US 4,381,307 AGranted

Soft tertiary amine esters of bio-affecting carboxylic acids

AssigneeMerck & Co., Inc.

InventorKenneth B. Sloan

Life of this patent

Estimating the term…

Loading patent…

Abstract

Novel derivatives of known bio-affecting carboxylic acids R-COOH are disclosed, said derivatives having the structural formula ##STR1## wherein Y and Y' are each H or C.sub.1 -C.sub.4 alkyl; n is 0 or 1; R.sub.1 and R.sub.2 are each selected from a variety of unsubstituted or substituted hydrocarbon radicals, or are combined so that --NR.sub.1 R.sub.2 represents the residue of a saturated or unsaturated heterocyclic compound containing one secondary nitrogen atom; and R.sub.3 is H or one of a variety of other substituents. Salts and N-oxides of compounds of formula (I) and the corresponding diacyloxy derivatives of known bio-affecting carboxylic acids HOOC-R'-COOH are disclosed also. The parent acids from which the subject soft tertiary amine esters can be derived include such bio-affecting agents as cephalosporin and penicillin antibiotics, amino acids and structurally related compounds, prostaglandins and their metabolites, steroidal anti-inflammatory agents, and non-steroidal anti-inflammatory/non-narcotic analgesic/antipyretic agents.

Claims31

Dependent claims

A compound selected from the group consisting of:

(a) compounds having the structural formula:
##STR523## wherein R--COO-- is the acyloxy residue of the cephalosporin antibiotic containing one carboxylic acid function;
Y and Y', which can be the same or different, and each hydrogen or alkyl of 1 to 4 carbon atoms;
n is zero or one;
the depicted phenylene group is oriented such that R--COO-- and ##STR524## are positioned ortho or para to each other;
R.sub.1 and R.sub.2, which can be the same or different, are each alkyl or 1 to 10 carbon atoms;
alkenyl of 2 to 10 carbon atoms;
aryl of 6 to 10 carbon atoms;
cycloalkyl or 3 to 8 carbon atoms;
cycloalkenyl of 4 to 8 carbon atoms;
alkynyl or 2 to 10 carbon atoms;
aralkyl, alkaryl, aralkenyl, aralkynyl, alkenylaryl, or alkynylaryl, wherein the alkyl, alkenyl, alkynyl, and aryl portions are defined as above;
or a substituted derivative of one of the above-defined alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, alkynyl, aralkyl, alkaryl, aralkenyl, aralkynyl, alkenylaryl and alkynylaryl radicals, said derivative having one or more substituents each of which are selected from the group consisting of C.sub.1 -C.sub.8 alkyl, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkanoyl, C.sub.1 -C.sub.8 alkanoyloxy, halo, cyano, C.sub.2 -C.sub.9 carbalkoxy, C.sub.1 -C.sub.8 alkylthio, nitro, C.sub.1 -C.sub.8 haloalkyl having 1 or more halo substituents, dialkylamino wherein the alkyl portions each contain 1 to 8 carbon atoms, carboxy, dialkylcarbamyl wherein the alkyl portions each contain 1 to 8 carbon atoms, and C.sub.1 -C.sub.8 alkylsulfonyl;
or R.sub.1 and R.sub.2 are combined so that --NR.sub.1 R.sub.2 represents the residue of a saturated or unsaturated heterocyclic compound containing one secondary nitrogen atom;
and R.sub.3 is hydrogen, R.sub.1', ##STR525## --CH.sub.2 OCOR.sub.1', --CH.sub.2 ONO.sub.2, CX.sub.3, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, cyano, carbamyl or C.sub.2 -C.sub.9 alkylcarbamyl, wherein R.sub.1 and R.sub.2 are as defined above, X is Cl or Br and R.sub.1' is any radical encompassed by the definition of R.sub.1 above;
and
(b) the non-toxic pharmaceutically acceptable acid addition salts and N-oxides thereof.

