 1, 3, 4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, pyridinolinyl, pyridyl, pyrimidyl, pyrrolidinyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyridoimidazolyl, pyridinonyl, pyridinothiazolyl, thiomorpholinyl, thienyl, triazinyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, 1, 2, 5-triazolyl, 1, 3, 4-triazolyl and xanthenyl, and these radicals are unsubstituted or substituted, independently of one another, once, twice or three times by G,
ring 4 is
1)-(C6-C14) -aryl, wherein aryl is a group selected from the following series: phenyl, naphthyl, 1-naphthyl, 2-naphthyl, anthracenyl and fluorenyl, and these radicals are unsubstituted or substituted, independently of one another, once, twice or three times by G,
2) a 4-to 15-membered Het ring, wherein Het ring is a group selected from the following series:acridinyl, azaA group, an azetidinyl group, an aziridinyl group, a benzimidazolyl group, a benzofuranyl group, a benzothienyl group, a benzothiophenyl group, a benzoxazolyl group, a benzothiazolyl group, a benzotriazolyl group, a benzotetrazolyl group, a benzisoxazolyl group, a benzisothiazolyl group, a carbazolyl group, a 4 aH-carbazolyl group, a carbolinyl group, a quinazolinyl group, a quinolyl group, a 4H-quinolizinyl group, a quinoxalinyl group, a quinuclidinyl group, a chromanyl group, a chromenyl group, a cinnolinyl group, a decahydroquinolyl group, a dibenzofuranyl group, a dibenzothiophenyl group, a dihydrofuran [2]Tetrahydrofuranyl, dihydrofuranyl, dioxolyl, dioxacyclohexyl, 2H, 6H-1, 5, 2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolidinyl, 2-isothiazolinyl, isothiazolyl, isoxazolyl, isoxazolidinyl, 2-isoxazolinyl, morpholinyl, naphthyridinyl, octahydroisoquinolyl, oxadiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, etc, Oxazolidinyl, oxazolyl, oxathiolanyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridothienyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyridinyl, 6H-1, 2, 5-thiadiazinyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, 1, 3, 4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, phenothiazinyl, pyridoxalinyl, pyridothiazolyl, pyridoxalyl, pyrrolinyl, pyrroli, Thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiomorpholinyl, thienyl, triazinyl, 1, 2, 3-triazolyl, 1, 2,4-triazolyl, 1, 2, 5-triazolyl, 1, 3, 4-triazolyl and xanthyl, and these radicals are unsubstituted or substituted, independently of one another, once, twice or three times by G, or
3) Is one of the following radicals, and these radicals are unsubstituted or substituted once by G,
g is 1) a hydrogen atom,
2) the halogen(s) are selected from the group consisting of,
3)＝O，
4)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or substituted by halogen, - (C)3-C6) -cycloalkyl, - (C)2-C6) -alkynyl, - (C)6-C14) -the aryl or Het ring is substituted once, twice or three times, wherein aryl and Het ring are as defined above,
5)-(C6-C14) -aryl, wherein aryl is as defined above,
6) a Het ring, wherein Het ring is as defined above,
7) -C (O) -O-R10 wherein R10 is
a)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or is- (C)3-C6) -cycloalkyl, - (C)2-C6) -alkynyl, - (C)6-C14) -aryl or Het ring is substituted once or twice, wherein aryl and Het ring are as defined above, or
b)-(C6-C14) -an aryl or Het ring, wherein aryl and Het ring are as defined above,
8) -C (S) -O-R10, wherein R10 is as defined above,
9) -C (O) -NH-R11, wherein R11 is
a)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or is- (C)3-C6) -cycloalkyl, - (C)2-C6) -alkynyl, - (C)6-C14) -aryl or Het ring is substituted once or twice, wherein aryl and Het ring are as defined above, or
b)-(C6-C14) -aryl, wherein aryl is as defined above, or
c) Het ring, wherein aryl and Het ring are as defined above,
10) -C (S) -NH-R11, wherein R11 is as defined above,
11) -O-R12 wherein R12 is
a) A hydrogen atom, and a nitrogen atom,
b)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or substituted by halogen, - (C)3-C6) -cycloalkyl, - (C)2-C6) -alkynyl, - (C)6-C14) -the aryl or Het ring is substituted once, twice or three times, wherein aryl and Het ring are as defined above,
c)-(C6-C14) -aryl, wherein aryl is as defined above,
d) a Het ring, wherein Het ring is as defined above,
e) -C (O) -O-R13 wherein R13 is
e)1)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or is- (C)3-C6) -cycloalkyl, - (C)2-C6) -alkynyl, - (C)6-C14) -aryl or Het ring is substituted once or twice, wherein aryl and Het ring are as defined above, or
e)2)-(C6-C14) -an aryl or Het ring, wherein aryl and Het ring are as defined above,
f) -C (S) -O-R13, wherein R13 is as defined above,
g) -C (O) -NH-R14, wherein R14 is
g)1)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or is- (C)3-C6) -cycloalkyl, - (C)2-C6) -alkynyl, - (C)6-C14) -aryl or Het ring is substituted once or twice, wherein aryl and Het ring are as defined above, or
g)2)-(C6-C14) -an aryl or Het ring, wherein aryl and Het ring are as defined above, or
h) -C (S) -NH-R14, wherein R14 is as defined above,
12) -C (O) -R10, wherein R10 is as defined above,
13)-S(O)p-R12, wherein R12 is as defined above and p is an integer 0, 1 or 2,
14)-NO2，
15)-CN，
16) -N (R15) -R12, wherein R12 is as defined above and R15 is
a) A hydrogen atom, and a nitrogen atom,
b)-(C1-C6) -alkyl, or
c)-SO2-(C1-C6) -alkyl, wherein alkyl is unsubstituted or is- (C)3-C6) -cycloalkyl, - (C)2-C6) -alkynyl, - (C)6-C14) -aryl or Het ring is substituted once or twice, wherein aryl and Het ring are as defined above, or
17)-SO2-N (R12) -R16, wherein R12 is as defined above and R16 is as defined below,
x is-OH or-NH-OH,
m is an integer of 0, 1 or 2,
n is an integer 0, 1 or 2, with the proviso that the sum of m and n is equal to 2,
o is an integer of 1 or 2,
partial structure of the Compound of formula IIs selected fromOrThe radicals in the series are, in each case,
wherein
R2 is a hydrogen atom, a methyl group or an ethyl group,
r3 and R4 are the same or different and are each independently
1) A hydrogen atom, and a nitrogen atom,
2)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or is- (C)3-C6) -cycloalkyl, - (C)2-C6) -alkynyl, - (C)6-C14) -aryl or Het ring substituted once or twice, wherein aryl and Het ring are as defined above,
3) -C (O) -O-R8 wherein R8 is
a) A hydrogen atom, and a nitrogen atom,
b)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or is- (C)3-C6) -cycloalkyl, - (C)2-C6) -alkynyl, - (C)6-C14) -aryl or Het ring substituted once or twice, wherein aryl and Het ring are as defined above, or once to five times by fluorine,
c)-(C6-C14) -aryl, wherein aryl is as defined above, or
d) A Het ring, wherein Het ring is as defined above,
4) -O-R8, wherein R8 has the meaning described above.
5)-(C3-C6) -a cycloalkyl group,
6) -a halogen, in the form of a halogen,
7)-NO2，
8) -CN, or
9) R3 and R4, together with the carbon atom to which they are bonded, form a ring of the phenyl, naphthyl, 1-naphthyl, 2-naphthyl, anthracenyl or fluorenyl series, wherein the ring is unsubstituted or substituted once or twice by G, or
10) R3 and R4 together with the carbon atom to which they are bonded form a cyclopentyl, cyclohexyl or cycloheptyl ring, or
11) R3 and R4, together with the carbon atom to which they are bonded, form a 5-membered Het ring of the thiophene, furan, thiazole or oxazole series, which ring is unsubstituted or substituted once by G,
y1 is the same as or different from Y2 and independently of one another,
1) a hydrogen atom, and a nitrogen atom,
2) the halogen(s) are selected from the group consisting of,
3)-CN，
4)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or substituted by halogen, - (C)3-C6) -cycloalkyl, - (C)2-C6) -alkynyl, - (C)6-C14) -aryl or Het ring is substituted once, twice or three times, wherein aryl and Het ring are as defined above,
5)-(C6-C14) -aryl, wherein aryl is as defined above,
6) a Het ring, wherein Het ring is as defined above,
7) -C (O) -O-R10, wherein R10 is as defined above,
8) -C (S) -O-R10, wherein R10 is as defined above,
9) -C (O) -NH-R11, wherein R11 is as defined above,
10) -C (S) -NH-R11, wherein R11 is as defined above,
11) -O-R12, wherein R12 is as defined above,
12) -O- (CO) -R10, wherein R10 is as defined above,
13) -C (O) -R10, wherein R10 is as defined above,
14)-S(O)w-R12, wherein R12 is as defined above and w is an integer 0, 1 or 2,
15) -N (R15) -R12, wherein R15 is as defined above, or
16)-SO2-N (R12) -R16, wherein R12 is as defined above, and
r16 is a) a hydrogen atom,
b)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or is- (C)3-C6) -cycloalkyl, - (C)2-C6) -alkynyl, - (C)6-C14) -aryl or Het ring substituted once or twice, wherein aryl and Het ring are as defined above,
c) -C (O) -O-R8, wherein R8 is as defined above,
d) -O-R8, wherein R8 is as defined above, or
e)-(C3-C6) -cycloalkyl, or
Y1 forms together with Y2
a)＝O，
b)＝S，
c) N-R17 wherein R17 is
c)1)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or is- (C)3-C6) -cycloalkyl, - (C)2-C6) -alkynyl, - (C)6-C14) Aryl or Het ring substituted once or twice, whichWherein the aryl or Het ring is as defined above,
c)2)-(C6-C14) -aryl, wherein aryl is as defined above,
c)3) a hydrogen atom or,
c)4) a Het ring, wherein Het ring is as defined above, or
d) N-O-R17 wherein R17 is as defined above, or
Y1 and Y2 form- (C) together with the carbon atom to which they are bonded3-C7) -cycloalkyl, wherein cycloalkyl is unsubstituted or is- (C)1-C6) Alkyl, - (C)2-C6) -alkynyl, - (C)3-C6) -cycloalkyl, - (C)6-C14) Aryl or halogen substituted once or twice, wherein aryl is as defined above, or
Y1 and Y2 together with the carbon atom to which they are bonded form part of the structure of the compound of formula I
OrWherein q and r are each independently of the other an integer 2, 3 or 4, and the radical- (CH)2)q-or- (CH)2) r-is unsubstituted or substituted by- (C)1-C6) Alkyl, - (C)2-C6) -alkynyl, - (C)3-C6) -cycloalkyl, - (C)6-C14) Aryl or halogen, wherein aryl is as defined above, once or twice.
