# US 5,707,978 A · Heteroaryl-substituted deoxy glycero-phosphoethanolamines > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 5,707,978 A - Document ID: US5707978A - Status: Granted - Kind: A - Application number: 08/485,427 - Filed: 1995-06-07 - Granted: 1998-01-13 - Earliest claimed: 1994-11-22 - Assignees: Clarion Pharmaceuticals Inc. - Inventors: Friedrich Paltauf; Albin Hermetter; Rudolf Franzmair - Web page: https://patentgrep.com/patent/US5707978A ## CPC - C07F 9/65188: {condensed with carbocyclic rings or carbocyclic ring systems} - A61P 17/00: Drugs for dermatological disorders - A61P 17/06: Antipsoriatics - A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] - A61P 35/00: Antineoplastic agents - C07F 9/10: Phosphatides, e.g. lecithin - C07F 9/572: Five-membered rings - C07F 9/5728: {condensed with carbocyclic rings or carbocyclic ring systems} - C07F 9/65031: {having the nitrogen atoms in the positions 1 and 2} - C07F 9/6506: having the nitrogen atoms in positions 1 and 3 - C07F 9/6518: Five-membered rings - C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract Therapeutically active, heteroaryl-substituted deoxy glycero-phosphoethanolamines are disclosed having the general Formula I: ##STR1## wherein one of X, Y or Z is a fatty ether substituent, one is a heteroaryl ring substituent with 1-4 nitrogens as the only heteroatoms, one of which is bonded to a carbon of the glyceryl backbone, and one is a phosphoethanolamine substituent substituted at the nitrogen, provided that each of X, Y and Z is a different substituent, and the pharmaceutical compositions comprising the therapeutically active compounds and methods of using the therapetically active compounds to treat cancerous tumors, psoriasis and inflammation are also disclosed. ## Claims ### Claim 1 Heteroaryl substituted glycero-phosphoethanolamines of formulas Ia, Ib and Ic: ##STR13## and enantiomeric and cis- and trans-geometric isomers thereof, wherein R represents a substituted or unsubstituted straight or branched chain C.sub.10-24 alkyl or alkenyl, said substituent being one or more of halo, C.sub.1-3 alkoxy or cyano, provided that a double bond of said alkenyl does not involve the carbon atom of said alkenyl that is bonded to the oxygen atom of the glyceryl chain; Het represents a 5- to 9-membered heteroaryl mono- or bicyclic ring system with 1 to 4 nitrogen atoms as the sole hetero atoms, one of which nitrogen atoms is bonded to the carbon atom of the glyceryl chain; and PEA, together with the oxygen atom of the glyceryl chain to which PEA is bonded, represents a phosphoethanolamine of the formula: ##STR14## wherein R.sup.1, R.sup.2 and R.sup.3 are each hydrogen or methyl, provided that at least one of R.sup.1, R.sup.2 and R.sup.3 is methyl; and the pharmaceutically acceptable salts thereof. ### Claim 2 (depends on 1) A glycerophosphoethanolamine of claim 1 wherein Het is imidazolyl or 1-triazolyl. ### Claim 3 (depends on 1) A glycerophosphoethanolamine of claim 1 which is of Formula Ia. ### Claim 4 (depends on 1) A glycerophosphoethanolamine of claim 1 which is of Formula Ia wherein Het is imidazolyl or 1-triazolyl. ### Claim 5 (depends on 1) A glycerophosphoethanolamine of claim 1 wherein said R is C.sub.14-20 alkyl or C.sub.14-20 alkenyl. ### Claim 6 (depends on 1) A glycerophosphoethanolamine of claim 1 wherein said R is C.sub.16-18 alkyl or C.sub.16-18 alkenyl. ### Claim 7 (depends on 1) A glycerophosphoethanolamine of claim 1 wherein R.sup.1, R.sup.2, and R.sup.3 are methyl. ### Claim 8 (depends on 1) A glycerophosphoethanolamine of claim 1 which is of Formula Ia wherein Het is imidazolyl or 1-triazolyl, R is C.sub.16-18 alkyl, and R.sup.1, R.sup.2, and R.sup.3 are methyl. ### Claim 9 (depends on 1) A compound of claim 1 which is selected from the group consisting of: 1-O-octadecyl-2-(1-imidazolyl)-2-deoxy-glycero-3-phosphocholine; 1-O-octadecyl-2-(1-triazolyl)-2-deoxy-glycero-3-phosphocholine; and 1-O-hexadecyl-2-(1-imidazolyl)-2-deoxy-glycero-3-phosphocholine. ### Claim 10 A method of treating a tumor in a mammal comprising administering to said mammal an anti-tumor-effective amount of a