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EP0509795A2 Expired / Lapsed EP ⏱️ 0.0 years remaining

Carbamates of rapamycin

Assignee: Wyeth LLC
•
Filing: 1992-04-15
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Granted: —
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Expires: 2012-04-15
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Abstract

Abstract The invention concerns a compound of the structure: wherein R l and R 2 are each, independently, hydrogen, -CONH(CR 3 R 4 ) n -X or CONHSO 2 -Ar; R 3 and R 4 are each independently, hydrogen, alkyl, aralkyl, cycloalkyl of 3-8 carbon atoms, halogen, or trifluoromethyl; providing that when more than one R 3 or R 4 group is present then they may be the same or different; X is hydrogen, lower alkyl, cycloalkyl, trifluoromethyl, nitro, alkoxy, carboalkoxy, aralkyl, halo, dialkylamino, thioalkyl, or Y; Y is a phenyl group which may be optionally mono-, di-, or tri- substituted; Ar is phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, quinoxalyl, thienyl, thionaphthyl, furyl, benzofuryl, benzodioxyl, benzoxazolyl, benzoisoxazolyl, or benzodioxolyl; wherein the Ar group may be optionally mono-, di-, or tri-subsrituted, and n = 0-5; with the proviso that R 1 and R 2 are not both hydrogen and when n = 0, X is lower alkyl, cycloalkyl , aralkyl, or Y; or a pharmaceutically acceptable salt thereof when X is dialkylamino, when the Ar group contains a basic nitrogen, or when the Ar group is substituted by dialklyamino, SO 3 H, -PO 3 H, or -CO 2 H, which by virtue of its immunosuppressive activity is useful in treating transplantation rejection, host vs. graft disease, autoimmune diseases and discases of inflammation; by virtue of its antitumor activity is useful in treating solid tumors; and by virtue of its antifungal activity is useful in treating fungal infections.

Inventors

  • 👤 Wenling Kao
  • 👤 Robert Lewis Vogel
  • 👤 John Henry Musser

Bibliographic Details

Application Number —
Jurisdiction EP
Data Source google_patents
Last Synchronized 2026-11-08 10:01
CPC Classifications
C; C07; C07D; C07D498/00; C07D498/12; C07D498/18; A; A61; A61P; A61P29/00; A61P37/00; A61P37/02; A61P37/06; A61P7/00; A61P7/08; A61P9/00; A61P9/12

