American Home Products Corporation

Robert L Vogel

Wenling Kao

Magid A Abou-Gharbia

John H Musser

Amedeo A Failli

Robert J Steffan

Michael G Kelly

Craig E Caufield

Wayne Everett Childers

Annmarie Louise Sabb

Yvette L Palmer

The present invention provides compounds of the general formula (1):

Diazole derivatives as serotonergic agents

A compound of the structure ##STR1## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, A, B and Ar are all defined in the body of the specification or a pharmaceutically acceptable salt thereof which is useful as an immuno-suppressive, antiinflammatory, antifungal, antiprliferative and antitumor agent.

Carbamates of rapamycin

A compound of the structure ##STR1## wherein R.sup.1 and R.sup.2 are each, independently, hydrogen, --CONH--[(CR.sup.3 R.sup.4).sub.m (--A--(CR.sup.5 R.sup.6).sub.n).sub.p ].sub.q --B; ##STR2## R.sup.3, R.sup.4, R.sup.5, R.sup.6, and B are each, independently, hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylalkyl, cycloalkyl, --OR.sup.7, --SR.sup.7, halogen, --CN, --NO.sub.2, --CF.sub.3, --COR.sup.7, --CO.sub.2 R.sup.7, --CONHR.sup.7, --SO.sub.2 R.sup.7, --OSO.sub.3 R.sup.7, --NR.sup.7 R.sup.8, --NHCOR.sup.7, --NHSO.sub.2 R.sup.7, or Ar;

A compound of the structure ##STR1## wherein R.sup.1 and R.sup.2 are each, independently, hydrogen, --CONH--[(CR.sup.3 R.sup.4).sub.m (--A--(CR.sup.5 R.sup.6).sub.n).sub.p ].sub.q --B; ##STR2## The remaining terms are defined in the specification. The compounds are useful as antitumor, antiinflammatory, antifungal, antiproliferative and immunosuppressive agents.

A compound of the structure ##STR1## wherein R.sup.1 and R.sup.2,

A derivative of rapamycin of general formula (1) and (2) ##STR1## wherein ##STR2## R.sup.2 =hydrogen, or lower alkyl having 1 to 6 carbon atoms; ##STR3## wherein X=hydrogen, lower alkyl having 1 to 6 carbon atoms, --CF.sub.3, --NO.sub.2, --OR.sup.2, NR.sup.2, SR.sup.2, or halogen;

Rapamycin 31-ester with N,N-dimethylglycine derivatives useful as

A compound of the structure ##STR1## wherein R.sup.1 and R.sup.2 are each, independently, hydrogen, --CONH.sub.a --{{(CR.sup.3 R.sup.4).sub.m (--A--(CR.sup.5 R.sup.6).sub.n).sub.p }.sub.q --B}.sub.r ; --SO.sub.2 R.sup.7 ; --SO.sub.3 H; --CHR.sup.8 O(CH.sub.2).sub.t R.sup.9 ; or ##STR2## R.sup.3, R.sup.4, R.sup.5, R.sup.6, and B are each, independently, hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylalkyl, cycloalkyl, --OR.sup.10, --SR.sup.10, halogen, --CN, --NO.sub.2, --CF.sub.3, --COR.sup.10, --CO.sub.2 R.sup.10, --CONHR.sup.10, --SO.sub.2 R.sup.10, --OSO.sub.3 R.sup.10, --NR.sup.10 R.sup.11, --NHCOR.sup.10, --NHSO.sub.2 R.sup.10, or Ar;

Rapamycin oximes and hydrazones

A derivative of rapamycin of general formula (1) and (2) ##STR1## wherein ##STR2## or hydrogen; R.sup.2 =hydrogen, or lower alkyl having 1 to 6 carbon atoms; ##STR3## wherein X=hydrogen, lower alkyl having 1 to 6 carbon atoms, --CF.sub.3, --NO.sub.2, --OR.sup.2, NR.sup.2, SR.sup.2, or halogen; R.sup.4 =lower alkyl, alkenyl or alkynyl having 1 to 6 carbon atoms or an aromatic or heterocyclic moiety selected from the group consisting of phenyl, naphthyl, thiophenyl and quinolinyl;

The invention concerns compounds of formula (I) ##STR1## where R.sup.1 is alkyl, haloalkyl, alkenyl, or alkynyl containing 1 to 6 carbon atoms; or an aromatic moiety selected from phenyl, naphthyl and 4-(phenylaza) phenyl wherein said aromatic group is optionally substituted by one or more substituents selected from C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, hydroxy, amino, mono- or di-(C.sub.1 -C.sub.6)alkylamino, carboxy, (C.sub.1 -C.sub.6 alkoxy)carbonyl, C.sub.2 -C.sub.7 alkanoyl, (C.sub.1 -C.sub.6) thioalkyl, halo, cyano, nitro, trifuluoromethyl, trifluoromethoxy or R.sup.1 is a heteroaromatic group of 5 to 10 ring atoms containing oxygen, nitrogen and/or sulfur as heteroatom(s) wherein said heteroaromatic group is optionally substituted by one or more substituents selected form C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, hydroxy, amino, mono- or di-(C.sub.1 -C.sub.6)alkylamino, carboxy, (C.sub.1 -C.sub.6 alkoxy)carbonyl, C.sub.2 -C.sub.7 alkanoyl, (C.sub.1 -C.sub.6) thioalkyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy or R.sup.1 is NHCO.sub.2 R.sup.2 wherein R.sup.2 is lower alkyl containing 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof, which compounds are useful in the treatment of transplantation rejection, host versus graft disease, autoimmune diseases and diseases of inflammation.

Rapamycin 42-sulfonates and 42-(N-carbalkoxy) sulfamates useful as

A derivative of rapamycin of general formula (I) ##STR1## where R.sup.1 is alkyl, alkenyl, or alkynyl containing 1 to 6 carbon atoms; or an aromatic moiety selected from the group consisting of phenyl and naphthyl or a heterocyclic moiety selected from the group consisting of thiophenyl and quinolinyl or NHCO.sub.2 R.sup.2 wherein R.sup.2 is lower alkyl containing 1 to 6 carbon atoms or a pharmaceutically acceptable salt thereof, which by virtue of its immunosuppressive activity is useful in treating transplantation rejection, host versus graft disease, autoimmune diseases, and diseases of inflammation.

Rapamycin 42-sulfonates and 42-(N-Carboalkoxy)Sulfamates Useful as

Rapamycin 42-sulfonates and 42-(N-carboalkoxy) sulfamates useful as

A bicyclic derivative of rapamycin of general formula (1) ##STR1## wherein ##STR2## n=2 to 10, m=2 to 10 and

Bicyclic rapamycins

A rapamycin dimer of general formula (1) ##STR1## wherein A is --(CH.sub.2).sub.n --, --(CH.sub.2)n--(CH.dbd.CH)--(CH.sub.2).sub.m --, --(CH.sub.2)n--(--C.tbd.C--)--(CH.sub.2).sub.m --, ##STR2## substituted alkyl, substituted alkenyl, substituted alkynyl, and substituted aromatic; n=1-10, m=1-10 and n=m or n .noteq.m or a pharmaceutically acceptable salt thereof, which is by virtue of its immunosuppressive activity is useful in treating transplantation rejection host vs. graft disease, autoimmune diseases, and diseases of inflammation.

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Stratford, NJ, United States of America

Robert L Vogel