ADJUVANT COMPOUNDS, SALT FORMS, AND FORMULATIONS
20230128815 · 2023-04-27
Inventors
- J Tyler MARTIN (Roca, NE, US)
- Jared William WENGER (Lincoln, NE, US)
- Stephan D PARENT (West Lafayette, IN, US)
- Courtney S JOHNSON (West Lafayette, IN, US)
- Eric Jon FARRIS (Lincoln, NE, US)
- Gui LIU (Wayland, MA, US)
Cpc classification
A61K31/704
HUMAN NECESSITIES
A61K39/39
HUMAN NECESSITIES
International classification
A61K39/39
HUMAN NECESSITIES
A61K31/704
HUMAN NECESSITIES
Abstract
The present application relates to triterpene glycoside saponin-derived adjuvants, syntheses thereof, and intermediates thereto. The application also provides salt forms, formulations, and pharmaceutical compositions comprising compounds of the present invention and methods of using said compounds, salt forms, or compositions in the treatment of and immunization for infectious diseases.
Claims
1. A pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of Formula I ##STR00057## wherein is a single or double bond; W is —CHO; V is hydrogen or OR.sup.x; Y is CH.sub.2, —O—, —NR—, or —NH—; Z is hydrogen; a cyclic or acyclic, optionally substituted moiety selected from the group consisting of acyl, aliphatic, heteroaliphatic, aryl, arylalkyl, heteroacyl, and heteroaryl; or a carbohydrate domain having the structure: ##STR00058## wherein each occurrence of R.sup.1 is R.sup.x or a carbohydrate domain having the structure: ##STR00059## wherein: each occurrence of a, b, and c is independently 0, 1, or 2; d is an integer from 1-5, wherein each d bracketed structure may be the same or different; with the proviso that the d bracketed structure represents a furanose or a pyranose moiety, and the sum of b and c is 1 or 2; R.sup.0 is hydrogen; an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, carbamates, and carbonates; or an optionally substituted moiety selected from the group consisting of acyl, C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; each occurrence of R.sup.a, R.sup.b, R.sup.0, and R.sup.d is independently hydrogen, halogen, OH, OR, OR.sup.x, NR.sub.2, NHCOR, or an optionally substituted group selected from acyl, C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, sulfur; 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; R.sup.2 is hydrogen, halogen, OH, OR, OC(O)R.sup.4, OC(O)OR.sup.4, OC(O)NHR.sup.4, OC(O)NRR.sup.4, OC(O)SR.sup.4, NHC(O)R.sup.4, NRC(O)R.sup.4, NHC(O)OR.sup.4, NHC(O)NHR.sup.4, NHC(O)NRR.sup.4, NHR.sup.4, N(R.sup.4).sub.2, NHR.sup.4, NRR.sup.4, N.sub.3, or an optionally substituted group selected from C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; R.sup.3 is hydrogen, halogen, CH.sub.2OR.sup.1, or an optionally substituted group selected from the group consisting of acyl, C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, R.sup.4 is -T-R.sup.z, —C(O)-T-R.sup.z, —NH-T-R.sup.z, —O-T-R.sup.z, —S-T-R.sup.z, —C(O)NH-T-R.sup.z, C(O)O-T-R.sup.z, C(O)S-T-R.sup.z, C(O)NH-T-O-T-R.sup.z, —O-T-R.sup.z, -T-O-T-R.sup.z, -T-S-T-R.sup.z, or ##STR00060## wherein X is —O—, —NR—, or T-R.sup.z; T is a covalent bond or a bivalent C.sub.1-26 saturated or unsaturated, straight or branched, aliphatic or heteroaliphatic chain; and R.sup.z is hydrogen, halogen, —OR, —OR.sup.x, —OR.sup.1, —SR, NR.sub.2, —C(O)OR, —C(O)R, —NHC(O)R, —NHC(O)OR, NC(O)OR, or an optionally substituted group selected from acyl, arylalkyl, heteroarylalkyl, C.sub.1-6 aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; each occurrence of R.sup.x is independently hydrogen or an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, carbamates, and carbonates; each occurrence of R is independently hydrogen, an optionally substituted group selected from acyl, arylalkyl, 6-10-membered aryl, C.sub.1-6 aliphatic, or C.sub.1-6 heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, or: two R on the same nitrogen atom are taken with the nitrogen atom to form a 4-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. In one aspect, the present application provides compounds of Formula II: ##STR00061## or a pharmaceutically acceptable salt thereof, wherein
is a single or double bond; W is Me, —CHO, or ##STR00062## V is hydrogen or OR.sup.x; Y is CH.sub.2, —O—, —NR—, or —NH—; Z is hydrogen; a cyclic or acyclic, optionally substituted moiety selected from the group consisting of acyl, aliphatic, heteroaliphatic, aryl, arylalkyl, heteroacyl, and heteroaryl; or a carbohydrate domain having the structure: ##STR00063## wherein each occurrence of R.sup.1 is R.sup.x or a carbohydrate domain having the structure: ##STR00064## wherein: each occurrence of a, b, and c is independently 0, 1, or 2; d is an integer from 1-5, wherein each d bracketed structure may be the same or different; with the proviso that the d bracketed structure represents a furanose or a pyranose moiety, and the sum of b and c is 1 or 2; R.sup.0 is hydrogen; an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, carbamates, and carbonates; or an optionally substituted moiety selected from the group consisting of acyl, C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; each occurrence of R.sup.a, R.sup.b, R.sup.c, and R.sup.d is independently hydrogen, halogen, OH, OR, OR.sup.x, NR.sub.2, NHCOR, or an optionally substituted group selected from acyl, C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, sulfur; 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; R.sup.2 is hydrogen, halogen, OH, OR, OC(O)R.sup.4, OC(O)OR.sup.4, OC(O)NHR.sup.4, OC(O)NRR.sup.4, OC(O)SR.sup.4, NHC(O)R.sup.4, NRC(O)R.sup.4, NHC(O)OR.sup.4, NHC(O)NHR.sup.4, NHC(O)NRR.sup.4, NHR.sup.4, N(R.sup.4).sub.2, NHR.sup.4, NRR.sup.4, N.sub.3, or an optionally substituted group selected from C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; R.sup.3 is hydrogen, halogen, CH.sub.2OR.sup.1, or an optionally substituted group selected from the group consisting of acyl, C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, R.sup.4 is -T-R.sup.z, —C(O)-T-R.sup.z, —NH-T-R.sup.z, —O-T-R.sup.z, —S-T-R.sup.z, —C(O)NH-T-R.sup.z, C(O)O-T-R.sup.z, C(O)S-T-R.sup.z, C(O)NH-T-O-T-R.sup.z, —O-T-R.sup.z, -T-O-T-R.sup.z, -T-S-T-R.sup.z, or ##STR00065## wherein X is —O—, —NR—, or T-R.sup.z; T is a covalent bond or a bivalent C.sub.1-26 saturated or unsaturated, straight or branched, aliphatic or heteroaliphatic chain; and R.sup.z is hydrogen, halogen, —OR, —OR.sup.x, —OR.sup.1, —SR, NR.sub.2, —C(O)OR, —C(O)R, —NHC(O)R, —NHC(O)OR, NC(O)OR, or an optionally substituted group selected from acyl, arylalkyl, heteroarylalkyl, C.sub.1-6 aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; each occurrence of R.sup.x is independently hydrogen or an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, carbamates, and carbonates; R.sup.y is —OH, —OR, or a carboxyl protecting group selected from the group consisting of ester, amides, and hydrazides; R.sup.s is ##STR00066## each occurrence of R.sup.x′ is independently an optionally substituted group selected from 6-10-membered aryl, C.sub.1-6 aliphatic, or C.sub.1-6 heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or: two R.sup.x′ are taken together to form a 5-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; each occurrence of R is independently hydrogen, an optionally substituted group selected from acyl, arylalkyl, 6-10-membered aryl, C.sub.1-6 aliphatic, or C.sub.1-6 heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, or: two R on the same nitrogen atom are taken with the nitrogen atom to form a 4-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
2. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt is a choline salt of Compound I-4: ##STR00067##
3. The pharmaceutical composition of claim 2, wherein the choline salt of Compound I-4 has a ratio of choline:Compound I-4 of approximately 1:1.
4. The pharmaceutical composition of claim 2, wherein the choline salt of Compound I-4 has a crystalline structure.
5. The pharmaceutical composition of claim 4, wherein a unit cell of the crystalline structure has four Compound I-4 anions and four choline cations.
6. The pharmaceutical composition of claim 4, wherein a unit cell of the crystalline structure has a volume of approximately 1757 to 1726 Å.sup.3.
7. The pharmaceutical composition of claim 4, wherein the crystalline structure is a variable hydrate.
8. The pharmaceutical composition of claim 4, wherein the crystalline structure exhibits hydration dependent peaks in an XRPD pattern derived using Cu K-alpha radiation.
9. The pharmaceutical composition of claim 8, wherein the crystalline structure exhibits peaks as shown in
10. The pharmaceutical composition of claim 8, wherein the crystalline structure exhibits peaks as shown in
11. The pharmaceutical composition of claim 8, wherein the crystalline structure exhibits peaks as shown in
12. The pharmaceutical composition of claim 8, wherein the crystalline structure exhibits at least three peaks, wherein each peak lies within one of three ranges of theta values, wherein the ranges of theta values correspond to groupings of peaks as shown in
13. The pharmaceutical composition of claim 7, wherein in a fully hydrated state, the crystalline structure accommodates greater than 3 mol/mol water.
14. The pharmaceutical composition of claim 7, wherein the crystalline structure converts to another crystalline structure above 65% relative humidity.
15. The pharmaceutical composition of claim 4, wherein a melt and decomposition onset is near 222° C.
16. A liquid formulation comprising Compound I-4: ##STR00068## or a pharmaceutically acceptable salt thereof,
17. The liquid formulation of claim 16, wherein the liquid formulation comprises a solvent selected from the group consisting of water, methanol, and ethanol.
18. The liquid formulation of claim 16, further comprising a buffer selected from the group consisting of carbonate-bicarbonate, citrate, acetate, phosphate, or tris(hydroxymethyl)aminomethane (Tris or tromethamine) buffer.
19. The liquid formulation of claim 16, further comprising an excipient selected from the group consisting of dextran, sorbitol, dextrose, trehalose, mannitol, HPMC, PEG400, PS20, PS80, PVP K12, Kolliphor HS15, and cyclodextrin.
