Lactone compounds for treating patients with precancerous lesions

• US 5,696,159 A
• Filed: 08/03/1994
• Issued: 12/09/1997
• Est. Priority Date: 08/03/1994
• Status: Expired due to Fees

• Current Assignee: University of Arizona
• Original Assignee: Cell Pathways, Inc. (Astellas Pharma Incorporated)
• Inventors: Gross, Paul, Sperl, Gerhard, Pamukcu, Rifat, Brendel, Klaus
• Primary Examiner(s): OWENS, AMELIA A
• Application Number:
  US08/265,396
• Time in Patent Office: 1,224 Days
• Field of Search: 549/299, 514/468
• US Class Current: 514/468
• CPC Class Codes: A61K 31/365 Lactones
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/4192 1,2,3-Triazoles
• CPC Class Codes: A61K 31/655 Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07D 307/93 condensed with a ring other than six-membered
• CPC Class Codes: C07D 491/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/10 Spiro-condensed systems
• CPC Class Codes: C07K 5/0215 containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu

Abstract

Substituted lactone compounds are useful in the treatment of precancerous lesions.

Claims

1. A compound comprising:

##STR3## R₁ and R₂ are independently selected from the group consisting of hydrogen, amino, lower alkyl, lower alkoxy, azide, hydroxy, halogen, acetoxyl, benzoxy, or substituted phenyl where the substituents are selected from the group consisting of halogen, lower alkyl, or lower alkoxy;

or R₁ and R₂ form a carbonyl or imine;

or

R₂ and R₃ together form a double bond, aziridin, epoxide or triazole;

or a dioxolane,

R₃ is selected from the group consisting of hydrogen, halogen, azide, lower alkyl, lower alkoxy, cyano, hydroxy, di(lower)alkyl amino(lower)alkylthio, loweralkylthio, phenylthio, or lower(dialkyl)amino.

R₄ is selected from the group consisting of hydrogen, hydroxy, halogen, lower alkoxy or lower alkyl, or lower dialkyl amino,

R₅ is selected from the group consisting of hydrogen, hydroxy, halogen, lower alkoxy, lower alkyl, amino, or lower dialkyl amino,

R₆ is selected from the group consisting of hydrogen, lower alkyl, hydroxy, lower alkoxy, halogen or R₆ and R₈ together from a double bond,

R₇ is selected from the group consisting of hydrogen, lower alkyl, phenyl, halo(lower)alkyl, hydroxy(lower)alkyl, acetoxy(lower)alkyl, benzyloxy(lower)alkyl, or (lower)alkyl(lower)alkoxy, or di(lower)alkylamino(lower)alkyl,

R₈ and R₉ are independently selected from the group consisting of hydrogen, lower alkyl, hydroxy, lower alkoxy, or halogen;

R₁₀ and R₁₁ are independently selected from the group consisting of hydrogen, halogen, lower alkoxy, or lower alkyl,

R₁₂ is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, loweralkylthio, loweralkylsulfinyl, lower alkyl sulfonyl, or amidosulfonyl.

2. The compound of claim 1 wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, amino, lower alkyl, lower alkoxy, azide, hydroxy, or halogen, or R₁ and R₂ form a carbonyl;

or R₂ and R₃ form a double bond, aziridin, epoxide, triazole or dioxolane;

R₄ and R₅ are selected from the group consisting of hydrogen, halogen or lower alkoxy;

R₆ is hydrogen or together with R₈ forms a double bond;

R₇ is selected from the group consisting of hydrogen, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, acetoxy(lower)alkyl, benzyloxy(lower)alkyl, or (lower)alkyl(lower)alkoxy, and

R₈ -R₁₁ are hydrogen.

3. The compound of claim 2 wherein R₄ and R₅ are independently selected from the group consisting of hydrogen and halogen.

