Ukokinase inhibitors

Details Ukokinase inhibitors Ukokinase inhibitors

1999-01-25

2001-09-04

Kumar, Shailendra (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C564S164000

Reexamination Certificate

active

06284796

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention provides naphthamidine compounds which inhibit the urokinase enzyme, pharmaceutical compositions containing these compounds and medical methods of treatment using these compounds.
TECHNICAL FIELD
Urokinase (urinary-type plasminogen activator or uPA (International Union of Biochemistry classification number: EC3.4.21.31)) is a proteolytic enzyme which is highly specific for a single peptide bond in plasminogen. Plasminogen activation (cleavage of this bond by the urokinase enzyme) results in formation of plasmin, a potent general protease.
Many cell types use urokinase as a key initiator of plasmin-mediated proteolytic degradation or modification of extracellular support structures such as extracellular matrix (ECM) and basement membrane (BM). Cells exist, move and interact with each other in tissues and organs within the physical framework provided by ECM and BM. Movement of cells within ECM or across BM requires local proteolytic degradation or modification of the structures and allows cells to invade adjacent areas previously unavailable prior to the degradation or modification.
Cellular invasiveness intiated by urokinase is central to a variety of normal and disease-state physiological processes (Blasi, F., Vassalli, J. D., and Dano, K. J. Cell Biol. 104:801-804, 1987; Dano, K., Anderson, P. A., Grondahl-Hansen, J., Kristensen, P., Nielsen, L. S., and Skriver, L Adv. Cancer Res. 44:139-266, 1985; Littlefield, B. A. Ann. N. Y. Acad. Sci. 622: 167-175, 1991; Saksela, O., Biochim. Biophys. Acta 823: 35-65, 1985; Testa, J. E. and Quigley, J. P. Cancer Metast. Rev. 9:353-367, 1990). Such processes include, but are not limited to, angiogenesis (neovascularization), 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, tumor invasion, metastatic spread of tumor cells from primary to secondary sites and tissue destruction in arthritis. Amiloride, for example, a known urokinase inhibitor of only moderate potency, has been reported to inhibit tumor metastasis in vivo (Kellen, J. A., Mirakian, A. Kolin, A. Anticancer Res. 8:1373-1376, 1988) and angiogenesis/capillary network formation in vitro (Alliegro, M. C. and Glaser, B. M. J. Cell Biol. 115[3 Pt 2]: 402a, 1991).
Inhibitors of urokinase, therefore, have mechanism-based anti-angiogenic, anti-arthritic, anti-inflammatory, anti-retinopathic (for angiogenesis-dependent retinopathies), contraceptive and tumoristatic uses.
SUMMARY OF THE INVENTION
In its principle embodiment, the present invention provides a compound or a pharmaceutically acceptable salt, ester or prodrug thereof, of formula (I)
wherein Z is seleted from the group consisting of
(1) nitrogen;
(2) methine; and
(3) methine substituted with —NR
1
R
2
;
Z
3
is selected from the group consisting of
(1) methine and
(2) nitrogen;
Z4 is selected from the group consisting of
(1) hydrogen and
(2) hydroxy;
A is selected from the group consisting of
(1) hydrogen and
(2) -L
A
R
A
;
B is selected from the group consisting of
(1) hydrogen and
(2) -L
B
R
B
and
C is selected from the group consisting of
(1) hydrogen and
(2) -L
C
R
C
,
with the proviso that at least one of A, B or C is other than hydrogen; and with the proviso that when A is other than hydrogen, at least one of B or C is other than hydrogen,
wherein for A, B, and C, L
A
, L
B
and L
C
are independently selected from the group consisting of
(1) a covalent bond,
(2) —(CH
2
)m—,
(3) —NR
1
—,
(4) —NR
2
C(X)NR
3
—,
(5) —C(X)—,
(6) —NR
2
C(X)—,
(7) —C(X)NR
2
—,
(8) —CH═CH—,
(9) —C≡C—,
(10) —O—,
(11) —S(O)
t
—,
(12) —C≡C(CH
2
)
n
NR
2
