Antifibrotic compounds and related methods
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.
1. 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 3-methylvaleramide, myristic amide, 2,4-dichlorobenzamide, 2-(P-Toluoyl)-benzamide, 1-methyl-2-pyrrolecarboxylamide, 4-isobutyl-alpha-methylphenylacetamide, 4-bromobenzamide, pentafluorophenyacetamide, and phenylacetamide;
(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, where R6 is selected from H, an aliphatic group, an alkylaryl group, a cycloalkyl group, an alkylcycloalkyl group, and an aryl group.
2. The composition 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.
3. The composition of claim 1 , wherein R3 is an amide group.
4. The composition 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; and
R3 is an amide group.
5. The composition of claim 1 , wherein the pharmaceutical dosage form is at least one of a pill or an injectable dosage form.
6. The composition of claim 1 , wherein the compound is substantially non-toxic.
7. A method comprising administering to a patient having a fibrotic condition a therapeutically amount of the composition of claim 1 to the patient.
8. The method of claim 7 , 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.
9. The method of claim 7 , wherein R3 is an amide group.
10. The method of claim 7 , 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; and
R3 is an amide group.
11. The method of claim 7 , wherein the fibrotic 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.
12. The method of claim 7 , wherein administering is oral administration and/or administration by injection.
13. The method of claim 7 , wherein the pharmaceutical dosage form is at least one of a pill or an injectable dosage form.
14. A method of inhibiting collagen production, the method comprising contacting a cell capable of producing type 1 collagen with the composition of claim 1 , the composition being effective for inhibiting collagen production.
15. The method of claim 14 , 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.
16. The method of claim 14 , wherein R3 is an amide group.
17. The method of claim 14 , 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; and
R3 is an amide group.
18. 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 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
(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, NH 2 , where R6 is selected from H, an aliphatic group, an alkylaryl group, a cycloalkyl group, an alkylcycloalkyl group, and an aryl group.
19. composition of claim 18 , 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.
20. The composition of claim 18 , wherein R3 is an amide group.
21. The composition of claim 18 , 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; and
R3 is an amide group.
22. The composition of claim 18 , wherein the pharmaceutical dosage form is at least one of a pill or an injectable dosage form.
23. The composition of claim 18 , wherein the compound is substantially non-toxic.
24. A method comprising administering to a patient having a fibrotic condition a therapeutically amount of the composition of claim 18 to the patient.
25. The method of claim 24 , 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.
26. The method of claim 24 , wherein R3 is an amide group.
27. The method of claim 24 , 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; and
R3 is an amide group.
28. The method of claim 24 , wherein the fibrotic 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.
29. The method of claim 24 , wherein administering is oral administration and/or administration by injection.
30. The method of claim 24 , wherein the pharmaceutical dosage form is at least one of a pill or an injectable dosage form.
31. A method of inhibiting collagen production, the method comprising contacting a cell capable of producing type 1 collagen with the composition of claim 18 , the composition being effective for inhibiting collagen production.
32. The method of claim 31 , 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.
33. The method of claim 31 , wherein R3 is an amide group.
34. The method of claim 31 , 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; and
R3 is an amide group.
35. A composition comprising a pharmaceutical dosage form including a compound of the formula
and/or a pharmaceutically effective salt thereof 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; and
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.
36. The composition of claim 35 , wherein the pharmaceutical dosage form is at least one of a pill or an injectable dosage form.
37. The composition of claim 35 , wherein the compound is substantially non-toxic.
38. A method comprising administering to a patient having a fibrotic condition a therapeutically amount of the composition of claim 35 to the patient.
39. The method of claim 38 , wherein the fibrotic 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.
40. The method of claim 38 , wherein administering is oral administration and/or administration by injection.
41. The method of claim 38 , wherein the pharmaceutical dosage form is at least one of a pill or an injectable dosage form.
42. A method of inhibiting collagen production, the method comprising contacting a cell capable of producing type 1 collagen with the composition of claim 35 , the composition being effective for inhibiting collagen production.
43. A method comprising administering to a patient having a fibrotic condition a therapeutically amount of a composition to the patient, the 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 an amide group.
44. The method of claim 43 , 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.
45. The method of claim 43 , 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.
46. The method of claim 43 , 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; and
R2 is selected from 3,4-dichlorophenylacetamide, 2-ethylbutyramide, 4-phenylbutyramide, 1-phenyl-1-cyclopentane carboxylamide, 2,4-dichlorobenzamide, 3,5-dinnethylbenzamide, phenylacetamide, 3,4,5-trimethoxybenzamide, 2-benzoylbenzamide, and myristic amide.
47. The method of claim 43 , wherein the fibrotic 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.
48. The method of claim 43 , wherein administering is oral administration and/or administration by injection.
49. The method of claim 43 , wherein the pharmaceutical dosage form is at least one of a pill or an injectable dosage form.
50. A method of inhibiting collagen production, the method comprising contacting a cell capable of producing type 1 collagen with a composition effective for inhibiting collagen production, the 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 an amide group.
51. The method of claim 50 , 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.
52. The method of claim 50 , wherein R2 is selected from 3,4-dichlorophenylacetamide, 2-ethylbutyramide, 4-phenylbutyramide, 1-phenyl-1-cyclopentane carboxylamide, 2,4-dichlorobenzamide, 3,5-dinnethylbenzamide, phenylacetamide, 3,4,5-trimethoxybenzamide, 2-benzoylbenzamide, and myristic amide.
53. The method of claim 50 , 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; and
R2 is selected from 3,4-dichlorophenylacetamide, 2-ethylbutyramide, 4-phenylbutyramide, 1-phenyl-1-cyclopentane carboxylamide, 2,4-dichlorobenzamide, 3,5-dinnethylbenzamide, phenylacetamide, 3,4,5-trimethoxybenzamide, 2-benzoylbenzamide, and myristic amide.