Analogs of L-Glu-L-Trp having pharmacological activity

Abstract

This invention provides analogs of L-Glu-L-Trp and methods of using them for immunomodulation and treatment of pathological neovascular conditions. The analogs include the substitution of a carbon atom for a nitrogen atom in the indole ring of tryptophan.

What is claimed is:  
     
         1 . An analog compound of L-Glu-L-Trp of the structure: 
 (a) a compound of formula 2;    (b) a cyclic form of the compound of formula 2;    (c) a linear or cyclic polymer of the compound of formula 2, the polymer being no more than a 20-mer;    (d) an analog of any of the foregoing wherein the Glu moiety is replaced by an Ile moiety or a Leu moiety; and    (e) a derivative of any of the foregoing compounds which hydrolyses in aqueous solution into any of the foregoing compounds.    
     
     
         2 . The compound of  claim 1  having the structure of part (a), or a pharmaceutically acceptable salt thereof.  
     
     
         3 . The compound of  claim 2  wherein X and Y are both H.  
     
     
         4 . A pharmaceutical composition comprising an amount of a compound of  claim 1  effective for immunomodulation and a pharmaceutically acceptable career.  
     
     
         5 . The pharmaceutical composition of  claim 4  comprising 0.001% to 0.01% by weight of the compound.  
     
     
         6 . The pharmaceutical composition of  claim 4  in the form of an injectable solution, a tablet, a suppository or a capsule.  
     
     
         7 . The pharmaceutical composition of  claim 4  in the form of an eye film, an inhalant, a mucosal spray, a toothpaste, an ointment or a water soluble based cream.  
     
     
         8 . The pharmaceutical composition of  claim 4  in unit dosage form comprising about 10 μg to about 100 μg of the compound.  
     
     
         9 . A method for treating an immunodeficient, immunodepressed or hyperactive immune state in an animal subject comprising administering to the subject a pharmacologically effective amount of a compound of  claim 1 .  
     
     
         10 . The method of  claim 9  wherein the subject is a human.  
     
     
         11 . The method of  claim 10  wherein the compound has the structure of  claim 1 , part (a), or a pharmaceutically acceptable salt thereof.  
     
     
         12 . The method of  claim 11  wherein X and Y are both H.  
     
     
         13 . The method of  claim 9  wherein the subject suffers from an immunodeficient or immunodepressed state.  
     
     
         14 . The method of  claim 9  wherein the subject suffers from eczema, psoriasis, allergy or bronchial asthma.  
     
     
         15 . The method of  claim 13  wherein the subject has been subject to thymectomy.  
     
     
         16 . The method of  claim 13  wherein the subject has an immunodepressed state resulting from exposure to radiation.  
     
     
         17 . The method of  claim 13  wherein the subject has an immunodepressed state resulting from exposure to radiation in the treatment of cancer.  
     
     
         18 . A method for the treatment of an infectious disease in an animal subject comprising administering to the subject a pharmacologically effective amount of a compound of  claim 1 .  
     
     
         19 . The method of  claim 18  wherein the subject is a human.  
     
     
         20 . The method of  claim 19  wherein the compound has the structure of  claim 1 , part (a), or a pharmaceutically acceptable salt thereof.  
     
     
         21 . The method of  claim 20  wherein X and Y are both H.  
     
     
         22 . The method of  claim 19  wherein the disease results from viral infection, bacterial infection or parasitic infection.  
     
     
         23 . The method of  claim 19  wherein the disease results from infralymphatic infection, a gynecological infection or a skin infection.  
     
     
         24 . The method of  claim 19  wherein the disease is lymphangitis, an acute respiratory disease, sinusitis or parsinusitus, Otitis media, conjunctivitis, uveitis, keratitis, dental caries, gingival disease, is periapical granuloma.  
     
     
         25 . The method of  claim 22  wherein the infection is a viral disease selected from herpes infection, herpes Type I or Type II infection, Herpes Zoster infection, influenza virus infection Type A or Type B, Hepatitis A or Hepatitis B infection or hemorrhagic dengue fever.  
     
