Polyamine compounds and compositions for use in conjunction with cancer therapy

Abstract

The invention provides novel polyamine compounds and pharmaceutical compositions for administration in conjunction with cancer chemotherapy or radiation therapy. The compounds are administered locally to provide protection against the adverse side-effects of chemotherapy or radiation therapy, such as alopecia, mucositis and dermatitis. Pharmaceutical preparations comprising one or more chemoprotective polyamines formulated for topical or local delivery to epithelial or mucosal cells are disclosed. Methods of administering the pharmaceutical preparations are also disclosed.

What is claimed:  
     
         1 . A compound of Formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 each Z is independently A or R 1 ;  
 each A is independently:  
                     
 J is a single bond or —CH(Y)—;  
 X is D or —R 2 -D;  
 Y is H, alkyl, or R 3 -D;  
 D is —OH, —SH, —SR 4 , or —NR 4 R 5 ;  
 each R 1  is independently C 3-8  alkylene;  
 each R 2 , R 3 , R 6 , and R 7  is independently C 1-6  alkylene;  
 R 4  is H or lower alkyl;  
 R 5  is H, lower alkyl, or —R 6 -D;  
 Q is H, lower alkyl, or —R 7 —SR 4 ;  
 k is an integer from 2 to about 16;  
 or a stereoisomer, prodrug, pharmaceutically acceptable salt, or mono or polyprotonated acid salt thereof.  
 
     
     
         2 . A compound of  claim 1 , wherein each A is independently:  
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound of  claim 1 , wherein each A is independently:  
       
         
           
           
               
               
           
         
       
     
     
         4 . A compound of  claim 2 , wherein Y is H or R 3 -D.  
     
     
         5 . A compound of  claim 4 , wherein Y is H.  
     
     
         6 . A compound of  claim 4 , wherein Y is R 3 -D.  
     
     
         7 . A compound of  claim 5 , wherein X is D.  
     
     
         8 . A compound of  claim 5 , wherein X is R 2 -D.  
     
     
         9 . A compound of  claim 6 , wherein X is D.  
     
     
         10 . A compound of  claim 6 , wherein X is R 2 -D.  
     
     
         11 . A compound of  claim 2 , wherein k is an integer from 2 to 8.  
     
     
         12 . A compound of  claim 2 , wherein k is an integer from 9 to about 16.  
     
     
         13 . A compound of  claim 2 , wherein k is an integer from 9 to 12.  
     
     
         14 . A compound of  claim 2 , wherein k is 2.  
     
     
         15 . A compound of  claim 2 , wherein k is 3.  
     
     
         16 . A compound of  claim 2 , wherein k is 4.  
     
     
         17 . A compound of  claim 2 , wherein k is 5.  
     
     
         18 . A compound of  claim 2 , wherein k is 6.  
     
     
         19 . A compound of  claim 2 , wherein k is 7.  
     
     
         20 . A compound of  claim 2 , wherein k is 8.  
     
     
         21 . A compound of  claim 2 , wherein: 
 k is the integer 2;    each R 1  is butylene;    X is D, D is —NR 4 R 5 , R 4  is H, and R 5  is ethyl; and    Q is ethyl.    
     
     
         22 . A compound of  claim 2 , wherein: 
 k is the integer 8;    each R 1  is butylene;    X is D, D is —NR 4 R 5 , R 4  is H, and R 5  is ethyl; and    Q is ethyl.    
     
     
         23 . A compound of  claim 2 , wherein: 
 k is the integer 2;    each R 1  is butylene;    X is D, and D is —SH; and    Q is ethyl.    
     
     
         24 . A compound of  claim 2 , wherein: 
 k is the integer 4;    each R 1  is butylene;    X is D, and D is —SH; and    Q is ethyl.    
     
     
         25 . A compound of  claim 2 , wherein: 
 k is the integer 6;    each R1 is butylene;    X is D, and D is —SH; and    Q is ethyl.    
     
     
         26 . A compound of  claim 2 , wherein: 
 k is the integer 8;    each R1 is butylene;    X is D, and D is —SH; and    Q is ethyl.    
     
     
         27 . A compound of  claim 2 , wherein: 
 k is the integer 4;    each R 1  is butylene;    X is D, D is —NR 4 R 5 , R 4  is H, and R 5  is methyl; and    Q is ethyl.    
     
     
         28 . A compound of  claim 4  wherein Q is H or lower alkyl.  
     
     
         29 . A compound of  claim 3 , wherein Y is H or R 3 -D.  
     
     
         30 . A compound of  claim 29 , wherein Y is H.  
     
     
         31 . A compound of  claim 29 , wherein Y is R 3 -D.  
     
     
         32 . A compound of  claim 30 , wherein X is D.  
     
     
         33 . A compound of  claim 30 , wherein X is R 2 -D.  
     
