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Title:
BIPYRIDINE MANGANESE COMPLEXES
Document Type and Number:
WIPO Patent Application WO/2000/009512
Kind Code:
A2
Abstract:
Compounds and methods of preparing compounds represented by structural formula (I) wherein X represents any suitable counter-anion; R?1¿ and R?2¿ independently represent hydrogen, C¿1-6? alkoxy or nitro; R?3¿, R?4¿, R?5¿ and R?6¿ each independently represents hydrogen, hydroxy, halo, C¿1-6? alkyl, C¿2-6? alkenyl or C¿1-6? alkoxy; and R?7¿, R?8¿, R?9¿ and R?10¿ each independently represents hydrogen, hydroxy, halo, C¿1-6? alkyl, C¿2-6? alkenyl or C¿1-6? alkoxy. Compounds represented by structural formula (I) are useful in treating or preventing free radical-associated diseases or conditions in mammals.

Inventors:
CAMPBELL IAN BAXTER
WALKER ANN LOUISE
BOX PHILIP CHARLES
GIBLIN GERARD MARTIN PAUL
TRANTER GEORGE EDWARD
Application Number:
PCT/US1999/018629
Publication Date:
February 24, 2000
Filing Date:
August 17, 1999
Export Citation:
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Assignee:
EUKARION INC (US)
International Classes:
A61K31/4402; C07D213/38; A61K31/4418; A61K31/444; A61K33/32; A61P1/00; A61P1/02; A61P1/18; A61P9/00; A61P9/10; A61P9/12; A61P11/00; A61P11/02; A61P11/06; A61P17/00; A61P17/04; A61P17/06; A61P19/02; A61P25/00; A61P25/08; A61P25/16; A61P25/28; A61P27/00; A61P27/12; A61P31/18; A61P35/00; A61P37/06; A61P37/08; A61P39/04; A61P39/06; C07C53/10; C07D213/53; C07F5/02; C07F5/04; C07F13/00; (IPC1-7): C07F/
Domestic Patent References:
WO1997032853A11997-09-12
WO1994027949A11994-12-08
Foreign References:
US5696109A1997-12-09
Other References:
CAPDEVIELLE, P. ET AL: "Electroactive polymers exchanging transition metal ions;synthesis of new monomers and polymers based on 6,6'-bis(2- hydroxyphenyl)bipyridine complexes" NEW J. CHEM. (1994), 18(4), 519-24, XP002121132
BENAGLIA, MAURIZIO ET AL: "Synthesis of pyridylstannanes from halopyridines and hexamethyldistannane with catalytic palladium" TETRAHEDRON LETT. ( 1997 ), 38(27), 4737-4740, XP002119996
UENISHI, JUNICHI ET AL: "Ipso Substitution of 2-alkylsulfinylpyridine by 2-pyridyllithium;a new preparation of oligopyridine and their bromomethyl derivatives" TETRAHEDRON LETT. (1990), 31(32), 4625-8, XP002119997
CONSTABLE, EDWIN C. ET AL: "A novel rearrangement of 2,2'-bipyridine N,N'-dioxides. The characterization of dipyrido[1,2-b:2,3-dÜisoxazolinium salts as intermediates in the formation of 3-hydroxy-2,2'-bipyridines" TETRAHEDRON (1983), 39(2), 291-5, XP002119998
NEUMANN, UWE ET AL: "4,4'-Donor-substituted and 6,6'-difunctionalized 2,2'-bipyridines" CHEM. BER. (1989), 122(3), 589-91, XP002119999
Attorney, Agent or Firm:
Wagner, Richard W. (Brook Smith & Reynold, P.C. Two Militia Drive Lexington MA, US)
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Claims:
CLAIMS What is claimed is:
1. A compound represented by Structural Formula (I): and solvates thereof, wherein: X represents a counteranion; R'and R2 each, independently, represent hydrogen, C1_6 alkoxy or nitro; R3R'0 each, independently, represents hydrogen, hydroxy, halo, C16 alkyl, C26 alkenyl or Cl 6 alkoxy.
2. The compound of Claim 1, wherein R'and R2 each, independently, are selected from the group consisting of hydrogen, methoxy and ethoxy.
