# US 11,439,656 B2 · Pharmaceutical compounds and uses thereof

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- Number: US 11,439,656 B2
- Document ID: US11439656B2
- Status: Granted
- Kind: B2
- Application number: 16/556,690
- Filed: 2019-08-30
- Published: 2020-03-05
- Granted: 2022-09-13
- Earliest claimed: 2018-08-30
- Assignees: Regents of the University of Minnesota
- Applicants: Regents of the University of Minnesota
- Inventors: DaQing Yang; Carston R. Wagner; Aniekan Okon
- Web page: https://patentgrep.com/patent/US11439656B2

## CPC

- A61K 31/708: having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
- A61K 31/175: having the group [IMAGE cpc-sch-A61K-0950.gif] , >N—C(O)—N=N— or[IMAGE cpc-sch-A61K-0951.gif] , e.g. carbonohydrazides, carbazones, semicarbazides, semicarbazones; Thioanalogues thereof
- A61K 31/196: the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
- A61K 31/197: the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid (carnitine A61K31/205)
- A61K 31/365: Lactones
- A61K 31/366: having six-membered rings, e.g. delta-lactones
- A61K 31/426: 1,3-Thiazoles
- A61K 31/495: having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53})
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 47/545: {Heterocyclic compounds (A61K47/558 takes precedence)}
- A61K 47/6809: {Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin}
- A61P 35/00: Antineoplastic agents
- C07H 17/02: Heterocyclic radicals containing only nitrogen as ring hetero atoms
- 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
- 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)

## Abstract

Described herein are small molecule cap-dependent inhibitors, including the compound of the formula: which compounds that can induce the accumulation of the p53 tumor suppressor protein in cancer cells that still express wild-type p53, as well as methods of using those compounds to, among other things, treat neuroblastoma, pediatric glioblastoma multiforme or breast cancer.

## Claims

### Claim 1

A compound of the formula (I):
or a pharmaceutically acceptable salt thereof;
wherein:
X− represents a counterion;
R1 and R2 are each independently H, OH or alkoxy;
R3 is alkyl, aryl or heterocyclyl;
R4 is alkyl or aryl;
R5 is aryl; and
X1 is NH, S or O;
wherein the heterocyclyl is selected from the group consisting of piperidinyl, piperazinyl, morpholinyl, furanyl, pyrrolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, thiophenyl, tetrahydrofuranyl, pyrrolyl, oxazolyl, imidazolyl, triazolyl, tetrazolyl, indolyl, benzoxazolinyl, and benzimidazolinyl groups.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound has the formula (II):
or a pharmaceutically acceptable salt thereof
wherein:
X− represents a counterion;
R1 and R2 are each independently H, OH or alkoxy;
R4 is alkyl or aryl;
R5 is aryl;
X1 and X2 are each independently NH, S or O;
R6 and R7 can each independently be H, alkyl, aryl or R6 and R7, together with the carbon atoms to which they are attached, form an aryl group selected from the group consisting of phenyl, napthalenyl, azulenyl, biphenylyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl or anthracenyl.

### Claim 3 (depends on 1)

The compound of claim 1, wherein the compound has the formula:
or a pharmaceutically acceptable salt thereof, wherein X− represents a counterion.

### Claim 4 (depends on 1)

The compound of claim 1, wherein the compound has the formula:
or a pharmaceutically acceptable salt thereof, wherein X− and Y+ represent counterions.

### Claim 5 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 and at least one pharmaceutically acceptable excipient.

### Claim 6

A method for treating neuroblastoma, pediatric glioblastoma multiforme or breast cancer comprising administering a therapeutically effective amount of a compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein X− represents a counterion, to a subject in need thereof.

### Claim 7

A compound having the formula:
or a pharmaceutically acceptable salt thereof, wherein X− represents a counterion.