Porphyrin Compounds and Compositions Useful for Treating Cancer

Abstract

A porphyrin compound of Formula III and composition made therefrom comprising a therapeutically effective dose of a porphyrin bound via a linker to an anti-cancer agent useful in treating cancer in a patient in need thereof or to treat cancer cells in-vitro. The compounds and compositions may be delivered by a drug delivery device as disclosed here and be part of a kit.

1 - 47 . (canceled) 
     
     
         48 . A composition comprising:
 a compound of Formula III   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         an A 1 , A2, A3 and A4 are each covalently attached to a porphyrin ring of Formula III and A 1 , A2, A3, and A4 are independently selected from a substituted aromatic ring or a six membered heteroaromatic ring containing a single nitrogen atom at the 2, 3 or 4 position relative to the porphyrin ring; 
         B 1  is a covalent linker moiety which connects A 1  to a cytotoxic agent Z 1  and is selected from 
       
       
         
           
           
               
               
           
         
         wherein n is selected from 1-12; and 
         the Z 1  is a cytotoxic agent selected from 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         49 . The composition of  claim 48  or the pharmaceutically acceptable salt thereof, further including a pharmaceutical acceptable carrier. 
     
     
         50 . The composition of  claim 49  or the pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable carrier is a liquid carrier selected from saline, glucose, alcohols, glycols, esters, amides, and any combination thereof. 
     
     
         51 . The composition of  claim 48  or the pharmaceutically acceptable salt thereof, wherein the compound is in a dosage form and the dosage form is parenteral and the dosage form is selected from intradermal dosage form, a subcutaneous dosage form, an intramuscular dosage form, a subcutaneous dosage form, an intravenous dosage form, an intrathecal dosage form, and an epidural dosage form. 
     
     
         52 . The composition of  claim 48  or the pharmaceutically acceptable salt thereof, wherein the compound is in a dosage form and the dosage form is nonparenteral and the dosage form is selected from oral dosage form, sublingual dosage form, topical dosage form, transdermal dosage form, ophthalmic dosage form, otic dosage form, nasal dosage form, rectal dosage form, and vaginal dosage form. 
     
     
         53 . The composition of  claim 48  or the pharmaceutically acceptable salt thereof, wherein the substituted aromatic ring of the A 1  comprises a carboxylic amide functional group at either an ortho, meta, or para position with respect to the porphyrin ring and wherein A2, A3 and A4 are each a substituted aromatic ring wherein each A2, A3, and A4 substituted aromatic ring has a substituent at either a ortho, meta or para position with respect to the porphyrin ring and the substituent is either a carboxylic acid or carboxylic methyl ester. 
     
     
         54 . The composition of  claim 48  or the pharmaceutically acceptable salt thereof, wherein the substituted aromatic ring of the A2, A3, and A4 comprises a carboxylic methyl ester in a para position with respect to the porphyrin ring and the carboxylic amide of A1 is in the para position with respect to the porphyrin ring. 
     
     
         55 . The composition of  claim 48  or the pharmaceutically acceptable salt thereof, wherein B 1  is L11 or L13. 
     
     
         56 . The composition of  claim 48  or the pharmaceutically acceptable salt thereof, wherein Z 1  is selected from T1b, 1 and T4c. 
     
     
         57 . The composition of  claim 48  or the pharmaceutically acceptable salt thereof, wherein the substituted aromatic ring of A 1  comprises an aromatic ether functional group at either an ortho, meta or para position with respect to the porphyrin ring, and wherein A2, A3 and A4 are each the substituted aromatic ring wherein each A2, A3, and A4 substituted aromatic ring has a substituent located at an ortho, meta or para position with respect to the porphyrin ring wherein the substituent on each A2, A3, and A4 substituted aromatic ring is independently selected from lower alkyl, branched lower alkyl, cycloalkyl, halogens (F, Cl, Br, I), cyano, amino or substituted amino, sulfonic acid or sulfonamide, aromatic ether, aromatic hydroxyl, carboxylic acid alkyl esters or carboxylic acid amide. 
     
     
         58 . The composition of  claim 48  or the pharmaceutically acceptable salt thereof, wherein B 1  is selected from L9, L10, L15, and L16. 
     
