USRE35706EExpiredUtilityPatentIndex 42

Lipophila derivatives of muramylpeptides having properties of activating macrophages and compositions containing them

Assignee: VACSYN INCPriority: May 11, 1984Filed: Oct 25, 1994Granted: Dec 30, 1997

Est. expiryMay 11, 2004(expired)· nominal 20-yr term from priority

Inventors:PHILLIPS NIGEL AUDIBERT FRANCOISE BERNARD JEAN-MARIE CHEDID LOUIS LEFRANCIER PIERRE LEVEL MICHEL PARANT MONIQUE

A61P 37/00A61P 35/00C07K 9/005B82Y 5/00A61K 38/00C07K 9/001A61K 9/127A61K 9/1271

PatentIndex Score

Cited by

References

Claims

Abstract

The invention relates to muramyleptide derivatives resulting essentially from the conjugation or the coupling, as the case may require, through an arm, between a muramylpeptide and a group containing two atoms contiguous with one another to each of which is attached a lipophile chain comprising from 8 to 100 carbon atoms, preferably from 14 to 24 carbon atoms. The derivatives according to the invention are endowed with remarkable stimulating properties with respect to the activation of macrophages, of which they amplify the tumoricidal properties.

Claims

exact text as granted — not AI-modified

We claim: 
     
       1. A muramylpeptide of the formula: ##STR6## wherein: R 1  is --H or --CH 3  ; R 2  is --NH 2 , --OH or --OD, with D being a hydrocarbon group of 1 to 10 carbon atoms;   R 11  is . .--H or a phenylamino groups.!. .Iadd.--OH.Iaddend.;   R 14  is --H or an acyl group of 1 to 4 carbon atoms;   X is an aminoacyl residue which is selected from the group consisting of alanyl, valyl, isoleucyl, norleucyl, leucyl, seryl, threonyl, prolyl, glutaminyl, asparaginyl, methionyl, tryptophanyl, phenylalanyl, tyrosyl and glycycl and which may be N-substituted by a lower alkyl group;   Y is --NH 2 , --OH, --OD or a . .--OCH 2  --CHO(R 3 )CH 2  O(R 4 ).!. .Iadd.--OCH 2  --CH(OR 3 )CH 2  O(R 4 ) .Iaddend.lipophile group in which a hydrogen on a methylene in its glyceryl group may be replaced by a lower alkyl group; R 3  and R 4  being identical or different and being individually an acyl or alkyl group of 8 to 100 carbon atoms .Iadd.and D is as defined above.Iaddend.;   Z is --NH 2 , --OH, --OD or a . .--CO--CHO(R 3 )CH 2  O(R 4 ).!. .Iadd.--OCO--CH(OR 3 )CH 2  O(R 4 ).Iaddend., lipophile group in which a hydrogen on a methylene in its glyceryl group may be replaced by a lower alkyl group; Y or Z or both being a lipophile group .Iadd.and D is as defined above.Iaddend.;   . .W is --O-- or, when Z is a lipophile group, --NH--; and.!.   A . .and B are.!. .Iadd.is .Iaddend.either .Iadd.a .Iaddend.direct linkage. .s.!. or .Iadd.a .Iaddend.bridging arm. .s.!. which . .are identical or different and which.!. comprise.Iadd.s .Iaddend.. .individually.!. one to three aminoacyl residues, themselves identical or different from one another, said aminoacyl residues being selected from the group consisting of alanyl, valyl, isoleucyl, norleucyl, leucyl, seryl, threonyl, prolyl, glutaminyl, asparaginyl, methionyl, tryptophanyl, phenylalanyl, tyrosyl and glycyl and which may be N-substituted by a lower alkyl group, or a --NH--(CH 2 ) 2  --O-- group;   a hydrogen on a methylene in a glutamyl group of said muramylpeptide being replaceable by a lower alkyl group.   
     
     
       2. The muramylpeptide of claim 1 wherein X is a levogyratory aminoacyl residue or is glycyl. 
     
     
       3. The muramylpeptide of claim 2 wherein X is L-alanyl, L-seryl, L-valyl, L-leucyl, L-isoleucyl, L-threonyl or glycyl. 
     
     
       4. The muramylpeptide of claim 1 wherein A . .and B are.!. .Iadd.is .Iaddend.L-alanyl or L-lysyl. 
     
     
       5. The muramylpeptide of claim 1 wherein R 2  is an alkoxy group. 
     
     
       6. The muramylpeptide of claim 1 wherein A . .and B are.!. .Iadd.is a .Iaddend.direct linkage. .s.!., Z is a lipophile group, and R 3  and R 4  are acyl groups. 
     
