# US 12,180,188 B2 · Antifibrotic compounds and related methods

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- Number: US 12,180,188 B2
- Document ID: US12180188B2
- Status: Granted
- Kind: B2
- Application number: 17/992,371
- Filed: 2022-11-22
- Published: 2023-03-23
- Granted: 2024-12-31
- Earliest claimed: 2020-05-19
- Assignees: The Florida State University Research Foundation, Inc.; The Florida International University Board of Trustees
- Applicants: Florida State University Research Foundation, Inc.; The Florida International University Board of Trustees
- Inventors: Branko Stefanovic; Adel Nefzi
- Web page: https://patentgrep.com/patent/US12180188B2

## CPC

- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- 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

This discloses that compounds of Formula 1 have antifibrotic properties. In particular, this discloses a pharmaceutical composition including one or more compounds of Formula 1 and methods of using compounds of Formula 1 in fibrosis treatment and inhibiting type 1 collagen synthesis.

## Claims

### Claim 1

A method comprising administering to a patient having a fibrotic condition a therapeutically amount of a composition comprising a pharmaceutical dosage form including a compound of the formula
and/or a pharmaceutically effective salt thereof wherein:
(a) R1 is selected from a halogen, a hydrogen, a saturated or unsaturated alkyl group, a saturated or unsaturated cycloalkyl group, an aryl group, an alkoxy group, a hydroxy group, a carboxy group, a carbonyl group, an amine group, an amide group, an ester group, a haloalkyl group, a haloaryl group, a thio group, a thioamide group, a urea group, a thiourea group, a valeramide group, a myristic amide group, a benzamide group, a carboxylamide group, and a phenylacetamide group;
(b) R2 maintains the six-membered ring and is selected from:
(i) an amide group, a thioamide group, a valeramide group, a myristic amide group, a benzamide group, a carboxylamide group, and a phenylacetamide group;
(ii) O, S, CR4R5 where R4 and R5 are independently selected from a hydrogen, a halogen, a saturated or unsaturated alkyl group, a saturated or unsaturated cycloalkyl group, an aryl group, an alkoxy group, a hydroxy group, a carboxy group, a carbonyl group, an amine group, an amide group, an ester group, a haloalkyl group, a haloaryl group, a thio group, a thioamide group, a urea group, a thiourea group, a valeramide group, a myristic amide group, a benzamide group, a carboxylamide group, and a phenylacetamide group; or
(iii) N—R2′ where R2′ is selected from a saturated or unsaturated alkyl group, a saturated or unsaturated cycloalkyl group, an aryl group, an alkoxy group, a hydroxy group, a carboxy group, a carbonyl group, an amine group, an amide group, an ester group, a haloalkyl group, a haloaryl group, a thio group, a thioamide group, a urea group, and a thiourea group; and
(c) R3 is selected from:
(i) a halogen, a hydrogen, a saturated or unsaturated alkyl group, a saturated or unsaturated cycloalkyl group, an aryl group, an alkoxy group, a hydroxy group, a carboxy group, a carbonyl group, an amine group, an amide group, an ester group, a haloalkyl group, a haloaryl group, a thio group, a thioamide group, a urea group, a thiourea group, a valeramide group, a myristic amide group, a benzamide group, a carboxylamide group, and a phenylacetamide group; or
(ii) OH, OR6, NH2, and NR7R8 where R6 is selected from H, an aliphatic group, an alkylaryl group, a cycloalkyl group, an alkylcycloalkyl group, and an aryl group; R7 and R8 are independently selected from H, an aliphatic group, an alkylaryl group, a cycloalkyl group, an alkylcycloalkyl group, and an aryl group
wherein the fibrotic condition is condition is at least one of a pulmonary fibrosis, a heart fibrosis, a circulatory system fibrosis, a skin fibrosis, and an intestinal fibrosis.

### Claim 2 (depends on 1)

The method of claim 1, wherein R1 is selected from 3-methylvaleramide, myristic amide, 2,4-dichlorobenzamide, 2-(P-Toluoyl)-benzamide, 1-methyl-2-pyrrolecarboxylamide, 4-isobutyl-alpha-methylphenylacetamide, 4-bromobenzamide, pentafluorophenyacetamide, and phenylacetamide.

### Claim 3 (depends on 1)

The method of claim 1, wherein R2 is selected from 3,4-dichlorophenylacetamide, 2-ethylbutyramide, 4-phenylbutyramide, 1-phenyl-1-cyclopentane carboxylamide, 2,4-dichlorobenzamide, 3,5-dimethylbenzamide, phenylacetamide, 3,4,5-trimethoxybenzamide, 2-benzoylbenzamide, and myristic amide.

### Claim 4 (depends on 1)

The method of claim 1, wherein R3 is an amide group.

### Claim 5 (depends on 1)

The method of claim 1, wherein:
R1 is selected from 3-methylvaleramide, myristic amide, 2,4-dichlorobenzamide, 2-(P-Toluoyl)-benzamide, 1-methyl-2-pyrrolecarboxylamide, 4-isobutyl-alpha-methylphenylacetamide, 4-bromobenzamide, pentafluorophenyacetamide, and phenylacetamide;
R2 is selected from 3,4-dichlorophenylacetamide, 2-ethylbutyramide, 4-phenylbutyramide, 1-phenyl-1-cyclopentane carboxylamide, 2,4-dichlorobenzamide, 3,5-dimethylbenzamide, phenylacetamide, 3,4,5-trimethoxybenzamide, 2-benzoylbenzamide, and myristic amide; and
R3 is an amide group.