20. The liquid formulation of claim 16, wherein the formulation contains a choline salt of Compound I-4.
21. The liquid formulation of claim 16, wherein the formulation contains an arginine salt of Compound I-4.
22. The liquid formulation of claim 16, wherein the formulation contains a free acid form of Compound I-4.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0114]
[0115]
[0116]
[0117]
[0118]
[0119]
[0120]
[0121]
[0122]
[0123] All XRPD patterns depicted in the above figures were obtained using Cu K-alpha radiation.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
[0124] Compounds
[0125] Compounds of this invention include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. In some embodiments, provided compounds are analogs of naturally occurring triterpene glycoside saponins and intermediates thereto. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999, and March's Advanced Organic Chemistry, 5th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.
[0126] In some embodiments, provided compounds are analogs of Quillaja saponins. In some embodiments, provided compounds are prosapogenins. In certain embodiments, provided compounds are analogs of QS-7 and QS-21 and possess potent adjuvant activity.
[0127] In one aspect, the present application provides compounds of Formula I:
##STR00012##
[0128] or a pharmaceutically acceptable salt thereof, wherein
[0129] is a single or double bond;
[0130] W is —CHO;
[0131] V is hydrogen or OR.sup.x;
[0132] Y is CH.sub.2, —O—, —NR—, or —NH—; [0133] Z is hydrogen; a cyclic or acyclic, optionally substituted moiety selected from the group consisting of acyl, aliphatic, heteroaliphatic, aryl, arylalkyl, heteroacyl, and heteroaryl; or a carbohydrate domain having the structure:
##STR00013## [0134] wherein each occurrence of R.sup.1 is R.sup.x or a carbohydrate domain having the structure:
##STR00014## [0135] wherein: [0136] each occurrence of a, b, and c is independently 0, 1, or 2; [0137] d is an integer from 1-5, wherein each d bracketed structure may be the same or different; with the proviso that the d bracketed structure represents a furanose or a pyranose moiety, and the sum of b and c is 1 or 2; [0138] R.sup.0 is hydrogen; an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, carbamates, and carbonates; or an optionally substituted moiety selected from the group consisting of acyl, C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; [0139] each occurrence of R.sup.a, R.sup.b, R.sup.c, and R.sup.d is independently hydrogen, halogen, OH, OR, OR.sup.x, NR.sub.2, NHCOR, or an optionally substituted group selected from acyl, C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, sulfur; 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; [0140] R.sup.2 is hydrogen, halogen, OH, OR, OC(O)R.sup.4, OC(O)OR.sup.4, OC(O)NHR.sup.4, OC(O)NRR.sup.4, OC(O)SR.sup.4, NHC(O)R.sup.4, NRC(O)R.sup.4, NHC(O)OR.sup.4, NHC(O)NHR.sup.4, NHC(O)NRR.sup.4, NHR.sup.4, N(R.sup.4).sub.2, NHR.sup.4, NRR.sup.4, N.sub.3, or an optionally substituted group selected from C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; [0141] R.sup.3 is hydrogen, halogen, CH.sub.2OR.sup.1, or an optionally substituted group selected from the group consisting of acyl, C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, [0142] R.sup.4 is -T-R.sup.z, —C(O)-T-R.sup.z, —NH-T-R.sup.z, —O-T-R.sup.z, —S-T-R.sup.z, —C(O)NH-T-R.sup.z, C(O)O-T-R.sup.z, C(O)S-T-R.sup.z, C(O)NH-T-O-T-R.sup.z, —O-T-R.sup.z, -T-O-T-R.sup.z, -T-S-T-R.sup.z, or
##STR00015## [0143] wherein [0144] X is —O—, —NR—, or T-R.sup.z; [0145] T is a covalent bond or a bivalent C.sub.1-26 saturated or unsaturated, straight or branched, aliphatic or heteroaliphatic chain; and [0146] R.sup.z is hydrogen, halogen, —OR, —OR.sup.x, —OR.sup.1, —SR, NR.sub.2, —C(O)OR, —C(O)R, —NHC(O)R, —NHC(O)OR, NC(O)OR, or an optionally substituted group selected from acyl, arylalkyl, heteroarylalkyl, C.sub.1-6 aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; [0147] each occurrence of R.sup.x is independently hydrogen or an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, carbamates, and carbonates; [0148] each occurrence of R is independently hydrogen, an optionally substituted group selected from acyl, arylalkyl, 6-10-membered aryl, C.sub.1-6 aliphatic, or C.sub.1-6 heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, or: [0149] two R on the same nitrogen atom are taken with the nitrogen atom to form a 4-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
[0150] In one aspect, the present application provides compounds of Formula II:
##STR00016##
[0151] or a pharmaceutically acceptable salt thereof, wherein
[0152] is a single or double bond;
[0153] W is Me, —CHO, or
##STR00017##
[0154] V is hydrogen or OR.sup.x;
[0155] Y is CH.sub.2, —O—, —NR—, or —NH—; [0156] Z is hydrogen; a cyclic or acyclic, optionally substituted moiety selected from the group consisting of acyl, aliphatic, heteroaliphatic, aryl, arylalkyl, heteroacyl, and heteroaryl; or a carbohydrate domain having the structure:
##STR00018## [0157] wherein each occurrence of R.sup.1 is R.sup.x or a carbohydrate domain having the structure:
##STR00019## [0158] wherein: [0159] each occurrence of a, b, and c is independently 0, 1, or 2; [0160] d is an integer from 1-5, wherein each d bracketed structure may be the same or different; with the proviso that the d bracketed structure represents a furanose or a pyranose moiety, and the sum of b and c is 1 or 2; [0161] R.sup.0 is hydrogen; an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, carbamates, and carbonates; or an optionally substituted moiety selected from the group consisting of acyl, C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; [0162] each occurrence of R.sup.a, R.sup.b, R.sup.c, and R.sup.d is independently hydrogen, halogen, OH, OR, OR.sup.x, NR.sub.2, NHCOR, or an optionally substituted group selected from acyl, C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, sulfur; 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; [0163] R.sup.2 is hydrogen, halogen, OH, OR, OC(O)R.sup.4, OC(O)OR.sup.4, OC(O)NHR.sup.4, OC(O)NRR.sup.4, OC(O)SR.sup.4, NHC(O)R.sup.4, NRC(O)R.sup.4, NHC(O)OR.sup.4, NHC(O)NHR.sup.4, NHC(O)NRR.sup.4, NHR.sup.4, N(R.sup.4).sub.2, NHR.sup.4, NRR.sup.4, N.sub.3, or an optionally substituted group selected from C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; [0164] R.sup.3 is hydrogen, halogen, CH.sub.2OR.sup.1, or an optionally substituted group selected from the group consisting of acyl, C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, [0165] R.sup.4 is -T-R.sup.z, —C(O)-T-R.sup.z, —NH-T-R.sup.z, —O-T-R.sup.z, —S-T-R.sup.z, —C(O)NH-T-R.sup.z, C(O)O-T-R.sup.z, C(O)S-T-R.sup.z, C(O)NH-T-O-T-R.sup.z, —O-T-R.sup.z, -T-O-T-R.sup.z, -T-S-T-R.sup.z, or
##STR00020## [0166] wherein [0167] X is —O—, —NR—, or T-R.sup.z; [0168] T is a covalent bond or a bivalent C.sub.1-26 saturated or unsaturated, straight or branched, aliphatic or heteroaliphatic chain; and [0169] R.sup.z is hydrogen, halogen, —OR, —OR.sup.x, —OR.sup.1, —SR, NR.sub.2, —C(O)OR, —C(O)R, —NHC(O)R, —NHC(O)OR, NC(O)OR, or an optionally substituted group selected from acyl, arylalkyl, heteroarylalkyl, C.sub.1-6 aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; [0170] each occurrence of R.sup.x is independently hydrogen or an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, carbamates, and carbonates; [0171] R.sup.y is —OH, —OR, or a carboxyl protecting group selected from the group consisting of ester, amides, and hydrazides; [0172] R.sup.s is
##STR00021## [0173] each occurrence of R.sup.x is independently an optionally substituted group selected from 6-10-membered aryl, C.sub.1-6 aliphatic, or C.sub.1-6 heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or: [0174] two R.sup.x′ are taken together to form a 5-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; [0175] each occurrence of R is independently hydrogen, an optionally substituted group selected from acyl, arylalkyl, 6-10-membered aryl, C.sub.1-6 aliphatic, or C.sub.1-6 heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, or: [0176] two R on the same nitrogen atom are taken with the nitrogen atom to form a 4-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
[0177] In one aspect, the present application provides compounds of Formula I:
##STR00022##
[0178] or a pharmaceutically acceptable salt thereof, wherein
[0179] is a single or double bond;
[0180] W is —CHO;
[0181] V is —OH;
[0182] Y is —O—;
[0183] wherein Z is a carbohydrate domain having the structure:
##STR00023##
[0184] wherein: [0185] R.sup.1 is independently H or
##STR00024## [0186] R.sup.2 is NHR.sup.4; [0187] R.sup.3 is CH.sub.2OH; and [0188] R.sup.4 is -T-R.sup.z, —C(O)-T-R.sup.z, —NH-T-R.sup.z, —O-T-R.sup.z, —S-T-R.sup.z, —C(O)NH-T-R.sup.z, C(O)O-T-R.sup.z, C(O)S-T-R.sup.z, C(O)NH-T-O-T-R.sup.z, —O-T-R.sup.z, -T-O-T-R.sup.z, -T-S-T-R.sup.z, or
##STR00025## [0189] wherein: [0190] X is —O—, —NR—, or T-R.sup.z; [0191] T is a covalent bond or a bivalent C.sub.1-263 saturated or unsaturated, straight or branched, aliphatic or heteroaliphatic chain; and [0192] R.sup.z is hydrogen, halogen, —OR, —OR.sup.x, —OR.sup.1, —SR, NR.sub.2, —C(O)OR, —C(O)R, —NHC(O)R, —NHC(O)OR, NC(O)OR, or an optionally substituted group selected from acyl, arylalkyl, heteroarylalkyl, C.sub.1-6 aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
[0193] It will be appreciated by one of ordinary skill in the art that the compounds of the present application include but are not necessarily limited to those compounds encompassed in the genus definitions set forth as part of the present section. The compounds encompassed by this application include at least all of the compounds disclosed in the entire specification as a whole, including all individual species within each genus.
