# US 9,040,078 B2 · Use of lipid conjugates in the treatment of diseases of the nervous system > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 9,040,078 B2 - Document ID: US9040078B2 - Status: Granted - Kind: B2 - Application number: 10/919,523 - Filed: 2004-08-17 - Published: 2005-04-14 - Granted: 2015-05-26 - Earliest claimed: 2000-01-10 - Assignees: Yissum Research Development Company of the Hebrew University of Jerusalem - Applicants: Saul Yedgar - Inventors: Saul Yedgar - Web page: https://patentgrep.com/patent/US9040078B2 ## CPC - A61K 47/544: {Phospholipids} - 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 provides a method for treating a subject suffering from a disease of the central nervous system which is associated with an inflammatory response, including, inter alia, multiple sclerosis, Amyotrophic Lateral Sclerosis (ALS), meningitis, Alzheimer's disease, pain, HIV-associated dementia, stroke, traumatic brain injury, encephalomyelitis, chronic inflammatory demyelinating polyneuropathy, cerebral ischemia-induced injury or any combination thereof. This invention further provides for the use of a conjugate, or composition comprising the same, for treating the subject, wherein the conjugate comprises a lipid or phospholipid moiety bonded to a physiologically acceptable monomer, dimer, oligomer, or polymer. ## Claims ### Claim 1 A method of ameliorating damage to the nervous system in a subject suffering from multiple sclerosis in need thereof, comprising administering to said subject an effective amount of a conjugate having the general structure of formula (I): wherein R1 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms; R2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms; Y is either nothing or a spacer group ranging in length from 2 to 30 atoms, wherein said spacer comprises —CO-alkylene-NH—, —CO-alkylene-CO— or a combination thereof; wherein if Y is nothing the phospholipid moiety is directly linked to X via an amide bond and if Y is a spacer group, the spacer group is directly linked to X via an amide or an ester bond and to the phospholipid moiety via an amide bond; X is a glycosaminoglycan; and n is the number of lipid moiety molecules bound to a molecule of X, wherein n is a number from 1 to 1000; wherein said damage to the nervous system in said subject is ameliorated. ### Claim 2 (depends on 1) The method of claim 1, wherein said glycosaminoglycan is hyaluronic acid, heparin, heparin sulfate, heparin, heparan sulfate, chondroitin sulfate, keratin, keratan sulfate, dermatan sulfate or a derivative thereof. ### Claim 3 (depends on 1) The method of claim 1, wherein said glycosaminoglycan is hyaluronic acid. ### Claim 4 (depends on 1) The method of claim 1, wherein said glycosaminoglycan is chondroitin sulfate. ### Claim 5 (depends on 4) The method of claim 4, wherein said chondroitin sulfate is chondroitin-4-sulfate. ### Claim 6 (depends on 4) The method of claim 4, wherein said chondroitin sulfate is chondroitin-6-sulfate. ### Claim 7 (depends on 1) The method of claim 1, wherein said glycosaminoglycan is di- and trisaccharide unit monomers of glycosaminoglycans. ### Claim 8 A method of ameliorating damage to the nervous system in a subject suffering from multiple sclerosis in need thereof, comprising administering to said subject an effective amount of a conjugate having the general structure of formula (II): wherein R1 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms; R2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms; Y is either nothing or a spacer group ranging in length from 2 to 30 atoms, wherein said spacer comprises —CO-alkylene-NH—, —CO-alkylene-CO— or a combination thereof; wherein if Y is nothing the phospholipid moiety is directly linked to X via an amide bond and if Y is a spacer group, the spacer group is directly linked to X via an amide or an ester bond and to the phospholipid moiety via an amide bond; X is a glycosaminoglycan; and n is the number of lipid moiety molecules bound to a molecule of X wherein n is a number from 1 to 1000; wherein said damage to the nervous system in said subject is ameliorated. ### Claim 9 A method of ameliorating damage to the nervous system in a subject suffering from multiple sclerosis in need thereof, comprising administering to said subject an effective amount of a conjugate having the general structure of formula (III): wherein R1 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms; R2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms; Z is either nothing, inositol, choline, or glycerol; Y is either nothing or a spacer group ranging in length from 2 to 30 atoms, wherein said spacer comprises —CO-alkylene-NH—, —CO-alkylene-CO— or a combination thereof; wherein if Y is nothing the phospholipid moiety is directly linked to X via an amide bond and if Y is a spacer group, the spacer group is directly linked to X via an amide or an ester bond and to the phospholipid moiety via an amide bond; X is a glycosaminoglycan; and n is the number of lipid moiety molecules bound to a molecule of X wherein n is a number from 1 to 1000; wherein said damage to the nervous system in said subject is ameliorated. ### Claim 10 A method of ameliorating damage to the nervous system in a subject suffering from multiple sclerosis in need thereof, comprising administering to said subject an effective amount of a conjugate having the general structure of formula (IV): wherein R1 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms; R2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms; Z is either nothing, ethanolamine, serine, inositol, choline, or glycerol; Y is either nothing or a spacer group ranging in length from 2 to 30 atoms, wherein said spacer comprises —CO-alkylene-NH—, —CO-alkylene-CO— or a combination thereof; wherein if Y is nothing the phospholipid moiety is directly linked to X via an amide bond and if Y is a spacer group, the spacer group is directly linked to X via