Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-07-24
2003-01-28
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S063000, C540S558000, C540S561000, C540S562000, C540S565000
Reexamination Certificate
active
06511974
ABSTRACT:
The present invention concerns novel compounds having vasopressin agonist activity, as well as methods of treatment and pharmaceutical compositions utilizing the same.
BACKGROUND OF THE INVENTION
Vasopressin (antidiuretic hormone, ADH), a nine amino acid peptide hormone and neurotransmitter, is synthesized in the hypothalamus of the brain and is transported through the supraopticohypophyseal tract to the posterior pituitary where it is stored. Upon sensing an increase of plasma osmolality by brain osmoreceptors or a decrease of blood volume or blood pressure detected by the baroreceptors and volume receptors, vasopressin is released into the blood circulation and it activates vasopressin V
1a
receptors on blood vessels to cause vasoconstriction to raise blood pressure and vasopressin V
2
receptors of the nephrons of the kidney to retain mainly water, and to a lesser degree electrolytes, to expand the blood volume (Cervoni P. and Chan P. S., 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, H. and Schaefer,
J. Physiol
. (London) 18: 277-279, 1895). The determination of the structure and the complete synthesis of vasopressin were accomplished by duVigneaud and co-workers in 1954 (duVigneaud, V., Gish, D. T., and Katsoyannis,
J. Am. Chem. Soc
. 76: 4751-4752, 1954.).
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 so as 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 the vasopressin V
2
receptors by vasopressin or vasopressin-like (peptide or nonpeptide) 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 of urine volume and an increase of 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 tubules, 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, and 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 high as 10 times the urine volume 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 help provide the ability of the recipient to temporarily delay urination, whenever desirable.
Vasopressin, through activation of its V
1a
receptors, exerts vasoconstricting effects so as to raise the 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, E. K., Vasopressin and other agents affecting the renal conservation of water. In: Goodman's and Gilman's The Pharmacological Basis of Therapeutics, 9th ed., Eds. Hardman, Limbird, Molinoff, Ruddon and Gilman, McGraw-Hill, New York, pp. 715-731, 1996, Lethagen, S.,
Ann. Hematol
., 69; 173-180 (1994), Cash, J. D. et al.,
Brit. J. Haematol
. 27; 363-364, 1974., David, J-L.,
Regulatory Peptides
, 45; 311-317, 1993, and Burggraaf, J., et al., Clin. Sci. 86; 497-503 (1994).
The following prior art references describe peptide vasopressin antagonists: M. Manning et al.,
J. Med. Chem
., 35, 382(1992); M. Manning et al.,
J. Med. Chem
., 35, 3895(1992); H. Gavras and B. Lammek, U.S. Pat. No. 5,070,187 (1991); M. Manning and W. H. Sawyer, U.S. Pat. No. 5,055,448(1991) F. E. Ali, U.S. Pat. No. 4,766,108(1988); R. R. Ruffolo et al.,
Drug News and Perspective
, 4(4), 217, (May 1991). P. D. Williams et al., have reported on potent hexapeptide oxytocin antagonists [
J. Med. Chem
., 35, 3905(1992)] which also exhibit weak vasopressin antagonist activity in binding to V
1
and V2 receptors. Peptide vasopressin antagonists suffer from a lack of oral activity and many of these peptides are not selective antagonists since they also exhibit partial agonist activity.
Non-peptide vasopressin antagonists have recently been disclosed. Albright et al. describe tricyclic diazepines as vasopressin and oxytocin antagonists in U.S. Pat. No. 20 5,516,774 (May 14, 1996); tetrahydrobenzodiazepine derivatives as vasopressin antagonists are disclosed in JP 08081460-A (Mar. 26, 1996); Ogawa, et al. disclose benzoheterocyclic derivatives as vasopressin and oxytocin antagonists, and as vasopressin agonists in WO 9534540-A; Albright, et al. disclose tricyclic benzazepine derivatives as vasopressin antagonists in U.S. Pat. No. 5,512,563 (Apr. 30, 1996); and Venkatesan, et al. disclose tricyclic benzazepine derivatives as vasopressin and oxytocin antagonists in U.S. Pat. No. 5,521,173 (May 28, 1996).
As mentioned above, desmopressin (1-desamino-8-D-arginine vasopressin) (Huguenin, 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 by intranasal administration.
The compounds of this invention are non-peptidic and have good oral bioavailability. They are specific vasopressin V
2
agonists, and have no V
1a
agonist effects so they do not raise blood pressure. In contrast, the prior art compounds of Ogawa, H. et al. WO 9534540-A are vasopressin/oxytocin antagonists.
SUMMARY OF THE INVENTION
This invention relates to new compounds selected from those of the general formula (I):
wherein:
A, B, E, G are, independently, CH or nitrogen;
D is, independently, C—W or nitrogen;
R
1
is alkanoyl of 2 to 7 carbon atoms, a group selected from CN, COOH,
or a moiety selected from the group:
R
2
, R
3
and R
5
are, independently, hydrogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, or perfluoroalkyl of 1 to 6 carbons;
R
4
is hydrogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkoxyalkyl of 2 to 7 carbon atoms, or an acyl substituent selected from the group consisting of alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, cycloalkanoyl of 3 to 7 carbon atoms, aroyl, or arylalkanoyl;
X and Y are, independently, hydrogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 ca
Albright Jay D.
Ashwell Mark A.
Bagli Jehan F.
Caggiano Thomas J.
Chan Peter S.
Coleman Brenda
Mazzarese Joseph M.
Wyeth
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