Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-11-25
2003-09-23
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S144000
Reexamination Certificate
active
06624164
ABSTRACT:
A subject of the present invention is novel 1,3-dihydro-2H-indol-2-one derivatives, a process for their preparation and the pharmaceutical compositions comprising them.
The compounds according to the present invention exhibit an affinity and a selectivity for arginine-vasopressin (AVP) V
1b
receptors or for both V
1b
and V
1a
receptors.
AVP is a hormone known for its antidiuretic effect and its effect in regulating arterial pressure. It stimulates several types of receptors: V
1
(V
1a
, V
1b
) or V
2
. These receptors are located in particular in the liver, vessels (coronary, renal, cerebral), platelets, kidney, uterus, adrenal glands, pancreas, central nervous system or pituitary gland. AVP thus exerts cardiovascular, hepatic, pancreatic, antidiuretic and platelet-aggregating effects and effects on the central and peripheral nervous system and on the uterine sphere.
The localization of various receptors is described in: S. Jard et al., Vasopressin and oxytocin receptors: an overview, in Progress in Endocrinology, H. Imura and K. Shizurne ed., Experta Medica, Amsterdam, 1988, 1183-1188, and in the following articles: J. Lab. Clin. Med., 1989, 114 (6), 617-632 and Pharmacol. Rev., 1991, 43 (1), 73-108.
More particularly, AVP V
1a
receptors are located in numerous peripheral organs and in the brain. They have been cloned in the rat and man and they regulate the majority of known effects of AVP: platelet aggregation; uterine contractions; vessel contraction; the secretion of aldosterone, of cortisol, of CRF (corticotropin-releasing factor) and of adrenocorticotrophic hormone (ACTH); hepatic glycogenolysis, cell proliferation and the main central effects of AVP (hypothermia, memory, and the like).
The V
1b
receptors were initially identified in the adenohypophysis of various animal species (rat, pig, cow, sheep, and the like), including in man (S. Jard et al., Mol. Pharmacol., 1986, 30, 171-177; Y. Arsenijevic et al., J. Endocrinol., 1994, 141, 383-391; J. Schwartz et al., Endocrinology, 1991, 129 (2), 1107-1109; Y. de Keyser et al., FEBS Letters, 1994, 356, 215-220), where they stimulate the release of adrenocorticotrophic hormone by AVP and potentiate the effects of CRF on the release of ACTH (G. E. Gillies et al., Nature, 1982, 299, 355). In the hypothalamus, the V
1b
receptors also induce a direct release of CRF (Neuroendocrinology, 1994, 60, 503-508) and are, in these various respects, implicated in stress situations.
These V
1b
receptors have been cloned in the rat, man and mouse (Y. de Keyser, FEBS Letters, 1994, 356, 215-220; T. Sugimoto et al., J. Biol. Chem., 1994, 269 (43), 27088-27092; M. Saito et al., Biochem. Biophys. Res. Commun., 1995, 212 (3), 751-757; S. J. Lolait et al., Neurobiology, 1996, 92, 6783-6787; M. A. Ventura et al., Journal of Molecular Endocrinology, 1999, 22, 251-260) and various studies (in situ hybridization, PCR (Polymerase Chain Reaction), and the like) reveal ubiquitous localization of these receptors in various central tissues (brain, hypothalamus and adenohypophysis, in particular) and peripheral tissues (kidney, pancreas, adrenal glands, heart, lungs, intestine, stomach, liver, mesentery, bladder, thymus, spleen, uterus, retina, thyroid, and the like) and in some tumors (hypophyseal or pulmonary tumors, and the like), suggesting a broad biological and/or pathological role of these receptors and potential involvement in various diseases.
By way of examples, in the rat, studies have shown that AVP, via the V
1b
receptors, regulates the endocrine pancreas, stimulating the secretion of insulin and of glucagon (B. Lee et al., Am. J. Physiol., 269 (Endocrinol. Metab. 32), E1095-E1100, 1995) or the production of catecholamines in the medulloadrenal, which is the site of a local synthesis of AVP (E. Grazzini et al., Endocrinology, 1996, 137 (a), 3906-3914). Thus, in the last tissue, AVP, via these receptors, would have a crucial role in some types of adrenal pheochromocytomas which secrete AVP and which, for this reason, bring about a sustained production of catecholamines which are the cause of hypertensions which are resistant to angiotensin-II receptor antagonists and to converting enzyme inhibitors. The adrenal cortex is also rich in V
1a
receptors involved in the production of gluco- and mineralocorticoids (aldosterone and cortisol). V
1a
these receptors, AVP (circulating or synthesized locally) can bring about production of aldosterone with an effectiveness comparable to that of angiotensin II (G. Guillon et al., Endocrinology, 1995, 136 (3), 1285-1295). Cortisol is a powerful regulator of the production of ACTH, the stress hormone.
