Compounds and adjuvant formulations useful in pneumococcal vaccines

Abstract

The invention relates to novel compounds and formulations. Further, the invention relates to novel compounds and formulations useful in pneumococcal and pneumococcal conjugate vaccines. More specifically, the invention relates to compositions comprising pneumococcal conjugates and one or more compounds of Formula I, Ia, II, IIa, III, IIIa, IV, or IVa, or a pharmaceutically acceptable salt thereof, prepared as stable nanoemulsions (herein referred to as "SNE adjuvant compositions" or "SNEs").

Description

Abstract This invention relates to novel compounds and formulations. Furthermore, this invention relates to novel compounds and formulations that can be used in pneumococcal vaccines and pneumococcal conjugate vaccines. More specifically, this invention relates to compositions comprising pneumococcal conjugates and one or more compounds of formula I, Ia, II, IIa, III, IIIa, IV, or IVa, or pharmaceutically acceptable salts thereof, said compositions being formulated as stable nanoemulsions (hereinafter referred to as "SNE adjuvant compositions" or "SNE").

Claims

25694 WHAT IS CLAIMED IS:

1. An immunogenic composition comprising: (i) at least one Streptococcus pneumoniae polysaccharide-carrier protein conjugate; and (ii) a compound having the structure set forth in Formula I: wherein: aR is selected - C6)alkenyl, (C1-C6)alkynyl, -O(C1- C6)alkyl, -O(C1-C6)alkenyl, -O(C1-C6)alkynyl, chlorine, fluorine, and NR’R’’, wherein said (C1- C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, -O(C1-C6)alkyl, -O(C1-C6)alkenyl, and -O(C1- C6)alkynyl are optionally substituted with one to four substituents, independently selected from the group consisting of -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine and fluorine; Ra’is selected from H, -OH, (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, -O(C1- C6)alkyl, -O(C1-C6)alkenyl, -O(C1-C6)alkynyl, chlorine, fluorine, and -NR’R’’, wherein said (C1- C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, -O(C1-C6)alkyl, -O(C1-C6)alkenyl, and -O(C1- C6)alkynyl are optionally substituted with one to four substituents, independently selected from the group consisting of -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine and fluorine; Ra’’is selected from H, -OH, (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, -O(C1- C6)alkyl, -O(C1-C6)alkenyl, -O(C1-C6)alkynyl, chlorine, fluorine, and -NR’R’’, wherein said (C1- C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, -O(C1-C6)alkyl, -O(C1-C6)alkenyl, and -O(C1- C6)alkynyl are optionally substituted with one to four substituents, independently selected from the group consisting of -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine and fluorine; R’ and R’’ are independently selected from H, (C1-C6)alkyl, (C1-C6)alkenyl, and (C1-C6)alkynyl, wherein said (C1-C6)alkyl, (C1-C6)alkenyl and (C1-C6)alkynyl are optionally substituted with one to four substituents, independently selected from the group consisting of - OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine and fluorine, or R’ and R’’, together with the nitrogen to which they are attached, join together to form a (C3- C6)heterocycloalkyl, wherein said (C3-C6)heterocycloalkyl is optionally substituted with one to25694 2. The immunogenic composition of claim 1, wherein the compound has the structure set forth in Formula Ia: wherein: R’ and R’’ are independently selected from H, (C1-C6)alkyl, (C1-C6)alkenyl, and (C1-C6)alkynyl, wherein said (C1-C6)alkyl, (C1-C6)alkenyl and (C1-C6)alkynyl are optionally substituted with one to four substituents, independently selected from the group consisting of - OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine and fluorine, or R’ and R’’, together with the nitrogen to which they are attached, join together to form a (C3- C6)heterocycloalkyl, wherein said (C3-C6)heterocycloalkyl is optionally substituted with one to four substituents, independently selected from the group consisting of -OH, -O(C1-C4)alkyl, - O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine and fluorine; each occurrence of Rbis -O(C1-C4)alkyl, wherein said -O(C1-C4)alkyl is optionally substituted with one or two substituents, independently selected from the group;each occurrence of Rzis independently H or (C1-C6)alkyl; each occurrence of Rdis independently selected from -OH, (C1-C4)alkyl, -O(C1- C4)alkyl, chlorine and fluorine; B is ; D is a lipid chain selected from: - 181 -25694 , wherein any carbon on the -OH, -O(C1-C4)alkyl, -O(C1- C4)alkenyl, -O(C1-C4)alkynyl,wherein is cis or trans stereochemistry, X1is -O-, -C(R)2-, or -NR-, and each occurrence of R is independently selected from H, (C1-C4)alkyl, (C1- C4)alkenyl, (C1-C4)alkynyl, -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine and fluorine; m is 0, 1 or 2; n is 0, 1, 2 or 3; p is 0, 1 or 2; q is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9; s is, 1, 2, 3, 4, 5, 6, 7 or 8; and t is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18; or a pharmaceutically acceptable salt thereof.serotype.

