# US 2017/0143688 A1 · Multi-Tyrosine Kinase Inhibitors Derivatives and Methods of Use

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- Number: US 2017/0143688 A1
- Document ID: US20170143688A1
- Status: Published application
- Kind: A1
- Application number: 15/403,139
- Filed: 2017-01-10
- Published: 2017-05-25
- Earliest claimed: 2015-06-29
- Assignees: Ontogenesis, LLC
- Applicants: Ontogenesis, LLC
- Inventors: Gerald Horn
- Web page: https://patentgrep.com/patent/US20170143688A1

## CPC

- A61K 31/47: Quinolines; Isoquinolines
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 9/1075: {Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers (A61K9/0026 takes precedence)}
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 47/542: {Carboxylic acids, e.g. a fatty acid or an amino acid}
- A61K 47/643: {Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]}
- C07D 215/20: Oxygen 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)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention is directed to multi-tyrosine kinase inhibitor compounds. The present invention is further directed to compositions comprising those compounds. Finally, the present invention is directed to methods of treating eye conditions including, but not limited to, diabetic background retinopathy, diabetic macular edema, diabetic proliferative retinopathy, diabetic macular edema with proliferative retinopathy, proliferative fibrovascular disease, diabetic macular edema with proliferative fibrovascular disease, retinopathy of prematurity, dry macular degeneration, dry macular degeneration with drusen and wet macular degeneration, using compounds and compositions of the invention.

## Claims

### Claim 1

A compound comprising a multi-tyrosine kinase inhibitor (MTKI) modified by a moiety comprising an optionally substituted C2 to C25 alkyl group bound to a peptide or a protein, wherein the moiety attaches to the MTKI at one or more nitrogens and or the moiety replaces one or more carbonyl or methoxy groups of the MTKI and wherein if the MTKI has n carbonyl and methoxy groups and n is greater than 1, then n−1 of the carbonyl or methoxy groups are each individually and optionally replaced by hydrogen, oxygen, carbon, potassium, sulfur, phosphorus, nitrogen, a carbonyl, a sulfhydryl, a phosphatyl, an amide, an amine, a quaternary amine, a phosphate, a phosphonate, a sulfate, a sulfonate, a carboxylate or a urethane.

### Claim 2 (depends on 2)

The compound of claim 2 wherein the MTKI has an IC50 of 10 nanomolar or less for one or more proteins selected from the group consisting of VEGFR2, c-MET PDGF, FGF, FLT, c-KIT, RON and TIE.

### Claim 3 (depends on 1)

The compound of claim 1 wherein the MTKI is selected from the group consisting of cabozantinib, axitinib, cediranib, ponatinib, foretinib, MGCD-265, motesanib, regorafenib, tivozanib and sunitinib.

### Claim 4 (depends on 1)

The compound of claim 1 wherein the MTKI is selected from cabozantinib and foretinib.

### Claim 5 (depends on 1)

The compound of claim 1 wherein the moiety is a C2 to C25 alkyl group bound to a peptide of 10 amino acids or less.

### Claim 6 (depends on 1)

The compound of claim 1, wherein the moiety comprises albumin.

### Claim 7 (depends on 1)

The compound of claim 1, wherein the moiety is a C4 to C25 alkyl group bound to a peptide or a protein.

### Claim 8 (depends on 1)

The compound of claim 1, wherein the moiety renders the compound amphiphilic.

### Claim 9 (depends on 6)

The compound of claim 6, wherein the C2 to C25 alkyl group is substituted at one or more hydrogens and or one or more carbons with optionally substituted polar groups selected from the group consisting of a carbonyl, a sulfhydryl, a phosphate, a phosphatyl, a phosphonate, an amide, an amine, a quaternary amine, a sulfate, a sulfonate, and a carboxylate.

### Claim 10 (depends on 9)

The compound of claim 9, wherein the carbonyl, the sulfhydryl, the phosphate, the phosphonate, the phosphatyl, the amide, the amine, the quaternary amine, the sulfate, the sulfonate or the carboxylate are each individually substituted with a fatty acid or a second alkyl.