glycero-phosphoethanolamine of Formula Ia, Ib, or Ic: ##STR15## or any of the enantiomeric and cis- and trans-geometric isomers thereof, wherein R represents a substituted or unsubstituted straight or branched chain C.sub.10-24 alkyl or alkenyl, said substituent being one or more of halo, C.sub.1-3 alkoxy or cyano, provided that a double bond of said alkenyl does not involve the carbon atom of said alkenyl that is bonded to the oxygen atom of the glyceryl chain; Het represents a 5- to 9-membered heteroaryl mono- or bicyclic ring system with 1 to 4 nitrogen atoms as the sole hetero atoms, one of which nitrogen atoms is bonded to the carbon atom of the glyceryl chain; and PEA, together with the oxygen atom of the glyceryl chain to which PEA is bonded, represents a phosphoethanolamine of the formula: ##STR16## wherein R.sup.1, R.sup.2 and R.sup.3 are each hydrogen or methyl, provided that at least one of R.sup.1, R.sup.2 and R.sup.3 is methyl; or a pharmaceutically acceptable salt thereof. ### Claim 11 (depends on 10) The method of claim 10 wherein said glycero-phosphoethanolamine is a compound of Formula Ia. ### Claim 12 (depends on 10) The method of claim 10 wherein said glycero-phosphoethanolamine is a compound of Formula Ia in which Het is imidazolyl or 1-triazolyl, R is C.sub.16-18 alkyl and R.sup.1, R.sup.2 and R.sup.3 are methyl. ### Claim 13 (depends on 10) The method of claim 10 wherein said glycero-phosphoethanolamine is selected from the group consisting of: 1-O-octadecyl-2-(1-imidazolyl)-2-deoxy-glycero-3-phosphocholine; 1-O-octadecyl-2-(1-triazolyl)-2-deoxy-glycero-3-phosphocholine; and 1-O-hexadecyl-2-(1-imidazolyl)-2-deoxy-glycero-3-phosphocholine. ### Claim 14 A method of treating psoriasis in a mammal comprising administering to said mammal an anti-psoriatic-effective amount of a glycerophosphoethanolamine of Formula Ia, Ib or Ic: ##STR17## or any of the enantiomeric and cis- and trans-geometric isomers thereof, wherein R represents a substituted or unsubstituted straight or branched chain C.sub.10-24 alkyl or alkenyl, said substituent being one or more of halo, C.sub.1-3 alkoxy or cyano, provided that a double of said alkenyl does not involve the carbon atom of said alkenyl that is bonded to the oxygen atom of the glyceryl chain; Het represents a 5- to 9-membered heteroaryl mono- or bicyclic ring system with 1 to 4 nitrogen atoms as the sole hetero atoms, one of which nitrogen atoms is bonded to the carbon atom of the glyceryl chain; and PEA, together with the oxygen atom of the glyceryl chain to which PEA is bonded, represents a phosphoethanolamine of the formula: ##STR18## wherein R.sup.1, R.sup.2 and R.sup.3 are each hydrogen or methyl, provided that at least 1 of R.sup.1, R.sup.2 and R.sup.3 is methyl; or a pharmaceutically acceptable salt thereof. ### Claim 15 (depends on 14) The method of claim 14 wherein said glycero-phosphoethanolamine is a compound of Formula Ia. ### Claim 16 (depends on 14) The method of claim 14 wherein said glycero-phosphoethanolamine is a compound of Formula Ia in which Het is imidazolyl or 1-triazolyl, R is C.sub.16-18 alkyl, and R.sup.1, R.sup.2 and R.sup.3 are methyl. ### Claim 17 (depends on 14) The method of claim 14 wherein said glycero-phosphoethanolamine is selected from the group consisting of: 1-O-octadecyl-2-(1-imidazolyl)-2-deoxy-glycero-3-phosphocholine; 1-O-octadecyl-2-(1-triazolyl)-2-deoxy-glycero-3-phosphocholine; and 1-O-hexadecyl-2-(1-imidazolyl)-2-deoxy-glycero-3-phosphocholine. ### Claim 18 A method of treating inflammation in a mammal comprising administering to said mammal an anti-inflammatory-effective amount of a glycerophosphoethanolamine of Formula Ia, Ib or Ic: ##STR19## or any of the enantiomeric and cis- and trans-geometric isomers thereof, wherein R represents a substituted or unsubstituted straight or branched chain C.sub.10-24 alkyl or alkenyl, said substituent being one or more of halo, C.sub.1-3 alkoxy or cyano, provided that a double bond of said alkenyl does not involve the carbon atom of said alkenyl that is bonded to the oxygen atom of the glyceryl chain; Het represents a 5- to 9-membered heteroaryl mono- or bicyclic ring