Homogenous suspension of immunopotentiating compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-9408907-B2
Application number	US-201013516227-A
Country	US
Kind code	B2
Filing date	Dec 15, 2010
Priority date	Dec 15, 2009
Publication date	Aug 9, 2016
Grant date	Aug 9, 2016

Abstract

The present invention generally relates to homogeneous suspensions of small molecule immune potentiators (SMIPs) that are capable of stimulating or modulating an immune response in a subject in need thereof. The homogeneous suspensions may be used in combinations with various antigens or adjuvants for vaccine therapies.

First claim

The invention claimed is:

1. A composition comprising an aluminum salt and a homogeneous suspension comprising (a) a Benzonaphthyridine compound of Formula I or Formula II:

pharmaceutically acceptable salt, pharmaceutically acceptable solvate, individual isomer or mixture of isomers thereof; (b) a surfactant, and (c) a suspension agent that is different from the surfactant, wherein the suspension is stable for at least about four weeks at 4° C., wherein the homogenous suspension was produced by high pressure homogenization and wherein:
R 4 is selected from H, halogen, —C(O)OR 7 , —C(O)R 7 , —C(O)N(R 11 R 12 ), —N(R 11 R 12 ), —N(R 9 ) 2 , —NHN(R 9 ) 2 , —SR 7 , —(CH 2 ) n OR 7 , —(CH 2 ) n R 7 , —LR 8 , —LR 10 , —OLR 8 , —OLR 10 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 heterocycloalkyl groups of R 4 are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —NO 2 , —R 7 , —OR 8 , —C(O)R 8 , —OC(O)R 8 , —C(O)OR 8 , —N(R 9 ) 2 , —P(O)(OR 8 ) 2 , —OP(O)(OR 8 ) 2 , —P(O)(OR 10 ) 2 , —OP(O)(OR 10 ) 2 , —C(O)N(R 9 ) 2 , —S(O) 2 R 8 , —S(O)R 8 , —S(O) 2 N(R 9 ) 2 , and —NR 9 S(O) 2 R 8 ;
each L is independently selected from a bond, —(O(CH 2 ) m ) t —, C 1 -C 6 alkyl, C 2 -C 6 alkenylene and C 2 -C 6 alkynylene, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenylene and C 2 -C 6 alkynylene of L are each optionally substituted with 1 to 4 substituents independently selected from halogen, —R 8 , —OR 8 , —N(R 9 ) 2 , —P(O)(OR 8 ) 2 , —OP(O)(OR 8 ) 2 , —P(O)(OR 10 ) 2 , and —OP(O)(OR 10 ) 2 ;
R 7 is selected from H, C 1 -C 6 alkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and C 3 -C 8 heterocycloalkyl, wherein the C 1 -C 6 alkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and C 3 -C 8 heterocycloalkyl groups of R 7 are each optionally substituted with 1 to 3 R 13 groups;
each R 8 is independently selected from H, —CH(R 10 ) 2 , C 1 -C 8 alkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, C 1 -C 6 hydroxyalkyl and C 1 -C 6 haloalkoxy, wherein the C 1 -C 8 alkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, C 1 -C 6 hydroxyalkyl and C 1 -C 6 haloalkoxy groups of R 8 are each optionally substituted with 1 to 3 substituents independently selected from —CN, R 11 , —OR 11 , —SR 11 , —C(O)R 11 , —OC(O)R 11 , —C(O)N(R 9 ) 2 , —C(O)OR 11 , —NR 9 C(O)R 11 , —NR 9 R 10 , —NR 11 R 12 , —N(R 9 ) 2 , —OR 9 , —OR 10 , —C(O)NR 11 R 12 , —C(O)NR 11 OH, —S(O) 2 R 11 , —S(O)R 11 , —S(O) 2 NR 11 R 12 , —NR 11 S(O) 2 R 11 , —P(O)(OR 11 ) 2 , and —OP(O)(OR 11 ) 2 ;
each R 9 is independently selected from H, —C(O)R 8 , —C(O)OR 8 , —C(O)R 10 , —C(O)OR 10 , —S(O) 2 R 10 , —C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl and C 3 -C 6 cycloalkyl, or each R 9 is independently a C 1 -C 6 alkyl that together with N they are attached to form a C 3 -C 8 heterocycloalkyl, wherein the C 3 -C 8 heterocycloalkyl ring optionally contains an additional heteroatom selected from N, O and S, and wherein the C 1 -C 6 alkyl, C heteroalkyl, C 3 -C 6 cycloalkyl, or C 3 -C 8 heterocycloalkyl groups of R 9 are each optionally substituted with 1 to 3 substituents independently selected from —CN, R 11 , —OR 11 , —SR 11 , —C(O)R 11 , —OC(O)R 11 , —C(O)OR 11 , —NR 11 R 12 , —C(O)NR 11 R 12 , —C(O)NR 11 OH, —S(O) 2 R 11 , —S(O)R 11 , —S(O) 2 NR 11 R 12 , —NR 11 S(O) 2 R 11 , —P(O)(OR 11 ) 2 , and —OP(O)(OR 11 ) 2 ;
