(12) United States Patent
`Metcalf, 111 et al.
`
`US 7,091,213 B2
`(io) Patent No.:
`(45) Date of Patent:
`Aug. 15, 2006
`
`US007091213B2
`
`(54) PHOSPHORUS-CONTAINING COMPOUNDS
`AND USES THEREOF
`
`(75)
`
`Inventors: Chester A. Metcalf, 111, Needham, MA
`(US); Leonard W. Rozamus, Bedford,
`MA (US); Yihan Wang, Newton, MA
`(US); David L. Berstein, Waban, MA
`(US)
`
`(73) Assignee: ARIAD Gene Therapeutics, Inc.,
`Cambridge, MA (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.: 10/862,149
`
`(22) Filed:
`
`Jun. 4, 2004
`
`(65)
`
`Prior Publication Data
`
`US 2005/0032825 Al
`
`Feb. 10, 2005
`
`Related U.S. Application Data
`
`(63) Continuation-in-part of application No. 10/635,054,
`filed on Aug. 6, 2003, now abandoned, and a con(cid:173)
`tinuation-in-part of application No. 10/357,152, filed
`on Feb. 3, 2003, now abandoned.
`
`(60) Provisional application No. 60/433,930, filed on Dec.
`17, 2002, provisional application No. 60/428,383,
`filed on Nov. 22, 2002, provisional application No.
`60/426,928, filed on Nov. 15, 2002, provisional appli(cid:173)
`cation No. 60/353,252, filed on Feb. 1, 2002.
`
`(51)
`
`(52)
`(58)
`
`(56)
`
`Int. CI.
`CO 7D 491/06
`A61K 31/395
`A61P 35/00
`A61P 35/02
`U.S. CI
`Field of Classification Search
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`514/291; 540/456
`540/456;
`514/291
`See application file for complete search history.
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5,206,018 A
`5,234,456 A
`5,310,903 A
`5,385,910 A
`5,391,730 A
`5,434,260 A
`5,489,680 A
`
`4/1993 Sehgal et al.
`8/1993 Silvestrini
`5/1994 Goulet et al.
`1/1995 Ocain et al.
`2/1995 Skotnicki et al.
`7/1995 Skotnicki et al.
`2/1996 Failli et al.
`
`5,491,231
`5,516,781
`5,665,591
`5,851,217
`5,968,091
`6,146,358
`6,152,141
`6,585,764
`2001/0010920
`
`A
`A
`A
`A
`A
`A
`A
`Bl
`Al
`
`2/1996
`5/1996
`9/1997
`12/1998
`10/1999
`11/2000
`11/2000
`7/2003
`8/2001
`
`Nelson et al.
`Morris et al.
`Sonenshein et al.
`Wolff et al.
`Pinchuk et al.
`Rowe
`Stevens et al.
`Wright et al.
`Molnar-Kimber et al.
`
`FOREIGN PATENT DOCUMENTS
`
`WO 90/13332
`WO
`WO 92/06992
`WO
`WO WO 2003/064383 A3
`
`11/1990
`4/1992
`8/2003
`
`Primary Examiner—Bruck Kifle
`(74) Attorney, Agent, or Firm—David L. Berstein
`
`(57)
`
`ABSTRACT
`
`This invention concerns a new family of phosphorus-con(cid:173)
`taining compounds containing a moiety JQA- in which:
`A is absent or is — O —, — S— or —NR2—;
`Q is absent or (if A is — O —, — S— or —NR2—) Q may be
`—V—, —OV—, —SV—, or —NR2V—, where V is an
`aliphatic, heteroaliphatic, aryl, or heteroaryl moiety, such
`that J is linked to the cyclohexyl ring directly, through A or
`through VA, OVA, SVA or NR2VA;
`
`K
`R5Y\I|
`P-
`
`R5Y
`
`J=
`
`R'Y^
`
`R^Y
`
`K
`
`P-
`
`R ^ ||
`
`,/
`R6G
`
`K is O or S;
`each occurrence of Y is independently — O —, — S —,
`—NR2—, or a bond linking a R5 moiety to P;
`each occurrence of R2 and R5 is independently an ali(cid:173)
`phatic, heteroaliphatic, aryl, or heteroaryl moiety, or H;
`and
`is independently —PK(YR5)
`each occurrence of R6
`(YR5), —S02(YR5) or —C(0)(YR5); so long as any
`R2, or R5 moiety linked directly to P is not H;
`wherein two R2, R5 and/or R6 moieties may be chemically
`linked to one another to form a ring;
`each occurrence of G is independently — O —, — S —,
`—NR2— or (M)x;
`each occurrence of M is independently a substituted or
`unsubstituted methylene moiety, and any M-M' moiety
`may be saturated or unsaturated;
`each occurrence of x is independently an integer from
`1-6; and the other variables are as defined herein.
