Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-04-19
2003-11-11
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S200000, C514S481000, C514S471000
Reexamination Certificate
active
06645959
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a method for preventing or treating postoperative ileus by administering a composition which inhibits the action of vasopressin and/or other substances which bind to vasopressin receptors.
BACKGROUND OF THE INVENTION
Gastric and colonic motility disturbances are quite common after intra-abdominal surgery. The small bowel is largely unaffected, and motility and absorption are normal within a few hours after operation. Stomach emptying is usually impaired for about 24 hours, but the colon may remain inert for 48 to 72 hours or more. This condition is known as postoperative ileus and its occurrence not only prolongs hospitalization, but also fosters postoperative complications, especially aspiration pneumonia. Symptoms and signs include abdominal distension, vomiting, obstipation, and cramps. Auscultation reveals a silent abdomen and minimum peristalsis. X-rays show gaseous distension of isolated segments of both small and large bowel. Treatment usually involves continuous nasogastric suction, nothing by mouth, intravenous (IV) fluids and electrolytes, and a minimal amount of sedatives. Sometimes colonic ileus can be relieved by colonoscopic decompression, but rarely cecostomy is required. Ileus persisting for a fill week or longer may be caused by a mechanical obstruction.
Studies using isolated canine jejunal segments have shown that following exposure to vasopressin, the jejunum becomes atonic with intraluminal pooling of perfusate. Transit time was prolonged, and intestinal absorption of water was decreased. Radionuclide imaging confirmed loss of intestinal motility. The studies concluded that the high plasma levels of vasopressin which are known to follow laparotomy may be a factor in the development of postoperative ileus.
Studies using monkeys who had strain gauge transducers implanted in the colon showed that the frequency of basal colonic contractions was reduced with increasing doses of vasopressin. The results suggest that the physiological concentrations of serum vasopressin present postoperatively may transiently inhibit colon contractions.
Vasopressin, also known as antidiuretic hormone (ADH), is a peptide synthesized in the magnocellular neurosecretory cells of the paraventricular and supraoptic nuclei of the hypothalamus, and is stored in the posterior pituitary. Vasopressin is released into the circulation in response to an increase in plasma osmolality (mediated by osmoreceptors) or a decrease in plasma volume or blood pressure (mediated by baroreceptors). However, there are other stimuli for vasopressin release, including circulating norepinephrine, angiotensin II, pain, hypoxia, nausea and vomiting, and fever. During laparoscopy a decrease in circulating plasma volume, pneumoperitoneum, and a neuronal impulse from the surgical site may result in raised levels of circulating arginine vasopressin (AVP). This rise in AVP may in turn lead to increased splachnic vascular resistance and mesenteric vasoconstriction, reduction of superior mesenteric artery blood flow and mesenteric microcirculation reduction ineffective perfusion pressure, and finally, splachnic ischemia. Splachnic ischemia, in turn, can cause an increase in splachnic free redical formation, a decrease in gut metabolic activity, and bacterial translocation—factors resulting in paralytic ileus.
The cellular effects of vasopressin are mediated by interaction of the hormone with two principal types of receptors, V
1
and V
2
. V
1
receptors have been subclassified further as V
1a
and V
1b
. The V
1a
receptor is the most widespread subtype and is found in vascular smooth muscle, myometrium, the bladder, adipocytes, hepatocytes, platelets, renal medullary interstitial cells, vasa recta in the renal microcirculation, epithelial cells in the renal cortical collecting duct, spleen, testis, and in many CNS tissues. Only the adrenohypophysis is known to contain V
1b
receptors. The V
2
receptors are predominantly located in principal cells of the renal collecting duct system.
Vasopressin is one of the most potent vasoconstrictors known (V
1
receptor mediated) and the vasopressin response to hypovolemia or hypotension serves as a mechanism to stave off cardiovascular collapse during periods of severe blood loss and/or hypotension (Laszlo, et al.,
Pharmacol Rev
., 1991;43:73-108). Vascular smooth muscle in the skin, skeletal muscle, fat, pancreas, and thyroid gland appear most sensitive, with significant vasoconstriction also occurring in the coronary vessels, brain, and gastrointestinal tract. It has been shown (Thibonnier, 1988) that administration of a peptide V
1
receptor antagonist improves hemodynamic function in patients with increased peripheral resistance due to heart failure.
We have discovered that compounds which inhibit binding of vasopressin to vasopressin receptors in the gastrointestinal tract can significantly reduce the incidence of postoperative ileus.
SUMMARY OF THE INVENTION
This invention provides a method for treating or preventing postoperative ileus comprising administering to a patient an effective amount of a vasopressin antagonist. The vasopressin antagonist to be employed is any chemical compound that is effective in inhibiting the biological activity of any known vasopressin or antidiuretic hormone. Numerous compounds are known to be vasopressin antagonists, and any of such compounds can be utilized in the method of this invention.
In a preferred embodiment, the vasopressin antagonist to be utilized is a condensed benzazepine such as those described in U.S. Pat. No. 5,723,606, incorporated herein by reference. In a further preferred embodiment, the vasopressin antagonist is an imidazo benzazepine of the Formula I:
wherein:
R and R
5
are independently hydrogen or lower alkyl;
R
1
, R
2
, and R
3
independently are hydrogen, halo, lower alkyl, lower alkoxy, amino, alkylamino, or dialkylamino; and
R
4
is hydrogen, phenyl or substituted phenyl, and pharmaceutically acceptable salts thereof.
An especially preferred vasopressin antagonist to be used in accordance with this invention is conivaptan, which is N-[4-(2-methyl-4,5,6- tetrahydromidazo [4,5-d][1]benzazepin-6-ylcarbonyl)phenyl]biphenyl-2-carboxamide hydrochloride. Conivaptan is also referred to as YM087 and CI-1025, and has the structural Formula II below:
Other vasopressin antagonists that can be employed according to this invention include the benzoheterocyclic compounds described in U.S. Pat. No. 5,258,510, incorporated herein by reference. Preferred compounds from this class to be used herein include the following:
5-Dimethylamino-1-[4-(2-methylbenzoylamino)-benzoyl ]-2,3,4,5-tetrahydro-1H-benzazepine;
5-Dimethylamino-1-[2-chloro-4-(2-methylbenzoylamino) benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine;
5-Methylamino-1-[2-chloro-4-(2-methylbenzoylamino) benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine;
5-Cyclopropylamino-1-[2-chloro-4-(2-methylbenzoylamino) benzoxyl]-2,3,4,5-tetrahydro
5-Cyclopropylamino-1-[2-chloro-4-(2-chlorobenzoylamino) benzoxyl]-2,3,4,5-tetrahydro-1H-benzazepine;
5-Dimethylamino-1-[2-methyl-4-(2-methylbenzoylamino) benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine;
5-Dimethylamino-1-[2-methoxy4-(2-methylbenzoylamino) benzoyl]-1,2,3,4-tetrahydroquinoline;
7-Chloro-5-methylamino-1 -[4-(2-methylbenzoylamino) benzoxyl]-2,3,4,5-tetrahydro-1H-benzazepine; and
7-Chloro-5-methylamino-1-[4-(2-chlorobenzoylamino) benzoxyl]-2,3,4,5-tetrahydro-1H-benzazepine.
DETAILED DESCRIPTION OF THE INVENTION
In Formula I above, R and R
5
are hydrogen or lower alkyl. The term “lower alkyl” means a straight or branched carbon chain having from 1 to 6 carbon atoms. Typical lower alkyl groups include methyl, ethyl, isopropyl, n-butyl, neopentyl, and 1,1-dimethylbutyl.
“Halo” is a halogen atom such as fluoro, chloro, bromo, and iodo. “Lower alkoxy” means the C
1
-C
6
alkyl groups mentioned above linked through an oxygen atom. Examples of lower alkoxy include methoxy, ethoxy
Bakker-Arkema Rebecca Guggemos
Pressler Milton Lethan
Ashbrook Charles W.
Fay Zohreh
Kwon Brian Yong S.
Warner-Lambert & Company
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