Histamine derivatives as immune modulators

Abstract

Histamine derivatives are disclosed which find use as effect and tissue-specific immune modulators. Specifically, the primary terminal nitrogen in histamine is derivatized to introduce a variable length side chain having 0 to 1 branch of from 1 to 3 carbons; 0 to 2 non-oxo-carbonyl groups; 0 to 4 heteroatoms, other than the non-oxo carbonyl oxygen; 0 to 1 aryl or alkylaryl group; and 0 to 1 functionally bound amino acid, polypeptide, or protein or derivative thereof.

What is claimed is: 
     
       1. Histamine derivatives having binding specificity for H 1  or H 2  receptors of lymphocytes being characterized by being mono-substituted at the side chain amine of a histamine molecule with a substituent having an aliphatic chain of from 2 to 10 carbon atoms, wherein the alpha-carbon of the chain is substituted with oxo or alkyl of from 1 to 3 carbon atoms, said chain terminating in . .hydrogen or.!. carboxamido, wherein the carboxamido nitrogen is substituted with alkyl of from 1 to 6 . .amido.!. carbon atoms, tolyl or trifluoromethylphenyl. ., with the proviso that when said chain terminates in hydrogen, the chain length is 5 or 6 atoms.!.. 
     
     
       2. Histamine derivatives according to claim 1, wherein said alpha-carbon is substituted with methyl and said aliphatic chain is polymethylene. 
     
     
       3. Histamine derivatives according to claim 1. wherein said carboxamido nitrogen is substituted with tolyl or trifiuoromethylphenyl. 
     
     
       4. Histamine derivatives having binding specificity for H 1  or H 2  receptors of lymphocytes and of the formula ##STR11## wherein: X is CO or CHR, where R is an alkyl group of from 1 to 3 carbon atoms; n is an integer of from 2 to 6;   Y is .!.CH 3  or.!.CONHZ, wherein Z is H; (CH 2 ) m  CH 3 , where m is .Badd.1 to 4; or substituted phenyl, where the substituent is methyl or trifluoromethyl;   A is a physiologically acceptable counterion; and   b is an integer of from 0 to 2. . .   
     
     
       5.  Histamine derivatives according to claim 4, wherein Y is CH 3 ..!.. .6. Histamine derivatives according to claim 4, wherein Y is 
     
     
        (CO)NHZ..!.7. Histamine derivatives according to claim . .6.!. 4, wherein Z is substituted phenyl, where the substituent is methyl or 
     
     
        trifluoromethyl. 8. Histamine derivatives according to claim 4, wherein b 
     
     
        is 0. 9. Histamine derivatives having binding specificity for H 1  or H 2  receptors of lymphocytes and of the formula ##STR12## wherein: n' is 2 to 5; X' is CO, CH 2 , or CHCH 3  ;   D is methyl or trifluoromethyl;   phi is phenylene;   A is a physiologically acceptable counterion; and   
     
     
       b' is an integer of from 0 to 2. . .10.  Histamine derivatives having binding specificity for H 1  or H 2  receptors of lymphocytes and of the formula ##STR13## wherein: X' is CO, CH 2  ; or CHCH 3  ; and   
     
     
       n' is 2 or 3..!.11. A method of modulating an immune response of lymphocytes, which comprises contacting said lymphocytes with an 
     
     
        immunomodulating amount of a compound according to claim 1. 12. A method of modulating an immune response of lymphocytes, which comprises contacting said lymphocytes with an immunomodulating amount of a compound 
     
     
        according to claim 2. 13. A method of modulating an immune response of lymphocytes, which comprises contacting said lymphocytes with an 
     
     
        immunomodulating amount of a compound according to claim 4. 14. A . .formulating.!. .Iadd.formulation .Iaddend.comprising a histamine derivative according to claim 1 in a physiologically acceptable carrier. 
     
     
          . A formulation comprising a histamine derivative according to claim 2 
     
     
        in a physiologically acceptable carrier. 16. A formulation comprising at least 2 histamine derivatives according to claim 1 in a physiologically 
     
     
        acceptable carrier. .Iadd.17.  Histamine derivatives having binding specificity for H 1  or H 2  receptors of lymphocytes and of the following formula   His--NH--X--(CH.sub.2).sub.n --Y(HA).sub.b     His--NH is a histaminyl residue;   X is CO, CH 2 , or CHR, where R is an alkyl group of from 1 to 3 carbon atoms;   n is an integer from 0 to 10;   Y is CONHZ wherein Z is H; (CH 2 ) m  CH 3 , where m is 0 to 10; phenyl; or a phenyl group substituted with methyl or halomethyl;     A is a physiologically acceptable counterion; and   
     
     
       b is an integer from 0 to 2. .Iaddend..Iadd.18.  Histamine derivatives according to claim 17, wherein R is CH 3 . .Iaddend..Iadd.19. Histamine derivatives according to claim 17, wherein n is an integer from 2 to 6. .Iaddend..Iadd.20. Histamine derivatives according to claim 17, wherein n is an integer from 2 to 5. .Iaddend..Iadd.21. Histamine derivatives according to claim 17, wherein m is 2 to 6. .Iaddend..Iadd.22. Histamine derivatives according to claim 17, wherein m is 2 to 5. .Iaddend..Iadd.23. Histamine derivatives according to claim 17, wherein Z is phi-D, where phi is phenylene and D is trifluoromethyl. .Iaddend.