Title:
NITRATE ESTERS AND THEIR USE FOR INTRODUCING NEUROPROTECTION AND COGNITION ENHANCEMENT
Document Type and Number:
WIPO Patent Application WO/2000/054756
Kind Code:
A2
Abstract:
Compounds and methods for mitigating neurodegeneration, effecting neuroprotection and/or effecting cognition enhancement in a subject are described. Neurological or cognitive conditions are treated by administering to a subject an effective amount of a therapeutic compound comprising a nitrate ester, or a pharmaceutically acceptable salt or ester thereof.
Inventors:
THATCHER GREGORY R J
BENNETT BRIAN M
REYNOLDS JAMES N
BOEGMAN ROLAND J
JHAMANDAS KHEM
BENNETT BRIAN M
REYNOLDS JAMES N
BOEGMAN ROLAND J
JHAMANDAS KHEM
Application Number:
PCT/CA2000/000280
Publication Date:
September 21, 2000
Filing Date:
March 15, 2000
Export Citation:
Assignee:
UNIV KINGSTON (CA)
International Classes:
A61K31/21; A61K31/255; A61K31/26; A61K31/275; A61K31/34; A61K31/341; A61K31/381; A61K31/385; A61K31/39; A61K31/426; A61K31/506; A61K31/513; A61K31/575; A61K31/662; A61P25/00; A61P25/28; A61P39/06; A61P43/00; C07C203/04; C07C255/14; C07C317/18; C07C323/12; C07C327/28; C07C331/10; C07C381/02; C07D277/24; C07D307/33; C07D327/04; C07D333/48; C07D339/08; C07D411/04; C07F9/09; C07F9/40; C07J9/00; C07J41/00; (IPC1-7): A61K31/00
Domestic Patent References:
| WO1998043621A1 | 1998-10-08 |
Foreign References:
| US4540654A | 1985-09-10 | |||
| US5389623A | 1995-02-14 | |||
| US5166320A | 1992-11-24 | |||
| US4522811A | 1985-06-11 | |||
| US5374548A | 1994-12-20 | |||
| US5399331A | 1995-03-21 | |||
| US5416016A | 1995-05-16 | |||
| US5807847A | 1998-09-15 | |||
| US5883122A | 1999-03-16 |
Other References:
LIPTON, S. A. ET AL: "NO-related species can protect from focal cerebral ischemia/reperfusion" PHARMACOL. CEREB. ISCHEMIA 1996, [INT. SYMP.], 6TH (1996), 183-191. EDITOR(S): KRIEGLSTEIN, JOSEF. PUBLISHER: MEDPHARM SCIENTIFIC PUBLISHERS, STUTTGART, GERMANY. , XP000956443
LIPTON, S. A. ET AL: "S-nitrosylation of NMDA receptor and caspases affords neuroprotection from NMDA receptor-mediated insults" PHARMACOL. CEREB. ISCHEMIA 1998, [INT. SYMP.], 7TH (1999), MEETING DATE 1998, 217-226. EDITOR(S): KRIEGLSTEIN, JOSEF. PUBLISHER: MEDPHARM SCIENTIFIC PUBLISHERS, STUTTGART, GERMANY. , XP000956442
UCHIYAMA-TSUYUKI, YOSHIMI ET AL: "VA-045, a novel apovincaminic acid derivative attenuates neuronal injury induced by hypoxia or by excitatory amino acids in cultures of rat cortices" LIFE SCI. (1996), 59(18), 1571-1578 , XP000956386
RAMOS-ZUNIGA R ET AL: "Neuroprotection in selective focal ischemia in rats by nitrates, an alternative redox manipulation on nitric oxide: Experimental model." MINIMALLY INVASIVE NEUROSURGERY, vol. 41, no. 3, 1998, pages 152-160, XP000956402 ISSN: 0946-7211
LIPTON, S. A. ET AL: "S-nitrosylation of NMDA receptor and caspases affords neuroprotection from NMDA receptor-mediated insults" PHARMACOL. CEREB. ISCHEMIA 1998, [INT. SYMP.], 7TH (1999), MEETING DATE 1998, 217-226. EDITOR(S): KRIEGLSTEIN, JOSEF. PUBLISHER: MEDPHARM SCIENTIFIC PUBLISHERS, STUTTGART, GERMANY. , XP000956442
UCHIYAMA-TSUYUKI, YOSHIMI ET AL: "VA-045, a novel apovincaminic acid derivative attenuates neuronal injury induced by hypoxia or by excitatory amino acids in cultures of rat cortices" LIFE SCI. (1996), 59(18), 1571-1578 , XP000956386
RAMOS-ZUNIGA R ET AL: "Neuroprotection in selective focal ischemia in rats by nitrates, an alternative redox manipulation on nitric oxide: Experimental model." MINIMALLY INVASIVE NEUROSURGERY, vol. 41, no. 3, 1998, pages 152-160, XP000956402 ISSN: 0946-7211
Attorney, Agent or Firm:
Scribner, Stephen J. (Ontario K7L 3N6, CA)
Download PDF:
Claims:
What is claimed is:
| 1. | A method for effecting cognition enhancement in a subject in need thereof comprising administering to said subject an effective amount of a therapeutic compound such that cognition enhancement occurs, wherein the therapeutic compound has the formula (Formula 1): wherein E, F, G are organic radicals which may contain inorganic counterions. |
| 2. | A method for mitigating cellular damage due to ischemia in a subject in need thereof comprising administering to said subject an effective amount of a therapeutic compound such that cellular damage is mitgated, wherein the therapeutic compound has the formula (Formula I): wherein E, F, G are organic radicals which may contain inorganic counterions. |
| 3. | A method for mitigating neurodegeneration in a subject, comprising administering to said subject an effective amount of a therapeutic compound such that mitigation of neurodegeneration occurs, wherein the therapeutic compound has the formula (Formula: wherein E, F, G are organic radicals which may contain inorganic counterions, with the proviso that when E is methylene, F and G are not both Cl organic radicals each bearing one nitrate group. |