3. The compound of Claim 1, wherein Rl and R2 are the same.
4. The compound of Claim 2, wherein R'and W are hydrogen.
5. The compound of Claim 1, wherein R3 to R'° are each, independently, selected from the group consisting of hydrogen, hydroxy, fluoro, methyl, ethyl, isopropyl, tertbutyl, nhexyl, propenyl, methoxy and ethoxy.
6. The compound of Claim 5, wherein R3 is hydrogen or methoxy.
7. The compound of Claim 5, wherein R5, and R8 are each, independently, hydrogen, methyl or ethyl.
8. The compound of Claim 5, wherein R'° is hydrogen or methoxy.
9. The compound of Claim 1, wherein the phenyl carrying groups R3 to R6 is substituted identically to the phenyl ring carrying the groups R7 to R'°.
10. The compound of Claim 1, wherein X is acetate or chloride.
11. The compound of Claim 1, wherein: R', R2, R3, R8 and R'° are each hydrogen; R4 and R9 are each, independently, hydrogen or methoxy; RS is hydrogen or methyl; R6 and R7 are each, independently, hydrogen, methyl and methoxy; and X is acetate or chloride.
12. The compound of Claim 1 selected from the group consisting of : 6,6'Bis (2hydroxyphenyl)2,2'bipyridinemanganese (III) acetate or chloride; 6,6'Bis (2hydroxy5methoxyphenyl)2,2'bipyridinemanganese (III) acetate or chloride; 6,6'Bis (2hydroxy3methoxyphenyl)2,2'bipyridinemanganese (III) acetate or chloride; 6,6'Bis (2hydroxy3ethoxyphenyl)2,2'bipyridinemanganese (III) acetate or chloride; 6,6'Bis (2hydroxy3methoxy5methylphenyl)2,2'bipyridinemanganese (III) acetate or chloride; 6,6'Bis (2hydroxy5fluorophenyl)2,2'bipyridinemanganese (III) acetate or chloride; 6,6'Bis (2hydroxy5methylphenyl)2,2'bipyridinemanganese (III) acetate or chloride; 6,6'Bis (2hydroxy3methylphenyl)2,2'bipyridinemanganese (III) acetate or chloride; 6,6'Bis (2hydroxy3,5dimethylphenyl)2,2'bipyridinemanganese (III) acetate or chloride; 6,6'Bis (2hydroxy3fluorophenyl)2,2'bipyridinemanganese (III) acetate or chloride; 6,6'Bis (2hydroxy4methylphenyl)2,2'bipyridinemanganese (III) acetate or chloride; 6,6' Bis (2,3dihydroxyphenyl)2,2'bipyridinemanganese (III) acetate or chloride; 6,6'Bis (2hydroxy6methoxyphenyl)2,2'bipyridinemanganese (III) acetate or chloride; 6,6'Bis (2hydroxy5tbutylphenyl)2,2'bipyridinemanganese (III) acetate or chloride; 6,6'Bis (5allyl2hydroxy3methoxyphenyl)2,2'bipyridinemanganese (III) acetate or chloride; 6 (2Hydroxy5methoxyphenyl)6' (2hydroxy3methylphenyl)2,2' bipyridinemanganese (III) acetate or chloride; 6,6'Bis (3allyl2hydroxyphenyl)2,2'bipyridinemanganese (III) acetate or chloride; 6,6'Bis (3hexyl2hydroxyphenyl)2,2'bipyridinemanganese (III) acetate or chloride; 6 (2Hydroxyphenyl)6' (2hydroxy4methylphenyl)2,2' bipyridinemanganese (III) acetate or chloride; 6 (2Hydroxy3methoxyphenyl)6' (2hydroxy4methylphenyl)2,2' bipyridinemanganese (III) acetate or chloride; 6 (2Hydroxy5methoxyphenyl)6' (2hydroxy4methylphenyl)2,2' bipyridinemanganese (III) acetate or chloride; 6 (2Hydroxy3methylphenyl)6' (2hydroxy4methylphenyl)2,2' bipyridinemanganese (III) acetate or chloride; 6 (3Fluoro2hydroxyphenyl)6' (2hydroxy4methylphenyl)2,2' bipyridinemanganese (III) acetate or chloride; 6 (3, 4Dimethyl2hydroxyphenyl)6' (2hydroxy4methylphenyl)2,2' bipyridinemanganese (III) acetate or chloride; 6 (2Hydroxy4methylphenyl)6' (2hydroxy5methylphenyl)2,2' bipyridinemanganese (III) acetate or chloride; 6 (2Hydroxyphenyl)6' (2hydroxy3methoxyphenyl)2,2' bipyridinemanganese (III) acetate or chloride; 6 (2Hydroxy3methoxyphenyl)6' (2hydroxy5methoxyphenyl)2,2' bipyridinemanganese (III) acetate or chloride; 6 (2Hydroxy3methoxyphenyl)6' (2hydroxy3methylphenyl)2,2' bipyridinemanganese (III) acetate or chloride; 6 (2Hydroxy3hexylphenyl)6' (2hydroxy3methoxyphenyl)2,2' bipyridinemanganese (III) acetate or chloride; 6 (3, 4Dimethyl2hydroxyphenyl)6' (2hydroxy3methoxyphenyl)2,2' bipyridinemanganese (III) acetate or chloride; 6 (2Hydroxy3methoxyphenyl)6' (2hydroxy5methylphenyl)2,2' bipyridinemanganese (III) acetate; 6 (2Hydroxyphenyl)6' (2hydroxy5methoxyphenyl)2,2' bipyridinemanganese (III) acetate or chloride; 6 (3Hexyl2hydroxyphenyl)6' (2hydroxy5methoxyphenyl)2,2' bipyridinemanganese (III) acetate or chloride; 6 (5Fluoro2hydroxyphenyl)6' (2hydroxy5methoxyphenyl)2,2' bipyridinemanganese (III) acetate or chloride; 6 (3, 4Dimethyl2hydroxyphenyl)6' (2hydroxy5methoxyphenyl)2,2' bipyridinemanganese (III) acetate or chloride; 6 (2Hydroxy5methoxyphenyl)6' (2hydroxy5methylphenyl)2,2' bipyridinemanganese (III) acetate or chloride; 6 (2Hydroxy5methoxyphenyl)6' (2hydroxy3methoxy5 methylphenyl)2,2'bipyridinemanganese (III) acetate or chloride; 6 (2Hydroxy5methoxyphenyl)6' (5allyl2hydroxy3methoxyphenyl) 2,2'bipyridinemanganese (III) acetate or chloride; 6 (2Hydroxy3methoxyphenyl)6' (5allyl2hydroxy3methoxyphenyl) 2,2'bipyridinemanganese (III) acetate or chloride; 6,6'Bis (5ethyl2hydroxyphenyl)2,2'bipyridinemanganese (III) acetate or chloride; 6,6'Bis (2hydroxy5isopropylphenyl)2,2'bipyridinemanganese (III) acetate or chloride; and 6,6'Bis (4ethyl2hydroxyphenyl)2,2'bipyridinemanganese (III) acetate or chloride.
13. The compound of Claim 1 selected from the group consisting of : 6,6'Bis (2hydroxyphenyl)2,2'bipyridinemanganese (III) acetate or chloride; 6,6'Bis (2hydroxy5methoxyphenyl)2,2'bipyridinemanganese (III) acetate or chloride; 6,6'Bis (2hydroxy3methoxyphenyl)2,2'bipyridinemanganese (III) acetate or chloride; 6,6'Bis (2hydroxy3methylphenyl)2,2'bipyridinemanganese (III) acetate or chloride; 6 (3, 4Dimethyl2hydroxyphenyl)6' (2hydroxy5methoxyphenyl)2,2' bipyridinemanganese (III) acetate or chloride; 6 (2Hydroxy5methoxyphenyl)6' (2hydroxy5methylphenyl)2,2' bipyridinemanganese (III) acetate or chloride; and solvates thereof.
