(12J United States Patent
`Zhu et al.
`
`I 111111111111111111111111111111111111 lllll 111111111111111111111111111111111
`US006432973Bl
`US 6,432,973 Bl
`Aug. 13, 2002
`
`(10) Pateut No.:
`(45) Date of Patent:
`
`(54) WATER SOLUBLE RAPAMYCIN ESTERS
`
`(75)
`
`Inventors: Tianmin Zhu, Monroe, NY (US);
`Mahdi Fawzi, Morristown, NJ (US)
`
`(73) Assignee: Wyeth, Madison, NJ (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 09/954,782
`
`(22) Filed:
`
`Sep. 18, 2001
`
`Related U.S. Application Data
`(60) Provisional application No, 60/233,776, filed on Sep, 19,
`2000.
`
`(51)
`
`Int. Cl.' .................... C07D 498/16; C07D 498/18;
`C07D 491/06; A61K 31/395; A61K 31/445
`(52) U.S. Cl . ........................................ 514/291; 540/456
`(58) Field of Search ........................... 540/456; 514/291
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,9'29,992 A
`3,993,749 A
`4,316,885 A
`4,375,464 A
`4,401,653 A
`4,650,803 A
`4,885,171 A
`5,023,262 A
`5,023,263 A
`5,078,999 A
`5,080,899 A
`5,093,338 A
`5,093,339 A
`5,100,883 A
`5,100,899 A
`5,102,876 A
`5,118,677 A
`5,118,678 A
`5,120,842 A
`5,130,307 A
`5,151,413 A
`5,162,333 A
`5,177,203 A
`5,206,018 A
`5,221,670 A
`5,233,036 A
`5,256,790 A
`5,258,389 A
`5,260,300 A
`5,262,423 A
`5,2&5,730 A
`5,2&5,731 A
`5,288,711 A
`5,302,584 A
`5,321,009 A
`5,362,718 A
`5,385,908 A
`5,385,909 A
`
`12./1975 Sehgal et al. ............... 424/122
`11/1976 Sehgal et al. ............... 424/122
`2./1982 Rakhit ........................ 424/122
`3/1983 Sehgal et al. ............... 424/122
`8/1983 Eng ..................... , ..... 424/114
`3/1987 Stella et al.
`................ 514/291
`12./1989 Surendra et al. ............ 424/122
`6/1991 Caulfield et al.
`........... 514/291
`6/1991 Von Burg ................... 514/291
`1/1992 Warner et al. .............. 424/122
`1/1992 Strum et al. ................ 424/122
`3/1992 Byrne et al. ................ 514/291
`3/1992 Kasama et al. ............. 514/291
`3/1992 Schiehser ................... 514/183
`3/1992 Caine ......................... 514/291
`4/1992 Caulfield .................... 514/183
`6/1992 Caufield ..................... 514/183
`6/1992 Kao et al. ................... 514/183
`6/1992 Failli cl al. ................. 540/452
`* 7/1992 Failli et al. ................. 514/321
`9/1992 Caufield et al.
`.............. 514/63
`11/1992 Failli et al. ................. 514/291
`1/1993 Failli ct al. ................. 540/456
`4/1993 Sehgal et al, ............... 424/122
`* 6/1993 Caufield ..................... 514/183
`8/1993 Hughes ...................... 540/455
`10/1993 Nelson ....................... 514/291
`11/1993 Goulcl et al. ............... 514/291
`11/1993 Hu ............................. 514/291
`11/1993 Kao ........................... 514/291
`2/1994 Caufield et al.
`............ 514/291
`2/1994 Caufield et al.
`............ 514/291
`2/1994 Mitchell et al.
`.............. 514/56
`4/1994 Kao et al. ..................... 514/80
`6/1994 Bneder et al ................. 514/15
`11/1994 Skotnicki ..................... 514/63
`1/1995 Nelson et al ............... 514/291
`1/1995 Nelson et al.
`.............. 514/291
`
`5,385,910 A
`5,387,589 A
`5,389,639 A
`5,391,730 A
`5,411,967 A
`5,434,260 A
`5,463,048 A
`5,480,988 A
`5,480,989 A
`5,489,680 A
`5,491,231 A
`5,496,832 A
`5,504,091 A
`5,516,770 A
`5,516,781 A
`5,530,006 A
`5,536,729 A
`5,559,121 A
`5,561,138 A
`5,616,588 A
`5,665,772 A
`5,780,462 A
`5,985,325 A
`5,989,591 A
`
`1/1995 Ocain ct al. ...... , .... , .... 514/291
`2/1995 Kulkarni ..................... 514/291
`2/1995 Failli et al. ................. 514/291
`2/1995 Skotnicki et al. .......... , 540/456
`5/1995 Kao et al. ................... 514/291
`7/1995 Skotnicki et al. .......... , 514/291
`10/1995 Skotnicki et al. ........... 540/456
`1/1996 Failli et al. ................. 540/456
`1/1996 Kao et al. ................... 540/456
`2/1996 Failli et al. ................. 540/456
`2/1996 Nelson et al.
