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US 5,846,979 AGranted
N-oxides of heterocyclic esters, amides, thioesters, and ketones
AssigneeGPI NIL Holdings, Inc.
InventorsGregory S. Hamilton, Joseph P. Steiner, Eric S. Burak
Life of this patent
Estimating the term…
Abstract
This invention relates to neurotrophic low molecular weight, small molecule N-oxides of heterocyclic esters, amides, thioesters, and ketones having an affinity for FKBP-type immunophilins, and their use as inhibitors of the enzyme activity associated with immunophilin proteins, particularly peptidyl-prolyl isomerase, or rotamase, enzyme activity.
Claims20
A compound of the formula ##STR6## or a pharmaceutically acceptable salt thereof, wherein:
- A and B are taken together, with the nitrogen and carbon atoms to which they are respectively attached, to form a 5-7 membered saturated or unsaturated heterocyclic ring having only one heteroatom which is nitrogen, the remaining ring members being carbon, in any chemically stable oxidation state;
- W is O, S, CH.sub.2, or H.sub.2 ;
- R is a C.sub.1 -C.sub.6 straight or branched chain alkyl or alkenyl group optionally substituted with C.sub.3 -C.sub.8 cycloalkyl, C.sub.3 or C.sub.5 cycloalkyl, C.sub.5 -C.sub.7 cycloalkenyl, or Ar.sub.1, where said alkyl, alkenyl, cycloalkyl, or cycloalkenyl groups may be optionally substituted with C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkenyl, or hydroxy, and where Ar.sub.1 is selected from the group consisting of 1-napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C.sub.1 -C.sub.6 straight or branched alkyl or alkenyl, C.sub.1 -C.sub.4 alkenyloxy, phenoxy, benzyloxy, and amino;
- X is O, NH, NR.sub.1, S, CH.sub.2, CHR.sub.1, or C(R.sub.1).sub.2 ;
- Y is a direct bond, or a C1-C.sub.6 straight or branched chain alkyl or alkenyl which is optionally substituted in one or more positions with C.sub.1 -C.sub.6 straight or branched chain alkyl or alkenyl, or C.sub.3 -C.sub.8 cycloalkyl, or C.sub.5 -C.sub.7 cycloalkenyl, or hydroxyl, or carbonyl oxygen, or with Ar, where said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally substituted with C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkenyl, or hydroxy, or carbonyl oxygen, or wherein any of the carbon atoms of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally replaced with O, NH, NR.sub.2, S, SO, or SO.sub.2, where R.sub.2 is selected from the group consisting of hydrogen, (C.sub.1 -C.sub.4)-straight or branched chain alkyl, (C.sub.3 -C.sub.4)-straight or branched chain alkenyl or alkynyl, and (C.sub.1 -C.sub.4) bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
- and
- Z is an aromatic or tertiary alkyl amine oxidized to a corresponding N-oxide, wherein the aromatic amine is Ar oxidized to a corresponding N-oxide where Ar is a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C.sub.1 -C.sub.6 straight or branched chain alkyl or alkenyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof;
- wherein the individual ring sizes are 5-6 members;
- wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof wherein at least one of the heteroatoms is N, and wherein the alkyl amine is oxidized to a corresponding N-oxide where alkyl is a C.sub.1 -C.sub.6 straight or branched chain alkyl or alkenyl which is optionally substituted in one or more positions with C.sub.1 -C.sub.6 straight or branched chain alkyl or alkenyl, or C.sub.3 -C.sub.8 cycloalkyl, or C.sub.5 -C.sub.7 cycloalkenyl, or hydroxyl, or carbonyl oxygen, or with Ar, where said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally substituted with C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkenyl, or hydroxy, or carbonyl oxygen, or wherein any of the carbon atoms of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally replaced with O, NH, NR.sub.1, S, SO, or SO.sub.2 ;
- Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl;
- and,
- R.sub.1 is hydrogen, (C.sub.1 -C.sub.4)-straight or branched chain alkyl, (C.sub.3 -C.sub.4)-straight or branched chain alkenyl or alkynyl, or R.sub.1 is Y--Z as defined above.