Recent studies have also shown that the adrenal glands are capable of directly releasing CRF and/or ACTH via the activation of the V
1b
and/or V
1a
receptors carried by the cells of the medulla (G. Mazzocchi et al., Peptides, 1997, 18(2), 191-195; E. Grazzini et al., J. Clin. Endocrinol. Metab., 1999, 84 (6), 2195-2203).
The V
1b
receptors are also regarded as a label for ACTH-secreting tumors, which are some pituitary tumors and some bronchial (Small Cell Lung Cancers or SCLC), pancreatic, adrenal and thyroid carcinomas, resulting in some cases in Cushing's syndrome (J. Bertherat et al., Eur. J. Endocrinol., 1996, 135, 173; G. A. Wittert et al., Lancet, 1990, 335, 991-994; G. Dickstein et al., J. Clin. Endocrinol. Metab., 1996, 81 (8), 2934-2941). The V
1a
receptors are, for their part, a more specific label for small cell lung cancers (SCLC) (P. J. Woll et al., Biochem. Biophys. Res. Commun., 1989, 164 (1), 66-73). Thus, the compounds according to the present invention are obvious diagnostic tools and offer a novel therapeutic approach in the proliferation and detection of these tumors, at an early stage too (radiolabeling; SPECT (Single Photon Emission Computed Tomography); PET Scan (Positron Emission Tomography Scanner)).
The lavish presence of the messenger of the V
1b
receptors in the stomach and intestine suggests involvement of AVP via this receptor in the release of gastrointestinal hormones, such as cholecystokinin, gastrin or secretin (T. Sugimoto et al., Molecular cloning and functional expression of V
1b
receptor gene, in Neurohypophysis: Recent Progress of Vasopressin and Oxytocin Research; T. Saito, K. Kurokawa and S. Yoshida ed., Elvesier Science, 1995, 409-413).
1,3-Dihydro-2H-indol-2-one derivatives have been disclosed in some patent applications as ligands of the arginine-vasopressin and/or oxytocin receptors: mention may be made of patent applications WO 93/15051, EP 636 608, EP 636 609, WO 95/18105, WO 97/15556 and WO 98/25901.
To date, no nonpeptide compound having an affinity and a selectivity for arginine-vasopressin V
1b
receptors or for both V
1b
and V
1a
receptors is known.
Novel 1,3-dihydro-2H-indol-2-one derivatives have now been found which exhibit an affinity and a selectivity for arginine-vasopressin V
1b
receptors or for both V
1b
and V
1a
receptors.
These compounds can be used for the preparation of medicaments of use in the treatment or prevention of any pathology where arginine-vasopressin and/or the V
1b
receptors or both the V
1b
receptors and the V
1a
receptors are implicated, in particular in the treatment or prevention of conditions of the cardiovascular system, for example hypertension of the central nervous system, for example stress, anxiety, depression, obsessive-compulsive disorder or panic attacks of the renal system or of the gastric system and in the treatment of small cell lung cancers, of obesity of type-II diabetes of insulin resistance of hypertriglyceridemia of atherosclerosis of Cushing's syndrome; or of any pathology resulting from stress and chronic stress conditions.
Thus, according to one of its aspects, the subject of the present invention is compounds of formula:
in which:
R
1
represents a halogen atom; a (C
1
-C
4
)alkyl; a (C
1
-C
4
)alkoxy; a trifluoromethyl radical; or a trifluoromethoxy radical;
R
2
represents a hydrogen atom; a halogen atom; a (C
1
-C
4
)alkyl; a (C
1-C
4
)alkoxy; or a trifluoromethyl radical;
Gal Claudine Serradeil-Le
Schoentjes Bruno
Wagnon Jean
Alexander Michael D.
Dupont Paul E.
Ramsuer Robert W.
Sanofi-Synthelabo
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