| 4. | A method for mitigating neurodegeneration in a subject, comprising administering to said subject an effective amount of a therapeutic compound such that mitigation of neurodegeneration occurs, wherein the therapeutic compound has the formula (Formula : in which: m, n, p are integers from 0 to 10; R3 t7 are each independently hydrogen, a nitrate group, or A; Rl 4 are each independently hydrogen or A; where A is selected from: a substituted or unsubstituted aliphatic group (preferably a branched, or straightchain aliphatic moiety having from 1 to 24 carbon atoms in the chain, which optionally contains O, S, NR6 and unsaturations in the chain, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups; an unsubstituted or substituted cyclic aliphatic moiety having from 3 to 7 carbon atoms in the aliphatic ring, which optionally contains O, S, NR6 and unsaturations in the ring, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups; an unsubstituted or substituted aliphatic moiety constituting a linkage of from 0 to 5 carbons, between R'and R'and/or between R'7 and R4, which optionally contains O, S, NR6 and unsaturations in the linkage, and optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups); a substituted or unsubstituted aliphatic group (preferably a branched, cyclic or straightchain aliphatic moiety having from 1 to 24 carbon atoms in the chain), containing carbonyl linkages (e. g. C=O, C=S, C=NOH), which optionally contains O, S, NR6and unsaturations in the chain, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups; a substituted or unsubstituted aryl group; a heterocyclic group; amino (including alkylamino, dialkylamino (including cyclic amino, diamino and triamino moieties), arylamino, diarylamino, and alkylarylamino); hydroxy; alkoxy; a substituted or unsubstituted aryloxy; R2, RI R'8, R19 are optionally hydrogen, A, or XY; where X is F, Br, Cl, NO2, CH2, CF2, O, NH, NMe, CN, NHOH, N2H,, N3,S,SCN,SCN2H2(R15)2,SCN2H3(R15),SC(O)N(R15)2,N2H2R13,N2HR13R14, SC (O) NHR15, S03M, SH, SR', SO2M, S (O) R8, S (O) 2R9, S (O) OR8, S (O) 2OR9, PO2HM, P(O)(OR15)(OR16),P(O)(OR16)(OM),P(O)(R15)(OR8),P(O)(OM)R15,PO3HM,PO3M2, CO2R11,C(O),C(O)R12,C(O)(OR13),PO2H,PO2M,P(O)(OR14),CO2M,CO2H, SO2,C(O)(SR13),SR5,SSR7orSSR5;P(O)(R13),SO, Y is F, Br, Cl, CH3, CF2H, CF3, OH, NH2, NHR6, NR'R', CN, NHOH, N2H3, N3,S,SCN,SCN2H2(R15)2,SCN2H3(R15),SC(O)N(R15)2,N2H2R13,N2HR13R14, SC (O) NHR15, SO3M, SH, SR', SO2M, S (O) R8, S (O) 2R9, S (O) OR8, S (O) 2OR9, PO2HM, P03M2, P (O) (OR") (OR16) P (0) (OR16) (OM), P (O) (R") (OR8), P(O)(OM)R15, CO2M, CO2H, CO2R11, C (O) R12, C (O) (OR"), C (O) (SR13), SR5, SSR7 or SSR5, or does not exist; R6, R', R8,R9,R11,R12,R13,R14,R15,R16 are the same or different alkyl or acyl groups containing 124 carbon atoms which may contain 14 ONO2 substituents; or C, C6 connections to R'R4 in cyclic derivatives; or are each independently hydrogen, a nitrate group, or A; and M is H, Na+, K+, NH4+, N+JHkR11(4k) where k is 03, or other pharmaceutically acceptable counterion; and with the proviso, when m = n = p = 1; Rut9, R2, R18, R1 = H ; Rut7, R'are nitrate groups; that R4 is not H or C,C, alkyl. |
| 5. | The method of claim 4, wherein: R'9 is XY. |
| 6. | The method of claim 5, wherein: R'and R'are the same or different and selected from H, C1C4, alkyl chains, which may include one O, linking R'and R3 to form pentosyl, hexosyl, cyclopentyl, or cycohexyl rings, which rings optionally bear hydroxyl substituents; R2 and R4, are the same or different and selected from H, a nitrate group, C1C4 alkyl optionally bearing 13 nitrate group, and acyl groups (C (O) R); R7, R"are the same or different C,C8, alkyl or acyl; R5, R6, R8,R9,R10,R12,R13,R14,R15,R16 are the same or different alkyl groups containing 112 carbon atoms which may contain 14 ONO2 substituents; or C1 or C2 connections to R'R'in cyclic derivatives; and M is H, NH4+,N+HkR11(4k)wherekis03.K+,. |
| 7. | The method of claim 6, wherein: 1,n=0,p=1.m=. |
| 8. | The method of claim 7, wherein: X is CH2, O, NH, NMe, CN, NHOH, N2H3, N2H2R13, N2HR13R14, N3, S, SCN, SC(O)N(R15)2,SC(O)NHR15,SO3M,SH,SR7,SO2M,S(O)R8,SCN2H2(R15)2,SCN2H3(R15), S(O)2OR9,PO3HM,PO3M2,P(O)(OR15)(OR16),P(O)(OR16)(OM),S(O)2R9,S(O)OR8, P (O) (R15) (OR8), P (O) (OM) Rt5, C02M, CO2H, CO2RI', C (O), C (O) R12, C (O) (OR"), PO, M, P (O) (OR'4), P (O) (R"), SO, SO2, C(O)(SR13), SSR4 ; and Y is CN, N3,SCN,SCN2H2(R15)2,SC(O)N(R15)2,N2HR13R14, SR4,SO2M,PO3HM,PO3M2,P(O)(OR15)(OR16),P(O)(OR16)(OM),SC(O)NHR15,SO3M, P (O) (R'5) (OR8), P (O) (OM) R15, CO2M, CO2H, CO2R11, C (O) R12, C (O) (SR'3), SR5, SSR5, or does not exist. |
