Integrin activator vaccine compositions

Patent metadata

Field	Value
Publication number	US-11311619-B2
Application number	US-202016920506-A
Country	US
Kind code	B2
Filing date	Jul 3, 2020
Priority date	Apr 28, 2016
Publication date	Apr 26, 2022
Grant date	Apr 26, 2022

Abstract

Vaccine compositions including one or more antigens and one or more integrin agonists or activating compounds present in an amount sufficient to increase an immune response of a patient to the one or more antigens.

First claim

We claim:

1. A vaccine composition comprising:
(A) an antigen, and
(B) an integrin agonist or activating compound present in an amount sufficient to increase an immune response of a patient to the antigen and/or to enhance antigen presentation between lymphocytes and antigen presenting cells.

2. The composition of claim 1 , wherein the antigen is administered with the at least one integrin agonist or activating compound.

3. The composition of claim 1 , wherein the integrin agonist or activating compound is administered before, during, or after antigen administration.

4. The composition of claim 1 , wherein:
the integrin is selected from the group consisting of α4β1, α4β7, α5β1, and αLβ2, and
the antigen is selected from the group consisting of a protein, a peptide, a cell, or a cell lysate.

5. The composition of claim 1 , wherein the integrin agonist or activating compound comprises a compound 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, benzy

Assignees

• 7 Hills Pharma LLC
• Texas Heart Inst
• 7 Hills Pharma Inc And Texas Heart Inst

Inventors

• Woodside Darren G
• Vanderslice Peter
• Marathi Upendra K

Classifications

• A61K39/0011 Primary

  Cancer antigens · CPC title

• C07C1/00 Primary

  Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon · CPC title

• A61K31/381

  having five-membered rings · CPC title

• A61K31/17

  having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine (isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64) · CPC title

• A61K39/39 Primary

  characterised by the immunostimulating additives, e.g. chemical adjuvants · CPC title