C(X)—,
(13) —C(X)NR
2
(CH
2
)
n
C≡C—,
(14) —(CH
2
)
n
NSO
2
—,
(15) —NR
2
SO
2
(CH
2
)
n
C—≡C—,
(16) —C≡C(CH
2
)
n
NR
2
SO
2
NR
3
—,
(17) —NR
2
SO
2
NR
3
(CH
2
)
n
C≡C—,
(18) —SO
2
NR
2
—,
(19) —NR
2
SO
2
—,
(20) —NR
2
SO
2
NR
3
—,
(21) —N═N—,
(22) —C(X)N(OR
2
)—,
(23) —N(OR
2
)C(X)—,
(24) —HC═CH(CH
2
)
n
NR
2
C(X)—,
(25) —(CH
2
)
n
NR
2
C(X)CH═CH—,
(26) —CH═CH(CH
2
)
n
NSO
2
—,
(27) —NR
2
SO
2
(CH
2
)
n
CH═CH—,
(28) —(CH
2
)
n
NR
2
SO
2
NR
3
—,
(29) —NR
2
SO
2
NR
3
(CH
2
)
n
CH═CH—,
(30) —NR
2
C(O)O—,
(31) —OC(O)NR
2
—,
(32) —CH═NO—,
(33) —ON═CH— and
(34) wherein W is selected from the group consisting of
(a) —O—,
(b) —S—,
(c) —NR
1
—,
(d) —(CH
2
)m—,
(35) —(CZ
1
═CZ
2
)—, wherein Z
1
and Z
2
are independently selected from the group consisting of
(a) hydrogen,
(b) halogen, and
(c) alkyl of one to ten carbon atoms,
(36) —NR
2
CH
2
—,
(37) —S(O)
t
CH═CH—, and
(38) —NR
1
—(CH
2
)m—,
wherein each functional group is depicted with its right-hand end being the end which is attached to the naphthyl or quinolyl ring and its left-hand end being the end which is attached to R
A
, R
B
or R
C
;
R
A
, R
B
and R
C
are independently selected from the group consisting of
(1) aryl;
(2) arylalkoxy, wherein the alkylene group is of one to six carbon atoms;
(3) alkyl of one to ten carbon atoms;
(4) alkenyl of two to ten carbon atoms;
(5) alkoxycarbonyl of one to six carbon atoms;
(6) alkynyl of two to ten carbon atoms;
(7) halogen;
(8) —NR
1
R
2
;
(9) heterocycle;
(10) cycloalkenyl of four to twelve carbon atoms;
(11) cycloalkyl of three to twelve carbon atoms;
(12) —NR
1
C(O)NR
2
R
3
; and
(13) —NR
1
C(O)R
50
, wherein R
50
is alkyl of one to six carbon atoms;
wherein, at each occurence, R
1
is selected from the group consisting of
(1) hydrogen;
(2) an N-protecting group;
(3) alkyl of one to six carbon atoms;
(4) alkenyl of two to six carbon atoms;
(5) alkynyl of two to six carbon atoms;
(6) aryl;
(7) arylalkyl, wherein the alkylene group is of one to six carbon atoms;
(8) cycloalkyl of three to eight carbon atoms and
(9) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms; and
wherein, at each occurence, R
2
and R
3
are independently selected from the group consisting of
(1) hydrogen;
(2) alkyl of one to six carbon atoms;
(3) alkenyl of two to six carbon atoms;
(4) alkynyl of two to six carbon atoms;
(5) aryl;
(6) arylalkyl, wherein the alkylene group is of one to six carbon atoms
(7) cycloalkyl of three to eight carbon atoms and
(8) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms; and
wherein, at each occurence, X is selected from the group consisting of
(1) 0 and
(2) S; and
wherein, at each occurence,
m is one to five,
n is zero to four and
t is zero to two; and
wherein, at each occurence, the alkyl, alkenyl, alkynyl, aryl, heterocycle, cycloalkyl, and cycloalkenyl groups are optionally substituted.
The present invention also relates to a method of inhibiting urokinase in a mammal, particularly humans, by administering a therapeutically effective amount of a composition comprising a compound of formula (I).
The present invention also relates to pharmaceutical compositions which comprise a therapeutically effective amount of a compound of formula (I) in combination with a pharmaceutically acceptable carrier.


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S.J. Teague et al., “The Synthesis of Highly Functionalized Naphthalene Derivatives”,Synthesis, vol. 5, (1986), pp. 427-429.
H.J.J. Loozen et al, “A Short Route to Functionalized Naphthalene”,Journal Of Organic Chemistry, vol. 40, No. 4 (1975), pp. 520-521.
O. Saksela, “Plasminogen Activation and Regulation of Pericellular Proteolysis”,Biochimica Et Biophysica Acta, vol. 823, (1985), pp. 35-36.
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M.A. Alliegro e

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