Integrin activator vaccine compositions

Patent metadata

Field	Value
Publication number	US-10709780-B2
Application number	US-201916394270-A
Country	US
Kind code	B2
Filing date	Apr 25, 2019
Priority date	Apr 29, 2015
Publication date	Jul 14, 2020
Grant date	Jul 14, 2020

Abstract

Compositions including one or more antigens and one or more integrin activating compounds capable of adjuvanting the one or more antigens contained and increasing an immune response to the one or more antigen in a vaccine preparation.

First claim

We claim:

1. A composition comprising:
(A) an antigen, and
(B) an adjuvanting amount of at least one integrin activating compound that increases an immune response to the antigen,
wherein the at least one integrin activating compound comprises one or more compounds of the general Formula (I):
R 1 -M 1 -N(R 2 )-M 2 -M 3 -M 4 -M 5 -M 6 -R 3   (I)

wherein a first class of the compounds of Formula (I) is defined by:
R 1 is selected from the group consisting of aryl and aralkyl,
R 2 is alkyl, aryl, or aralkyl,
M 1 is CH 2 ,
M 2 is CO,
M 3 is O, S, or NR 6 ,
R 6 when present is hydrogen or lower alkyl,

M 4 is absent or CH 2 ,
M 5 is (CR 11 R 12 ),
R 11 is hydrogen,
R 12 is selected from the group consisting of hydrogen, NR 21 CONR 22 R 23 , NR 21 COR 24 , NR 21 SO 2 R 24 , NR 21 COOR 24 , OCOR 24 , OR 24 , O(CH 2 CH 2 O) s R 24 , COOR 24 , alkyl, and hydroxyalkyl,
s is an integer of 1 to 6,
R 21 and R 22 when present are independently selected from the group consisting of hydrogen or lower alkyl,
R 23 when present is selected from the group consisting of hydroxyalkyl, alkoxyalkyl, alkyl, aryl, aralkyl and alkoxycarbonylalkyl,
 provided that when M 3 is NR 6 and M 4 is absent, then R 23 is not 1-(1,3-benzodioxol-5-yl)-3-ethoxy-3-oxopropyl,
R 24 when present is selected from the group consisting of alkyl, aryl, aralkyl, heterocyclyl, cycloalkyl, cycloalkylalkyl, and heterocyclylalkyl, and mixtures thereof,

M 6 is (CH 2 ) q , where
q is an integer from 0 to 6,

R 3 is selected from the group consisting of hydrogen, CONR 13 R 14 , NR 15 COOR 16 , NR 15 COR 16 , NR 15 CONR 13 R 14 , NR 15 SO2R 16 , OCOR 16 , COOR 16 , OR 16 , SR 16 , heterocyclyl, hydroxyl, hydroxyalkyl, guanadino, alkyl and aryl,
R 13 and R 15 when present are independently hydrogen or lower alkyl,
R 14 and R 16 when present are independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, and heterocyclylalkyl,

R 1 , R 2 , R 3 , R 12 , R 14 , R 16 , R 23 and R 24 when present may independently be either unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylaryl, hydroxy, alkoxy, azido, haloalkoxy, hydroxyalkyl, aryloxy, hydroxyaryl, alkoxyaryl, halo, haloalkyl, haloaryl, amino, alkylamino, dialkylamino, arylamino, diarylamino, —NHCO(alkyl), —NHCO(aryl), —NHCO(aralkyl), —NHCO(haloalkyl), —NHSO 2 (alkyl), —NHSO 2 (aryl), —NHSO 2 (aralkyl), alkoxycarbonyl, alkoxycarbonylalkyl, —OCO(alkylamino), —OCO(dialkylamino), and mixtures thereof;

or
wherein a second class of the compounds of Formula (I) is defined by:
R 1 is aryl or aralkyl,
R 2 is alkyl or aralkyl,
M 1 is CH 2 ,
M 2 is CO,
M 3 is absent or is O or CH 2 ,
M 4 is absent or is CH 2 ,
M 5 is absent or is O or (CR 11 R 12 ),
R 11 is hydrogen,
R 12 is selected from the group consisting of hydrogen, NR 21 CONR 22 R 23 ,
NR 21 COR 24 , NR 21 SO2R 24 and NR 21 COOR 24 ,
R 21 and R 22 each of which, when present is independently selected from the group of hydrogen and lower alkyl,
R 23 and R 24 , each of which, when present is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl and aralkyl,

M 6 is selected from the group consisting of (CH 2 ) q , (CH 2 ) q —CH═CH—(CH 2 ) r , (CH 2 ) q -arylene-(CH 2 ) r and (CH 2 CH 2 O) q , where
q and r are independently integers from 0 to 6,

R 3 is CONR 13 R 14 ,
R 13 and R 14 , each of which, when present is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl and aralkyl, and