14 more elements

A compound selected from the group consisting of:

(a) compounds having the structural formula:
##STR526## wherein --OOC--R'--COO-- is the di(acyloxy) residue of a bio-affecting dicarboxylic acid selected from the group consisting of methotrexate, carbenicillin, penicillin N, and glutathione;
Y and Y', which can be the same or different, and each hydrogen or alkyl of 1 to 4 carbon atoms;
n is zero or one;
the depicted phenylene group is oriented such that R--COO-- and ##STR527## are positioned ortho or para to each other;
R.sub.1 and R.sub.2, which can be the same or different, are each alkyl or 1 to 10 carbon atoms;
alkenyl of 2 to 10 carbon atoms;
aryl of 6 to 10 carbon atoms;
cycloalkyl or 3 to 8 carbon atoms;
cycloalkenyl of 4 to 8 carbon atoms;
alkynyl or 2 to 10 carbon atoms;
aralkyl, alkaryl, aralkenyl, aralkynyl, alkenylaryl, or alkynylaryl, wherein the alkyl, alkenyl, alkynyl, and aryl portions are defined as above;
or a substituted derivative of one of the above-defined alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, alkynyl, aralkyl, alkaryl, aralkenyl, aralkynyl, alkenylaryl and alkynylaryl radicals, said derivative having one or more substituents each of which are selected from the group consisting of C.sub.1 -C.sub.8 alkyl, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkanoyl, C.sub.1 -C.sub.8 alkanoyloxy, halo, cyano, C.sub.2 -C.sub.9 carbalkoxy, C.sub.1 -C.sub.8 alkylthio, nitro, C.sub.1 -C.sub.8 haloalkyl having 1 or more halo substituents, dialkylamino wherein the alkyl portions each contain 1 to 8 carbon atoms, carboxy, dialkylcarbamyl wherein the alkyl portions each contain 1 to 8 carbon atoms, and C.sub.1 -C.sub.8 alkylsulfonyl;
or R.sub.1 and R.sub.2 are combined so that --NR.sub.1 R.sub.2 represents the residue of a saturated or unsaturated heterocyclic compound containing one secondary nitrogen atom;
and R.sub.3 is hydrogen, R.sub.1', ##STR528## --CH.sub.2 OCOR.sub.1', --CH.sub.2 ONO.sub.2, CX.sub.3, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, cyano, carbamyl or C.sub.2 -C.sub.9 alkylcarbamyl, wherein R.sub.1 and R.sub.2 are as defined above, X is Cl or Br and R.sub.1' is any radical encompassed by the definition of R.sub.1 above;
and
(b) the non-toxic pharmaceutically acceptable acid addition salts and N-oxides thereof.

14 more elements

A pharmaceutical composition of matter comprising an antibiotic effective amount of a compound selected from the group consisting of:

