Title:
BENZYLGLYCOSYLAMIDES AS INHIBITORS OF SMOOTH MUSCLE CELL PROLIFERATION
Document Type and Number:
WIPO Patent Application WO/2000/031094
Kind Code:
A2
Abstract:
This invention provides smooth muscle cell proliferation inhibitors of formula (I) having the structure (a) wherein Y is C or N; where n is 0 - 3; X is (II); or a pharmaceutically acceptable salt thereof.
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Inventors:
MCDEVITT ROBERT EMMETT
ADEBAYO FOLAKE OLUWEMIMO
ADEBAYO FOLAKE OLUWEMIMO
Application Number:
PCT/US1999/027823
Publication Date:
June 02, 2000
Filing Date:
November 23, 1999
Export Citation:
Assignee:
AMERICAN HOME PROD (US)
International Classes:
C07H13/06; A61K31/7024; A61K31/706; A61P9/00; A61P9/10; A61P9/12; A61P11/06; A61P29/02; A61P35/00; A61P43/00; C07H13/08; C07H15/203; C07H15/26; (IPC1-7): C07H13/04; A61K31/70; A61P9/00; A61P21/00; A61P35/00
Domestic Patent References:
| WO2000031093A2 | 2000-06-02 |
Foreign References:
| EP0714903A1 | 1996-06-05 |
Other References:
DEFERRARI, JORGE O. ET AL: "Reaction of ammonia with acylated disaccharides. X. Octa-O-benzoyllactose and other benzoyl derivatives of lactose" CARBOHYD. RES. (1973), 29 (1), 141-6, XP000938501
NG, KEN ET AL: "Specificity of binding of.beta.-glucoside activators of ryegrass (1.fwdarw.3)-.beta.-glucan synthase and the synthesis of some potential photoaffinity activators" PLANT PHYSIOL. (1996), 111(4), 1227-1231 , XP002149381
DATABASE WPI Section Ch, Week 199604 Derwent Publications Ltd., London, GB; Class A11, AN 1996-035887 XP002149382 & JP 07 304788 A (MITSUI TOATSU CHEM INC), 21 November 1995 (1995-11-21) -& JP 07 304788 A 21 November 1995 (1995-11-21)
NG, KEN ET AL: "Specificity of binding of.beta.-glucoside activators of ryegrass (1.fwdarw.3)-.beta.-glucan synthase and the synthesis of some potential photoaffinity activators" PLANT PHYSIOL. (1996), 111(4), 1227-1231 , XP002149381
DATABASE WPI Section Ch, Week 199604 Derwent Publications Ltd., London, GB; Class A11, AN 1996-035887 XP002149382 & JP 07 304788 A (MITSUI TOATSU CHEM INC), 21 November 1995 (1995-11-21) -& JP 07 304788 A 21 November 1995 (1995-11-21)
Attorney, Agent or Firm:
Milowsky, Arnold S. (NJ, US)
Wileman, David Francis (Wyeth Laboratories Huntercombe Lane South Taplow Maidenhead Berkshire SL6 OPH, GB)
Wileman, David Francis (Wyeth Laboratories Huntercombe Lane South Taplow Maidenhead Berkshire SL6 OPH, GB)
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Claims:
WHAT IS CLAIMED IS:
| 1. | A compound of formula I having the structure wherein YisCorN; where n is 03; X is R', and R7 are each independently, hydrogen, alkyl of 1 to 6 carbon atoms, halo, acetyl, phenyl, CF3, CN, OH, NO2, NH2, alkoxy of 1 to 6 carbon atoms, or cyanoalkoxy of 2 to 7 carbon atoms; R3 is hydrogen, acylamide of 2 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms; R4, R5, R6, R7, and R8 are each, independently, hydrogen, acyl of 1 to 6 carbon atoms, benzyl substituted with R', and R2 ; or benzoyl substituted with R' and R2; R9 and R'° are each, independently, acyl of 1 to 6 carbon atoms, or the R9 and R'° groups on the 4'and 6'positions of the maltose may be taken together to form a cyclic acetal which may be substituted with alkyl of 1 to 6 carbon atoms, two alkyl groups each having 1 to 6 carbon atoms, pyridine substituted with R', phenyl substituted with R', benzyl substituted with R', 2phenylethyl substituted with R', or 3phenylpropyl substituted with R' ; with the provisio that when RI or R2 are cyanoalkoxy of 27 carbon atoms, R3 is not acylamide, and further provided that when Rl, R2, or R3 are alkoxy of 16 carbon atoms, at least one of R1, R2, R3, or R4 are not hydrogen; or a pharmaceutically acceptable salt thereof. |
