Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Patent
1997-06-03
1999-10-19
Gerstl, Robert
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
514566, 560 34, 562439, C07C27518, A61K 31215
Patent
active
059689803
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a novel 1,3-dialkylurea derivative which has inhibitory effects on endopeptidase 24.11 and is useful as a therapeutic agent for cardiovascular diseases such as heart failure and hypertension, renal diseases such as renal failure, gastroenteric disorders such as diarrhea and hyperchlorhydria, endocrine and metabolic diseases such as obesity, and autoimmune diseases such as rheumatic disease, and as analgestics for myosalgia, migraine, etc. The novel 1,3-dialkylurea derivative has a group wherein a plurality of aromatic monocyclic hydrocarbons are combined or condensed, such as a biphenylyl group and a naphthyl group, and has carboxyl group(s) and/or phosphonic group(s) which are introduced into each terminal end of both alkylene chains.
BACKGROUND ART
Endopeptidase 24.11, which is one of neutral endopeptidases, is a metal-containing neutral peptidase which is required to contain zinc in its active center and it is also called enkephalinase or an antigen of acute lymphoblast leukemia (CD10).
Endopeptidase 24.11 is an enzyme which distributes widely, for example, in the kidney, lungs, central nervous system, the intestinal canal, neutrophil, fibroblast, vascular endothelial cells, etc. and hydrolyzes various physiologically active peptides such as artial natriuretic polypeptide (ANP), enkephaline, bradykinin and substance P. Accordingly, the enzyme is known to take part in various biofunctions and to exhibit various therapeutic effects by inhibiting the above-mentioned enzymatic activity.
These effects are exemplified by an effect on cardiovascular diseases such as heart failure indicating symptoms of edema and hypertension, an effect on renal diseases such as renal failure indicating symptom of edema or an increase of ascites, an effect on gastroenteric disorders such as diarrhea and hyperchlorhydria, an analgestic effect, an effect on endocrine and metabolic diseases such as obesity, and an effect on autoimmune diseases such as rheumatic disease.
Substances inhibiting endopeptidase 24.11 are described below in more detail.
The following effects of compounds inhibiting endopeptidase 24.11 have been observed. An increasing effect of total urine volume and urinary sodium excretion has been observed on heart failure models by rapid ventricular pacing method (J. Cardiovasc. Pharmacol., 19, 635-640 (1992)). An increasing effect of urinary ANP excretion and urinary cyclic GMP excretion has been observed (J. Pharmacol. Exp. Ther., 266, 872-883 (1993)). A hypotensive effect has been observed using spontaneously hypertensive rats or deoxycorticosteron acetate induced hypertensive rats (J. Pharmacol. Exp. Ther., 265, 1339-1347 (1993)). An increasing effect of urinary sodium excretion has been observed using rats subjected to five-sixths renal ablation (Circ. Res., 65, 640-646 (1989)). An inhibitory effect, which is derived from the effect on the central nervous system, upon pentagastrin-stimulated gastric secretion has been observed (Eur. J. Pharmacol., 154, 247-254 (1988)). An improvement effect of acute diarrhea caused by castor oil has been observed (Gut, 33, 753-758 (1992)). An analgestic effect has been observed by the tail-withdrawal test and the hotplate jump test (Nature, 288, 286-288 (1980)). In addition, since bonbesin (Proc. Natl. Acad. Sci., 88, 10662-10666 (1991)), which is known as one of substrates of endopeptidase 24.11, has been reported to reduce food intake (J. Clin. Endocrinol. Metab., 76, 1495-1498 (1993)), a compound inhibiting endopeptidase 24.11 is expected to be a therapeutic agent for endocrine and metabolic disease such as obesity. Since an endopeptidase 24.11 activity in blood and synovial fluid has been reported to be higher in patients with rheumatoid arthritis than in healthy men and patients with osteoarthritis (Rheumatol. Int., 13,1-4 (1993)), a compound inhibiting endopeptidase 24.11 is expected to be a therapeutic agent for autoimmune disease where an immune function is lowered such as rheumatic disease.
