The Upjohn Co.

Allergan, Inc.

Lester J Kaplan

Moses W McMillan

Jacob Szmuszkovicz

Michael E Garst

Charles Gluchowski

John M McCall

James H Ludens

Robert James Collins

Philip F Von Voigtlander

Achiral compounds of a 2H-pyran-2,6(3H)-dione derivative of the formula ##STR1## or a pharmaceutically acceptable salt thereof, where R is --(CH.sub.2).sub.m OH or --CH((CH.sub.2).sub.n CH.sub.2 OH).sub.2 where m is 1-5 and n is 0-4. These compounds are useful in the treatment of allergic conditions.

2H-pyran-2,6-(3H)-dione derivatives with anti-allergic activity

OMEGA-(Hydroxy, ether and ester) alkyl-2-Amino-Cycloalkenyl and -cycloalkyl amide compounds of the formula: ##STR1## where the wavy line bonds, m, n, p, A, R, R.sub.1, R.sub.2, X, Y and Z are as defined in the specification, e.g., 3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-3-(3-acetyloxypropyl)cyclohexe nyl]benzamide, and pharmacologically acceptable salts thereof, are useful as analgesic drug compounds having low physical dependence liability, compared to morphine and methadone. Pharmaceutical compositions and methods for using these compounds and compositions as analgesics are disclosed. Processes for preparing this class of compounds are also disclosed.

Omega-(hydroxy-, ether and ester)-alkyl-2-amino-cycloalkyl- and

N-[2-(2,5-dihydro-1H-pyrrol-1-yl)cycloaliphatic)]benzeneacetamide and -benzamide compounds, e.g., (1.alpha.,2.beta.)-(.+-.)-3,4-dichloro-N-[2-(2,5-dihydro-1H-pyrrol-1-yl)cy clohexyl]-N-methylbenzeneacetamide, and salts thereof, have useful analgesic activity, low abuse or physical dependence liability properties. Processes for their preparation are disclosed. Pharmaceutical compositions containing such compounds and methods for their use are also disclosed.

2-pyrrolyl-cycloalkyl-amide analgesics

Analgesic 2-oxa-spirocyclic compounds of the formula ##STR1## where the wavy line bonds, p, n, m, A, q, X, Y, R, R.sub.1, R.sub.2 and E are as defined in the specification, e.g., trans-4-bromo-N-methyl-N-[7-(1-pyrrolidinyl)-2-oxaspiro[4.5]dec-8-yl]benza mide, and trans-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-2-oxaspiro[4.5]dec-8-yl] benzeneacetamide, and acid addition salts thereof. Pharmaceutical compositions and methods of using these compounds as analgesics are disclosed. Processes for preparing the class of compounds are also disclosed.

Analgesic 2-oxa-spirocyclic compounds

1,2-Cycloaliphatic diamines and protected diamines of the formulas II and IIa ##STR1## and ##STR2## wherein the wavy line bonds, p, n, R, R.sub.1, R.sub.2, Z, m and Q are as defined in the specification, e.g., (.+-.)-(5.xi.,6.alpha.,7.beta.)-1-[6-methylamino-1-oxaspiro[4.5]dec-7-yl]p yrrolidine, are disclosed and claimed herein. These diamines and protected diamines are useful as intermediates for preparing mono-oxa, and thiaspirocyclic-benzene acetamide and benzamide analgesic compounds.

Amine intermediates for analgesic compounds

Conditions of inappropriate hyperhydration in warm blooded animals can be treated with an essentially water only diuretic drug compound selected from the group ##STR1## wherein m, n, p, A, E, R, R.sub.1, R.sub.2, X, Y and Z are as defined in the specification, e.g., trans-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]dec-8 -yl]benzeneacetamide, or a pharmaceutically acceptable salt thereof, ##STR2## wherein R, R.sub.1, R.sub.2, R.sub.3, P, Q, X and Y are as defined in the specification, e.g., 3,4-dichloro-N-[[8-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]-dec-8-yl]methyl]be nzeneacetamide, or a pharmaceutically acceptable salt thereof, or ##STR3## where R, R.sup.1, R.sup.2, X and Y are as defined in the specification, e.g., trans-(1)-2-(3,4-dichlorophenyl)-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] acetamide,

Oxygen substituted amino-cyclohexyl-benzeneacetamides and -benzamides as

Cis- and trans-N-[2-amino(adjacenty substituted bis(alkyloxy), bis(alkylthio), alkylthio or mercapto group substituted)-cycloaliphatic]benzeneacetamide and -benzamide compounds, e.g., (.+-.)-(1.alpha.,2.beta.)-4-bromo-N-[3,3-dimethoxy-2-(1-pyrrolidinyl)cyclo hexyl]-N-methylbenzamide, and salts thereof, are provided. These compounds have analgesic properties. Processes for their preparation are disclosed. Pharmaceutical compositions and methods of use are also provided.

Adjacently substituted ketal derivatives of cycloalkane-amide analgesics

Mono-Oxa-, thiaspirocyclic-benzene-acetamide and -benzamide compounds of the formula ##STR1## wherein p, n, m, A, E, R, R.sub.1, R.sub.2, X, Y and Z are as defined in the specification, e.g., (.+-.)-(5.alpha.,7.alpha.,9.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidi nyl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide, and the pharmacologically acceptable salts thereof, are useful as analgesic compounds having low physical dependence liability, compared to morphine and methodone, and low dysphoria side effects. Some of these compounds have potent analgesic activity when administered orally, and some have low CNS sedative side effects. Pharmaceutical compositions and methods for using these compounds as analgesics are disclosed. Processes for preparing this class of compounds are also disclosed.

Analgesic 1-oxa-, aza- and thia-spirocyclic compounds

N-[2-Amino(oxy or thio group) substituted-cycloaliphatic]phenylacetamide and -benzamide compounds, having the oxy- or thio group substituents on a cycloaliphatic ring carbon adjacent to either of the nitrogen bearing carbons of the cycloaliphatic ring, e.g., cis- and trans-4-bromo-N-[3-methoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzamide , and trans-3,4-dichloro-N-methyl-N-[7-(1-pyrridolinyl)-1,4-dioxaspiro[4.5]dec-6 -yl]benzeneacetamide, and salts thereof, have useful analgesic activity and low abuse liability in humans and valuable warm blooded animals. Processes for their production and pharmaceutical compositions and method of use are also disclosed.

Growing community of inventors

Kalamazoo, MI, United States of America

Lester J Kaplan