Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1992-05-27
1995-08-29
Richter, Johann
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546133, 546137, A61K 31435, C07D21170
Patent
active
054460506
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to novel azabicyclo amides and esters which are antagonists at the serotonin 5-HT.sub.3 receptor and useful as anti-emetic agents in warm blooded animals, particularly the emesis associated with the anticancer drug cisplatin. The 5-HT.sub.3 receptor antagonists of the present invention are also useful in the treatment of schizophrenia, migraine, anxiety, cognitive disorders, Alzheimer's disease, pain and gastrointestinal disorders, such as irritable bowel syndrome.
Compounds recognized for their ability to act as antagonists at the serotonin 5-HT.sub.3 receptor sites are described in U.S. Pat. Nos. 4,593,034 and 4,749,718 and U.K. Patent Applications 2,125,398A, 2,166,726A, 2,166,727A, 2,166,728A and 2,193,633A.
SUMMARY OF THE INVENTION
The novel amides and esters of the present invention are of formula I and II: ##STR1## and a pharmaceutically acceptable acid addition salt, wherein Ar is an aromatic group such as phenyl, naphthyl, 3-indolyl, 3'-indazolyl, 1-methyl-3-indolyl, 2-methoxyphenyl or 2-methoxy-4-amino-5-chlorophenyl; and X is O or NH.
Preferred are the compounds of formula I, where X is NH and Ar is 3-indolyl, 3-indazolyl or 2-methoxy-4-amino-5-chlorophenyl.
A second preferred group of compounds are those of formula II wherein X is O and Ar is 3-indolyl or 1-methyl-3-indolyl.
Also considered part of the present invention are the useful intermediates of the formula ##STR2## wherein Y is Cl, N.sub.3, OH or NH.sub.2.
The present invention also includes a method for treating emesis in a human being by administration of an anti-emetic amount of the compounds of formulae I and II and a pharmaceutical composition for said method comprising an effective amount of compounds of formulae I and II.
As previously indicated, the present invention embraces pharmaceutically acceptable salts of the biologically active compounds. Such salts are those which are non-toxic at the dosages administered. Since compounds of the invention contain basic groups, acid addition salts are possible. Pharmaceutically acceptable acid addition salts include e.g., the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, maleate, mesylate, fumarate, citrate, acid citrate, tartrate, bitartrate, succinate, gluconate, glutamate, aspartate and saccharate salts.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of formulae I and II wherein X is NH are prepared by acylation of the requisite amine with the appropriate acid as some reactive derivative. Such derivatives include acid halides, acid azides, acid cyanides, mixed acid anhydrides, active esters or active amides. Particularly preferred are acid halides, such as acid chlorides and active amides, such as acylimidazoles.
Acid chlorides are prepared by methods known to those skilled in the art and usually consist of reacting the acid with a chlorinating agent such as phosgene, thionyl chloride, phosphorous trichloride, phosphorus oxychloride, phosphorus pentachloride or. oxalylchloride.
Acyl imidazoles are readily prepared by reacting the appropriate acid with carbonyldiimidazole. The acyl imidazole can be generated in situ and used directly in the reaction, or it can be isolated prior to its use in the acylation reaction.
The acylation of the amine reagent is usually carried out in a reaction-inert solvent which is miscible with water. Such solvents include acetone, dimethylformamide, tetrahydrofuran, dimethylsulfoxide and dioxane.
In practice, equimolar amounts of the amine and acylating agent are combined in the appropriate solvent. Lesser or greater molar amounts of either reagents can be employed without changing the course of the reaction. When an acid chloride is employed as the acylating agent, it is preferred that a corresponding molar amount of acid scavenger be employed. Such scavengers include pyridine, triethylamine, etc.
Reaction temperature is not critical, and the acylation can readily be conducted at room temperature. At such a preferred reaction temperatu
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CA 69(7): 27579 g Bender.
Bender, D. R. and Coffen, D. L., J. Org. Chem., 33(6), pp. 2504-2509, 1968.
Benson Gregg C.
Pfizer Inc.
Richardson Peter C.
Richter Johann
Scalzo Catherine
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