Immunomodulatory compounds and methods of use thereof
The present invention is directed to methods of treating diseases and disorders related to immune responses by administering one or more immunomodulatory compounds. In particular, the invention is directed to methods of stimulating and reducing immune responses, therapeutic and prophylactic treatment of cancer, treating autoimmune conditions, treating allergic reactions and asthma, and preventing ischemic damage and asthma by administering one or more immunomodulatory compounds.
1. A method of desensitizing a subject individual in need thereof against the occurrence of an allergic reaction in response to contact with a particular antigen or allergen, comprising administering to the subject an effective amount of one or more compounds of the formulae (II), (III), (IV), and (V):
wherein:
R 1 is:
(a) —C(O)—;
(b) —C(O)—C 1-14 alkyl-C(O)— or —C(O)—C 1-14 alkenyl-C(O)—;
wherein the —C 1-14 alkyl- or —C 1-14 alkenyl- is optionally substituted with one or more substituents selected from hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyldioxy, C 1-5 alkylamino, carboxy, C 1-6 alkoxycarbonyl, C 1-6 carbamoyl, C 1-6 acylamino, and/or (aryl)C 1-6 alkyl; and
wherein the aryl moiety of the (aryl)C 1-6 -alkyl is optionally substituted with one or more substituents selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkoxyamino, C 1-6 alkylamino-C 1-6 alkoxy, —O—C 1-6 alkylamino-C 1-6 alkoxy, —O—C 1-6 alkylamino-C(O)—C 1-6 alkyl-C(O)OH, —O—C 1-6 alkylamino-C(O)—C 1-6 alkyl-C(O)—C 1-6 alkyl, —O—C 1-6 alkyl-NH—C 1-6 alkyl-O—C 1-6 alkyl, —O—C 1-6 alkyl-NH—C(O)—C 1-6 alkyl-C(O)OH, and/or —O—C 1-6 alkyl-NH—C(O)—C 1-6 alkyl-C(O)—C 1-6 alkyl;
(c) a C 2 to C 15 straight or branched chain alkyl group optionally substituted with one or more hydroxy and/or alkoxy groups; or
(d) —C(O)—C 6-12 aryl-C(O)— wherein the aryl is optionally substituted with one or more hydroxy, halo, nitro, amino, C 1-6 alkyl and/or C 1-6 alkoxy groups;
a and b are each independently 0, 1, 2, 3 or 4;
a′ and b′ are independently 2, 3, 4, 5, 6, 7 or 8;
d and e are each independently 1, 2, 3, 4, 5 or 6;
d′ and e′ are each independently 0, 1, 2, 3 or 4;
d″ and e″ are each independently 0, 1, 2, 3 or 4;
T is oxygen or sulfur;
X 1 and Y 1 are each independently oxygen, NH, —N(C(O)C 1-4 alkyl)-, or —N(C 1-4 -alkyl)-;
X 2 and Y 2 are each independently null, oxygen, NH, —N(C(O)C 1-4 alkyl)-, or —N(C 1-4 alkyl)-;
W 1 and W 2 are each independently carbonyl, methylene, sulfone or sulfoxide;
R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently:
(a) C 2 to C 20 straight chain or branched chain alkyl, which is optionally substituted with one or more oxo, halo, hydroxy and/or alkoxy groups;
(b) C 2 to C 20 straight chain or branched chain alkenyl, which is optionally substituted with one or more of oxo, halo, hydroxy and/or alkoxy groups;
(c) C 2 to C 20 straight chain or branched chain alkoxy, which is optionally substituted with one or more oxo, halo, hydroxy and/or alkoxy groups;
(d) —NH—C 2-20 straight chain or branched chain alkyl, wherein the alkyl group is optionally substituted with one or more oxo, halo, hydroxy and/or alkoxy groups;