4. The compound of claim 3 wherein R₁₂ is lower alkyl sulfonyl.

5. The compound of claim 3 wherein R₄ is halogen and R₅ is hydrogen.

6. The compound of claim 5 wherein R₉ is hydrogen.

7. The compound of claim 6 wherein R₇ is lower alkyl.

8. rac-(E)-1-(Buten-1'"'"',4'"'"'-olido)- 3'"'"',4'"'"':

1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan.

9. A method of treating a patient having precancerous lesions in need of treatment, comprising administering to the patient a physiologically effective amount of a compound of the formula:

##STR4## R₁ and R₂ are independently selected from the group consisting of hydrogen, amino, lower alkyl, lower alkoxy, azide, hydroxy, halogen, acetoxyl, benzoxy, or phenyl or substiaited phenyl where the substituents are selected from the group consisting of halogen, lower alkyl, or lower alkoxy;

or R₁ and R₂ form a carbonyl or imine;

or

R₂ and R₃ together form a double bond, aziridin, epoxide or triazole;

or a dioxolane,

R₃ is selected from the group consisting of hydrogen, halogen, azide, lower alkyl, lower alkoxy, cyano, hydroxy, di(lower)alkyl amino(lower)alkylthio, loweralkylthio, phenylthio, or lower(dialkyl)amino,

R₄ is selected from the group consisting of hydrogen, hydroxy, halogen, lower alkoxy or lower alkyl, or lower dialkyl amino,

R₅ is selected from the group consisting of hydrogen, hydroxy, halogen, lower alkoxy, lower alkyl, amino, or lower dialkyl amino,

R₆ is selected from the group consisting of hydrogen, lower alkyi, hydroxy, lower alkoxy, halogen or R₆ and R₈ together from a double bond,

R₇ is selected from the group consisting of hydrogen, lower alkyl, phenyl, halo(lower)alkyl, hydroxy(lower)alkyl, acetoxy(lower)alkyl, benzyloxy(lower)alkyl, or (lower)alkyl(lower)alkoxy, or di(lower)alkylamino(lower)alkyl,

R₈ and R₉ are independently selected from the group consisting of hydrogen, lower alkyl, hydroxy, lower alkoxy, or halogen;

R₁₀ and R₁₁ are independently selected from the group consisting of hydrogen, halogen, lower alkoxy, or lower alkyl,

R₁₂ is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, loweralkylthio, loweralkylsulfinyl, lower alkyl sulfonyl, or amidosulfonyl.

10. The method of claim 9 wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, amino, lower alkyl, lower alkoxy, azide, hydroxy, or halogen, or R₁ and R₂ form a carbonyl;

or R₂ and R₃ form a double bond, aziridin, epoxide, triazole or dioxolane;

R₄ and R₅ are selected from the group consisting of hydrogen, halogen or lower alkoxy;

R₆ is hydrogen or together with R₈ forms a double bond;

R₇ is selected from the group consisting of hydrogen, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, acetoxy(lower)alkyl, benzyloxy(lower)alkyl, or (lower)alkyl(lower)alkoxy, and

R₈ -R₁₁ are hydrogen.

11. The method of claim 9 wherein R₄ and R₅ are independently selected from the group consisting of hydrogen and halogen.

12. The method of claim 10 wherein R₁₂ is lower alkyl sulfonyl.

13. The method of claim 11 wherein R₄ is halogen and R₅ is hydrogen.

14. The method of claim 12 wherein R₉ is hydrogen.

15. The method of claim 13 wherein R₇ is lower alkyl.

16. The method of claim 9 wherein said compound is rac-threo-(E)-1-bromo-1-(butan-1'"'"',4'"'"'-olido) - 3'"'"',4'"'"':

1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan.

17. The method of claim 9 wherein said compound is rac-(E)-1-(buten-1'"'"',4'"'"'-olido)- 3'"'"',4'"'"':

1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan.

18. rac-(E)-1-bromo-1-(buten-1'"'"',4'"'"'-olido)- 3'"'"',4'"'"':

1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan.