Isoquinolines as urokinase inhibitors

Details Isoquinolines as urokinase inhibitors Isoquinolines as urokinase inhibitors

2000-05-30

2001-06-19

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S253050, C514S310000, C544S128000, C544S363000, C546S143000

Reexamination Certificate

active

06248738

ABSTRACT:

This invention relates to certain isoquinolines useful as urokinase inhibitors, and in particular to isoquinolinylguanidines useful as urokinase inhibitors.
Urokinase (urinary-type plasminogen activator or uPA; International Union of Biochemistry classification number EC.3.4.21.31) is a serine protease produced by a large variety of cell types (smooth muscle cells, fibroblasts, endothelial cells, macrophages and tumour cells). It has been implicated as playing a key role in cellular invasion and tissue remodelling. A principal substrate for uPA is plasminogen which is converted by cell surface-bound uPA to yield the serine protease plasmin. Locally produced high plasmin concentrations mediate cell invasion by breaking down the extracellular matrix. Important processes involving cellular invasion and tissue remodelling include wound repair, bone remodelling, angiogenesis, tumour invasiveness and spread of metastases.
Beneficial effects of urokinase inhibitors have been reported using anti-urokinase monoclonal antibodies and certain other known urokinase inhibitors. For instance, anti-urokinase monoclonal antibodies have been reported to block tumour cell invasiveness in vitro (W. Hollas, et al,
Cancer Res.
51:3690; A. Meissauer, et al,
Exp.Cell Res.
192:453 (1991); tumour metastases and invasion in vivo (L. Ossowski,
J. Cell Biol.
107:2437 (1988)); L. Ossowski, et al,
Cancer Res.
51:274 (1991)) and angiogenesis in vivo (J. A. Jerdan et al,
J.Cell Biol.
115[3Pt 2]: 402a (1991). Also, Amiloride™, a known urokinase inhibitor of only moderate potency, has been reported to inhibit tumour metastasis in vivo (J. A. Kellen et al,
Anticancer Res.,
8:1373 (1988)) and angiogenesis/capillary network formation in vitro (M. A. Alliegro et al,
J.Cell Biol.
115[3Pt 2]:402a).
Conditions of particular interest for treatment by urokinase inhibitors include chronic dermal ulcers (including venous ulcers, diabetic ulcers and pressure sores), which are a major cause of morbidity in the ageing population and cause a significant economic burden on healthcare systems. Chronic dermal ulcers are characterised by excessive uncontrolled proteolytic degradation resulting in ulcer extension, loss of functional matrix molecules (e.g. fibronectin) and retardation of epithelisation and ulcer healing. A number of groups have investigated the enzymes responsible for the excessive degradation in the wound environment, and the role of plasminogen activators has been highlighted (M. C. Stacey et al.,
Br. J. Surgery,
80, 596; M. Palolahti et al.,
Exp. Dermatol.,
2, 29, 1993; A. A. Rogers et al.,
Wound Repair and Regen.,
3, 273, 1995). Normal human skin demonstrates low levels of plasminogen activators which are localised to blood vessels and identified as tissue type plasminogen activator (tPA). In marked contrast, chronic ulcers demonstrate high levels of urokinase type plasminogen activator (uPA) localised diffusely throughout the ulcer periphery and the lesion, and readily detectable in wound fluids.
uPA could affect wound healing in several ways. Plasmin, produced by activation of plasminogen, can produce breakdown of extracellular matrix by both indirect (via activation of matrix metalloproteases) and direct means. Plasmin has been shown to degrade several extracellular matrix components, including gelatin, fibronectin, proteoglycan core proteins as well as its major substrate, fibrin. Whilst activation of matrix metalloproteases (MMPs) can be performed by a number of inflammatory cell proteases (e.g. elastase and cathepsin G), the uPA/plasmin cascade has been implicated in the activation of MMPs in situ, providing a broad capacity for degrading all components of the extracellular matrix. Furthermore, in addition to its effect on production of plasmin, uPA has been shown to catalyse direct cleavage of fibronectin yielding antiproliferative peptides. Thus, over-expression of uPA in the wound environment has the potential to promote uncontrolled matrix degradation and inhibition of tissue repair. Inhibitors of the enzyme thus have the potential to promote healing of chronic wounds.
