2-alkylidene hydroxycumaranone derivatives

Details 2-alkylidene hydroxycumaranone derivatives 2-alkylidene hydroxycumaranone derivatives

1999-09-22

2001-03-13

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S254110, C514S470000, C544S368000, C546S196000, C549S466000

Reexamination Certificate

active

06200989

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to derivatives of 2-alkylidene hydroxycumaranones wherein the hydroxy group is substituted by a nitrogen-containing residue. These compounds possess uPA-uPAR antagonist activity and are useful as anti-tumor and/or antimetastatic agents.
BACKGROUND OF THE INVENTION
The serine proteases uPA (urokinase-type plasminogen activator) catalyzes the activation of plasminogen to plasmin which is involved in a variety of physiological and pathological processes. uPA is a multi-domain protein having a catalytic “B” chain (amino-acids 144-411) and an amino-terminal fragment (“ATF”, aa 1-143) comprised of a growth factor-like domain (aa 4-43) and a kringle domain (aa 47-135). uPA is a multifunctional protein involved in tissue proteolysis, cellular migration, cellular proliferation and growth factor activation. uPA is released from cells as a virtually inactive pro-enzyme, pro-uPA. The activation of the single-chain pro-uPA by plasmin (leading to the active two-chain form) is regulated by tight control mechanisms which are not completely understood yet. Most of the uPA activities are confined to the cell surface and the pericellular environment. This is accomplished by binding to a specific, high-affinity receptor on the cell surface (uPAR). Both forms of uPA bind to uPAR with similar affinity. The binding interaction is mediated by the growth factor-like domain [S. A. Rabbani et al., J. Biol. Chem., 267, 14151-56, 1992].
The uPA receptor is a three domain glycoprotein where each triplicated motif comprises a cysteine rich consensus sequence of approximately 90 amino acids [M. Plough et al., J. Biol. Chem., 268, 17539-46, 1993]. uPAR is anchored to cell membrane by a glycosyl-phosphatidylinositol moiety (GPI anchor). uPAR binds uPA with KD values between
10-10
and
10-9
M, depending on the experimental system. The major determinants for uPA binding are located in the N-terminal domain 1. uPAR can be cleaved by uPA and plasmin, liberating a water soluble domain 1 and by the action of phospholipase C, three domains uPAR (1+2+3) can be released from the cell surface. This latter form of uPAR is also water soluble because the GPI-anchor is missing.
The inhibition of uPA dependent phenomena can principally be approached in two ways, either by direct inhibition of the proteolytic activity or by inhibition of uPA receptor binding. The latter strategy has the potential of achieving greater specificity since inhibition might be localized to the pericellular environment.
Bacteriophage display technique and protein engineering have recently been used to discover peptidic and species-specific uPAR antagonists [Goodson et al., PNAS, 91, 7129, 1994; Stratton-Thomas et al., Prot. Eng., 5, 463-470, 1995, respectively].
The uPA/uPAR system has been shown to be implicated in a variety of invasive biological processes such as tumor metastasis, trophoblast implantation, inflammation and angiogenesis. Therefore, uPAR antagonists block tumor invasiveness, metastasis and angiogenesis. Formulations containing uPAR antagonists represent therapeutic treatments for a number of highly invasive and metastazising cancers where uPA and uPAR have been found to be consistently present at the invasive foci of the tumor [Dano et al., Proteolysis and Protein Turnover, eds. Barret+Bond, Portlan Press, 1994, London] (e.g. breast, lung, colon, ovarian cancers). In patients with breast cancer and non-small cell lung cancer increased levels of uPAR in plasma have been detected. Therefore, the amount of soluble uPAR appears to reflect the degree of proteolysis in the tumor and this might be closely related to patient prognosis. Both uPA and uPAR levels in tumor tissue are prognostic factors in many types of cancers.