14. A compound represented by the following structural formula:.
15. A compound represented by the following structural formula:.
16. A method of preparing a compound represented by Structural Formula (I): and solvates thereof, wherein: X represents a counteranion; R'and R2 each, independently, represents hydrogen, C 16alkoxy or nitro; R3, R4, R5 and R6 each, independently, represents hydrogen, hydroxy, halo, Cl 6 alkyl, C26 alkenyl or Cl 6 alkoxy; and R7, R8, R9 and Rl° each, independently, represents hydrogen, hydroxy, halo, C, 6 alkyl, C26 alkenyl or Cl 6 alkoxy, comprising the steps of : a) reacting a bipyridine derivative represented by Structural Formula (III): wherein L'and L2 are each, independently, a leaving group, with a first boronic acid derivative represented by Structural Formula (IV): wherein Ra and Rb are each, independently, hydrogen or a Cl 6 alkyl, or Ra and Rb together form a straightchain or branched alkylene, to form a first intermediate represented by Structural Formula (VI): b) reacting the first intermediate with a second boronic acid derivative represented by Structural Formula (VII): to form a second intermediate represented by Structural Formula (II): c) contacting the second intermediate with a manganese (II) salt, thereby forming said compound.
17. The method of Claim 16, wherein X is acetate.
18. The method of Claim 17, further comprising contacting said compound with a chloride salt, thereby forming said compound wherein X is chloride.
19. The method of Claim 16, wherein L'and L are bromine.
20. A method of preparing a compound represented by Structural Formula (I): and solvates thereof, wherein: X represents a counteranion; R'and R2 each, independently, represent hydrogen, C, 6 alkoxy or nitro; and R3, R4, R5 and R6 each, independently, represents hydrogen, hydroxy, halo, Cl 6 alkyl, C26 alkenyl or C, 6 alkoxy, comprising the steps of : a) reacting a bipyridine derivative represented by Structural Formula (III) : wherein L'and L2 are each, independently, a leaving group, with a first boronic acid derivative represented by Structural Formula (IV): wherein Ra and Rb are each, independently, hydrogen or a CI6 alkyl, or Ra and Rb together form a straightchain or branched alkylene, to form a first intermediate represented by the following structural formula ; and b) contacting the second intermediate with a manganese (II) salt, thereby forming said compound.
21. Use of a compound in the preparation of a medicament for prophylaxis or treatment of a free radicalassociated disease or condition in a mammal, said compound represented by Structural Formula (I): and solvates thereof, wherein: X represents a counteranion; Rl and R2 each, independently, represents hydrogen, Cl 6 alkoxy or nitro; R3, R4, R5 and R6 each, independently, represents hydrogen, hydroxy, halo, C, 6 alkyl, C26 alkenyl or Cl 6 alkoxy; and R7, R8, R9 and R'° each, independently, represents hydrogen, hydroxy, halo, C, 6 alkyl, C26 alkenyl or C, 6 alkoxy.
22. A pharmaceutical formulation comprising one or more pharmaceutically acceptable carriers, diluents or excipients and a therapeutically effective amount of at least one compound represented by Structural Formula (I): and solvates thereof, wherein: X represents a counteranion; R'and R each, independently, represents hydrogen, C, 6 alkoxy or nitro; R3, R4, R5 and R6 each, independently, represents hydrogen, hydroxy, halo, Cl 6 alkyl, C26 alkenyl or C, 6 alkoxy; and R7, R8, R9 and Rl° each, independently, represents hydrogen, hydroxy, halo, Cl 6 alkyl, C26 alkenyl or Cl 6 alkoxy.
23. A compound for use in therapy represented by Structural Formula (I): and solvates thereof, wherein: X represents a counteranion; Rl and R2 each, independently, represent hydrogen, C, 6 alkoxy or nitro; R3R'0 each, independently, represents hydrogen, hydroxy, halo, Cl 6 alkyl, C26 alkenyl or Cl 6 alkoxy.
24. A method of treating, preventing or arresting a free radical associated disease or condition comprising administering a therapeutically effective amount of a compound represented by Structural Formula (I): and solvates thereof, wherein: X represents a counteranion; Rl and R2 each, independently, represent hydrogen, C, 6 alkoxy or nitro; R3R'° each, independently, represents hydrogen, hydroxy, halo, Cl 6 alkyl, C26 alkenyl or C, 6 alkoxy.