Claims Analysis

Total Claims: 15
Claim 1
Independent Claim 350 words
A compound of formula: wherein R l and R 2 are each, independently, hydrogen, -CONH(CR 3 R 4 ) n -X or -CONHSO 2 -Ar; R 3 and R 4 are each, independently, hydrogen, alkyl of l-6 carbon atoms, aralkyl of 7-l0 carbon atoms, cycloalkyl of 3-8 carbon atoms, halogen, or trifluoromethyl, providing that when more than one R 3 or R 4 group is present then they may each be the same or different; X is hydrogen, lower alkyl of l-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, trifluoromethyl, nitro, alkoxy of l-6 carbon atoms, carboalkoxy of 2-7 carbon atoms, aralkyl of 7-l0 carbon atoms, halo, dialkylamino of l-6 carbon atoms per alkyl group, thioalkyl of l-6 carbon atoms, or Y: Y is a phenyl- group which may be optionally mono-, di-or tri- substituted with a group selected from alkyl of l-6 carbon atoms, aralkyl of 7-l0 carbon atoms, alkoxy of l-6 carbon atoms, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, dialkylamino of l-6 carbon atoms per alkyl group, or alkylthio of l-6 carbon atoms; Ar is phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, quinoxalyl, thienyl, thionaphthyl, furyl, benzofuryl, benzodioxyl, benzoxazolyl, benzoisoxazolyl, or benzodioxolyl; wherein the Ar group may be optionally mono-, di- or tri-substituted with a group selected from alkyl of l-6 carbon atoms, arylalkyl of 7-l0 carbon atoms, alkoxy of l-6 carbon atoms, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, dialkyl-amino of l-6 carbon atoms per alkyl group, alkylthio of l-6 carbon atoms, -SO 3 H,-PO 3 H, and -CO 2 H; and n = 0-5; with the proviso that R l and R 2 are not both hydrogen and when n = 0, X is lower alkyl of l-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, aralkyl of 7-l0 carbon atoms, or Y; or a pharmaceutically acceptable salt thereof when X is dialkylamino of l-6 carbon atoms per alkyl group, when the Ar group contains a basic nitrogen, or when the Ar group is substituted by dialkylamino of l-6 carbon atoms per alkyl group, -SO 3 H,-PO 3 H, or -CO 2 H.
Claim 2
Dependent Claim 12 words
A compound as claimed on Claim l where R l is hydrogen.
Claim 3
Dependent Claim 12 words
A compound as claimed on Claim l where R 2 is hydrogen.
Claim 4
Dependent Claim 20 words
A compound as claimed in any one of Claims l to 3 where n is 0 and X is Y.
Claim 5
Dependent Claim 21 words
A compound as claimed in any one of Claims l to 4 where Y is phenyl, 4-fluorophenyl, 2,4-difluorophenyl, 4-nitrophenyl, or 4-methylphenyl.
Claim 6
Dependent Claim 31 words
A compound as claimed in any one of Claims l to 3 wherein Ar is phenyl; the phenyl group being optionally mono-, di-, or tri-substituted or a pharmaceutically acceptable salt thereof.
Claim 7
Dependent Claim 20 words
A compound as claimed in Claim 6 wherein the substituent is selected from halogen and C l -C 4 alkyl.
Claim 8
Dependent Claim 87 words
A compound as claimed in Claim l which is one of the following: rapamycin 42-ester with (4-fluorophenyl)- carbamic acid; rapamycin 42-ester with phenylcarbamic acid; rapamycin -3l,42-diester with [4-(trifluoromethyl)-phenyl]carbamic acid; rapamycin-42-ester with [4-(trifluoromethyl)phenyl]carbamic acid; rapamycin-3l,42-diester with (4-nitrophenyl)carbamic acid; rapamycin-42-ester with (4-nitrophenyl)carbamic acid; rapamycin-3l,42-diester with(4-methylphenyl)carbamic acid; rapamycin-42-ester with (4-methylphenyl)carbamic acid; rapamycin-42-ester with (2,4-difluorophenyl)carbamic acid; rapamycin-3l,42-diester with (2,4-difluorophenyl)carbamic acid; rapamycin-3l,42-diester with phenylcarbamic acid; rapamycin-3l,42-diester with (4-flurophenyl)carbamic acid; rapamycin-3l-ester with (2,4-difluorophenyl)carbamic acid; rapamycin 42-ester with phenylsulfonylcarbamic acid; rapamycin-3l-ester with phenylsulfonylcarbamic acid; rapamycin 42-ester with (4-chlorophenylsulfonyl)-carbamic acid; rapamycin 42-ester with (3-methylphenylsulfonyl)-carbamic acid;
Claim 9
Dependent Claim 49 words
A modification of a compound as claimed in Claim l wherein R l is a silyl protecting group and R 2 is -CONH(CR 3 R 4 ) n -X or CONHSO 2 Ar wherein n, X, R 3 , R 4 and Ar are as defined in Claim l.
Claim 10
Dependent Claim 16 words
A compound as claimed in Claim 9 wherein the silyl protecting group is a tertbutyldimethylsilyl group.
Claim 11
Dependent Claim 15 words
A compound as claimed on Claim 9 which is rapamycin 42-tertbutyldimethylsilyl ether-3l-ester with phenylsulfonylcarbamic acid.
Claim 12
Dependent Claim 14 words
A compound as claimed in Claim 9 which is rapamycin-42-tert-butyldimethylsilyl ether-3l-ester with (2,4-difluorophenyl)carbamic acid.
Claim 13
Dependent Claim 90 words
A process for preparing a compound as claimed on Claim l which comprises carbamylating rapamycin; 42-R l - substituted or 3l-R 2 - substituted rapamycin in which R l and R 2 are as defined on Claim l or a 42 protected derivative of rapamycin using an isocyanate of formula O=N=C-Q wherein Q represents -(CR 3 R 4 ) n -X or -SO 2 -Ar wherein n, R 3 , R 4 , X and Ar are as defined in Claim l and if required removing the 42 protecting group.
Claim 14
Dependent Claim 15 words
A process as claimed in Claim l3 wherein the protecting group is a tertbutyldimethylsilyl group.
Claim 15
Dependent Claim 21 words
A pharmaceutical composition comprising a compound as claimed on any one of Claims l to 8 and a pharmaceutically acceptable carrier.

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