Vitronectin receptor antagonists

Details Vitronectin receptor antagonists Vitronectin receptor antagonists

2000-10-05

2002-10-01

Qazi, Sabiha (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S221000, C514S219000, C514S213010, C540S504000, C540S512000, C540S513000, C540S514000

Reexamination Certificate

active

06458784

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to pharmaceutically active compounds which inhibit the vitronectin receptor and are useful for the treatment of osteoporosis.
BACKGROUND OF THE INVENTION
Mammalian bone is constantly undergoing bone remodeling, which is a dynamic process of bone resorption and bone formation. These processes are mediated by specialized cell types: bone formation is the result of the deposition of mineralized bone by osteoblast cells, and bone resorption is the result of the dissolution of bone matrix by osteoclast cells. Many bone diseases are brought about by an imbalance of bone formation relative to bone resorption. For instance, diseases such as osteoporosis are characterized by a net loss of bone matrix. Thus, agents which inhibit bone resorption are useful for the treatment of such diseases.
An activated osteoclast resorbs bone by attaching to the bone matrix, and secreting proteolytic enzymes, organic acids and protons into the sealed compartment formed between its cell membrane and the bone matrix. The acidic environment and proteolytic enzymes effect the dissolution of bone in the sealed compartment to create pits, or lacuna, in the bone surface, which are apparent when the osteoclast detaches from the bone.
Recent studies have indicated that the attachment of osteoclasts to the bone matrix is mediated through cell surface adhesion receptors called integrins. For instance, Davies, et al.,
J. Cell Biol.,
1989, 109, 1817, disclose that the osteoclast functional antigen, which is implicated in the regulation of bone resorption, is biochemically related to the vitronectin receptor. The vitronectin receptor, or the &agr;
v
&bgr;
3
integrin, is known to bind to bone matrix proteins, such as osteopontin, bone sialoprotein and thrombospondin, which contain the tri-peptide Arg-Gly-Asp (or RGD) motif. Thus, Horton, et al.,
Exp. Cell Res.
1991, 195, 368, disclose that RGD-containing peptides and an anti-vitronectin receptor antibody (23C6) inhibit dentine resorption and cell spreading by osteoclasts. In addition, Sato, et al.,
J. Cell Biol.
1990, 111, 1713 disclose that echistatin, a snake venom peptide which contains the RGD sequence, is a potent inhibitor of bone resorption in tissue culture, and inhibits attachment of osteoclasts to bone. Fisher, et al.,
Endocrinology
1993, 132, 1411, has further shown that echistatin inhibits bone resorption in vivo in the rat EP 528 587 and 528 586 report substituted phenyl derivatives which inhibit osteoclast mediated bone resorption.
Bondinell, et al., in WO 93/00095 (PCT/US92/05463) and PCT/US93/12436 disclose that certain compounds which have a substituted 6-7 bicyclic ring system are useful for inhibiting the fibrinogen receptor, which is an integrin (&agr;
IIb
&bgr;
3
) protein founds on platelets. Other 6-7 bicyclic ring systems which inhibit the fibrinogen receptor are disclosed by Blackburn et al. in WO 93/08174 (PCT/US92/08788). It has now been discovered that certain appropriately substituted 1,4-benzodiazepine, -benzothiazepine, -benzoxazepine and 2-benzazepine compounds are potent inhibitors of the vitronectin receptor. In particular, it has been discovered that certain such compounds are suprisingly more potent inhibitors of the vitronectin receptor than the fibrinogen receptor and consequently are more useful in the treatment of diseases such as osteoporosis, cancer, atherosclerosis and for inhibiting restenosis of an artery.
SUMMARY OF THE INVENTION
This invention comprises compounds of the formula (I) as described hereinafter, which have pharmacological activity for the inhibition of the vitronection receptor and are useful in the treatment of osteoporosis.
