Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-09-15
2004-11-09
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S217040, C514S307000, C514S314000, C540S593000, C546S113000, C546S135000, C546S148000
Reexamination Certificate
active
06815451
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel 1,2,3,4-tetrahydroisoquinoline derivatives of the general formula 1 and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of the general formula 1 and especially their use as neurohormonal antagonists.
BACKGROUND OF THE INVENTION
Urotensin II is a cyclic 11-amino acid peptide that has some sequence similarity to, but is not homologous with, somatostatin-14. Urotensin II was first isolated and sequenced from fish spinal cord (Bern H A, Pearson D, Larson B A, Nishioka R S. Neurohormones from fish tails: the caudal neurosecretory system. I. “Urophysiology” and the caudal neurosecretory system of fishes. Recent Prog. Horm. Res. (1985) 41, 533-552), and has since been found in a wide variety of vertebrate and invertebrate species. Human urotensin II is synthesized in a prepro-form from a single gene located at chromosome 1p36.21, and two cDNA splice variants which differ in their putative signal peptide sequence have been isolated from human colon tumor and human placenta (GenBank Accession Nr. O95399). The putative prohormone convertase dibasic cleavage site is strictly conserved across species. The mature 11-amino acid peptide contains a C-terminal disulfide-bridged 6-amino acid loop which is also strictly conserved, while the N-terminal portion of the mature cyclic peptide can vary considerably across species.
Urotensin II exerts potent and complex hemodynamic actions in mammals (Douglas S A, Sulpizio A C, Piercy V, Sarau H M, Ames R S, Alyar N V, Ohlstein E H, Willette R N. “Differential vasoconstrictor activity of human urotensin-II in vascular tissue isolated from the rat, mouse, dog, pig, marmoset and cynomolgus monkey.” Br. J. Pharmacol. (2000) 131, 1262-1274. Douglas, S A, Ashton D J, Sauermelch C F, Coatney R W, Ohlstein D H, Ruffolo M R, Ohlstein E H, Alyar N V, Willette R “Human Urotensin-II is a potent vasoactive peptide: pharmacological characterization in the rat, mouse, dog and primate.” J. Cardiovasc. Pharmacol. (2000) 36, Suppl 1:S163-6). The peptide effectively constricts isolated mammalian arteries. The potency of vasoconstriction is an order of magnitude greater than that of endothelin-1. These effects appear to be mediated at least in part via the actions of urotensin II on a G-protein coupled receptor named GPR-14 or SENR (Ames R S, et al. “Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14.” Nature. (1999) 401, 282-6. Mori M, Sugo T, Abe M, Shimomura Y, Kurihara M, Kitada C, Kikuchi K, Shintani Y, Kurokawa T, Onda H, Nishimura 0, Fujino M. “Urotensin II is the endogenous ligand of a G-protein-coupled orphan receptor, SENR (GPR14)” Biochem. Biophys. Res. Commun. (1999) 265, 123-9. Liu Q, Pong S S, Zeng Z, et al. “Identification of urotensin II as the endogenous ligand for the orphan G-protein-coupled receptor GPR14” Biochem. Biophys. Res. Commun. (1999) 266, 174-178.) GPR14 is expressed in arterial (but not venous) smooth muscle cells, on atrial and ventricular cardiac myocytes, in pancreas, kidney, and in the brain.
In addition to its vasoconstrictive actions, urotensin II potently affects atrial and ventricular muscle contraction (Russell F D, Molenaar P, and O'Brien D M “Cardiostimulant effects of urotensin-II in human heart in vitro”. Br J Pharmacol (2001) 132, 5-9).
Urotensin II stimulates cellular proliferation, migration and collagen synthesis in cardiac fibroblasts (Tzandis A, et al., “Urotensin II stimulates collagen synthesis by cardiac fibroblasts and hypertrophic signaling cardiomyocytes via G(alpha)q- and Ras-dependent pathways”. J. Am. Coll. Cardiol. (2001) 37, 164A.) and in neonatal myocytes (Zou Y, Nagai R, and Yamazaki T, “Urotensin II induces hypertrophic responses in cultured cardiomyocytes from neonatal rats”. FEBS Lett (2001) 508, 57-60). Urotensin II is produced by cancer cell lines and its receptor is also expressed in these cells. (Takahashi K, et al., “Expression of urotensin II and urotensin II receptor mRNAs in various human tumor cell lines and secretion of urotensin II-like immunoreactivity by SW-13 adrenocortical carcinoma cells”. Peptides (2001) 22, 1175-9).