(e) —C(O)—C 2-20 straight chain or branched chain alkyl or alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more oxo, halo, hydroxy and/or alkoxy groups;
Z is O or NH; and M and N are each independently C 2 to C 20 straight chain or branched chain alkyl, alkenyl, alkoxy, acyloxy, alkylamino, or acylamino;
R 8 is C 1-6 straight or branched chain alkyl or C 2-6 straight or branched chain alkenyl or alkynyl;
R 9 and R 10 are independently selected from the group consisting of
(i) C 1 to C 20 straight chain or branched chain alkyl, which is optionally substituted with one or more halo, oxo, hydroxy and/or alkoxy; and
(ii) C 2 to C 20 straight chain or branched chain alkenyl or alkynyl which is optionally substituted with one or more halo, oxo, hydroxy and/or alkoxy;
G 1 , G 2 , G 3 , G 4 and G 5 are each independently oxygen, methylene, —NH—, thiol, —N(C 1-4 alkyl)-, —N[C(O)—C 1-4 alkyl]-, —NH—C(O)—, —NH—SO 2 —, —C(O)—O—, —C(O)—NH—, —O—C(O)—, —O—C(O)—NH—, —O—C(O)—O—, —NH—C(O)—NH—, —C(O)NH—, —C(O)N(C 1-4 alkyl), aryl, and —S(O) n —, where n is 0, 1, or 2;
or G 1 R 2 , G 2 R 4 , G 3 R 5 and/or G 4 R 7 may together be a hydrogen atom or hydroxyl;
Z 1 and Z 2 are each independently selected from —OP(O)(OH) 2 , —P(O)(OH) 2 , —OP(O)(OR 8 )(OH) {where R 8 is a C 1-4 alkyl}, —OS(O) 2 OH, —S(O) 2 OH—, —CO 2 H, —OB(OH) 2 , —OH, —CH 3 , —NH 2 , and —N(R 9 ) 2 {where R 9 is a C 1-4 alkyl};
R 12 is H or a C 1-4 straight or branched alkyl; and
M is independently selected from a hydrogen atom and a pharmaceutically acceptable cation {a monovalent cation will take the place of one M, while a divalent cation will take the place of two M variables};
and/or a pharmaceutically acceptable salt, stereoisomer, amorphous solid thereof, or any combination thereof.
2. The method of claim 1 , wherein the subject individual suffers from asthma, atopic dermatitis, or allergic rhinitis.
3. A method of reducing ischemic damage in a subject individual in need thereof, the method comprising administering to the subject an effective amount of one or more compounds of the formulae (II), (III), (IV), and (V):
wherein:
R 1 is:
(a) —C(O)—;
(b) —C(O)—C 1-14 alkyl-C(O)— or —C(O)—C 1-14 alkenyl-C(O)—;
wherein the —C 1-14 alkyl- or —C 1-14 alkenyl- is optionally substituted with one or more substituents selected from hydroxy, C 1-6 alkoxy, C 1-6 alkyldioxy, C 1-5 alkylamino, carboxy, C 1-6 alkoxycarbonyl, C 1-6 carbamoyl, C 1-6 acylamino, and/or (aryl)C 1-6 alkyl; and
wherein the aryl moiety of the (aryl)C 1-6 -alkyl is optionally substituted with one or more substituents selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkoxyamino, C 1-6 alkylamino-C 1-6 alkoxy, —O—C 1-6 alkylamino-C(O)—C 1-6 alkyl-C(O)OH, —O—C 1-6 alkylamino-C(O)—C 1-6 alkyl-C(O)—C 1-6 alkyl, —O—C 1-6 alkyl-NH—C 1-6 alkyl-O—C 1-6 alkyl, —O—C 1-6 alkyl-NH—C(O)—C 1-6 alkyl-C(O)OH, and/or —O—C 1-6 alkyl-NH—C(O)—C 1-6 alkyl-C(O)—C 1-6 alkyl;
(c) a C 2 to C 15 straight or branched chain alkyl group optionally substituted with one or more hydroxy and/or alkoxy groups; or
