CA2495260A1 - Resolvins: biotemplates for novel therapeutic interventions - Google Patents

Resolvins: biotemplates for novel therapeutic interventions Download PDF

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CA2495260A1
CA2495260A1 CA002495260A CA2495260A CA2495260A1 CA 2495260 A1 CA2495260 A1 CA 2495260A1 CA 002495260 A CA002495260 A CA 002495260A CA 2495260 A CA2495260 A CA 2495260A CA 2495260 A1 CA2495260 A1 CA 2495260A1
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membered
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CA2495260C (en
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Charles N. Serhan
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Brigham and Womens Hospital Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/48—Unsaturated compounds containing hydroxy or O-metal groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Abstract

The present invention is generally drawn to novel isolated therapeutic agent s, termed resolvins, generated from the interaction between a dietary omega-3 polyunsaturated fatty acid (PUFA) such as eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), cyclooxygenase-II (COX-2) and an analgesic, such as aspirin (ASA). Surprisingly, careful isolation of compounds generated fro m the combination of components in an appropriate environment provide di- and tri-hydroxy EPA or DHA compounds having unique structural and physiological properties. The present invention therefore provides for many new useful therapeutic di- or tri-hydroxy derivatives of EPA or DHA (resolvins) that diminish, prevent, or eliminate inflammation or PMN migration, for example. The present invention also provides methods of use, methods of preparation, and packaged pharmaceuticals for use as medicaments for the compounds disclosed throughout the specification.

Claims (12)

1. A compound having the formula:
wherein P1 and P2 each individually are protecting groups, hydrogen atoms or combinations thereof;
wherein Z is -C(O)OR d, -C(O)NR c R c, -C(O)H, -C(NH)NR c R c, -C(S)H, -C(S)OR d, -C(S)NR c R c, -CN;
each R a, is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, {C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl;
each R b, is a suitable group independently selected from the group consisting of =O, -OR d, (C1-C3) haloalkyloxy, -OCF3, =S, -SR d, =NR d, =NOR
d, -NR c R c, halogen, -CF3, -CN, -NC, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)R d, -S(O)2R d, -S(O)2OR d, -S(O)NR c R c, -S(O)2NR c R c, -OS{O)R d, -OS(O)2R d, -OS(O)2OR d, -OS(O)2NR c R c, -C(O)R d, -C(O)OR d, -C(O)NR c R c, -C(NH)NR c R
c, -C(NR a)NR c R c, -C(NOH)R a, -C(NOH)NR c R c, -OC(O)R d, -OC(O)OR d, -OC(O)NR c R c, -OC(NH)NR c R c, -OC(NR a)NR c R c, -[NHC(O)]n R d, -[NR a C(O)]n R d, -[NHC(O)]n OR d, -[NR a C(O)]n OR d -[NHC(O)]n NR c R c, -[NR a C(O)]n NR c R
c, -[NHC(NH)]n NR c R c and -[NR a C(NR a)]n NR c R c;
each R c, is independently a protecting group or R a, or, alternatively, each R c is taken together with the nitrogen atom to which it is bonded to form a 5 to membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R a or suitable R b groups;
each n, independently is an integer from 0 to 3;
each R d, independently is a protecting group or R a;
and pharmaceutically acceptable salts thereof.
2. The compound of claim 1 wherein P1 and P2 are hydrogen atoms and Z is carboxylic acid or a carboxylic ester.
3. The compound of claim 1 wherein Z is a carboxylic acid salt.
4. The compound of claim 3 wherein the salt is an ammonium salt.
5. A compound having the formula:
wherein P1, P2 and P3 each individually are protecting groups, hydrogen atoms or combinations thereof;
wherein Z is -C(O)OR d, -C(O)NR c R c, -C(O)H, -C(NH)NR c R c, -C(S)H, -C(S)OR d, -C(S)NR c R c, -CN;