`.............. 540/456
`3/1996 Armstrong ................. , 514/291
`4/1996 Molnar-Kimber .......... , 514/291
`5/1996 Waranis et al .............. 514/183
`5/1996 Morris et al. ............... 514/291
`6/1996 Waranis et al. ............. 514/291
`7/1996 Waranis et al. ............. 514/291
`9/1996 Harrison et al. ............ 514/291
`10/1996 Armstrong .. , .............. , 514/291
`4/1997 Waranis el al. ............. 514/291
`9/1997 Cottcns et al. .............. 514/514
`* 7/1998 Lee et al.
`................... 514/183
`11/1999 Nagi .......................... 424/482
`11/1999 Nagi .............. ,., ........ , 424/493
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`WO
`
`0 525 960 Al
`781 776
`WO 94/25072
`
`2/1993
`* 7/1997
`• 11/1994
`
`OTHER PUBLICATIONS
`
`C.V. Vezina et al., J, Anitbiol., 1975, 721,28.
`H.A. Baker et al., J. Antibiot., 1978, 539,31.
`FASEB, 1989, 3411,3.
`FASEB, 1989, 5256,3.
`R.Y. Calne et al., Lancet, 1978, 1183.
`R. Martel et al., Can. J. Physiol. Pharmacol., 1977, 48, 55.
`T. Matsumoto et al., Alheroschlerosis, 1998, 95, 139.
`S.E. Roselaar el al., J. Clio. Invest., 1995, 1906, 96.
`K.B. Lemstmm et al., Arterioscler. Thomb. Vase. Biol. 1996,
`553, 16(4).
`T. Quaschning el al., Kidney In!., 1999, S235, 56(71).
`E.E. Emeson el al., Am. J. Pathol., 1993, 1906, 142(6).
`J. Gibbons et al., Proc. Am. Assoc. Can. Res., 1999, 301, 40.
`B. Geoerger et al., Proc. Am. A<;.,;;oc. Can. Res,, 1999, 603,
`40.
`.J. Alexandre, Bull. Cancer, 1999, 808-811, 86.
`.J. Alexandre et al., Clio. Cancer Res., 1999,Abstract 7, Nov.
`Suppl.
`* cited by examiner
`Primary Examiner---Rruck Kifle
`(74) Attorney, Agent, or Firm-Arnold S. Milowsky
`ABSTRACT
`
`(57)
`
`This invention provide pegylated hydroxyesters of rapamy~
`cin which are useful in inducing immunosuppression and in
`the treatment of transplantation rejection, autoimmune
`diseases, solid tumors, fungal infections, and vascular dis(cid:173)
`ease.
`
`18 Claims, No Drawings
`
`A J'l'EXHil31T~
`De~·ll·?·l ny·. e,_ r I,· ,s
`I,· ':J'{/;/ "'
`ih l
`rf~te-~-O_Rptr,~
`,WWW.DEPOBOOK.COM
`
`Breckenridge Exhibit 1092
`Zhu '973 Patent
`Page 001
`
`
`Zhu et al.
`
`I 111111111111111111111111111111111111 lllll 111111111111111111111111111111111
`US006432973Bl
`US 6,432,973 Bl
`Aug. 13, 2002
`
`(10) Pateut No.:
`(45) Date of Patent:
`
`(54) WATER SOLUBLE RAPAMYCIN ESTERS
`
`(75)
`
`Inventors: Tianmin Zhu, Monroe, NY (US);
`Mahdi Fawzi, Morristown, NJ (US)
`
`(73) Assignee: Wyeth, Madison, NJ (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 09/954,782
`
`(22) Filed:
`
`Sep. 18, 2001
`
`Related U.S. Application Data
`(60) Provisional application No, 60/233,776, filed on Sep, 19,
`2000.