[0194] In certain embodiments, V is OR.sup.x. In certain embodiments V is OH. In certain embodiments, V is H.
[0195] In certain embodiments, Y is —O—. In certain embodiments, Y is —NH—. In certain embodiments, Y is —NR—. In certain embodiments, Y is CH.sub.2.
[0196] In certain embodiments, Z is hydrogen. In certain embodiments, Z is a cyclic or acyclic, optionally substituted moiety. In certain embodiments, Z is an acyl. In certain embodiments, Z is an aliphatic. In certain embodiments, Z is a heteroaliphatic. In certain embodiments, Z is aryl. In certain embodiments Z is arylalkyl. In certain embodiments, Z is heteroacyl. In certain embodiments, Z is heteroaryl. In certain embodiments, Z is a carbohydrate domain having the structure:
##STR00026##
[0197] In some embodiments Z is a carbohydrate domain having the structure:
##STR00027##
[0198] wherein: [0199] R.sup.1 is independently H or
##STR00028##
[0200] R.sup.2 is NHR.sup.4,
[0201] R.sup.3 is CH.sub.2OH, and
[0202] R.sup.4 is selected from:
##STR00029## ##STR00030##
[0203] In some embodiments, R.sup.1 is R.sup.x. In other embodiments, R.sup.1 a carbohydrate domain having the structure:
##STR00031##
[0204] In some aspects, each occurrence of a, b, and c is independently 0, 1, or 2. In some embodiments, d is an integer from 1-5. In some embodiments, each d bracketed structure may be the same. In some embodiments, each d bracketed structure may be different. In some embodiments, the d bracketed structure represents a furanose or a pyranose moiety. In some embodiments, and the sum of b and c is 1 or 2.
[0205] In some embodiments, R.sup.0 is hydrogen. In some embodiments, R.sub.0 is an oxygen protecting group selected from the group. In some embodiments, R.sup.0 is an alkyl ether. In some embodiments, R.sup.0 is a benzyl ether. In some embodiments, R.sup.0 is a silyl ether. In some embodiments, R.sup.0 is an acetal. In some embodiments, R.sup.0 is ketal. In some embodiments, R.sup.0 is an ester. In some embodiments, R.sup.0 is a carbamate. In some embodiments, R.sup.0 is a carbonate. In some embodiments, R.sup.0 is an optionally substituted moiety. In some embodiments, R.sup.0 is an acyl. In some embodiments, R.sup.0 is a C.sub.1-10 aliphatic. In some embodiments, R.sup.0 is a C.sub.1-6 heteroaliphatic. In some embodiments, R.sup.0 is a 6-10-membered aryl. In some embodiments, R.sup.0 is a arylalkyl. In some embodiments, R.sup.0 is a 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R.sup.0 is a 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
[0206] In some embodiments, R.sup.a is hydrogen. In some embodiments, R.sup.a is a halogen. In some embodiments, R.sup.a is OH. In some embodiments, R.sup.a is OR. In some embodiments, R.sup.a is OR.sup.x. In some embodiments, R.sup.a is NR.sub.2. In some embodiments, R.sup.a is NHCOR. In some embodiments, R.sup.a an acyl. In some embodiments, R.sup.a is C.sub.1-10 aliphatic. In some embodiments, R.sup.a is C.sub.1-6 heteroaliphatic. In some embodiments, R.sup.a is 6-10-membered aryl. In some embodiments, R.sup.a is arylalkyl. In some embodiments, R.sup.1 is 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, sulfur. In some embodiments, R.sup.a is 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
[0207] In some embodiments, R.sup.b is hydrogen. In some embodiments, R.sup.b is a halogen. In some embodiments, R.sup.b is OH. In some embodiments, R.sup.b is OR. In some embodiments, R.sup.b is OR.sup.x. In some embodiments, R.sup.b is NR.sub.2. In some embodiments, R.sup.b is NHCOR. In some embodiments, R.sup.b an acyl. In some embodiments, R.sup.b is C.sub.1-10 aliphatic. In some embodiments, R.sup.b is C.sub.1-6 heteroaliphatic. In some embodiments, R.sup.b is 6-10-membered aryl. In some embodiments, R.sup.b is arylalkyl. In some embodiments, R.sup.b is 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, sulfur. In some embodiments, R.sup.b is 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
[0208] In some embodiments, R.sup.b is hydrogen. In some embodiments, R.sup.b is a halogen. In some embodiments, R.sup.b is OH. In some embodiments, R.sup.b is OR. In some embodiments, R.sup.b is OR.sup.x. In some embodiments, R.sup.b is NR.sub.2. In some embodiments, R.sup.b is NHCOR. In some embodiments, R.sup.b an acyl. In some embodiments, R.sup.b is C.sub.1-10 aliphatic. In some embodiments, R.sup.b is C.sub.1-6 heteroaliphatic. In some embodiments, R.sup.b is 6-10-membered aryl. In some embodiments, R.sup.b is arylalkyl. In some embodiments, R.sup.b is 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, sulfur. In some embodiments, R.sup.b is 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
[0209] In some embodiments, R.sup.c is hydrogen. In some embodiments, R.sup.c is a halogen. In some embodiments, R.sup.c is OH. In some embodiments, R.sup.c is OR. In some embodiments, R.sup.c is OR.sup.x. In some embodiments, R.sup.c is NR.sub.2. In some embodiments, R.sup.c is NHCOR. In some embodiments, R.sup.c an acyl. In some embodiments, R.sup.c is C.sub.1-10 aliphatic. In some embodiments, R.sup.c is C.sub.1-6 heteroaliphatic. In some embodiments, R.sup.0 is 6-10-membered aryl. In some embodiments, R.sup.c is arylalkyl. In some embodiments, R.sup.c is 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, sulfur. In some embodiments, R.sup.c is 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
[0210] In some embodiments, R.sup.d is hydrogen. In some embodiments, R.sup.d is a halogen. In some embodiments, R.sup.d is OH. In some embodiments, R.sup.d is OR. In some embodiments, R.sup.d is OR.sup.x. In some embodiments, R.sup.d is NR.sub.2. In some embodiments, R.sup.d is NHCOR. In some embodiments, R.sup.d an acyl. In some embodiments, R.sup.d is C.sub.1-10 aliphatic. In some embodiments, R.sup.d is C.sub.1-6 heteroaliphatic. In some embodiments, R.sup.d is 6-10-membered aryl. In some embodiments, R.sup.d is arylalkyl. In some embodiments, R.sup.d is 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, sulfur. In some embodiments, R.sup.d is 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
[0211] In some embodiments, R.sup.2 is hydrogen. In some embodiments, R.sup.2 is a halogen. In some embodiments, R.sup.2 is OH. In some embodiments, R.sup.2 is OR. In some embodiments, R.sup.2 is OC(O)R.sup.4. In some embodiments, R.sup.2 is OC(O)OR.sup.4. In some embodiments, R.sup.2 is OC(O)NHR.sup.4. In some embodiments, R.sup.2 is OC(O)NRR.sup.4. In some embodiments, R.sup.2 is OC(O)SR.sup.4. In some embodiments, R.sup.2 is NHC(O)R.sup.4. In some embodiments, R.sup.2 is NRC(O)R.sup.4. In some embodiments, R.sup.2 is NHC(O)OR.sup.4. In some embodiments, R.sup.2 is NHC(O)NHR.sup.4. In some embodiments, R.sup.2 is NHC(O)NRR.sup.4. In some embodiments, R.sup.2 is NHR.sup.4. In some embodiments, R.sup.2 is N(R.sup.4).sub.2. In some embodiments, R.sup.2 is NHR.sup.4. In some embodiments, R.sup.2 is NRR.sup.4. In some embodiments, R.sup.2 is N.sub.3. In some embodiments, R.sup.2 is C.sub.1-10 aliphatic. In some embodiments, R.sup.2 is C.sub.1-6 heteroaliphatic. In some embodiments, R.sup.2 is 6-10-membered aryl. In some embodiments, R.sup.2 is arylalkyl. In some embodiments, R.sup.2 is 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, R.sup.2 is 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
[0212] In some embodiments, R.sup.3 is hydrogen. In some embodiments, R.sup.3 is a halogen. In some embodiments, R.sup.3 is CH.sub.2OR.sup.1. In some embodiments, R.sup.3 is an acyl. In some embodiments, R.sup.3 is C.sub.1-10 aliphatic. In some embodiments, R.sup.3 is C.sub.1-6 heteroaliphatic. In some embodiments, R.sup.3 is 6-10-membered aryl. In some embodiments, R.sup.3 is arylalkyl. In some embodiments, R.sup.3 is 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, R.sup.3 is 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
[0213] In some embodiments, R.sup.4 is -T-R.sup.z. In some embodiments, R.sup.4 is —C(O)-T-R.sup.z. In some embodiments, R.sup.4 is —NH-T-R.sup.z. In some embodiments, R.sup.4 is —O-T-R.sup.z. In some embodiments, R.sup.4 is —S-T-R.sup.z. In some embodiments, R.sup.4 is —C(O)NH-T-R.sup.z. In some embodiments, R.sup.4 is C(O)O-T-R.sup.z. In some embodiments, R.sup.4 is C(O)S-T-R.sup.z. In some embodiments, R.sup.4 is C(O)NH-T-O-T-R.sup.z. In some embodiments, R.sup.4 is —O-T-R.sup.z. In some embodiments, R.sup.4 is -T-O-T-R.sup.z. In some embodiments, R.sup.4 is -T-S-T-R.sup.z. In some embodiments, R.sup.4 is
##STR00032##
[0214] In some embodiments, X is —O—. In some embodiments, X is —NR—. In some embodiments, X is T-R.sup.z.
[0215] In some embodiments, T is a covalent bond or a bivalent C.sub.1-26 saturated or unsaturated, straight or branched, aliphatic or heteroaliphatic chain.