(d) —C(O)—C 6-12 aryl-C(O)— wherein the aryl is optionally substituted with one or more hydroxy, halo, nitro, amino, C 1-6 alkyl and/or C 1-6 alkoxy groups;
a and b are each independently 0, 1, 2, 3 or 4;
a′ and b′ are independently 2, 3, 4, 5, 6, 7 or 8;
d and e are each independently 1, 2, 3, 4, 5 or 6;
d′ and e′ are each independently 0, 1, 2, 3 or 4;
d″ and e″ are each independently 0, 1, 2, 3 or 4;
T is oxygen or sulfur;
X 1 and Y 1 are each independently oxygen, NH, —N(C(O)C 1-4 alkyl)-, or —N(C 1-4 alkyl)-;
X 2 and Y 2 are each independently null, oxygen, NH, —N(C(O)C 1-4 alkyl)-, or —N(C 1-4 alkyl)-;
W 1 and W 2 are each independently carbonyl, methylene, sulfone or sulfoxide;
R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently:
(a) C 2 to C 20 straight chain or branched chain alkyl, which is optionally substituted with one or more oxo, halo, hydroxy and/or alkoxy groups;
(b) C 2 to C 20 straight chain or branched chain alkenyl, which is optionally substituted with one or more of oxo, halo, hydroxy and/or alkoxy groups;
(c) C 2 to C 20 straight chain or branched chain alkoxy, which is optionally substituted with one or more oxo, halo, hydroxy and/or alkoxy groups;
(d) —NH—C 2-20 straight chain or branched chain alkyl, wherein the alkyl group is optionally substituted with one or more oxo, halo, hydroxy and/or alkoxy groups;
(e) —C(O)—C 2-20 straight chain or branched chain alkyl or alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more oxo, halo, hydroxy and/or alkoxy groups;
Z is O or NH; and M and N are each independently C 2 to C 20 straight chain or branched chain alkyl, alkenyl, alkoxy, acyloxy, alkylamino, or acylamino;
R 8 is C 1-6 straight or branched chain alkyl or C 2-6 straight or branched chain alkenyl or alkynyl;
R 9 and R 10 are independently selected from the group consisting of
(i) C 1 to C 20 straight chain or branched chain alkyl, which is optionally substituted with one or more halo, oxo, hydroxy and/or alkoxy; and
(ii) C 2 to C 20 straight chain or branched chain alkenyl or alkynyl which is optionally substituted with one or more halo, oxo, hydroxy and/or alkoxy;
G 1 , G 2 , G 3 , G 4 and G 5 are each independently oxygen, methylene, —NH—, thiol, —N(C 1-4 alkyl)-, —N[C(O)—C 1-4 alkyl]-, —NH—C(O)—, —NH—SO 2 —, —C(O)—O—, —C(O)—NH—, —O—C(O)—, —O—C(O)—NH—, —O—C(O)—O—, —NH—, —C(O)—NH—, —C(O)NH—, —C(O)N(C 1-4 alkyl), aryl, and —S(O) n —, where n is 0, 1, or 2;
or G 1 R 2 , G 2 R 4 , G 3 R 5 and/or G 4 R 7 may together be a hydrogen atom or hydroxyl;
Z 1 and Z 2 are each independently selected from —OP(O)(OH) 2 , —P(O)(OH) 2 , —OP(O)(OR 8 )(OH) {where R 8 is a C 1-4 alkyl}, —OS(O) 2 OH, —S(O) 2 OH—, —CO 2 H, —OB(OH) 2 , —OH, —CH 3 , —NH 2 , and —N(R 9 ) 2 {where R 9 is a C 1-4 alkyl};
R 12 is H or a C 1-4 straight or branched alkyl; and
M is independently selected from a hydrogen atom and a pharmaceutically acceptable cation {a monovalent cation will take the place of one M, while a divalent cation will take the place of two M variables};
and/or a pharmaceutically acceptable salt, stereoisomer, amorphous solid thereof, or any combination thereof prior to performing surgery on the individual.
