Compositions and methods for reparation and prevention of fibrotic lesions

• US 5,716,632 A
• Filed: 05/09/1996
• Issued: 02/10/1998
• Est. Priority Date: 11/22/1989
• Status: Expired due to Term

• Current Assignee: Solomon B. Margolin
• Original Assignee: Solomon B. Margolin
• Inventors: Margolin, Solomon B.
• Primary Examiner(s): Spear, James M.
• Application Number:
  US08/647,006
• Time in Patent Office: 642 Days
• Field of Search: 424/423, 424/427, 424/434, 424/435, 424/436, 424/451, 424/464, 424/489, 514/838, 514/866, 514/879, 514/913, 514/824
• US Class Current: 424/423
• CPC Class Codes: A61K 31/4412 having oxo groups directly attached to the heterocyclic ring
• CPC Class Codes: A61K 31/4436 containing a heterocyclic ring having sulfur as a ring hetero atom
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/4725 containing further heterocyclic rings
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics

Abstract

In a preferred embodiment, drugs having pharmacological properties which are useful in the medicinal therapy of fibrotic disease for the reparation and prevention of fibrotic lesional tissues, such drugs including as active ingredient(s) one or more N-substituted 2-(1H) pyridone(s) and/or N-substituted 3-(1H) pyridones. The composition of this invention is novel as an anti-fibrotic drug, namely, as an agent for treating fibrosis. Any existing compounds have not been shown to be effective for the reparation and prevention of fibrotic lesions.

Claims

1. A method for the reparation of, and prophylaxis against, fibrotic lesional tissue in a mammal, comprising administering internally to said mammal a pharmaceutical composition having one or more compounds selected from the group consisting of N-substituted 2-(1H) pyridones and N-substituted 3-(1H) pyridones as active anti-fibrotic ingredient(s), said composition being administered to said mammal at a rate of from about 5 mg per kilogram of body weight per day to about 300 mg per kilogram of body weight per day, said group excluding 5-methyl-1-phenyl-2-(1H) pyridone, wherein the general structural formula of said N-substituted 2(1) pyridones is:

##STR3## where;

R1 is selected from the group consisting of (1) an alkyl group, with R3 hydrogen, and (2) hydrogen, with R3 consisting of an alkyl group;

A is an aryl group; and

R2 and R4 are hydrogen;

and wherein the general structural formula of said N-substituted 3(1H) pyridones is;

##STR4## where;

R2 is selected;

from the group consisting of (1) an alkyl group, with R3 hydrogen, and (2) hydrogen, with R3 consisting of an alkyl group;

A is an aryl group; and

R1 and R4 are hydrogen.

4. A method, as defined in claim 1, wherein said pharmaceutical substance includes one or more compounds selected from the group consisting of:

5-Methyl-1-(3-nitrophenyl)-2-(1H) pyridone, 5-Methyl-1-(4'"'"'-methoxyphenyl)-2-(1H) pyridone, 5-Methyl-1-p-tolyl-2-(1H) pyridone, 5-Methyl-1-(3'"'"'-trifluoromethylphenyl)-2-(1H)-pyridone, 1-(4'"'"'Chlorophenyl)-5-Methyl-2-(1H) pyridone, 5-Methyl-1-(2'"'"'-naphthyl)-2-(1H) pyridone, 5-Methyl-1-(1'"'"'naphthyl)-2-(1H) pyridone, 3-Methyl-1-phenyl-2-(1H) pyridone, 3-Ethyl-1-phenyl-2-(1H) pyridone, 6-Methyl-1-phenyl-2-(1H) pyridone, 3,6-Dimethyl-1-phenyl-2-(1H) pyridone, 5-Methyl-1-(2'"'"'-Thienyl)-2-(1H) pyridone, 1-(2'"'"'-Furyl)-5-Methyl-2-(1H) pyridone, 5-Methyl-1-(5'"'"'-quinolyl)-2-(1H) pyridone, 5-Methyl-1-(4'"'"'-pyridyl)-2-(1H) pyridone, 5-Methyl-1-(3'"'"'-pyridyl)-2-(1H) pyridone, 5-Methyl-1-(2'"'"'-pyridyl)-2-(1H) pyridone, 5-Methyl-1-(2'"'"'-quinolyl)-2-(1H) pyridone, 5-Methyl-1-(4'"'"'-quinolyl)-2-(1H) pyridone, 5-Methyl-1-(2'"'"'-thiazolyl)-2-(1H) pyridone, 1-(2'"'"'-Imidazolyl)-5-Methyl-2-(1H) pyridone, 5-Ethyl-1-phenyl-2-(1H) pyridone, 1-Phenyl-2-(1H) pyridone, 1-(4'"'"'-Nitrophenyl)-2-(1H) pyridone, 1,3-Diphenyl-2-(1H) pyridone, 1-Phenyl-3-(4'"'"'-chlorophenyl)-2-(1H) pyridone, 1,3-Diphenyl-5-methyl-2-(1H) pyridone, 3-(4'"'"'-Chlorophenyl)-5-Methyl-1-phenyl-2-(1H) pyridone, 5-Methyl-3-phenyl-1-(2'"'"'-thienyl)-2-(1H) pyridone, 5-Methyl-1-phenyl-3-(1H) pyridone, 5-Methyl-1-(4'"'"'-methoxyphenyl)-3-(1H) pyridone, 5-Methyl-1-p-tolyl-3-(1H) pyridone, 1-(4'"'"'-Chlorophenyl)-5-methyl-3-(1H) pyridone, 5-Methyl-1-(2'"'"'-naphthyl)-3-(1H) pyridone, 4-Methyl-1-phenyl-3-(1H) pyridone, 6-Methyl-1-phenyl-3-(1H) pyridone, 5-Methyl-1-(2'"'"'-Thienyl)-3-(1H) pyridone, 1-(2'"'"'-Furyl)-5-methyl-3-(1H) pyridone, 5-Methyl-1-(5'"'"'-quinolyl)-3-(1H) pyridone, 5-Methyl-1-(3'"'"'-pyridyl)-3-(1H) pyridone, 5-Methyl-1-(2'"'"'-pyridyl)-3-(1H) pyridone, 5-Methyl-1-(2'"'"'-quinolyl)-3-(1H) pyridone, 5-Ethyl-1-phenyl-3-(1H) pyridone, and 1-Phenyl-3-(1H) pyridone.

5. A method, as defined in claim 1, further comprising administering said pyridone(s) in an amount of from about 25 mg to about 9600 mg per day.

6. A method, as defined in claim 1, further comprising administering said pyridone(s) in an amount of from about 75 mg to about 9600 mg per day.

7. A method, as defined in claim 1, further comprising administering said pyridone(s) in an amount of from about 25 mg to about 3200 mg contained in a capsule.

8. A method, as defined in claim 1, wherein said fibrotic lesional tissue is associated with a condition in the group consisting of pulmonary fibrosis, benign prostate hypertrophy, coronary infarcts, cerebral infarcts, myocardiac fibrosis, musculoskeletal fibrosis, post-surgical adhesions, liver cirrhosis, renal fibrotic disease, fibrotic vascular disease, scleroderma, Alzheimer'"'"'s disease, diabetic retinopathy, and skin lesions.

9. A method, as defined in claim 1, wherein said pharmaceutical composition is administered by means selected from the group consisting of capsules, tablets, powders, granules, syrups, injectable fluids, creams, ointments, inhalable fluids, eye drops, suppositories, and pills.

10. A method, as defined in claim 1, wherein said mammal is a human.

2. A method, for the reparation of, and prophylaxis against, fibrotic lesional tissue in a mammal, comprising administering topically to said mammal a pharmaceutical composition containing one or more compounds selected from the group consisting of N-substituted 2-(1H) pyridones and N-substituted 3-(1H) pyridones as active anti-fibrotic ingredient(s) in an amount of from about 1% to about 20%, said group excluding 5-methyl-1-phenyl-2-(1H) pyridone, wherein the general structural formula of said N-substituted 2(1) pyridones is:

##STR5## where;

R1 is selected from the group consisting of (1) an alkyl group, with R3 hydrogen, and (2) hydrogen, with R3 consisting of an alkyl group;

A is an aryl group; and

R2 and R4 are hydrogen;

and wherein the general structural formula of said N-substituted 3(1H) pyridones is;

##STR6## where;

R2 is selected;

from the group consisting of (1) an alkyl group, with R3 hydrogen, and (2) hydrogen, with R3 consisting of an alkyl group;

A is an aryl group; and

R1 and R4 are hydrogen.