The invention also relates to compounds of the formula I, in which
A is- (C)0-C4) -an alkylene group,
B. d and E are the same or different and are independently- (C)0-C2) An alkylene group or a group-B1-B2-B3-,
wherein
B1 is- (CH)2)v-, where v is an integer 0, 1 or 2,
b3 is- (CH)2)w-, where w is an integer 0, 1 or 2,
provided that the sum of v and w is equal to 0, 1 or 2, and
b2 is
1) A vinylidene group which is a vinyl group having a linear structure,
2) an ethynylene group, wherein the ethynylene group,
3)-C(O)-
4) -N (R6) -C (O) -, wherein R6 is a hydrogen atom, a methyl group or an ethyl group,
5) -C (O) -N (R6) -, wherein R6 is as defined above,
6) -O-, or
7)-S-，
Ring 1, ring 2 and ring 3, which are identical or different, independently of one another are
1) A covalent bond is formed between the first and second substrate,
2) phenyl or naphthyl, which are unsubstituted or substituted once or twice independently of one another by G, or
3) A Het ring, wherein Het ring is a group selected from the following series: dihydrofuranyl, furanyl, pyridyl, pyrimidyl, pyrrolyl, thiadiazolyl, thiazolyl or thienyl, and which are unsubstituted or substituted, independently of one another, once or twice by G,
with the proviso that at least one of the radicals ring 1, ring 2 or ring 3 is a phenyl, naphthyl or Het ring and ring 4 is
1) Phenyl or naphthyl, unsubstituted or substituted once or twice independently of one another by G,
2) a Het ring, wherein Het ring is a group selected from the following series: benzofuranyl, dihydrofuranyl, dibenzofuranyl, dibenzothienyl, furanyl, morpholinyl, piperazinyl, piperidinyl, pyridinyl, pyrimidinyl, pyridothienyl, pyrrolyl, pyrrolidinyl, thiazolyl or thienyl, and is unsubstituted or substituted, independently of one another, once or twice by G, or
3) And which is unsubstituted or substituted once by G,
g is 1) a hydrogen atom,
2) br, Cl or F, in the presence of a catalyst,
3)-(C1-C4) -alkyl, wherein alkyl is unsubstituted or substituted once or twice by a Br, Cl, F, phenyl, cyclopropyl or Het ring, wherein Het ring is as defined for ring 4 above,
4) a phenyl group,
5) a Het ring, wherein Het ring is as defined for ring 4 above,
6) -C (O) -O-R10 wherein R10 is
a)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or substituted once or twice by a cyclopropyl, phenyl or Het ring, wherein Het ring is as defined for ring 4 above,
b) phenyl, or
c) A Het ring, wherein Het ring is as defined for ring 4 above,
7) -C (O) -NH-R11, wherein R11 is
a)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or substituted once or twice by a cyclopropyl, phenyl or Het ring, wherein Het ring is as defined for ring 4 above,
b) phenyl, or
c) A Het ring, wherein Het ring is as defined for ring 4 above,
8) -O-R12 wherein R12 is
a) A hydrogen atom, and a nitrogen atom,
b)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or substituted one, two or three times by halogen, cyclopropyl, phenyl or a Het ring, wherein Het ring is as defined for ring 4 above,
c) a phenyl group,
d) a Het ring, wherein Het ring is as defined for ring 4 above,
e) -C (O) -O-R13 wherein R13 is
e)1)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or substituted once or twice by a cyclopropyl, phenyl or Het ring, wherein Het ring is as defined for ring 4 above, or
e)2) phenyl or a Het ring, wherein Het ring is as defined for ring 4 above,
f) -C (S) -O-R13, wherein R13 is as defined above, or
g) -C (O) -NH-R14, wherein R14 is
g)1)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or substituted once or twice by phenyl or a Het ring, wherein Het ring is as defined for ring 4 above, or
g)2) phenyl or a Het ring, wherein Het ring is as defined for ring 4 above,
9) -C (O) -R10, wherein R10 is as defined above,
10)-S(O)p-R12, wherein R12 is as defined above and p is the integer 1 or 2,
11)-NO2，
12) -CN or
13) -N (R15) -R12, wherein R15 is
a) A hydrogen atom, or
b)-(C1-C6) -alkyl, and R12 is as defined above,
x is-OH or-NH-OH,
o is an integer of 1 or 2,
r2 is a hydrogen atom or a methyl group,
partial structure of the Compound of formula IIs selected fromOrA group of the series, wherein
R3 and R4 are the same or different and are each independently a hydrogen atom or a methyl group,
y1 is the same as Y2 and is a hydrogen atom, or
Y1 together with Y2 forms ═ O or-O-CH2-CH2-O-。
The invention further relates to compounds of the formula I, in which
A is a covalent bond, or-CH2-CH2-，
B. D and E are identical or different and independently of one another are- (C)0-C2) Alkylene or a group-B1-B2-B3-
Wherein
B1 is- (CH)2)v-, where v is an integer 0, 1 or 2,
b3 is- (CH)2)w-, where w is an integer 0, 1 or 2,
provided that the sum of v and w is 0, 1 or 2, and
b2 is
1)-C(O)-
2) An ethynylene group, wherein the ethynylene group,
3)-S-，
4) -N (R6) -C (O) -, wherein R6 is a hydrogen atom,
5) -C (O) -N (R6) -, wherein R6 is a hydrogen atom, or
6)-O-，
Ring 1, ring 2 or ring 3 are identical or different and, independently of one another, are
1) A covalent bond is formed between the first and second substrate,
2) is phenyl and is unsubstituted or substituted once or twice, independently of one another, by G, or
3) A Het ring, wherein the Het ring is a radical selected from furanyl, pyridinyl, pyrimidinyl or thienyl and is unsubstituted or substituted once or twice independently of one another by G,
with the proviso that at least one of the groups ring 1, ring 2 or ring 3 is phenyl or Het ring and ring 4 is
1) Phenyl and is unsubstituted or substituted once or twice independently of one another by G,
2) het ring, wherein Het ring is a radical from the series benzofuranyl, dibenzofuranyl, furanyl, morpholinyl, piperazinyl, piperidinyl, pyridinyl, pyrimidinyl, pyridothienyl, pyrrolyl, pyrrolidinyl, thiazolyl or thienyl, and is unsubstituted or substituted once or twice independently of one another by G, or
3) The following groups
And this radical is unsubstituted or substituted once by G,
g is 1) a hydrogen atom,
2) br, Cl or F, in the presence of a catalyst,
3)-(C1-C4) -alkyl, wherein alkyl is unsubstituted or substituted once, twice or three times by Br, Cl, F, phenyl, cyclopropyl or Het ring, wherein Het ring is as defined above for ring 4,
4) a phenyl group,
5) a Het ring, wherein Het ring is as defined above for ring 4,
6) -C (O) -O-R10 wherein R10 is
a)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or substituted once or twice by a cyclopropyl, phenyl or Het ring, wherein Het ring is as defined above for ring 4,
b) phenyl, or
c) A Het ring, wherein Het ring is as defined above for ring 4,
7) -C (O) -NH-R11 wherein R11 is
a)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or substituted once or twice by a cyclopropyl, phenyl or Het ring, wherein Het ring is as defined above for ring 4,
b) phenyl, or
c) A Het ring, wherein Het ring is as defined above for ring 4,
8) -O-R12 wherein R12 is
a) A hydrogen atom, and a nitrogen atom,
b)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or substituted once, twice or three times by halogen, cyclopropyl, phenyl or Het ring, wherein Het ring is as defined above for ring 4
c) Phenyl radical
d) A Het ring, wherein Het ring is as defined above for ring 4,
e) -C (O) -O-R13 wherein R13 is
e)1)-(C1-C6) -alkyl, wherein alkyl is unsubstituted or substituted once or twice by a cyclopropyl, phenyl or Het ring, wherein Het ring is as defined above for ring 4, or
e)2) phenyl or a Het ring, wherein Het ring is as defined above for ring 4,
f) -C (S) -O-R13, wherein R13 is as defined above, or
g) -C (O) -NH-R14 wherein R14 is
g)1) - (C1-C6) -alkyl, wherein alkyl is unsubstituted or substituted once or twice by phenyl or a Het ring, wherein Het ring is as defined above for ring 4, or
g)2) phenyl or a Het ring, wherein Het ring is as defined above for ring 4,
9) -C (O) -R10, wherein R10 is as defined above
10)-S(O)p-R12, wherein R12 is as defined above and p is an integer 0, 1 or 2,
11)-NO2，
12) -CN or
13) -N (R15) -R12, wherein R15 is
a) A hydrogen atom or
b)-(C1-C6) -alkyl, and R12 is as defined above,
x is-OH or-NH-OH,
r2 is a hydrogen atom
o is an integer of 1 or 2, and partial structure of the compound of formula IIs a groupWherein
R3 is the same as R4, and is a hydrogen atom, an
Y1 is the same as Y2 and is a hydrogen atom.