4. The immunogenic composition of either of claims 1-2, wherein the composition comprises more than twenty-five Streptococcus pneumoniae polysaccharide-carrier protein polysaccharides of a particular Streptococcus pneumoniae serotype.- 182 -25694 5. The immunogenic composition of either of claims 1-2, wherein the composition comprises 26 Streptococcus pneumoniae polysaccharide-carrier protein conjugates, serotype conjugated of 1, 3, 4, 5, 6A, 19F, 22F, 23A, the compound has thewherein: R1is (C1-C6)alkyl, wherein said (C1-C6)alkyl is optionally substituted with one to four substituents independently selected from -OH and -O(CH3); R2is H, methyl or -O(CH3); each occurrence of R3is independently H, (C1-C4)alkyl, (C1-C4)alkenyl, (C1- C4)alkynyl or -O(C1-C4)alkyl wherein said (C1-C4)alkyl, (C1-C4)alkenyl, (C1-C4)alkynyl or - O(C1-C4)alkyl are optionally substituted with one or two substituents independently selected from -OH and -O(CH3); each occurrence of R4is independently H, (C1-C4)alkyl, (C1-C4)alkenyl, (C1- C4)alkynyl or -O(C1-C4)alkyl wherein said (C1-C4)alkyl, (C1-C4)alkenyl, (C1-C4)alkynyl or - O(C1-C4)alkyl are optionally substituted with one or two substituents independently selected from -OH and -O(CH3); R5is ; R6is selected from (C6-C20)alkyl, (C6-C20)alkenyl and (C6-C20)alkynyl, wherein said (C6-C20)alkyl, (C6-C20)alkenyl, and (C6-C20)alkynyl are optionally substituted with one to six substituents independently selected from -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, -O(C1- C4)alkynyl, chlorine and fluorine; and - 183 -25694 each occurrence of n is 4; or a pharmaceutically acceptable salt thereof.

7. The immunogenic composition of claim 6, wherein the compound has the structure set forth in Formula IIa: wherein: R1is butyl, with one or two -OH; each ; and R5isR6is selected from (C10-C20)alkyl, (C10-C20)alkenyl and (C10-C20)alkynyl; or a pharmaceutically acceptable salt thereof.

8. The immunogenic composition of either of claims 6-7, wherein the composition comprises more than twenty Streptococcus pneumoniae polysaccharide-carrier protein conjugates, each comprising polysaccharides of a particular Streptococcus pneumoniae serotype.

9. The immunogenic composition of either of claims 6-7, wherein the composition comprises more than twenty-five Streptococcus pneumoniae polysaccharide-carrier protein conjugates, each comprising polysaccharides of a particular Streptococcus pneumoniae serotype.of either of claims 6-7, wherein the composition comprises 26 Streptococcus pneumoniae polysaccharide-carrier protein conjugates, each comprising polysaccharides of a particular Streptococcus pneumoniae serotype conjugated to a carrier protein, wherein the Streptococcus pneumoniae serotypes consist of 1, 3, 4, 5, 6A, - 184 -25694 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F and 35B.

11. The immunogenic composition of claim 1, wherein the compound has the structure set forth in Formula III: wherein:R1is (C1-C6)alkyl, wherein said (C1-C6)alkyl is optionally substituted with one to four substituents independently selected from -OH and -O(CH3); R2is H, methyl or -O(CH3); H, (C1-C4)alkyl, (C1-C4)alkenyl, (C1- C4)alkynyl orC4)alkyl, (C1-C4)alkenyl, (C1-C4)alkynyl or - O(C1-C4)alkyl are optionally substituted with one or two substituents independently selected from -OH and -O(CH3); R4is selected from (C6-C20)alkyl, (C6-C20)alkenyl and (C6-C20)alkynyl, wherein said (C6-C20)alkyl, (C6-C20)alkenyl and (C6-C20)alkynyl are optionally substituted with one to six substituents independently selected from -OH, -O(C1-C4)alkyl, -O(C1-C4)alkenyl, -O(C1- C4)alkynyl, chlorine and fluorine; and n is 4; or a pharmaceutically acceptable salt thereof.

12. The immunogenic composition of claim 11, wherein the compound has the structure set forth in Formula IIIa: - 185 -25694 wherein: R1is with one or two -OH; each ; and R4is (C10-C20)alkynyl; or a pharmaceutically13. 11-12, wherein the composition comprises more than twenty Streptococcus pneumoniae polysaccharide-carrier protein conjugates, each comprising polysaccharides of a particular Streptococcus pneumoniae serotype.