9 more elements
A compound of formula II comprising:
- ##STR7## or a pharmaceutically acceptable salt thereof, wherein:
- E, F, G and H are independently CH.sub.2 ;
- W is O, S, CH.sub.2, or H.sub.2 ;
- R is a C.sub.1 -C.sub.6 straight or branched chain alkyl or alkenyl group optionally substituted with C.sub.3 -C.sub.8 cycloalkyl, C.sub.3 or C.sub.5 cycloalkyl, C.sub.5 -C.sub.7 cycloalkenyl, or Ar.sub.1, where said alkyl, alkenyl, cycloalkyl, or cycloalkenyl groups may be optionally substituted with C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkenyl, or hydroxy, and where Ar.sub.1 is selected from the group consisting of 1-napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C.sub.1 -C.sub.6 straight or branched alkyl or alkenyl, C.sub.1 -C.sub.4 alkenyloxy, phenoxy, benzyloxy, and amino;
- X is O, NH, NR.sub.1, S, CH.sub.2, CHR.sub.1, or C(R.sub.1).sub.2 ;
- Y is a direct bond, or a C1-C.sub.6 straight or branched chain alkyl or alkenyl which is optionally substituted in one or more positions with C.sub.1 -C.sub.6 straight or branched chain alkyl or alkenyl, or C.sub.3 -C.sub.8 cycloalkyl, or C.sub.5 -C.sub.7 cycloalkenyl, or hydroxyl, or carbonyl oxygen, or with Ar, where said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally substituted with C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkenyl, or hydroxy, or carbonyl oxygen, or wherein any of the carbon atoms of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally replaced with O, NH, NR.sub.2, S, SO, or SO.sub.2, where R.sub.2 is selected from the group consisting of hydrogen, (C.sub.1 -C.sub.4)-straight or branched chain alkyl, (C.sub.3 -C.sub.4)-straight or branched chain alkenyl or alkynyl, and (C.sub.1 -C.sub.4) bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
- and
- Z is an aromatic or tertiary alkyl amine oxidized to a corresponding N-oxide, wherein the aromatic amine is Ar oxidized to a corresponding N-oxide where Ar is a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C.sub.1 -C.sub.6 straight or branched chain alkyl or alkenyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof;
- wherein the individual ring sizes are 5-6 members;
- wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof wherein at least one of the heteroatoms is N, and wherein the alkyl amine is oxidized to a corresponding N-oxide where alkyl is a C.sub.1 -C.sub.6 straight or branched chain alkyl or alkenyl which is optionally substituted in one or more positions with C.sub.1 -C.sub.6 straight or branched chain alkyl or alkenyl, or C.sub.3 -C.sub.8 cycloalkyl, or C.sub.5 -C.sub.7 cycloalkenyl, or hydroxyl, or carbonyl oxygen, or with Ar, where said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally substituted with C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkenyl, or hydroxy, or carbonyl oxygen, or wherein any of the carbon atoms of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally replaced with O, NH, NR.sub.1, S, SO, or SO.sub.2 ;
- Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl;
- and,
- R.sub.1 is hydrogen, (C.sub.1 -C.sub.4)-straight or branched chain alkyl, (C.sub.3 -C.sub.4)-straight or branched chain alkenyl or alkynyl, or R.sub.1 is Y--Z as defined above.
10 more elements
A compound of formula III comprising:
- ##STR8## or a pharmaceutically acceptable salt thereof, wherein:
- E, F, and G are independently CH.sub.2 ;
- W is O, S, CH.sub.2, or H.sub.2 ;
- R is a C.sub.1 -C.sub.6 straight or branched chain alkyl or alkenyl group optionally substituted with C.sub.3 -C.sub.8 cycloalkyl, C.sub.3 or C.sub.5 cycloalkyl, C.sub.5 -C.sub.7 cycloalkenyl, or Ar.sub.1, where said alkyl, alkenyl, cycloalkyl, or cycloalkenyl groups may be optionally substituted with C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkenyl, or hydroxy, and where Ar.sub.1 is selected from the group consisting of 1-napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C.sub.1 -C.sub.6 straight or branched alkyl or alkenyl, C.sub.1 -C.sub.4 alkenyloxy, phenoxy, benzyloxy, and amino;
- X is O, NH, NR.sub.1, S, CH.sub.2, CHR.sub.1, or C(R.sub.1).sub.2 ;
- Y is a direct bond, or a C1-C.sub.6 straight or branched chain alkyl or alkenyl which is optionally substituted in one or more positions with C.sub.1 -C.sub.6 straight or branched chain alkyl or alkenyl, or C.sub.3 -C.sub.8 cycloalkyl, or C.sub.5 -C.sub.7 cycloalkenyl, or hydroxyl, or carbonyl oxygen, or with Ar, where said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally substituted with C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkenyl, or hydroxy, or carbonyl oxygen, or wherein any of the carbon atoms of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally replaced with O, NH, NR.sub.2, S, SO, or SO.sub.2, where R.sub.2 is selected from the group consisting of hydrogen, (C.sub.1 -C.sub.4)-straight or branched chain alkyl, (C.sub.3 -C.sub.4)-straight or branched chain alkenyl or alkynyl, and (C.sub.1 -C.sub.4) bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
- and
- Z is an aromatic or tertiary alkyl amine oxidized to a corresponding N-oxide, wherein the aromatic amine is Ar oxidized to a corresponding N-oxide where Ar is a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C.sub.1 -C.sub.6 straight or branched chain alkyl or alkenyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof;
- wherein the individual ring sizes are 5-6 members;
- wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof wherein at least one of the heteroatoms is N, and wherein the alkyl amine is oxidized to a corresponding N-oxide where alkyl is a C.sub.1 -C.sub.6 straight or branched chain alkyl or alkenyl which is optionally substituted in one or more positions with C.sub.1 -C.sub.6 straight or branched chain alkyl or alkenyl, or C.sub.3 -C.sub.8 cycloalkyl, or C.sub.5 -C.sub.7 cycloalkenyl, or hydroxyl, or carbonyl oxygen, or with Ar, where said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally substituted with C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkenyl, or hydroxy, or carbonyl oxygen, or wherein any of the carbon atoms of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally replaced with O, NH, NR.sub.1, S, SO, or SO.sub.2 ;
- Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl;
- and,
- R.sub.1 is hydrogen, (C.sub.1 -C.sub.4)-straight or branched chain alkyl, (C.sub.3 -C.sub.4)-straight or branched chain alkenyl or alkynyl, or R.sub.1 is Y--Z as defined above.