     
         59 . The composition of  claim 58  or the pharmaceutically acceptable salt thereof, wherein a substituent of the substituted aromatic ring at position A2, A3 and A4 is a hydroxyl and may occupy the ortho, meta or para position with respect to the porphyrin ring and B 1  is L9 or L15. 
     
     
         60 . The composition of  claim 48  or the pharmaceutically acceptable salt thereof, wherein the substituted aromatic ring A 1  comprises an aromatic ether functional group, where the position of the aromatic ether is meta with respect to the porphyrin ring, and wherein A2, A3 and A4 are each the substituted aromatic ring wherein the substituent on the substituted aromatic ring is an aromatic hydroxyl in the meta position with respect to the porphyrin ring, B 1  is L9 or L15 and Z 1  is selected from T1b, 1 and T4c. 
     
     
         61 . The composition of  claim 48  or the pharmaceutically acceptable salt thereof, wherein the six membered heteroaromatic ring of A 1  comprises a nitrogen atom where a position of the nitrogen atom on the six membered heteroaromatic ring may occupy one of a 2, 3 or 4 position with respect to the porphyrin ring, A2, A3 and A4 are each a pyridine ring where the position of a pyridine nitrogen on each pyridine ring of A2, A3 and A4 may independently occupy one of the 2, 3 or 4 position with respect to the porphyrin ring. 
     
     
         62 . The composition of  claim 61  or the pharmaceutically acceptable salt thereof, wherein, B 1  is selected from L9, L10, L15, and L16. 
     
     
         63 . The composition of  claim 61  or the pharmaceutically acceptable salt thereof, wherein the six membered heteroaromatic ring comprising the nitrogen atom at A 1  is a pyridinium where the position of the nitrogen is in the 4 position with respect to the porphyrin ring, B 1  is L9 or L15, and Z 1  is selected from T1b, 1 or T4c. 
     
     
         64 . The composition of  claim 63  or the pharmaceutically acceptable salt thereof, wherein the B 1  is L9. 
     
     
         65 . The composition of  claim 53  or the pharmaceutically acceptable salt thereof, wherein the compound is selected from 
       
         
           
           
               
               
           
         
       
     
     
         66 . The composition of  claim 57  or the pharmaceutically acceptable salt thereof, wherein the compound is selected from OS0023 and OS0024. 
     
     
         67 . The composition of  claim 61  or the pharmaceutically acceptable salt thereof, wherein the compound is selected from 
       
         
           
           
               
               
           
         
       
     
     
         68 . The composition of  claim 48  or the pharmaceutically acceptable salt thereof, for use in the treatment of cancer. 
     
     
         69 . The composition of  claim 48  or the pharmaceutically acceptable salt thereof, for use in the treatment of cancer cells in vitro. 
     
     
         70 . The composition of  claim 48  further comprising a cytotoxic agent wherein the cytotoxic agent is a formula that is the same or different than Z 1  of the compound of claim  1 . 
     
     
         71 . The composition of  claim 63  wherein the different formula of the cytotoxic agent is selected from a class that is different as compared to Z 1  of the compound of claim  1 . 
     
     
         72 . A drug delivery device comprising the compound of Formula III of  claim 48  enmeshed with a biodegradable polymer. 
     
     
         73 . The drug delivery device of  claim 72  wherein the biodegradable polymer is selected from poly lactic co-glycolic acid, alginate, and polycaprolactone. 
     
     
         74 . The drug delivery device of  claim 72  wherein the compound is released over time when the drug delivery device is implanted into a patient. 
     
     
         75 . A kit comprising a compound of Formula III of  claim 48  or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. 
     
     
         76 . A method of treating cancer in a patient in need thereof comprising the steps of:
 administering to a patient in need thereof a therapeutically effective amount of a compound of Formula III of  claim 48  or a pharmaceutically acceptable salt thereof.   
     
     
         77 . The method of  claim 76  wherein the pharmaceutically acceptable carrier is a liquid carrier selected from saline, glucose, alcohols, glycols, esters, amides, and any combination thereof. 
     
     
         78 . The method of  claim 76  wherein the compound is in a dosage form and the dosage form is parenteral and the dosage form is selected from intradermal dosage form, a subcutaneous dosage form, an intramuscular dosage form, a subcutaneous dosage form, an intravenous dosage form, an intrathecal dosage form, and an epidural dosage form. 
     