| 9. | The method of claim 6, wherein: R5, R6, R8,R9,R10,R12,R13,R14,R15,R16 are the same or different alkyls containing 1<BR> 12 carbon atoms; or Cl or C2 connections to R'or R3 in cyclic derivatives; X is CH2, O, NH, NMe, S, SO, M, SH, SR', SO2M, S (O) R8, S (O) 2R9, S (O) OR8, P(O)(OR15)(OR16),P(O)(OR16)(OM),P(O)(R15)(OR8),PO3HMorS(O)2OR9,PO3M2, P (O) (OM) R"; and Y is SO2M, SO3M, PO3HM, PO3M2, P (O) (OR") (OR16), P (O) (OR'6) (OM), SR', SR4 or SSR5, or does not exist. |
| 10. | The method of claim 3, wherein the therapeutic compound is administered orally, intravenously, buccally, transdermally or subcutaneously. |
| 11. | The method of claim 3, further comprising administering the therapeutic compound in a pharmaceutically acceptable vehicle. |
| 12. | The method of claim 3, wherein administering the therapeutic compound to the subject modulates an activity of the glutamate neuroreceptor. |
| 13. | The method of claim 3, wherein administering the therapeutic compound to the subject modulates an activity of a nonglutamate neuroreceptor. |
| 14. | The method of claim 3, wherein administering the therapeutic compound to the subject modulates cerebral guanylyl cyclase activity. |
| 15. | The method of claim 3, wherein administering the therapeutic compound to the subject modulates apoptosis. |
| 16. | The method of claim 3, wherein administering the therapeutic compound to the subject modulates cerebral free radical damage. |
| 17. | A method for treating a disease state associated with neurodegeneration in a subject, comprising administering to said subject an effective amount of a therapeutic compound such that a disease state associated with neurodegeneration is treated, wherein the therapeutic compound has the formula (Formula Il): in which: m, n, p are integers from 0 to 10; R317 are each independently hydrogen, a nitrate group, or A; Rt 4 are each independently hydrogen or A; where A is selected from: a substituted or unsubstituted aliphatic group (preferably a branched, or straightchain aliphatic moiety having from 1 to 24 carbon atoms in the chain, which optionally contains O, S, NR6 and unsaturations in the chain, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups; an unsubstituted or substituted cyclic aliphatic moiety having from 3 to 7 carbon atoms in the aliphatic ring, which optionally contains O, S, NR6 and unsaturations in the ring, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups; an unsubstituted or substituted aliphatic moiety constituting a linkage of from 0 to 5 carbons, between R'and R'and/or between R"and R4, which optionally contains O, S, NR6 and unsaturations in the linkage, and optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups); a substituted or unsubstituted aliphatic group (preferably a branched, cyclic or straightchain aliphatic moiety having from 1 to 24 carbon atoms in the chain), containing carbonyl linkages (e. g. C=0, C=S, C=NOH), which optionally contains O, S, NR6and unsaturations in the chain, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups; a substituted or unsubstituted aryl group; a heterocyclic group; amino (including alkylamino, dialkylamino (including cyclic amino, diamino and triamino moieties), arylamino, diarylamino, and alkylarylamino); hydroxy; alkoxy; a substituted or unsubstituted aryloxy; R2, R5, Rut8, R19 are optionally hydrogen, A, or XY; where X is F, Br, Cl, NO2, CH2, CF2, O, NH, NMe, CN, NHOH, N2H3, N3,S,SCN,SCN2H2(R15)2,SCN2H3(R15),SC(O)N(R15)2,N2H2R13,N2HR13R14, SH,SR7,SO2M,S(O)R8,S(O)2R9,S(O)OR8,S(O)2OR9,PO2HM,SC(O)NHR15,SO3M, P(O)(OR15)(OR16),P(O)(OR16)(OM),P(O)(R15)(OR8),P(O)(OM)R15,PO3HM,PO3M2, C02M, CO2H, CO2R'1, C (O), C (O) R, C (O) (OR"), PO2H, PO2M, P (O) (OR14), P (O) (R13), SO, SO2, C (O) (SR"), SR5, SSR'or SSRS; Y is F, Br, Cl, CH3, CF2H, CF3, OH, NH2, NHR6, NR6R7, CN, NHOH, N2H3, N3,S,SCN,SCN2H2(R15)2,SCN2H3(R15),SC(O)N(R15)2,N2H2R13,N2HR13R14, SH,SR7,SO2M,S(O)R8,S(O)2R9,S(O)OR8,S(O)2OR9,PO2HM,SC(O)NHR15,SO3M, PO3M2,PO3M2,P(O)(OR15)(OR16), P(O)(OM)R15,CO2M,P(O)(R15)(OR8), CO2H, CO2R11, C (O) R12, C (O) (OR13), C (O) (SR"), SR5, SSR'or SSR, or does not exist; R6, R', R8,R9,R10,R11,R12,R13,R14,R15,R16 are the same or different alkyl or acyl groups containing 124 carbon atoms which may contain 14 ONO2 substituents; or C1 C6 connections to RlR4 in cyclic derivatives; or are each independently hydrogen, a nitrate group, or W; and M is H, Na+, K+, NH4+, N+HkR11(4k) where k is 03, or other pharmaceutically acceptable counterion; and with the proviso, when n= = 1;= R18,R1=H;R17,R3arenitrategroups;R2, that R4 is not H or C,C3alkyl. |
| 18. | The method of claim 17, wherein: R'9 is XY. |
