[(5,6,9a-Substituted-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]alka noic and cycloalkanoic acids and their analogs, esters, salts and derivatives
AssigneeMerck & Co., Inc.
InventorsEdward J. Cragoe, Jr., Gerald E. Stokker, Norman P. Gould
Life of this patent
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Abstract
The invention relates to novel [(5,6,9a-substituted-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)-oxy]alkano ic and cycloalkanoic acids and their analogs, esters, salts and derivatives. These compounds are synthesized by methods selected from a number of synthetic routes depending on the particular structure, choice of intermediate or preferred reaction sequence. The compounds are useful in the treatment and prevention of injury to the brain and spinal chord due to accidents, ischemic stroke and hydrocephalus; compositions for such uses are also disclosed.
Claims32
A compound of the formula:
- ##STR21## wherein R is H, and lower alkyl, branched or unbranched;
- R.sup.1 is H, lower alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl and the like;
- lower alkenyl, such as, allyl, 2-butenyl and the like;
- lower alkynyl, such as propargyl, butynyl and the like;
- lower cycloalkyl, such as cyclobutyl, cyclopentyl and the like;
- substituted lower alkyl, where the substituent is carboxy, lower alkoxycarbonyl, oxo, hydroxy, lower alkoxy, halo, lower acyloxy, lower dialkylamino, sulfamoyl, pyridyl, furyl, tetrahydrofuryl, aryl 1-methylpiperidyl, morpholinyl, substituted cycloalkyl, such as carboxycycloalkyl, and the like;
- pyrrolidinyl, 1-methylpiperazinyl, thienyl, and the like;
- heterocyclic, such as imidazolyl, pyridyl, thiazolyl, pyrazinyl, furyl, and the like;
- aryl, such as phenyl, carboxyphenyl hydroxymethylphenyl and the like;
- Y.sup.1 and Y.sup.2 are independently Cl and Ch.sub.3 ;
- A is (CH.sub.2).sub.2 or ##STR22## where R.sup.2 is H, methyl or ethyl, R.sup.3 is H, F or methyl and R.sup.2 and R.sup.3, may be joined together to form the ring >C(CH.sub.2).sub.n where n is the integer 2, 3 or 4;
- and pharmaceutically acceptable salts thereof.
The (+) enantiomer of [(5,6-dichloro-9a-methyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]ace tic acid.
The (+) enantiomer [(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acet ic acid.
The (+) enantiomer of [(5,6-dichloro-3-oxo-9a-propyl-1,2,9,9a-tetrahydro-3H-fluoren-7-yl) oxy]acetic acid.
The (+) enantiomer of [(5,6-dichloro-9a-isopropyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy] acetic acid.
The (+) enantiomer of 1-carboxy-1-methylethyl [(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acet ate.
The (+) enantiomer of 1-carboxy-1-methylethyl [(5,6-dichloro-3-oxo-9a-propyl-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]ace tate.
The (+) enantiomer of 1-carboxy-1-methylethyl [(5,6-dichloro-9a-isopropyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy] acetate.
A composition in unit dosage form for the treatment of grey matter edema comprising a compound of the formula:
- ##STR24## wherein R is H, and lower alkyl;
- R.sup.1 is H, lower alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl and the like;
- lower alkenyl, such as, allyl, 2-butenyl, and the like;
- lower alkynyl, such as, propargyl, butynyl and the like;
- lower cycloalkyl, such as cyclobutyl, cyclopentyl and the like;
- substituted lower alkyl, where the substituent is carboxy, lower alkoxycarbonyl, oxo, hydroxy, lower alkoxy, halo, lower acyloxy, lower dialkylamino, sulfamoyl, pyridyl, furyl, tetrahydrofuryl, aryl, 1-methylpiperidyl, morpholinyl, pyrrolidinyl, 1-methylpiperazinyl, thienyl, and the like;
- substituted cycloalkyl, such as, carboxycycloalkyl, and the like;
- heterocyclic, such as imidazolyl, pyridyl, thiazolyl, pyrazinyl, furyl, and the like;
- aryl, such as phenyl, carboxyphenyl, hydroxymethylphenyl and the like;
- Y.sup.1 and Y.sup.2 are independently Cl and CH.sub.3 ;
- A is (CH.sub.2).sub.2 or ##STR25## where R.sup.2 is H, methyl or ethyl, R.sup.3 is H, F or methyl and R.sup.2 and R.sup.3, may be joined together to form the ring >C(CH.sub.2).sub.n where n is the integer 2, 3 or 4;
- and pharmaceutically acceptable salts thereof.
Dependencies are inferred from the claim text.