Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2000-05-15
2002-10-08
Lambkin, Deborah C. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C546S279100, C548S517000, C548S531000
Reexamination Certificate
active
06462194
ABSTRACT:
TECHNICAL FIELD
The present invention relates to compounds which are endothelin antagonists, processes for making such compounds, synthetic intermediates employed in these processes and methods and compositions for antagonizing endothelin.
BACKGROUND OF THE INVENTION
Endothelin (ET) is a 21 amino acid peptide that is produced by endothelial cells. ET is produced by enzymatic cleavage of a Trp-Val bond in the precursor peptide big endothelin (Big ET). This cleavage is caused by an endothelin converting enzyme (ECE). Endothelin has been shown to constrict arteries and veins, increase mean arterial blood pressure, decrease cardiac output, increase cardiac contractility in vitro, stimulate mitogenesis in vascular smooth muscle cells in vitro, contract non-vascular smooth muscle including guinea pig trachea, human urinary bladder strips and rat uterus in vitro, increase airway resistance in vivo, induce formation of gastric ulcers, stimulate release of atrial natriuretic factor in vitro and in vivo, increase plasma levels of vasopressin, aldosterone and catecholamines, inhibit release of renin in vitro and stimulate release of gonadotropins in vitro.
It has been shown that vasoconstriction is caused by binding of endothelin to its receptors on vascular smooth muscle (Nature 332 411 (1988), FEBS Letters 231 440 (1988) and Biochem. Biophys. Res. Commun. 154 868 (1988)). An. agent which suppresses endothelin production or an agent which binds to endothelin or which inhibits the binding of endothelin to an endothelin receptor will produce beneficial effects in a variety of therapeutic areas. In fact, an anti-endothelin antibody has been shown, upon intrarenal infusion, to ameliorate the adverse effects of renal ischemia on renal vascular resistance and glomerular filtration rate (Kon, et al., J. Clin. Invest. 83 1762 (1989)). In addition, an anti-endothelin antibody attenuated the nephrotoxic effects of intravenously administered cyclosporin (Kon, et al., Kidney Int. 37 1487 (1990)) and attenuated infarct size in a coronary artery ligation-induced myocardial infarction model (Watanabe, et al., Nature 344 114 (1990)).
Clozel et al. (Nature 365: 759-761 (1993)) report that Ro 46-2005, a nonpeptide ET-A/B antagonist, prevents post-ischaemic renal vasoconstriction in rats, prevents the decrease in cerebral blood flow due to subarachnoid hemorrhage (SAH) in rats, and decreases MAP in sodium-depleted squirrel monkeys when dosed orally. A similar effect of a linear tripeptide-like ET-A antagonist, BQ-485, on arterial caliber after SAH has also been recently reported (S. Itoh, T. Sasaki, K. Ide, K. Ishikawa, M. Nishikibe, and M. Yano, Biochem. Biophys. Res. Comm. , 195: 969-75 (1993). These results indicate that agents which antagonize ET/ET receptor binding will provide therapeutic benefit in the indicated disease states.
Agents with the ability to antagonize ET/ET receptor binding have been shown to be active in a number of animal models of human disease. For example, Hogaboam et al (EUR. J. Pharmacol. 1996, 309, 261-269), have shown that an endothelin receptor antagonist reduced injury in a rat model of colitis. Aktan et al (Transplant Int 1996, 9, 201-207) have demonstrated that a similar agent prevents ischemia-reperfusion injury in kidney transplantation. Similar studies have suggested the use of endothelin antagonists in the treatment of angina, pulmonary hypertension, Raynaud's disease, and migraine. (Ferro and Webb, Drugs 1996, 51, 12-27).
Abnormal levels of endothelin or endothelin receptors have also been associated with a number of disease states, including prostate cancer (Nelson et al, Nature Medicine 1995, 1, 944-949), suggesting a role of endothelin in the pathophysiology of these diseases.
Wu-Wong et al (Lfe Sciences 1996, 58, 1839-1847) have shown hat both endothelin and endothelin antagonists bind tightly to plasma proteins, e.g., serum albumin. This plasma protein binding can decrease the effectiveness with which the antagonists inhibit endothelin's action. Thus, endothelin antagonists with reduced plasma protein binding may be more effective than highly bound congeners.