| 19. | The method of claim 18, wherein: R1 and R3 are the same or different and selected from H, C1C4, alkyl chains, which may inlude one O, linking R'and R'to form pentosyl, hexosyl, cyclopentyl, or cycohexyl rings, which rings optionally bear hydroxyl substituents; R2 and R4, are the same or different and selected from H, a nitrate group, C1C4 alkyl optionally bearing 13 nitrate group, and acyl groups (C (O) R'); R7,R11 are the same or different C,C8, alkyl or acyl; R5, R6, R8,R9,R10,R12,R13,R14,R15,R16 are the same or different alkyl groups containing 112 carbon atoms which may contain 14 ONO2 substituents; or C1 or C2 connections to R1 R3 in cyclic derivatives; and M is H, Na+, N+HkR11(4k)wherekis03.NH4+,. |
| 20. | The method of claim 19, wherein: 1,n=0,p=1.m=. |
| 21. | The method of claim 20, wherein: X is CH2, O, NH, NMe, CN, NHOH, N2H3, N2H2R, N2HR13R14, N3, S, SCN, SC(O)N(R15)2,SC(O)NHR15,SO3M,SH,SR7,SO2M,S(O)R8,SCN2H2(R15)2,SCN2H3(R15), S (O) R', S (O) OR', S(O)2OR9, PO3HM, PO3M2, P (O) (OR15) (OR'6), P (O) (OR16) (OM), P(O)(R15)(OR8), P(O)(OM)R15, CO2M, CO2H, CO2R11, C (O), C (O) R'2, C (O) (OR'3), PO, M, P (O) (OR'4), P (O) (R"), SO, SO2, C (O) (SR"), SSR4; and Y is CN, N2H2R13, N2HR13R14, N3, SCN, SCN2H2(R15)2, SC(O) N (R'5) 21 SC (O) NHR15, SO3M, SR4, SO2M, PO3HM, PO3M2, P(O)(OR15)(OR16), P (O) (OR'6) (OM), CO2M,CO2H,CO2R11,C(O)R12,C(O)(SR13),SR5,SSR5,orP(O)(R15)(OR8),P(O)(OM)R15, does not exist. |
| 22. | The method of claim 20, wherein: R5, R, R8,R9,R10,R12,R13,R14,R15,R16 are the same or different alkyls containing 1 12 carbon atoms; or Ct or C2 connections to R'or R3in cyclic derivatives; X is CH2, O, NH, NMe, S, SO3M, SH, SR', SO, M, S (O) R8, S (0) 2R9, S (O) OR, S(O)2OR9,P(O)(OR16)(OM),P(O)(R15)(OR8),PO3HMorP(O)(OR15)(OR16), P (O) (OM) Rl5 ; and SO2M,SO3M,PO3HM,PO3M2,P(O)(OR15)(OR16),P(O)(OR16)(OM),SR5,SR4Yis or SSR5, or does not exist. |
| 23. | The method of claim 2, wherein administering the therapeutic compound to the subject modulates levels of cyclic nucleotide cGMP and/or cAMP. |
| 24. | The method of claim 17, wherein the therapeutic compound is administered orally, intravenously, buccally, transdermally or subcutaneously. |
| 25. | The method of claim 17 further comprising administering the therapeutic compound in a pharmaceutically acceptable vehicle. |
| 26. | A method for effecting neuroprotection in a subject, comprising administering to said subject an effective amount of a therapeutic compound such that neuroprotection occurs, wherein the therapeutic compound has the formula (Formula Il): in which: m, n and p are integers from 0 to 10; R3,17 are each independently hydrogen, a nitrate group, or A; R1,4 are each independently hydrogen or A; where A is selected from: a substituted or unsubstituted aliphatic group (preferably a branched, or straightchain aliphatic moiety having from 1 to 24 carbon atoms in the chain, which optionally contains O, S, NR6 and unsaturations in the chain, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups; an unsubstituted or substituted cyclic aliphatic moiety having from 3 to 7 carbon atoms in the aliphatic ring, which optionally contains O, S, NR6 and unsaturations in the ring, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups; an unsubstituted or substituted aliphatic moiety constituting a linkage of from 0 to 5 carbons, between Rl and R'and/or between Rl'and R4, which optionally contains O, S, NR6 and unsaturations in the linkage, and optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups); a substituted or unsubstituted aliphatic group (preferably a branched, cyclic or straightchain aliphatic moiety having from 1 to 24 carbon atoms in the chain), containing carbonyl linkages (e. g. C=O, C=S, C=NOH), which optionally contains O, S, NR6 and unsaturations in the chain, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups; a substituted or unsubstituted aryl group; a heterocyclic group; amino (including alkylamino, dialkylamino (including cyclic amino, diamino and triamino moieties), arylamino, diarylamino, and alkylarylamino); hydroxy; alkoxy; a substituted or unsubstituted aryloxy; R2, R5 R18, R"are optionally hydrogen, A, or XY; where X is F, Br, Cl, NO2, O,NH,NMe,CN,NHOH,N2H3,CF2, N3,S,SCN,SCN2H2(R15)2,SCN2H3(R15),SC(O)N(R15)2,N2H2R13,N2HR13R14, SC (O) NHR15, SO, M, SH, SR', SO2M, S(O)R8, S (O) 2R9, S (O) OR8, S (O) 2OR9, PO2HM, P(O)(OR15)(OR16),P(O)(OR16)(OM),P(O)(R15)(OR8),P(O)(OM)R15,PO3HM,PO3M2, CO2R11,C(O),C(O)R12,C(O)(OR13),PO2H,PO2M,P(O)(OR14),CO2M,CO2H, SO2,C(O)(SR13),SR5,SSR7orSSR5;P(O)(R13),SO, Y is F, Br, Cl, CH3, CF2H, CF3, OH, NH2, NHR6, NR6R', CN, NHOH, N2H3, N2H2R", N2HRI'Rl4, N3, S, SCN, SCN2H2(R15)2, SCN2H3(R15), SC (O) N (R15)2 , SC (O) NHRl5, SO3M, SH, SR', SO, M, S (O) R8, S (O) 2R9, S (O) OR8, S (O) 2OR9, PO2HM, PO3M2,PO3M2,P(O)(OR15)(OR16), P(O)(OM)R15,CO2M,P(O)(R15)(OR8), CO2H, CO2R11, C (O) Rl2, C (O) (OR13), C (O) (SR"), SR5, SSR'or SSR5, or does not exist; R6,R7,R8,R9,R10,R11,R12,R13,R14,R15, R16 are the same or different alkyl or acyl groups containing 124 carbon atoms which may contain 14 ONO2 substituents; or C, C6 connections to R'R4 in cyclic derivatives; or are each independently hydrogen, a nitrate group, or W; and M is H, Na+, K+, NH4+, N+HkR11(4k) where k is 03, or other pharmaceutically acceptable counterion; and with the proviso, when m = n = p = 1; R'9, R2, R'8, R'= H; Rut', R'are nitrate groups; that R4 is not H or C,C3 alkyl. |
