Pyrrolobenzodiazepine carboxyamide vasopressin agonists

Details Pyrrolobenzodiazepine carboxyamide vasopressin agonists Pyrrolobenzodiazepine carboxyamide vasopressin agonists

2000-02-01

2002-02-05

Coleman, Brenda (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S561000

Reexamination Certificate

active

06344451

ABSTRACT:

This invention concerns tricyclic benzoheterocyclic carboxyamides which act as vasopressin V
2
agonists, as well as methods of treatment and pharmaceutical compositions utilizing these compounds.
BACKGROUND OF THE INVENTION
Vasopressin (antidiuretic hormone, ADH) a nonapeptide hormone and neurotransmitter, is synthesized in the supraoptic nuclei of the hypothalamus of the brain and transported through the supraoptico-hypophyseal tract to the posterior pituitary where it is stored. Upon sensing an increase in plasma osmolality by brain osmoreceptors or a decrease in blood volume or blood pressure (detected by the baroreceptors and volume receptors), vasopressin is released into the blood circulation and activates vasopressin V
1a
receptors on blood vessels causing vasoconstriction to raise blood pressure; and vasopressin V
2
receptors of the nephron of the kidney causing reabsorption of water and to a lesser degree electrolytes, to expand the blood volume (Cervoni and Chan, Diuretic Agents, in Kirk-Othmer, Encyclopedia of Chemical Technology, 4th ed., Wiley, Volume 8, 398-432, (1993)). The existence of vasopressin in the pituitary was known as early as 1895 (Oliver and Schaefer,
J. Physiol
. (London), 18, 277-279, (1895)). The determination of the structure and the total synthesis of vasopressin were accomplished by du Vigneaud and coworkers in 1954 (du Vigneaud, Gish and Katsoyannis,
J. Am. Chem. Soc
., 76, 4751-4752, (1954)).
The actions of vasopressin V
1a
receptors are mediated through the phosphatidylinositol pathway. Activation of vasopressin V
1a
receptors causes contraction of the smooth muscle of the blood vessels to raise blood pressure. The actions of the vasopressin V
2
receptors are mediated through activation of the adenylate cyclase system and elevation of intracellular levels of cAMP. The activation of vasopressin V
2
receptors by vasopressin or vasopressin-like (peptidic or non-peptidic) compounds increases water permeability of the collecting ducts of the nephron and permits the reabsorption of a large quantity of free water. The end result is the formation and excretion of a concentrated urine, with a decrease in urine volume and an increase in urinary osmolality.
Vasopressin plays a vital role in the conservation of water by concentrating the urine at the site of the collecting ducts of the kidney. The collecting ducts of the kidney are relatively impermeable to water without the presence of vasopressin at the receptors and therefore, the hypotonic fluid formed after filtering through the glomeruli, passing the proximal convoluted tubule, the loops of Henle, and the distal convoluted tubules, will be excreted as dilute urine. However, during dehydration, volume depletion or blood loss, vasopressin is released from the brain and activates the vasopressin V
2
receptors in the collecting ducts of the kidney rendering the ducts very permeable to water; hence water is reabsorbed and a concentrated urine is excreted. In patients and animals with central or neurogenic diabetes insipidus, the synthesis of vasopressin in the brain is defective and therefore, they produce no or very little vasopressin, but their vasopressin receptors in the kidneys are normal. Because they cannot concentrate the urine, they may produce as much as 10 times the urine volumes of their healthy counterparts and they are very sensitive to the action of vasopressin and vasopressin V
2
agonists. Vasopressin and desmopressin, which is a peptide analog of the natural vasopressin, are being used in patients with central diabetes insipidus. Vasopressin V
2
agonists are also useful for the treatment of nocturnal enuresis, nocturia, urinary incontinence and temporary delay of urination whenever desirable.
Vasopressin, through activation of its V
1a
receptors, exerts vasoconstricting effects so as to raise blood pressure. A vasopressin V
1a
