# US 4,397,844 A · Antigen derivatives and processes for their preparation > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 4,397,844 A - Document ID: US4397844A - Status: Granted - Kind: A - Application number: 06/303,244 - Filed: 1981-09-17 - Granted: 1983-08-09 - Earliest claimed: 1978-02-24 - Assignees: Ciba-Geigy Corporation - Inventors: Gerhard Baschang; Felix M. Dietrich; Roland Gisler; Albert Hartmann; Jaroslav Stanek; Lajos Tarcsay - Web page: https://patentgrep.com/patent/US4397844A ## CPC - C07H 9/04: Cyclic acetals - A61K 39/00: Medicinal preparations containing antigens or antibodies (materials for immunoassay G01N33/53) - A61K 39/385: Haptens or antigens, bound to carriers - C07H 23/00: Compounds containing boron, silicon or a metal, e.g. chelates or vitamin B12 (esters with inorganic acids C07H11/00) - 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 2039/55583: {Polysaccharides} - A61K 2039/6062: {Muramyl peptides} - Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change - Y10S 530/806: Antigenic peptides or proteins - Y10S 530/807: Hapten conjugated with peptide or protein - C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13) - 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) - 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) - Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE - Y10S: TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS ## Abstract The invention relates to novel antigen derivatives comprising an antigen and at least one muramylpeptide covalently bonded thereto, if appropriate via a spacer, to pharmaceutical preparations which contain such compounds and to their use as a vaccine. The novel antigen derivatives produce a pronounced increase in the immuno-response to the antigen, and in particular also a cell-medicated immunity under clinically acceptable conditions of administration. ## Claims ### Claim 1 A compound of the formula I ##STR10## in which X is a carbonyl group, R.sub.1, R.sub.4 and R.sub.6 independently of one another represent hydrogen tri-lower alkyl-silyl, alkyl having from 1 to 18 carbon atoms, benzyl which is unsubstituted or substituted in the aromatic nucleus by lower alkyl, hydroxyl, lower alkoxy, lower alkylenedioxy, mercapto, lower alkylmercapto, trifluoromethyl and/or halogen, or represent alkanoyl having from 2 to 18 carbon atoms, benzoyl or naphthoyl which are unsubstituted or substituted by halogen, lower alkyl, lower alkoxy, trifluoromethyl, hydroxyl or lower alkanoyloxy, or represent an acyl radical of a lower alkanesulfonic acid or of phenylsulfonic acid, which is unsubstituted or substituted by lower alkyl or halogen, or represent carbamoyl, lower alkyl-carbamoyl or phenyl-carbamoyl, R.sub.2 represents alkyl having 1 to 18 carbon atoms which is unsubstituted or substituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, mercapto, lower alkylmercapto, lower alkanoylmercapto, carboxy, lower alkoxycarbonyl and/or carbamoyl, or represents phenyl which is unsubstituted or substituted by lower alkyl, hydroxy, lower alkoxy, lower alkanoyl, lower alkylenedioxy, halogen and/or trifluoromethyl, R.sup.3 represent hydrogen or lower alkyl, at least one of the radicals R.sub.7, R.sub.9 and R.sub.13 represents lower alkyl, and the others represent hydrogen, R.sub.8 is hydrogen, lower alkyl which is unsubstituted or substituted by hydroxy, lower alkoxy, lower alkanoyloxy, mercapto, lower alkylmercapto, lower alkanoylmercapto, amino, lower alkanoylamino, carbamoylamino or cycloalkyl having 5 or 6 carbon atoms, or represents cycloalkyl-lower alkyl having 5 or 6 carbon atoms, in the cyclic moiety, phenyl or phenyl-lower alkyl, in which the phenyl radicals are unsubstituted or substituted as defined above, or heterocyclyl or heterocyclyl-lower alkyl wherein the heterocyclyl radicals are 5- or 6-membered, contain one or two nitrogen atoms in the ring and may or may not contain a fused phenyl radical, R.sub.7 and R.sub.8 together can also represent alkylene having 3 or 4 carbon atoms, R.sub.10, R.sub.11 and R.sub.12 independently of one another represent carboxyl, lower alkoxycarbonyl or carbamoyl which is unsubstituted or mono- or disubstituted at the nitrogen atom by unsubstituted, or carboxy- or carbamoyl-substituted, lower alkyl or by phenyl, benzyl, tetramethylene or pentamethylene or R.sub.11 can also be hydrogen, or a salt of such a compound having a salt-forming group. ### Claim 2 (depends on 1) Compounds of the formula I according to claim 1, in which at least one of the radicals R.sub.7, R.sub.9 and R.sub.13 represents methyl, and salts thereof. ### Claim 3 (depends on 1) Compounds of the formula I according to claim 1, in which R.sub.1, R.sub.4, R.sub.6, R.sub.11 and R.sub.13 represent hydrogen, R.sub.2 represents methyl or phenyl, R.sub.3 represents hydrogen or methyl, R.sub.7 represents methyl, ethyl or propyl, R.sub.8 represents hydrogen, methyl or ethyl, R.sub.9 represents hydrogen or methyl, R.sub.10 represents carbamoyl and R.sub.12 represents carboxy, and salts thereof. ### Claim 4 (depends on 1) Compounds of the formula I according to claim 1, in which R.sub.7 represents lower alkyl and R.sub.13 represents hydrogen, and salts thereof. ### Claim 5 (depends on 4) Compounds of the formula I according to claim 4, in which R.sub.3 represents methyl, and salts thereof. ### Claim 6 (depends on 1) N-acetyl-normuramyl-L-(N-methyl)-alanyl-D-isoglutamine .tbd.2-acetylamino-3-O-{[L-1-(D-1-carbamoyl-3-carboxy-propyl)-carbamoyl-et hyl]-N-methyl-carbamoylmethyl}-2-deoxy-D-glucose and salts thereof according to claim 1. ### Claim 7 (depends on 1) N-benzoyl-normuramyl-L-(N-ethyl)-.alpha.