The invention further relates to compounds of the formula II, in which
A is a covalent bond, and A is a bond,
B. d and E are identical or different and are, independently of one another, a covalent bond or a group-O-, ring 1, ring 2 or ring 3 are identical or different and are, independently of one another
1) A covalent bond, or
2) Is phenyl and is unsubstituted or substituted once or twice, independently of one another, by G,
with the proviso that at least one of the radicals ring 1, ring 2 or ring 3 is phenyl, ring 4 is phenyl and is unsubstituted or substituted once or twice independently of one another by G,
g is 1) a hydrogen atom,
2) br, Cl or F, in the presence of a catalyst,
3)-(C1-C4) -alkyl, wherein alkyl is unsubstituted or substituted once, twice or three times, independently of one another, by Br, Cl or F,
4) -SO 2-methyl group,
5)-O-(C1-C4) -alkyl, wherein alkyl is unsubstituted or substituted once, twice or three times, independently of one another, by Br, Cl or F, or
6)-CN，
X is-OH or-NH-OH, and
r2, R3, R4, Y1 and Y2 are the same and are a hydrogen atom.
The invention also relates to compounds of formula I selected from the following series:
5- (4' -chlorobiphenyl-4-sulfonyl) octahydrofuro [3, 2-c ] pyridine-4-carboxylic acid,
5- (4' -chlorobiphenyl-4-sulfonyl) octahydrofuro [3, 2-c ] pyridine-4- (N-hydroxy) -carboxamide,
5- [4- (4-fluorophenoxy) benzenesulfonyl ] octahydrofuro [3, 2-c ] pyridine-4-carboxylic acid,
5- [4- (4-fluorophenoxy) benzenesulfonyl ] octahydrofuro [3, 2-c ] pyridine-4- (N-hydroxy) -carboxamide,
5- [4- (4-cyanophenoxy) benzenesulfonyl ] octahydrofuro [3, 2-c ] pyridine-4-carboxylic acid,
5- [4- (4-methanesulfonylphenoxy) benzenesulfonyl ] octahydrofuro [3, 2-c ] pyridine-4-carboxylic acid,
5- (4' -fluorobiphenyl-4-sulfonyl) octahydrofuro [3, 2-c ] pyridine-4- (N-hydroxy) -carboxamide,
5- (4' -trifluoromethylbiphenyl-4-sulfonyl) octahydrofuro [3, 2-c ] pyridine-4- (N-hydroxy) -carboxamide,
5- [4- (4-chlorophenoxy) benzenesulfonyl ] octahydrofuro [3, 2-c ] pyridine-4- (N-hydroxy) -carboxamide,
5- [4- (4-cyanophenoxy) benzenesulfonyl ] octahydrofuro [3, 2-c ] pyridine-4- (N-hydroxy) -carboxamide or 5- [4- (4-methanesulfonylphenoxy) benzenesulfonyl ] octahydrofuro [3, 2-c ] pyridine-4- (N-hydroxy) carboxamide.
Term "(C)1-C6) Alkyl "denotes a hydrocarbon group whose carbon chain is linear or branched and which contains 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, 2, 3-dimethylbutane or neohexyl.
The term "- (C)0-C4) Alkylene "denotes a hydrocarbon radical whose carbon chain is linear or branched and which contains from 1 to 4 carbon atoms, e.g. methyleneEthylene, propylene, isopropylene, isobutylene, butylene or tert-butylene. "-C0-alkylene "is a covalent bond.
The term "- (CH)2)n-, where n is the integer 0, 1 or 2 "represents a covalent bond where n is 0, a methylene group where n is 1, an ethylene group where n is 2. The term "- (CH)2)m-”、“-(CH2)v-”、“-(CH2)w- "represents and- (CH)2)n- "analogous groups.
The term "- (C)2-C4) By alkenylene "is understood a hydrocarbon radical whose carbon chain is linear or branched and which contains from 2 to 4 carbon atoms and which, depending on the chain length, may have one or two double bonds, such as, for example, ethenylene, propenylene, isopropenylene, isobutenylene or butenylene; within the scope of the possibility in principle, the substituents at the double bond can be arranged in the E position or in the Z position.
The term "- (C)2-C6) -alkynylene "denotes a hydrocarbon radical whose carbon chain is straight-chain or branched and which contains 2 to 6 carbon atoms and which may have one or two triple bonds depending on the chain length, for example an ethynylene, propynyl, isopropynyl, isobutynyl, butynyl, pentynyl or pentynyl isomer or an hexynyl or hexynyl isomer.
If more than one of the groups A, B, D, E, ring 1, ring 2 or ring 3 are joined together in each case in covalent bond sequence and in each case only one covalent bond remains, the other covalent bonds are omitted. If, for example, a and ring 1 each represent a covalent bond, one covalent bond can be omitted and only one covalent bond remains. If, for example, B, ring 2, D and ring 3 each represent a covalent bond, 3 covalent bonds can be omitted and only one covalent bond remains.
Term "(C)3-C6) -cycloalkyl "denotes a group of compounds derived, for example, from a 3-to 6-membered monocyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The term "(C5-C7) -cycloalkyl" denotes, for example, a compound which is derived from a 5-7 membered monocyclic ring such as cyclopentyl, cyclohexyl or cycloheptyl.
The term "-S (O) x-, where x is an integer 0, 1 or 2" means that the "-S-" group x equals 0, "-S (O) -then x equals 1, and the" -S (O)2 "group x equals 2. The term "-S (O) p-" or "-S (O) w-" denotes groups similar to "-S (O) x-".
The term "- (C)6-C14) -aryl "represents an aromatic hydrocarbon group having 6 to 14 carbon atoms in the ring. - (C)6-C14) Aryl is, for example, phenyl, naphthyl, such as 1-naphthyl or 2-naphthyl, anthryl or fluorenyl. Naphthyl, especially phenyl, is a preferred aryl group.
The term "4-to 15-membered Het ring" or "Het ring" denotes ring systems having 4 to 15 carbon atoms, which are present as one, two or three ring systems connected to one another and contain one, two, three or four identical or different heteroatoms selected from oxygen, nitrogen or sulfur. Examples of such ring systems are the groups acridinyl, azaA group, an azetidinyl group, an aziridinyl group, a benzimidazolyl group, a benzofuranyl group, a benzothienyl group, a benzothiophenyl group, a benzoxazolyl group, a benzothiazolyl group, a benzotriazolyl group, a benzotetrazolyl group, a benzisoxazolyl group, a benzisothiazolyl group, a carbazolyl group, a 4 aH-carbazolyl group, a carbolinyl group, a quinazolinyl group, a quinolyl group, a 4H-quinolizinyl group, a quinoxalinyl group, a quinuclidinyl group, a chromanyl group, a chromenyl group, a cinnolinyl group, a decahydroquinolyl group, a dibenzofuranyl group, a dibenzothiophenyl group, a dihydrofuran [2]Tetrahydrofuranyl, dihydrofuranyl, dioxolyl, dioxacyclohexyl, 2H, 6H-1, 5, 2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolylAlkyl, 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, oxathiolanyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridothienyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrazolinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridothienyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyridoxalyl, 2H-pyrrolyl, and the like, Pyrrolyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyridinyl, 6H-1, 2, 5-thiadiazinyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, 1, 3, 4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiomorpholinyl, thienyl, triazinyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, 1, 2, 5-triazolyl, 1, 3, 4-triazolyl, and xanthenyl.
Preferred Het rings are benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothienyl, 1, 3-benzodioxolyl, quinazolinyl, quinolyl, quinoxalinyl, chromanyl, cinnolinyl, furanyl such as 2-furanyl and 3-furanyl; imidazolyl, indolyl, indazolyl, isoquinolyl, isochromanyl, isoindolyl, isothiazolyl, isoxazolyl, oxazolyl, phthalazinyl, pteridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridoimidazolyl, pyridopyridyl, pyridopyrimidinyl, pyridyl such as 2-pyridyl, 3-pyridyl or 4-pyridyl; pyrimidinyl, pyrrolyl such as 2-pyrrolyl and 3-pyrrolyl; purinyl, thiazolyl, tetrazolyl or thienyl such as 2-thienyl and 3-thienyl.
The term "R3 and R4 together with the carbon atoms to which they are bonded form a 5, 6 or 7 membered Het ring" denotes a ring system of 5, 6 or 7 carbon atoms containing one, two or three heteroatoms such as oxygen, nitrogen or sulfur which may be the same or different, e.g. azepane, 1, 4-diazepane, dioxazole, dioxazine, dioxole, 1, 3-dioxolene, 1, 3-dioxolane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isoxazole, isoxazoline, isoxazolidine, 2-isoxazoline, morpholine, 1, 2-oxathiolane, 1, 4-oxazepane, 1, 2-oxazine, 1, 3-oxazine, 1, 4-oxazine, oxazole, oxepane, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyrazine, etc, Pyrazinone, pyridazine, hydroxypyridazine, pyridine, pyridone, pyrimidine, pyrimidinone, pyrrole, pyrrolidine, pyrrolidone, pyrroline, tetrahydrofuran, tetrahydropyran, tetrahydropyridine, thiadiazine, thiadiazole, 1, 4-thiazepane, 1, 2-thiazine, 1, 3-thiazine, 1, 4-thiazine, 1, 3-thiazole, thiazolidine, thiazoline, thiepane, thiomorpholine, thiophene, thiopyran, 1, 2, 3-triazine, 1, 2, 4-triazine, 1, 3, 5-triazine, 1, 2, 3-triazole or 1, 2, 4-triazole.
The term "halogen" denotes fluorine, chlorine, bromine or iodine.
The following is the structural formula of the compound of formula I:
the invention also relates to a method for producing a compound of the formula I and/or a stereoisomeric form of a compound of the formula I and/or a physiologically tolerable salt of a compound of the formula I, which method comprises
a) A compound of formula IV
Wherein Re is a hydrogen atom or an ester protecting group, the groups Y1, Y2, R3, R4 and o are as defined for the compounds of formula IPart of structure ofIs an unsaturated ring having 5 ring atoms, in which one of the ring atoms Z1, Z2 or Z3 is an oxygen atom and the other two ring atoms are carbon atoms and are each independently substituted by R3 or R4, and is converted by hydrogenation under the appropriate conditions into the compound of the formula V
In the partial structure of the compounds of the formula IIn (B) is a saturated ring having 5 ring atoms, in which one of the ring atoms Z1, Z2 or Z3 is an oxygen atom and the other two ring atoms are carbon atoms, which may be substituted independently of one another by R3 or R4, and the radicals Y1, Y2, R3, R4 and o are as defined for the compounds of the formula IV,
b) then reacting the compound of formula V with the compound of formula VI
Wherein A, B, D, E and Ring 1, Ring 2, Ring 3, Ring 4 are as defined in formula I, wherein Rz is a chlorine atom, a bromine atom, an imidazolyl group or OH,
in the presence of a base, or after silylation with a suitable silylating agent, or with a suitable dehydrating agent in the presence of Rz ═ OH to give compounds of the formula VII
Wherein A, B, D, E, Re and ring 1, ring 2, ring 3 and ring 4 are as defined above, and b) in the case of the Re ═ ester group, the compounds of the formula VII are prepared by a) reaction with an alkali metal hydroxide solution, for example NaOH or LiOH, followed by treatment with acid to give the carboxylic acids of the formula I according to the invention, where X is OH, with a modification in one of the side chains of ring 1 to ring 4, which have been treated appropriately beforehand, or by conversion of the esters into the free carboxylic acids of the formula VIII by treatment with a mineral acid, for example hydrochloric acid
Or the compounds of the formula VIII in which X is NH-OH, c) are prepared by process a) or the appropriate precursors of the formula I, which, owing to their chemical structure, are present in enantiomeric form, are resolved into the pure enantiomers by salt formation with an enantiomerically pure acid or base, are derivatized with chromatographic methods using a chiral stationary phase or with a chiral, enantiomerically pure compound, for example an amino acid, in such a way that separation of the diastereomers is obtained and the chiral auxiliary groups are eliminated, or
d) The compounds of the formula I are prepared by processes b) or c), isolated in free form or, in the presence of acidic or basic groups, converted into physiologically tolerated salts.
Compounds of the type of formulae IV to VIII represent bicyclic compounds containing a functionalized ring having six or seven ring atoms. The second ring is an unsaturated furan (formula IV) or a saturated heterocyclic tetrahydrofuran system in which the oxygen atom may be in any of three possible positions according to formula I. Both rings may also be substituted according to formula I.
The compounds of the type of formula IV can be prepared by known methods. For example, when o ═ 1, the compounds are prepared from the corresponding furan derivatives by known methods. The preparation of these compounds is known to the person skilled in the art and can be carried out in different ways. The synthesis of furans is described, for example, in Sciences of Synthesis9, 183-285 (2002). Useful methods for preparing bicyclic starting compounds start, for example, from 2-aminoethyl-or 3-aminopropyl- (2-or 3-furyl) derivatives. Cyclization takes place in a Pictet-Spengler reaction with glyoxylic acid or an ester thereof under acidic conditions. This reaction is also described, for example, in J.Med.chem.37, 2138-2144 (1994). However, other methods for constructing similar furan systems that can yield the tetrahydrofurans of the invention may also be used. The skilled person will select the appropriate synthetic method depending on the particular substituents or ring size. The furan synthesis is followed by conversion to tetrahydrofuran. This usually requires catalytic hydrogenation. A number of methods are described in the literature. It is necessary to select appropriate conditions depending on the reactivity of the basic structure, any functional groups or substituents present, and the degree of chiral compounds produced by using chiral auxiliary means with the catalyst. Thus, the following catalysts and reagents are frequently described for hydrogenation, but only one reference is mentioned as an example in each case: h2, Pd/C (e.g. in Arch. pharm.336, 381-4(2003) or Synthesis2004, PP.2069-2077), and also the use of ammonium formate as transfer hydrogenation: heterocycles35, 737-754(1993)), sodium in liquid ammonia (e.g. j. Heterocycles chem.37, 751-55 (2000)); raney nickel (Synth. Commun.25, 2895-2900(1995)) or nickel with a supporting material (J.mol. Catal.57, 397 (1990); J.heterocyclic. chem.3, 101 (1966)); rhodium with support material (j. org. chem.37, 4260 (1972)); PdO (org. synth.1943, II, 566)); LiAlH4(J.chem.Soc.1957, p.1788) can likewise be used. It has also been found that the chiral selective homogeneous hydrogenation with specific Rh catalysts (Monatsh. chem.131, 1335-1343(2000), or chiral differential hydrogenation using specifically modified Raney nickel (chem. Lett.1999, pp.1055-56.) Furan derivatives still having substituents Y1 and Y2 can also be obtained by other methods.A similar synthesis of compounds where, for example, Y1 and Y2 are equal to C ═ O is also described in WO 2002/100860. such compounds represent important starting materials and can be converted into compounds having other substituents Y1 and Y2 by many methods known to the person skilled in the art.
＊＊＊Part B ends
The synthesis of tetrahydrofuran has been described previously and is well known to those skilled in the art. It is also possible to prepare the compounds of the invention by selecting appropriate starting materials and substituents without using furan as an intermediate. Novel synthetic methods can be found, for example, in Progress in Heterocyclic Chemistry14, 139(2002) or Progress in Heterocyclic Chemistry7, 130 (1995).
A group used as an ester protecting group in "protecting group in organic synthesis" (t.h. greene, p.g. m.wuts, Wiley-Interscience, 1999) can be used as the ester protecting group Re. Examples of preferred ester protecting groups are methyl, ethyl, isopropyl, tert-butyl or benzyl.
Under certain conditions it is desirable to use compounds of formula IV in an N-protected state. For example, it is easier to purify a compound protected in this way than to purify the free imino acid; likewise, these protected compounds can sometimes be more readily used to prepare enantiomerically or diastereomerically pure compounds. The group described in "protecting group in organic synthesis" (T.H.Greene, P.G.M.Wuts, Wiley-Interscience, 1999) can be used as a protecting group for amino group. Preferred examples of amino-or imino-protecting groups are Z, Boc, Fmoc, Aloc, acetyl, trifluoroacetyl, benzoyl, benzyl and similar protecting groups.
The starting compounds and reagents used may be prepared by known methods or purchased commercially.
The reaction is carried out, for example, as described in WO 97/18194. The reaction described in process step a) takes place in the presence of a base such as KOH, NaOH, LiOH, N-methylmorpholine (NMM), N-ethylmorpholine (NEM), Triethylamine (TEA), Diisopropylethylamine (DIPEA), pyridine, collidine, imidazole or sodium carbonate in a solvent such as Tetrahydrofuran (THF), Dimethylformamide (DMF), dimethylacetamide, dioxane, acetonitrile, toluene, chloroform or dichloromethane or in the presence of water. If the reaction is carried out using a silylating agent, the imino acid is silylated, for example, with N, O-bis (trimethylsilyl) acetamide (BSA) or N, O-bis (trimethylsilyl) trifluoroacetamide (BSTFA) for subsequent formation of the sulfonamide.