4. A method of ameliorating or delaying asthma in a subject individual in need thereof, the method comprising administering to the subject an effective amount of one or more compounds of the formulae (II), (III), (IV), and (V):
wherein:
R 1 is:
(a) —C(O)—;
(b) —C(O)—C 1-14 alkyl-C(O)— or —C(O)—C 1-14 alkenyl-C(O)—;
wherein the —C 1-14 alkyl- or —C 1-14 alkenyl- is optionally substituted with one or more substituents selected from hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyldioxy, C 1-5 alkylamino, carboxy, C 1-6 alkoxycarbonyl, C 1-6 carbamoyl, C 1-6 acylamino, and/or (aryl)C 1-6 alkyl; and
wherein the aryl moiety of the (aryl)C 1-6 -alkyl is optionally substituted with one or more substituents selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkoxyamino, C 1-6 alkylamino-C 1-6 alkoxy, —O—C 1-6 alkylamino-C 1-6 alkoxy, —O—C 1-6 alkylamino-C(O)—C 1-6 alkyl-C(O)OH, —O—C 1-6 alkylamino-C(O)—C 1-6 alkyl-C(O)—C 1-6 alkyl, —O—C 1-6 alkyl-NH—C 1-6 alkyl-O—C 1-6 alkyl, —O—C 1-6 alkyl-NH—C(O)—C 1-6 alkyl-C(O)OH, and/or —O—C 1-6 alkyl-NH—C(O)—C 1-6 alkyl-C(O)—C 1-6 alkyl;
(c) a C 2 to C 15 straight or branched chain alkyl group optionally substituted with one or more hydroxy and/or alkoxy groups; or
(d) —C(O)—C 6-12 aryl-C(O)— wherein the aryl is optionally substituted with one or more hydroxy, halo, nitro, amino, C 1-6 alkyl and/or C 1-6 alkoxy groups;
a and b are each independently 0, 1, 2, 3 or 4;
a′ and b′ are independently 2, 3, 4, 5, 6, 7 or 8;
d and e are each independently 1, 2, 3, 4, 5 or 6;
d′ and e′ are each independently 0, 1, 2, 3 or 4;
d″ and e″ are each independently 0, 1, 2, 3 or 4;
T is oxygen or sulfur;
X 1 and Y 1 are each independently oxygen, NH, —N(C(O)C 1-4 alkyl)-, or —N(C 1-4 alkyl)-;
X 2 and Y 2 are each independently null, oxygen, NH, —N(C(O)C 1-4 alkyl)-, or —N(C 1-4 alkyl)-;
W 1 and W 2 are each independently carbonyl, methylene, sulfone or sulfoxide;
R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently:
(a) C 2 to C 20 straight chain or branched chain alkyl, which is optionally substituted with one or more oxo, halo, hydroxy and/or alkoxy groups;
(b) C 2 to C 20 straight chain or branched chain alkenyl, which is optionally substituted with one or more of oxo, halo, hydroxy and/or alkoxy groups;
(c) C 2 to C 20 straight chain or branched chain alkoxy, which is optionally substituted with one or more oxo, halo, hydroxy and/or alkoxy groups;
(d) —NH—C 2-20 straight chain or branched chain alkyl, wherein the alkyl group is optionally substituted with one or more oxo, halo, hydroxy and/or alkoxy groups;
(e) —C(O)—C 2-20 straight chain or branched chain alkyl or alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more oxo, halo, hydroxy and/or alkoxy groups;
Z is O or NH; and M and N are each independently C 2 to C 20 straight chain or branched chain alkyl, alkenyl, alkoxy, acyloxy, alkylamino, or acylamino;
R 8 is C 1-6 straight or branched chain alkyl or C 2-6 straight or branched chain alkenyl or alkynyl;
R 9 and R 10 are independently selected from the group consisting of
(i) C 1 to C 20 straight chain or branched chain alkyl, which is optionally substituted with one or more halo, oxo, hydroxy and/or alkoxy; and
(ii) C 2 to C 20 straight chain or branched chain alkenyl or alkynyl which is optionally substituted with one or more halo, oxo, hydroxy and/or alkoxy;
G 1 , G 2 , G 3 , G 4 and G 5 are each independently oxygen, methylene, —NH—, thiol, —N(C 1-4 alkyl)-, —N[C(O)—C 1-4 alkyl]-, —NH—C(O)—, —NH—SO 2 —, —C(O)—O—, —C(O)—NH—, —O—C(O)—, —O—C(O)—NH—, —O—C(O)—O—, —NH—C(O)—NH—, —C(O)NH—, —C(O)N(C 1-4 alkyl), aryl, and —S(O) n —, where n is 0, 1, or 2;
or G 1 R 2 , G 2 R 4 , G 3 R 5 and/or G 4 R 7 may together be a hydrogen atom or hydroxyl;
Z 1 and Z 2 are each independently selected from —OP(O)(OH) 2 , —P(O)(OH) 2 , —OP(O)(OR 8 )(OH) {where R 8 is a C 1-4 alkyl}, —OS(O) 2 OH, —S(O) 2 OH—, —CO 2 H, —OB(OH) 2 , —OH, —CH 3 , —NH 2 , and —N(R 9 ) 2 {where R 9 is a C 1-4 alkyl};
R 12 is H or a C 1-4 straight or branched alkyl; and
M is independently selected from a hydrogen atom and a pharmaceutically acceptable cation {a monovalent cation will take the place of one M, while a divalent cation will take the place of two M variables};
and/or a pharmaceutically acceptable salt, stereoisomer, amorphous solid thereof, or any combination thereof.