-amino-butyryl-D-isoglutamine .tbd.2-benzoylamino-3-O-{[L-1-(D-1-carbamoyl-3-carboxy-propyl)-carbamoyl-p ropyl]-N-ethyl-carbamoylmethyl}-2-deoxy-D-glucose and salts thereof according to claim 1. ### Claim 8 (depends on 1) N-acetyl-muramyl-L-(N-methyl)-.alpha.-aminobutyryl-D-isoglutamine .tbd.2-acetylamino-3-O-{D-1-[L-1-(D-1-carbamoyl-3-carboxy-propyl)-carbamoy l-propyl]-N-methyl-carbamoyl-ethyl}-2-deoxy-D-glucose and salts thereof according to claim 1. ### Claim 9 (depends on 1) N-acetyl-muramyl-L-(N-ethyl)-alanyl-D-isoglutamine .tbd. 2-acetylamino-3-O-{D-1-[L-1-(D-1-carbamoyl-3-carboxy-propyl)-carbamoyl-eth yl]-N-ethyl-carbamoyl-ethyl}-2-deoxy-D-glucose and salts thereof according to claim 1. ### Claim 10 (depends on 1) Compounds of the formula I according to claim 1 in which R.sub.1, R.sub.4 and R.sub.6 represent hydrogen, X represents carbonyl, R.sub.2 represents lower alkyl which is unsubstituted or substituted by hydroxy or by methoxy, or phenyl which is unsubstituted or substituted by hydroxy, methoxy, methyl, ethyl or by halogen, R.sub.3 and R.sub.9 represent hydrogen or methyl, R.sub.8 represents methyl, ethyl, n-propyl, isopropyl, 2-methylpropyl, methylmercaptomethyl, hydroxymethyl, hydroxyethyl, phenyl, benzyl or p-hydroxybenzyl, R.sub.10, R.sub.11 and R.sub.12 represent carboxy, lower alkoxycarbonyl or carbamoyl and R.sub.11 also represents hydrogen, and salts thereof. ### Claim 11 (depends on 3) Compounds of the formula I according to claim 3, in which R.sub.3 represents methyl, and salts thereof. ### Claim 12 (depends on 1) A compound according to claim 1, wherein R, R.sub.4, and R.sub.6 are trimethylsilyl. ### Claim 13 (depends on 1) Pharmaceutical preparations for potentiating the immune-response of warm blooded animals, including man, containing an effective amount of a compound according to claim 1 together with a pharmaceutically acceptable carrier. ### Claim 14 (depends on 13) A pharmaceutical preparation according to claim 13, in which R.sub.1, R.sub.4 and R.sub.6 represent hydroen, X represents carbonyl, R.sub.2 represents lower alkyl which is unsubstituted or substituted by hydroxy or by methoxy, or phenyl which is unsubstituted or substituted by hydroxy, methoxy, methyl, ethyl or by halogen, R.sub.3 and R.sub.9 represent hydrogen or methyl, R.sub.8 represents methyl, ethyl, n-propyl, isopropyl, 2-methylpropyl, methylmercaptomethyl, hydroxymethyl, hydroxyethyl, phenyl, benzyl or p-hydroxybenzyl, R.sub.10, R.sub.11 and R.sub.12 represent carboxy, lower alkoxycarbonyl or carbamoyl and R.sub.11 also represents hydrogen, and salts thereof. ### Claim 15 (depends on 13) A pharmaceutical preparation according to claim 13, in which R.sub.1, R.sub.4, R.sub.6, R.sub.11 and R.sub.13 represent hydrogen, R.sub.2 represents methyl or phenyl, R.sub.3 represents hydrogen or methyl, R.sub.7 represents methyl, ethyl or propyl, R.sub.8 represents hydrogen, methyl or ethyl, R.sub.9 represents hydrogen, or methyl, R.sub.10 represents carbamoyl and R.sub.12 represents carboxy, and salts thereof. ### Claim 16 (depends on 13) A pharmaceutical preparation according to claim 13, in which R.sub.7 is lower alkyl and R.sub.13 is hydrogen. ### Claim 17 (depends on 15) A pharmaceutical preparation according to claim 15, in which R.sub.3 is methyl, and salts thereof. ### Claim 18 (depends on 10) A compound according to claim 10, in which R.sub.7 is lower alkyl and R.sub.13 is hydrogen. ### Claim 19 (depends on 18) A compound according to claim 18, in which R.sub.7 is methyl. ### Claim 20 (depends on 1) A method for potentiating the immune-response of warm blooded animals, including man, which comprises administering an effective amount of a compound according to claim 1. ### Claim 21 (depends on 10) A method for potentiating the immune-response of warm blooded animals, including man, which comprises administering an effective amount of a compound according to claim 10. ### Claim 22 (depends on 4) A method for potentiating the immune-response of warm blooded animals, including man, which comprises administering an effective amount of a compound according to claim 4. ### Claim 23 (depends on 18) A method for potentiating the immune-response of warm blooded animals, including man, which comprises administering an effective amount of a compound according to claim 18. ### Claim 24 (depends on 19) A method for potentiating the immune-response of warm blooded animals, including man, which comprises administering an effective amount of a compound according to claim 19.