an amide or an ester bond and to the phospholipid moiety via an amide bond; X is a glycosaminoglycan; and n is the number of lipid moiety molecules bound to a molecule of X wherein n is a number from 1 to 1000; wherein said damage to the nervous system in said subject is ameliorated. ### Claim 11 A method of ameliorating damage to the nervous system in a subject suffering from multiple sclerosis in need thereof, comprising administering to said subject an effective amount of a conjugate having the general structure of formula (V): wherein R1 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms; R2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms; Z is either nothing, ethanolamine, serine, inositol, choline, or glycerol; Y is either nothing or a spacer group ranging in length from 2 to 30 atoms, wherein said spacer comprises —CO-alkylene-NH—, —CO-alkylene-CO— or a combination thereof; wherein if Y is nothing the phospholipid moiety is directly linked to X via an amide bond and if Y is a spacer group, the spacer group is directly linked to X via an amide or an ester bond and to the phospholipid moiety via an amide bond; X is a glycosaminoglycan; and n is the number of lipid moiety molecules bound to a molecule of X wherein n is a number from 1 to 1000; wherein said damage to the nervous system in said subject is ameliorated. ### Claim 12 A method of ameliorating damage to the nervous system in a subject suffering from multiple sclerosis in need thereof, comprising administering to said subject an effective amount of a conjugate having the general structure of formula (VI): wherein R1 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms; R2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms; Z is either nothing, ethanolamine, serine, inositol, choline, or glycerol; Y is either nothing or a spacer group ranging in length from 2 to 30 atoms, wherein said spacer comprises —CO-alkylene-NH—, —CO-alkylene-CO— or a combination thereof; wherein if Y is nothing the phospholipid moiety is directly linked to the glycosaminoglycan via an amide bond and if Y is a spacer group, the spacer group is directly linked to the glycosaminoglycan via an amide or an ester bond and to the phospholipid moiety via an amide bond; X is a glycosaminoglycan; and n is the number of lipid moiety molecules bound to a molecule of X wherein n is a number from 1 to 1000; wherein said damage to the nervous system in said subject is ameliorated. ### Claim 13 A method of ameliorating damage to the nervous system in a subject suffering from multiple sclerosis in need thereof, comprising administering to said subject an effective amount of a conjugate having the general structure of formula (VII): wherein R1 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms; Y is either nothing or a spacer group ranging in length from 2 to 30 atoms, wherein said spacer comprises —CO-alkylene-NH—, —CO-alkylene-CO— or a combination thereof; wherein if Y is nothing the lipid moiety is directly linked to the glycosaminoglycan via an amide bond and if Y is a spacer group, the spacer group is directly linked to the glycosaminoglycan via an amide or an ester bond and to the lipid moiety via an amide bond; X is a glycosaminoglycan; and n is the number of lipid moiety molecules bound to a molecule of X wherein n is a number from 1 to 1000; wherein said damage to the nervous system in said subject is ameliorated. ### Claim 14 A method of ameliorating damage to the nervous system in a subject suffering from multiple sclerosis in need thereof, comprising administering to said subject an effective amount of a conjugate having the general structure of formula (VIII): wherein R1 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms; R2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms; Z is either ethanolamine, serine, inositol, choline, or glycerol; Y is either nothing or a spacer group ranging in length from 2 to 30 atoms, wherein said spacer comprises —CO-alkylene-NH—, —CO-alkylene-CO— or a combination thereof; wherein if Y is nothing the lipid moiety is directly linked to the glycosaminoglycan via an amide bond and if Y is a spacer group, the spacer group is directly linked to the glycosaminoglycan via an amide or an ester bond and to the lipid moiety via an amide bond; X is a glycosaminoglycan; and n is the number of lipid moiety molecules bound to a molecule of X wherein n is a number from 1 to 1000; wherein said damage to the nervous system in said subject is ameliorated. ### Claim 15 A method of ameliorating damage to the nervous system in a subject suffering from multiple sclerosis in need thereof, comprising administering to said subject an effective amount of a conjugate having the general structure of formula (IX): wherein R1 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms; R2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms; Z is either choline, phosphate, inositol, or glycerol; Y is either nothing or a spacer group ranging in length from 2 to 30 atoms, wherein said spacer comprises —CO-alkylene-NH—, —CO-alkylene-CO— or a combination thereof; wherein if Y is nothing the lipid moiety is directly linked to the glycosaminoglycan via an amide bond and if Y is a spacer group, the spacer group is directly linked to the glycosaminoglycan via an amide or an ester bond and to the lipid moiety via an amide bond; X is a glycosaminoglycan; and n is the number of lipid moiety molecules bound to a molecule of X wherein n is a number from 1 to 1000; wherein said damage to the nervous system in said subject is ameliorated. ### Claim 16 (depends on 1) The method of claim 1, wherein said subject is administered a composition comprising said conjugate. ### Claim 17 (depends on 16) The method of claim 16, wherein said composition further comprises a pharmaceutically acceptable carrier or excipient. ### Claim 18 (depends on 1) The method of claim 1, wherein said damage to the nervous system is caused by inflammation.