### Claim 6 (depends on 1)

The method of claim 1, wherein the fibrotic condition is condition is at least one of a pulmonary fibrosis, a liver fibrosis, a heart fibrosis, a circulatory system fibrosis, a skin fibrosis, and an intestinal fibrosis.

### Claim 7 (depends on 1)

The method of claim 1, wherein administering is oral administration and/or administration by injection.

### Claim 8 (depends on 1)

The method of claim 1, wherein the pharmaceutical dosage form is at least one of a pill or an injectable dosage form.

### Claim 9

A method of inhibiting collagen production, the method comprising contacting a cell capable of producing type 1 collagen with a composition comprising a pharmaceutical dosage form including a compound of the formula
and/or a pharmaceutically effective salt thereof wherein:
(a) R1 is selected from a halogen, a hydrogen, a saturated or unsaturated alkyl group, a saturated or unsaturated cycloalkyl group, an aryl group, an alkoxy group, a hydroxy group, a carboxy group, a carbonyl group, an amine group, an amide group, an ester group, a haloalkyl group, a haloaryl group, a thio group, a thioamide group, a urea group, a thiourea group, a valeramide group, a myristic amide group, a benzamide group, a carboxylamide group, and a phenylacetamide group;
(b) R2 maintains the six-membered ring and is selected from:
(i) an amide group, a thioamide group, a valeramide group, a myristic amide group, a benzamide group, a carboxylamide group, and a phenylacetamide group;
(ii) O, S, CR4R5 where R4 and R5 are independently selected from a hydrogen, a halogen, a saturated or unsaturated alkyl group, a saturated or unsaturated cycloalkyl group, an aryl group, an alkoxy group, a hydroxy group, a carboxy group, a carbonyl group, an amine group, an amide group, an ester group, a haloalkyl group, a haloaryl group, a thio group, a thioamide group, a urea group, a thiourea group, a valeramide group, a myristic amide group, a benzamide group, a carboxylamide group, and a phenylacetamide group; or
(iii) N—R2′ where R2′ is selected from a saturated or unsaturated alkyl group, a saturated or unsaturated cycloalkyl group, an aryl group, an alkoxy group, a hydroxy group, a carboxy group, a carbonyl group, an amine group, an amide group, an ester group, a haloalkyl group, a haloaryl group, a thio group, a thioamide group, a urea group, and a thiourea group; and
(c) R3 is selected from:
(i) a halogen, a hydrogen, a saturated or unsaturated alkyl group, a saturated or unsaturated cycloalkyl group, an aryl group, an alkoxy group, a hydroxy group, a carboxy group, a carbonyl group, an amine group, an amide group, an ester group, a haloalkyl group, a haloaryl group, a thio group, a thioamide group, a urea group, a thiourea group, a valeramide group, a myristic amide group, a benzamide group, a carboxylamide group, and a phenylacetamide group; or
(ii) OH, OR6, NH2, and NR7R8 where R6 is selected from H, an aliphatic group, an alkylaryl group, a cycloalkyl group, an alkylcycloalkyl group, and an aryl group; R7 and R8 are independently selected from H, an aliphatic group, an alkylaryl group, a cycloalkyl group, an alkylcycloalkyl group, and an aryl group;
the composition being effective for inhibiting collagen production.

### Claim 10 (depends on 9)

The method of claim 9, wherein R1 is selected from 3-methylvaleramide, myristic amide, 2,4-dichlorobenzamide, 2-(P-Toluoyl)-benzamide, 1-methyl-2-pyrrolecarboxylamide, 4-isobutyl-alpha-methylphenylacetamide, 4-bromobenzamide, pentafluorophenyacetamide, and phenylacetamide.

### Claim 11 (depends on 9)

The method of claim 9, wherein R2 is selected from 3,4-dichlorophenylacetamide, 2-ethylbutyramide, 4-phenylbutyramide, 1-phenyl-1-cyclopentane carboxylamide, 2,4-dichlorobenzamide, 3,5-dimethylbenzamide, phenylacetamide, 3,4,5-trimethoxybenzamide, 2-benzoylbenzamide, and myristic amide.

### Claim 12 (depends on 9)

The method of claim 9, wherein R3 is an amide group.

### Claim 13 (depends on 9)

The method of claim 9, wherein:
R1 is selected from 3-methylvaleramide, myristic amide, 2,4-dichlorobenzamide, 2-(P-Toluoyl)-benzamide, 1-methyl-2-pyrrolecarboxylamide, 4-isobutyl-alpha-methylphenylacetamide, 4-bromobenzamide, pentafluorophenyacetamide, and phenylacetamide;
R2 is selected from 3,4-dichlorophenylacetamide, 2-ethylbutyramide, 4-phenylbutyramide, 1-phenyl-1-cyclopentane carboxylamide, 2,4-dichlorobenzamide, 3,5-dimethylbenzamide, phenylacetamide, 3,4,5-trimethoxybenzamide, 2-benzoylbenzamide, and myristic amide; and
R3 is an amide group.

### Claim 14

A composition comprising a pharmaceutical dosage form including a compound of the formula
and/or a pharmaceutically effective salt thereof wherein:
(a) R1 is a myristic amide group;
(b) R2 maintains the six-membered ring and is 3,5 dimethyl benzamide; and
(c) R3 is an amide group.

### Claim 15 (depends on 1)

The composition of claim 1, wherein the pharmaceutical dosage form is at least one of a pill or an injectable dosage form.

### Claim 16 (depends on 1)

The composition of claim 1, wherein the compound is substantially non-toxic.