In addition to cancer, other diseases mediated by cell-surface activity of uPA are addressed by uPAR antagonists. Inhibitors of plasmin generation by receptor bound uPA therefore have mechanism-based tumoristatic, anti-invasive, anti-metastatic, anti-angiogenic, anti-arthritic, anti-inflammatory, anti-osteoporotic, anti-retinopathic and contraceptive activities.
We have now discovered that derivatives of 2-alkylidene hydroxycumaranones wherein the hydroxy group is substituted by a nitrogen-containing residue have a significant activity of inhibition of the uPA/uPAR system functions by antagonizing the uPA receptor. These compounds are useful as antitumor and antimetastatic agents.
Some 6- and 4-piperidinoalkyloxy-2-alkylidenecumaranones are disclosed in EP 0 088 986 as antihistaminic agents and as inhibitors of the anaphylactic shock. No antitumor or antimetastatic activity of those compounds has been reported so far.
BRIEF DESCRIPTION OF THE INVENTION
In one aspect, the invention relates to a method of treating a solid tumor, or metastases thereof, comprising administering to a host in need of such treatment an effective amount of a compound of the formula (I):
wherein:
R and R′ are independently hydrogen, C
1-6
-alkyl, styryl or C
3-6
-cycloalkyl or, taken together with the carbon to which they are linked, form a C
3-6
-cycloalkyl group;
x is 0 or 1;
A is —(CH
2
)
n
—, —CH
2
CH═CHCH
2
—, —CH
2
—CH═CH—CH═CH—CH
2
—, —CH
2
—CH═CH—CH
2
—CH
2
—, —CH
2
—CH
2
—CH═CH—CH
2
—, —CH
2
—CH═CH—CH
2
—CH
2
—CH
2
—, —CH
2
—CH
2
—CH═CH—CH
2
—CH
2
—, —CH
2
—CH
2-
CH
2
—CH═CH—CH
2
—, —CH
2
—CHOH—CHOH—CH
2
—, —(CH
2
)
q
—O—(CH
2
)
q
—, or —CH
2
—A′—CH
2
—, wherein q is an integer from 2 to 3 and n is an integer from 2 to 6, and A′ is a C
3-7
cycloalkyl group;
B is
(i) —N(R
1
)—(CH
2
)
m
—N(R
2
)—, in which m is an integer from 2 to 6, R
1
is hydrogen, methyl, ethyl, propyl, or isopropyl, and R
2
is C
1-6
-alkyl, benzyl, phenyl, naphtyl or indanyl, unsubstituted or substituted by chlorine, bromine, iodine, fluorine, C
1-6
—alkyl, hydroxy, amino, carboxy, C
1-4
-alkoxy, C
1-4
-mono- or di-alkyl amino, C
1-4
—alkoxycarbonyl, mercapto, C
1-4
-alkylthio; or
T is —CH
2
—C≡CH, —C≡CH, —(CH
2
)
p
—R
3
, —CH═CH—R
3
, —CH
2
—NHCO—R
3
, —(CH
2
)
p
—O—R
3
, or —CH(NH
2
)—CH
2
R
3
, in which p is 0 or an integer from 1 to 4, R
3
is phenyl, naphthyl or biphenyl, unsubstituted or substituted by chlorine, bromine, iodine, fluorine, (C1-C6)alkyl, cyano, nitro, mono- or polyfluoroalkyl, —SO
2
(C
1-4
)alkyl, —SO
2
NH
2
, —SO
2
NH(C
1-4
)alkyl, —SO
2
N[(C
1-4
)alkyl]
2
, —CONH
2
, —CONH(C
1-4
)alkyl, hydroxy, amino, carboxy, C
1-4
-alkoxy, (C
1-4
)mono- or di-alkyl amino, (C
1-4
)alkoxycarbonyl, mercapto, or C
1-4
alkylthio, or is a 5- or 6-membered heterocycle which contains 1 or 2 heteroatom(s) selected from oxygen, sulfur or nitrogen and which is or is not benzocondensed,
or an enantiomer, diastereoisomer, or racemate of a compound of formula I, or a mixture thereof, or a pharmaceutically acceptable salt of a compound of formula I.
Preferably, the O-substituted residue on the cumaranone ring is in the 4 position.
In another aspect, the invention relates to a compound of formula IA
wherein R, R′, x, A, B, and T are as above, provided the compound of formula IA is not 4(3-(4-(4-fluorobenzamido)piperidin)propoxy)-2-isopropylidencumaran-3-one.
Preferably, A is a —(CH
2
)
n
— group and n is an integer from 2-6, —CH
2
CH═CHCH
2
—, or —(CH
2
)
q
—O—(CH
2
)
q
— and q is an integer from 2 to 3.
Preferably, x is 1.
Preferably, B is the moiety
Preferably, T is phenyl or phenyl substituted by one or two trifluoro, bromo, chloro, fluoro, cyano, nitro, methyl or aminosulfonyl groups.
Preferably, R and R′ are C
1-6
-alkyl.
More preferably, x is 1, and B is the moiety
Even more preferably, when R and R′ are C
1-6
-alkyl, x is 1, and B is the moiety
Even more preferably, when R and R′ are C
1-6
-alkyl, x is 1, and B is the moiety
A is a —(CH
2
)
n
- group and n is an integer from 2-6, —CH
2
CH═CHCH
2
—, or —(CH
2
)
q
—O—(CH
2
)
q
— and q is an integer from 2 to 3, and T is phenyl or phenyl substituted by one or two trifluoro, bromo, chloro, flu

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