`
`36 Claims, No Drawings
`
`West-Ward Pharm.
`Exhibit 1049
`Page 001
`
`

`

`US 7,091,213 B2
`
`RELATED APPLICATIONS
`
`BACKGROUND OF THE INVENTION
`
`1
`PHOSPHORUS-CONTAINING COMPOUNDS
`AND USES THEREOF
`
`2
`tical industry and academic researchers has been a sustained
`o ne o v er the past few decades. This has led to the explora(cid:173)
`tion of materials and methods for effecting chemical trans-
`D
`..
`.
`.
`.
`f
`f
`..
`lormations ol rapamycin, including reductions ol ketones,
`demethylations, epimerizations, various acylations and alky-
`PTT^
`..
`.
`..
`.
`.
`_,
`.
`i ne present application is a continuation-in-part ol U.S.
`l a t l 0 nS 0± hyd r o xyl s' e t c-
`patent application Ser. No. 10/635,054, filed Aug. 6, 2003
`A
`l a rge number of structural variants of rapamycin have
`now abandoned and U.S. patent application Ser. No. 10/357,
`now been reported, typically arising as alternative fermen-
`152, filed Feb. 3, 2003 now abandoned and claims priority
`thereto and under 35 U.S.C. § 119(e) to U.S. Provisional 10 tation products and/or from synthetic efforts. For example,
`Patent Application No. 60/353,252, filed Feb. 1, 2002, U.S.
`the extensive literature on analogs, homologs, derivatives
`Provisional Patent Application No. 60/426,928, filed Nov.
`and other compounds related structurally to rapamycin ("ra-
`15, 2002, U.S. Provisional Patent Application No. 60/428,
`palogs") include, among others, variants of rapamycin hav-
`383,
`filed Nov. 22, 2002, and U.S. Provisional Patent 15 ing one or more of the following modifications relative to
`Application No. 60/433,930, filed Dec. 17, 2002, the entire
`rapamycin: demethylation, elimination or replacement of the
`contents of each of these applications are hereby incorpo-
`methoxy at C7, C42 and/or C29; elimination, derivatization
`rated by reference.
`or replacement of the hydroxy at C13, C43 and/or C28;
`reduction, elimination or derivatization of the ketone at C14,
`C 24 ^^
`C 3 0. r e p l a c e m e nt of t he 6-membered pipecolate
`ring with a 5-membered prolyl ring; and alternative substi-
`^
`. .
`.
`.
`.
`^ „ ^
`.
`^ i.
`Rapamycin is a macrolide antibiotic produced by Strep-
`tution on the cyclohexyl ring or replacement 01 the cyclo-
`.
`T^T,™, . . ..
`:
`,
`T . .
`,
`.
`.
`, , , . .,
`,
`.
`.,
`,
`,
`,
`,
`tomyces hygroscopicus.
`It binds to a FK506-binding protein,
`hexyl ring with a substituted cyclopentyl ring. Additional
`• ^T^T^T^
`^T^^T^-,,
`• , , .,
`^
`•
`n
`,.
`.
`,
`f
`FKBP12, with high affinity to form a rapamycin:FKBP „ ,
`.
`.
`.
`,
`,
`p
`1
`^ 1 T^ 1 1
`1
`histoncal inlormation is presented in the background sec-
`r.
`j-
`J ^ • ^
`*.•
`complex. Reported Kd values lor that interaction are as low
`-.an n* TT,
`• -cvD-n
`i U-A
`vt, t,- i,
`tions of U.S. Pat. Nos. 5,525,610; 5,310,903 and 5,362,718.
`as 200 pM. 1 he rapamycin: FKBP complex binds with high
`to the large cellular protein, FRAP, to form a
`S ee a l so U-S- P at N o- 5,527,907. Materials and methods
`affinity
`tripartite,
`[FKBP:rapamycin]:[FRAP], complex.