system with 1 to 4 nitrogen atoms as the sole hetero atoms, one of which nitrogen atoms is bonded to the carbon atom of the glycero chain; and PEA, together with the oxygen atom of the glyceryl chain to which PEA is bonded, represents a phosphoethanolamine of the formula: ##STR20## wherein R.sup.1, R.sup.2 and R.sup.3 are each hydrogen or methyl, provided that at least one of R.sup.1, R.sup.2 and R.sup.3 is methyl; or a pharmaceutically acceptable salt thereof. ### Claim 19 (depends on 18) The method of claim 18 wherein said glycero-phosphoethanolamine is a compound of Formula Ia. ### Claim 20 (depends on 18) The method of claim 18 wherein said glycero-phosphoethanolamine is a compound of Formula Ia in which Het is imidazolyl or 1-triazolyl, R is C.sub.16-18 alkyl, and R.sup.1, R.sup.2 and R.sup.3 are methyl. ### Claim 21 (depends on 18) The method of claim 18 wherein said glycero-phosphoethanolamine is selected from the group consisting of: 1-O-octadecyl-2-(1-imidazolyl)-2-deoxy-glycero-3-phosphocholine; 1-O-octadecyl-2-(1-triazolyl)-2-deoxy-glycero-3-phosphocholine; and 1-O-hexadecyl-2-(1-imidazolyl)-2-deoxy-glycero-3-phosphocholine. ### Claim 22 A pharmaceutical composition comprising an anti-tumor, anti-psoriatic or anti-inflammation-effective amount of a heteroaryl substituted glycero-phosphoethanolamine of Formulas Ia, Ib or Ic: ##STR21## or any of the enantiomeric cis- and trans-geometric isomers thereof, wherein R represents a substituted or unsubstituted straight or branched chain C.sub.10-24 alkyl or alkenyl, said substituent being one or more of halo, C.sub.1-3 alkoxy or cyano, provided that a double bond of said alkenyl does not involve the carbon atom of said alkenyl that is bonded to the oxygen atom of the glyceryl chain; Het represents a 5- to 9-membered heteroaryl mono- or bicyclic ring system with 1 to 4 nitrogen atoms as the sole hetero atoms, one of which nitrogen atoms is bonded to the carbon atom of the glyceryl chain; and PEA, together with the oxygen atom of the glyceryl chain to which PEA is bonded, represents a phosphoethanolamine of the formula: ##STR22## wherein R.sup.1, R.sup.2 and R.sup.3 are each hydrogen or methyl, provided that at least one of R.sup.1, R.sup.2 and R.sup.3 is methyl; or a pharmaceutically acceptable salt thereof. ### Claim 23 (depends on 22) The composition of claim 22 wherein Het is imidazolyl or 1-triazolyl. ### Claim 24 (depends on 22) The composition of claim 22 wherein said glycero-phosphoethanolamine is a compound of Formula Ia. ### Claim 25 (depends on 22) The composition of claim 22 wherein R is selected from the group consisting of C.sub.14-20 alkyl and C.sub.14-20 alkenyl. ### Claim 26 (depends on 22) The composition of claim 22 wherein R is selected from the group consisting of C.sub.16-18 alkyl and C.sub.16-18 alkenyl. ### Claim 27 (depends on 22) The composition of claim 22 wherein said glycero-phosphoethanolamine is a compound of Formula Ia wherein Het is imidazolyl or 1-triazolyl, R is C.sub.16-18 alkyl, and R.sup.1, R.sup.2 and R.sup.3 are methyl. ### Claim 28 (depends on 22) The composition of claim 22 wherein said glycero-phosphoethanolamine is selected from the group consisting of: 1-O-octadecyl-2-(1-imidazolyl)-2-deoxy-glycero-3-phosphocholine; 1-O-octadecyl-2-(1-triazolyl)-2-deoxy-glycero-3-phosphocholine; and 1-O-hexadecyl-2-(1-imidazolyl)-2-deoxy-glycero-3-phosphocholine. ### Claim 29 (depends on 1) A pharmaceutical composition for topical use comprising from about 0.1 to about 5.0 weight percent of a compound of claim 1 and a pharmaceutically acceptable carrier in ointment form. ### Claim 30 (depends on 29) The topical composition of claim 29 wherein said compound is a compound of Formula Ia wherein Het is imidazolyl or 1-triazolyl, R is C.sub.16-18 alkyl, and R.sup.1, R.sup.2 and R.sup.3 are methyl. ### Claim 31 (depends on 29) The topical composition of claim 29 wherein said compound is selected from the group consisting of: 1-O-octadecyl-2-(1-imidazolyl)-2-deoxy-glycero-3-phosphocholine; 1-O-octadecyl-2-(1-triazolyl)-2-deoxy-glycero-3-phosphocholine; and 1-O-hexadecyl-2-(1-imidazolyl)-2-deoxy-glycero-3-phosphocholine.