Aminobutyric acid derivatives

Details Aminobutyric acid derivatives Aminobutyric acid derivatives

2000-04-07

2002-07-16

Owens, Amelia (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C544S153000, C548S338100, C548S504000, C548S561000, C546S192000, C546S216000, C514S233500, C514S327000, C514S331000, C514S399000, C514S427000, C514S466000, C514S469000, C514S470000, C514S471000, C514S562000, C514S563000, C514S616000, C514S618000, C549S214000, C549S467000, C549S487000, C564S154000, C564S155000, C564S158000, C562S430000, C562S444000, C562S450000

Reexamination Certificate

active

06420427

ABSTRACT:

SUMMARY
This invention relates to aminobutyric acid derivatives, processes for the preparation thereof and pharmaceutical agents containing them as active ingredient. More particularly, this invention relates to:
aminobutyric acid derivatives of the formula (I):
wherein all the symbols are as hereinafter defined, and non-toxic salts thereof, processes for the preparation thereof and pharmaceutical agents containing them as active ingredient.
BACKGROUND
The matrix metalloproteinases (MMPS) are neutral metalloproteinases and zinc (Zn
2+
) is essential in the active site for their activation. They degrade collagen, laminin, proteoglycans, fibronectin, elastin, gelatin etc. under physiological conditions and therefore, are effective on growth and tissue remodeling of articulation tissue, bone tissue and connective tissue. At least 10 classes of MMPs which differ in primary structure are identified. Concretely, there are Interstitial Coliagenase (MMP-1), Neutrophil Collagenase (MMP-8), Gelatinase A (MMP-2), Gelatinase B (MMP-9), Stromelysin-1 (MMP-3), Stromelysin-2 (MMP-10), Matrilysin (MMP-7), metalloerastase (MMP-12) etc.
As common characteristics of these enzymes, MMPs
(1) have Zn
2+
in the active site and the activity depends on calcium ion (Ca
2+
),
(2) are secreted as an inactive proenzyme and activated outside of cells,
(3) have high homology on amino acid sequence,
(4) have an ability to degrade on various extracellular matrix components in vivo,
(5) are regulated by tissue inhibitors of metalloproteinases (TIMP) which are specific to MMPs.
MMP inhibitors are useful for prevention and/or treatment of various diseases induced by overexpression and excess activation of MMP. Such diseases are, for example, rheumatoid disease, arthrosteitis, unusual bone resorption, osteoporosis, periodontitis, interstitial nephritis, arteriosclerosis, pulmonary emphysema, cirrhosis, cornea injury, metastasis of, invasion of or growth of tumor cells, autoimmune diseases (e.g. Crohn's disease, Sjogren's syndrome), diseases caused by vascular emigration or infiltration of leukocytes, arterialization, multiple sclerosis, aorta aneurysm, endometriosis.
Some compounds possessing inhibitory activity against MMP are known. A sequence in the vicinity of cleavage site of collagen (Gly-Ile-Ala-Gly or Gly-Leu-Ala-Gly) has high affinity for collagenase.
Much research and development on substrate analogous MMP inhibitors, which are chemically modified so as to have zinc affinity groups on a cleaving site of the substrate, has energetically been carried out [Inhibitors of matrix metalloproteinases (MMP's), Nigel R A Beeley, Phillip R J Ansell, Andrew J P Docherty et al., Curr. Opin. Ther. Patents., 4, 7-16 (1994), Current Drugs Ltd ISSN 0962-2594]. However, these substrate-analogues inhibitors might have various problems. Therefore, it is desired to obtain a non-peptide inhibitor and some compounds are reported.
For example, in the specification of EP 757037 as the Example, sulfonylamino acid derivatives of the formula (W):
are disclosed to have an activity of inhibiting matrix metalloproteinase.
In the specification of EP 757984 as the Example, hydroxamic acid derivatives of the formula (X):
are disclosed to have an activity of inhibiting matrix metalloproteinase.
In the specification of WO 9723459 as the Example, aromatic keto-acid derivatives of the formula (Y):
are disclosed to have an activity of inhibiting matrix metalloproteinase.
In the specification of WO 9718188 as the Example, hydroxamic acid derivatives of the formula (Z):
are disclosed to have an activity of inhibiting matrix metalloproteinase and TNF&agr; secretion.
DISCLOSURE OF THE INVENTION
