Substituted phenyl compounds

Details Substituted phenyl compounds Substituted phenyl compounds

1997-06-27

2001-04-03

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S521000, C514S522000, C514S568000, C514S570000, C558S411000, C558S414000, C558S415000, C558S423000

Reexamination Certificate

active

06211234

ABSTRACT:

FIELD OF THE INVENTION
This invention is directed to substituted phenyl compounds, their preparation, pharmaceutical compositions containing these compounds, and their pharmaceutical use in the treatment of disease states associated with endothelin peptides.
Endothelins are a family of peptides, mainly synthesized and released by endothelial cells. The term endothelin (ET) refers to a family of homologous 21-amino acid peptides found in three distinct isoforms: ET-1, ET-2 and ET-3, and in the present specification the term “endothelin” is intended to refer to any or all of the isoforms of endothelin. Each endothelin isopeptide is encoded by a distinct gene with a distinct chromosomal locus for each human gene.
Receptor subtypes ET
A
and ET
B
specific for endothelin have been identified (H. Arai, et al.,
Nature,
348, 730 (1990) and T. Sakurai et al.,
Nature,
348, 732 (1990)). ET-1 and ET-2 bind more potently than ET-3 to ET
A
, and stimulation of this receptor subtype promotes vasoconstriction. ET-1, ET-2 and ET-3 bind with equal affinity to ET
B
receptors, and stimulation of this receptor subtype can evoke vasodilation or promote vasoconstriction.
Thus, endothelin is an important potent vasoconstrictor producing long-lasting effects in arteries and veins. Consequently, endothelin causes profound actions on the cardiovascular system in particular the coronary, renal, mesenteric and cerebral circulation. Other biological activities by endothelin are also observed. Thus, disease states associated with a physiologically detrimental excess of endothelin are treatable according to the invention.
Intravenous infusion of ET-1 to rats causes a transient hypotensive effect, followed by a sustained increase in blood pressure. Even low doses of endothelin, which alone are without pressor actions, potentiate the effects of other vasoconstrictor agents. Significantly elevated plasma immunoreactive ET-1 levels have been reported in patients with disorders such as myocardial infarction including acute myocardial infarction, coronary heart disease, unstable angina including vasospastic angina, preeclampsia, essential and pulmonary hypertension and congestive heart failure.
Renal blood vessels are particularly sensitive to the vasoconstrictor effect of ET. It produces a marked reduction in renal blood flow accompanied by reductions in glomerular filtration rate, urine volume and urinary sodium and potassium excretion. Endothelin is also mitogenic for mesangial cells. Thus, endothelin has a role in a number of renal disorders such as acute renal insufficiency and chronic renal insufficiency and cyclosporin induced nephrotoxicity. Furthermore, erythropoetin causes endothelin release and that release plays a role in renal complications and hypertension occurring as side effects in dialysis patients.
Endothelin induces a proliferative response in vascular smooth muscle cells and this, combined with observations of elevated circulating levels of ET-1 in atherosclerosis, indicates that endothelin contributes to the pathogenesis of this and related diseases. Levels of endothelin are also elevated after angioplasty and is implicated in the high level of restenosis after percutaneous transluminal angioplasty.
The cerebral vasculature is very sensitive to the pressor actions of the endothelins. A single intrathecal injection of ET-1 in dogs leads to a prolonged constriction of the basilar artery. Hypoxia and ischaemia are potent stimuli for increased release of endothelin by endothelial cells, while the secretion of endogenous vasodilators such as PGI
2
and endothelial derived relaxant factor are reduced. Therefore, endothelin plays an important role in cerebral ischaemia such as stroke and subarachnoid hemorrhage.