On the other hand, a struct
REFERENCES:
patent: 4028401 (1977-06-01), Fessler et al.
patent: 4515803 (1985-05-01), Henning et al.
patent: 4624962 (1986-11-01), Henning et al.
patent: 4728620 (1988-03-01), Haslanger et al.
patent: 5066658 (1991-11-01), Demers et al.
patent: 5140009 (1992-08-01), Haviv et al.
patent: 5175183 (1992-12-01), Brooks et al.
patent: 5262178 (1993-11-01), Malfroy-Camine et al.
patent: 5403585 (1995-04-01), Malfroy-Camine et al.
M.A. Fitzpatrick J.J. Rademaker, C.J. Charles, T.G. Yandle, E.A. Espiner, H. Ikam and C. Sybetz, Acute Hemodynamic, Hormonal, and Renal Effects of Neutral Endopeptidase Inhibition in Ovine Heart Failure, Journal of Cardiovascular Pharmacology, 19, 635-640 (1992).
Andrea A. Seymour, Magdi M. Asaad, Vita M. Lanoce, Kathleen M. Langenbacher, Susan A. Fennel, "Systemic Hemodynamics, Renal Function and Hormonal Levels During Inhibition of Neutral Endopeptidase 3.4.24.11 and Angiotensin-Converting Enzyme in Conscious Dogs With Pacing-Induced Heart Failure", The Journal of Pharmacology and Experimental Therapeutics, 266, 872-883 (1993).
I. Pham, W. Gonzalez, A.-I.K. El Amrani, M.-C. Fournie, M. Philippe, I. Laboulandine, B.P. Roques and J.-B. Michel, "Effects of Converting Enzyme Inhibitor and Neural Endopeptidase Inhibitor on Blood Pressure and Renal Function in Experimental Hypertension", The Journal of Pharmacology and Experimental Therapeutics, 265, 1339-1347 (1993).
Helen M. Lafferty, Mark Gunning, Patricio Silva, Mark B. Zimmerman, Barry M. Brenner and Sharon Anderson, "Enkephalinase Inhibition Increases Plasma Atrial Natriuretic Peptide Levels, Glomerular Filtration Rate, and Urinary Sodium Excretion in Rats With Reduced Renal Mass", Circulation Research, 65, 640-646 (1989).
Maria Chicau-Chovet, Marcelle Dubrasquet, Jacques Chariot, Annick Tsocas Jeanne-Marie Lecomte and Claude Roze, "Thiorphan and acetorphan inhibit gastric secretion by a central, non-opioid mechanism in the rat", European Journal of Pharmacology, 154, 247-254 (1988).
Ph. Baumer, E. Danquechin Dorval, J. Bertrand, J.M. Vetel, J.C. Schwartz, J.M. Lecomte, "Effects of acetorphan, an enkephalinase inhibitor, on experimental and acute diarrhoea", Gut, 33, 753-758 (1992).
Margaret A. Shipp, George E. Tarr, Chang-Yan Chen, Stephanie N. Switzer, Louis B. Hersh, Harald Stein, Mary E. Sunday and Ellis L. Reinherz, "CD10
eutral endopeptidase 24.11 hydrolyzes bombesin-like peptides and regulates the growth of small cell carcinomas of the lung", Proc. Natl. Acad. Sci. USA, 88, 10662-10666 (1991).
B.P. Roques, M.C. Fournie-Zaluski, E. Soroca, J.M. Lecomte, B. Malfroy, C. Llorens and J.-C. Schwartz, "The enkephalinase inhibitor thiorphan shows antinociceptive activity in mice", Nature, 286-288 (1980).
R.J. Lieverse, J.B.M.F. Jansen, A. van de Zwan, L. Samson, A.A.M. Masclee, L.C. Rovati and C.B.H.W. Lamers, "Bombesin Reduces Food Intake in Lean Man by a Cholecystokinin-Independent Mechanism", Journal of Chemical Endocrinology and Metabolism, 76, 1495-1498 (1993).
M. Matucci-Cerinic, A. Lombardi, G. Leoncini, A. Pignone, L. Sacerdoti, M.G. Spillantini and G. Partsch, "Neutral endopeptidase (3.4.24.11) in plasma and synovial fluid of patients with rheumatoid arthritis. A marker of disease activity or a regulator of pain and inflammation?", Rheumatol Int, 13, 1-4 (1993).
Fujimura Ken-ichi
Fujita Yuko
Kawashima Yoichi
Matsumoto Hiromi
Miyawaki Nobuaki
Gerstl Robert
Santen Pharmaceutical Co. Ltd.
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