     
       7. The muramylpeptide of claim 6 wherein R 2  is alkoxy of 1 to 10 carbon atoms and Y is --NH 2 . 
     
     
       8. The muramylpeptide of claim 7 wherein R 2  is alkoxy of 4 carbon atoms. 
     
     
       9. The muramylpeptide of claim 8 wherein R 2  is n-butoxy. 
     
     
       10. The muramylpeptide of claim 6 wherein R 3  and R 4  are palmitoyl groups. 
     
     
       11. The muramylpeptide of claim 10 which is 6-O-(beta,gamma-dipalmitoyl-L-. .gylceryl.!..Iadd.glyceryl).Iaddend.-N-acetyl-muramyl-L-alanyl-D-glutamine-n-butyl ester. 
     
     
       12. The muramylpeptide of claim 10 which is 6-O-(beta,gamma-dipalmitoyl-L-glyceryl)-capryl-N-acetyl-muramyl-L-alanyl-D-glutamine-butyl ester. 
     
     
       13. The muramylpeptide of claim 1 wherein A . .and B are.!. .Iadd.is a .Iaddend.direct linkage. .s.!., . .ZB.!. .Iadd.Z .Iaddend.is --OH, Y is a lipophile group, R 3  and R 4  are acyl groups and R 2  is --NH 2 . 
     
     
       14. The muramylpeptide of claim 13 wherein R 3  and R 4  are palmitoyl groups. 
     
     
       15. The muramylpeptide of claim 14 which is alpha(N-acetyl-muramyl-L-alanyl-D-isoglutamine), beta, gamma-dipalmitoyl-sn-glycerol. 
     
     
       16. The muramylpeptide of claim 14 which is alpha(N-acetyl-muramyl-D-alanyl-D-isoglutamine), beta, gamma-dipalmitoyl-sn-glycerol. 
     
     
       17. The muramylpeptide of claim 14 which is alpha(N-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L-alanine), beta, gamma-dipalmitoyl-sn-glycerol. 
     
     
       18. The muramylpeptide of claim 14 which is alpha(N-acetyl-muramyl-D-alanyl-D-isoglutaminyl-L-alanine), beta, gamma-dipalmitoyl-sn-glycerol. 
     
     
       19. A pharmaceutical composition for stimulating the activity of macrophage which comprises a physiologically acceptable carrier and a macrophage stimulant effective amount of said muramylpeptide of claim 1. 
     
     
       20. A method for activating macrophages in a host which comprises the step of: administering to said host a macrophage activating amount said muramylpeptide of claim 1. 
     
     
       21. A method for stimulating anti-infectious activity of macrophages in a host which comprises administering to said host a macrophage stimulating amount of said muramylpeptide of claim 1. 
     
     
       22. A muramylpeptide of claim 1 having the formula: ##STR7## wherein: R 1  is --H or --CH 3  ; R 2  is --NH 2 , --OH or --OD, with D being a hydrocarbon group of 1 to 10 carbon atoms;   R 11  is --OH;   . .R 1  .!. .Iadd.R 14  .Iaddend.is --H;   X is an aminoacyl residue which is selected from the group consisting of alanyl, valyl, isoleucyl, norleucyl, leucyl, seryl, threonyl, prolyl, glutaminyl, asparaginyl, methionayl, tryptophanyl, phenylalanyl, tyrosyl and glycyl;   Y is --NH 2 , --OH, --OD or a . .--OCH 2  --CH(R 3 )CH 2  O(R 4 ).!. .Iadd.--OCH 2  --CH(OR 3 )CH 2  O(R 4 ) .Iaddend.lipophile group; R 3  and R 4  being identical or different and being individually an acyl lipophile group of 8 to 100 carbon atoms and D is as defined above;   Z is --NH 2 , --OH, --OD or a . .--CO--CHO(R 3 )CH 2  O(R 4 ).!. .Iadd.--OCO--CH(OR 3 )CH 2  O(R 4 ) .Iaddend.lipophile group; Y or Z or both being a lipophile group and D is as defined above;   . .W is --O--;.!. and   A . .and B are either.!. .Iadd.is a .Iaddend.direct linkage. .s.!. or bridging arm. .s.!. which . .are identical or different and which.!. comprise.Iadd.s .Iaddend.. .individually.!. one to three aminoacyl residues, themselves identical or different from one another, said aminoacyl residues being selected from the group consisting of alanyl, valyl, isoleucyl, norleucyl, leucyl, seryl, threonyl, prolyl, glutaminyl, asparaginyl, methionyl, tryptophanyl, phenylalanyl, tyrosyl, and glycyl and which may be N-substituted by a lower alkyl group, or a --NH--(CH 2 ) P  --CO-- group with p being an integer of 2 to 10.

Cited by (0)

No later patents cite this yet.

References (0)

No backward citations on record.