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US5252579A Expired / Lapsed US ⏱️ 0.0 years remaining

Macrocyclic immunomodulators

Assignee: Wyeth LLC
•
Filing: 1993-02-16
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Granted: 1993-10-12
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Expires: 2013-02-16
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Abstract

Abstract This invention provides a compound of the structure ##STR1## wherein X is selected from the group consisting of --NR 1 CR 2 R 3 (CR 4 R 5 ) m S--, --NR 1 CR 2 R 3 (CR 4 R 5 ) m O--, --OCR 2 R 3 (CR 4 R 5 ) m O--, --NR 1 CR 2 R 3 (CR 4 R 5 ) p --, --OCR 2 R 3 (CR 4 R 5 ) p --, --NR 1 CR 2 R 3 (CR 4 R 5 ) m NR 6 --, --OCR 2 R 3 (CR 4 R 5 ) m NR 6 --, --SCR 2 R 3 (CR 4 R 5 ) m NR 6 --, --SCR 2 R 3 (CR 4 R 5 ) m S--, --NOR 1 --, and --NR 1 --; R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each, independently, hydrogen, alkyl, fluorine, trifluoromethyl, aryl, arylalkyl, or any pair taken together to form a 3-6 membered ring; m=1-6; and p=0-6 or a pharmaceutically acceptable salt thereof which is useful as an immunosuppressive, antiinflamatory, antifungal, antiproliferative, and antitumor agent. This invention also covers derivatives of I and the use of I in combination with other immunoregulatory agents.

Inventors

  • 👤 Jerauld S. Skotnicki
  • 👤 Amedeo A. Failli
  • 👤 Robert J. Steffan
  • 👤 Robert M. Kearney

Bibliographic Details

Application Number —
Jurisdiction US
Data Source google_patents
Last Synchronized 2026-10-23 21:24
CPC Classifications
C; C07; C07D; C07D498/00; C07D498/12; C07D498/18; A; A61; A61P; A61P37/00; A61P37/02; A61P37/06