This invention is also a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically carrier.
This invention is also a method of treating diseases which are mediated by ligands which bind to the vitronectin receptor. In a particular aspect, the compounds of this invention are useful for treating osteoporosis, atherosclerosis, restenosis and cancer.
DETAILED DESCRIPTION
This invention comprises compounds of formula (I):
wherein
X—X′ is NR
1
—CH, NC(O)R
3
—CH, N═C, CR
1
═C, CHR
1
—CH, O—CH or S—CH;
R
1
is H, C
1-6
alkyl or benzyl;
R
2
is (CH
2
)
n
CO
2
H;
R
3
is H, C
1-6
alkyl, Ar—C
0-6
alkyl, Het-C
0-6
alkyl, or C
3-6
cycloalkyl-C
0-6
alkyl;
R
4
is W—U, Y—(CHR
5
)
m
—U or Z—C(O);
R
5
and R
6
are independently chosen from H, C
1-6
alkyl, Ar—C
0-6
alkyl, Het-C
0-6
alkyl and C
3-6
cycloalkyl-C
0-6
alkyl;
m is 1 or 2;
n is 1 or 2;
U is NR
1
C(O), C(O)NR
1
, CH═CH, C≡C, CH
2
—CH
2
, O—CH
2
, CH
2
—O or —CH
2
OCONR
1
;
W is
R
a
is H, OH, NO
2
, N(R
6
)
2,
CON(R
6
)
2
, CH
2
N(R
6
)
2
, or R
6
HN—C(═NH);
Y is NH
2
, NHR
6
, N(R
6
)
2
, C(O)N(R
6
)
2
, OH, ═N—OR
6
,
Z is
R
d
is H, N(R
1
), C
1-4
alkyl, CON(R
1
)
2
, OH, OR
1
, or Ar—C
0-4
alkyl;
R
e
is H, C
1-4
alkyl, Het-C
0-4
alkyl or Ar—C
0-4
alkyl;
and pharmaceutically acceptable salts thereof,
provided that R
3
is not phenylethyl when R
4
is (3-amidino)phenylaminocarbonyl and X—X′ is NH—CH.
The compounds of formula (I) inhibit the binding of vitronectin and other RGD-containing peptides to the vitronectin (&agr;
v
&bgr;
3
) receptor. Inhibition of the vitronectin receptor on osteoclasts inhibits osteoclastic bone resorption and is useful in the treatment of diseases wherein bone resorption is associated with pathology, such as osteoporosis.
Suitably, X—X′ is NH—CH or CH
2
—CH.
Preferably, U is NR
1
CO, CONR
1
or CH
2
OCONR
1
. More preferably U is NR
1
CO.
Suitably R
a
is hydroxy or amino. Preferably R
a
is amino.
Suitably W is
Preferably, W is
or (3-amidino)phenyl.
Suitably Y is
OH or NHR
6
. Suitably R
5
is H, phenyl or C
1-6
alkyl. Suitably R
6
is benzyl, 2-pyridinyl or H.
Suitably Z is 1-piperazinyl or 1-piperidinyl.
Suitably R
4
is Y—(CH
2
)
m
NCH
3
CO.
Suitably R
e
is H or substituted or unsubstituted phenyl, benzyl, 2- or 3-pyridinyl, 2- or 4-pyrimidinyl or 1-, 2- or 3-piperidinyl. When Z is 1-piperazinyl, R
e
is preferably 2- or 3-pyridinyl or 2- or 4-pyrimidinyl. When Z is piperidinyl, R
e
is preferably 1-piperidinyl.
Preferably Y is NH
2
or pyridinyl.
Preferably n is 1.
Preferably R
1
is H, methyl or phenylethyl.
Representative of the novel compounds of this invention are the following:
(±)-7-[[(6-Amino-2-pyridinyl)amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid;
(±)-8-[[(6-amino-2-pyridinyl)amino]carbonyl]-2-methyl-3-oxo-2,3,4,5-tetrahydro1H-2-benzazepine-4-acetic acid;
(±)-7-[[(6-amino-3-pyridinyl)amino]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid;
(±)-1-Acetyl-7-[[(6-amino-2-pyridinyl)amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid;
(±)-2-methyl-3-oxo-8-[[2-(pyridinyl)carbonyl]amino]-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(±)-8-[(benzyloxycarbonyl)amino]-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(±)-7-[[[3-(aminoiminomethyl)phenyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid;
(±)-7-[[[3-(aminocarbonyl)phenyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid;
(±)-4-methyl-3-oxo-7-[1-(4-phenylpiperazinyl)carbonyl]-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid;
(±)-4-methyl-3-oxo-7-[(1-piperazinyl)carbonyl]-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid;
(±)-4-methyl-3-oxo-7-[1-[4-(1-piperidinyl)piperidinyl]carbonyl]-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid;
(±)-4-methyl-3-oxo-7-[1-[4-(2-pyridinyl)piperazinyl]carbonyl]-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid;
(±)-4-methyl-3

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