# US 4,396,607 A · Muramyl peptide derivatives and pharmaceutical compositions > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 4,396,607 A - Document ID: US4396607A - Status: Granted - Kind: A - Application number: 06/259,450 - Filed: 1981-05-01 - Granted: 1983-08-02 - Earliest claimed: 1978-03-20 - Assignees: Agence Nationale de Valorisation de la Recherche (ANVAR) - Inventors: Pierre Lefrancier; Monique Parant; Francoise Audibert; Edgar Sache; Louis Chedid; Jean Choay; Edgar Lederer - Web page: https://patentgrep.com/patent/US4396607A ## CPC - C07K 9/005: {containing within the molecule the substructure [IMAGE cpc-sch-C07K-1009.gif] with m, n > 0 and m+n > 0, A, B, D, E being heteroatoms; X being a bond or a chain, e.g. muramylpeptides} - A61K 9/1271: Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers (liposomes as conjugates {A61K47/6911}) - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) ## Abstract The invention relates to new compounds useful notably as regulator of immune responses and which are derivatives of muramyl peptides substituted at the end of the peptide chain by a group containing at least four carbon atoms. ## Claims ### Claim 1 A compound which is an immunological adjuvant and effective against Klebsiella, which compound has the formula: ##STR18## in which the substituents R, R.sub.1, R.sub.2, R.sub.4, R.sub.6, X, Y and Z has the following definition: R is hydrogen or an alkyl group having 1 to 4 carbon atoms, R.sub.1 is hydrogen hydroxyl or phenylamino, R.sub.2 is hydrogen or methyl, R.sub.4 is hydrogen or acyl group having 1 to 4 carbon atoms, R.sub.6 is hydrogen, saturated or unsaturated acyl having from 1 to about 4 carbon atoms, mycolyl group having 80 to 90 carbon atoms or corynomycoyl, X is L-alanyl, L-seryl, L-valyl, or glycyl, Y is -OH, an alkoxy radical having from 1 to 10 carbon atoms, or -NH.sub.2, the hydrogens of the amino group being optionally substituted by alkyl residues having 1 to 10 carbon atoms, or an aminoacyl residue, A is an aminoacyl residue selected from the group consisting of L-alanyl, L-arginyl, L-asparagyl, L-aspartyl, L-cystenyl, L-glutaminyl, L-glutamyl, glycyl, L-histidyl, L-hydroxyprolyl, L-isoleucyl, L-leucyl, L-lysyl, L-methionyl, L-orinthyl, L-phenylalanyl, L-prolyl, L-seryl, L-threonyl, L-tryptophanyl, L-tyrosyl and L-valyl or an aminoalcohol residue (-NH-CH-CH.sub.2 -O-) corresponding to these aminoacyls (-NH-CH-CO-), wherein when the A groups are present in the same compound they may be identical or different, n is zero or 1, Z is selected from the group consisting of -OR', -NHR', -OCH.sub.2 -CH.sub.2 O-COR' or -OCH.sub.2 -CHOH-CH.sub.2 O-R.degree., wherein R.degree. is a mycolic acid group having from 80 to 90 carbon atoms, or corynomycoyl and R' is a linear or branched alkyl group having 4 to 20 carbon atoms. ### Claim 2 (depends on 1) The compound according to claim 1, wherein X is the L-alanyl residue. ### Claim 3 (depends on 1) The compound according to claim 1 wherein Z is -OCH.sub.2 -CHOH-CH.sub.2 O-R.degree., wherein R.degree., is a mycolic acid group having from 80 to 90 carbon atoms or corynomycolyl. ### Claim 4 (depends on 1) The compound according to claim 1, wherein A is L-alanyl. ### Claim 5 (depends on 1) The compound according to claim 1, wherein Y is -OH. ### Claim 6 (depends on 1) The compound according to claim 1, wherein Y is -OCH.sub.3. ### Claim 7 (depends on 1) The compound according to claim 1, wherein Y is -OC.sub.4 H.sub.9. ### Claim 8 (depends on 1) The compound according to claim 1, wherein Y is -NH.sub.2. ### Claim 9 (depends on 1) The compound according to claim 1, wherein R is hydrogen. ### Claim 10 (depends on 1) The compound according to claim 1, wherein R is -CH.sub.3. ### Claim 11 (depends on 1) The compound according to claim 1, wherein R.sub.1, R.sub.4 and R.sub.6 are hydrogen. ### Claim 12 (depends on 1) The compound according to claim 1, wherein R.sub.1, R.sub.6 is selected from the group consisting of hydrogen, acetyl and succinyl. ### Claim 13 (depends on 12) The compound according to claim 12, wherein R.sub.6 is hydrogen. ### Claim 14 (depends on 13) The compound according to claim 13 wherein A is L-alanyl. ### Claim 15 (depends on 14) The compound according to claim 14 wherein Y is amine. ### Claim 16 (depends on 1) The compound according to claim 1, wherein R.sub.6 is acyl of 1 to 4 carbon atoms. ### Claim 17 (depends on 1) The compound according to claim 1 wherein R' is an alkyl group having 15 to 20 carbon atoms. ### Claim 18 A compound which has anti-Listeria activity, which compound has the formula ##STR19## wherein Y is selected from the group consisting of hydroxy, amino and alkoxy of 1 to 10 carbon atoms, and R.sup.1 is a linear or branched alkyl group having 4 to 20 carbon atoms or -OCH.sub.2 -OCHOH-CH.sub.2 O-R.degree., wherein R.degree. a mycolic acid group having from 80 to 90 carbon atoms. ### Claim 19 (depends on 18) The compound of claim 18 wherein R' is alkyl of 4 to 10 carbon atoms. ### Claim 20 (depends on 18) The compound of claim 18 wherein Y is an alkoxy of 3 to 5 carbon atoms. ### Claim 21 (depends on 18) The