| 27. | The method of claim 26, wherein: R'9 is XY. |
| 28. | The method of claim 27, wherein: R1 and R3 are the same or different and selected from H, C1C4, alkyl chains which may inlude one O, linking R'and R3 to form pentosyl, hexosyl, cyclopentyl, or cycohexyl rings, which rings optionally bear hydroxyl substituents; R and R4, are the same or different and selected from H, a nitrate group, ClC4 alkyl optionally bearing 13 nitrate group, and acyl groups (C (O) R); R7, R"are the same or different C,C8, alkyl or acyl; R5, R6, R8,R9,R10,R12,R13,R14,R15,R16 are the same or different alkyl groups containing 112 carbon atoms which may contain 14 ONO2 substituents; or Ct or Cz connections to R1 R3 in cyclic derivatives; and M is H, Na+, K+, NH4+, N+HkR11(4k) where k is 03. |
| 29. | The method of claim 28, wherein: 1,n=0,p=1.m=. |
| 30. | The method of claim 29, wherein: X is NH,NMe,CN,NHOH,N2H3,N2H2R13,N2HR13R14,N3,S,SCN,O, SCN2H2(R15)2, SCN2H3(R15), SC (O) N (Rl5) 2 , SC(O)NHR15, SO3M, SH, SR', SO2M, S (O) R8, S(O)2OR9,PO3HM,PO3M2,P(O)(OR15)(OR16),P(O)(OR16)(OM),S(O)2R9,S(O)OR8, CO2M,CO2H,CO2R11,C(O),C(O)R12,C(O)(OR13),P(O)(R15)(OR8),P(O)(OM)R15, PO2M, SO2,SO2,C(O)(SR13),SSR4;andP(O)(R13), Y is CN, N3,SCN,SCN2H2(R15)2,SC(O)N(R15)2,N2HR13R14, SR4,SO2M,PO3HM,PO3M2,P(O)(OR15)(OR16),P(O)(OR16)(OM),SC(O)NHR15,SO3M, P (O) (R") (OR8), P (O) (OM) R", CO2M, CO2H, CO2R11, C (O) R12, C (O) (SR'3), SR, SSR', or does not exist. |
| 31. | The method of claim 28, wherein: R5, R6, R8,R9,R10,R12,R13,R14,R15,R16 are the same or different alkyls containing 1 12 carbon atoms; or C, or C2 connections to R'or R3 in cyclic derivatives; X is CH2, O, NH, NMe, S, SO3M, SH, SR', SO2M, S (O) R8, S (O) 2R9, S (O) OR', P(O)(OR15)(OR16),P(O)(OR16)(OM),P(O)(R15)(OR8),PO3HMorS(O)2OR9,PO3M2, P (O) (OM) R15; and Y is SO2M, SO3M, PO3HM, PO3M2, P (O) (OR15) (OR'6), P (O) (OR") (OM), SURS, SR4 or SSR5, or does not exist. |
| 32. | The method of claim 26, wherein the therapeutic compound is administered orally, intravenously, buccally, transdermally or subcutaneously. |
| 33. | The method of claim 26, further comprising administering the therapeutic compound in a pharmaceutically acceptable vehicle. |
| 34. | A method for effecting cognition enhancement in a subject comprising administering to said subject an effective amount of a organic nitrate, or therapeutically acceptable salt thereof, having the formula (Formula Il): in which: m, n, p are integers from 0 to 10; R3,17 are each independently hydrogen, a nitrate group, or A; R1,4 are each independently hydrogen, or A; where A is selected from: a substituted or unsubstituted aliphatic group (preferably a branched, or straightchain aliphatic moiety having from 1 to 24 carbon atoms in the chain, which optionally contains O, S, NR6and unsaturations in the chain, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups; an unsubstituted or substituted cyclic aliphatic moiety having from 3 to 7 carbon atoms in the aliphatic ring, which optionally contains O, S, NR6 and unsaturations in the ring, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups; an unsubstituted or substituted aliphatic moiety constituting a linkage of from 0 to 5 carbons, between R'and R3 and/or between R"and R4, which optionally contains O, S, NR6 and unsaturations in the linkage, and optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups); a substituted or unsubstituted aliphatic group (preferably a branched, cyclic or straightchain aliphatic moiety having from 1 to 24 carbon atoms in the chain), containing carbonyl linkages (e. g. C = 0, C = S, C=NOH), which optionally contains O, S, NR6 and unsaturations in the chain, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups; a substituted or unsubstituted aryl group; a heterocyclic group; amino (including alkylamino, dialkylamino (including cyclic amino, diamino and triamino moieties), arylamino, diarylamino, and alkylarylamino); hydroxy; alkoxy; a substituted or unsubstituted aryloxy; R2, Rs, Rus8, R'9 are optionally hydrogen, A, or XY; where X is