25. The method of Claim 24, wherein the free radical associated disease or condition is damage resulting from stroke, Alzheimer's disease, dementia, Parkinson's disease, Lou Gehrig disease, motor neurone disorders, Huntington's disease, cancer, multiple sclerosis, systemic lupus erythematosus, scleroderma, eczema, dermatitis, delayed type hypersensitivity, psoriasis, gingivitis, adult respiratory distress syndrome, septic shock, multiple organ failure, asthma, allergic rhinitis, pneumonia, emphysema, chronic bronchitis, AIDS, inflammatory bowel disease, pancreatitis, transplantation rejection, atherosclerosis, hypertension, congestive heart failure, myocardial ischemic disorders, angioplasty, endocarditis, retinopathy of premanurity, cataract formation, uveitis, rheumatoid arthritis and osteoarthritis.
26. A compound represented by Structural Formula (Ia): and solvates thereof, wherein: R'and R2 each, independently, represent hydrogen, C, 6 alkoxy or nitro; R3, R4, R5 and R6 each, independently, represents hydrogen, hydroxy, halo, C, 6 alkyl, C26 alkenyl or C, 6 alkoxy; and R7, R8, R9 and R'° each, independently, represents hydrogen, hydroxy, halo, C, 6 alkyl, C26 alkenyl or C, 6 alkoxy.
27. A compound represented by Structural Formula (II): and solvates thereof, wherein: R'and R2 each, independently, represent hydrogen, C, 6 alkoxy or nitro; R3, R4, R5 and R6 each, independently, represents hydrogen, hydroxy, halo, C, 6 alkyl, C26 alkenyl or C, 6 alkoxy; and R', R8, R9 and R'° each, independently, represents hydrogen, hydroxy, halo, Cl 6 alkyl, C26 alkenyl or Cl 6 alkoxy, provided that R'R'° are not all hydrogen.
28. A compound represented by Structural Formula (III): wherein: R'and R2 each, independently, represents hydrogen, C, 6 alkoxy or nitro; and L'and L2 are each, independently a leaving group, provided that the compound is not 6,6'dibromo2,2'bipyridyl or 6,6'dibromo4,4'dimethoxy 2,2'bipyridyl.
29. A compound represented by Structural Formula (IV): wherein: R3, R4, R'and R'each, independently, represents hydrogen, hydroxy, halo, C, 6 alkyl, C26 alkenyl or C, 6 alkoxy; and Ra and Rb are each, independently, hydrogen or a C, 6 alkyl, or Ra and Rb together form a straightchain or branched alkylene, provided that the compound is not 2hydroxyphenylboronic acid.
30. A compound represented by Structural Formula (VI): wherein: R'and R'each, independently, represents hydrogen, C16 alkoxy or nitro; R3, R4, R5 and R6 each, independently, represents hydrogen, hydroxy, halo, Cl 6 alkyl, C26 alkenyl or C, 6 alkoxy; and L'is a leaving group.
Description:
INTERNATIONAL SEARCH REPORT PCT/US99/18629 G (Co) DOCUMENTS CONSIDERED TO BE RELEVANT Category ° CItallon of doament, wMh hdcaUan, where appropdate, af the relevant paages Relevant to daYn No. X WO 97 32853 A (MANLEY PAUL WILLIAM ; CIBA 29 GEIGY AG (CH)) 12 September 1997 (1997-09-12) see the examples X BENAGLIA, MAURIZIO ET AL :"Synthesis of 28 pyridylstannanes from halopyridines and hexamethyldistannane with catalytic palladium" TETRAHEDRON LETT. (1997), 38 (27), 4737-4740, XP002119996 page 4739 X UENISHI, JUNICHI ET AL:"Ipso 28 Substitution of 2-alkylsulfinylpyridine by 2-pyridyllithium ; a new preparation of oligopyridine and their bromomethyl derivatives" TETRAHEDRON LETT. (1990), 31 (32), 4625-8, XP002119997 page 4262 X CONSTABLE, EDWIN C. ET AL :"A novel 28 rearrangement of 2,2'-bipyridine N, N'-dioxides. The characterization of dipyrido'1, 2-b: 2,3-d! isoxazolinium salts as intermediates in the formation of 3-hydroxy-2,2'-bipyridines" TETRAHEDRON (1983), 39 (2), 291-5, XP002119998 page 291 X NEUMANN, UWE ET AL: 28 "4, 4'-Donor-substituted and 6,6'-difunctionalized2,2'-bipyridines" CHEM. BER. (1989), 122 (3), 589-91, XP002119999 page 18; example 28 A WO 94 27949 A (RHONE POULENC RORER SA 29 ; INST NAT SANTE RECH MED (FR); GARBAY CHRIS) 8 December 1994 (1994-12-08) page 5 4 il national application No. INTERNATIONAL SEARCH REPORT PCT/US 99/18629 Box I Observations where certain claims were found unsearchable (Continuation of item 1 of first sheet) This international Search Report has not been established in respect of certain claims under Article 17 (2) (a) for the following reasons: 1. Fx Claims Nos. :. 