Several related enzymes such as tPA, which also acts via production of plasmin, play a key role in the fibrinolytic cascade. Because of this it is important that an inhibitor has adequate potency and selectivity for uPA relative to both tPA and plasmin to avoid the possibility of anti-fibrinolytic side effects.
The utility of such potent and selective urokinase inhibitors is highlighted by the broad range of invasive biological processes mediated by urokinase. These processes include, but are not limited to, wound healing, angiogenesis-dependent conditions such as retinopathy, bone restructuring, embryo implantation in the uterus, infiltration of immune cells into inflammatory sites, ovulation, spermatogenesis, tissue remodelling during wound repair and organ differentiation, fibrosis, local invasion of tumours into adjacent areas, metastatic spread of tumour cells from primary to secondary sites, and tissue destruction in arthritis.
Various aromatic amidines have been reported to inhibit uPA (J. D. Geratz, M. C.-F. Cheng, Thromb. Diathes. haemorrh. (Stuttg.), 33, 230, 1975; J. Stürzebecher, F. Markwardt, Pharmazie, 33, 599, 1978; J. D. Geratz et al., Thromb. Res., 24, 73, 1981). The compounds reported in these publications are generally relatively weak and/or non-selective for uPA relative to other related serine proteases. EP 0 568 289 A2 discloses a series of benzo[b]thiophene-2-carboxamidines with significantly greater potency and selectivity with respect to tPA and plasmin (see also M. J. Towle et al.,
Cancer Res.,
53, 2553, 1993; A. J. Bridges et al.,
Bioorg. Med. Chem.,
1, 403, 1993).
There are few reports of guanidine derivatives as uPA inhibitors. Amiloride™ (see below) is a weak but selective inhibitor of uPA (J.-D. Vassalli, D. Belin,
FEBS Letters,
214, 187, 1987), and various substituted phenylguanidines are reported to have a similar level of potency (H. Yang et al.,
J. Med. Chem.,
33, 2956, 1990).
The compounds described herein are potent reversibly-competitive inhibitors of urokinase enzymatic activity, with selectivity for urokinase relative to certain other important proteases, including the fibrinolytic enzymes tissue-type plasminogen activator (tPA) and plasmin.
The selectivity of the instantly-claimed compounds for inhibition of urokinase over inhibition of other proteases such as tPA and plasmin, and the fact that they inhibit reversibly, prevents them from having thrombogenic properties.
Thus, according to the present invention, there is provided an isoquinolinylguanidine derivative of formula (I):
or a pharmaceutically acceptable salt thereof, wherein
one of R
1
and R
2
is H and the other is N═C(NH
2
)
2
or NHC(═NH)NH
2
,
R
3
is H, halogen, C
1-6
alkyl optionally substituted by one or more halogen, or C
1-6
alkoxy optionally substituted by one or more halogen,
R
4
, R
5
, R
6
and R
7
are each independently H, OH, halogen, C
1-6
alkyl optionally substituted by one or more substituents independently selected from halogen or OH, C
1-6
alkoxy optionally substituted by one or more halogen, CN, CO(C
1-6
alkyl optionally substituted by one or more halogen), (C
m
-alkylene)CO
2
R
8
, (C
n
-alkylene)CN, O(C
n
-alkylene)CN, O(C
n
-alkylene)CO
2
R
8
, (C
m
-alkylene)CONR
9
R
10
, (C
m
-alkylene)NH
9
COR
10
, O(C
n
-alkylene)CONR
9
R
10
, (C
m
-alkylene)NR
9
SO
2
R
11
, (C
m
-alkylene)S(O)
p
R
11
, (C
m
-alkylene)SO
2
NR
9
R
10
, CH═CHCOR
8
, CH═CHCONR
9
R
10
, CH═CHSO
2
R
8
, CH═CHSO
2
NR
9
R
10
, CH═CHSO
2
aryl, or
a group of formula X-aryl or X-het,
or, where two of R
4
, R
5
, R
6
and R
7
are attached to adjacent carbon atoms, they can be taken together to form an —O(C
n
-alkylene)O-moiety,
R
8
is H, C
1-6
alkyl optionally substituted by one or more halogen, or aryl(C
1-6
alkylene),
R
9
and R
10
are each independently H, C
1-6
alkyl optionally substituted by one or more halogen, aryl(C
1-6
alkylene), aryl, h

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