5. A method of inducing or stimulating an immune response in a subject individual, comprising administering an effective amount of one or more compounds of formula (I):
wherein:
R 1 is selected from the group consisting of:
(a) —C(O)—;
(b) C(O)—C 2-15 alkyl-C(O)—, optionally substituted with hydroxy or alkoxy;
(c) a C 2 to C 15 straight or branched chain alkyl optionally substituted with hydroxy or alkoxy;
a and b are independently 2, 3 or 4;
d and e are independently an integer from 1 to 4;
d′ and e′ are 1;
d″ and e″ are 2;
T is oxygen;
X 1 and Y 1 are NH;
X 2 and Y 2 are independently selected from the group consisting of oxygen and NH;
W 1 and W 2 are carbonyl,
R 2 and R 5 are each independently:
(a) C 2 to C 20 straight chain or branched chain alkyl which is optionally substituted with hydroxy or alkoxy;
(b) C 2 to C 20 straight chain or branched chain alkenyl which is optionally substituted with hydroxy or alkoxy;
(c) CH 2 -alkyl carbonyl;
(d) CH 2 -alkenyl carbonyl;
wherein Z is selected from the group consisting of O and NH, and M and N are independently selected from the group consisting of C 2 to C 20 straight chain or branched chain alkyl, alkenyl, alkoxy, acyloxy, alkylamino, and acylamino;
R 3 and R 6 are independently selected from the group consisting of C 2 to C 20 straight chain or branched chain alkyl or alkenyl;
R 4 and R 7 are independently selected from the group consisting of hydrogen, C 2 to C 20 straight chain or branched chain alkyl or alkenyl; C 2 to C 20 straight chain or branched chain alkyl carbonyl; C 2 to C 20 straight chain or branched chain alkenyl carbonyl; optionally substituted with hydroxy or alkoxy;
G 1 , G 2 , G 3 , and G 4 are oxygen
or a pharmaceutically acceptable salt, thereof.
6. A method for upregulation of the immune system in a subject individual, comprising administering a therapeutically effective amount of one or more compounds of formula (I):
wherein:
R 1 is selected from the group consisting of:
(a) —C(O)—;
(b) C(O)—C 2-15 alkyl-C(O)—, optionally substituted with hydroxy or alkoxy
(c) a C 2 to C 15 straight or branched chain alkyl optionally substituted with hydroxy or alkoxy;
a and b are independently 2, 3 or 4;
d and e are independently an integer from 1 to 4;
d′ and e′ are 1;
d″ and e″ are 2;
T is oxygen;
X 1 and Y 1 are NH;
X 2 and Y 2 are independently selected from the group consisting of oxygen and NH;
W 1 and W 2 are carbonyl;
R 2 and R 5 are each independently:
(a) C 2 to C 20 straight chain or branched chain alkyl which is optionally substituted with hydroxy or alkoxy;
(b) C 2 to C 20 straight chain or branched chain alkenyl which is optionally substituted with hydroxy or alkoxy;
(c) CH 2 -alkyl carbonyl;
(d) CH 2 -alkenyl carbonyl;
wherein Z is selected from the group consisting of O and NH, and M and N are independently selected from the group consisting of C 2 to C 20 straight chain or branched chain alkyl, alkenyl, alkoxy, acyloxy, alkylamino, and acylamino;
R 3 and R 6 are independently selected from the group consisting of C 2 to C 20 straight chain or branched chain alkyl or alkenyl;
R 4 and R 7 are independently selected from the group consisting of hydrogen, C 2 to C 20 straight chain or branched chain alkyl or alkenyl; C 2 to C 20 straight chain or branched chain alkyl carbonyl; C 2 to C 20 straight chain or branched chain alkenyl carbonyl; optionally substituted with hydroxy or alkoxy;
G 1 , G 2 , G 3 , and oxygen
or a pharmaceutically acceptable salt, thereof.