Endothelin is a potent contractor of isolated airway tissue including human bronchus. In addition, endothelin has been shown to induce eicosanoid release, possess mitogenic properties for airway smooth muscle and has pronounced inflammatory actions. All of these actions confirm an important role for endothelin in pulmonary pathophysiology and in asthma and related conditions.
Endothelin levels are elevated during septic shock and other endotoxin induced conditions such as disseminated intravascular coagulation, migraine, gastrointestinal disorders such as ulceration and irritable bowel syndrome, Raynauds disease and haemangioendothelioma.
Normal bone remodelling involves the coupling of osteoclast and osteoblast functions, an imbalance of these events leading to pathophysiological bone loss. Both cell types produce endothelin and possess endothelin receptors. Antagonists of selected actions of endothelin would therefore be useful in the treatment of clinical conditions of bone loss, such as osteoporosis.
Endothelin-1 is produced in the human prostrate and endothelin receptors have been identified in this tissue. Since endothelin is a paracrine contractile and proliferative factor in the prostrate gland, a role is indicated for endothelin in benign prostatic hyperplasia.
The further actions of endothelin on neurotransmitter release are also observed, indicating a role in certain disorders of the central nervous system.
SUMMARY OF THE INVENTION
This invention is directed to compounds useful for inhibiting the production or physiological effects of endothelin in the treatment of a patient suffering from a disease state associated with a physiologically detrimental excess of endothelin. Thus, according to a first aspect of the present invention, we provide a compound of formula I as follows:
wherein
R
1
is hydrogen, -(lower alkyl)
q
(CO
2
R
6
or OH), —CN, —C(R
7
)═NOR
8
, —NO
2
, —O(lower alkyl)R
9
, —C≡C—R
10
, —CR
11
═C(R
12
)(R
13
), —C(═O)CH
2
C(═O)CO
2
H, —CO(R
14
), alkylthio, alkylsulphinyl, alkylsulphonyl, carbamoyl, thiocarbamoyl, substituted carbamoyl, substituted thiocarbamoyl, sulphamoyl or an optionally substituted nitrogen-containing ring;
R
2
is aryl lower alkoxy, heteroaryl lower alkoxy, aryl lower alkylthio or heteroaryl lower alkylthio;
R
3
is hydroxy, alkoxy, aryloxy, cycloalkyl(lower alkyl)oxy, cycloalkenyl(lower alkyl)oxy, aryl lower alkoxy, heteroaryl lower alkoxy, aryl lower alkylthio, heteroaryl lower alkylthio or aralkynyl;
R
4
is —Y—CH(R
15
)(alkyl or alkenyl)R
16
;
R
5
is alkyl, alkenyl or halo;
R
6
, R
7
, R
17
, R
18
and
19
are independently hydrogen or alkyl;
R
8
is hydrogen, aralkyl or -(lower alkyl)CO
2
R
17
;
R
9
is —CN, —CO
2
R
19
, —CH
2
OH, or carbamoyl;
R
10
is —CO
2
H or carboxyphenyl;
R
11
is hydrogen, alkyl or aralkyl;
R
12
and R
13
are independently hydrogen, —CO
2
R
18
, —CN, aryl lower alkyl, heteroaryl lower alkyl or —NHC(═O)aryl, provided that one of R
12
and R
13
is —CO
2
H;
R
14
is hydrogen, alkyl, -(lower alkyl)carboxy, aralkenyl, heteroaralkenyl or carboxy;
R
15
is aryl or heteroaryl;
R
16
is carboxy or acid isostere;
Y is oxygen or carbonyl; and
m, n, o, p and q are independently zero or 1,
with the provisos that (i) when o is zero then m and n are both 1 (ii) when o is 1 then at least one of m and n is 1 (iii) when o is zero then R
1
cannot represent hydrogen,
or a pharmaceutically acceptable salt, N-oxide or prodrug thereof.
DETAILED DESCRIPTION OF THE INVENTION
As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
Definitions
“Patient” includes both human and other mammals.
“Pharmaceutically acceptable salt” means a salt form of the parent compound of formula I which is relatively innocuous to a patient when used in therapeutic doses so that the beneficial pharmaceutical properties of the parent compound of formula I are not vitiated by side-effects ascribable to a counter ion of that salt form. Pharmaceutically acceptable salt also includes a zwitterion or internal salt of the compound of formula I.
“Alkyl” means an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 6 carbon atoms in the chain. Preferred alkyl groups have 1 to about 4 carbo

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