(a) compounds having the structural formula:
##STR529## wherein R--COO-- is the acyloxy residue of a cephalosporin antibiotic containing one carboxylic acid function;
Y and Y', which can be the same or different, and each hydrogen or alkyl of 1 to 4 carbon atoms;
n is zero or one;
the depicted phenylene group is oriented such that R--COO-- and ##STR530## are positioned ortho or para to each other;
R.sub.1 and R.sub.2, which can be the same or different, are each alkyl or 1 to 10 carbon atoms;
alkenyl of 2 to 10 carbon atoms;
aryl of 6 to 10 carbon atoms;
cycloalkyl or 3 to 8 carbon atoms;
cycloalkenyl of 4 to 8 carbon atoms;
alkynyl or 2 to 10 carbon atoms;
aralkyl, alkaryl, aralkenyl, aralkynyl, alkenylaryl, or alkynylaryl, wherein the alkyl, alkenyl, alkynyl, and aryl portions are defined as above;
or a substituted derivative of one of the above-defined alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, alkynyl, aralkyl, alkaryl, aralkenyl, aralkynyl, alkenylaryl and alkynylaryl radicals, said derivative having one or more substituents each of which are selected from the group consisting of C.sub.1 -C.sub.8 alkyl, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkanoyl, C.sub.1 -C.sub.8 alkanoyloxy, halo, cyano, C.sub.2 -C.sub.9 carbalkoxy, C.sub.1 -C.sub.8 -alkylthio, nitro, C.sub.1 -C.sub.8 haloalkyl having 1 or more halo substitutents, dialkylamino wherein the alkyl portions each contain 1 to 8 carbon atoms, carboxy, dialkylcarbamyl wherein the alkyl portions each contain 1 to 8 carbon atoms, and C.sub.1 -C.sub.8 alkylsulfonyl;
or R.sub.1 and R.sub.2 are combined so that --NR.sub.1 R.sub.2 represents the residue of a saturated or unsaturated heterocyclic compound containing one secondary nitrogen atom;
and R.sub.3 is hydrogen, R.sub.1', ##STR531## --CH.sub.2 OCOR.sub.1', --CH.sub.2 ONO.sub.2, CX.sub.3, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, cyano, carbamyl or C.sub.2 -C.sub.9 alkylcarbamyl, wherein R.sub.1 and R.sub.2 are as defined above, X is Cl or Br and R.sub.1 and R.sub.2, which can be the same or different, are each alkyl or 1 to 10 carbon atoms;
alkenyl of 2 to 10 carbon atoms;
aryl of 6 to 10 carbon atoms;
cycloalkyl or 3 to 8 carbon atoms;
cycloalkenyl of 4 to 8 carbon atoms;
alkynyl or 2 to 10 carbon atoms;
aralkyl, alkaryl, aralkenyl, aralkynyl, alkenylaryl, or alkynylaryl, wherein the alkyl, alkenyl, alkynyl, and aryl portions are defined as above;
or a substituted derivative of one of the above-defined alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, alkynyl, aralkyl, alkaryl, aralkenyl, aralkynyl, alkenylaryl and alkynylaryl radicals, said derivative having one or more substituents each of which are selected from the group consisting of C.sub.1 -C.sub.8 alkyl, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkanoyl, C.sub.1 -C.sub.8 alkanoyloxy, halo, cyano, C.sub.2 -C.sub.9 carbalkoxy, C.sub.1 -C.sub.8 alkylthio, nitro, C.sub.1 -C.sub.8 haloalkyl having 1 or more halo substituents, dialkylamino wherein the alkyl portions each contain 1 to 8 carbon atoms, carboxy, dialkylcarbamyl wherein the alkyl portions each contain 1 to 8 carbon atoms, and C.sub.1 -C.sub.8 alkylsulfonyl;
or R.sub.1 and R.sub.2 are combined so that --NR.sub.1 R.sub.2 represents the residue of a saturated or unsaturated heterocyclic compound containing one secondary nitrogen atom;
and R.sub.3 is hydrogen, R.sub.1', ##STR532## --CH.sub.2 OCOR.sub.1', --CH.sub.2 ONO.sub.2, CX.sub.3, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, cyano, carbamyl or C.sub.2 -C.sub.9 alkylcarbamyl, wherein R.sub.1 and R.sub.2 are as defined above, X is Cl or Br R.sub.1' is any radical encompassed by the definition of R.sub.1 above;
and
(b) the non-toxic pharmaceutically acceptable acid addition salts and N-oxides thereof, and a pharmaceutically acceptable carrier therefor.

23 more elements

A pharmaceutical composition of matter comprising an antibiotic effective amount of a compound selected from the group consisting of:

(a) compounds having the structural formula:
##STR535## wherein --OOC--R'--COO-- is the di(acyloxy) residue of a bio-affecting dicarboxylic acid selected from the group consisting of methotrexate, carbenicillin, penicillin n, and glutathione;
Y and Y', which can be the same or different, and each hydrogen or alkyl of 1 to 4 carbon atoms;
n is zero or one;
the depicted phenylene group is oriented such that R--COO-- and ##STR536## are positioned ortho or para to each other;
R.sub.1 and R.sub.2, which can be the same or different, are each alkyl or 1 to 10 carbon atoms;
alkenyl of 2 to 10 carbon atoms;
aryl of 6 to 10 carbon atoms;
cycloalkyl or 3 to 8 carbon atoms;
cycloalkenyl of 4 to 8 carbon atoms;
alkynyl or 2 to 10 carbon atoms;
aralkyl, alkaryl, aralkenyl, aralkynyl, alkenylaryl, or alkynylaryl, wherein the alkyl, alkenyl, alkynyl, and aryl portions are defined as above;
or a substituted derivative of one of the above-defined alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, alkynyl, aralkyl, alkaryl, aralkenyl, aralkynyl, alkenylaryl and alkynylaryl radicals, said derivative having one or more substituents each of which are selected from the group consisting of C.sub.1 -C.sub.8 alkyl, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkanoyl, C.sub.1 -C.sub.8 alkanoyloxy, halo, cyano, C.sub.2 -C.sub.9 carbalkoxy, C.sub.1 -C.sub.8 alkylthio, nitro, C.sub.1 -C.sub.8 haloalkyl having 1 or more halo substituents, dialkylamino wherein the alkyl portions each contain 1 to 8 carbon atoms, carboxy, dialkylcarbamyl wherein the alkyl portions each contain 1 to 8 carbon atoms, and C.sub.1 -C.sub.8 alkylsulfonyl;
or R.sub.1 and R.sub.2 are combined so that --NR.sub.1 R.sub.2 represents the residue of a saturated or unsaturated heterocyclic compound containing one secondary nitrogen atom;
and R.sub.3 is hydrogen, R.sub.1', ##STR537## --CH.sub.2 OCOR.sub.1', --CH.sub.2 ONO.sub.2, CX.sub.3, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, cyano, carbamyl or C.sub.2 -C.sub.9 alkylcarbamyl, wherein R.sub.1 and R.sub.2 are as defined above, X is Cl or Br and R.sub.1, is any radical encompassed by the definition of R.sub.1 above;
and
(b) the non-toxic pharmaceutically acceptable acid addition salts and N-oxides thereof, and a pharmaceutically acceptable carrier therefor.

14 more elements

A method of eliciting an antibiotic response in a warm-blooded animal, which comprises administering to such animal an antibiotic effective amount of a compound selected from the group consisting of:

(a) compounds having the structural formula:
##STR538## wherein --OOC--R'--COO-- is the di(acyloxy) residue of a bio-affecting dicarboxylic acid selected from the group consisting of methotrexate, carbenicillin, penicillin N, and glutathione;
Y and Y', which can be the same or different, and each hydrogen or alkyl of 1 to 4 carbon atoms;
n is zero or one;
the depicted phenylene group is oriented such that R--COO-- and ##STR539## are positioned ortho or para to each other;
R.sub.1 and R.sub.2, which can be the same or different, are each alkyl or 1 to 10 carbon atoms;
alkenyl of 2 to 10 carbon atoms;
aryl of 6 to 10 carbon atoms;
cycloalkyl or 3 to 8 carbon atoms;
cycloalkenyl of 4 to 8 carbon atoms;
alkynyl or 2 to 10 carbon atoms;
aralkyl, alkaryl, aralkenyl, aralkynyl, alkenylaryl, or alkynylaryl, wherein the alkyl, alkenyl, alkynyl, and aryl portions are defined as above;
or a substituted derivative of one of the above-defined alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, alkynyl, aralkyl, alkaryl, aralkenyl, aralkynyl, alkenylaryl and alkynylaryl radicals, said derivative having one or more substituents each of which are selected from the group consisting of C.sub.1 -C.sub.8 alkyl, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkanoyl, C.sub.1 -C.sub.8 alkanoyloxy, halo, cyano, C.sub.2 -C.sub.9 carbalkoxy, C.sub.1 -C.sub.8 alkylthio, nitro, C.sub.1 -C.sub.8 haloalkyl having 1 or more halo substituents, dialkylamino wherein the alkyl portions each contain 1 to 8 carbon atoms, carboxy, dialkylcarbamyl wherein the alkyl portions each contain 1 to 8 carbon atoms, and C.sub.1 -C.sub.8 alkylsulfonyl;
or R.sub.1 and R.sub.2 are combined so that --NR.sub.1 R.sub. 2 represents the residue of a saturated or unsaturated heterocyclic compound containing one secondary nitrogen atom;
and R.sub.3 is hydrogen, R.sub.1', ##STR540## --CH.sub.2 OCOR.sub.1', --CH.sub.2 ONO.sub.2, CX.sub.3, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, cyano, carbamyl or C.sub.2 -C.sub.9 alkylcarbamyl, wherein R.sub.1 and R.sub.2 are as defined above, X is Cl or Br and R.sub.1' is any radical encompassed by the definition of R.sub.1 above;
and
(b) the non-toxic pharmaceutically acceptable acid addition salts and N-oxides thereof.

14 more elements

Dependencies are inferred from the claim text.