| 2. | The compound according to claim 1, wherein nis01; R', and R2 are each independently, hydrogen, halogen, CF3, OH, NO2, NH2, methoxy, butoxy, or butoxynitrile; R3 is hydrogen, acetamide, or methoxy; R4, R5, R6, R', and R3 are each, independently, hydrogen, an acyl of 16 carbon atoms, or benzoyl; R9 and R'° are each, independently, acyl of 16 carbon atoms, or the R9 and R'° groups on the 4'and 6'positions of the maltose are taken together form a benzylidene ring; or a pharmaceutically acceptable salt thereof. |
| 3. | The compound of claim 2, wherein 0;nis R', and R2 are each independently, hydrogen or halogen; R3 is hydrogen; or a pharmaceutically acceptable salt thereof. |
| 4. | The compound of claim 1, which is (R)3(acetylamino)N6O benzoyl40 4, 6 O (phenylmethylene)aDglucopyranosylpDglucopyranosyl 4chlorobenzamide or a pharmaceutically acceptable salt thereof. |
| 5. | The compound of claim 1, which is 4chloroN(2, 2', 3, 3'tetraO acetyl6benzoyl4', 6'O benzylidene)ßDmaltosyl3nitrobenzamide. |
| 6. | The compound of claim 1, which is (R)N2Oacetyl402O acetyl4,6O(phenylmethylene)aDglucopyranosyl]6ObenzoylßD glucopyranosyl3 (acetylamino)4chlorobenzamide chlorobenzamide or a pharmaceutically acceptable salt thereof. |
| 7. | The compound of claim 1, which is N(6Obenzoyl4', 6'O benzylideneßDmaltosyl)3chloro4(4nitrilobutoxy)phenylamide chlorobenzamide or a pharmaceutically acceptable salt thereof. |
| 8. | The compound of claim 1, which is N(6Obenzoyl4',6'O benzylidenepDmaltosyl)4chloro3methoxybenzamide chlorobenzamide or a pharmaceutically acceptable salt thereof. |
| 9. | The compound of claim 1, which is N(6Obenzoyl4', 6'O benzylideneßDmaltosyl)4(4nitrilobutoxy)3nitrobenzamide(4nitrilobutoxy)3nitrobenzamide chlorobenzamide or a pharmaceutically acceptable salt thereof. |
| 10. | The compound of claim 1, which is 3acetylaminoN(6Obenzoyl4', 6'ObenzylideneßDmaltosyl)4(4nitrilobutoxy)benzamide(4nitrilobutoxy)benzamide chlorobenzamide or a pharmaceutically acceptable salt thereof. |
| 11. | The compound of claim 1, which is N (heptaOacetylpDmaltosyl) 3chloro4methoxybenzamide. |
| 12. | The compound of claim 1, which is N (6Obenzoyl4', 6'O benzylideneßDmaltosyl)2(3, 4dimethoxyphenyl)acetamide chlorobenzamide or a pharmaceutically acceptable salt thereof. |
| 13. | The compound of claim 1, which is 2 3acetylamino)4chloro phenylN(6Obenzoyl4', 6'ObenzylideneßDmaltosyl)acetamide chlorobenzamide or a pharmaceutically acceptable salt thereof. |