Claims Analysis

Total Claims: 19
Claim 1
Independent Claim 283 words
A compound of the structure ##STR6## wherein X is selected from the group consisting of --NR 1 CR 2 R 3 (CR 4 R 5 ) m S--, --NR 1 CR 2 R 3 (CR 4 R 5 ) m O--, --OCR 2 R 3 (CR 4 R 5 ) m O--, --NR 1 CR 2 R 3 (CR 4 R 5 ) p --, --OCR 2 R 3 (CR 4 R 5 ) p --, --NR 1 CR 2 R 3 (CR 4 R 5 ) m NR 6 --, --OCR 2 R 3 (CR 4 R 5 ) m NR 6 --, --SCR 2 R 3 (CR 4 R 5 ) m NR 6 --, --SCR 2 R 3 (CR 4 R 5 ) m S--, --NOR 1 --, and --NR 1 --; R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, fluorine, trifluoromethyl, aryl, arylalkyl or 7-10 carbon atoms, or any pair taken together to form a 3-6 membered ring, wherein the aryl moiety of the aryl and arylalkyl groups is selected from the group consisting of phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, quinoxalyl, thienyl, thionaphthyl, furyl, benzofuryl, benzodioxyl, benzoxazolyl, benzoisoxazolyl, and benzodioxolyl which may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, dialkylamino of 1-6 carbon atoms per alkyl group, alkylthio of 1-6 carbon atoms, --SO 3 H, --PO 3 H, and --CO 2 H; m=1-6; and p=0-6 or a pharmaceutically acceptable salt thereof.
Claim 2
Dependent Claim 283 words
A compound of the structure ##STR6## wherein X is selected from the group consisting of --NR 1 CR 2 R 3 (CR 4 R 5 ) m S--, --NR 1 CR 2 R 3 (CR 4 R 5 ) m O--, --OCR 2 R 3 (CR 4 R 5 ) m O--, --NR 1 CR 2 R 3 (CR 4 R 5 ) p --, --OCR 2 R 3 (CR 4 R 5 ) p --, --NR 1 CR 2 R 3 (CR 4 R 5 ) m NR 6 --, --OCR 2 R 3 (CR 4 R 5 ) m NR 6 --, --SCR 2 R 3 (CR 4 R 5 ) m NR 6 --, --SCR 2 R 3 (CR 4 R 5 ) m S--, --NOR 1 --, and --NR 1 --; R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, fluorine, trifluoromethyl, aryl, arylalkyl or 7-10 carbon atoms, or any pair taken together to form a 3-6 membered ring, wherein the aryl moiety of the aryl and arylalkyl groups is selected from the group consisting of phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, quinoxalyl, thienyl, thionaphthyl, furyl, benzofuryl, benzodioxyl, benzoxazolyl, benzoisoxazolyl, and benzodioxolyl which may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, dialkylamino of 1-6 carbon atoms per alkyl group, alkylthio of 1-6 carbon atoms, --SO 3 H, --PO 3 H, and --CO 2 H; m=1-6; and p=0-6 or a pharmaceutically acceptable salt thereof.
Claim 3
Dependent Claim 30 words
The compound of claim 1 in which X is --NR 1 CR 2 CR 2 R 3 (CR 4 R 5 ) m S-- or a pharmaceutically acceptable salt thereof.
Claim 4
Dependent Claim 37 words
The compound of claim 2 wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each, independently, hydrogen or alkyl of 1-6 carbon atoms or a pharmaceutically acceptable salt thereof.
Claim 5
Dependent Claim 14 words
The compound of claim 1 which is 23,25-deepoxy-23,25-(2-aminoethanethio)rapamycin or a pharmaceutically acceptable salt thereof.
Claim 6
Independent Claim 304 words
A method of inducing immunosuppression in a mammal in need thereof which comprises, administering to said mammal an immunosuppressive amount of a compound of the structure ##STR7## wherein X is selected from the group consisting of --NR 1 CR 2 R 3 (CR 4 R 5 ) m S--, --NR 1 CR 2 R 3 (CR 4 R 5 ) m O--, --OCR 2 R 3 (CR 4 R 5 ) m O--, --NR 1 CR 2 R 3 (CR 4 R 5 ) p --, --OCR 2 R 3 (CR 4 R 5 ) p --, --NR 1 CR 2 R 3 (CR 4 R 5 ) m NR 6 --, --OCR 2 R 3 (CR 4 R 5 ) m NR 6 --, --SCR 2 R 3 (CR 4 R 5 ) m NR 6 --, --SCR 2 R 3 (CR 4 R 5 ) m S--, --NOR 1 --, and --NR 1 --; R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, fluorine, trifluoromethyl, aryl, arylalkyl or 7-10 carbon atoms, or any pair taken together to form a 3-6 membered ring, wherein the aryl moiety of the aryl and arylalkyl groups is selected from the group consisting of phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, quinoxalyl, thienyl, thionaphthyl, furyl, benzofuryl, benzodioxyl, benzoxazolyl, benzoisoxazolyl, and benzodioxolyl which may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, dialkylamino of 1-6 carbon atoms per alkyl group, alkylthio of 1-6 carbon atoms, --SO 3 H, --PO 3 H, and --CO 2 H; m=1-6; and p=0-6 or a pharmaceutically acceptable salt thereof.
Claim 7
Independent Claim 304 words
A method of inducing immunosuppression in a mammal in need thereof which comprises, administering to said mammal an immunosuppressive amount of a compound of the structure ##STR7## wherein X is selected from the group consisting of --NR 1 CR 2 R 3 (CR 4 R 5 ) m S--, --NR 1 CR 2 R 3 (CR 4 R 5 ) m O--, --OCR 2 R 3 (CR 4 R 5 ) m O--, --NR 1 CR 2 R 3 (CR 4 R 5 ) p --, --OCR 2 R 3 (CR 4 R 5 ) p --, --NR 1 CR 2 R 3 (CR 4 R 5 ) m NR 6 --, --OCR 2 R 3 (CR 4 R 5 ) m NR 6 --, --SCR 2 R 3 (CR 4 R 5 ) m NR 6 --, --SCR 2 R 3 (CR 4 R 5 ) m S--, --NOR 1 --, and --NR 1 --; R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, fluorine, trifluoromethyl, aryl, arylalkyl or 7-10 carbon atoms, or any pair taken together to form a 3-6 membered ring, wherein the aryl moiety of the aryl and arylalkyl groups is selected from the group consisting of phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, quinoxalyl, thienyl, thionaphthyl, furyl, benzofuryl, benzodioxyl, benzoxazolyl, benzoisoxazolyl, and benzodioxolyl which may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, dialkylamino of 1-6 carbon atoms per alkyl group, alkylthio of 1-6 carbon atoms, --SO 3 H, --PO 3 H, and --CO 2 H; m=1-6; and p=0-6 or a pharmaceutically acceptable salt thereof.
Claim 8
Dependent Claim 23 words
The method according to claim 5 wherein the induced immunosuppression is used to prevent or treat transplantation rejection or host versus graft disease.
Claim 9
Dependent Claim 23 words
The method according to claim 5 wherein the induced immunosuppression is used to treat autoimmune diseases, diseases of inflammation, or hyperproliferative vascular disorders.
Claim 10
Dependent Claim 296 words
A pharmaceutical composition which comprises an effective amount of a compound of the structure ##STR8## wherein X is selected from the group consisting of --NR 1 CR 2 R 3 (CR 4 R 5 ) m S--, --NR 1 CR 2 R 3 (CR 4 R 5 ) m O--, --OCR 2 R 3 (CR 4 R 5 ) m O--, --NR 1 CR 2 R 3 (CR 4 R 5 ) p --, --OCR 2 R 3 (CR 4 R 5 ) p --, --NR 1 CR 2 R 3 (CR 4 R 5 ) m NR 6 --, --OCR 2 R 3 (CR 4 R 5 ) m NR 6 --, --SCR 2 R 3 (CR 4 R 5 ) m NR 6 --, --SCR 2 R 3 (CR 4 R 5 ) m S--, --NOR 1 --, and --NR 1 --; R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, fluorine, trifluoromethyl, aryl, arylalkyl or 7-10 carbon atoms, or any pair taken together to form a 3-6 membered ring, wherein the aryl moiety of the aryl and arylalkyl groups is selected from the group consisting of phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, quinoxalyl, thienyl, thionaphthyl, furyl, benzofuryl, benzodioxyl, benzoxazolyl, benzoisoxazolyl, and benzodioxolyl which may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, dialkylamino of 1-6 carbon atoms per alkyl group, alkylthio of 1-6 carbon atoms, --SO 3 H, --PO 3 H, and --CO 2 H; m=1-6; and p=0-6 or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.
Claim 11
Dependent Claim 296 words