21 24 25 because they relate to subject'matter not required to be searched by this Authority, namely: Rule 39.1 (iv) PCT-Method for treatment of the human or animal body by therapy 2. Claims Nos.: because they relate to parts of the Intemational Application that do not comply with the prescribed requirements to such an extent that no meaningful International Search can be carried out, specifically: 3. Claims Nos.: because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4 (a). Box 11 Observations where unity of invention is lacking (Continuation of item 2 of first sheet) This International Searching Authority found multiple inventions in this international application, as follows : see additional sheet 1. As all required additional search fees were timely paid by the applicant, this International Search Report covers all searchable claims. 2. As a ! ! searchable claims could be searched without effort justifying an additional fee, this Authority did not invite payment of any additional fee. 3. As only some of the required additional search fees were timely paid by the applicant, this International Search Report covers only those claims for which fees were paid, specifically claims Nos.: 4. g No required additional search fees were timely paid by the applicant. Consequently, this International Search Report is restricted to the invention first mentioned in the claims ; it is covered by claims Nos.: Remark on Protest The additional search fees were accompanied by the applicant's protest. u FXI No protest accompanied the payment of additional search fees. u FURTHER INFORMATION CONTINUED FROM PCT/ISA/210 This International Searching Authority found multiple (groups of) inventions in this international application, as follows: 1. Claims: 1-26 1.1. Claims: 1-25 Complexes containing manganese as depicted in claim 1 by structural formula I. The preparation of compounds of structural formula I as described in claims 16-20 and the therapeutic use of these compounds according to formula I as in claims 21,24,25. 1.2. Claim: 26 The compounds as depicted in claim 26 by structural formulaIa. 2. Claims: 27,29 A compound represented by structural formulae II, IV and VI. 3. Claim: 28 A compound represented by structural formula III. INTERNATIONAL SEARCH REPORT ) nt MMtApp<) C<t) e « Mo PCT/US 99/18629 Patentdocument PtcationPatenttamtfyPdJtcation Gted In search report date mertber (s) date US 5696109 A 09-12-1997 US 5827880 A 27-10-1998 US 5403834 A 04-04-1995 AU 6272596 A 30-12-1996 AU 6332896 A 30-12-1996 CA 2223510 A 19-12-1996 EP 0831836 A 01-04-1998 JP 11507646 T 06-07-1999 WO 9640148 A 19-12-1996 WO 9640149 A 19-12-1996 AU 697399 B 08-10-1998 AU 5741994 A 04-07-1994 EP 0746321 A 11-12-1996 GB 2277873 A, B 16-11-1994 JP 8504211 T 07-05-1996 LV 10924 A 20-12-1995 NO 952237 A 01-08-1995 PL 309334 A 02-10-1995 SK 74595 A 08-05-1996 US 5834509 A 10-11-1998 CA 2150937 A 23-06-1994 CZ 9501442 A 16-10-1996 GB 2305107 A, B 02-04-1997 HU 72967 A 28-06-1996 LV 10924 B 20-10-1996 NZ 259200 A 24-06-1997 WO 9413300 A 23-06-1998 WO 9732853 A 12-09-1997 AU 2025497 A 22-09-1997 BR 9708011 A 27-07-1999 CA 2249546 A 12-09-1997 CN 1216980 A 19-05-1999 CZ 9802850 A 13-01-1999 EP 0885193 A 23-12-1998 Hü 9902103 A 28-10-1999 NO 984120 A 09-11-1998 PL 328488 A 01-02-1999 SK 121698 A 02-12-1998 ZA 9702007 A 07-09-1998 ZA 9702007 A 07-09-1998 WO 9427949 A 08-12-1994 FR 2705671 A 02-12-1994 AU 6850094 A 20-12-1994