| 14. | The compound of claim 1, which is: a) N(heptaOacetyl1deoxyßDmaltosyl)4chloro3nitrobenzamide; b) 3amino4chloroN 2,3, 6triOacetyl4O(2, 3,4,6tetraOacetylaD glucopyranosyl)ßDglucopyranosyl}benzamide; c) 3 (acetylamino)4chloroN 2,3,6triOacetyl40 (2,3,4, 6tetraOacetylα Dglucopyranosyl)ßDglucopyranosyl}benzamide; d) (R)3 (acetylamino)4chloroN 40 4, 6 O (phenylmethylene)aD glucopyranosylßDglucopyranosylbenzamide or a pharmaceutically acceptable salt thereof; e) (R)4chloro3nitroN 40 4, 6 O (phenylmethylene)aD glucopyranosylßDglucopyranosylbenzamide or a pharmaceutically acceptable salt thereof; f) (R)4chloroN(6Obenzoyl4', 6'Obenzylidene) ßDmaltosyl3nitro benzamide or a pharmaceutically acceptable salt thereof; g) N (HeptaOacetyl (3Dmaltosyl)4chlorobenzamide; h) N (4', 6'ObenzylideneßDmaltosyl)4chlorobenzamide or a pharmaceutically acceptable salt thereof ; i) N (6Obenzoyl4', 6'ObenzylideneßDmaltosyl)4chlorobenzamide or a pharmaceutically acceptable salt thereof; j) N[(2,2',3,3'4',6,6'heptaOacetylßDmaltosyl]3chloro4nitrilobutoxy benzoic acid amide; k) N (2,2', 3,3'4', 6, 6'heptaOacetylaDmaltosyl]3chloro4nitrilobutoxy benzoic acid amide; l) N(4',6'ObenzylideneßDmaltosyl)3chloro4(4nitrilobutoxy) benzamide or a pharmaceutically acceptable salt thereof; m) N (2,2', 3,3'tetraOacetyl6Obenzoyl4', 6'ObenzylideneßDmaltosyl) 3chloro4 (4nitrilobutoxy)benzamide; n) 4butoxy3chloroN 2,3,6triOacetyl40(2,3,4, 6tetraOacetylαD glucopyranosyl) (3Dglucopyranosyl benzamide; o) 4butoxy3chloroN(6Obenzoyl4', 6'Obenzylidene)ßDmaltosyl benzamide or a pharmaceutically acceptable salt thereof; p) 4butoxy3chloroN (2,3,2', 3'tetraOacetyl6Obenzoyl4', 6'O benzylidene)ßDmaltosylbenzamide; q) 4chloro3methoxyN 4, 6tetraOacetylαD glucopyranosyl)pDglucopyranosyl benzamide; r) N (2, 2', 3, 3', 4,6,6'hepta OacetylPDmaltosyl4butoxy5chloro3 methoxybenzamide; s) N (6Obenzoyloxy4', 6'Obenzylidene)ßDmaltosyl4butoxy3chloro 5methoxybenzamide or a pharmaceutically acceptable salt thereof; t) N(2, 2', 3, 3'4', 6, 6'heptaOacetylßDmaltosyl 4(4nitrilobutoxy)3 nitrobenzamide; u) N(4',6'ObenzylideneßDmaltosyl)4(4nitrilobutoxy)3nitro benzamide or a pharmaceutically acceptable salt thereof; v) N (2,2', 3,3'tetraOacetyl6Obenzoyl4', 6'ObenzylideneßDmaltosyl) 4 (4nitrilobutoxy)3nitrobenzamide; w) N [(2, 2', 3, 3'4', 6,6'hepta0acetylPDmaltosyl]3amino4 (4nitrilo butoxy)benzamide; x) N (2,2', 3,3'4', 6, 6'heptaOacetylßDmaltosyl]6chloropyridine3 carboxamide or a pharmaceutically acceptable salt thereof; y) N (heptaOacetylßDmaltosyl)2, 6dimethoxypyridine3carboxamide or a pharmaceutically acceptable salt thereof; z) N (heptaOacetylßDmaltosyl)5bromopyridine3carboxamide or a pharmaceutically acceptable salt thereof; aa) N(heptaOacetylßDmaltosyl)3(trifluoromethyl)benzamide; bb) N (4', 6'ObenzylideneßDmaltosyl)3(trifluoromethyl)benzamide or a pharmaceutically acceptable salt thereof; cc) N {6Obenzoyl4', 6'Obenzylidene}ßDmaltosyl3(trifluoromethyl) benzamide or a pharmaceutically acceptable salt thereof; dd) N (heptaOacetylßDmaltosyl)6methylpyridine3carboxamide or a pharmaceutically acceptable salt thereof; ee) N(2,2',3, 3', 4', 6,6'heptaOacetylßmaltosyl)4butoxy3,5dichloro benzylamide; ff) N(4',6'ObenzylideneßDmaltosyl)4butoxy3,5dichlorobenzamide or a pharmaceutically acceptable salt thereof; gg) N (2,2', 3,3', 4', 6, 6'heptaOacetylßDmaltosyl)1(3, 4dimethoxy)phenyl acetamide; hh) N(heptaOacetylßDmaltosyl)2(4hydroxy3nitrophenyl)acetamide or a pharmaceutically acceptable salt thereof ; or ii) N(2, 2', 3, 3', 4', 6, 6'heptaOacetylßDmaltosyl)2(4chloro3nitro phenyl)acetamide;. |