10 more elements
A compound of formula IV comprising:
- ##STR9## or a pharmaceutically acceptable salt thereof, wherein:
- n is 1, 2 or 3 forming a 5-7 member heterocyclic ring;
- W is O, S, CH.sub.2, or H.sub.2 ;
- R is a C.sub.1 -C.sub.6 straight or branched chain alkyl or alkenyl group optionally substituted with C.sub.3 -C.sub.8 cycloalkyl, C.sub.3 or C.sub.5 cycloalkyl, C.sub.5 -C.sub.7 cycloalkenyl, or Ar.sub.1, where said alkyl, alkenyl, cycloalkyl, or cycloalkenyl groups may be optionally substituted with C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkenyl, or hydroxy, and where Ar.sub.1 is selected from the group consisting of 1-napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or phenyl, having one to three substituents which are independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C.sub.1 -C.sub.6 straight or branched alkyl or alkenyl, C.sub.1 -C.sub.4 alkenyloxy, phenoxy, benzyloxy, and amino;
- X is O, NH, NR.sub.1, S, CH.sub.2, CHR.sub.1, or C(R.sub.1).sub.2 ;
- Y is a direct bond, or a C1-C.sub.6 straight or branched chain alkyl or alkenyl which is optionally substituted in one or more positions with C.sub.1 -C.sub.6 straight or branched chain alkyl or alkenyl, or C.sub.3 -C.sub.8 cycloalkyl, or C.sub.5 -C.sub.7 cycloalkenyl, or hydroxyl, or carbonyl oxygen, or with Ar, where said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally substituted with C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkenyl, or hydroxy, or carbonyl oxygen, or wherein any of the carbon atoms of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally replaced with O, NH, NR.sub.2, S, SO, or SO.sub.2, where R.sub.2 is selected from the group consisting of hydrogen, (C.sub.1 -C.sub.4)-straight or branched chain alkyl, (C.sub.3 -C.sub.4)-straight or branched chain alkenyl or alkynyl, and (C.sub.1 -C.sub.4) bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
- and
- Z is an aromatic or tertiary alkyl amine oxidized to a corresponding N-oxide, wherein the aromatic amine is Ar oxidized to a corresponding N-oxide where Ar is a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C.sub.1 -C.sub.6 straight or branched chain alkyl or alkenyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof;
- wherein the individual ring sizes are 5-6 members;
- wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof wherein at least one of the heteroatoms is N, and wherein the alkyl amine is oxidized to a corresponding N-oxide where alkyl is a C.sub.1 -C.sub.6 straight or branched chain alkyl or alkenyl which is optionally substituted in one or more positions with C.sub.1 -C.sub.6 straight or branched chain alkyl or alkenyl, or C.sub.3 -C.sub.8 cycloalkyl, or C.sub.5 -C.sub.7 cycloalkenyl, or hydroxyl, or carbonyl oxygen, or with Ar, where said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally substituted with C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkenyl, or hydroxy, or carbonyl oxygen, or wherein any of the carbon atoms of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally replaced with O, NH, NR.sub.1, S, SO, or SO.sub.2 ;
- Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl;
- and,
- R.sub.1 is hydrogen, (C.sub.1 -C.sub.4)-straight or branched chain alkyl, (C.sub.3 -C.sub.4)-straight or branched chain alkenyl or alkynyl, or R.sub.1 is Y--Z as defined above.
10 more elements
A compound selected from the group consisting of:
- 3-(2-Pyridyl)-1-propyl(2S)-1-(1,1-Dimethyl-1,2-dioxo-pentyl)-2-pyrrolidinec arboxylate, N-oxide;
- 3-(3-Pyridyl)-1-propyl(2S)-1-(1,1-Dimethyl-1,2-dioxo-pentyl)-2-pyrrolidinec arboxylate, N-oxide;
- 3-(4-Pyridyl)-1-propyl(2S)-1-(1,1-Dimethyl-1,2-dioxo-pentyl)-2-pyrrolidinec arboxylate, N-oxide;
- 3-(2-Quinolyl)-1-propyl(2S)-1-(1,1-Dimethyl-1,2-dioxo-pentyl)-2-pyrrolidine carboxylate, N-oxide;
- 3-(3-Quinolyl)-1-propyl(2S)-1-(1,1-Dimethyl-1,2-dioxo-pentyl)-2-pyrrolidine carboxylate, N-oxide;
- and
- 3-(4-Quinolyl)-1-propyl(2S)-1-(1,1-Dimethyl-1,2-dioxo-pentyl)-2-pyrrolidine carboxylate, N-oxide.
4 more elements
Dependencies are inferred from the claim text.