[0216] In some embodiments, R.sup.z is hydrogen. In some embodiments, R.sup.z is a halogen. In some embodiments, R.sup.z is —OR. In some embodiments, R.sup.z is —OR.sup.x. In some embodiments, R.sup.z is —OR.sup.1. In some embodiments, R.sup.z is —OR.sup.1′. In some embodiments, R.sup.z is —SR. In some embodiments, R.sup.z is NR.sub.2. In some embodiments, R.sup.z is —C(O)OR. In some embodiments, R.sup.z is —C(O)R. In some embodiments, R.sup.z is —NHC(O)R. In some embodiments, R.sup.z is —NHC(O)OR. In some embodiments, R.sup.z is NC(O)OR. In some embodiments, R.sup.z is an acyl. In some embodiments, R.sup.z is arylalkyl. In some embodiments, R.sup.z is heteroarylalkyl. In some embodiments, R.sup.z is C.sub.1-6 aliphatic. In some embodiments, R.sup.z is 6-10-membered aryl. In some embodiments, R.sup.z is 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R.sup.z is 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
[0217] In some embodiments, R.sup.x is hydrogen. In some embodiments, R.sup.x is an oxygen protecting group. In some embodiments, R.sup.x is an alkyl ether. In some embodiments, R.sup.x is a benzyl ether. In some embodiments, R.sup.x is silyl ether. In some embodiments, R.sup.x is an acetal. In some embodiments, R.sup.x is ketal. In some embodiments, R.sup.x is ester. In some embodiments, R.sup.x is carbamate. In some embodiments, R.sup.x is carbonate.
[0218] In some embodiments, R.sup.y is —OH. In some embodiments, R.sup.y is —OR. In some embodiments, R.sup.y is a carboxyl protecting group. In some embodiments, R.sup.y is an ester. In some embodiments, R.sup.y is an amide. In some embodiments, R.sup.y is a hydrazide.
[0219] In some embodiments, R.sup.s is
##STR00033##
[0220] In some embodiments, R.sup.x is optionally substituted 6-10-membered aryl. In some embodiments, R.sup.x′ is optionally substituted C.sub.1-5 aliphatic. In some embodiments, R.sup.x′ is optionally substituted or C.sub.1-6 heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, two R.sup.x′ are taken together to form a 5-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
[0221] In some embodiments, R is hydrogen. In some embodiments, R is an acyl. In some embodiments, R is arylalkyl. In some embodiments, R is 6-10-membered aryl. In some embodiments, R is C.sub.1-6 aliphatic. In some embodiments, R is C.sub.1-6 heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, two R on the same nitrogen atom are taken with the nitrogen atom to form a 4-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
[0222] In some embodiments, R.sup.1′ has the same embodiments as R.sup.1.
[0223] Exemplary compounds of Formula I are set forth in Table 1 below:
TABLE-US-00001 TABLE 1 EXEMPLARY COMPOUNDS OF FORMULA I
[0224] It will be appreciated that it is not an object of the present subject matter to claim compounds disclosed in the prior art that are the result of isolation or degradation studies on naturally occurring prosapogenins or saponins.
[0225] Synthesis
[0226] The compounds of the present application may be synthesized as provided in PCT/US2009/039954, PCT/US2015/33567, PCT/US2016/67530, POT/US2016/60564, and/or PCT/US2018/027462.
[0227] Adjuvants
[0228] The present application encompasses the recognition that synthetic access to and structural modification of QS-21 and related Quillaja saponins may afford compounds with high adjuvant potency and low toxicity, as well as having more stability and being more cost effective. Accordingly, compounds of the present application, including TQL-1055, have industrial applicability and are useful as adjuvants, in free form acid or base form or in pharmaceutically acceptable salt form.
[0229] Salt Forms
[0230] Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. In some embodiments, the counterion is selected from chloride, sulfate, bromide, mesylate, maleate, citrate, nitrate, tosylate, tartrate, phosphate, acetate, camsylate, formate, fumarate, oxalate, thiocyanate, adipate, caprate, caproate, caprylate, dodecylsulfate, glutarate, laurate, oleate, palmitate, sebacate, stearate, undecylenate, iodide, choline (e.g. choline hydroxide), L-lysine, sodium (e.g. sodium carbonate or sodium hydroxide), calcium (e.g. calcium hydroxide), potassium (e.g. potassium carbonate), magnesium (e.g. magnesium hydroxide), meglumine, ammonium, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, 1-Pyrrolidineethanol, trimethyltetradecylammonium (e.g. trimethyltetradecylammonium-hydroxide), tetraethanol-ammonium (e.g. tetraethanol-ammonium hydroxide), procaine, benzathine, aluminum, zinc, piperazine, tromethamine, diethylamine, ethylenediamine, arginine, histidine, glycine, lithium tetrakis(pentafluorophenyl)borate, tetraphenylboranuide, hexafluorophosphate, tetrafluoroborate, bis(triphenylphosphine)iminium chloride, tetraphenylphosphonium chloride, tetra-n-butylammonium bromide (TBAB), alkali metals bound by crown ethers, and mixtures thereof. In some embodiments, the counterion is a quaternary ammonium salt.
[0231] In other cases, the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically-acceptable salts with pharmaceutically acceptable bases. The term “pharmaceutically acceptable salts” in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C.sub.1-4alkyl).sub.4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
[0232] Further pharmaceutically acceptable salts include, when appropriate, choline, L-lysine, magnesium, meglumine, potassium, sodium, arginine, histidine, and TEA.
[0233] Certain embodiments of the present application include salt forms of synthetic saponin-derived adjuvants. In some embodiments, the adjuvants are compounds of Formula I as described herein. In some embodiments, the adjuvant is the compound TQL-1055.
[0234] In one preferred embodiment of the present application, an arginine salt form of TQL-1055 is provided.
[0235] In another preferred embodiment of the present application, a choline salt form of TQL-1055 is provided as Form A. In one aspect, Form A has an orthorhombic unit cell. In one aspect, the ratio of TQL-1055:choline is approximately 1:1, or exactly 1:1. Without being bound by theory, the proton NMR spectra depicted in
[0236] In one aspect, each until cell has a volume of approximately 1757 to 1726 Å.sup.3. Without being bound by theory, the XRPD spectra shown in
[0237] In another aspect, the solubility of Form A is greater than 6 mg/mL in water. In another aspect, the solubility of Form A is approximately 12 mg/mL in water. In another aspect, Choline Material B exhibits aqueous solubility of greater than 12 mg/mL.
[0238] In particular, as shown in
[0239] In another aspect, Form A has a dynamic vapor sorption isotherm as shown in
[0240] In another aspect, thermograms for Choline Form A are depicted in
[0241] In another aspect, Material B is a highly hydrated form of TQL-1055 Choline salt. In one aspect, Material B is only stable above 65% relative humidity. In another aspect, Material C exhibits similar XRPD peaks as Form A, however some peaks shown in Form A are missing in Material C. A comparison of exemplary XRPD data of Form A, Material B, and Material C is shown in
Vaccines
[0242] Compositions in this application and their pharmaceutically acceptable salts are useful as vaccines to induce active immunity towards antigens in subjects. Any animal that may experience the beneficial effects of the compositions of the present application is within the scope of subjects that may be treated. In some embodiments, the subjects are mammals. In some embodiments, the subjects are humans.
[0243] The vaccines of the present application may be used to confer resistance to infection by either passive or active immunization. When the vaccines of the present application are used to confer resistance through active immunization, a vaccine of the present application is administered to an animal to elicit a protective immune response which either prevents or attenuates a proliferative or infectious disease. When the vaccines of the present application are used to confer resistance to infection through passive immunization, the vaccine is provided to a host animal (e.g., human, dog, or mouse), and the antisera elicited by this vaccine is recovered and directly provided to a recipient suspected of having an infection or disease or exposed to a causative organism.
[0244] The present application thus concerns and provides a means for preventing or attenuating a proliferative disease resulting from organisms which have antigens that are recognized and bound by antisera produced in response to the immunogenic antigens included in vaccines of the present application. As used herein, a vaccine is said to prevent or attenuate a disease if its administration to an animal results either in the total or partial attenuation (i.e., suppression) of a symptom or condition of the disease, or in the total or partial immunity of the animal to the disease.
[0245] The administration of the vaccine (or the antisera which it elicits) may be for either a “prophylactic” or “therapeutic” purpose. When provided prophylactically, the vaccine(s) are provided in advance of any symptoms of proliferative disease. The prophylactic administration of the vaccine(s) serves to prevent or attenuate any subsequent presentation of the disease. When provided therapeutically, the vaccine(s) is provided upon or after the detection of symptoms which indicate that an animal may be infected with a pathogen. The therapeutic administration of the vaccine(s) serves to attenuate any actual disease presentation. Thus, the vaccines may be provided either prior to the onset of disease proliferation (so as to prevent or attenuate an anticipated infection) or after the initiation of an actual proliferation.
[0246] One of ordinary skill in the art will appreciate that vaccines may optionally include a pharmaceutically acceptable excipient or carrier. Thus, according to another aspect, provided vaccines may comprise one or more antigens that are optionally conjugated to a pharmaceutically acceptable excipient or carrier. In some embodiments, said one or more antigens are conjugated covalently to a pharmaceutically acceptable excipient. In other embodiments, said one or more antigens are non-covalently associated with a pharmaceutically acceptable excipient.
[0247] As described above, adjuvants may be used to increase the immune response to an antigen. According to the present application, provided vaccines may be used to invoke an immune response when administered to a subject. In certain embodiments, an immune response to an antigen may be potentiated by administering to a subject a provided vaccine in an effective amount to potentiate the immune response of said subject to said antigen.
Formulations
[0248] The compounds of the present application and/or their salts may be combined with one or a mixture of pharmaceutically acceptable excipients to form a pharmaceutical composition. In certain embodiments, formulations of the present application include injectable formulations. In certain embodiments, the pharmaceutical composition includes a pharmaceutically acceptable amount of a compound of the present application. In certain embodiments, the compounds of the application and an antigen form an active ingredient. The amount of active ingredient(s) which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, and the particular mode of administration. The amount of active ingredient(s) that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, this amount will range from about 1% to about 99% of active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30%, or from about 1% to 99%, preferably from 10% to 90%, 20% to 80%, 30% to 70%, 40% to 60%, 45% to 55%, or about 50%.
[0249] Thus, one aspect of the present application is certain formulations containing salt forms or free forms of saponin derivatives, including free acid and salt forms of TQL-1055. Particularly preferred embodiments of such solutions remain relatively stable in solution even near physiological pH values without precipitating and without denaturing an antigen present in solution.