| 15. | A method of treating or inhibiting hyperproliferative vascular disorders in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of formula I having the structure wherein Y is C or N; where n is 03; X is R', and R2 are each independently, hydrogen, alkyl of 1 to 6 carbon atoms, halo, acetyl, phenyl, CF3, CN, OH, NO2, NH2, alkoxy of 1 to 6 carbon atoms, or cyanoalkoxy of 2 to 7 carbon atoms; R3 is hydrogen, acylamide of 2 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms; R4, R5, R6, R7, and R3 are each, independently, hydrogen, acyl of 1 to 6 carbon atoms, benzyl substituted with R', and R2; or benzoyl substituted with R' andR2; R9 and R'° are each, independently, acyl of 1 to 6 carbon atoms, or the R9 and R10 groups on the 4'and 6'positions of the maltose may be taken together to form a cyclic acetal which may be substituted with alkyl of 1 to 6 carbon atoms, two alkyl groups each having 1 to 6 carbon atoms, pyridine substituted with R', phenyl substituted with R', benzyl substituted with R', 2phenylethyl substituted with R', or 3phenylpropyl substituted with R' ; with the provisio that when R1 or R2 are cyanoalkoxy of 27 carbon atoms, R3 is not acylamide, and further provided that when RI, R2, or R3 are alkoxy of 16 carbon atoms, at least one of R1, R2, R3, or R4 are not hydrogen; or a pharmaceutically acceptable salt thereof. |
| 16. | A method of treating or inhibiting restenosis in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of formula I having the structure wherein YisCorN; where n is 03; X is R', and R2 are each independently, hydrogen, alkyl of 1 to 6 carbon atoms, halo, acetyl, phenyl, CF3, CN, OH, NO2, NH2, alkoxy of 1 to 6 carbon atoms, or cyanoalkoxy of 2 to 7 carbon atoms; R3 is hydrogen, acylamide of 2 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms; R4, R5, R6, R7, and R8 are each, independently, hydrogen, acyl of 1 to 6 carbon atoms, benzyl substituted with R', and R2; or benzoyl substituted with R' and R R9 and R'° are each, independently, acyl of 1 to 6 carbon atoms, or the R9 and R'° groups on the 4'and 6'positions of the maltose may be taken together to form a cyclic acetal which may be substituted with alkyl of 1 to 6 carbon atoms, two alkyl groups each having 1 to 6 carbon atoms, pyridine substituted with R', phenyl substituted with R', benzyl substituted with R', 2phenylethyl substituted with R', or 3phenylpropyl substituted with R' ; with the provisio that when Rl or R2 are cyanoalkoxy of 27 carbon atoms, R3 is not acylamide, and further provided that when R1, R2, or R3 are alkoxy of 16 carbon atoms, at least one of RI, R2, R3, or R4 are not hydrogen; or a pharmaceutically acceptable salt thereof. |
| 17. | The method according to claim 16, wherein the restenosis results from a vascular angioplasty procedure, vascular reconstructive surgery, or organ or tissue transplantation. |
