# US 9,518,053 B2 · Fluorinated integrin antagonists

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- Number: US 9,518,053 B2
- Document ID: US9518053B2
- Status: Granted
- Kind: B2
- Application number: 14/766,322
- Filed: 2014-02-07
- Published: 2016-03-17
- Granted: 2016-12-13
- Earliest claimed: 2013-02-07
- Assignees: SciFluor Life Sciences, Inc.
- Applicants: SciFluor Life Sciences, Inc.
- Inventors: Ben C. Askew; Richard W. Heidebrecht; Takeru Furuya; Mark E. Duggan; D. Scott Edwards
- Web page: https://patentgrep.com/patent/US9518053B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 31/4375: the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/02: Inorganic compounds
- A61K 47/183: {Amino acids, e.g. glycine, EDTA or aspartame}
- A61K 47/34: Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence)
- A61K 47/40: Cyclodextrins; Derivatives thereof
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 27/00: Drugs for disorders of the senses
- A61P 27/02: Ophthalmic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

## Abstract

The present invention relates to fluorinated compounds of formula I and methods of synthesizing these compounds. The present invention also relates to pharmaceutical compositions containing the fluorinated compounds of the invention, and methods of treating macular degeneration, diabetic retinopathy (DR), macular edema, diabetic macular edema (DME), and macular edema following retinal vein occlusion (RVO), by administering these compounds and pharmaceutical compositions to subjects in need thereof.

## Claims

### Claim 1

A compound of formula I:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
Z is
R and R′ are each independently H or F, or R and R′, together with the carbon atom to which they are attached, form a 3- or 4-membered carbocyclic or heterocyclic ring;
Q is
X is CH or N;
Y is CH or N;
R1 is C1-C4 alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, or C1-C6 alkoxy substituted with 0, 1, 2, 3, 4, 5, 6, or 7 fluorine atoms; and
R2 and R3 are each independently H, F, CH2F, CHF2, or CF3, provided that one of R2 and R3 is not H,
provided that the compound of formula (I) contains at least one fluorine atom.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R and R′ are each H.

### Claim 3 (depends on 1)

The compound of claim 1, wherein Q is

### Claim 4 (depends on 3)

The compound of claim 3, wherein X is N and Y is CH.

### Claim 5 (depends on 3)

The compound of claim 3, wherein X and Y are each CH.

### Claim 6 (depends on 3)

The compound of claim 3, wherein X and Y are each N.

### Claim 7 (depends on 3)

The compound of claim 3, wherein R1 is straight chain C1-C4 or branched C3-C4 alkyl, and is substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms.

### Claim 8 (depends on 3)

The compound of claim 3, wherein R1 is methyl substituted with 1, 2, or 3 fluorine atoms.

### Claim 9 (depends on 3)

The compound of claim 3, wherein R1 is straight chain C1-C6 or branched C3-C6 alkoxy, and is substituted with 0, 1, 2, 3, 4, 5, 6, or 7 fluorine atoms.

### Claim 10 (depends on 9)

The compound of claim 9, wherein R1 is methoxy substituted with 0, 1, 2, or 3 fluorine atoms.

### Claim 11 (depends on 3)

The compound of claim 3, wherein Z is
R and R′ are each H; and R1 is methyl substituted with 1, 2, or 3 fluorine atoms or methoxy substituted with 0, 1, 2, or 3 fluorine atoms.

### Claim 12 (depends on 11)

The compound of claim 11, wherein X is N and Y is CH; and R1 is OCHF2.

### Claim 13 (depends on 11)

The compound of claim 11, wherein X and Y are each N; and R1 is CF3.

### Claim 14 (depends on 3)

The compound of claim 3, wherein Z is
R and R′ are each H; X is N and Y is CH; and R1 is methoxy substituted with 0, 1, 2, or 3 fluorine atoms.

### Claim 15 (depends on 1)

The compound of claim 1, having formula II:
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 16 (depends on 1)

The compound of claim 1, selected from the group consisting of:
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 17 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

### Claim 18 (depends on 17)

The pharmaceutical composition of claim 17, further comprising an active ingredient selected from the group consisting of a) an antagonist of integrin α5β1, b) a cytotoxic/antiproliferative agent, c) an inhibitor of epidermal-derived, fibroblast-derived, or platelet-derived growth factor, d) an inhibitor of VEGF, e) an inhibitor of Flk-1/KDR, Flt-1, Tck/Tie-2, or Tic-1, and f) an inhibitor of phosphoinositide 3-kinase, and a mixture thereof.