[0250] At the outset, it is important to note the formulation approaches discussed herein are not necessarily mutually exclusive. Rather, the formulations of the present application may include combinations of different approaches discussed below, e.g. a formulation including liposomes and an emulsion. Furthermore, it should be appreciated that certain portions of the formulation may include some ingredients, whereas others contain other ingredients. For example, a formulation may include liposomes having a toll-like receptor agonist, as well as an emulsion containing a compound of Formula I in the dispersed phase. In other words, the compound of Formula I and the other ingredients need not be present in every part of the formulation. Rather, individual ingredients may be included in individual parts to maximize formulation properties, including efficacy, stability, and pH.
[0251] In certain embodiments, the solvent selected for the formulation may include water, alcohols (including but not limited to methanol, ethanol, butanol, etc.), polyols (including but not limited to glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
[0252] In certain embodiments, the formulation includes a buffered solution having a pH near physiological pH, i.e. between approximately 7.0 and 7.5, between approximately 7.0 and 8.0, between approximately 7.5 and 8.0, or approximately 7.4. In certain embodiments, the buffer is a carbonate-bicarbonate, citrate, acetate, histidine, glycine, phosphate, or tris(hydroxymethyl)aminomethane (Tris or tromethamine) buffer. In certain embodiments, the formulation contains excipients selected from the group consisting of dextran, sorbitol, dextrose, trehalose, mannitol, HPMC, PEG400, PS20, PS80, PVP K12, Kolliphor HS15, and Cyclodextrin. Certain preferred embodiments of the present application include PS20 (polysorbate 20) or PS80 (polysorbate 80). In certain embodiments, the excipients prevent precipitation of dissolved saponin derivatives, including TQL-1055, when these solutions have or are brought to physiological pH values. In certain embodiments, certain excipients provide synergistic effects.
[0253] In certain embodiments, the formulation includes a compound of Formula I and a counterion. In a preferred embodiment, the compound of formula I is Compound I-4 and the counterion is choline. Acceptable counterions maintain electric neutrality and potentially increase solubility of the compound of Formula I in solution. In a preferred embodiment, the counterion is a cation. In some embodiments, the counterion is an anion. In some embodiments, the counterion is lipophilic. In some embodiments, the counterion is lipophobic. In some embodiments, the counterion is hydrophilic. In some embodiments, the counterion is hydrophobic. In some embodiments, the counterion is selected from the group consisting of chloride, sulfate, bromide, mesylate, maleate, citrate, nitrate, tosylate, tartrate, phosphate, acetate, camsylate, formate, fumarate, oxalate, thiocyanate, adipate, caprate, caproate, caprylate, dodecylsulfate, glutarate, laurate, oleate, palmitate, sebacate, stearate, undecylenate, iodide, choline (e.g. choline hydroxide), L-lysine, sodium (e.g. sodium carbonate or sodium hydroxide), calcium (e.g. calcium hydroxide), potassium (e.g. potassium carbonate), magnesium (e.g. magnesium hydroxide), meglumine, ammonium, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, 1-Pyrrolidineethanol, trimethyltetradecylammonium (e.g. trimethyltetradecylammonium-hydroxide), tetraethanol-ammonium (e.g. tetraethanol-ammonium hydroxide), procaine, benzathine, aluminum, zinc, piperazine, tromethamine, diethylamine, ethylenediamine, arginine, histidine, glycine, lithium tetrakis(pentafluorophenyl)borate, tetraphenylboranuide, hexafluorophosphate, tetrafluoroborate, bis(triphenylphosphine)iminium chloride, tetraphenylphosphonium chloride, tetra-n-butylammonium bromide (TBAB), alkali metals bound by crown ethers, and mixtures thereof. In some embodiments, the counterion is a quaternary ammonium salt. Other pharmaceutically acceptable counterions adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.
[0254] In certain embodiments, the formulation includes an emulsion. An emulsion is generally a thermodynamically unstable multi-phase system containing immiscible materials, the first of which is relatively uniformly dispersed as globules throughout a second, continuous phase. A third emulsifying agent is added to stabilize the system and prevent the dispersed phase from coalescing and/or precipitating. In some embodiments, the emulsifying agent reduces the interfacial tension between the dispersed phase and the continuous phase. In some embodiments, the emulsifying agent provides a barrier between the dispersed phase and the continuous phase. In some embodiments, the emulsifying agent is a surfactant. Suitable surfactants according to embodiments of the present application are discussed herein. In some embodiments, the emulsifying agent is selected from gum acacia, tween, veegum, tragacanth, methylcellulose, saponins, and soaps formed from monovalent bases like Na+, K+, and NH.sub.4+. In some embodiments, the emulsifying agent is wool fat, resins, beeswax, and soaps from divalent bases like Ca+, Mg.sup.2+, and Zn.sup.2+. In some embodiments, the emulsifying agent is selected from agar, albumin, alginates, casein, ceatyl Icohol, cholic acid, desoxycholic acid, diacetyl tartaric acid esters, egg yolk, glycerol, triglycerides, gums, irish moss (carrageenan), lecithin, mono- and diglycerides, monosodium phosphate, monostearate, ox bile extract, propylene glycol, soaps, taurocholic acid, and sodium oleate (or its sodium salt).
[0255] In some embodiments, the emulsion is an oil-in-water emulsion. In some embodiments, the emulsion is a water-in-oil emulsion. In some embodiments, the emulsion is a multiple emulsion, such as a water-in-oil-in-water emulsion, or an oil-in-water-in-oil emulsion.
[0256] In some embodiments, the continuous phase is selected from water, alcohols (including but not limited to methanol, ethanol, butanol, etc.), polyols (including but not limited to glycerol, propylene glycol, polyethylene glycol, etc.), oils, vegetable oils, such as olive oil, injectable organic esters, such as ethyl oleate, and suitable mixtures thereof.
[0257] The dispersed phase is generally immiscible with the continuous phase. In some embodiments, the dispersed phase is selected from water, alcohols (including but not limited to methanol, ethanol, butanol, etc.), polyols (including but not limited to glycerol, propylene glycol, polyethylene glycol, etc.), oils, vegetable oils, such as olive oil, injectable organic esters, such as ethyl oleate, and suitable mixtures thereof. In some embodiments, the dispersed phase contains a compound of Formula I, preferably Compound I-4. In some embodiments, the dispersed phase is a free form of a compound of Formula I. In some embodiments, the dispersed phase is a salt form of a compound of Formula I, as discussed herein.
[0258] In certain embodiments, the formulation includes a surfactant. In some embodiments, the surfactant is an emulsifying agent, as described above. In some embodiments, the surfactant forms micelles. The structure of a micelle is such that hydrophobic (non-polar) tails of the surfactant are oriented toward the center of the micelle while the hydrophilic (polar) heads orient towards the aqueous phase, which the micelles are in an aqueous solution. In some embodiments, the micelles contain a compound of Formula I, preferably Compound I-4. In some embodiments, the micelles contain a toll-like receptor agonist, such as a TLR4 agonist. Suitable hydrophilic polymers for surrounding the liposomes include, without limitation, PEG, polyvinylpyrrolidone, polyvinylmethylether, polymethyloxazoline, polyethyloxazoline, polyhydroxypropyloxazoline, polyhydroxypropylmethacrylamide, polymethacrylamide, polydimethylacrylamide, polyhydroxypropylmethacrylate, polyhydroxethylacrylate, hydroxymethylcellulose, hydroxyethylcellulose, polyethyleneglycol, polyaspartamide and hydrophilic peptide sequences as described in U.S. Pat. Nos. 6,316,024; 6,126,966; 6,056,973; and 6,043,094. Other acceptable micelle forming compounds include as well PEGylated lipids such as 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000]. Liposomes can be made without hydrophilic polymers. Therefore, liposome formulations may or may not contain hydrophilic polymers.
[0259] Liposomes may be comprised of any lipid or lipid combination known in the art. For example, the vesicle-forming lipids may be naturally-occurring or synthetic lipids, including phospholipids, such as phosphatidylcholine, phosphatidylethanolamine, phosphatide acid, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, and sphingomyelin as disclosed in U.S. Pat. Nos. 6,056,973 and 5,874,104.
[0260] The vesicle-forming lipids may also be glycolipids, cerebrosides, or cationic lipids, such as 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol) (DOPG), 1,2-dipalmitoyl-sn-glycero-3-phospho-(1′-rac-glycerol) (DPPG), 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPS), L-α-phosphatidylserine (Brain, Porcine) (Brain PS), 1,2-dimyristoyl-sn-glyero-3-phospho-(1′ rac-glycerol) (DMPG), 1,2-dioleoyl-sn-glycero-3-phosphoethanol (Phosphatidylethanol), L-α-phosphatidic acid (Egg, Chicken) (Egg PA), DDA (dimethyldioctadecylammonium), DC-cholesterol (3β-[N—(N′,N′-dimethylaminoethane)-carbamoyl]cholesterol), PS (phosphatidylserine), PA (1,2-dioleoyl-sn-glycero-3-phosphate), POPG (1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1′-rac-glycerol)), PC (phosphatidylcholine), DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), DLPC (1,2-dilauroyl-sn-glycero-3-phosphocholine), DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine), dimyristoyl phosphatidylcholine (DMPC), 1,2-dioleyloxy-3-(trimethylamino)propane (DOTAP); N—[I-(2,3-ditetradecyloxy)propyl]-N,N-dimethyl-N-hydroxyethylammonium bromide (DMRIE); N—[I -(2,3-dioleyloxy)propyl]-N,N-dimethyl-N-hydroxy ethylammonium bromide (DORIE); N—[I-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA); 3 [N—(N′,N′-dimethylaminoethane) carbamoly] cholesterol (DCChol); or dimethyldioctadecylammonium (DDAB) also as disclosed in U.S. Pat. No. 6,056,973. Cholesterol may also be present in the proper range to impart stability to the liposome vesicle, as disclosed in U.S. Pat. Nos. 5,916,588 and 5,874,104. Additional liposomal technologies are described in U.S. Pat. Nos. 6,759,057; 6,406,713; 6,352,716; 6,316,024; 6,294,191; 6,126,966; 6,056,973; 6,043,094; 5,965,156; 5,916,588; 5,874,104; 5,215,680; and 4,684,479. These described liposomes and lipid-coated microbubbles, and methods for their manufacture. Thus, one skilled in the art, considering both the present disclosure and the disclosures of these other patents could produce a liposome for the purposes of the present embodiments. Liposomes may comprise phospholipid or nonphospholipid bilayers. Phospholipid bilayers may comprise hydrocarbon chains, optionally having a melting temperature in water of at least 23° C. Such phospholipids may comprise, for example, dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphatidylglycerol (DMPG), cholesterol (Chol), or similar molecules, and mixtures thereof. The liposome may optionally comprise a neutral lipid that is non-crystalline at room temperature, such as dioleoyl phosphatidylcholine or similar compounds. See U.S. Published Patent Application No. 2011/0206758.