| 18. | A method of inhibiting angiogenesis in a malignant tumor, sarcoma, or neoplastic tissue in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of formula I having the structure wherein YisCorN; where n is 03; X is R', and R2 are each independently, hydrogen, alkyl of 1 to 6 carbon atoms, halo, acetyl, phenyl, CF3, CN, OH, NO2, NH2, alkoxy of 1 to 6 carbon atoms, or cyanoalkoxy of 2 to 7 carbon atoms; R3 iS hydrogen, acylamide of 2 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms; R4, R5, R6, R7, and R3 are each, independently, hydrogen, acyl of 1 to 6 carbon atoms, benzyl substituted with R', and R; or benzoyl substituted with R' and R2; R9 and R'° are each, independently, acyl of 1 to 6 carbon atoms, or the R9 and R'° groups on the 4'and 6'positions of the maltose may be taken together to form a cyclic acetal which may be substituted with alkyl of 1 to 6 carbon atoms, two alkyl groups each having 1 to 6 carbon atoms, pyridine substituted with R', phenyl substituted with R', benzyl substituted with R', 2phenylethyl substituted with R', or 3phenylpropyl substituted with R' ; with the provisio that when R1 or R2 are cyanoalkoxy of 27 carbon atoms, R3 is not acylamide, and further provided that when Rl, R2, or R3 are alkoxy of 16 carbon atoms, at least one of Rl, R2, R3, or R4 are not hydrogen; or a pharmaceutically acceptable salt thereof. |
| 19. | A pharmaceutical composition which comprises a compound of formula I having the structure wherein Y is C or N; where n is 03; X is R', and R2 are each independently, hydrogen, alkyl of 1 to 6 carbon atoms, halo, acetyl, phenyl, CF3, CN, OH, NO2, NH2, alkoxy of 1 to 6 carbon atoms, or cyanoalkoxy of 2 to 7 carbon atoms; is hydrogen, acylamide of 2 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms; R', R5, R6, R', and R8 are each, independently, hydrogen, acyl of 1 to 6 carbon atoms, benzyl substituted with R', and R2; or benzoyl substituted with R' and R2 ; R9 and R'° are each, independently, acyl of 1 to 6 carbon atoms, or the R9 and R'° groups on the 4'and 6'positions of the maltose may be taken together to form a cyclic acetal which may be substituted with alkyl of 1 to 6 carbon atoms, two alkyl groups each having 1 to 6 carbon atoms, pyridine substituted with R', phenyl substituted with R', benzyl substituted with R', 2phenylethyl substituted with R', or 3phenylpropyl substituted with R' ; with the provisio that when R1 or R2 are cyanoalkoxy of 27 carbon atoms, R3 is not acylamide, and further provided that when Rl, R2, or R3 are alkoxy of 16 carbon atoms, at least one of RI, R2, R3, or R4 are not hydrogen; or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier. |
Description:
INTERNATIONALSEARCHREPORT PCT/US99/27823 C.(Continuation)DOCUMENTSCONSIDEREDTOBERELEVANT CategoryCitabon of document, with in dicati on,whereappropnate,oftherelevantpassagesRelevanttoclaimNo. ADATABASEWPI1 SectionCh,Week199604 DerwentPublicationsLtd.,London,GB; ClassAll,AN1996-035887 XP002149382 &JP07304788A(MITSUITOATSUCHEMINC), 21November1995(1995-11-21) abstract -&JP07304788A 21November1995(1995-11-21) figures AEP0714903A(HOECHSTAG)15-19 5June1996(1996-06-05) page13,line43-page14,line49 EWO0031093A(AMERICANHOMEPROD)1-19 2June2000(2000-06-02) claims 14 2 INTERNATIONALSEARCHREPORT,, latlonal Application No ).attonaAppHcationNo Informationon patentfamily members PCT/US 99/27823 PatentdocumentPublication Patent family Publication citedinsearchreportdatemember(s)date JP7304788A21-11-1995NONE EP0714903A05-06-1996DE4436164A11-04-1996 CA2160100A11-04-1996 JP8325286A10-12-1996 US5858994A12-01-1999 WO0031093A02-06-2000AU1743700A13-06-2000