In process step c), when the compounds of the formula I occur as diastereomers or mixtures of enantiomers or are produced as mixtures thereof in the selected synthesis, the compounds of the formula I are isolated as pure stereoisomers by chromatography on optionally chiral carrier materials or, if the racemic compounds of the formula I are capable of forming salts, by formation of diastereomeric salts with optically active bases or acids which can be used as excipients and fractional crystallization. Examples of chiral stationary phases suitable for separating enantiomers by thin layer chromatography or column chromatography are modified silica gel supports (known as Pirkle phase) and high molecular weight carbohydrates such as triacetyl cellulose. For analytical purposes, it is also possible to use chiral stationary phase gas chromatography after appropriate derivatization, known to the skilled person. For the resolution of racemic carboxylic acids into their enantiomers, optically active bases which are generally commercially available, such as (-) -nicotine, (+) -and (-) -phenethylamine, quinine, L-lysine or L-and D-arginine, can be used to form diastereomeric salts of different solubilities, the less soluble components being separated as solids, the more soluble diastereomers being removed from the mother liquor, and the pure enantiomers being obtained from the diastereomeric salts thus separated. Likewise, compounds of the formula I containing a basic group such as amino can 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. It is also possible to convert chiral compounds containing alcohol or amino functions into the corresponding esters or amides, or vice versa, using suitably activated and, where appropriate, N-protected, enantiomerically pure amino acids; it is also possible to convert chiral carboxylic acids into amides using carboxy-protected, enantiomerically pure amino acids; alternatively, it is also possible to convert enantiomerically pure hydroxycarboxylic acids, such as lactic acid, into the corresponding chiral esters. The chirality of amino acid groups or alcohol groups which have been introduced in enantiomerically pure form can then be exploited to separate the now-present diastereomers by crystallization or chromatography on a suitable stationary phase, thereby separating the isomers, and then the resulting chiral molecular moiety can be removed again using suitable methods.
Furthermore, for some compounds of the invention, it is possible to use diastereomerically or enantiomerically pure starting compounds to prepare the backbone structure. This makes it possible to purify the end product, where appropriate, also using other methods or simplified methods. These initial compounds are prepared beforehand in enantiomerically pure form or in diastereomerically pure form by methods known from the literature. For example, as mentioned and referenced above, it is possible to use 4, 5, 6, 7-tetrahydrofuran [3, 2-c ] pyridine-4-carboxylic acid directly in the process for preparing octahydrofuran [3, 2-c ] pyridine-4-carboxylic acid. Due to the presence of 3 chiral centers, in this case a maximum of 8 stereoisomers (4 enantiomeric diastereomers) may be formed. However, the properties of the preparation, such as hydrogenation, are significantly favoured for certain stereoisomers. Thus, as described in the literature, it should be possible to attach hydrogen with a significant preference at the position of the ring attachment, for example by suitably selecting the hydrogenation conditions (catalyst, pressure, solvent and temperature). Therefore, a cis-form connecting ring may be formed under a predetermined condition. Thus, only the problem of determining the position of the carboxylic acid will remain, since the number of possible stereoisomers has been defined as 4. Due to the nature of the hydrogenation mechanism, it is particularly easy to attach hydrogen on one side of the bridgehead hydrogen, i.e. thereby one may expect to further limit the possibility of isomer formation. Thus, at best, it is assumed that the formation of only one pair of enantiomers will be possible. It should therefore be possible to resolve the pair of enantiomers into enantiomers using the methods described above. However, in relation to these considerations, it must also be assumed that complete stereoselection never occurs, but that, in fact, other isomers will always form or be detected in different proportions, even in very small amounts, when appropriate methods are used.
When using enantiomerically pure derivatives of tetrahydrofuran [3, 2-c ] pyridine-4-carboxylic acid, it would be desirable that only the preferred stereoisomer is formed again; in such a case, it should be significantly preferred to have only one single enantiomer, since when the hydrogenation process is carried out under conditions similar to those which produce cis-ring linkages, the H atom may be attached again from only one side, with the result that a similar product will be formed. Identification of the structure can be established by appropriate 2D NMR experiments, X-ray methods such as co-crystallization and the like, as well as reference analysis or chemical derivation methods and appropriate analysis or chemical derivation methods that yield known and said isomers.
Another possibility for the synthesis of enantiomerically or diastereomerically pure compounds is to use starting compounds which are suitably chirally substituted to introduce chirality at other chiral centers via chiral substituents. For example, as already mentioned above, chiral glyoxylic esters can be used for the Pictet-Spengler cyclization to obtain chiral furan derivatives and subsequent hydrogenation of these derivatives.
The acidic or basic products of the compounds of formula I may be present in the form of their salts or in free form. Preference is given to pharmacologically tolerable salts, such as alkali metal or alkaline earth metal salts, or hydrochlorides, hydrobromides, sulfates, hemisulfates and all possible phosphates, as well as amino acid salts, natural base salts or carboxylates.
Physiologically tolerable salts are prepared in a manner known per se, according to process step d), from the compounds of the formula I which are capable of salt formation, including the stereoisomeric forms thereof. The compounds of formula I can form stable alkali metal, alkaline earth metal or optionally substituted ammonium salts with basic agents such as hydroxides, carbonates, bicarbonates or alkoxides and ammonia or organic bases such as trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine or tromethamine or other basic amino acids such as lysine, ornithine or arginine. If the compounds of the formula I have basic groups, it is also possible to use strong acids for the preparation of stable acid addition salts. Both inorganic and organic acids are suitable for this purpose, for example hydrochloric acid, hydrobromic acid, sulfuric acid, hemisulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 4-bromobenzenesulfonic acid, cyclohexylsulfamic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, acetic acid, oxalic acid, tartaric acid, succinic acid, phosphoglyceric acid, lactic acid, malic acid, adipic acid, citric acid, fumaric acid, maleic acid, gluconic acid, glucuronic acid, palmitic acid or trifluoroacetic acid.
The invention also relates to a medicament having the following characteristics: an effective amount of at least one compound of the formula I and/or a physiologically tolerable salt of the compound of the formula I and/or optionally stereoisomeric forms of the compound of the formula I, and suitable pharmaceutically and physiologically tolerable carriers, additives and/or other active compounds and excipients.
Due to their pharmacological profile, the compounds of the invention are suitable for the selective prevention and treatment of all diseases whose processes involve an increase in the activity of metalloproteinases. These include degenerative joint diseases such as osteoarthropathy, spondylosis and chondrolysis after joint trauma or after relatively long periods of joint fixation after meniscus or patella damage or torn ligaments. They also include connective tissue diseases such as collagenous diseases, periodontal diseases, wound healing disorders and chronic diseases of the motor system such as inflammation, immune-or metabolic-related acute and chronic arthritis, arthrosis, myalgia and bone metabolism disorders. The compounds of formula I are also suitable for the treatment of ulcers, atherosclerosis and stenosis. In addition, the compounds of formula I are also suitable for the treatment of inflammation, cancer, tumor metastasis, cachexia, anorexia, heart failure and septic shock. The compounds are also suitable for the prevention of myocardial and cerebral infarctions.
The medicaments of the invention can be administered orally, by inhalation, rectally or transdermally or by subcutaneous, intra-articular, intraperitoneal or intravenous injection. Oral administration is preferred.
The invention also relates to a process for the preparation of a medicament, which comprises bringing at least one compound of the formula I together with pharmaceutically and physiologically tolerable excipients and, where appropriate, further suitable active compounds, additives or excipients into suitable dosage forms.
Examples of suitable solid or pharmaceutical preparations are granules, powders, sugar-coated tablets, (micro) capsules, suppositories, syrups, oral solutions, suspensions, emulsions, drops or injections, and preparations which bring about a sustained release of the active compound, which preparations can be prepared using customary excipients, such as carriers, disintegrants, binders, coatings, swelling agents, glidants, lubricants, flavoring agents, sweeteners and solubilizers. As usual excipients there may be mentioned 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 mono-or polyhydric alcohols such as glycerol.
Pharmaceutical preparations are preferably prepared and administered in dosage units, each unit containing as active ingredient a defined dose of a compound of formula I according to the invention. For solid dosage units such as tablets, capsules, sugar-coated tablets or suppositories, the dosage may be up to about 1000mg, but preferably from about 50 to 300mg, and for injections in the form of ampoules, up to about 300mg, but preferably from about 10 to 100 mg.
A daily dose of about 2mg to 1000mg, preferably 50mg to 500mg, of active compound is indicated for the treatment of adult patients weighing about 70kg, depending on the activity of the compound of formula I. However, higher or lower daily doses may sometimes be appropriate. The daily dose may be administered by administration only once in the form of a single dose unit or several smaller dose units or by administering divided doses multiple times at specified intervals.
The final product is usually determined by mass spectrometry (FAB-, ESI-MS) and1H-NMR (500MHz in DMSO-D6); the main peak or two main peaks are given individually. Temperatures are given in degrees Celsius and RT denotes room temperature (21 ℃ to 24 ℃). The abbreviations used are explained or are in accordance with common practice.
The present invention is illustrated in more detail below by way of examples.