receptor antagonist will counteract this effect. Vasopressin and vasopressin agonists release factor VIII and von Willebrand factor so they are useful for the treatment of bleeding disorders, such as hemophilia. Vasopressin and vasopressin-like agonists also release tissue-type plasminogen activator (t-PA) into the blood circulation so they are useful in dissolving blood clots such as in patients with myocardial infarction and other thromboembolic disorders (Jackson, “Vasopressin and other agents affecting the renal conservation of water”, in Goodman and Gilman,
The Pharmacological Basis of Therapeutics
, 9th ed., Hadman, Limbird, Molinoff, Ruddon and Gilman Eds., McGraw-Hill, New York, pp. 715-731 (1996);
Lethagen, Ann. Hematol
. 69, 173-180 (1994); Cash et al.,
Brit. J. Haematol
., 27, 363-364 (1974); David,
Regulatory Peptides
, 45, 311-317 (1993); Burggraaf et al.,
Cli. Sci
., 86, 497-503 (1994)).
The following prior art references describe peptidic vasopressin antagonists: Manning et al.,
J Med. Chem
., 35, 382 (1992); Manning et al.,
J. Med. Chem
., 35, 3895 (1992); Gavras and Lammek, U.S. Pat. No. 5,070,187 (1991); Manning and Sawyer, U.S. Pat. No. 5,055,448 (1991); Ali, U.S. Pat. No. 4,766,108 (1988); Ruffolo et al.,
Drug News and Perspectives
4(4), 217 (May 1991); Albright and Chan,
Curr. Pharm. Des
. 3(6), 615 (1997). Williams et al., have reported on potent hexapeptide oxytocin antagonists [
J. Med. Chem
., 35, 3905 (1992)] which also exhibit weak vasopressin antagonistic activity in binding to V
1
and V
2
receptors. Peptidic vasopressin antagonists suffer from a lack of oral activity and many of these peptides are non-selective antagonists since they also exhibit partial agonist activity.
Non-peptidic vasopressin antagonists have recently been disclosed. Albright et al. describe tricyclic azepines as vasopressin and oxytocin antagonists in U.S. Pat. No. 5,516,774 (1996); tetrahydrobenzodiazepine derivatives as vasopressin antagonists are disclosed in J. P. 0801460-A (1996); Ogawa et al., disclose benzoheterocyclic derivatives as vasopressin and oxytocin antagonists, and as vasopressin agonists in WO 9534540-A; and Venkatesan et al., disclose tricyclic benzazepine derivatives as vasopressin and oxytocin antagonists in U.S. Pat. No. 5,521,173 (1996).
As mentioned above, desmopressin (1-desamino-8-D-arginine vasopressin) (Huguenin and Boissonnas,
Helv. Chim. Acta
, 49, 695 (1966)) is a vasopressin agonist. The compound is a synthetic peptide with variable bioavailability. An intranasal route is poorly tolerated and an oral formulation for nocturnal enuresis requires a 10-20 fold greater dose than the intranasal administration.
Albright et al. broadly disclose a subset of tricyclic pyrrolo benzodiazepine indole carboxyamides of the present application, as V
1
and/or V
2
vasopressin receptor antagonists and oxytocin receptor antagonists in U.S. Pat. No. 5,512,563 (1996); U.S. Pat. No. 5,516,774 (1996); U.S. Pat. No. 5,624,923 (1997); U.S. Pat. No. 5,733,905 (1998); U.S. Pat. No. 5,736,540 (1998); EP 640592 A1 (1995); EP 0 636 625 A2 (1995), inter alia.
Compounds of general structure 16b in Scheme 4 of the above applications, are taught by Albright et al. to possess vasopressin and oxytocin receptors antagonist properties.
wherein Y=(CH
2
)
n
with n=0-2; and R
4
=H, or lower alkyl (C
1
-C
3
).
However, the above indole carboxyamides of general structure 16b, have been found unexpectedly to be vasopressin V
2
receptor agonists in vivo, and thus possess different biological profile and clinical utility from those originally disclosed. Thus, rather than having an aquaretic effect, they unexpectedly cause reabsorption of water, i.e. they reduce urine volume and increase urine osmolality.
The compounds of this invention are non-peptidic and have a good oral bioavailability. They are vasopressin V
2
receptor agonists, and as such they promote reabsorption of water. They demonstrate no vasopressin V
1a
receptor agonist effects and, thus, do not raise blood pressure. In contrast, the prior art compounds (except some in WO 9534540-A) are described as vasopressin antagonists at both the V
1a
and V
2

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