F, Br, Cl, NO2, CH2, CFZ, O, NH, NMe, CN, NHOH, N2H3, N2H2Rt3, N2HRt3Rt4, N3, S, SCN, SCN2H2tR'5) 2 SCN2H3 (Rl5), SC (O) N (R15) 2 , SC(O)NHR15,SO3M, SH, SR7, SO, M, S (O) R8, S (O) 2R9, S (O) OR8, S (O) 2OR9, PO2HM, PO3HM, PO3M2, P(O)(OR15)(OR16), P(O)(OR16)(OM), P(O)(R15)(OR8), P (O) (OM) R'5, C02M, CO2H, CO2R11, C (O), C (O) R'2, C (O) (OR13), PO2H, PO2M, P (O) (OR'4), P (O) (Rl'), SO, SO2, C (O) (SR13), SR5, SSR7 or SSR5 ; Y is F, Br, Cl, CH3, CF2H, CF3, OH, NH2, NHR6, NR6R7, CN, NHOH, N2H3, N3,S,SCN,SCN2H2(R15)2,SCN2H3(R15),SC(O)N(R15)2,N2H2R13,N2HR13R14, SC (O) NHR15, SO3M, SH, SR', SO, M, S (O) R S (O) 2R9, S (O) OR8, S (O) 2OR9, PO2HM, P(O)(OR16)(OM),P(O)(R15)(OR8),P(O)(OM)R15,CO2M,PO3M2,P(O)(OR15)(OR16), CO2H, CO2R11, C (O) R12, C (O) (OR"), C (O) (SRl3), SR5, SSR7 or SSR5, or does not exist; thesameordifferentalkyloracylR6,R7,R8,R9,R10,R11,R12,R13,R14,R15,R16are groups containing 124 carbon atoms which may contain 14 ONO2 substituents; or C1 C6 connections to R'R4 in cyclic derivatives; or are each independently hydrogen, a nitrate group, or W; and M is H, Na+, K+, NH4+, N+HkR11(4k) where k is 03, or other pharmaceutically acceptable counterion; and with the proviso, when m = n = p = 1; R'9, R2, R'8, R'= H; R", R3 are nitrate groups; that Ris not H or C,C3 alkyl. |
| 35. | The method of claim 34, wherein: R"is XY. |
| 36. | The method of claim 35, wherein: R1 and R3 are the same or different and selected from H, C1C4, alkyl chains which may inlude one O, linking R'and R'to form pentosyl, hexosyl, cyclopentyl, or cycohexyl rings, which rings optionally bear hydroxyl substituents; R2 and R4, are the same or different and selected from H, a nitrate group, ClC4 alkyl optionally bearing 13 nitrate group, and acyl groups (C (O) R); R7, R"are the same or different C,C8, alkyl or acyl; R5, R6,R8,R9,R10,R12,R13,R14,R15,R16 are the same or different alkyl groups containing 112 carbon atoms which may contain 14 ONO2 substituents; or C1 or C2 connections to R1 R3 in cyclic derivatives; and M is H, Na+, K+, NH4+, N+HkR11(4k) where k is 03. |
| 37. | The method of claim 36, wherein: 1,n=0,p=1;m= CH2,O,NH,NMe,CN,NHOH,N2H3,N2H2R13,N2HR13R14,N3,S,SCN,Xis SCN2H2(R15)2, SCN2H3(R15), SC (O) N (RI5) 2, SC (O) NHR15, SO, M, SH, SR7, SO, M, S (O) R8, S(O)2OR9,PO3HM,PO3M2,P(O)(OR15)(OR16),P(O)(OR16)(OM),S(O)2R9,S(O)OR8, CO2M,CO2H,CO2R11,C(O),C(O)R12,C(O)(OR13),P(O)(R15)(OR8),P(O)(OM)R15, PO2M,PO2M,P(O)(OR14), SO2,C(O)(SR13),SSR4;andSO, Y is CN, N2H2R13, N2HR13R14, N3, SCN, SCN2H2(R15)2, SC (O) N (R") 2 SR4,SO2M,PO3HM,PO3M2,P(O)(OR15)(OR16),P(O)(OR16)(OM),SC(O)NHR15,SO3M, CO2M,CO2H,CO2R11,C(O)R12,C(O)(SR13),SR5,SSR5,orP(O)(R15)(OR8),P(O)(OM)R15, does not exist. |
| 38. | The method of claim 36, wherein: <BR> <BR> <BR> <BR> m=1, n=0, p=1;<BR> <BR> <BR> <BR> <BR> R5,R6,R8,R9,R10,R12,R13,R14,R15,R16 are the same or different alkyls containing 1 12 carbon atoms; or Ct or C2 connections to R1 or R3 in cyclic derivatives; X is CH2, O, NH, NMe, S, SO3M, SH, SR', SO2M, S (O) R8, S (O) 2R9, S (O) OR', S (0) 2OR9, PO3M2, P (O) (OR15) (OR16) P (0) (OR16) (OM), P (O) (RI5) (OR8) PO3HM or P (O) (OM) R15; and SO2M,SO3M,PO3HM,PO3M2,P(O)(OR15)(OR16),P(O)(OR16)(OM),SR5,SR4Yis or SSR5, or does not exist. |
| 39. | A method for mitigating neurodegeneration in a subject, comprising administering to said subject an effective amount of a therapeutic compound such that mitigation of neurodegeneration occurs, wherein guanylyl cyclase is activated and cGMP level is increased. |
| 40. | The method of claim 34, wherein the therapeutic compound is administered orally, intravenously, buccally, transdermally or subcutaneously. |
| 41. | The method of claim 34, further comprising administering the therapeutic compound in a pharmaceutically acceptable vehicle. |
| 42. | Organic nitrates containing at least one nitrate group having the general formula (Formula ION: in which: m is an integer from 1 to 10; n is an integer from 0 to 10; R', 4," are each independently hydrogen, a nitrate group, or A; where A is selected from: a substituted or unsubstituted aliphatic group (preferably a branched, or straightchain aliphatic moiety having from 1 to 24 carbon atoms in the chain, which optionally contains O, S, NR6 and unsaturations in the chain, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups; an unsubstituted or substituted cyclic aliphatic moiety having from 3 to 7 carbon atoms in the aliphatic ring, which optionally contains O, S, NR6 and unsaturations in the ring, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups; an unsubstituted or substituted aliphatic moiety constituting a linkage of from 0 to 5 carbons, between R'and R'and/or between R"and R4, which optionally contains O, S, NR6 and unsaturations in the linkage, and optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups); a substituted or unsubstituted aliphatic group (preferably a branched, cyclic or straightchain aliphatic moiety having from 1 to 24 carbon atoms in the chain), containing carbonyl linkages (e. g. C=O, C=S, C=NOH), which optionally contains O, S, NR6 and unsaturations in the chain, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups; a substituted or unsubstituted aryl group; a heterocyclic group; amino (including alkylamino, dialkylamino (including cyclic amino, diamino and triamino moieties), arylamino, diarylamino, and alkylarylamino); hydroxy; alkoxy; a substituted or unsubstituted aryloxy; R2, R5, R'8, are optionally hydrogen, A, or XY; where X is F, Br, Cl, NO2, CH2, CF2, O, NH, NMe, CN, NHOH, N2H3, N3,S,SCN,SCN2H2(R15)2,SCN2H3(R15),SC(O)N(R15)2,N2H2R13,N2HR13R14, SC (O) NHR15, S03M, SH, SR', SO2M, S (O) R8, S (O) 2R9, S (O) OR8, S(O)2OR9, PO2HM, P(O)(OR15)(OR16),P(O)(OR16)(OM),P(O)(R15)(OR8),P(O)(OM)R15,PO3HM,PO3M2, CO2R11,C(O),C(O)R12,C(O)(OR13),PO2H,PO2M,P(O)(OR14),CO2M,CO2H, P (O) (R13), SO, SO2, C (O) (SR"), SR', SSR7 or SSR5 ; Y is F, Br, Cl, CH3, CF2H, CF3, OH, NH2, NHR6, NR6R', CN, NHOH, N2H3, N3,S,SCN,SCN2H2(R15)2,SCN2H3(R15),SC(O)N(R15)2,N2H2R13,N2HR13R14, SC (O) NHR15, SO3M, SH, SR', SO2M, S(O)(R8, S (O) 2R9, S (O) OR8, S (O) 2OR9, PO2HM, P(O)(OR16)(OM),P(O)(R15)(OR8),P(O)(OM)R15,CO2M,PO3M2,P(O)(OR15)(OR16), C(O)R12,C(O)(OR13),C(O)(SR13),SR5,SSR7orSSR5,ordoesnotexist;CO2H,CO2R11, thesameordifferentalkyloracylR6,R7,R8,R9,R10,R11,R12,R13,R14,R15,R16are groups containing 124 carbon atoms which may contain 14 ONO2 substituents; or Cí C6 connections to R'R4 in cyclic derivatives; or are each independently hydrogen, a nitrate group, or W; and M is H, Na+, K+, NH4+, N+HkR11(4k) where k is 03, or other pharmaceutically acceptable counterion; and with the proviso that, when m=0 ; n=1; R18 and R3 are the same or different and selected from H, a nitrate group, ClC4 alkyl and chains, which may include one O, linking R18 and R3 to form pentosyl, hexosyl, cyclopentyl, or cyclohexyl rings, which rings optionally bear hydroxyl substituents; R17 and R4, are the same or different and selected from H, a nitrate group, C1C4 alkyl optionally bearing 13 nitrate group, and acyl groups (C (O) R5); R5, R6, R8, R9,R10,R12,R13,R14,R15,R16 are the same or different alkyl groups containing 112 carbon atoms which may contain 14 ONO2 substituents; or Cl or C2 connections to R18, Rl7, or R3 in cyclic derivatives; R', R"are C,C8 alkyl or acyl; M is H, Na+, K+, NH4+, N+HkR11(4k) where k is 03; X is NH,NMe,CN,NHOH,N2H3,N2H2R13,N2HR13R14,N3,S,SCN,O, SC(O)N(R15)2,SC(O)NHR15,SO3M,SH,SR7,SO2M,S(O)R8,SCN2H2(R15)2,SCN2H3(R15), S(O)2R9,PO3HM,PO3M2,P(O)(OR15)(OR16),P(O)(OR16)(OM),S(O)2OR9, CO2M,CO2H,CO2R11,C(O),C(O)R12,C(O)(OR13),P(O)(R15)(OR8),P(O)(OM)R15, PO, M, P (O) (OR"), P (O) (R'3), SO, SO2, C(O)(SR13), or SSR4; that Y is not CN, N2H2R13, N2HR13R14, N3, SCN, SCN2H2(R15)2, SC (O) N (R15)2 , SC(O)NHR15, SO2M,PO3M2,PO3HM,P(O)(OR15)(OR16),P(O)(OR16)(OM),SH, CO2H,CO2R11,C(O)R12,C(O)(SR13),SR4,SR5,orSSR5,ordoesnotP(O)(OM)R15,CO2M, exist. |
| 43. | A method for preparing a compound represented by the formula (Formula V): in which m, n = 010; R4 is hydrogen, a nitrate group, or A; R3, Rt7, Rl8 are each independently hydrogen or A; and R'is A; where A is selected from: a substituted or unsubstituted aliphatic group (preferably a branched, or straightchain aliphatic moiety having from 1 to 24 carbon atoms in the chain, which optionally contains O, S, NR6 and unsaturations in the chain, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups; an unsubstituted or substituted cyclic aliphatic moiety having from 3 to 7 carbon atoms in the aliphatic ring, which optionally contains O, S, NR6 and unsaturations in the ring, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups; an unsubstituted or substituted aliphatic moiety constituting a linkage of from 0 to 5 carbons, between R, and R3 and/or between R2 and R4, which optionally contains O, S, NR6 and unsaturations in the linkage, and optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups); a substituted or unsubstituted aliphatic group (preferably a branched, cyclic or straightchain aliphatic moiety having from 1 to 24 carbon atoms in the chain), containing carbonyl linkages (e. g. C=O, C=S, C=NOH), which optionally contains O, S, NR6 and unsaturations in the chain, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups; a substituted or unsubstituted aryl group; a heterocyclic group; amino (including alkylamino, dialkylamino (including cyclic amino, diamino and triamino moieties), arylamino, diarylamino, and alkylarylamino); hydroxy; alkoxy; a substituted or