General procedure 1: preparation of sulfonamides from sulfonyl chlorides and carboxylic acids
The carboxylic acid (6.45mmol) was dissolved in 20ml Dimethylformamide (DMF) and 3 equivalents of 3N NaOH solution (6.45ml) were added at 0 ℃. After 10 minutes, a solution of arylsulfonyl chloride (1.1 eq, 7.1mmol) in 10 to 15ml of DMF was slowly added dropwise; after reaching Room Temperature (RT), the mixture was stirred further at a temperature between 20 ℃ and 80 ℃ for a maximum of 12 hours (h). The exact time depends on when the transition is complete, which can be determined by mass spectrometry. Then, the solvent was removed under reduced pressure. Aqueous work-up is subsequently carried out (by shaking with 1N HCl and saturated NaCl solution, drying of the organic phase, for example ethyl acetate, dichloromethane or chloroform, over magnesium sulfate or sodium sulfate and then concentration). The crude product is directly subjected to further reaction or purified by chromatography.
General procedure 2: preparation of sulfonamides from sulfonyl chlorides and carboxylic acids
The carboxylic acid is dissolved in 0.5 to 2 mol of NaOH, if appropriate in the additional presence of 10 to 50% of Tetrahydrofuran (THF) or DMF. The acid chloride (1-1.2 equivalents, preferably 1.1) is dissolved in THF (concentration 0.05 to 1M) and the solution is slowly added dropwise. 2N NaOH was added automatically at room temperature using an autotitrator to maintain a constant pH. The set pH was: 8 to 12, preferably 9 to 11. After the reaction was complete (which can be determined by no more consumption of NaOH), the organic co-solvent was removed on a rotary evaporator, the aqueous solution or suspension was mixed with ethyl acetate and acidified with 1N HCl. After separating the organic phase and re-extracting the aqueous phase with ethyl acetate, the organic phases are combined and dried over sodium sulfate. The solvent was then removed under reduced pressure. The crude product is directly subjected to further reaction or purified by chromatography.
General procedure 3: preparation of sulfonamides from sulfonyl chlorides and carboxylic acids
This method is particularly useful for the reaction of biphenyl ethanesulfonyl chloride with a carbamic acid (see examples 6 and 7) or similarly more hydrolyzable sulfonyl chlorides.
8mmol of the imino acid are dissolved or suspended in 30ml of acetonitrile. At room temperature under an inert gas (N)2) 2.3g (9mmol) of BSTFA (bis (trimethylsilyl) trifluoroacetamide) were added and the mixture was heated at reflux for 2 h. To this solution was added 2.84g (9mmol) of 4-chlorobiphenylethanesulfonyl chloride dissolved in 30ml of acetonitrile, and the whole was heated under reflux conditions for 3 hours again. After the reaction mixture was cooled, 1N was addedAqueous HCl and the mixture was stirred for 1 hour; then removing the solvent on a rotary evaporator under reduced pressure, and then adding ethyl acetate or chloroform; the organic phase is then separated, extracted with saturated NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. The reaction product may be subjected directly to further reaction or it may be necessary to subject it to prior chromatography on silica gel, depending on the purity of the reaction product.
General procedure 4: preparation of hydroxamic acids from carboxylic acids via chloroformate activation
The sulfonated carboxylic acid was dissolved in 10ml of DMF, and then 1.1 equivalents of ethyl chloroformate and 2.2 equivalents of N-ethylmorpholine were added at 0 ℃ and after preactivation for 30 minutes to 1 hour, 3 equivalents of trimethylsilylhydroxylamine were added. After heating the mixture at 80 ℃ for at least 4 hours, the solvent is removed under reduced pressure and the crude product is purified by chromatography.
General procedure 5: preparation of hydroxamic acids by means of the corresponding phosgene
The sulfonated carboxylic acid was first added to anhydrous chloroform (no ethanol) (about 5ml per 0.5 mmol) and 3 equivalents of oxalyl chloride were added at room temperature. The mixture was then heated at 45 ℃ for about 30 minutes. To monitor the formation of chloride, a small sample was taken from the reaction flask and mixed with a small amount of benzylamine in THF. It is possible to determine when the reaction is complete by quantitative formation of benzylamide and the carboxylic acid is no longer detectable (monitored by HPLC-MS). Heating for a longer time or under reflux conditions may be necessary. Then, the solvent was distilled off under reduced pressure, and then the residue was dissolved in anhydrous toluene, and evaporation was performed in a rotary evaporator, and the operation was repeated several times. The acid chloride was redissolved in chloroform (10 ml per 0.5 mmol) and the mixture was added to 3 equivalents of O-trimethylsilylhydroxylamine at room temperature. After at least 30 minutes of reaction (monitoring the reaction by HPLC-MS), the reaction mixture was evaporated under reduced pressure and the residue was directly purified by chromatography.
Detailed description of the invention
Example 1: octahydrofuro [3, 2-c ] pyridine-4-carboxylic acid
2.5g of the appropriate furan derivative 4, 5, 6, 7-tetrahydrofuro [3, 2-c ] pyridine-4-carboxylic acid (167.16; 14.96mmol) are dissolved in 45ml of methanol and the hydrogenation is carried out for 38 hours at room temperature with 0.5g of rhodium on alumina and 5 bar. After checking the reaction, the catalyst was removed by filtration and washed with acetonitrile, 15ml of 1M HCI was added to the remaining yellow solution, and concentrated under reduced pressure. The aqueous residue was frozen and freeze dried.
Yield: 1.51g (53% of theory)
Example 2: n- (4-chlorobiphenyl sulfonyl) -4, 5, 6, 7-tetrahydrofuro [3, 2-c ] pyridine-4-carboxylic acid
The imino acid 4, 5, 6, 7-tetrahydrofuro [3, 2-c ] pyridine-4-carboxylic acid (250mg, 1.5mmol) prepared by the method described in the above-mentioned document was dissolved or suspended in 15ml of acetonitrile, and heated together with N, O-bis- (trimethylsilyl) acetamide (671mg, 0.82ml, 3.3mmol) under reflux for 45 minutes. After cooling 4-chlorobiphenyl sulfonyl chloride (473.8ml, 1.65mmol, 1.1eq.) dissolved in 5ml acetonitrile was added. After refluxing for another 1 hour, the reaction mixture was concentrated under reduced pressure, then dissolved in ethyl acetate and extracted with dilute hydrochloric acid or saturated sodium chloride solution. The combined organic phases were dried over sodium sulfate. The oily residue is obtained after the solvent is removed, the oily residue is changed into a solid after the oil pump is dried in vacuum, and the purity can ensure the subsequent reaction.
Yield: 455mg g (73% of theory). Analyzing data: see table 1.
Example 3: n- (4-chlorobiphenyl sulfonyl) -4, 5, 6, 7-tetrahydrofuro [3, 2-c ] pyridine-4-N-hydroxyformamide
The carboxylic acid (430mg, 1.03mmol) obtained in example 2 was dissolved in 20ml of chloroform, oxalyl chloride (2.176g, 17.14mmol, 1.501ml) was added dropwise over 10 minutes, and the resulting reaction mixture was heated at 45 ℃ for 1 hour. After that time, a small amount of the reaction mixture (0.1ml) was taken out and mixed with 0.05ml of benzylamine, and the progress of the reaction was checked by HPLC-MS. The solvent was distilled off under reduced pressure, and the resulting oily residue was washed with toluene to remove oxalyl chloride or HCl as much as possible, and left under reduced pressure for 15 minutes. Then dissolved in 15ml of chloroform again at room temperature and O- (trimethylsilyl) hydroxylamine (325.1mg, 3.09mmol, 0.378ml) was added. After two hours, the solvent was removed under reduced pressure and the residue was dissolved in a small amount of acetonitrile-water-0.01% trifluoroacetic acid mixture and injected directly into preparative RP-HPLC. The product fractions were combined, acetonitrile was removed under reduced pressure and the remaining aqueous phase was freeze dried.
Yield: 20mg (7% of theory, while obtaining 110mg of impure fraction), analytical data:
see table 1.
The following examples were prepared analogously to the general methods or the specific methods described above. Table 1 shows the results.
TABLE 1
Pharmacological examples
Determination of enzymatic Activity of the catalytic Domain of human collagenase-1 (MMP-1)
The protein was obtained as an inactive zymogen from Biocol, Potsdam (catalog number MMP 1). The activation of the proenzyme is as follows: 2 volumes of zymogen and 1 volume of APMA solution were incubated at 37 ℃ for 1 hour. APMA solution was prepared from a 10mmol/l solution of mercury p-aminophenylacetate in 0.1mmol/l NaOH by diluting it with 3 volumes of tris/HCl buffer pH7.5 (see below). The pH was adjusted to between 7.0 and 7.5 by addition of 1mmol/l HCl. After the enzyme was activated, it was diluted with tris/HCl buffer to a concentration of 2.5. mu.g/ml.
To determine the enzyme activity, 10. mu.l of the enzyme solution was incubated with 10. mu.l of 3% (v/v) dimethyl sulfoxide buffer solution for 15 minutes (reaction 1). To determine the activity of the enzyme inhibitor, 10. mu.l of the enzyme solution was incubated with 10. mu.l of 3% (v/v) dimethyl sulfoxide buffer solution containing the enzyme inhibitor (reaction 2).
