Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Patent
1995-04-06
1997-09-16
Bernhardt, Emily
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
544 62, 544232, 544237, C07D23732, C07D40104, C07D40904, C07D41310
Patent
active
056682794
DESCRIPTION:
BRIEF SUMMARY
INTRODUCTION OF THE INVENTION
This invention relates to novel substituted phthalazinone compounds represented by formula I: ##STR2## which are antagonists of peptide hormone neurotensin. The invention is also concerned with the use of aforementioned neurotensin antagonists in the treatment of states meditated by neurotensin.
BACKGROUND OF THE INVENTION
Neurotensin (NT) is a tridecapeptide hormone (pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu-OH), originally isolated from the bovine hypothalamus [Carraway, R. and Leeman, S. E., J. Biol. Chem., 248, 6854 (1973)], has subsequently been shown to be distributed in the brain [Uhl, G. R., et al., Proc. Natl. Acad. Sci. USA, 74, 4059-4063 (1977)], gastrointestinal tract [1). Kitabgi, P., Carraway, R. and Leeman, S. E., J. Biol. Chem., 251, 7053 (1976); 2). Carraway, R., Kitabgi, P., and Leeman, S. E., J. Biol. Chem., 253, 7996 (1978); 3).Helmstadler, V., Taugner, C., Feurle, G. E. and Frossman, W. G., Histochemistry, 53, 35-41 (1977)] and pancreas [Feurle, G. E. and Niestroj, S., Pancreas, 6, 202-207 (1991) and references cited therein] of various animals including human [Mai, J. K., et al., Neuroscience, 22, 499-524 (1987)]. Although the physiological role of neurotensin has not yet been clearly understood, this endogenous peptide participates in a wide spectrum of central [1). Prange, A. J. and Nemeroff, C. B., Annal. NY Acad. Sciences, 400, 368-375 (1982); 2). Stowe, Z. N.and Nemeroff, C. B., Life Sci., 49, 987-1002; (1991); 3) Kitabgi, P., Neurochem. Int., 14, 111-119 (1989); 4). Levant and Nemeroff, C. B., Current topics in Neuroendocrinology, 8, 231-262 (1988)] and peripheral [Leeman, S. E., Aronin, N. and Ferris, C., Hormone Res., 38, 93-132 (1982)] biological functions.
Neurotensin is also known to release mast cell histamine, indicating that antagonists will be useful in the treatment of allergic and inflammatory conditions, as well. [See, Rossei, S. S. and Miller, R. J., Life Sci., 31, 509-516 (1982) and Kurose, M. and Saeki, K., Eur. J. Pharmacol., 76, 129-136 (1981).]
Neurotensin, like most other peptides, is unable to cross the blood-brain barrier (BBB). However, certain peripheral effects of neurotensin have been observed after central administration of the peptide [Prange, A. J. and Nemeroff, C. B., Annal. NY Acad. Sciences, 400, 368-391 (1982)]. The direct application of neurotensin into the brain causes hypothermia, potentiation of barbiturate induced sedation, catalepsy. antinociception, blockade of psychostimulant-induced locomotor activity and reduced food consumption. In the central nervous system (CNS), neurotensin behaves as a neurotransmitter or neuromodulator [1) Uhl, G. R. and Snyder, S. H., Eur. J. Pharmacol., 41, 89-91 (1977); 2) Uhl, G. R., Annal. NY Acad. Sciences, 400, 132-149 (1982)], and has been shown to have close anatomical and biochemical associations with the dopaminergic (DA) system [Nemeroff, C. B., et al. Annal. NY Acad. Sciences, 400, 330-344 (1982)]. Neurotensin increases the synthesis and the turnover of DA in rat brain. Acute and chronic treatment with clinically efficacious antipsychotic drugs (e.g., haloperidol, chloropromazine) have consistently demonstrated an increase in neurotensin concentrations in the nucleus accumbens and striatum while phenothiazines that are not antipsychotics did not produce this increase. Behaviorally, neurotensin, after central administration, mimics the effects of systemically administered neuroleptics. However, unlike classical neuroleptics (which primarily acts on D.sub.2 receptors), neurotensin fails to bind to dopamine receptors or inhibit cAMP accumulation following DA receptor activation. Neurotensin does not block the stereotypy induced by DA agonists. The post-mortem studies of patients with schizophrenia showed an increase in the level of neurotensin in the Brodman's area 32 of human brain [Nemeroff, C. B., et. al., Science., 221, 972-975 (1983) and references cited therein], which suggest possible roles of neurotensin in the pathophysiology of this disease. Neurotens
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Chakravarty Prasun K.
Chen Anna
Naylor Elizabeth M.
Bernhardt Emily
Camara Valerie J.
Daniel Mark R.
Merck & Co. , Inc.
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