7. A method of desensitizing a subject individual in need thereof against the occurrence of an allergic reaction in response to contact with a particular antigen or allergen, comprising administering to the subject an effective amount of one or more compounds of formula (I):
wherein:
R 1 is selected from the group consisting of:
(a) —C(O)—;
(b) —C(O)—C 1-14 alkyl-C(O)—, wherein said —C 1-14 alkyl- is optionally substituted with hydroxy, C 1-5 alkoxy, C 1-5 alkylenedioxy, C 1-5 alkylamino, or C 1-5 -alkyl-aryl, wherein said aryl moiety of said C 1-5 -alkyl-aryl is optionally substituted with C 1-5 alkoxy, C 1-5 alkylamino, C 1-5 alkoxy-amino, C 1-5 alkylamino-C 1-5 alkoxy, —O—C 1-5 alkylamino-C 1-5 alkoxy, —O—C 1-5 alkylamino-C(O)—C 1-5 alkyl-C(O)OH, —O—C 1-5 alkylamino-C(O)—C 1-5 alkyl-C(O)—C 1-5 alkyl;
(c) a C 2 to C 15 straight or branched chain alkyl optionally substituted with hydroxy or alkoxy; and
(d) —C(O)—C 6-12 arylene-C(O)— wherein said arylene is optionally substituted with hydroxy, halogen, nitro or amino;
a and b are independently 0, 1, 2, 3 or 4;
d, d′, d″, e, e′, and e″ e are independently an integer from 1 to 4;
T is oxygen;
X 1 , X 2 , Y 1 , and Y 2 are independently selected from the group consisting of a null, oxygen, NH, N(C(O)C 1-4 alkyl), and N(C 1-4 alkyl) 2 ;
W 1 and W 2 are independently selected from the group consisting of carbonyl, methylene, sulfone and sulfoxide;
R 2 and R 5 are each independently:
(a) C 2 to C 20 straight chain or branched chain alkyl which is optionally substituted with oxo, hydroxy or alkoxy;
(b) C 2 to C 20 straight chain or branched chain alkenyl or dialkenyl which is optionally substituted with oxo, hydroxy or alkoxy;
(c) C 2 to C 20 straight chain or branched chain alkoxy which is optionally substituted with oxo, hydroxy or alkoxy;
(d) —NH—C 2 to C 20 straight chain or branched chain alkyl, wherein said alkyl group is optionally substituted with oxo, hydroxy or alkoxy;
wherein Z is selected from the group consisting of O and NH, and M and N are independently selected from the group consisting of C 2 to C 20 straight chain or branched chain alkyl, alkenyl, alkoxy, acyloxy, alkylamino, and acylamino;
R 3 and R 6 are independently selected from the group consisting of C 2 to C 20 straight chain or branched chain alkyl or alkenyl optionally substituted with oxo or fluoro;
R 4 and R 7 are independently selected from the group consisting of C(O)C 2 to C 20 straight chain or branched chain alkyl or alkenyl; C 2 to C 20 straight chain or branched chain alkoxy;
C 2 to C 20 straight chain or branched chain alkenyl; wherein said alkyl, alkenyl, or alkoxy groups can be independently and optionally substituted with hydroxy, fluoro or C 1 to C 5 alkoxy;
G 1 , G 2 , G 3 , and G 4 are independently selected from the group consisting of oxygen, methylene, amino, thiol, —NHC(O)—, and —NC(O)C 1-4 alkyl)-;
or G 2 R 4 or G 4 R 7 may together be a hydrogen atom or hydroxyl;
or a pharmaceutically acceptable salt, stereoisomer, amorphous solid thereof, or any combination thereof.