A pharmaceutical composition which comprises an effective amount of a compound of the structure ##STR8## wherein X is selected from the group consisting of --NR 1 CR 2 R 3 (CR 4 R 5 ) m S--, --NR 1 CR 2 R 3 (CR 4 R 5 ) m O--, --OCR 2 R 3 (CR 4 R 5 ) m O--, --NR 1 CR 2 R 3 (CR 4 R 5 ) p --, --OCR 2 R 3 (CR 4 R 5 ) p --, --NR 1 CR 2 R 3 (CR 4 R 5 ) m NR 6 --, --OCR 2 R 3 (CR 4 R 5 ) m NR 6 --, --SCR 2 R 3 (CR 4 R 5 ) m NR 6 --, --SCR 2 R 3 (CR 4 R 5 ) m S--, --NOR 1 --, and --NR 1 --; R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, fluorine, trifluoromethyl, aryl, arylalkyl or 7-10 carbon atoms, or any pair taken together to form a 3-6 membered ring, wherein the aryl moiety of the aryl and arylalkyl groups is selected from the group consisting of phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, quinoxalyl, thienyl, thionaphthyl, furyl, benzofuryl, benzodioxyl, benzoxazolyl, benzoisoxazolyl, and benzodioxolyl which may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, dialkylamino of 1-6 carbon atoms per alkyl group, alkylthio of 1-6 carbon atoms, --SO 3 H, --PO 3 H, and --CO 2 H; m=1-6; and p=0-6 or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.
Claim 12
Independent Claim 312 words
A method of inducing immunosuppression in a mammal which comprises administering to said mammal an immunosuppressive effective amount of a combustion of a compound of the structure ##STR9## wherein X is selected from the group consisting of --NR 1 CR 2 R 3 (CR 4 R 5 ) m S--, --NR 1 CR 2 R 3 (CR 4 R 5 ) m O--, --OCR 2 R 3 (CR 4 R 5 ) m O--, --NR 1 CR 2 R 3 (CR 4 R 5 ) p --, --OCR 2 R 3 (CR 4 R 5 ) p --, --NR 1 CR 2 R 3 (CR 4 R 5 ) m NR 6 --, --OCR 2 R 3 (CR 4 R 5 ) m NR 6 --, --SCR 2 R 3 (CR 4 R 5 ) m NR 6 --, --SCR 2 R 3 (CR 4 R 5 ) m S--, --NOR 1 --, and --NR 1 --; R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, fluorine, trifluoromethyl, aryl, arylalkyl or 7-10 carbon atoms, or any pair taken together to form a 3-6 membered ring, wherein the aryl moiety of the aryl and arylalkyl groups is selected from the group consisting of phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, quinoxalyl, thienyl, thionaphthyl, furyl, benzofuryl, benzodioxyl, benzoxazolyl, benzoisoxazolyl, and benzodioxolyl which may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, dialkylamino of 1-6 carbon atoms per alkyl group, alkylthio of 1-6 carbon atoms, --SO 3 H, --PO 3 H, and --CO 2 H; m=1-6; and p=0-6 or a pharmaceutically acceptable salt thereof and at least one other immunoregulatory agent.
Claim 13
Independent Claim 312 words
A method of inducing immunosuppression in a mammal which comprises administering to said mammal an immunosuppressive effective amount of a combustion of a compound of the structure ##STR9## wherein X is selected from the group consisting of --NR 1 CR 2 R 3 (CR 4 R 5 ) m S--, --NR 1 CR 2 R 3 (CR 4 R 5 ) m O--, --OCR 2 R 3 (CR 4 R 5 ) m O--, --NR 1 CR 2 R 3 (CR 4 R 5 ) p --, --OCR 2 R 3 (CR 4 R 5 ) p --, --NR 1 CR 2 R 3 (CR 4 R 5 ) m NR 6 --, --OCR 2 R 3 (CR 4 R 5 ) m NR 6 --, --SCR 2 R 3 (CR 4 R 5 ) m NR 6 --, --SCR 2 R 3 (CR 4 R 5 ) m S--, --NOR 1 --, and --NR 1 --; R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, fluorine, trifluoromethyl, aryl, arylalkyl or 7-10 carbon atoms, or any pair taken together to form a 3-6 membered ring, wherein the aryl moiety of the aryl and arylalkyl groups is selected from the group consisting of phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, quinoxalyl, thienyl, thionaphthyl, furyl, benzofuryl, benzodioxyl, benzoxazolyl, benzoisoxazolyl, and benzodioxolyl which may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, dialkylamino of 1-6 carbon atoms per alkyl group, alkylthio of 1-6 carbon atoms, --SO 3 H, --PO 3 H, and --CO 2 H; m=1-6; and p=0-6 or a pharmaceutically acceptable salt thereof and at least one other immunoregulatory agent.