`In
`that
`have even been developed for the remarkably effective and
`complex rapamycin can be viewed as a dimerizer or adapter 30 selective epimerization of the C-28 hydroxyl group (WO
`to join FKBP to FRAP. Formation of the complex is asso-
`01/14387).
`ciated with rapamycin's various biological activities.
`New rapalogs with reduced immunosuppressive activity
`Rapamycin is a potent immunosuppressive agent and is
`and/or interesting pharmacokinetic or bioavailability pro-
`used clinically to prevent rejection of transplanted organs. 35 files would be very desirable for use as multimerizing agents
`Rapamycin and/or its analogs, CCI 779 (Wyeth) and SDZ
`or antifungal agents.
`Rad ("RAD001", Novartis) are promising agents for treating
`r apai0gS wi th attractive physicochemical or func-
`N ew
`certain cancers, for immune suppression and/or for helping
`t i o n al characteristics, e.g., in therapeutic index, bioavailabil-
`to decrease the incidence of restenosis following interven-
`^
`p h a r m a c o k i n e t i c S: s t a b i l i t y: e t c.: w o u ld a l so be of
`i n t e r.
`tional cardiology. Rapamycin has also been shown to have
`^
`u s es
`p h a r m a c e u t i c al
`of
`f Qr & v a r i e ty
`,,
`,
`.
`,
`,
`,.
`activity as an antifungal agent, in the experimental allergic
`J
`mentioned above, including among others use as immuno-
`o
`o
`oi
`f
`.
`. .
`.
`.
`^
`.
`^
`i.
`encephalomyelitis model (a model for multiple sclerosis), in
`suppressants, as anticancer agents and in reducing the inci-
`.
`..
`.
`. „
`.. .
`.
`,
`_
`.
`.
`.
`.
`the adjuvant arthritis model (lor rheumatoid arthritis), in
`dence ol restenosis lollowing interventional cardiology (e.g.
`.
`. , . , ..
`.
`.
`.
`. -, „ ...
`..
`..
`.
`inhibiting the
`formation ol IgE-hke antibodies, and for A*
`.
`.
`.
`on drug-beanng stents),
`.,
`,
`,
`o
`o
`y
`lupus erythematosus, pulmonary
`treating or preventing
`T he only rapalogs thought to be in clinical development
`insulin dependent diabetes mellitus, adult
`inflammation,
`as immunosuppressants at present are those with rather
`T-cell leukemia/lymphoma, and smooth muscle cell prolif-
`modest, conventional structural modifications, i.e., acylation
`eration and intimal thickening following vascular injury. See
`50 or alkylation at C-43 (CCI 779 and SDZ RAD, respectively;
`e.g. U.S. Pat. appln 2001/0010920.
`see e.g., Yu, K. et al., Endocrine-Related Cancer (2001) 8,
`Because it serves as an adapter to complex FKBP with
`249-258; Geoerger, B. et al., Cancer Res. (2001) 61
`FRAP, rapamycin is also capable of multimerizing appro-
`1527-1532) and Dancey, Hematol Oncol Clin N Am 16
`priately designed chimeric proteins incorporating domains
`tetrazole-substituted
`derived from FKBP and FRAP, respectively; Because of that 55 (2002):1101-1114. Stents bearing a
`activity, rapamycin and various derivatives or analogs
`rapalog, ABT-578, but having only a shortened biological
`thereof have also been used as multimerizing agents for
`half-life (see e.g. WO 03/022807 and 99/15530) are report-
`activating biological switches based on such chimeric pro-
`edly being studied too.
`teins. See e.g., W096/41865; WO 99/36553; WO 01/14387;
`The invention described below represents a rather dra-
`Rivera et al, Proc Natl Acad Sci USA 96, 8657-8662; and 60
` m at ic departure in the design of new rapalogs based on the
`Ye, X. et al (1999) Science 283, 88-91.
`incorporation of a phosphorus-containing moiety.