compound of claim 18 wherein Y is butoxy and R' is decyl. ### Claim 22 (depends on 18) The compound of claim 18 wherein Y is amino, n is 0 and R' is butyl. ### Claim 23 (depends on 18) The compound of claim 18 wherein Y is amino, n is 1 and R' is butyl. ### Claim 24 (depends on 18) The compound of claim 18 wherein Y is propoxy, n is 0 and R.sub.1 is butyl. ### Claim 25 (depends on 18) The compound of claim 18 wherein Y is propoxy, n is 1 and R' is butyl. ### Claim 26 (depends on 18) The compound of claim 18 wherein Y is pentoxy, n is 0 and R' is butyl. ### Claim 27 (depends on 18) The compound of claim 18 wherein Y is pentoxy, n is 1 and R is butyl. ### Claim 28 (depends on 18) The compound of claim 18 wherein Y is amino, n is 0 and R' is -OCH.sub.2 -CHOH-CH.sub.2 O-R.degree., wherein R.degree. is a mycolic acid group having 80 to 90 carbon atoms. ### Claim 29 (depends on 18) The compound of claim 18 wherein Y is ethoxy, n is zero and R is decyl. ### Claim 30 (depends on 1) A pharmaceutical composition for stimulating the immune response in warm-blooded animals, which comprises a biologically acceptable carrier and an effective dose of at least one effective compound of claim 1. ### Claim 31 (depends on 30) The pharmaceutical composition according to claim 30, wherein the lipid portion of the liposomes have a lipid portion. ### Claim 32 (depends on 31) The pharmaceutical composition according to claim 31 wherein the lipid portion of the liposomes is constituted by a phospholipid. ### Claim 33 (depends on 32) The pharmaceutical composition according to claim 32 wherein the compound is N-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L-alanyl-D-glyceryl-mycolate. ### Claim 34 (depends on 30) The pharmaceutical composition according to claim 30 wherein the aqueous phase is buffered to a pH at or near neutrality. ### Claim 35 (depends on 30) The pharmaceutical composition according to claim 30, wherein the injectable medium is constituted by an aqueous injectable isotonic and sterile saline or glucose solution. ### Claim 36 (depends on 30) The pharmaceutical composition according to claim 30, wherein the active compound is suitable for oral administration. ### Claim 37 (depends on 36) The pharmaceutical composition according to claim 36 wherein the compound is N-acetyl-muramyl-1-alanyl-D-isoglutaminyl-L-alanyl-butyl ester. ### Claim 38 (depends on 36) The pharmaceutical composition according to claim 36 wherein the compound is N-acetyl-muranyl-L-alanyl-D-isoglutaminyl-butyl ester. ### Claim 39 (depends on 30) The pharmaceutical composition according to claim 30 for anti-infectious treatment and parenteral administration, in the form of unit doses containing from 10 to 20,000 mg of the effective compound. ### Claim 40 (depends on 18, 19, 20, 21, 22, 23, 24, 25, 27, 28, 29) A biological composition for stimulating in a warm-blooded animal an immune response against Listeria comprising a biologically acceptable carrier and an effective dose of at least one compound of claim 18, 19, 20, 21, 22, 23, 24, 25, 27, 28 or 29. ### Claim 41 (depends on 1) A method for modifying the immune responses of a warm blooded animal comprising administering to said warm-blooded animal a composition comprising a biologically acceptable carrier and an effective amount of at least one compound of claim 1. ### Claim 42 (depends on 41) The method according to claim 41 wherein the compound is administered orally. ### Claim 43 (depends on 1) A method for treating infectious diseases in warm-blooded animals comprising administering an effective amount of at least one compound of claim 1 to said animal. ### Claim 44 (depends on 43) The method according to claim 43 wherein the compound administered is N-acetyl-muramyl-alanyl-D-isoglutaminyl-L-alanyl-butyl ester. ### Claim 45 (depends on 43) The method according to claim 43 wherein the compound is N-acetyl-muranyl-L-alanyl-D-isoglutaminyl-butyl ester. ### Claim 46 (depends on 18) A method of stimulating an immune response in a warm-blooded animal against Listeria which comprises administering to said animal a composition comprising a biologically acceptable carrier and an effective amount of at least one compound of the formula of claim 18, wherein Y is selected from the group consisting of hydroxy, amino and alkoxy of 1 to 10 carbon atoms, and R.sub.1 is a linear or branched alkyl group having 4 to 20 carbon atoms or -OCH.sub.2 -CHOH-CH.sub.2 O-R.degree., wherein R.degree. is a mycolic acid group having from 80 to 90 carbon atoms. ### Claim 47 (depends on 46) The method of claim 46 wherein the compound is N-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L-acyl-D-glyceryl-mycolate, wherein the mycolic acid radical contains from 80 to 90 carbon atoms. ### Claim 48 (depends on 47) The method of claim 47 wherein the compound is N-acetyl-murmyl-L-alanyl-D-isoglutaminyl-butyl ester. ### Claim 49 (depends on 18) A method for producing a delayed type hypersensitivity reaction to antigens in warm-blooded animals which comprises administering to said animal an effective amount of the compound of claim 18 and a biologically acceptable carrier.