### Claim 11

A compound of formula (I):
wherein: wherein R1, R2, R3, R4 and R5 are each individually selected from hydrogen, oxygen, carbon, potassium, sulfur, phosphorus, nitrogen, —O—C, a carbonyl, a sulfhydryl, a phosphatyl, an amide, an amine, a quaternary amine, a phosphate, a phosphonate, a sulfate, a sulfonate, a carboxylate, a urethane, and an optionally substituted C2 to C25 alkyl group bound to a peptide or a protein and at least one of R1, R2, R3, R4 and R5 is not hydrogen, oxygen, carbon, potassium, sulfur, phosphorus, nitrogen, —O—C, a carbonyl, a sulfhydryl, a phosphatyl, an amide, an amine, a quaternary amine, a phosphate, a phosphonate, a sulfate, a sulfonate, a carboxylate, or a urethane, and wherein the C4 to C25 alkyl group is optionally substituted at one or more hydrogens or one or more carbons with optionally substituted polar groups selected from the group consisting of a carbonyl, a sulfhydryl, a phosphate, a phosphatyl, a phosphonate, an amide, an amine, a quaternary amine, a sulfate, a sulfonate, and a carboxylate.

### Claim 12 (depends on 11)

The compound of claim 11, wherein the compound is of formula (I) and wherein R1 and R2 are each individually selected from hydrogen, oxygen, carbon, potassium, sulfur, phosphorus, nitrogen, —O—C, a carbonyl, a sulfhydryl, a phosphatyl, an amide, an amine, a quaternary amine, a phosphate, a phosphonate, a sulfate, a sulfonate, a carboxylate, a urethane, and an optionally substituted C4 to C25 alkyl group bound to a peptide or a protein and wherein R3, R4 and R5 are each H and wherein at least one of R1 and R2 is not hydrogen, oxygen, carbon, potassium, sulfur, phosphorus, nitrogen, —O—C, a carbonyl, a sulfhydryl, a phosphatyl, an amide, an amine, a quaternary amine, a phosphate, a phosphonate, a sulfate, a sulfonate, a carboxylate, a urethane.

### Claim 13

A compound selected from
wherein X is a peptide or a protein.

### Claim 14 (depends on 1)

A composition comprising a compound of claim 1 and one or more pharmaceutically acceptable excipients.

### Claim 15 (depends on 1)

A method of treating a condition of the eye comprising administering via intravitreal injection or topical application of a therapeutically effective amount of a compound of claim 1 to a subject in need thereof.

### Claim 16 (depends on 15)

The method of claim 15 wherein the condition is selected from diabetic background retinopathy, diabetic macular edema, diabetic proliferative retinopathy, diabetic macular edema with proliferative retinopathy, neovascular glaucoma, retinopathy of prematurity, proliferative fibrovascular disease, diabetic macular edema with proliferative fibrovascular disease, retinopathy of prematurity, dry macular degeneration, any retinopathies with vascular leakage such as Coat's disease or Bescet's disease, dry macular degeneration with drusen and wet macular degeneration.

### Claim 17 (depends on 15)

The method of claim 15 wherein the condition is diabetic macular edema and wherein proliferative retinopathy is prevented.

### Claim 18 (depends on 15)

The method of claim 15 wherein the condition is diabetic macular edema with proliferative retinopathy and proliferative retinopathy is suppressed.

### Claim 19 (depends on 15)

The method of claim 15 wherein the condition is diabetic macular edema and wherein fibrovascular proliferative disease is prevented.

### Claim 20 (depends on 15)

The method of claim 15 wherein the condition is diabetic macular edema with fibrovascular proliferative disease and wherein fibrovascular proliferative disease is suppressed.

### Claim 21 (depends on 15)

The method of claim 15 wherein the condition is dry macular degeneration or dry macular degeneration with drusen and wherein wet macular degeneration is suppressed or prevented.

### Claim 22 (depends on 1)

A method of treating a condition of the eye comprising administering via intravitreal injection or topical application of a therapeutically effective amount of a compound of claim 1 to a subject in need thereof, wherein the administration occurs no more than once every 3 months.

### Claim 23 (depends on 22)

The method of claim 22 wherein the administration occurs no more than once every 6 months.

### Claim 24 (depends on 23)

The method of claim 23 wherein the administration occurs no more than once every 9 months.