Energetic investigations have been carried out in order to make a matrix metalloproteinase, e.g. gelatinase, stromelysin or collagenase, inhibitor. The present inventors have found that novel compounds of aminobutyric acid derivatives of the formula (I) which are carboxylic amino derivatives of &ggr;-amino acid, accomplished the present purpose.
The present invention relates to:
1) an aminobutyric acid derivative of the formula (I):
 wherein
R
1
is —COOR
10
, —CONHOR
10
, —CONHNHR
10
, —(CH
2
)
n
SR
50
or —Y—P(OR
51
)
2
;
R
10
is (i) hydrogen, (ii) C1-8 alkyl, (iii) phenyl, (iv) C1-8 alkyl substituted by phenyl or C1-8 alkoxy, or (v) oxycarbonyl substituted by phenyl, benzyl or C1-8 alkyl;
n is 0-3;
R
50
is (i) hydrogen, (ii) C1-8 alkyl, (iii) —COR
52
, in which R
52
C1-8 alkyl or phenyl; or (iv) —SR
53
, in which R
53
is hydrogen, C1-8 alkyl or phenyl;
R
51
is hydrogen, C1-8 alkyl or phenyl;
Y is a single bond, —CH
2
— or —O—;
R
2
, R
3
, R
4
, R
5
, R
6
and R
7
each, independently, is
(1) hydrogen,
(2) C1-8 alkyl,
(3) C2-8 alkenyl,
(4) —OR
11
,
(5) —SR
11
,
(6) —NR
12
R
13
,
(7) —COR
14
,
(8) Cyc1,
(9) C1-8 alkyl substituted by —OR
11
, —SR
11
, —NR
12
R
13
, —COR
14
, guanidino or Cyc1, or
(10) C2-8 alkenyl substituted by —OR
11
, —SR
11
, —NR
12
R
13
, —COR
14
, guanidino or Cyc1, or
R
2
and R
4
, taken together is C1-8 alkylene, R
5
and R
6
, taken together is C1-8 alkylene, R
3
and R
6
, taken together is C1-8 alkylene, R
2
and R
3
, taken together is C2-8 alkylene, R
4
and R
5
, taken together is C2-8 alkylene, or R
6
and R
7
, taken together is C2-8 alkylene;
in which Cyc1 is carbocyclic ring or heterocyclic ring and these carbocyclic ring and heterocyclic ring may be substituted by one or more of (i) C1-8 alkyl, (ii) C1-8 alkoxy, (iii) nitro, (iv) guanidino, (v) amidino, (vi) halogen atom, (vii) nitrile (viii) hydroxy, (ix) benzyloxy, (x) —NR
101
R
102
, in which R
101
and R
102
each, independently, is hydrogen or C1-8 alkyl, (xi) —COOR
103
, in which R
103
is hydrogen or C1-8 alkyl, (xii) trifluoromethyl, (xiii) trifluoromethyloxy, (xiv) phenyl, (xv) phenyl substituted by C1-8 alkyl or C1-8 alkoxy, (xvi) phenyloxy, (xvii) phenylsulfonyl, (xviii) C1-8 alkyl substituted by phenyl or nitrile, (xix) heterocyclic ring, (xx) keto, and (xxi) C1-8 alkoxy substituted by —CONR
104
R
105
, in which R
104
and R
105
each, independently, is hydrogen, C1-8 alkyl or phenyl;
R
11
is (i) hydrogen, (ii) C1-8 alkyl, (iii) Cyc1, or (iv) —COR
18
, or C1-8 alkyl substituted by —OR
15
, —SR
15
, —NR
16
R
17
, —COR
18
, guanidino or Cyc1;
R
15
is hydrogen, C1-8 alkyl, Cyc1 or C1-8 alkyl substituted by Cyc1 or C1-8 alkoxy;
R
16
is hydrogen or C1-8 alkyl;
R
17
is hydrogen, C1-8 alkyl or —COR
19
, in which R
19
is C1-8 alkyl, Cyc1 or C1-8 alkyl substituted by Cyc1;
R
18
is hydroxy, C1-8 alkyl, C1-8 alkoxy or —NR
20
R
21
, in which R
20
and R
21
, each independently, is hydrogen, C1-8 alkyl, Cyc1 or C1-8 alkyl substituted by Cyc1;
R
12
is hydrogen, C1-8 alkyl, Cyc1 or C1-8 alkyl substituted by Cyc1;
R
13
is hydrogen, C1-8 alkyl, Cyc1, C1-8 alkyl substituted by Cyc1, or —COR
22
, in which R
22
is C1-8 alkyl, Cyc1 or C1-8 alkyl substituted by Cyc1;
R
14
is hydroxy, C1-8 alkyl, C1-8 alkoxy, Cyc1, C1-8 alkyl substituted by Cyc1, or —NR
23
R
24
, in which R
23
and R
24
, each independently, is (i) hydrogen, (ii) C1-8 alkyl, (iii) Cyc1 or (iv) C1-8 alkyl substituted by Cyc1 or hydroxy;
(1) R
8
is
1) hydrogen,
2) C1-8 alkyl,
3) C1-8 alkoxycarbonyl,
4) C1-8 alkyl substituted by —OR
26
, —SR
26
, —NR
27
R
28
or —COR
29
, or
5) C1-8 alkoxycarbonyl substituted by Cyc2, and
R
9
is
(2) R
8
is
R
9
is
1) C1-8 alkyl,
2) C1-8 alkoxy,
3) C1-8 alkoxy substituted by Cyc2,
4) C1-8 alkyl substituted by —OR
26
, —SR
26
, —NR
27
R
28
, —COR
29
or Cyc2 or
5)
 in which Cyc2 is carbocyclic ring or heterocyclic ring and these carbocyclic ring and heterocyclic ring may be substituted by one or more of (i) C1-8 alkyl, (ii) C1-8 alkoxy, (iii) nitro, (iv) guanidino, (v) amidino, (vi) halogen atom, (vii) nitrile (viii) hydroxy, (ix) benzyloxy, (x) —NR
201
R
202
, in which R
201
and R
202
each, independently, is hydrogen or C1-8 alkyl, (xi) —COOR
203
, in which R
203
is hydrogen or C1-8 alkyl, (xii) trifluoromethyl, (xiii) trifluoromethyloxy, (xiv) phenyl, (xv) phenyl substituted by C1-8 alkyl or C1-8 alko

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