each R a, is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and
6-16 membered heteroarylalkyl;
each R b, is a suitable group independently selected from the group consisting of =O, -OR d, (C1-C3) haloalkyloxy, -OCF3, =S, -SR d, =NR d, =NOR
d, -NR c R c, halogen, -CF3, -CN, -NC, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)R d, -S(O)2R d, -S(O)2OR d, -S(O)NR c R c, -S(O)2NR c R c, -OS(O)R d, -OS(O)2R d, -OS(O)2OR d, -OS(O)2NR c R c, -C(O)R d, -C(O)OR d, -C(O)NR c R c, -C(NH)NR c R
c, -C(NR a)NR c R c, -C(NOH)R a, -C(NOH)NR c R c, -OC(O)R d, -OC(O)OR d, -OC(O)NR c R c, -OC(NH)NR c R c, -OC(NR a)NR c R c, -[NHC(O)]n R d, -[NR a C(O)]n R d, -[NHC(O)]n OR d -[NR a C(O)]n OR d, -[NHC(O)]n NR c R c -[NR a C(O)]n NR c R c -[NHC(NH)]n NR c R c and -[NR a C(NR a)]n NR c R c;
each R c, is independently a protecting group or R a, or, alternatively, each R c is taken together with the nitrogen atom to which it is bonded to form a 5 to membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R a or suitable R b groups;
each n, independently is an integer from 0 to 3;
each R d, independently is a protecting group or R a;
and pharmaceutically acceptable salts thereof.
6. The compound of claim 5 wherein P1, P2 and P3 each axe hydrogen atoms and Z is a carboxylic acid or a carboxylic ester.
7. The compound of claim 5 wherein Z is a carboxylic acid salt.
8. The compound of claim 7 wherein the salt is an ammonium salt.
9. A compound having the formula:
wherein P1 is a protecting group or a hydrogen atom;
wherein X is a substituted or unsubstituted methylene, an oxygen atom, a substituted or unsubstituted nitrogen atom, or a sulfur atom;
wherein Z is -C(O)OR d, -C(O)NR c R c, -C(O)H, -C(NH)NR c R c, -C(S)H, -C(S)OR d, -C(S)NR c R c, -CN;
each R a, is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl;
each R b, is a suitable group independently selected from the group consisting of =O, -OR d, (C1-C3) haloalkyloxy, -OCF3, =S, -SR d, =NR d, =NOR
d, -NR c R c, halogen, -CF3, -CN, -NC, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)R d, -S(O)2R d, -S(O)2OR d, -S(O)NR c R c, -S(O)2NR c R c, -OS(O)R d, -OS(O)2R d, -OS(O)2OR d, -OS(O)2NR c R c, -C(O)R d, -C(O)OR d, -C(O)NR c R c, -C(NH)NR c R
c, -C(NR a)NR c R c, -C(NOH)R a, -C(NOH)NR c R c, -OC(O)R d, -OC(O)OR d, -OC(O)NR c R c, -OC(NH)NR c R c, -OC(NR a)NR c R c, -[NHC(O)]n R d, -[NR a C(O)]n R d, -[NHC(O)]n OR d, -[NR a C(O)]n OR d, -[NRC(O)]n NR c R c, -[NR a C(O)]n NR c R
c, -[NHC(NH)]n R c R c and -[NR aC(NR a)]n NR c R c;

each R c, is independently a protecting group or R a, or, alternatively, each R c is taken together with the nitrogen atom to which it is bonded to form a 5 to membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R a or suitable R b groups;
each n, independently is an integer from 0 to 3;
each R d, independently is a protecting group or R a;
and pharmaceutically acceptable salts thereof.
10. The compound of claim 9 wherein P1 is a hydrogen atom, X is an oxygen atom and Z is a carboxylic acid or a carboxylic ester.
11. The compound of claim 9 wherein Z is a carboxylic acid salt.
12. The compound of claim 11 wherein the salt is an ammonium salt.
CA2495260A 2002-08-12 2003-08-12 Resolvins: biotemplates for novel therapeutic interventions Expired - Lifetime CA2495260C (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US40279802P 2002-08-12 2002-08-12
US60/402,798 2002-08-12
US10/639,714 US7585856B2 (en) 2002-08-12 2003-08-12 Resolvins: Biotemplates for novel therapeutic interventions
US10/639,714 2003-08-12
PCT/US2003/025336 WO2004014835A2 (en) 2002-08-12 2003-08-12 Resolvins: biotemplates for therapeutic interventions

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CA2495260C CA2495260C (en) 2012-05-29

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EP (3) EP1537067B1 (en)
JP (7) JP4845378B2 (en)
AT (1) ATE449057T1 (en)
AU (2) AU2003258194B2 (en)
CA (1) CA2495260C (en)
DE (1) DE60330154D1 (en)
DK (1) DK2216318T3 (en)
ES (1) ES2700133T3 (en)
HU (1) HUE041471T2 (en)
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