# US 10,500,204 B2 · Vitamin receptor drug delivery conjugates for treating inflammation

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- Number: US 10,500,204 B2
- Document ID: US10500204B2
- Status: Granted
- Kind: B2
- Application number: 15/811,600
- Filed: 2017-11-13
- Published: 2018-08-09
- Granted: 2019-12-10
- Earliest claimed: 2007-06-25
- Assignees: Endocyte, Inc.
- Applicants: Endocyte, Inc.
- Inventors: Christopher Paul Leamon; Iontcho Radoslavov Vlahov; Yingjuan June Lu; Kevin Yu Wang; Fei You; Paul Joseph Kleindl; Hari Krishna R. Santhapuram
- Web page: https://patentgrep.com/patent/US10500204B2

## CPC

- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/436: the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
- A61K 47/545: {Heterocyclic compounds (A61K47/558 takes precedence)}
- A61K 47/551: {one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid}
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- C07K 7/06: having 5 to 11 amino acids
- 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
- 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)

## Abstract

Described herein are compositions, methods, compounds, conjugates, and kits for use in targeted drug delivery using drug delivery conjugates containing hydrophilic spacer linkers for use in treating disease states caused by pathogenic cell populations, such as inflammatory cells.

## Claims

### Claim 1

A compound of the formula
BLA
or a pharmaceutically acceptable salt thereof; wherein
B is a vitamin receptor binding ligand;
L is a linker that comprises one or more hydrophilic spacer linkers selected from the group consisting of
wherein
R is selected from the group consisting of H, alkyl, cycloalkyl, and arylalkyl; m is an integer from 1 to about 3; n is an integer from 1 to about 6; p is an integer from 1 to about 5; and (*) indicates the point of attachment to the rest of the compound and
a fragment of the formula
wherein
each Ra and Rb is independently hydrogen or alkyl; or Ra and Rb are taken together with the attached carbon atom to form a carbocyclic ring;
n1 is an integer selected from 1 to 4; and
(**) indicates points of attachment for other parts of the conjugate; and
A is an adrenocorticoid or a corticosteroid.

### Claim 2 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A is an adrenocorticoid.

### Claim 3 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A is a corticosteroid.

### Claim 4 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the linker comprises three hydrophilic spacer linkers.

### Claim 5 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the one or more hydrophilic spacer linkers each comprise five hydroxyl groups.

### Claim 6 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the linker further comprises one or more naturally occurring amino acids' and stereoisomers thereof.

### Claim 7 (depends on 6)

The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein the linker further comprises one or more amino acids selected from the group consisting of asparagine, aspartic acid, cysteine, glutamic acid, lysine, glutamine, arginine, serine, ornithine, threonine, and stereoisomers thereof.

### Claim 8 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the linker further comprises a releasable linker.

### Claim 9 (depends on 8)

The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein the linker further comprises a disulfide group.

### Claim 10 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the purity of the compound is at least 98%.

### Claim 11 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the vitamin receptor binding ligand is a folate.

### Claim 12 (depends on 2)

The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein the vitamin receptor binding ligand is a folate.

### Claim 13 (depends on 3)

The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein the vitamin receptor binding ligand is a folate.

### Claim 14 (depends on 11)

The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein the vitamin receptor binding ligand is of the formula
wherein * indicates the point of attachment to the linker.

### Claim 15 (depends on 12)

The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein the vitamin receptor binding ligand is of the formula
wherein * indicates the point of attachment to the linker.

### Claim 16 (depends on 13)

The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein the vitamin receptor binding ligand is of the formula
wherein * indicates the point of attachment to the linker.

### Claim 17

A pharmaceutical composition comprising a compound of the formula
BLA
or a pharmaceutically acceptable salt thereof; wherein
B is a vitamin receptor binding ligand;
L is a linker that comprises one or more hydrophilic spacer linkers selected from the group consisting of
wherein
R is selected from the group consisting of H, alkyl, cycloalkyl, and arylalkyl; m is an integer from 1 to about 3; n is an integer from 1 to about 6; p is an integer from 1 to about 5; and (*) indicates the point of attachment to the rest of the compound and
a fragment of the formula
wherein
each Ra and Rb is independently hydrogen or alkyl; or Ra and Rb are taken together with the attached carbon atom to form a carbocyclic ring;
n1 is an integer selected from 1 to 4; and
(**) indicates points of attachment for other parts of the conjugate; and
A is an adrenocorticoid or a corticosteroid.

### Claim 18 (depends on 17)

The pharmaceutical composition of claim 17, wherein, in the compound, or the pharmaceutically acceptable salt thereof, the vitamin receptor binding ligand is a folate and A is an adrenocorticoid.

### Claim 19 (depends on 17)

The pharmaceutical composition of claim 17, wherein, in the compound, or the pharmaceutically acceptable salt thereof, the vitamin receptor binding ligand is a folate and A is a corticosteroid.

### Claim 20 (depends on 17)

The pharmaceutical composition of claim 17, further comprising one or more carriers, diluents, or excipients, or a combination thereof.