     
         34 . A compound of  claim 31 , wherein X is D.  
     
     
         35 . A compound of  claim 31 , wherein X is R 2 -D.  
     
     
         36 . A compound of  claim 3 , wherein k is an integer from 2 to 8.  
     
     
         37 . A compound of  claim 3 , wherein k is an integer from 9 to about 16.  
     
     
         38 . A compound of  claim 3 , wherein k is an integer from 9 to 12.  
     
     
         39 . A compound of  claim 3 , wherein k is 2.  
     
     
         40 . A compound of  claim 3 , wherein k is 3.  
     
     
         41 . A compound of  claim 3 , wherein k is 4.  
     
     
         42 . A compound of  claim 3 , wherein k is 5.  
     
     
         43 . A compound of  claim 3 , wherein k is 6.  
     
     
         44 . A compound of  claim 3 , wherein k is 7.  
     
     
         45 . A compound of  claim 3 , wherein k is 8.  
     
     
         46 . A compound of  claim 29  wherein Q is H or lower alkyl.  
     
     
         47 . A compound of  claim 3  wherein J is a single bond.  
     
     
         48 . A compound of  claim 3  wherein J is —CH(Y)—.  
     
     
         49 . A pharmaceutical preparation for reducing or preventing hair loss, dermatitis, mucositis or gastrointestinal distress caused by treatment with a chemotherapeutic agent or radiation therapy, which comprises at least one compound of Formula I and a topical delivery vehicle for locally delivering the compound to dermal or mucosal cells of skin, scalp, mouth, nasoesophageal, gastrointestinal or urogenital system, wherein Formula I is  
       
         
           
           
               
               
           
         
       
       wherein: 
 each Z is independently A or R 1 ;  
 each A is independently:  
                     
 J is a single bond or —CH(Y)—;  
 X is D or —R 2 -D;  
 Y is H, alkyl, or R 3 -D;  
 D is —OH, —SH, —SR 4 , or —NR 4 R 5 ;  
 each R 1  is independently C 3-8  alkylene;  
 each R 2 , R 3 , R 6 , and R 7  is independently C 1-6  alkylene;  
 R 4  is H or lower alkyl;  
 R 5  is H, lower alkyl, or —R 6 -D;  
 Q is H, lower alkyl, or —R 7 —SR 4 ;  
 k is an integer from 2 to about 16;  
 or a stereoisomer, prodrug, pharmaceutically acceptable salt, or mono or polyprotonated acid salt thereof.  
 
     
     
         50 . The pharmaceutical preparation of  claim 49 , which further comprises at least one other agent that reduces or prevents hair loss, dermatitis, mucositis or gastrointestinal distress caused by treatment with a chemotherapeutic agent or radiation therapy.  
     
     
         51 . The pharmaceutical preparation of  claim 50 , wherein the other agent is an anti-proliferative agent.  
     
     
         52 . The pharmaceutical preparation of  claim 50 , wherein the other agent is a chemoprotective inducing agent.  
     
     
         53 . The pharmaceutical preparation of  claim 50 , wherein the other agent is a free radical scavenger.  
     
     
         54 . The pharmaceutical preparation of  claim 49 , wherein the topical delivery vehicle comprises one or more of liposomes, lipid droplet emulsions, oils, aqueous emulsions of polyoxyethylene ethers, aqueous alcohol mixtures, aqueous ethanol mixtures containing propylene glycol, aqueous ethanol mixtures containing phosphatidyl choline, lysophosphatidyl choline and triglycerides, xanthan gum in aqueous buffer, hydroxypropymethylcellulose in aqueous buffer or aqueous alcohol mixtures, diethylene glycol monoethyl ether in aqueous buffer, and biodegradable microparticles.  
     
     
         55 . The pharmaceutical preparation of  claim 54 , formulated for topical delivery to skin or hair follicles, wherein the delivery vehicle comprises an aqueous alcohol mixture.  
     
     
         56 . The pharmaceutical preparation of  claim 55 , wherein the delivery vehicle further comprises propylene glycol.  
     
     
         57 . The pharmaceutical preparation of  claim 56 , formulated as a cream, lotion, ointment or gel.  
     
     
         58 . The pharmaceutical preparation of  claim 54 , formulated for topical delivery to the oral cavity or naso-esophageal passages, wherein the delivery vehicle comprises a mucoadhesive substance.  
     
     
         59 . The pharmaceutical preparation of  claim 58 , formulated as an aerosol, oral rinse, ointment or gel.  
     
     
         60 . The pharmaceutical preparation of  claim 54 , formulated for vaginal or rectal delivery, wherein the delivery vehicle comprises a mucoadhesive substance.  
     
     
         61 . The pharmaceutical preparation of  claim 60 , formulated as a cream, ointment, lotion, gel, foam or suppository.  
     