[0261] During manufacture of liposomal formulations containing, for example, QS-21, small unicellular liposomal vesicles (SUV) are first created. The SUV is then added to an aqueous environment having QS-21 or another saponin and the SUV takes up QS-21 or the saponin from the aqueous environment. The liposomal composition also may have certain optional ingredients, such as for example MPL, synthetic MPL such as MPLA, CpG 7909 or CpG 1018, or similar substances.
[0262] In some embodiments, the liposomes are formed using the thin-film hydration method. Such technique involves creating a thin film by removing an organic solvent containing lipids/cholesterol, and, upon adding and agitating a dispersion medium, heterogeneous liposomes are formed. The heterogeneous mixture may be extruded through a membrane to obtain homogeneous small liposomes. Thus, in some embodiments, a compound of Formula I, preferably Compound I-4, or a salt thereof, and lipids/cholesterol are dissolved in methanol:chloroform solvent, dried, and then hydrated in a buffer (e.g., PBS) to form liposomes containing the compound of Formula I. In some embodiments, the liposomes are formed by combining a lipid such as a cholesterol and methanol in the presence of a compound of Formula I, preferably Compound I-4, or a salt thereof. In such an embodiment, the liposomes are then added to an aqueous environment having, for example, MPL or other compositions as set forth above.
[0263] Thus, in one aspect the present application provides formulations comprising a liposome formulation of MPL and Compound I-4. In another aspect the present application provides formulations comprising MPL, Compound I-4, and a squalene emulsion. In another aspect the present application provides formulations comprising MPL, Compound I-4, and CpG 7909 or CpG 1018. MPL is a heterogeneous mixture of molecules from a biological source including both agonists and antagonists for TLR4. CpG 7909 is an immunomodulating synthetic oligonucleotide designed to specifically agonise the Toll-like receptor 9 (TLR9).
[0264] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
[0265] Non-limiting examples of pharmaceutically-acceptable antioxidants include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
[0266] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
[0267] Non-limiting examples of suitable aqueous and nonaqueous carriers, which may be employed in the pharmaceutical compositions of the present application include water, alcohols (including but not limited to methanol, ethanol, butanol, etc.), polyols (including but not limited to glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
[0268] These compositions may also contain additives such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
[0269] In some cases, in order to prolong the effect of a formulation, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which in turn, may depend upon crystal size and crystalline form.
[0270] Regardless of the route of administration selected, the compounds of the present application, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present application, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
[0271] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present application may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
[0272] The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present application employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
[0273] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the present application employed in the pharmaceutical composition at levels lower than that required to achieve the desired therapeutic effect and then gradually increasing the dosage until the desired effect is achieved.
[0274] In some embodiments, a compound or pharmaceutical composition of the present application is provided to a subject chronically. Chronic treatments include any form of repeated administration for an extended period of time, such as repeated administrations for one or more months, between a month and a year, one or more years, or longer. In many embodiments, a chronic treatment involves administering a compound or pharmaceutical composition of the present application repeatedly over the life of the subject. Preferred chronic treatments involve regular administrations, for example one or more times a day, one or more times a week, or one or more times a month. In general, a suitable dose, such as a daily dose of a compound of the present application, will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
[0275] Generally, doses of the compounds of the present application for a patient, when used for the indicated effects, will range from about 0.0001 to about 100 mg per kg of body weight per day. Preferably the daily dosage will range from 0.001 to 50 mg of compound per kg of body weight, and even more preferably from 0.01 to 10 mg of compound per kg of body weight. However, lower or higher doses can be used. In some embodiments, the dose administered to a subject may be modified as the physiology of the subject changes due to age, disease progression, weight, or other factors.
[0276] In some embodiments, provided adjuvant compounds of the present application are administered as pharmaceutical compositions or vaccines. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 1-2000 μg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 1-1000 μg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 1-500 μg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 1-250 μg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 100-1000 μg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 100-500 μg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 100-200 μg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 250-500 μg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 10-1000 μg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 500-1000 μg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 50-250 μg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 50-500 μg.
[0277] In some embodiments, provided adjuvant compounds of the present application are administered as pharmaceutical compositions or vaccines. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 1-2000 mg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 1-1000 mg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 1-500 mg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 1-250 mg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 100-1000 mg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 100-500 mg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 100-200 mg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 250-500 mg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 10-1000 mg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 500-1000 mg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 50-250 mg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 50-500 mg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 0.01-215.4 mg.
[0278] In certain embodiments, it is contemplated that the amount of adjuvant administered will be 1000-5000 μg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 1000-4000 μg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 1000-3000 μg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 1000-2000 μg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 2000-5000 μg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 2000-4000 μg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 2000-3000 μg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 3000-5000 μg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 3000-4000 μg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 4000-5000 μg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 1-500 μg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 500-1000 μg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 1000-1500 μg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 1 mg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 2 mg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 3 mg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 4 mg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 5 mg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 0.0029-5 mg/kg. In certain embodiments, the amount of adjuvant administered in females is less than the amount of adjuvant administered in males. In certain embodiments, the amount of adjuvant administered to infants is less than the amount of adjuvant administered to adults. In certain embodiments, the amount of adjuvant administered to pediatric recipients is less than the amount of adjuvant administered to adults. In certain embodiments, the amount of adjuvant administered to immunocompromised recipients is more than the amount of adjuvant administered to healthy recipients. In certain embodiments, the amount of adjuvant administered to elderly recipients is more than the amount of adjuvant administered to non-elderly recipients.
[0279] If desired, the effective dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
[0280] While it is possible fora compound of the present application to be administered alone, in certain embodiments the compound is administered as a pharmaceutical formulation or composition as described above.
[0281] The compounds according to the present application may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other pharmaceuticals.
[0282] Kits
[0283] The present application provides kits comprising pharmaceutical formulations or compositions of a compound of the present application. In some embodiments, the kits include two or more vials (or other pharmaceutically acceptable vessels) that must be combined prior to administration. In some embodiments, a first vial contains an antigen component, which may be in solution (in a formulation) or may be lyophilized, e.g., a powder. In some embodiments, a second vial contains an adjuvant formulation, which may be in an aqueous or lyophilized form, for example a formulation according to the present application. Such adjuvant formulations include compounds of Formula I, preferably Compound I-4, or a salt thereof. Such adjuvant formulations may include multiple formulation approaches, as discussed above. For example, the second vial may include an adjuvant formulation (e.g. Compound I-4) and a surfactant.
[0284] In some embodiments, the first vial contains a formulation including a compound of Formula I, preferably Compound I-4, or a salt thereof, and the second vial contains a surfactant, or a salt thereof. The first or second vial (or a third vial) may also contain an antigen and other excipients.
[0285] Some embodiments include a third vial having a TLR agonist, e.g. a TLR4 agonist formulation.
[0286] The vials may be packaged together or separately. In some embodiments, the kit includes instructions for combining the vials and administering the combined formulation to a patient in need thereof.
[0287] The kit optionally includes instructions for prescribing the medication. In certain embodiments, the kit includes multiple doses of each agent. The kit may include sufficient quantities of each component to treat one or more subject for a week, two weeks, three weeks, four weeks, or multiple months. The kit may include a full cycle of immunotherapy. In some embodiments, the kit includes a vaccine comprising one or more bacterial or viral-associated antigens, and one or more provided compounds.
[0288] Methods
[0289] The present application also encompasses methods of conferring immune resistance to an individual. Such methods include administering to an individual a vaccine comprising a therapeutically effective amount of a compound of Formula I, in free form or in pharmaceutically acceptable salt form, together with an antigen. In particular, the compound of Formula I may be a salt form of TQL-1055, preferably TQL-1055 Choline Form A.
[0290] The present application also encompasses methods of preparing salts according to the present application. Salts may be prepared according to the present application by adding a compound of Formula I, in particular TQL-1055, to an acidic or basic solution, followed by addition of a salt cation or anion of the present application, in particular choline, followed by drying or evaporating.
[0291] The present application also encompasses methods of formulation compounds of Formula I, or salts thereof, according to the present application. A person of ordinary skill in the art would understand how to prepare the formulations discussed herein based on the above disclosure of the present application.
Further Embodiments
[0292] 1.1. A pharmaceutical composition comprising
[0293] a pharmaceutically acceptable salt of a compound of Formula I
##STR00044##
[0294] wherein
[0295] is a single or double bond;
[0296] W is —CHO;
[0297] V is hydrogen or OR.sup.x;
[0298] Y is CH.sub.2, —O—, —NR—, or —NH—; [0299] Z is hydrogen; a cyclic or acyclic, optionally substituted moiety selected from the group consisting of acyl, aliphatic, heteroaliphatic, aryl, arylalkyl, heteroacyl, and heteroaryl; or a carbohydrate domain having the structure:
##STR00045## [0300] wherein each occurrence of R.sup.1 is R.sup.x or a carbohydrate domain having the structure:
##STR00046## [0301] wherein: [0302] each occurrence of a, b, and c is independently 0, 1, or 2; [0303] d is an integer from 1-5, wherein each d bracketed structure may be the same or different; with the proviso that the d bracketed structure represents a furanose or a pyranose moiety, and the sum of b and c is 1 or 2; [0304] R.sup.0 is hydrogen; an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, carbamates, and carbonates; or an optionally substituted moiety selected from the group consisting of acyl, C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; [0305] each occurrence of R.sup.a, R.sup.b, R.sup.c, and R.sup.d is independently hydrogen, halogen, OH, OR, OR.sup.x, NR.sub.2, NHCOR, or an optionally substituted group selected from acyl, C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, sulfur; 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; [0306] R.sup.2 is hydrogen, halogen, OH, OR, OC(O)R.sup.4, OC(O)OR.sup.4, OC(O)NHR.sup.4, OC(O)NRR.sup.4, OC(O)SR.sup.4, NHC(O)R.sup.4, NRC(O)R.sup.4, NHC(O)OR.sup.4, NHC(O)NHR.sup.4, NHC(O)NRR.sup.4, NHR.sup.4, N(R.sup.4).sub.2, NHR.sup.4, NRR.sup.4, N.sub.3, or an optionally substituted group selected from C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; [0307] R.sup.3 is hydrogen, halogen, CH.sub.2OR.sup.1, or an optionally substituted group selected from the group consisting of acyl, C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, [0308] R.sup.4 is -T-R.sup.z, —C(O)-T-R.sup.z, —NH-T-R.sup.z, —O-T-R.sup.z, —S-T-R.sup.z, —C(O)NH-T-R.sup.z, C(O)O-T-R.sup.z, C(O)S-T-R.sup.z, C(O)NH-T-O-T-R.sup.z, —O-T-R.sup.z, -T-O-T-R.sup.z, -T-S-T-R.sup.z, or
##STR00047## [0309] wherein [0310] X is —O—, —NR—, or T-R.sup.z; [0311] T is a covalent bond or a bivalent C.sub.1-26 saturated or unsaturated, straight or branched, aliphatic or heteroaliphatic chain; and [0312] R.sup.z is hydrogen, halogen, —OR, —OR.sup.x, —OR.sup.1, —SR, NR.sub.2, —C(O)OR, —C(O)R, —NHC(O)R, —NHC(O)OR, NC(O)OR, or an optionally substituted group selected from acyl, arylalkyl, heteroarylalkyl, C.sub.1-6 aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; [0313] each occurrence of R.sup.x is independently hydrogen or an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, carbamates, and carbonates; [0314] each occurrence of R is independently hydrogen, an optionally substituted group selected from acyl, arylalkyl, 6-10-membered aryl, C.sub.1-6 aliphatic, or C.sub.1-6 heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, or: [0315] two R on the same nitrogen atom are taken with the nitrogen atom to form a 4-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
[0316] In one aspect, the present application provides compounds of Formula II:
##STR00048##
[0317] or a pharmaceutically acceptable salt thereof, wherein
[0318] is a single or double bond;
[0319] W is Me, —CHO, or
##STR00049##
[0320] V is hydrogen or OR.sup.x;
[0321] Y is CH.sub.2, —O—, —NR—, or —NH—; [0322] Z is hydrogen; a cyclic or acyclic, optionally substituted moiety selected from the group consisting of acyl, aliphatic, heteroaliphatic, aryl, arylalkyl, heteroacyl, and heteroaryl; or a carbohydrate domain having the structure:
##STR00050## [0323] wherein each occurrence of R.sup.1 is R.sup.x or a carbohydrate domain having the structure:
##STR00051## [0324] wherein: [0325] each occurrence of a, b, and c is independently 0, 1, or 2; [0326] d is an integer from 1-5, wherein each d bracketed structure may be the same or different; with the proviso that the d bracketed structure represents a furanose or a pyranose moiety, and the sum of b and c is 1 or 2; [0327] R.sup.0 is hydrogen; an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, carbamates, and carbonates; or an optionally substituted moiety selected from the group consisting of acyl, C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; [0328] each occurrence of R.sup.a, R.sup.b, R.sup.0, and R.sup.d is independently hydrogen, halogen, OH, OR, OR.sup.x, NR.sub.2, NHCOR, or an optionally substituted group selected from acyl, C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, sulfur; 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; [0329] R.sup.2 is hydrogen, halogen, OH, OR, OC(O)R.sup.4, OC(O)OR.sup.4, OC(O)NHR.sup.4, OC(O)NRR.sup.4, OC(O)SR.sup.4, NHC(O)R.sup.4, NRC(O)R.sup.4, NHC(O)OR.sup.4, NHC(O)NHR.sup.4, NHC(O)NRR.sup.4, NHR.sup.4, N(R.sup.4).sub.2, NHR.sup.4, NRR.sup.4, N.sub.3, or an optionally substituted group selected from C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; [0330] R.sup.3 is hydrogen, halogen, CH.sub.2OR.sup.1, or an optionally substituted group selected from the group consisting of acyl, C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, [0331] R.sup.4 is -T-R.sup.z, —C(O)-T-R.sup.z, —NH-T-R.sup.z, —O-T-R.sup.z, —S-T-R.sup.z, —C(O)NH-T-R.sup.z, C(O)O-T-R.sup.z, C(O)S-T-R.sup.z, C(O)NH-T-O-T-R.sup.z, —O-T-R.sup.z, -T-O-T-R.sup.z, -T-S-T-R.sup.z, or
##STR00052## [0332] wherein [0333] X is —O—, —NR—, or T-R.sup.z; [0334] T is a covalent bond or a bivalent C.sub.1-26 saturated or unsaturated, straight or branched, aliphatic or heteroaliphatic chain; and [0335] R.sup.z is hydrogen, halogen, —OR, —OR.sup.x, —OR.sup.1, —SR, NR.sub.2, —C(O)OR, —C(O)R, —NHC(O)R, —NHC(O)OR, NC(O)OR, or an optionally substituted group selected from acyl, arylalkyl, heteroarylalkyl, C.sub.1-6 aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; [0336] each occurrence of R.sup.x is independently hydrogen or an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, carbamates, and carbonates; [0337] R.sup.y is —OH, —OR, or a carboxyl protecting group selected from the group consisting of ester, amides, and hydrazides; [0338] R.sup.s is
##STR00053## [0339] each occurrence of R.sup.x′ is independently an optionally substituted group selected from 6-10-membered aryl, C.sub.1-6 aliphatic, or C.sub.1-6 heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or: [0340] two R.sup.x′ are taken together to form a 5-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; [0341] each occurrence of R is independently hydrogen, an optionally substituted group selected from acyl, arylalkyl, 6-10-membered aryl, C.sub.1-6 aliphatic, or C.sub.1-6 heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, or: [0342] two R on the same nitrogen atom are taken with the nitrogen atom to form a 4-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
1.2. The pharmaceutical composition of 1.1,
[0343] wherein the pharmaceutically acceptable salt is a choline salt of Compound I-4:
##STR00054##
1.3. The pharmaceutical composition of 1.2,
[0344] wherein the choline salt of Compound I-4 has a ratio of choline:Compound I-4 of approximately 1:1.
1.4. The pharmaceutical composition of 1.2,
[0345] wherein the choline salt of Compound I-4 has a crystalline structure.
1.5. The pharmaceutical composition of 1.4,
[0346] wherein a unit cell of the crystalline structure has four Compound I-4 anions and four choline cations.
1.6. The pharmaceutical composition of 1.4,
[0347] wherein a unit cell of the crystalline structure has a volume of approximately 1757 to 1726 Å.sup.3.
1.7. The pharmaceutical composition of 1.4,
[0348] wherein the crystalline structure is a variable hydrate.
1.8. The pharmaceutical composition of 1.4,
[0349] wherein the crystalline structure exhibits hydration dependent peaks in an XRPD pattern derived using Cu K-alpha radiation.
1.9. The pharmaceutical composition of 1.8,
[0350] wherein the crystalline structure exhibits peaks as shown in
1.10. The pharmaceutical composition of 1.8,
[0351] wherein the crystalline structure exhibits peaks as shown in
1.11. The pharmaceutical composition of 1.8,
[0352] wherein the crystalline structure exhibits peaks as shown in
1.12. The pharmaceutical composition of 1.8,
[0353] wherein the crystalline structure exhibits at least three peaks, wherein each peak lies within one of three ranges of theta values, wherein the ranges of theta values correspond to groupings of peaks as shown in
1.13. The pharmaceutical composition of 1.7,
[0354] wherein in a fully hydrated state, the crystalline structure accommodates greater than 3 mol/mol water.
1.14. The pharmaceutical composition of 1.7,
[0355] wherein the crystalline structure converts to another crystalline structure above 65% relative humidity.
1.15. The pharmaceutical composition of 1.4,
[0356] wherein a melt and decomposition onset is near 222° C.
1.16. The pharmaceutical composition of 1.2,
[0357] further comprising an antigen.
1.17. The pharmaceutical composition of 1.16,
[0358] wherein the antigen is associated with a bacteria or virus.
1.18. The pharmaceutical composition of 1.17,
[0359] wherein the antigen is associated with SARS-CoV-2 virus.
1.19. The pharmaceutical composition of 1.17,
[0360] wherein the antigen is associated with Varicella Zoster.
1.20. A method of conferring resistance to an infection, the method comprising administering an antigen in combination with a pharmaceutical composition of 1.1.
1.21. A method for obtaining a pharmaceutical composition of 1.1, the method comprising:
[0361] adding a compound of Formula I to an acidic, basic, or amphoteric solution,
[0362] adding a salt cation or anion, and
[0363] drying, evaporating, or filtering the solution.
1.22. The method of 1.21,
[0364] wherein the salt cation or anion is choline.
1.23. The method of 1.22,
[0365] wherein choline is added using choline hydroxide.
1.24. A pharmaceutical composition comprising
[0366] a choline salt of Compound I-4:
##STR00055##
1.25. The pharmaceutical composition of 1.24,
[0367] wherein the choline salt of Compound I-4 has a ratio of choline:Compound I-4 of approximately 1:1.
1.26. The pharmaceutical composition of 1.24,
[0368] wherein the choline salt of Compound I-4 has a crystalline structure.
1.27. The pharmaceutical composition of 1.26,
[0369] wherein a unit cell of the crystalline structure has four Compound I-4 anions and four choline cations.
1.28. The pharmaceutical composition of 1.26, wherein a unit cell of the crystalline structure has a volume of approximately 1757 to 1726 Å.sup.3.
1.29. The pharmaceutical composition of 1.26,
[0370] wherein the crystalline structure is a variable hydrate.
1.30. The pharmaceutical composition of 1.26,
[0371] wherein the crystalline structure exhibits hydration dependent peaks in an XRPD pattern derived using Cu K-alpha radiation.
1.31. The pharmaceutical composition of 1.30,
[0372] wherein the crystalline structure exhibits peaks as shown in
1.32. The pharmaceutical composition of 1.30,
[0373] wherein the crystalline structure exhibits peaks as shown in
1.33. The pharmaceutical composition of 1.30,
[0374] wherein the crystalline structure exhibits peaks as shown in
1.34. The pharmaceutical composition of 1.30,
[0375] wherein the crystalline structure exhibits at least three peaks, wherein each peak lies within one of three ranges of theta values, wherein the ranges of theta values correspond to groupings of peaks as shown in
1.35. The pharmaceutical composition of 1.29,
[0376] wherein in a fully hydrated state, the crystalline structure accommodates greater than 3 mol/mol water.