unsubstituted aryloxy; the method comprising: reacting an appropriate haloalcohol with a nitrating reagent selected from a mixture of nitric and sulfuric acid in a mixture of water and a selected organic solvent, acetyl nitrate, nitronium tetrafluoroborate, or reacting an appropriate haloalkene with thallium nitrate in pentanes, under conditions such that an appropriate haloorganic nitrate is formed; reacting an appropriate haloorganic nitrate with a thiolsulfonate salt so as to produce a selected Bunte salt; reacting an appropriate Bunte salt, optionally with an oxidizing agent (e. g. 30% hydrogen peroxide) in the presence of an appropriate catalyst (e. g. sulfuric acid), under conditions such that the compound of Formula 5 is prepared; reacting an appropriate disulfide in a thiol/disulfide exchange reaction with an organic thiolate salt, under conditions such that a compound of Formula 5 is formed. |
| 44. | The method of claim 2, wherein administering the therapeutic compound to the subject modulates cellular free radical damage. |
Description:
INTERNATIONALSEARCHREPORT.------- PCT/CA00/00280 C. (Contlnualon) DOCUMENTS CONSIDEREDTOBERELEVANT CategoryCitationofdocument,withindkatio. where appropdate, of the relevant paesagee Relevant to daim No. XLIPTON,S.A.ETAL:"NO-relatedspecies1-42,44 canprotectfromfocalcerebral ischemia/reperfusion" PHARMACOL.CEREB.ISCHEMIA1996,'INT. SYMP. !,6TH(1996),183-191.EDITOR(S): KRIEGLSTEIN,JOSEF.PUBLISHER:MEDPHARM SCIENTIFICPUBLISHERS,STUTTGART,GERMANY. XP000956443 page188,column2,paragraph3 page183,column1,paragraph2-column2, paragraph1 XLIPTON,S.A.ETAL:"S-nitrosylation of1-42,44 NMDAreceptorandcaspasesaffords neuroprotectionfromNMDA receptor-mediatedinsults" PHARMACOL.CEREB.ISCHEMIA1998,'INT. SYMP.!,7TH(1999),MEETINGDATE1998, 217-226.EDITOR(S):KRIEGLSTEIN,JOSEF. PUBLISHER:MEDPHARMSCIENTIFICPUBLISHERS, STUTTGART,GERMANY., XP000956442 page221,column2,paragraph2 figure2 XUCHIYAMA-TSUYUKI,YOSHIMIET 44 anovelapovincaminicacidderivative attenuatesneuronalinjuryinducedby hypoxiaorbyexcitatoryaminoacidsin culturesofratcortices" LIFESCI.(1996),59(18),1571-1578, XP000956386 page1571,line6-page1572,line5 XRAMOS-ZUNIGARETAL:"Neuroprotectionin1-42,44 selectivefocalischemiainratsby nitrates,analternativeredox manipulationonnitricoxide:Experimental model." MINIMALLYINVASIVENEUROSURGERY, vol.41,no.3,1998,pages152-160, XP000956402 ISSN:0946-7211 page152,column2,paragraph3-page153, column1,paragraph3 page158,column2,paragraph4 5 FURTHER INFORMATION CONTINUE FROM PCTASA/210 Continuation of Box 1.2 Present claims 1-44 relate to an extremely large number of possible compounds. Support within the meaning of Article 6 PCT and/or disclosure within the meaning of Article 5 PCT is to be found, however, for only a very small proportion of the compounds claimed. In the present case, the claims so lack support, and the application so lacks disclosure, that a meaningful search over the whole of the claimed scope is impossible.
Consequently, the search has been carried out for those parts of the claims which appear to be supported and disclosed, namely those parts relating to the compounds for which experimental data have been provided in the description, with due regard to the general idea underlying the present invention.
Claims searched completely: none.
Claims searched incompletely: 1-44.
The applicant's attention is drawn to the fact that claims, or parts of claims, relating to inventions in respect of which no international search report has been established need not be the subject of an international preliminary examination (Rule 66.1 (e) PCT). The applicant is advised that the EPO policy when acting as an International Preliminary Examining Authority is normally not to carry out a preliminary examination on matter which has not been searched. This is the case irrespective of whether or not the claims are amended following receipt of the search report or during any Chapter II procedure. INTERNATIONALSEARCH REPORT mbnndionRCT/CA00/00280 PatentdocumentPublication PatentPublication aded in search report date member (s) date WO9843621A08-10-1998EP 0979073 A 16-02-2000 EP0882716A09-12-1998US 6046201 A 04-04-2000 CA 2243427 A 28-05-1998 CA 2243445 A 28-05-1998 EP 0885886 A 23-12-1998 WO 9822439 A 28-05-1998 WO 9822440 A 28-05-1998 US 5972943 A 26-10-1999 US5455279A03-10-1995US 5234956 A 10-08-1993 AU 5348194 A 12-04-1994 EP 0661973 A 12-07-1995 WO 9406428 A 31-03-1994 US 5747545 A 05-05-1998 US 5614560 A 25-03-1997 US 5801203 A 01-09-1998 US 5506231 A 09-04-1996 US 6071876 A 06-06-2000 AT 182076 T 15-07-1999 DE 69229598 D 19-08-1999 DE 69229598 T 04-11-1999 EP 0581856 A 09-02-1994 ES 2134804 T 16-10-1999 JP 6506690 T 28-07-1994 WO 9218112 A 29-10-1992