3. A method, as defined in claim 2, wherein said pharmaceutical substance includes one or more compounds selected from the group consisting of:

5-Methyl-1-(3nitrophenyl)-2-(1H) pyridone, 5-Methyl-1-(4'"'"'-methoxyphenyl)-2-(1H) pyridone, 5-Methyl-1-p-tolyl-2-(1H) pyridone, 5-Methyl-1-(3'"'"'-trifluoromethylphenyl)-2-(1H)-pyridone, 1-(4'"'"'Chlorophenyl)-5-Methyl-2-(1H) pyridone, 5-Methyl-1-(2'"'"'-naphthyl)-2-(1H) pyridone, 5-Methyl-1-(1'"'"'naphthyl)-2-(1H) pyridone, 3-Methyl-1-phenyl-2-(1H) pyridone, 3-Ethyl-1-phenyl-2-(1H) pyridone, 6-Methyl-1-phenyl-2-(1H) pyridone, 3,6-Dimethyl-1-phenyl-2-(1H) pyridone, 5-Methyl-1-(2'"'"'-Thienyl)-2-(1H) pyridone, 1-(2'"'"'-Furyl)-5-Methyl-2-(1H) pyridone, 5-Methyl-1-(5'"'"'-quinolyl)-2-(1H) pyridone, 5-Methyl-1-(4'"'"'-pyridyl)-2-(1H) pyridone, 5-Methyl-1-(3'"'"'-pyridyl)-2-(1H) pyridone, 5-Methyl-1-(2'"'"'-pyridyl)-2-(1H) pyridone, 5-Methyl-1-(2'"'"'-quinolyl)-2-(1H) pyridone, 5-Methyl-1-(4'"'"'-quinolyl)-2-(1H) pyridone, 5-Methyl-1-(2'"'"'-thiazolyl)-2-(1H) pyridone, 1-(2'"'"'-Imidazolyl)-5-Methyl-2-(1H) pyridone, 5-Ethyl-1-phenyl-2-(1H) pyridone, 1-Phenyl-2-(1H) pyridone, 1-(4'"'"'-Nitrophenyl)-2-(1H) pyridone, 1,3-Diphenyl-2-(1H) pyridone, 1-Phenyl-3-(4'"'"'-chlorophenyl)-2-(1H) pyridone, 1,3-Diphenyl-5-methyl-2-(1H) pyridone, 3-(4'"'"'-Chlorophenyl)-5-Methyl-1-phenyl-2-(1H) pyridone, 5-Methyl-3-phenyl-1-(2'"'"'-thienyl)-2-(1H) pyridone, 5-Methyl-1-phenyl-3-(1H) pyridone, 5-Methyl-1-(4'"'"'-methoxyphenyl)-3-(1H) pyridone, 5-Methyl-1-p-tolyl-3-(1H) pyridone, 1-(4'"'"'-Chlorophenyl)-5-methyl-3-(1H) pyridone, 5-Methyl-1-(2'"'"'-naphthyl)-3-(1H) pyridone, 4-Methyl-1-phenyl-3-(1H) pyridone, 6-Methyl-1-phenyl-3-(1H) pyridone, 5-Methyl-1-(2'"'"'-Thienyl)-3-(1H) pyridone, 1-(2'"'"'-Furyl)-5-methyl-3-(1H) pyridone, 5-Methyl-1-(5'"'"'-quinolyl)-3-(1H) pyridone, 5-Methyl-1-(3'"'"'-pyridyl)-3-(1H) pyridone, 5-Methyl-1-(2'"'"'-pyridyl)-3-(1H) pyridone, 5-Methyl-1-(2'"'"'-quinolyl)-3-(1H) pyridone, 5-Ethyl-1-phenyl-3-(1H) pyridone, and 1-Phenyl-3-(1H) pyridone.

11. A method, as defined in claim 2, wherein said fibrotic lesional tissue is associated with a condition in the group consisting of musculoskeletal fibrosis, post-surgical adhesions, scleroderma, glaucoma, and skin lesions.

12. A method, as defined in claim 2, wherein said pharmaceutical composition is administered by means selected from the group consisting of creams, ointments, hydrophillic ointments, inhalable fluids, eye drops, and suppositories.