     
         79 . The method of  claim 76  wherein the compound is in a dosage form and the dosage form is nonparenteral and the dosage form is selected from oral dosage form, sublingual dosage form, topical dosage form, transdermal dosage form, ophthalmic dosage form, otic dosage form, nasal dosage form, rectal dosage form, and vaginal dosage form. 
     
     
         80 . The method of  claim 76  wherein the substituted aromatic ring of the A 1  of the compound comprises a carboxylic amide functional group at either an ortho, meta, or para position with respect to the porphyrin ring and wherein A2, A3 and A4 are each a substituted aromatic ring wherein each A2, A3, and A4 substituted aromatic ring has a substituent at either a ortho, meta or para position with respect to the porphyrin ring and the substituent is either a carboxylic acid or carboxylic methyl ester. 
     
     
         81 . The method of  claim 80  wherein the substituted aromatic ring of the A2, A3, and A4 of the compound comprises a carboxylic methyl ester in a para position with respect to the porphyrin ring and the carboxylic amide of A 1  is in the para position with respect to the porphyrin ring. 
     
     
         82 . The method of  claim 76  wherein the B 1  of the compound is L11 or L13. 
     
     
         83 . The method of  claim 76  wherein Z 1  of the compound is selected from T1b, 1 or T4c. 
     
     
         84 . The method of  claim 76  wherein A2, A3 and A4 of the compound represent substituted aromatic rings wherein the substituent is a sulfonic acid or sulfonamide and may occupy the ortho, meta or para position with respect to the porphyrin ring. 
     
     
         85 . The method of  claim 76  wherein the substituted aromatic ring of A 1  of the compound comprises an aromatic ether functional group at either an ortho, meta or para position with respect to the porphyrin ring, and wherein A2, A3 and A4 of the compound are each the substituted aromatic ring wherein each A2, A3, and A4 substituted aromatic ring has a substituent located at an ortho, meta or para position with respect to the porphyrin ring wherein the substituent on each A2, A3, and A4 substituted aromatic ring is independently selected from lower alkyl, branched lower alkyl, cycloalkyl, halogens (F, Cl, Br, I), cyano, hydroxyl, amino or substituted amino, sulfonic acid or sulfonamide, aromatic ether, aromatic hydroxyl, carboxylic acid alkyl esters or carboxylic acid amide. 
     
     
         86 . The method of  claim 76  wherein B 1  of the compound may be independently selected from L9, L10, L15, L16. 
     
     
         87 . The method of  claim 79  wherein the substituent of the substituted aromatic ring at position A2, A3 and A4 of the compound is a hydroxyl and may occupy either the ortho, meta or para position with respect to the porphyrin ring and B 1  is L9 or L15. 
     
     
         88 . The method of  claim 76  wherein the substituted aromatic ring A 1  of the compound comprises an aromatic ether functional group, where the position of the aromatic ether is meta with respect to the porphyrin ring, and wherein A2, A3 and A4 are each the substituted aromatic ring wherein the substituent on the substituted aromatic ring is an aromatic hydroxyl in the meta position with respect to the porphyrin ring, B 1  is L9 or L15 and Z 1  is selected from T1b, 1 and T4c. 
     
     
         89 . The method of  claim 76  wherein the six membered heteroaromatic ring of A 1  of the compound comprises a nitrogen atom where a position of the nitrogen atom on the six membered heteroaromatic ring may occupy one of a 2, 3 or 4 position with respect to the porphyrin ring, A2, A3 and A4 of the compound are each a pyridine ring where the position of a pyridine nitrogen on each pyridine ring of A2, A3 and A4 may independently occupy one of the 2, 3 or 4 position with respect to the porphyrin ring. 
     
     
         90 . The method of  claim 82  wherein the six membered heteroaromatic ring comprising the nitrogen atom at A 1  is a pyridinium where the position of the nitrogen is in the 4 position with respect to the porphyrin ring, B 1  is L9 or L15, and Z 1  is selected from T1b, 1 or T4c. 
     
     
         91 . The method of  claim 80  wherein the compound is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         92 . The method of  claim 85  wherein the compound is selected from OS0023 and OS0024. 
     
     
         93 . The method of  claim 82  wherein the compound is selected from