Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-20
2002-01-01
Cook, Rebecca (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06335351
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to compositions of matter containing hydroxylansoprazole. The invention also relates to methods of treating and preventing ulcers, treating other conditions related to gastric hypersecretion, and treating psoriasis.
BACKGROUND OF THE INVENTION
Lansoprazole I is an orally active, potent,
irreversible inhibitor of H
+
,K
+
-ATPase. It is commercially available in the form of Prevacid® delayed release capsules from TAP Pharmaceuticals Inc. The compound is one of the class of compounds known as gastric “proton pump” inhibitors. These compounds are weak organic bases which diffuse passively from the plasma into the acid-containing intracellular canaliculi of gastric parietal cells. At the low pH found in the lumen of these canaliculi, the protonated compounds rearrange to form pyridinium sulfenamides, which react with sulfhydryl groups present on the ATPase localized in the membranes lining the intracellular canaliculi. The alkylation of the sulfhydryl inhibits the ability of the enzyme to catalyze the secretion of H
+
into the lumen in exchange for K
+
ions. This inhibition results in an overall reduction in hydrochloric acid secretion by the parietal cells into the cavity of the stomach, thus increasing intragastric pH. As a consequence of reduced acidity in the stomach, the activity of the proteolytic enzyme pepsin is also markedly decreased. Because the proton pump is the final step in acid production and the compounds of this class combine covalently with the associated H
+
,K
+
-ATPase, a profound and prolonged inhibition of gastric acid secretion can be achieved.
Proton pump inhibitors have also been reported as useful in treating psoriasis. [See PCT application WO95/18612]
The C
max
of racemic lansoprazole is at about 1.5 to 3.5 hours in humans after administration of enteric-coated granules, and the serum half-life is about 1 to 3 hours, although this is variable, depending on the subject's age and liver function, as discussed below. The major metabolites in human serum are 5-hydroxylansoprazole II (referred to as hydroxylansoprazole herein)and lansoprazole sulfone III.
The two major primary metabolites, lansoprazole sulfone and 5-hydroxylansoprazole, are formed by cytochromes P450 3A (CYP3A) and 2C 19 (CYP2C19), respectively. Both metabolites undergo further metabolism to the common metabolite 5-hydroxylansoprazole sulfone via CYP2C19 and CYP3A, respectively. Thus, both CYP enzymes are sequentially—but alternatively—involved in lansoprazole metabolism. CYP2C19, the S-mephenytoin hydroxylase, is polymorphically expressed in the human population. The mutant allele constitutes the recessive trait. Homozygous carriers of the mutation completely lack CYP2C19 and are referred to as poor metabolizers (PM's); persons homozygous and heterozygous for the “normal” allele are extensive metabolizers (EM's). A hereditary deficiency of the alternative enzyme, CYP3A, has not been demonstrated in the human population.
It would be desirable to find a compound with the advantages of lansoprazole which would provide a more predictable dosage regimen in the patient population and that would decrease the chances for drug-drug interactions.
SUMMARY OF THE INVENTION
This invention relates to the use of hydroxylansoprazole for treating ulcers of the stomach, duodenum and esophagus, gastroesophageal reflux diseases, Zollinger-Ellison Syndrome, and other disorders including those that would benefit from an inhibitory action on gastric acid secretion. Hydroxylansoprazole inhibits the H
+
,K
+
-ATPase associated with the gastric proton pump and the resulting secretion of gastric acid by parietal cells providing therapy in diseases associated with gastric hyperacidity. The invention also relates to a method of treating psoriasis using hydroxylansoprazole. Hydroxylansoprazole provides a more predictable dosage regimen in the patient population and decreases the chances for drug-drug interactions by avoiding oxidative metabolism for which the cytochrome P4502 C19 enzyme system is required.
The invention also relates to certain pharmaceutical compositions containing hydroxylansoprazole.
DETAILED DESCRIPTION OF THE INVENTION
The active compound of these compositions and methods is hydroxylansoprazole. Racemic hydroxylansoprazole may be prepared using methods well known to those skilled in the art, e.g. by a modification of the method described in U.S. Pat. Nos. 4,628,098 and 4,689,333. The compound identified in these patents as intermediate II
is provided with a substituent R
1
=methoxymethyl (MOM) by treatment of the corresponding hydroxy compound with dimethoxymethane (formaldehyde dimethyl acetal) in the presence of an acid catalyst (e.g. TsOH) and molecular sieves. Following condensation with the hydroxymethylpyridine III of the patents, and before oxidation, the MOM protecting group is cleaved with HCl in isopropanol/THF. Throughout this application, various references are referred to, often, although not always, within parentheses or square brackets. The disclosures of all of these publications in their entireties are hereby incorporated by reference as if written herein.
The index name for hydroxylansoprazole (II) in Chemical Abstracts is 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazol-5-ol; it is also known as 5-hydroxy-2-[3-methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-yl]methyl-sulfinylbenzimidazole. The registry number of racemic hydroxylansoprazole is 131926-998-2.
Hydroxylansoprazole possesses a center of asymmetry at the sulfoxide sulfur, giving rise to two enantiomers. Throughout the instant disclosure, when the term is not otherwise modified, hydroxylansoprazole includes the (+) enantiomer, the (−) enantiomer and any mixture of the two. The preparation of the individual enantiomers of the parent, lansoprazole, has been described in the literature, but the enantiomers of hydroxylansoprazole have not been previously disclosed. The individual enantiomers of hydroxylansoprazole can be obtained using methods well known to those skilled in the art, e.g. by asymmetric oxidation of the thioether precursor, or by achiral oxidation of the thioether precursor followed by separation of the enantiomers, e.g. by bioreduction of the racemate to eliminate one or the other enantiomer in analogous fashion to the procedure described for lansoprazole in PCT applications WO 9602535 and 9617077.
Inatomi et al. [Yakuri to Chiryo 19, 477-486 (1991);
Chem. Abst
. 115:21996] have indicated that although the parent lansoprazole inhibited acid formation in isolated parietal cells with an IC
50
of 0.09 &mgr;M, racemic hydroxylansoprazole did not inhibit acid formation in isolated parietal cells.
It has now been discovered that hydroxylansoprazole is a superior agent for treating ulcers of the stomach, duodenum and esophagus, gastroesophageal reflux diseases, Zollinger-Ellison Syndrome, psoriasis and other disorders, including those that would benefit from an inhibitory action on H
+
,K
+
-ATPase in that it provides this effective treatment while exhibiting fewer or less severe adverse effects than lansoprazole, less potential for drug-drug interactions than lansoprazole and a more predictable dosing regimen than lansoprazole. Adverse effects of lansoprazole include hepatocellular neoplasia, gastric carcinoids, headache, diarrhea and skin alterations.
The present invention encompasses a method of treating ulcers, which comprises administering to a human in need of such therapy, an amount of hydroxylansoprazole, or a pharmaceutically acceptable salt thereof, sufficient to alleviate the symptoms of ulcers. The present invention also encompasses an oral antiulcer composition for the treatment of a human in need of antiulcer therapy, which comprises a pharmaceutically acceptable carrier for oral administration and a therapeutically effective amount of hydroxylansoprazole or a pharmaceutically acce
Cook Rebecca
Heslin Rothenberg Farley & & Mesiti P.C.
Sepracor Inc.
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