Claim 14
Dependent Claim 33 words
The method according to claim 9 wherein the other immunoregulatory agent is selected from the group consisting of azathioprine, corticosteroids, such as prednisone and methylprednisone, cyclophosphamide, rapamycin, cyclosporin A, FK-506, OKT-3, and ATG.
Claim 15
Dependent Claim 302 words
A pharmaceutical composition which comprises an effective amount of a compound of the structure ##STR10## wherein X is selected from the group consisting of --NR 1 CR 2 R 3 (CR 4 R 5 ) m S--, --NR 1 CR 2 R 3 (CR 4 R 5 ) m O--, --OCR 2 R 3 (CR 4 R 5 ) m O--, --NR 1 CR 2 R 3 (CR 4 R 5 ) p --, --OCR 2 R 3 (CR 4 R 5 ) p --, --NR 1 CR 2 R 3 (CR 4 R 5 ) m NR 6 --, --OCR 2 R 3 (CR 4 R 5 ) m NR 6 --, --SCR 2 R 3 (CR 4 R 5 ) m NR 6 --, --SCR 2 R 3 (CR 4 R 5 ) m S--, --NOR 1 --, and --NR 1 --; R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, fluorine, trifluoromethyl, aryl, arylalkyl or 7-10 carbon atoms, or any pair taken together to form a 3-6 membered ring, wherein the aryl moiety of the aryl and arylalkyl groups is selected from the group consisting of phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, quinoxalyl, thienyl, thionaphthyl, furyl, benzofuryl, benzodioxyl, benzoxazolyl, benzoisoxazolyl, and benzodioxolyl which may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, dialkylamino of 1-6 carbon atoms per alkyl group, alkylthio of 1-6 carbon atoms, --SO 3 H, --PO 3 H, and --CO 2 H; m=1-6; and p=0-6 or a pharmaceutically acceptable salt thereof; at least one other immunoregulatory agents; and a pharmaceutical carrier.
Claim 16
Dependent Claim 302 words
A pharmaceutical composition which comprises an effective amount of a compound of the structure ##STR10## wherein X is selected from the group consisting of --NR 1 CR 2 R 3 (CR 4 R 5 ) m S--, --NR 1 CR 2 R 3 (CR 4 R 5 ) m O--, --OCR 2 R 3 (CR 4 R 5 ) m O--, --NR 1 CR 2 R 3 (CR 4 R 5 ) p --, --OCR 2 R 3 (CR 4 R 5 ) p --, --NR 1 CR 2 R 3 (CR 4 R 5 ) m NR 6 --, --OCR 2 R 3 (CR 4 R 5 ) m NR 6 --, --SCR 2 R 3 (CR 4 R 5 ) m NR 6 --, --SCR 2 R 3 (CR 4 R 5 ) m S--, --NOR 1 --, and --NR 1 --; R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, fluorine, trifluoromethyl, aryl, arylalkyl or 7-10 carbon atoms, or any pair taken together to form a 3-6 membered ring, wherein the aryl moiety of the aryl and arylalkyl groups is selected from the group consisting of phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, quinoxalyl, thienyl, thionaphthyl, furyl, benzofuryl, benzodioxyl, benzoxazolyl, benzoisoxazolyl, and benzodioxolyl which may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, dialkylamino of 1-6 carbon atoms per alkyl group, alkylthio of 1-6 carbon atoms, --SO 3 H, --PO 3 H, and --CO 2 H; m=1-6; and p=0-6 or a pharmaceutically acceptable salt thereof; at least one other immunoregulatory agents; and a pharmaceutical carrier.
Claim 17
Dependent Claim 33 words
The composition according to claim 11 wherein the other immunoregulatory agent is selected from the group consisting of azathioprine, corticosteroids, such as prednisone and methylprednisone, cyclophosphamide, rapamycin, cyclosporin A, FK-506, OKT-3, and ATG.
Claim 18
Dependent Claim 11 words
A compound which is 25,26-dehydro-24,25-secorapamycin or a base addition salt thereof.
Claim 19
Dependent Claim 11 words
A compound which is 25,26-dehydro-24,25-secorapamycin or a base addition salt thereof.

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