DISCLOSURE OF THE INVENTION
In accordance with the present invention there are compounds of the formula (I):
wherein
Z is —C(R
18
)(R
19
)— or —C(O)— wherein R
18
and R
19
are independently selected from hydrogen and loweralkyl;
n is 0 or 1;
R is —(CH
2
)
m
—W wherein m is an integer from 0 to 6 and W is
(a) —C(O)
2
—G wherein G is hydrogen or a carboxy protecting group,
(b) —PO
3
H
2
,
(c) —P(O)(OH)E wherein E is hydrogen, loweralkyl or arylalkyl,
(d) —CN,
(e) —C(O)NHR
17
wherein R
17
is loweralkyl,
(f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl,
(h) tetrazolyl,
(i) hydroxy,
(j) alkoxy,
(k) sulfonamido,
(l) —C(O)NHS(O)
2
R
16
wherein R
16
is loweralkyl, haloalkyl, aryl or dialkylamino,
(m) —S(O)
2
NHC(O)R
16
wherein R
16
is defined as above,
R
1
and R
2
are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (R
aa
)(R
bb
)N—R
cc
— wherein R
aa
is aryl or arylalkyl, R
bb
is hydrogen or alkanoyl and R
cc
is alkylene, with the proviso that one or both of R
1
and R
2
is other than hydrogen;
R
3
is (a) R
4
—C(O)—R
5
—, R
4
—R
5a
—, R
4
—C(O)—R
5
—N(R
6
)—, R
6
—S(O)
2
—R
7
— or R
26
—S(O)—R
27
—
wherein R
5
is (i) a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) —N(R
20
)—R
8
— or —R
8a
—N(R
20
)—R
8
— wherein R
8
and R
8a
are independently selected from the group consisting of alkylene and alkenylene and R
20
is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cylcoalkyl or cycloalkylalkyl or (v) —O—R
9
— or —R
9a
—O—R
9
— wherein R
9
and R
9a
are independently selected from alkylene;
R
5a
is (i) alkylene or (ii) alkenylene;
R
7
is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) —N(R
21
)—R
10
— or —R
10a
—N(R
21
)—R
10
— wherein R
10
and R
10a
are independently selected from the group consisting of alkylene and alkenylene and R
21
is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl;
R
4
and R
6
are independently selected from the group consisting of
(i) (R
11
)(R
12
)N— wherein R
11
and R
12
are independently selected from
(1) hydrogen,
(2) loweralkyl,
(3) haloalkyl,
(4) alkoxyalkyl,
(5) haloalkoxyalkyl,
(6) alkenyl,
(7) alkynyl,
(8) cycloalkyl,
(9) cycloalkylalkyl,
(10) aryl,
(11) heterocyclic,
(12) arylalkyl,
(13) (heterocyclic)alkyl,
(14) hydroxyalkyl,
(1 5) alkoxy,
(16) aminoalkyl,
(17) trialkylaminoalkyl,
(18) alkylaminoalkyl,
(19) dialkylaminoalkyl, and
(20) carboxyalky
1
,
(ii) loweralkyl,
(iii) alkenyl,
(iv) alkynyl,
(v) cycloalkyl,
(vi) cycloalkylalkyl,
(vii) aryl,
(viii) arylalkyl,
(ix) heterocyclic,
(x) (heterocyclic)alkyl,
(xi) alkoxyalkyl,
(xii) hydroxyalkyl,
(xiii) haloalkyl,
(xiv) haloalkenyl,
(xv) haloalkoxyalkyl,
(xvi) haloalkoxy,
(xvii) alkoxyhaloalkyl,
(xviii) alkylaminoalkyl,
(xix) dialkylaminoalkyl,
(xx) alkoxy, and
wherein z is 0-5 and R
7a
is alkylene;
R
26
is (i) loweralkyl, (ii) haloalkyl, (iii) alkenyl, (iv) alkynyl, (v) cycloalkyl, (vi) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) alkoxyalkyl or (xii) alkoxy-substituted haloalkyl; and
R
27
is alkylene or alkenylene;
(b) R
22
—O—C(O)—R
23
— wherein R
22
is a carboxy protecting group or heterocyclic and R
23
is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) —N(R
24
)—R
25
—wherein R
25
is alkylene and R
24
is hydrogen or loweralkyl,
(c) loweralkyl,
(d) alkenyl,
(e) alkynyl,
(f) cycloalkyl,
(g) cycloalkylalkyl,
(h) aryl,
(i) arylalkyl,
(j) aryloxyalkyl,
(k) heterocycli
Boyd Steven A.
Henry Kenneth J.
Hutchins Charles W.
Jae Hwan-Soo
Kester Jeffrey A.
Abbott Laboratories
Donner B. Gregory
Lambkin Deborah C.
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