R 1 , R 2 , R 13 , R 14 , R 23 and R 24 , when present, independently either are unsubstituted or are substituted with one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylaryl, hydroxy, alkoxy, azido, haloalkoxy, hydroxyalkyl, aryloxy, hydroxyaryl, alkoxyaryl, halo, haloalkyl, haloaryl, amino, alkylamino, dialkylamino, arylamino, diarylamino, —NHCO(alkyl), —NHCO(aryl), —NHCO(aralkyl), —NHCO(haloalkyl), —NHSO 2 (alkyl), —NHSO 2 (aryl), —NHSO 2 (aralkyl), alkoxycarbonyl, alkoxycarbonylalkyl, —OCO(alkylamino), —OCO(dialkylamino), and mixtures thereof;

or
wherein a third class of the compounds of Formula (I) is defined by:
R 1 is aryl or aralkyl,
R 2 is alkyl or aralkyl,
M 1 is CH 2 ,
M 2 is SO 2 , or CO,
M 3 is absent or is CH 2 ,
M 4 is absent or is CH 2 ,
M 5 is absent or is (CR 11 R 12 ),
R 11 , when present, is hydrogen,
R 12 , when present, is selected from the group consisting of hydrogen, alkyl,
NR 21 CONR 22 R 23 , NR 21 COR 24 , NR 21 SO2R 24 and NR 21 COOR 24 ,
R 21 and R 22 , each of which when present, is independently selected from the group of hydrogen, lower alkyl, and aralkyl,
R 23 and R 24 , each of which, when present is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl and aralkyl,

M 6 is (CH 2 ) q , or NR 34 (CH 2 ) q ,
q is an integer from 0 to 6,
R 34 , when present, is selected form the group consisting of alkyl, aralkyl, COR 35 , and SO 2 R 35 ,
R 35 when present, is selected form the group consisting of alkyl, aryl, and aralkyl, and

R 3 is selected from the group consisting of CONR 13 R 14 , SO 2 NR 13 R 14 , NR 15 COOR 16 , NR 15 COR 16 , NR 15 CONR 13 R 14 , and NR 15 SO 2 R 16 ,
R 13 and R 14 , each of which, when present, is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl and aralkyl,
R 15 and R 16 , each of which when present, is independently selected from the group of hydrogen, lower alkyl, and aralkyl,

R 1 , R 2 , R 13 , R 14 , R 15 , R 16 , R 23 , R 24 , R 34 and R 35 , when present, either are unsubstituted or are substituted with one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylaryl, hydroxy, alkoxy, azido, haloalkoxy, hydroxyalkyl, aryloxy, hydroxyaryl, alkoxyaryl, halo, haloalkyl, haloaryl, amino, alkylamino, dialkylamino, arylamino, diarylamino, —NHCO(alkyl), —NHCO(aryl), —NHCO(aralkyl), —NHCO(haloalkyl), —NHSO 2 (alkyl), —NHSO 2 (aryl), —NHSO 2 (aralkyl), alkoxycarbonyl, alkoxycarbonylalkyl, —OCO(alkylamino), and —OCO(dialkylamino), with the proviso that when M 2 is CO, then M 6 is NR 34 (CH 2 ) q ,
wherein q is not 0;

or
wherein a four class of the compounds of Formula (I) is defined by:
R 1 is alkyl, aryl or aralkyl,
R 2 is selected from the group consisting of aralkyl and alkyl,
provided that when R 1 is alkyl, R 2 is aralkyl,

M 1 is CO or SO 2 ,
provided that when M 1 is SO 2 and R 1 is phenyl, 4-methylphenyl or 2,4,6-trimethylphenyl, R 2 is not alkyl, 2-phenethyl, benzyl, or 2-methoxy-2-oxoethyl, and when M 1 is CO and R 1 is 2-furyl, 4-pyridyl, or 3,5-dinitrophenyl, R 2 is not alkyl, benzyl or 2-(1H-indol-2-yl)ethyl,

M 2 is absent or CH 2 ,
M 3 and M 4 are absent,
M 5 is (CR 11 R 12 ),
R 11 is hydrogen,
R 12 is selected from the group consisting of hydrogen, NR 21 CONR 22 R 23 , NR 21 COR 24 , NR 21 SO 2 R 24 , NR 21 COOR 24 , CONR 22 R 23 , COOR 24 , O(CH 2 CH 2 O) s R 24 , hydroxyalkyl, and alkoxyalkyl,
R 21 , and R 22 , when present, are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl, and
R 23 and R 24 , each of which, when present, is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalk

Assignees

• 7 Hills Pharma LLC
• Texas Heart Inst

Inventors

• Woodside Darren G
• Vanderslice Peter
• Marathi Upendra K

Classifications

• A61K40/15 Primary

  Natural-killer [NK] cells; Natural-killer T [NKT] cells · CPC title

• A61K39/0011

  Cancer antigens · CPC title

• A61K2239/46

  characterised by the cancer treated · CPC title

• A61K2239/39

  characterised by a specific adjuvant, e.g. cytokines or CpG · CPC title

• A61K39/39558

  against tumor tissues, cells, antigens · CPC title