     
         62 . The pharmaceutical preparation of  claim 54 , formulated for topical delivery to the gastrointestinal tract, wherein the delivery vehicle comprises one or more of nonionic liposomes and mucoadhesive substances.  
     
     
         63 . The pharmaceutical preparation of  claim 62 , formulated as a liquid for coating the surface of the gastrointestinal tract.  
     
     
         64 . A method for reducing or preventing hair loss dermatitis, mucositis or gastrointestinal distress in a patient undergoing treatment with a chemotherapeutic agent or radiation therapy, which comprises administering to the patient a prophylactically or therapeutically effective amount of a pharmaceutical preparation comprising at least one compound of Formula I and a topical delivery vehicle for locally delivering the compound to dermal or mucosal cells of skin, scalp, mouth, nasoesophageal, gastrointestinal or urogenital system, wherein Formula I is:  
       
         
           
           
               
               
           
         
       
       wherein: 
 each Z is independently A or R 1 ;  
 each A is independently:  
                     
 J is a single bond or —CH(Y)—;  
 X is D or —R 2 -D;  
 Y is H, alkyl, or R 3 -D;  
 D is —OH, —SH, —SR 4 , or —NR 4 R 5 ;  
 each R 1  is independently C 3-8  alkylene;  
 each R 2 , R 3 , R 6 , and R 7  is independently C 1-6  alkylene;  
 R 4  is H or lower alkyl;  
 R 5  is H, lower alkyl, or —R 6 -D;  
 Q is H, lower alkyl, or —R 7 —SR 4 ;  
 k is an integer from 2 to about 16;  
 or a stereoisomer, prodrug, pharmaceutically acceptable salt, or mono or polyprotonated acid salt thereof.  
 
     
     
         65 . The method of  claim 64 , wherein the pharmaceutical preparation is administered beginning at least one day prior to chemotherapy or radiation therapy.  
     
     
         66 . The method of  claim 65 , wherein the pharmaceutical preparation is administered beginning at least five days prior to chemotherapy or radiation therapy.  
     
     
         67 . The method of  claim 64 , wherein the pharmaceutical preparation is administered after initiation of chemotherapy or radiation therapy.  
     
     
         68 . The method of  claim 64 , wherein the pharmaceutical preparation is administered throughout a course of chemotherapy or radiation therapy.  
     
     
         69 . The method of  claim 64 , wherein the pharmaceutical preparation is administered following termination of a course of chemotherapy or radiation therapy.  
     
     
         70 . The method of  claim 64 , which further comprises administering to the patient at least one other agent that reduces or prevents hair loss, dermatitis, mucositis or gastrointestinal distress caused by treatment with a chemotherapeutic agent or radiation therapy.  
     
     
         71 . The pharmaceutical preparation of  claim 70 , wherein the other agent is an anti-proliferative agent.  
     
     
         72 . The pharmaceutical preparation of  claim 70 , wherein the other agent is a chemoprotective inducing agent.  
     
     
         73 . The pharmaceutical preparation of  claim 70 , wherein the other agent is a free radical scavenger.  
     
     
         74 . A method of treating cancer that increases a patient's tolerance to high doses of a chemotherapeutic agent or radiation therapy, the method comprising: 
 a) administering the high dose of the chemotherapeutic agent or radiation therapy to the patient; and    b) administering one or more pharmaceutical preparations for reducing or preventing one or more of chemotherapy- or radiation therapy-induced hair loss, dermatitis, mucositis or gastrointestinal distress, in an amount and for a time to reduce or prevent the one or more of the chemotherapy- or radiation therapy-induced hair loss, dermatitis, mucositis or gastrointestinal distress, thereby increasing the patient's tolerance to the high dose of the chemotherapeutic agent or radiation therapy, wherein the pharmaceutical preparation comprises compound of Formula I and a topical delivery vehicle for locally delivering the compound to dermal or mucosal cells of skin, scalp, mouth, nasoesophageal, gastrointestinal or urogenital system, wherein Formula I is:                          wherein:    each Z is independently A or R 1 ;    each A is independently:                          J is a single bond or —CH(Y)—;    X is D or —R 2 -D;    Y is H, alkyl, or R 3 -D;    D is —OH, —SH, —SR 4 , or —NR 4 R 5 ;    each R 1  is independently C 3-8  alkylene;    each R 2 , R 3 , R 6 , and R 7  is independently C 1-6  alkylene;    R 4  is H or lower alkyl;    R is H, lower alkyl, or —R 6 -D;    Q is H, lower alkyl, or —R 7 —SR 4 ;    k is an integer from 2 to about 16;    or a stereoisomer, prodrug, pharmaceutically acceptable salt, or mono or polyprotonated acid salt thereof.