8. The method of claim 7 , wherein the subject individual suffers from asthma, atopic dermatitis, or allergic rhinitis.
9. An immunostimulatory remedy containing, as the active ingredient, one or more compounds of formula (I):
wherein:
R 1 is selected from the group consisting of:
(a) —C(O)—;
(b) C(O)—C 2-15 alkyl-C(O)—, optionally substituted with hydroxy or alkoxy;
(c) a C 2 to C 15 straight or branched chain alkyl optionally substituted with hydroxy or alkoxy;
a and b are independently 2, 3 or 4;
d and e are independently an integer from 1 to 4;
d′ and e′ are 1;
d″ and e″ are 2;
T is oxygen;
X 1 and Y 1 are NH;
X 2 and Y 2 are independently selected from the group consisting of oxygen and NH;
W 1 and W 2 are carbonyl;
R 2 and R 5 are each independently:
(a) C 2 to C 20 straight chain or branched chain alkyl which is optionally substituted with hydroxy or alkoxy;
(b) C 2 to C 20 straight chain or branched chain alkenyl which is optionally substituted with hydroxy or alkoxy;
(c) CH 2 -alkyl carbonyl;
(d) CH 2 -alkenyl carbonyl;
wherein Z is selected from the group consisting of O and NH, and M and N are independently selected from the group consisting of C 2 to C 20 straight chain or branched chain alkyl, alkenyl, alkoxy, acyloxy, alkylamino, and acylamino;
R 3 and R 6 are independently selected from the group consisting of C 2 to C 20 straight chain or branched chain alkyl or alkenyl;
R 4 and R 7 are independently selected from the group consisting of hydrogen, C 2 to C 20 straight chain or branched chain alkyl or alkenyl; C 2 to C 20 straight chain or branched chain alkyl carbonyl; C 2 to C 20 straight chain or branched chain alkenyl carbonyl; optionally substituted with hydroxy or alkoxy;
G 1 , G 2 , G 3 , and G 4 are oxygen;
or a pharmaceutically acceptable salt, thereof.
10. A method of reducing ischemic damage in a subject individual in need thereof, the method comprising administering to the subject an effective amount of one or more compounds of formula (I):
wherein:
R 1 is selected from the group consisting of:
(a) —C(O)—;
(b) —C(O)—C 1-14 alkyl-C(O)—, wherein said —C 1-14 alkyl- is optionally substituted with hydroxy, C 1-5 alkoxy, C 1-5 alkylenedioxy, C 1-5 alkylamino, or C 1-5 -alkyl-aryl, wherein said aryl moiety of said C 1-5 -alkyl-aryl is optionally substituted with C 1-5 alkoxy, C 1-5 alkylamino, C 1-5 alkoxy-amino, C 1-5 alkylamino-C 1-5 alkoxy, —O—C 1-5 alkylamino-C 1-5 alkoxy, —O—C 1-5 alkylamino-C(O)—C 1-5 alkyl-C(O)OH, —O—C 1-5 alkylamino-C(O)—C 1-5 alkyl-C(O)—C 1-5 alkyl;
(c) a C 2 to C 15 straight or branched chain alkyl optionally substituted with hydroxy or alkoxy; and
(d) —C(O)—C 6-12 arylene-C(O)— wherein said arylene is optionally substituted with hydroxy, halogen, nitro or amino;
a and b are independently 0, 1, 2, 3 or 4;
d, d′, d″, e, e′, and e″ e are independently an integer from 1 to 4;
T is oxygen;
X 1 , X 2 , Y 1 , and Y 2 are independently selected from the group consisting of a null, oxygen, NH, N(C(O)C 1-4 alkyl), and N(C 1-4 alkyl) 2 ;
W 1 and W 2 are independently selected from the group consisting of carbonyl, methylene, sulfone and sulfoxide;
R 2 and R 5 are each independently:
(a) C 2 to C 20 straight chain or branched chain alkyl which is optionally substituted with oxo, hydroxy or alkoxy;
(b) C 2 to C 20 straight chain or branched chain alkenyl or dialkenyl which is optionally substituted with oxo, hydroxy or alkoxy;
(c) C 2 to C 20 straight chain or branched chain alkoxy which is optionally substituted with oxo, hydroxy or alkoxy;
(d) —NH—C 2 to C 20 straight chain or branched chain alkyl, wherein said alkyl group is optionally substituted with oxo, hydroxy or alkoxy;
wherein Z is selected from the group consisting of O and NH, and M and N are independently selected from the group consisting of C 2 to C 20 straight chain or branched chain alkyl, alkenyl, alkoxy, acyloxy, alkylamino, and acylamino;
R 3 and R 6 are independently selected from the group consisting of C 2 to C 20 straight chain or branched chain alkyl or alkenyl optionally substituted with oxo or fluoro;
R 4 and R 7 are independently selected from the group consisting of C(O)C 2 to C 20 straight chain or branched chain alkyl or alkenyl; C 2 to C 20 straight chain or branched chain alkoxy;
C 2 to C 20 straight chain or branched chain alkenyl; wherein said alkyl, alkenyl, or alkoxy groups can be independently and optionally substituted with hydroxy, fluoro or C 1 to C 5 alkoxy;
G 1 , G 2 , G 3 , and G 4 are independently selected from the group consisting of oxygen, methylene, amino, thiol, —NHC(O)—, and —NC(O)C 1-4 alkyl)-;
or G 2 R 4 or G 4 R 7 may together be a hydrogen atom or hydroxyl;
or a pharmaceutically acceptable salt, stereoisomer, amorphous solid thereof, or any combination thereof.