14. The immunogenic composition of either of claims 11-12, wherein the composition comprises more than twenty-five Streptococcus pneumoniae polysaccharide-carrier protein conjugates, each comprising polysaccharides of a particular Streptococcus pneumoniae serotype.

15. The immunogenic composition of either of claims 11-12, wherein the composition comprises 26 Streptococcus pneumoniae polysaccharide-carrier protein conjugates, each comprising polysaccharides of particular Streptococcus pneumoniae serotype conjugated to a carrier protein, wherein the Streptococcus pneumoniae serotypes consist of 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F and 35B.

16. The immunogenic composition of claim 1, wherein the compound has the structure set forth in Formula IV: - 186 -25694 wherein:R1is (C1-C6)alkyl, wherein said (C1-C6)alkyl is optionally substituted with one to four substituents independently selected from -OH and -O(CH3); R2is H, methyl or -O(CH3); each occurrence of R3is independently H, (C1-C4)alkyl, (C1-C4)alkenyl, (C1- C4)alkynyl, or -O(C1-C4)alkyl wherein said (C1-C4)alkyl, (C1-C4)alkenyl, (C1-C4)alkynyl, and - O(C1-C4)alkyl are optionally substituted with one or two substituents independently selected from -OH and -O(CH3); each occurrence of R4is independently selected from (C6-C20)alkyl, (C6- C20)alkenyl and (C6-C20)alkynyl, wherein said (C6-C20)alkyl, (C6-C20)alkenyl and (C6-C20)alkynyl are optionally substituted with one to six substituents independently selected from -OH, -O(C1- C4)alkyl, -O(C1-C4)alkenyl, -O(C1-C4)alkynyl, chlorine or fluorine; and n is 4; or a pharmaceutically acceptable salt thereof.

17. The immunogenic composition of claim 16, wherein the compound has the structure set forth in Formula IVa: wherein: - 187 -25694 R1is butyl, wherein said butyl is optionally substituted with one or two -OH; each occurrence of R3is independently H or -O(CH3); and each C20)alkyl, (C10- C20)alkenyl and (C10- or a pharmaceutically 18. 16-17, wherein the composition carrier protein conjugates, pneumoniae serotype.

19. The immunogenic composition of either of claims 16-17, wherein the composition comprises more than twenty-five Streptococcus pneumoniae polysaccharide-carrier protein conjugates, each comprising polysaccharides of a particular Streptococcus pneumoniae serotype.

20. The immunogenic composition of either of claims 16-17, wherein the composition comprises 26 Streptococcus pneumoniae polysaccharide-carrier protein conjugates, each comprising polysaccharides of a particular Streptococcus pneumoniae serotype conjugated to a carrier protein, wherein the Streptococcus pneumoniae serotypes consist of 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F and 35B.

21. The immunogenic composition of any one of claims 1-20, wherein the compound is selected from: (N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3,5- dimethoxyphenyl) (S)-N-(5-(4-(4-((5- [4,3-d]pyrimidin-2- yl)methyl)-3,5- N-(5-(4-(4-((5-amino- methyl)-3- methoxyphenyl) N-(5-(4-(4-((5-amino- methyl)-3- methoxyphenyl)- 188 -25694 N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)piperazin-1-yl)-5-oxopentyl)oleamide; (9Z,12Z)-N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)piperazin-1-yl)-5-oxopentyl)octadeca-9,12-dienamide; N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)-1,4-diazepan-1-yl)-5-oxopentyl)stearamide; N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)piperidin-1-yl)-5-oxopentyl)stearamide; N-(5-(3-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)azetidin-1-yl)-5-oxopentyl)stearamide; 1-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3-methoxyphenyl)-N- (3-stearamidopropyl)piperidine-4-carboxamide; (1s,3s)-3-(2-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)piperazin-1-yl)-2-oxoethyl)-N-hexadecylcyclobutane-1-carboxamide; N-(3-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)piperazin-1-yl)-3-oxopropyl)stearamide; N-(7-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)piperazin-1-yl)-7-oxoheptyl)stearamide; N-(3-(2-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)piperazin-1-yl)-2-oxoethyl)cyclobutyl)stearamide; N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)piperazin-1-yl)-4,4-dimethyl-5-oxopentyl)stearamide; N-(5-(4-(4-((5-amino-7-(butylamino)-3-methyl-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)piperazin-1-yl)-5-oxopentyl)stearamide; (9Z,12Z)-N-(4-((4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3,5- dimethoxybenzyl)(methyl)amino)butyl)octadeca-9,12-dienamide; N-(4-((4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3,5- dimethoxybenzyl)(methyl)amino)butyl)tetradecanamide; N-(4-((4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3,5- dimethoxybenzyl)(methyl)amino)butyl)oleamide; N-(4-((4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3,5- dimethoxybenzyl)(methyl)amino)butyl)stearamide; N-(4-((4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3,5- dimethoxybenzyl)(methyl)amino)-4-oxobutyl)stearamide; - 189 -25694 (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl (4-((4-((5-amino-7-(butylamino)-2H- pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3,5-dimethoxybenzyl)(methyl)amino)butyl)carbamate; 4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3-methoxyphenyl)-N- (3-stearamidopropyl)piperazine-1-carboxamide; and 3-stearamidopropyl 4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)piperazine-1-carboxylate; or a pharmaceutically acceptable salt thereof.

22. The immunogenic composition of any one of claims 1-21, wherein the compound is: N-(5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)piperazin-1-yl)-5-oxopentyl)stearamide; or a pharmaceutically acceptable salt thereof.

23. The immunogenic composition of any one of claims 1-22, further comprising (iii) sorbitan trioleate (SPAN-85); (iv) polysorbate-20 (PS-20) or polysorbate-80 (PS- 80); and (v) squalene.

24. The immunogenic composition of claim 23, wherein the compound is N- (5-(4-(4-((5-amino-7-(butylamino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)methyl)-3- methoxyphenyl)piperazin-1-yl)-5-oxopentyl)stearamide, or a pharmaceutically acceptable salt thereof.

25. The immunogenic composition of claim 24, wherein the composition comprises PS-20.

26. The immunogenic composition of any one of claims 23-25, wherein the composition comprises more than twenty Streptococcus pneumoniae polysaccharide-carrier protein conjugates, each comprising polysaccharides of a particular Streptococcus pneumoniae serotype.

27. The immunogenic composition of any one of claims 23-25, wherein the composition comprises more than twenty-five Streptococcus pneumoniae polysaccharide-carrier - 190 -25694 protein conjugates, each comprising polysaccharides of a particular Streptococcus pneumoniae serotype.

28. The immunogenic composition of any one of claims 23-25, wherein the composition comprises 26 Streptococcus pneumoniae polysaccharide-carrier protein conjugates, each comprising polysaccharides of a particular Streptococcus pneumoniae serotype conjugated to a carrier protein, wherein the Streptococcus pneumoniae serotypes consist of 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, de-O-acetylated 15B, 16F, 18C, 19A, 19F, 22F, 23A, 23B, 23F, 24F, 33F and 35B.

29. The immunogenic composition of any one of claims 1-28, further comprising (vi) a pharmaceutically acceptable carrier.

30. The immunogenic composition of any one of claims 1-29, wherein the carrier protein is CRM197.

31. The immunogenic composition of any one of claims 23-30, wherein the concentration of compound is 0.1 µg / mL to 100 µg / mL, the concentration of SPAN-85 is 0.01 mg / mL to 50 mg / mL, the concentration of PS-20 or PS-80 is 0.01 mg / mL to 50 mg / mL, and the concentration of squalene is 0.02 mg / mL to 20 mg / mL.

32. A method of treating or preventing pneumococcal disease in a human patient comprising administrating to the patient the immunogenic composition of any one of claims 1-31. - 191 -protein conjugates, each comprising polysaccharides of a particular Streptococcus pneumoniae serotype.

28. The immunogenic composition of any one of claims 23-25, wherein the composition comprises 26 Streptococcus pneumoniae polysaccharide-carrier protein conjugates, each comprising polysaccharides of a particular Streptococcus pneumoniae serotype conjugated to a carrier protein, wherein the Streptococcus pneumoniae serotypes consist of 1, 3.

4. 5, 6A, 6B, 7F, 8, 9V, 10A, 11 A, 12F, 14, 15 A, de-O-acetylated 15B, 16F, 18C, 19A, 19F, 22F, 23 A, 23B, 23F, 24F, 33F and 35B.

29. The immunogenic composition of any one of claims 1-28, further comprising (vi) a pharmaceutically acceptable carrier.

30. The immunogenic composition of any one of claims 1-29, wherein the carrier protein is CRM197.

31. The immunogenic composition of any one of claims 23-30, wherein the concentration of compound is 0.1 pg / mL to 100 pg / mL, the concentration of SPAN-85 is 0.01 mg / mL to 50 mg / mL, the concentration of PS-20 or PS-80 is 0.01 mg / mL to 50 mg / mL, and the concentration of squalene is 0.02 mg / mL to 20 mg / mL.

32. A method of treating or preventing pneumococcal disease in a human patient comprising administrating to the patient the immunogenic composition of any one of claims 1-31.

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