# US 2019/0167604 A1 · Arylfluorosulfate compounds and methods

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- Number: US 2019/0167604 A1
- Document ID: US20190167604A1
- Status: Published application
- Kind: A1
- Application number: 16/243,761
- Filed: 2019-01-09
- Published: 2019-06-06
- Earliest claimed: 2014-06-06
- Assignees: The Scripps Research Institute
- Applicants: The Scripps Research Institute
- Inventors: Jie LI; Zilei LIU; Suhua LI; Peng WU; K. Barry SHARPLESS
- Web page: https://patentgrep.com/patent/US20190167604A1

## CPC

- A61K 31/05: Phenols {(cannabinoids A61K31/658)}
- A61K 31/136: having the amino group directly attached to the aromatic ring, e.g. benzeneamine
- A61K 31/14: Quaternary ammonium compounds, e.g. edrophonium, choline (betaines A61K31/205)
- 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 31/198: Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00)
- A61K 31/397: having four-membered rings, e.g. azetidine
- A61K 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K 31/4045: Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
- A61K 31/407: condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
- A61K 31/4168: having a nitrogen attached in position 2, e.g. clonidine
- A61K 31/4245: Oxadiazoles
- A61K 31/4353: ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/439: the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46)
- A61K 31/47: Quinolines; Isoquinolines
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/473: ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 31/485: Morphinan derivatives, e.g. morphine, codeine
- A61K 31/505: Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K 31/515: Barbituric acids; Derivatives thereof, e.g. sodium pentobarbital
- A61K 31/53: having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495})
- A61K 31/5513: 1,4-Benzodiazepines, e.g. diazepam {or clozapine}
- A61K 31/56: Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K 31/65: Tetracyclines
- A61K 31/655: Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
- A61K 31/70: Carbohydrates; Sugars; Derivatives thereof (sorbitol A61K31/047)
- A61K 31/7048: having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin {, digitoxin or digoxin}
- A61K 38/31: Somatostatins
- A61K 47/54: the modifying agent being an organic compound
- A61K 51/0497: {conjugates with a carrier being an organic compounds}
- C07C 305/26: Halogenosulfates, i.e. monoesters of halogenosulfuric acids
- C07D 277/82: Nitrogen atoms
- C07D 295/088: to an acyclic saturated chain
- C07D 295/185: from aliphatic carboxylic acids
- C07D 295/26: Sulfur atoms
- C07K 1/02: in solution {(C07K1/003, C07K1/006 take precedence)}
- C07K 1/1136: {by reversible modification of the secondary, tertiary or quarternary structure, e.g. using denaturating or stabilising agents}
- C07K 2/00: Peptides of undefined number of amino acids; Derivatives thereof
- C40B 30/06: by measuring effects on living organisms, tissues or cells
- C07C 2601/14: The ring being saturated
- C07C 2603/18: Fluorenes; Hydrogenated fluorenes
- C12N 5/0693: {Tumour cells; Cancer cells}
- C12N 2503/02: Drug screening
- C40B 30/04: by measuring the ability to specifically bind a target molecule, e.g. antibody-antigen binding, receptor-ligand binding
- C40B 40/04: Libraries containing only organic compounds
- C40B 50/08: Liquid phase synthesis, i.e. wherein all library building blocks are in liquid phase or in solution during library creation; Particular methods of cleavage from the liquid support
- G01N 2500/00: Screening for compounds of potential therapeutic value
- 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)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C40B: COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES (in silico combinatorial libraries of nucleic acids, proteins or peptides G16B35/00; in silico combinatorial chemistry G16C20/60)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

Arylfluorosulfate compounds derived from anticancer drugs are disclosed herein, which exhibit improved anti-cancer cell proliferation activities compared to their phenolic drug precursors. Among these compounds, the fluorosulfate derivative of fulvestrant showed significantly enhanced activity to down-regulate estrogen receptor (ER) expression in ER+ breast cancer cell line MCF-7, and oral availability in vivo; the fluorosulfate derivative of combretastatin A4 exhibited a 70-fold increase in potency in the drug resistant colon cancer cell line HT-29; and the fluorosulfate derivative of ABT-751 showed enhanced activity relative to ABT-751.

## Claims

### Claim 1

A chemical compound comprising a fluorosulfate derivative of a phenolic anticancer medicinal agent, wherein at least one phenolic OH group of the medicinal agent is replaced by —OSO2F.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the medicinal agent is selected from the group consisting of ATB-751 (1), apigenin (2), ezetimibe (3), topotecan (4), ganetespib (5), etoposide (6), G100713 (7), estrone (8), PI-103 (9), raloxifene (10), fulvestrant (11), mycophenolic acid (12), gimeracil (13), flavopiridol (14), serotonin (15), PAC-1 (16), SKI II (17), endoxifen (18), vanillin (19), A-769662 (20), xanthohumol (21), sirtinol (22), IOX1 (23), TWS119 (24), combretastatin A4 (25), VER-50589 (26), luminespib (27), TW-37 (28), estrol (29), SB415286 (30), rotigotine (31), estradiol (32), RKI-1447 (33), licochalcone A (34), onalespib (35), 2-methoxyestrodiol (36), SB202190 (37), salidroside (38), 10-hydroxycamptothecin (39, 10-HCPT), lasofoxifene, lipid encapsulated 7-ethyl-10-hydroxycamptothecin, (LE-SN38), diethylstilbestrol, amrubicin, genistein, and phenoxodiol.

### Claim 3 (depends on 1)

The compound of claim 1, wherein the compound has a formula selected from the group consisting of Formula 1F, Formula 11F, and Formula 25F:

### Claim 4 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1 in a pharmaceutically acceptable carrier.

### Claim 5 (depends on 2)

A pharmaceutical composition comprising the compound of claim 2 in a pharmaceutically acceptable carrier.

### Claim 6 (depends on 3)

A pharmaceutical composition comprising the compound of claim 3 in a pharmaceutically acceptable carrier.

### Claim 7 (depends on 1)

A method of treatment of cancer in a patient, comprising administering an effective dose of the compound of claim 1 to the patient.

### Claim 8 (depends on 2)

A method of treatment of cancer in a patient, comprising administering an effective dose of the compound of claim 2 to the patient.

### Claim 9 (depends on 3)

A method of treatment of cancer in a patient, comprising administering an effective dose of the compound of claim 3 to the patient.

### Claim 10 (depends on 7)

The method of claim 7, wherein the patient is a human.

### Claim 11 (depends on 8)

The method of claim 8, wherein the patient is a human.

### Claim 12 (depends on 9)

The method of claim 9, wherein the patient is a human.

### Claim 13 (depends on 9)

The method of claim 9 wherein the compound is a compound of Formula 1F.

### Claim 14 (depends on 9)

The method of claim 9, wherein the compound is a compound of Formula 11F.

### Claim 15 (depends on 14)

The method of claim 14, wherein the cancer is hormone receptor positive metastatic breast cancer.

### Claim 16 (depends on 9)

The method of claim 9, wherein the compound is a compound of Formula 25F.