11. A method of ameliorating or delaying asthma in a subject individual in need thereof, the method comprising administering to the subject an effective amount of one or more compounds of formula (I):
wherein:
R 1 is selected from the group consisting of:
(a) —C(O)—;
(b) —C(O)—C 1-14 alkyl-C(O)—, wherein said —C 1-14 alkyl- is optionally substituted with hydroxy, C 1-5 alkoxy, C 1-5 alkylenedioxy, C 1-5 alkylamino, or C 1-5 -alkyl-aryl, wherein said aryl moiety of said C 1-5 -alkyl-aryl is optionally substituted with C 1-5 alkoxy, C 1-5 alkylamino, C 1-5 alkoxy-amino, C 1-5 alkylamino-C 1-5 alkoxy, —O—C 1-5 alkylamino-C 1-5 alkoxy, alkylamino-C(O)—C 1-5 alkyl-C(O)OH, —O—C 1-5 alkylamino-C(O)—C 1-5 alkyl-C(O)—C 1-5 alkyl;
(c) a C 2 to C 15 straight or branched chain alkyl optionally substituted with hydroxy or alkoxy; and
(d) —C(O)—C 6-12 arylene-C(O)— wherein said arylene is optionally substituted with hydroxy, halogen, nitro or amino;
a and b are independently 0, 1, 2, 3 or 4;
d, d′, d″, e, e′, and e″ e are independently an integer from 1 to 4;
T is oxygen;
X 1 , X 2 , Y 1 , and Y 2 are independently selected from the group consisting of a null, oxygen, NH, N(C(O)C 1-4 alkyl), and N(C 1-4 alkyl) 2 ;
W 1 and W 2 are independently selected from the group consisting of carbonyl, methylene, sulfone and sulfoxide;
R 2 and R 5 are each independently:
(a) C 2 to C 20 straight chain or branched chain alkyl which is optionally substituted with oxo, hydroxy or alkoxy;
(b) C 2 to C 20 straight chain or branched chain alkenyl or dialkenyl which is optionally substituted with oxo, hydroxy or alkoxy;
(c) C 2 to C 20 straight chain or branched chain alkoxy which is optionally substituted with oxo, hydroxy or alkoxy;
(d) —NH—C 2 to C 20 straight chain or branched chain alkyl, wherein said alkyl group is optionally substituted with oxo, hydroxy or alkoxy;
wherein Z is selected from the group consisting of O and NH, and M and N are independently selected from the group consisting of C 2 to C 20 straight chain or branched chain alkyl, alkenyl, alkoxy, acyloxy, alkylamino, and acylamino;
R 3 and R 6 are independently selected from the group consisting of C 2 to C 20 straight chain or branched chain alkyl or alkenyl optionally substituted with oxo or fluoro;
R 4 and R 7 are independently selected from the group consisting of C(O)C 2 to C 20 straight chain or branched chain alkyl or alkenyl; C 2 to C 20 straight chain or branched chain alkoxy;
C 2 to C 20 straight chain or branched chain alkenyl; wherein said alkyl, alkenyl, or alkoxy groups can be independently and optionally substituted with hydroxy, fluoro or C 1 to C 5 alkoxy;
G 1 , G 2 , G 3 , and G 4 are independently selected from the group consisting of oxygen, methylene, amino, thiol, —NHC(O)—, and —NC(O)C 1-4 alkyl)-;
or G 2 R 4 or G 4 R 7 may together be a hydrogen atom or hydroxyl;
or a pharmaceutically acceptable salt, stereoisomer, amorphous solid thereof, or any combination thereof.