For both reaction 1 and reaction 2, the enzyme reaction was monitored by fluorescence spectroscopy (328nm (extinction)/393 nm) after addition of 10. mu.l of a 3% (v/v) aqueous solution of dimethyl sulfoxide containing 0.3mmol of substrate per l. Enzyme activity is expressed as disappearance per minute increment.
Inhibition was calculated as percent inhibition using the formula: % inhibition was 100- [ (increase of disappearance/min in reaction 2)/(increase of disappearance/min in reaction 1) × 100 ].
IC50I.e., the concentration of inhibitor required to inhibit 50% of the enzyme activity, can be determined graphically by plotting the percent inhibition for different inhibitor concentrations.
The buffer solution contained 0.05% benzyl (Sigma, Deisenhofen, Germany) and 0.1mol of Tris/HCl/l, 0.1mol of NaCl/l, 0.01mol of CaCl2/l (pH 7.5).
The enzyme solution contained 2.5. mu.g/ml of enzyme domain.
The substrate solution contained 0.3mmol of the fluorogenic substrate (7-methoxycoumarin-4-yl) acetyl
-Pro-Leu-Gly-Leu-3- (2 ', 4' -dinitrophenyl) -L-2, 3-diaminopropionyl
-Ala-Arg-NH2L (Bachem, Heidelberg, Germany).
Preparation and determination of enzymatic Activity of the catalytic domains of human stromelysin (MMP-3) and neutrophilic collagenase (MMP-8)
Two enzymes, stromelysin (MMP-3) and neutrophil collagenase (MMP-8), were prepared as described by Ye et al (Biochemistry; 31(1992) pp. 11231-11235). To determine the enzymatic activity or the effect of the enzyme inhibitor, 10. mu.l of the enzyme solution are incubated for 15 minutes with 10. mu.l of 3% (v/v) dimethyl sulfoxide buffer, which if appropriate contains the enzyme inhibitor. After addition of 10. mu.l of a 3% (v/v) aqueous dimethyl sulfoxide solution containing 1mmol of the substrate per l, the enzyme reaction was monitored by fluorescence spectroscopy (328nm (ex)/393nm (em)).
Enzyme activity is expressed as disappearance per minute increment. IC listed in Table 250Values were determined as inhibitory concentrations each causing 50% inhibition of the enzyme.
The buffer solution contained 0.05% of benzyl (Sigma, Deisenhofen, Germany) and 0.1mol/ltris/HCl/l, 0.1mol of NaCl/l, 0.01mol of CaCl20.1mol of piperazine-N, N' -bis [ 2-ethanesulfonic acid]/l(pH＝7.5)。
MMP-3 enzyme solution contained 2.3. mu.g of one of the enzyme domains prepared according to the method described in Ye et al/ml, and MMP-8 enzyme solution contained 0.6. mu.g/ml. The substrate solution contained 1mmol of the fluorogenic substrate (7-methoxycoumarin-4-yl) acetyl-Pro-Leu-Gly-Leu-3- (2 ', 4' -dinitrophenyl) -L-2, 3-diaminopropionyl-Ala-Arg-NH2L (Bachem, Heidelberg, Germany).
Determination of enzymatic Activity of the catalytic Domain of human collagenase-3 (MMP-13)
The protein was obtained as an inactive zymogen from INVITEK, Berlin (Cat. No. 30100803). The activation of the proenzyme is as follows: 2 volumes of zymogen and 1 volume of APMA solution were incubated at 37 ℃ for 1.5 hours. APMA solution was prepared from a 10mmol/l solution of mercury p-aminophenylacetate in 0.1mmol/l NaOH by diluting it with 3 volumes of tris/HCl buffer pH7.5 (see below). The pH was adjusted to between 7.0 and 7.5 by addition of 1mmol/l HCl. After the enzyme was activated, it was diluted to a concentration of 1.67. mu.g/ml with tris/HCl buffer.
To determine the enzyme activity, 10. mu.l of the enzyme solution was incubated with 10. mu.l of 3% (v/v) dimethyl sulfoxide buffer solution for 15 minutes (reaction 1). To determine the activity of the enzyme inhibitor, 10. mu.l of the enzyme solution was incubated with 10. mu.l of 3% (v/v) dimethyl sulfoxide buffer solution containing the enzyme inhibitor (reaction 2).
For both reaction 1 and reaction 2, the enzyme reaction was monitored by fluorescence spectroscopy (328nm (disappearance)/393 nm (emission)) after addition of 10. mu.l of a 3% (v/v) aqueous solution of dimethyl sulfoxide containing 0.075mmol of substrate per l.
Enzyme activity is expressed as disappearance per minute increment. The effect of the inhibitor was calculated as percent inhibition according to the following formula:
% inhibition was 100- [ (increase of disappearance/min in reaction 2)/(increase of disappearance/min in reaction 1) × 100 ].
IC50I.e., the concentration of inhibitor required to inhibit 50% of the enzyme activity, can be determined graphically by plotting the percent inhibition for different inhibitor concentrations.
The buffer solution contained 0.05% benzyl (Sigma, Deisenhofen, Germany) and 0.1mol of Tris/HCl/l, 0.1mol of NaCl/l, 0.01mol of CaCl2(pH 7.5). The enzyme solution contained 1.67. mu.g enzyme domain/ml. The substrate solution contained 0.075mmol of fluorogenic substrate (7-methoxycoumarin-4-yl) acetyl-Pro-Leu-Gly-Leu-3- (2 ', 4' -dinitrophenyl) -L-2, 3-diaminopropionyl-Ala-Arg-NH2L (Bachem, Heidelberg, Germany).
Determination of enzymatic Activity of the catalytic Domain of human gelatinase A (MMP-2)
The protein was obtained as an inactive zymogen from INVITEK, Berlin (Cat. No. 30100602). The activation of the proenzyme is as follows: 2 volumes of zymogen and 1 volume of APMA solution were incubated at 37 ℃ for 0.5 hours. APMA solution was prepared from a 10mmol/l solution of mercury p-aminophenylacetate in 0.1mmol/l NaOH by diluting it with 3 volumes of tris/HCl buffer pH7.5 (see below). The pH was adjusted to between 7.0 and 7.5 by addition of 1mmol/l HCl. After the enzyme was activated, it was diluted with tris/HCl buffer to a concentration of 0.83. mu.g/ml.
To determine the enzyme activity, 10. mu.l of the enzyme solution was incubated with 10. mu.l of 3% (v/v) dimethyl sulfoxide buffer solution for 15 minutes (reaction 1). To determine the activity of the enzyme inhibitor, 10. mu.l of the enzyme solution was incubated with 10. mu.l of 3% (v/v) dimethyl sulfoxide buffer solution containing the enzyme inhibitor (reaction 2).
For both reaction 1 and reaction 2, the enzyme reaction was monitored by fluorescence spectroscopy (328nm (disappearance)/393 nm (emission)) after addition of 10. mu.l of a 3% (v/v) aqueous solution of dimethyl sulfoxide containing 0.3mmol of substrate per l.
Enzyme activity is expressed as disappearance per minute increment.
The effect of the inhibitor was calculated as percent inhibition according to the following formula: % inhibition was 100- [ (increase of disappearance/min in reaction 2)/(increase of disappearance/min in reaction 1) × 100 ].
IC50I.e., the concentration of inhibitor required to inhibit 50% of the enzyme activity, can be determined graphically by plotting the percent inhibition for different inhibitor concentrations.
The buffer solution contained 0.05% benzyl (Sigma, Deisenhofen, Germany) and 0.1mol of Tris/HCl/l, 0.1mol of NaCl/l, 0.01mol of CaCl2(pH 7.5). The enzyme solution contained 0.83. mu.g enzyme domain/ml. The substrate solution contained 0.3mmol of the fluorogenic substrate (7-methoxycoumarin-4-yl) acetyl-Pro-Leu-Gly-Leu-3- (2 ', 4' -dinitrophenyl) -L-2, 3-diaminopropionyl-Ala-Arg-NH2L (Bachem, Heidelberg, Germany).
Determination of enzymatic Activity of the catalytic Domain of human gelatinase A (MMP-9)
The protein was obtained as an inactive zymogen from Roche, mannheim (cat # 1758896).
The activation of the proenzyme is as follows:
2 volumes of zymogen and 1 volume of APMA solution were incubated at 37 ℃ for 4 hours. APMA solution was prepared from a 10mmol/l solution of mercury p-aminophenylacetate in 0.1mmol/l NaOH by diluting it with 3 volumes of tris/HCl buffer pH7.5 (see below). The pH was adjusted to between 7.0 and 7.5 by addition of 1mmol/l HCl. After the enzyme was activated, it was diluted to a concentration of 4.2mU/ml with tris/HCl buffer.
To determine the enzyme activity, 10. mu.l of the enzyme solution was incubated with 10. mu.l of 3% (v/v) dimethyl sulfoxide buffer solution for 15 minutes (reaction 1). To determine the activity of the enzyme inhibitor, 10. mu.l of the enzyme solution was incubated with 10. mu.l of 3% (v/v) dimethyl sulfoxide buffer solution containing the enzyme inhibitor (reaction 2).
For both reaction 1 and reaction 2, the enzyme reaction was monitored by fluorescence spectroscopy (328nm (disappearance)/393 nm (emission)) after addition of 10. mu.l of a 3% (v/v) aqueous solution of dimethyl sulfoxide containing 0.15mmol of substrate per l.