each R 10 is independently selected from aryl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl and heteroaryl, wherein the aryl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl and heteroaryl groups are optionally substituted with 1 to 3 substituents selected from halogen, —R 8 , —OR 8 , —LR 9 , —LOR 9 , —N(R 9 ) 2 , —NR 9 C(O)R 8 , —NR 9 CO 2 R 8 , —CO 2 R 8 , —C(O)R 8 and —C(O)N(R 9 ) 2 ;
R 11 and R 12 are independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 heterocycloalkyl groups of R 11 and R 12 are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, R 8 , —OR 8 , —C(O)R 8 , —OC(O)R 8 , —C(O)OR 8 , —N(R 9 ) 2 , —NR 8 C(O)R 8 , —NR 8 C(O)OR 8 , —C(O)N(R 9 ) 2 , C 3 -C 8 heterocycloalkyl, —S(O) 2 R 8 , —S(O) 2 N(R 9 ) 2 , —NR 9 S(O) 2 R 8 , C 1 -C 6 haloalkyl and C 1 -C 6 haloalkoxy;
or R 11 and R 12 are each independently C 1 -C 6 alkyl and taken together with the N atom to which they are attached form an optionally substituted C 3 -C 8 heterocycloalkyl ring optionally containing an additional heteroatom selected from N, O and S;
each R 13 is independently selected from halogen, —CN, —LR 9 , —LOR 9 , —OLR 9 , —LR 10 , —LOR 10 , —OLR 10 , —LR 8 , —LOR 8 , —OLR 8 , —LSR 8 , —LSR 10 , —LC(O)R 8 , —OLC(O)R 8 , —LC(O)OR 8 , —LC(O)R 10 , —LOC(O)OR 8 , —LC(O)NR 9 R 11 , —LC(O)NR 9 R 8 , —LN(R 9 ) 2 , —LNR 9 R 8 , —LNR 9 R 10 , —LC(O)N(R 9 ) 2 , —LS(O) 2 R 8 , —LS(O)R 8 , —LC(O)NR 8 OH, —LNR 9 C(O)R 8 , —LNR 9 C(O)OR 8 , —LS(O) 2 N(R 9 ) 2 , —OLS(O) 2 N(R 9 ) 2 , —LNR 9 S(O) 2 R 8 , —LC(O)NR 9 LN(R 9 ) 2 , —LP(O)(OR 8 ) 2 , —LOP(O)(OR 8 ) 2 , —LP(O)(OR 10 ) 2 and —OLP(O)(OR 10 ) 2 ;
each R A is independently selected from —R 8 , —R 7 , —OR 7 , —OR 8 , —R 10 , —OR 10 , —SR 8 , —NO 2 , —CN, —N(R 9 ) 2 , —NR 9 C(O)R 8 , —NR 9 C(S)R 8 , —NR 9 C(O)N(R 9 ) 2 , —NR 9 C(S)N(R 9 ) 2 , —NR 9 CO 2 R 8 , —NR 9 NR 9 C(O)R 8 , —NR 9 NR 9 C(O)N(R 9 ) 2 , —NR 9 NR 9 CO 2 R 8 , —C(O)C(O)R 8 , —C(O)CH 2 C(O)R 8 , —CO 2 R 8 , —(CH 2 ) n CO 2 R 8 , —C(O)R 8 , —C(S)R 8 , —C(O)N(R 9 ) 2 , —C(S)N(R 9 ) 2 , —OC(O)N(R 9 ) 2 , —OC(O)R 8 , —C(O)N(OR 8 )R 8 , —C(NOR 8 )R 8 , —S(O) 2 R 8 , —S(O) 3 R 8 , —SO 2 N(R 9 ) 2 , —S(O)R 8 , —NR 9 SO 2 N(R 9 ) 2 , —NR 9 SO 2 R 8 , —P(O)(OR 8 ) 2 , —OP(O)(OR 8 ) 2 , —P(O)(OR 10 ) 2 , —OP(O)(OR 10 ) 2 , —N(OR 8 )R 8 , —CH═CHCO 2 R 8 , —C(═NH)—N(R 9 ) 2 , and —(CH 2 ) n NHC(O)R 8 ; or in Formula I two adjacent R A substituents on the ring to which they are bonded form a 5-6 membered ring that contains up to two heteroatoms as ring members;
n is, independently at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7 or 8;
each m is independently selected from 1, 2, 3, 4, 5 and 6, and
t is 1, 2, 3, 4, 5, 6, 7 or 8.

2. The composition of claim 1 , wherein the homogeneous suspension comprises about 0.1% to about 10% surfactant.

3. The composition of claim 1 , wherein the homogeneous suspension comprises about 0.1% to about 10% suspension agent.

4. The composition of claim 1 , wherein the homogeneous suspension comprises about 0.5 mg/mL to about 50 mg/mL Benzonaphthyridine compound.

5. The composition of claim 1 , wherein the surfactant is polysorbate 80.

6. The composition of claim 1 , wherein the suspension agent is a viscosity-enhancing suspension agent.

7. The composi

Assignees

• Skibinski David
• Jain Siddhartha
• Singh Manmohan
• O'Hagan Derek
• Glaxosmithkline Biologicals Sa

Inventors

• Skibinski David
• Jain Siddhartha
• Singh Manmohan
• O'Hagan Derek

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• C12N2760/18534

  Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein · CPC title

• A61K31/683

  Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols · CPC title

• A61K2039/55555

  Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers · CPC title