1.36. The pharmaceutical composition of 1.29,
[0377] wherein the crystalline structure converts to another crystalline structure above 65% relative humidity.
1.37. The pharmaceutical composition of 1.26,
[0378] wherein a melt and decomposition onset is near 222° C.
1.38. The pharmaceutical composition of 1.24,
[0379] further comprising an antigen.
1.39. The pharmaceutical composition of 1.38,
[0380] wherein the antigen is associated with a bacteria or virus.
1.40. The pharmaceutical composition of 1.39,
[0381] wherein the antigen is associated with SARS-CoV-2 virus.
1.41. The pharmaceutical composition of 1.39,
[0382] wherein the antigen is associated with Varicella Zoster.
1.42. A method of conferring resistance to an infection, the method comprising administering an antigen in combination with a pharmaceutical composition of 1.24.
1.43. A method for obtaining a pharmaceutical composition of 1.24, the method comprising:
[0383] adding a compound of Formula I to an acidic, basic, or amphoteric solution,
[0384] adding a salt cation or anion, and
[0385] drying, evaporating, or filtering the solution.
1.44. The method of 1.43,
[0386] wherein the salt cation or anion is choline.
1.45. The method of 1.44,
[0387] wherein choline is added using choline hydroxide.
2.1. A liquid formulation comprising Compound I-4:
##STR00056##
or a pharmaceutically acceptable salt thereof,
2.2. The liquid formulation of 2.1,
[0388] wherein the liquid formulation comprises a solvent selected from the group consisting of water, methanol, and ethanol.
2.3. The liquid formulation of 2.1,
[0389] further comprising a buffer selected from the group consisting of carbonate-bicarbonate, citrate, acetate, histidine, glycine, phosphate, or tris(hydroxymethyl)aminomethane (Tris or tromethamine) buffer.
2.4. The liquid formulation of 2.1,
[0390] further comprising an excipient selected from the group consisting of dextran, sorbitol, dextrose, trehalose, mannitol, HPMC, PEG400, PS20, PS80, PVP K12, Kolliphor HS15, and cyclodextrin.
2.5. The liquid formulation of 2.1,
[0391] wherein the formulation contains a choline salt of Compound I-4.
2.6. The liquid formulation of 2.1,
[0392] wherein the formulation contains an arginine salt of Compound I-4.
2.7. The liquid formulation of 2.1,
[0393] wherein the formulation contains a free acid form of Compound I-4.
2.8. The liquid formulation of 2.1,
[0394] further comprising an antigen.
2.9. The liquid formulation of 2.8,
[0395] wherein the antigen is associated with a bacteria, virus, protozoa, or fungus.
2.10. The liquid formulation of 2.8,
[0396] wherein the antigen is associated with SARS-CoV-2 virus.
2.11. The liquid formulation of 2.8,
[0397] wherein the antigen is associated with Varicella Zoster.
2.12. A method of conferring resistance to an infection, the method comprising administering the liquid formulation of 2.8.
EXAMPLES
Example 1—Synthesis of Choline Form A (TQL-1055) Salt
[0398] 1.484 g of TQL-1055 (LIMS 539468, as-received) was stirred in 15 mL of MeOH producing a white slurry. 375 μL of choline hydroxide (45 wt % in MeOH) was added to the slurry. The slurry was capped and stirred at ambient temperature. After 2.5 hours, the slurry was very thick and barely stirring. An additional 2 mL of MeOH was added to the slurry. The vial was capped and continued to stir at ambient temperature. After 2 hours, the solids were collected by vacuum filtration on filter paper. Solids were rinsed with 2 to 3 mL of MeOH. Dry solids were determined by XRPD to contain a mixture of crystalline materials including TQL-1055 free acid.
[0399] The remaining filtrate was allowed to slowly evaporate at ambient temperature in a loosely capped vial. When the volume was approximately half, the resulting solids were filtered by positive pressure filtration on a 0.2-μm nylon filter. The filtrate was retained. The solids were again, determined to be a mixture of crystalline materials including TQL-1055 free acid, by XRPD.
[0400] All remaining TQL-1055 free acid, Choline Form A, and mixtures of crystalline materials discussed above were combined with the remaining concentrated filtrate and 1 mL of additional MeOH. 125 μL of choline hydroxide solution was added to the slurry. After stirring approximately 3 hours, the slurry was very thick and no longer stirring. An additional 1 mL of MeOH was added. The vial was capped and stirred at ambient temperature for one day. White solids were collected by vacuum filtration on a 0.2-μm nylon filter. The solids were determined to be a mixture of crystalline materials including TQL-1055 free acid, by XRPD.
[0401] The mixture (1.225 g) was gently crushed with a pestle and slurried in 5 mL of MeOH. 154 μL of choline hydroxide solution was added with an additional 2 mL of MeOH. Mixture was capped and stirred at ambient temperature for 3 days. Resulting solids were isolated by vacuum filtration on a 0.2-μm nylon filter. 1.095 g of Choline Form A was obtained.
Example 2—Analytical and Experimental Techniques
[0402] 1. Differential Scanning Calorimetry (DSC)
[0403] DSC was performed using a Mettler-Toledo DSC3+ differential scanning calorimeter. A tau lag adjustment is performed with indium, tin, and zinc. The temperature and enthalpy are adjusted with octane, phenyl salicylate, indium, tin and zinc. The adjustment is then verified with octane, phenyl salicylate, indium, tin, and zinc. The sample was placed into a hermetically sealed aluminum DSC pan, the weight was accurately recorded, the lid was pierced, and the sample was inserted into the DSC cell. A weighed aluminum pan configured as the sample pan was placed on the reference side of the cell. The pan lid was pierced prior to sample analysis. The sample was analyzed from −30° C. to 250° C. at 10° C./min.
[0404] 2. Dynamic Vapor Sorption (DVS)
[0405] Automated vapor sorption (VS) data were collected on a Surface Measurement System DVS Intrinsic instrument. Samples were not dried prior to analysis. Sorption and desorption data were collected over a range from 5% to 95% RH at 10% RH increments under a nitrogen purge. The equilibrium criterion used for analysis was less than 0.0100% weight change in 5 minutes with a maximum equilibration time of 3 hours. Data were not corrected for the initial moisture content of the samples.
[0406] 3. Karl Fischer Analysis (KF)
[0407] Coulometric Karl Fischer (KFC) analysis for water determination was performed using a Mettler Toledo DL39 KF titrator. A NIST-traceable water standard (Hydranal Water Standard 1.0) was analyzed to check the operation of the coulometer. A blank titration was carried out prior to sample analyses. The sample was prepared at ambient conditions, where ˜1.5-2.0 g of the sample was dissolved in approximately 1 mL Hydranal-Coulomat AD in a pre-dried vial. The entire solution was added to the KF coulometer through a septum and mixed for 10 seconds. The sample was then titrated by means of a generator electrode, which produces iodine by electrochemical oxidation: 2 I−.fwdarw.I2+2e−. One replicate was obtained to ensure reproducibility.
[0408] 4. Proton Nuclear Magnetic Resonance Spectroscopy (.sup.1H NMR)
[0409] The solution NMR spectra were acquired with an Avance 600 MHz NMR spectrometer. The samples were prepared by dissolving approximately 5 mg of sample in DMSO-d6 containing TMS. The data acquisition parameters are displayed in the first plot of the spectrum in the Data section of this report.
[0410] 5. Thermogravimetric Analysis (TGA)
[0411] TG analysis was performed using a Mettler-Toledo TGA/DSC3+ analyzer. Temperature and enthalpy adjustments were performed using indium, phenyl salicylate, tin, and zinc, and then verified with indium. The balance was verified with calcium oxalate. The sample was placed in an open aluminum pan. The pan was hermetically sealed, the lid pierced, then inserted into the TG furnace. A weighed aluminum pan configured as the sample pan was placed on the reference platform. The furnace was heated under nitrogen. The samples was analyzed from 25° C. to 350° C. at 10° C./min
[0412] 6. X-Ray Powder Diffraction (XRPD)
[0413] a. Transmission
[0414] XRPD patterns were collected with a PANalytical X'Pert PRO MPD or PANalytical Empyrean diffractometer using an incident beam of Cu radiation produced using a long, fine-focus source. An elliptically graded multilayer mirror was used to focus Cu Kα X-rays through the specimen and onto the detector. Prior to the analysis, a silicon specimen (NIST SRM 640e) was analyzed to verify the observed position of the Si 111 peak is consistent with the NIST-certified position. A specimen of the sample was sandwiched between 3-μm-thick films and analyzed in transmission geometry. A beam-stop, short antiscatter extension, and antiscatter knife edge were used to minimize the background generated by air. Soller slits for the incident and diffracted beams were used to minimize broadening and asymmetry from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen and Data Collector software v. 5.5. The data acquisition parameters are listed in the image of each pattern displayed in the Data section of this report. All images have the instrument labeled as X'Pert PRO MPD regardless of the instrument used.
[0415] b. Reflection-Variable Temperature
[0416] An Anton Paar TTK 450 stage was used to collect in-situ XRPD patterns as a function of temperature. The same experimental parameters as described above were used except for that the specimen was packed in a nickel-coated copper well. The sample was heated with a resistance heater located directly under the sample holder, and the temperature was monitored with a platinum-100 resistance sensor located in the specimen holder. The heater was powered and controlled by an Anton Paar TCU 100 interfaced with Data Collector.
Example 3—TQL-1055 Choline Salt and Free Acid Ethanol Solubility
[0417] An experiment was conducted to determine the solubility of TQL-1055 choline salt and TQL-1055 free acid in ethanol. Several samples were prepared, each containing either TQL-1055 choline salt or TQL-1055 free acid dissolved in a 100% ethanol solution at a concentration of 4 mg/ml. All samples were mixed using a vortex mixer and subsequently sonicated at 37° C. for five minutes. Neither the TQL-1055 choline salt nor the TQL-1055 free acid were fully dissolved at 4 mg/ml. Samples were then diluted to 3.5 mg/ml, 3 mg/ml, 2.5 mg/ml, or 2 mg/ml and re-sonicated. As depicted in