     
         26 . The method of  claim 22  wherein the disease is Hansen's disease, typhus of the para A or B category, tuberculosis of the lung, yersenia, pseudo-tuberculosis or Shigella dysentery.  
     
     
         27 . The method of  claim 22  wherein the disease is malaria.  
     
     
         28 . A method for the therapeutic treatment of tissue damage in an animal subject comprising administering to the subject a pharmacologically effective amount of a compound of  claim 1 .  
     
     
         29 . The method of  claim 28  wherein the subject is a human.  
     
     
         30 . The method of  claim 29  wherein the compound has the structure of  claim 1 , part (a), or a pharmaceutically acceptable salt thereof.  
     
     
         31 . The method of  claim 30  wherein X and Y are both H.  
     
     
         32 . The method of  claim 30  wherein the tissue damage results from a burn or frost bite.  
     
     
         33 . The method of  claim 30  wherein the tissue is corneal tissue.  
     
     
         34 . A method for treating toxemia or anemia in an animal subject during pregnancy comprising administering to the subject a pharmacologically effective amount of a compound of  claim 1 .  
     
     
         35 . The method of  claim 34  wherein the subject is a human.  
     
     
         36 . The method of  claim 35  wherein the compound has the structure of  claim 1 , part (a), or a pharmaceutically acceptable salt thereof.  
     
     
         37 . The method of  claim 36  wherein X and Y are both H.  
     
     
         38 . A method for enhancing the effect of a vaccination to a disease in an animal subject comprising the step of administering to the subject a pharmacologically effective amount of a compound of  claim 1 .  
     
     
         39 . The method of  claim 38  wherein the subject is a human.  
     
     
         40 . The method of  claim 39  wherein the compound has the structure of  claim 1 , part (a), or a pharmaceutically acceptable salt thereof.  
     
     
         41 . The method of  claim 40  wherein X and Y are both H.  
     
     
         42 . A method of treating a subject having a pathologic condition involving neovascularization comprising administering a pharmacologically effective amount of a compound of  claim 1 .  
     
     
         43 . The method of  claim 42  wherein the subject is a human.  
     
     
         44 . The method of  claim 43  wherein the compound has the structure of  claim 1 , part (a), or a pharmaceutically acceptable salt thereof.  
     
     
         45 . The method of  claim 44  wherein X and Y are both H.  
     
     
         46 . The method of  claim 43  wherein the condition is hemangioma.  
     
     
         47 . The method of  claim 43  wherein the condition is vascularized malignant tumor or vascularized benign tumor.  
     
     
         48 . The method of  claim 43  wherein the condition is neovascularization in post-recovery cerebrovascular accident; neovascularization due to head trauma; restenosis following angioplasty; or neovascularization due to heat or cold trauma.  
     
     
         49 . The method of  claim 43  wherein the condition is neovascularization associated with substance-induced neovascularization of the liver, angiogenic dysfunction related to an excess of hormone; neovascular sequelae of diabetes; neovascular sequelae to hypertension; or chronic liver infection.  
     
     
         50 . The method of  claim 43  comprising administering to the subject a dose of about 50 μg/kg to about 100 mg/kg.  
     
     
         51 . The method of  claim 50  wherein the effective amount is about 1 μg/kg to about 50 μg/kg body weight.  
     
     
         52 . The method of  claim 43  wherein the compound is administered intramuscularly, intravenously or intranasally.  
     
     
         53 . The method of  claim 43  wherein the subject suffers from AIDS and Kaposi's sarcoma.  
     
     
         54 . A method of treating HIV infection in a subject comprising administering to the subject a pharmacologically effective amount of a compound of  claim 1 .  
     
     
         55 . The method of  claim 54  wherein the compound has the structure of  claim 1 , part (a), or a pharmaceutically acceptable salt thereof.  
     
     
         56 . The method of  claim 55  wherein X and Y are both H.  
     
     
         57 . The method of  claim 54  wherein the treatment is a therapeutic treatment for a person who is infected with HIV.  
     
     
         58 . The method of  claim 54  wherein the treatment is a prophylactic treatment for a person who shows no sign of infection with HIV.