# US 2017/0283450 A1 · Triterpene saponins, methods of synthesis and uses thereof

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- Number: US 2017/0283450 A1
- Document ID: US20170283450A1
- Status: Published application
- Kind: A1
- Application number: 15/626,046
- Filed: 2017-06-16
- Published: 2017-10-05
- Earliest claimed: 2009-04-08
- Assignees: Memorial Sloan-Kettering Institute for Cancer Research
- Applicants: Memorial Sloan-Kettering Institute for Cancer Research
- Inventors: David GIN; Michelle ADAMS; Kai DENG; Philip LIVINGSTON; Govindaswami RAGUPATHI; Eric CHEA; Alberto FERNANDEZ-TEJADA; Lars Ulrik NORDSTROEM; William WALKOWICZ; Jeffrey GARDNER; Derek TAN
- Web page: https://patentgrep.com/patent/US20170283450A1

## CPC

- C07H 15/256: Polyterpene radicals
- A61K 31/7024: Esters of saccharides
- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 39/385: Haptens or antigens, bound to carriers
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 31/16: for influenza or rhinoviruses
- A61P 31/18: for HIV
- A61P 31/20: for DNA viruses
- A61P 31/22: for herpes viruses
- A61P 33/00: Antiparasitic agents
- A61P 33/02: Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/04: Immunostimulants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07H 5/06: Aminosugars
- C07H 13/08: having the esterifying carboxyl radicals directly attached to carbocyclic rings
- C07H 15/24: Condensed ring systems having three or more rings
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present invention relates to triterpene glycoside saponin-derived adjuvants, syntheses thereof, intermediates thereto, and uses thereof. QS-7 is a potent immuno-adjuvant that is significantly less toxic than QS-21, a related saponin that is currently the favored adjuvant in anticancer and antiviral vaccines. Tedious isolation and purification protocols have hindered the clinical development of QS-7. A novel semi-synthetic method is provided wherein a hydrolyzed prosapogenin mixture is used to synthesize QS-7, QS-21, and related analogs, greatly facilitating access to QS-7 and QS-21 analogs for preclinical and clinical evaluation.

## Claims

### Claim at position 1

1-36. (canceled)

### Claim 37

A compound of formula II-b:
or a pharmaceutically acceptable salt thereof, wherein:
is a single or double bond;
W is Me, —CHO,
—CH2ORx, or —C(O)Ry;
V is hydrogen or —ORx;
each occurrence of Rx 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;
RY is —OH, —OR, or a carboxyl protecting group selected from the group consisting of ester, amides, and hydrazides;
Rs is
each occurrence of Rx′ is independently an optionally substituted group selected from 6-10-membered aryl, C1-6 aliphatic, or C1-6 heteroaliphatic having 1-2 heteroatoms
independently elected from the group consisting of nitrogen, oxygen, and sulfur; or: two Rx′ 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, C1-12 aliphatic, or C1-12 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 to form a 4-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
each occurrence of R1 is Rx or a carbohydrate domain having the structure:
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 pyranose moiety, and the sum of b and c is 1 or 2;
R0 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, C1-10 aliphatic, C1-6 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;
R3 is hydrogen, halogen, CH2OR, or an optionally substituted group selected from the group consisting of acyl, C1-10 aliphatic, C1-6 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; with the proviso that R3 is not methyl;
R4 is
wherein X is —O— or —NR—; or
T-Rz, wherein:
T is a covalent bond or a bivalent C1-26 saturated or unsaturated, straight or branched, aliphatic or heteroaliphatic chain; and
Rz is hydrogen, halogen, —OR, —ORx, —OR1, —SR, —NR2, —NC(O)OR, or an optionally substituted group selected from acyl, arylalkyl, heteroarylalkyl, C1-6 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; or
two R4 on the same nitrogen atom are taken with the nitrogen to form a 4-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.

### Claim 38

A compound selected from:

### Claim 39 (depends on 37)

A pharmaceutical composition comprising a compound according to claim 37 and a pharmaceutically acceptable excipient.

### Claim 40 (depends on 39)

The pharmaceutical composition of claim 39 further comprising an immunologically effective amount of an antigen.

### Claim 41

(canceled)