`
`(51)
`
`Int. Cl.' .................... C07D 498/16; C07D 498/18;
`C07D 491/06; A61K 31/395; A61K 31/445
`(52) U.S. Cl . ........................................ 514/291; 540/456
`(58) Field of Search ........................... 540/456; 514/291
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,9'29,992 A
`3,993,749 A
`4,316,885 A
`4,375,464 A
`4,401,653 A
`4,650,803 A
`4,885,171 A
`5,023,262 A
`5,023,263 A
`5,078,999 A
`5,080,899 A
`5,093,338 A
`5,093,339 A
`5,100,883 A
`5,100,899 A
`5,102,876 A
`5,118,677 A
`5,118,678 A
`5,120,842 A
`5,130,307 A
`5,151,413 A
`5,162,333 A
`5,177,203 A
`5,206,018 A
`5,221,670 A
`5,233,036 A
`5,256,790 A
`5,258,389 A
`5,260,300 A
`5,262,423 A
`5,2&5,730 A
`5,2&5,731 A
`5,288,711 A
`5,302,584 A
`5,321,009 A
`5,362,718 A
`5,385,908 A
`5,385,909 A
`
`12./1975 Sehgal et al. ............... 424/122
`11/1976 Sehgal et al. ............... 424/122
`2./1982 Rakhit ........................ 424/122
`3/1983 Sehgal et al. ............... 424/122
`8/1983 Eng ..................... , ..... 424/114
`3/1987 Stella et al.
`................ 514/291
`12./1989 Surendra et al. ............ 424/122
`6/1991 Caulfield et al.
`........... 514/291
`6/1991 Von Burg ................... 514/291
`1/1992 Warner et al. .............. 424/122
`1/1992 Strum et al. ................ 424/122
`3/1992 Byrne et al. ................ 514/291
`3/1992 Kasama et al. ............. 514/291
`3/1992 Schiehser ................... 514/183
`3/1992 Caine ......................... 514/291
`4/1992 Caulfield .................... 514/183
`6/1992 Caufield ..................... 514/183
`6/1992 Kao et al. ................... 514/183
`6/1992 Failli cl al. ................. 540/452
`* 7/1992 Failli et al. ................. 514/321
`9/1992 Caufield et al.
`.............. 514/63
`11/1992 Failli et al. ................. 514/291
`1/1993 Failli ct al. ................. 540/456
`4/1993 Sehgal et al, ............... 424/122
`* 6/1993 Caufield ..................... 514/183
`8/1993 Hughes ...................... 540/455
`10/1993 Nelson ....................... 514/291
`11/1993 Goulcl et al. ............... 514/291
`11/1993 Hu ............................. 514/291
`11/1993 Kao ........................... 514/291
`2/1994 Caufield et al.
`............ 514/291
`2/1994 Caufield et al.
`............ 514/291
`2/1994 Mitchell et al.
`.............. 514/56
`4/1994 Kao et al. ..................... 514/80
`6/1994 Bneder et al ................. 514/15
`11/1994 Skotnicki ..................... 514/63
`1/1995 Nelson et al ............... 514/291
`1/1995 Nelson et al.
`.............. 514/291
`
`5,385,910 A
`5,387,589 A
`5,389,639 A
`5,391,730 A
`5,411,967 A
`5,434,260 A
`5,463,048 A
`5,480,988 A
`5,480,989 A
`5,489,680 A
`5,491,231 A
`5,496,832 A
`5,504,091 A
`5,516,770 A
`5,516,781 A
`5,530,006 A
`5,536,729 A
`5,559,121 A
`5,561,138 A
`5,616,588 A
`5,665,772 A
`5,780,462 A
`5,985,325 A
`5,989,591 A
`
`1/1995 Ocain ct al. ...... , .... , .... 514/291
`2/1995 Kulkarni ..................... 514/291
`2/1995 Failli et al. ................. 514/291
`2/1995 Skotnicki et al. .......... , 540/456
`5/1995 Kao et al. ................... 514/291
`7/1995 Skotnicki et al. .......... , 514/291
`10/1995 Skotnicki et al. ........... 540/456
`1/1996 Failli et al. ................. 540/456
`1/1996 Kao et al. ................... 540/456
`2/1996 Failli et al. ................. 540/456
`2/1996 Nelson et al.
`.............. 540/456
`3/1996 Armstrong ................. , 514/291
`4/1996 Molnar-Kimber .......... , 514/291
`5/1996 Waranis et al .............. 514/183
`5/1996 Morris et al. ............... 514/291
`6/1996 Waranis et al. ............. 514/291
`7/1996 Waranis et al. ............. 514/291
`9/1996 Harrison et al. ............ 514/291
`10/1996 Armstrong .. , .............. , 514/291
`4/1997 Waranis el al. ............. 514/291
`9/1997 Cottcns et al. .............. 514/514
`* 7/1998 Lee et al.
`................... 514/183
`11/1999 Nagi .......................... 424/482
`11/1999 Nagi .............. ,., ........ , 424/493
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`WO
`
`0 525 960 Al
`781 776
`WO 94/25072
`
`2/1993
`* 7/1997
`• 11/1994
`
`OTHER PUBLICATIONS
`
`C.V. Vezina et al., J, Anitbiol., 1975, 721,28.