Urotensin II modulates' glucose-stimulated pancreatic release of insulin (Silvestre R A, et al., “Inhibition of insulin release by urotensin II—a study on the perfused rat pancreas”. Horm Metab Res (2001) 33, 379-81).
Elevated circulating levels of urotensin II are detected in humans susceptible to high-altitude pulmonary edema, and in patients awaiting kidney transplantation (Totsune K, et al., “Role of urotensin II in patients on dialysis”. Lancet (2001) 358, 810-1).
Urotensin II and its receptor are found in spinal cord and brain tissue, and intracerebroventricular infusion of urotensin II into mice induces behavioral changes (Gartlon J, et al., “Central effects of urotensin-II following ICV administration in rats”. Psychopharmacology (Berlin) (2001) 155, 426-33).
Substances with the ability to block the actions of urotensin II are accordingly expected to prove useful in the treatment of various diseases. WO-2001/45694 discloses certain sulfonamides as urotensin II receptor antagonists, and their use to treat diseases associated with a urotensin II imbalance. WO-2001/45700 discloses certain pyrrolidines as urotensin II receptor antagonists and their use to treat diseases associated with a urotensin II imbalance. WO-2001/45711 discloses certain pyrrolyl and pyridyl derivatives as urotensin II receptor antagonists and their use to treat diseases associated with a urotensin II imbalance. WO-2002/00606 discloses certain biphenyl compounds useful as urotensin II receptor antagonists, and WO-2002/02530 also discloses certain compounds useful as urotensin II receptor antagonists.
The present invention comprises 1,2,3,4-tetrahydroisoquinoline derivatives which are novel compositions of matter and which are urotensin II receptor antagonists. EP 428434 discloses certain alkylureidopyridines as neurokinin and substance P antagonists. WO-99/21835 discloses certain ureidoquinolines as H+-ATPase and bone resorption inhibitors. WO-01/009088 discloses certain substituted heteroarylureas as inhibitors of the CCR-3 receptor.
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Ames R.S. et al., “Human Urotensin-II is a Potent Vasoconstrictor and Agonist for the Orphan Receptor GPR14”,Nature, vol. 401, Sep. 16, 1999, pp. 282-286.
Barlin G.B. and Tan Weng-Lai, “Potential Antimalarials. I 1,8-Naphthyridines”,Australian Journal of Chemistry,vol. 37, 1984, pp. 1065-1073.
Bern H.A. et al., “Neurohormones from Fish Tails: The Caudal Neurosecretory System I. “Urophysiology” and the Caudal Neurosecretory System of Fishes”,Recent Progress in Hormone Research,vol. 41, 1985, pp. 533-552.
Brasyunas V.B. et al., “Synthesis of Quinoline-4-Carboxylic Acid and Its Derivatives”, inChemistry of Heterocyclic Compounds,vol. 24, No. 6, Jun. 1988, pp. 670-672.
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Douglas S.A. et al., “Differential Vasoconstrictor Activity of Human Urotensin-II in Vascular Tissue Isolated from the Rat, Mouse, Dog, Pig, Marmoset and Cynomolgus Monkey”,British Journal of Pharmacology,vol. 131, No. 7, 2000, pp. 1262-1274.
Douglas S.A. et al., “Human Urotensin-II is a Potent Vasoactive Peptide: Pharmacological Characterization in the Rat, Mouse, Dog and Primate”,Jou
Aissaoui Hamed
Binkert Christoph
Clozel Martine
Mathys Boris
Mueller Claus
Actelion Pharmaceuticals Ltd.
Davis Zinna Northington
Dickstein Shapiro Morin & Oshinsky LLP.
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