Enzyme activity is expressed as disappearance per minute increment.
Inhibition was calculated as percent inhibition according to the following formula:
% inhibition was 100- [ (increase of disappearance/min in reaction 2)/(increase of disappearance/min in reaction 1) × 100 ].
IC50I.e., the concentration of inhibitor required to inhibit 50% of the enzyme activity, can be determined graphically by plotting the percent inhibition for different inhibitor concentrations.
The buffer solution contained 0.05% benzyl (Sigma, Deisenhofen, Germany) and 0.1mol of Tris/HCl/l, 0.1mol of NaCl/l, 0.01mol of CaCl2(pH 7.5). The enzyme solution contained 4.2mU enzyme domain/ml. The substrate solution contained 0.15mmol of the fluorogenic substrate (7-methoxycoumarin-4-yl) acetyl-Pro-Leu-Gly-Leu-3- (2 ', 4' -dinitrophenyl) -L-2, 3-diaminopropionyl-Ala-Arg-NH2L (Bachem, Heidelberg, Germany).
The results are shown in Table 2 below.
Table 2:
| example numbering | IC[nM]MMP-1 | IC[nM]MMP-2 | IC[nM]MMP-3 | IC[nM]MMP-8 | IC[nM]MMP-9 | IC[nM]MMP-13 |
| 6 | >10000 | 38 | 3500 | 54 | 2200 | 290 |
| 7 | 29 | 1.7 | 29 | 2.4 | 2.4 | 1.8 |
| 8 | 14 | 0.8 | 13 | 1 | 1.5 | 1 |
| 9 | 4100 | 71 | 1100 | 170 | 120 | 58 |
| 10 | >10000 | 440 | >10000 | 410 | 2500 | 520 |
| 11 | 39 | 2 | 34 | 6 | 3 | 2 |
| 12 | 10 | 0.8 | 14 | 2 | 1.3 | 0.7 |
| 13 | 1400 | 47 | 1500 | 150 | 150 | 63 |
| 18 | 43 | 2 | 27 | 24 | 2 | 1 |
| 21 | 59 | 1 | 17 | 2 | 8 | 1 |
| 23 | 640 | 1 | 15 | 2 | 5 | 1 |
By > is meant greater than.
Claims (8)
1. A compound of formula II wherein
A is a covalent bond, and A is a bond,
B. d and E are identical or different and, independently of one another, are a covalent bond or a group-O-,
ring 1, ring 2 or ring 3 are identical or different and independently of one another are
1) A covalent bond, or
2) Is phenyl and is unsubstituted or substituted once or twice, independently of one another, by G,
with the proviso that at least one of the radicals ring 1, ring 2 or ring 3 is phenyl,
ring 4 is phenyl and is unsubstituted or substituted once or twice independently of one another by G,
g is 1) a hydrogen atom,
2) br, Cl or F, in the presence of a catalyst,
3)C1-4alkyl, where alkyl is unsubstituted or substituted once, twice or three times, independently of one another, by Br, Cl or F,
4)-SO2-CH3，
5)-CN，
x is-OH or-NH-OH, and
r2, R3, R4, Y1 and Y2 are the same and are a hydrogen atom.
2. A compound of formula II according to claim 1, which is a compound of:
5- (4' -chlorobiphenyl-4-sulfonyl) octahydrofuro [3, 2-c ] pyridine-4-carboxylic acid,
5- (4' -chlorobiphenyl-4-sulfonyl) octahydrofuro [3, 2-c ] pyridine-4- (N-hydroxy) -carboxamide,
5- [4- (4-fluorophenoxy) benzenesulfonyl ] octahydrofuro [3, 2-c ] pyridine-4-carboxylic acid,
5- [4- (4-fluorophenoxy) benzenesulfonyl ] octahydrofuro [3, 2-c ] pyridine-4- (N-hydroxy) -carboxamide,
5- [4- (4-cyanophenoxy) benzenesulfonyl ] octahydrofuro [3, 2-c ] pyridine-4-carboxylic acid,
5- [4- (4-methanesulfonylphenoxy) benzenesulfonyl ] octahydrofuro [3, 2-c ] pyridine-4-carboxylic acid,
5- (4' -fluorobiphenyl-4-sulfonyl) octahydrofuro [3, 2-c ] pyridine-4- (N-hydroxy) -carboxamide,
5- (4' -trifluoromethylbiphenyl-4-sulfonyl) octahydrofuro [3, 2-c ] pyridine-4- (N-hydroxy) -carboxamide,
5- [4- (4-chlorophenoxy) benzenesulfonyl ] octahydrofuro [3, 2-c ] pyridine-4- (N-hydroxy) -carboxamide,
5- [4- (4-cyanophenoxy) benzenesulfonyl ] octahydrofuro [3, 2-c ] pyridine-4- (N-hydroxy) -carboxamide
Or 5- [4- (4-methanesulfonylphenoxy) benzenesulfonyl ] octahydrofuro [3, 2-c ] pyridine-4- (N-hydroxy) carboxamide.
3. A process for the preparation of a compound of formula II as claimed in claim 1 or 2, which process comprises
a) A compound of formula IV
Wherein Re is a hydrogen atom or an ester protecting group, the groups Y1, Y2, R3, R4 are as defined for the compounds of formula II, o is 1, the partial structure of the compounds of formula IVIs an unsaturated ring having 5 ring atoms in which the ring atom Z1 is an oxygen atom and the other two ring atoms Z2 and Z3 are carbon atoms which may be substituted independently of one another by R3 or R4 and which may be converted by hydrogenation under suitable conditions into compounds of the formula V
Wherein the partial structure of the compound of formula VIs a saturated ring having 5 ring atoms in which the ring atom Z1 is an oxygen atom and the other two ring atoms Z2 and Z3 are carbon atoms which may be substituted independently of one another by R3 or R4 and the radicals Y1, Y2, R3, R4 and o are as defined for the compounds of the formula IV,
b) then reacting the compound of formula V with the compound of formula VI
Wherein A, B, D, E and Ring 1, Ring 2, Ring 3, Ring 4 are as defined in formula II, wherein Rz is a chlorine atom, a bromine atom, an imidazolyl group or OH,
in the presence of a base, or after silylation with a suitable silylating agent, or with a suitable dehydrating agent in the presence of Rz ═ OH to give compounds of the formula VII
Wherein A, B, D, E, Re is as defined above for ring 1, ring 2, ring 3 and ring 4, and
c) in the case where Re is an ester group, the compound of the formula VII prepared as in b) is reacted with an alkali metal hydroxide solution and subsequently treated with acid to give the carboxylic acids of the formula II according to the invention in which X is OH, one of the side chains of ring 1 to ring 4 is modified, if appropriate beforehand, or the esters are converted into the free carboxylic acids of the formula VIII by treatment with mineral acid
Or the compound of formula VIII is then converted to the hydroxamic acid, wherein X in formula II is NH-OH,
d) the compounds of the formula II prepared by process a), or suitable precursors of the formula II, are, owing to their chemical structure, in enantiomeric form, resolved into the pure enantiomers by salt formation with an enantiomerically pure acid or base, derivatized by chromatographic methods with chiral stationary phases or with chiral, enantiomerically pure compounds, in such a way that separation of the diastereomers is obtained and the chiral auxiliary groups are eliminated, or
e) The compounds of the formula II prepared by processes b), c) or d) are isolated in free form or, in the presence of acidic or basic groups, converted into physiologically tolerated salts.
4. A medicament containing an effective amount of at least one compound of formula II as claimed in claim 1 or 2, together with suitable pharmaceutically and physiologically tolerable carriers, additives and/or other active compounds and excipients.
5. Use of a compound of formula II according to claim 1 or 2 for the preparation of a medicament for the prevention and treatment of degenerative joint diseases, connective tissue diseases and chronic diseases of the locomotor system, for the treatment of ulcers, atherosclerosis and stenosis, for the treatment of inflammation, cancer, tumor metastasis, cachexia, anorexia, heart failure and septic shock or for the prevention of myocardial and cerebral infarction.
6. Use according to claim 5, wherein the degenerative joint disease is osteoarthropathy, ankylosis of the vertebral joint and chondrolysis after trauma of the joint or after damage of the meniscus or damage of the patella or tear of the ligament for a relatively long time after fixation of the joint.
7. Use according to claim 5, wherein the connective tissue disease is a collagenous disease, a periodontal disease, a wound healing disorder.
8. Use according to claim 5, wherein said chronic diseases of the locomotor system are inflammatory, immune or metabolic-related acute and chronic arthritis, arthrosis, myalgia and bone metabolism disorders.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102005002500.5 | 2005-01-19 | ||
| DE102005002500A DE102005002500A1 (en) | 2005-01-19 | 2005-01-19 | Tetrahydrofuran derivatives as inhibitors of matrix metalloproteinases |
| PCT/EP2006/000047 WO2006077013A1 (en) | 2005-01-19 | 2006-01-05 | Tetrahydrofurane derivatives for use as inhibitors of matrix metalloproteinases |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1113367A1 HK1113367A1 (en) | 2008-10-03 |
| HK1113367B true HK1113367B (en) | 2011-06-30 |
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