`H.A. Baker et al., J. Antibiot., 1978, 539,31.
`FASEB, 1989, 3411,3.
`FASEB, 1989, 5256,3.
`R.Y. Calne et al., Lancet, 1978, 1183.
`R. Martel et al., Can. J. Physiol. Pharmacol., 1977, 48, 55.
`T. Matsumoto et al., Alheroschlerosis, 1998, 95, 139.
`S.E. Roselaar el al., J. Clio. Invest., 1995, 1906, 96.
`K.B. Lemstmm et al., Arterioscler. Thomb. Vase. Biol. 1996,
`553, 16(4).
`T. Quaschning el al., Kidney In!., 1999, S235, 56(71).
`E.E. Emeson el al., Am. J. Pathol., 1993, 1906, 142(6).
`J. Gibbons et al., Proc. Am. Assoc. Can. Res., 1999, 301, 40.
`B. Geoerger et al., Proc. Am. A<;.,;;oc. Can. Res,, 1999, 603,
`40.
`.J. Alexandre, Bull. Cancer, 1999, 808-811, 86.
`.J. Alexandre et al., Clio. Cancer Res., 1999,Abstract 7, Nov.
`Suppl.
`* cited by examiner
`Primary Examiner---Rruck Kifle
`(74) Attorney, Agent, or Firm-Arnold S. Milowsky
`ABSTRACT
`
`(57)
`
`This invention provide pegylated hydroxyesters of rapamy~
`cin which are useful in inducing immunosuppression and in
`the treatment of transplantation rejection, autoimmune
`diseases, solid tumors, fungal infections, and vascular dis(cid:173)
`ease.
`
`18 Claims, No Drawings
`
`A J'l'EXHil31T~
`De~·ll·?·l ny·. e,_ r I,· ,s
`I,· ':J'{/;/ "'
`ih l
`rf~te-~-O_Rptr,~
`,WWW.DEPOBOOK.COM
`
`Breckenridge Exhibit 1092
`Zhu '973 Patent
`Page 001
`
`
`
`US 6,432,973 Bl
`
`19
`
`5
`
`10
`
`15
`
`20
`R7 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7
`carbon atoms, alkynyl of 2-7 carbon atoms,
`---{CR'R'),OR'°, -CF,, -F, or -C02R";
`R8 and R9 are each, independently, hydrogen, alkyl of 1-6
`carbon atoms, alkenyl of2-7 carbon atoms, alkynyl of
`2-7 carbon atoms, ---(CR3R4)_f)R10
`, -CF3 , -F, or
`-C02R11
`;
`R 10 is hydrogen or -COCH2-S-CH2CH2-(0-
`CH2-CH:i),,-OCH3;
`R11 is hydrogen, alkyl of 1-6 carbon atoms, alkcnyl of
`2-7 carbon atoms, alkynyl of 2-7 carbon atoms, or
`phcnylalkyl of 7-10 carbon atoms;
`b=0-6;
`d=0-6;
`f=0-6;
`0=5--450;
`with the proviso that R1 and R2 are both not hydrogen and
`further provided that either R 1 or R2 contains at least one
`
`20 ---(CR3R'1)1OR10 group in which R10 is -COCH2......._.s(cid:173)
`Cil2Cil2---(0-Cll2-Cil2),,-0CI-I3, or a pharmaceuti~
`cally acceptable salt thereof, and a pharmaceutical carrier.
`17. A compound which is rapamycin 42-cster with
`3-h y droxy-2-(2- iodo- ace toxym e thy 1)-2-me thy 1-propioni c
`acid.
`18. A compound which is rapamycin 42-ester with 3-(2-
`Iodo-ace toxy )-2-( 2-iodo- ace to xy me thy 1 )-2-me thy 1-
`propionic acid,
`
`wherein
`R1 and R2 are each, independently, hydrogen or --CO
`(CR'R'MCR'R6)dCR'R8 R9
`;
`R3 and R'1 are each, independently, hydrogen, alkyl of 1-6
`carbon atoms, alkenyl of2-7 carbon atoms, alkynyl of 25
`2-7 carbon atoms, trifluoromethyl, or -F;
`R5 and R6 are each, independently, hydrogen, alkyl of 1-6
`carbon atoms, alkenyl of 2--7 carbon atoms, alkynyl of
`2-7 carbon atoms, -(CR3R4)pR10
`, -CF3 , -F, or
`--C02R11;
`
`* * * * *
`
`Breckenridge Exhibit 1092
`Zhu '973 Patent
`Page 0011
`
`
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
