# US RE35,706 E · Lipophila derivatives of muramylpeptides having properties of activating macrophages and compositions containing them

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- Number: US RE35,706 E
- Document ID: USRE35706E
- Status: Granted
- Kind: E
- Application number: 08/329,142
- Filed: 1994-10-25
- Granted: 1997-12-30
- Earliest claimed: 1984-05-11
- Assignees: Vacsyn S.A.
- Inventors: Nigel Phillips; Fran.cedilla.oise Audibert; Jean-Marie Bernard; Louis Chedid; Pierre Lefrancier; Michel Level; Monique Parant
- Web page: https://patentgrep.com/patent/USRE35706E

## 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

### Claim 1

A muramylpeptide of the formula: ##STR6## wherein: R.sub.1 is --H or --CH.sub.3 ;
R.sub.2 is --NH.sub.2, --OH or --OD, with D being a hydrocarbon group of 1 to 10 carbon atoms;
R.sub.11 is .›.--H or a phenylamino groups.!. --OH ;
R.sub.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.sub.2, --OH, --OD or a .›.--OCH.sub.2 --CHO(R.sub.3)CH.sub.2 O(R.sub.4).!. --OCH.sub.2 --CH(OR.sub.3)CH.sub.2 O(R.sub.4) lipophile group in which a hydrogen on a methylene in its glyceryl group may be replaced by a lower alkyl group; R.sub.3 and R.sub.4 being identical or different and being individually an acyl or alkyl group of 8 to 100 carbon atoms and D is as defined above ;
Z is --NH.sub.2, --OH, --OD or a .›.--CO--CHO(R.sub.3)CH.sub.2 O(R.sub.4).!. --OCO--CH(OR.sub.3)CH.sub.2 O(R.sub.4) , 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 and D is as defined above ;
.›.W is --O-- or, when Z is a lipophile group, --NH--; and.!.
A .›.and B are.!. is either a direct linkage.›.s.!. or a bridging arm.›.s.!. which .›.are identical or different and which.!. comprise s .›.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.sub.2).sub.2 --O-- group;
a hydrogen on a methylene in a glutamyl group of said muramylpeptide being replaceable by a lower alkyl group.

### Claim 2 (depends on 1)

The muramylpeptide of claim 1 wherein X is a levogyratory aminoacyl residue or is glycyl.

### Claim 3 (depends on 2)

The muramylpeptide of claim 2 wherein X is L-alanyl, L-seryl, L-valyl, L-leucyl, L-isoleucyl, L-threonyl or glycyl.

### Claim 4 (depends on 1)

The muramylpeptide of claim 1 wherein A .›.and B are.!. is L-alanyl or L-lysyl.

### Claim 5 (depends on 1)

The muramylpeptide of claim 1 wherein R.sub.2 is an alkoxy group.

### Claim 6 (depends on 1)

The muramylpeptide of claim 1 wherein A .›.and B are.!. is a direct linkage.›.s.!., Z is a lipophile group, and R.sub.3 and R.sub.4 are acyl groups.

### Claim 7 (depends on 6)

The muramylpeptide of claim 6 wherein R.sub.2 is alkoxy of 1 to 10 carbon atoms and Y is --NH.sub.2.

### Claim 8 (depends on 7)

The muramylpeptide of claim 7 wherein R.sub.2 is alkoxy of 4 carbon atoms.

### Claim 9 (depends on 8)

The muramylpeptide of claim 8 wherein R.sub.2 is n-butoxy.

### Claim 10 (depends on 6)

The muramylpeptide of claim 6 wherein R.sub.3 and R.sub.4 are palmitoyl groups.

### Claim 11 (depends on 10)

The muramylpeptide of claim 10 which is 6-O-(beta,gamma-dipalmitoyl-L-.›.gylceryl.!. glyceryl) -N-ace tyl-muramyl-L-alanyl-D-glutamine-n-butyl ester.

### Claim 12 (depends on 10)

The muramylpeptide of claim 10 which is 6-O-(beta,gamma-dipalmitoyl-L-glyceryl)-capryl-N-acetyl-muramyl-L-alanyl-D -glutamine-butyl ester.

### Claim 13 (depends on 1)

The muramylpeptide of claim 1 wherein A .›.and B are.!. is a direct linkage.›.s.!., .›.ZB.!. Z is --OH, Y is a lipophile group, R.sub.3 and R.sub.4 are acyl groups and R.sub.2 is --NH.sub.2.

### Claim 14 (depends on 13)

The muramylpeptide of claim 13 wherein R.sub.3 and R.sub.4 are palmitoyl groups.

### Claim 15 (depends on 14)

The muramylpeptide of claim 14 which is alpha(N-acetyl-muramyl-L-alanyl-D-isoglutamine), beta, gamma-dipalmitoyl-sn-glycerol.

### Claim 16 (depends on 14)

The muramylpeptide of claim 14 which is alpha(N-acetyl-muramyl-D-alanyl-D-isoglutamine), beta, gamma-dipalmitoyl-sn-glycerol.

### Claim 17 (depends on 14)

The muramylpeptide of claim 14 which is alpha(N-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L-alanine), beta, gamma-dipalmitoyl-sn-glycerol.

### Claim 18 (depends on 14)

The muramylpeptide of claim 14 which is alpha(N-acetyl-muramyl-D-alanyl-D-isoglutaminyl-L-alanine), beta, gamma-dipalmitoyl-sn-glycerol.

### Claim 19 (depends on 1)

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.

### Claim 20 (depends on 1)

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.

### Claim 21 (depends on 1)

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.

### Claim 22 (depends on 1)

A muramylpeptide of claim 1 having the formula: ##STR7## wherein: R.sub.1 is --H or --CH.sub.3 ;
R.sub.2 is --NH.sub.2, --OH or --OD, with D being a hydrocarbon group of 1 to 10 carbon atoms;
R.sub.11 is --OH;
.›.R.sub.1 .!. R.sub.14 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.sub.2, --OH, --OD or a .›.--OCH.sub.2 --CH(R.sub.3)CH.sub.2 O(R.sub.4).!. --OCH.sub.2 --CH(OR.sub.3)CH.sub.2 O(R.sub.4) lipophile group; R.sub.3 and R.sub.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.sub.2, --OH, --OD or a .›.--CO--CHO(R.sub.3)CH.sub.2 O(R.sub.4).!. --OCO--CH(OR.sub.3)CH.sub.2 O(R.sub.4) 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.!. is a direct linkage.›.s.!. or bridging arm.›.s.!. which .›.are identical or different and which.!. comprise s .›.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.sub.2).sub.P --CO-- group with p being an integer of 2 to 10.