`Rapamycin's potential for providing relief from such an
`important swath of cruel diseases has stimulated the search
`for rapamycin analogs with improved therapeutic index,
`pharmacokinetics, formulatability, ease or economy of pro-
`duction, etc. The resulting investigation by the pharmaceu-
`
`s u ch
`
`as
`
`are
`
`SUMMARY OF THE INVENTION
`
`65
`
`Compounds of this invention include a new family of
`compounds of Formula (I):
`
`West-Ward Pharm.
`Exhibit 1049
`Page 002
`
`

`

`US 7,091,213 B2
`
`—NRiJS02R'4 or —NRiJS02NR'4RiJ'; or R7a and R7*,
`taken together, are H in the tetraene moiety:
`
`J — Q — A,
`
`where R^ is R2 and where RB is OH or R2. In some cases one
`or both of RA and R* is H;
`R28 is hydrogen; J; or an aliphatic, heteroaliphatic, aryl,
`heteroaryl, acyl, aroyl or heteroaroyl moiety;
`and n is 1 or 2;
`wherein each of the foregoing aliphatic and heteroaliphatic
`moieties is independently linear or branched, or cyclic or
`acyclic, and substituted or unsubstituted, and each of the
`aryl, heteoraryl, acyl, aroyl or heteroaroyl moieties is
`independently substituted or unsubstituted;
`with the proviso that (a) if JQA- is (R2Y)(Me)(P=0)0—,
`then (R2Y) is (i) not an immunogenic carrier material,
`detector carrier material or a solid matrix, or (ii) R2
`contains 15 or fewer carbon atoms, preferably 10 or
`fewer); and (b) the compound is not
`
`.0
`
`15
`
`and pharmaceutically acceptable derivatives thereof. Com(cid:173)
`positions containing such compounds and uses thereof are
`also provided.
`In the compounds of this invention,
`A is —O—, —S— or —NR2—, or is absent (i.e., is a
`covalent bond linking JQ- to carbon 43);
`Q is absent (i.e., is a covalent bond linking J to A or to carbon
`43) or, if A is —O—, —S— or —NR2—, Q may be
`—V—, —OV—, —SV—, or —NR2V—, where V is an
`aliphatic, heteroaliphatic, aryl, or heteroaryl moiety, such
`that J is linked to the cyclohexyl ring directly, through A 35
`or through VA, OVA, SVA or NR2VA (i.e., as JA-, JVA-,
`JOVA-, JSVA- and JNR2VA-;
`
`30
`
`R5Y\I|
`
`R^
`
`J =
`
`R'Y
`
`R'Y
`
`R5Y\I|
`
`R^G
`
`40
`
`45
`
`55
`
`K is O or S;
`each occurrence of Y is independently —O—, —S—,
`—NR2—, or a chemical bond linking a R5 moiety to P;
`each occurrence of R2 and R5 is independently an aliphatic,
`heteroaliphatic, aryl, or heteroaryl moiety, or H; and each 50
`occurrence of R6 is independently —PK(YR5)(YR5),
`—S02(YR5) or —C(0)(YR5); so long as any R2 or R5
`moiety linked directly to P is not H (e.g., —PR2 and
`—PR cannot be —PH);
`wherein two R2, R5 and/or R6 moieties may be chemically
`linked to one another to form a ring;
`each occurrence of G is independently —O—, —S—,
`—NR2— or (M)x;
`each occurrence of M is independently a substituted or
`unsubstituted methylene moiety, and any M-M' moiety
`may be saturated or unsaturated;
`each occurrence of x is independently an integer from 1-6;
`one of R7a and R7* is H and the other is H, halo, —RA,
`—ORA, —SRA, —OC(0)RA,
`—OC(0)NRARB,
`—NRiJC(0)R'4,
`—NRiJC(0)OR'4,
`—NR^R*
`
`60
`
`65
`
`or a desmethyl or reduced analog thereof, or a salt of any of
`the foregoing, where W comprises a substituted or unsub(cid:173)
`stituted heterocycle comprising
`
`Q
`
`TT
`
`alone or fused to a six-membered aromatic ring, wherein U
`is substituted or unsubstituted amino, O, S, SO or S02;
`and (c) in compounds of the formula:
`
`West-Ward Pharm.
`Exhibit 1049
`Page 003
`
`

`

`J —Q —A",,
`
`US 7,091,213 B2
`
`unsubstituted, or in the case of —OR5 moieties, may alter(cid:173)
`natively be H. Also of current special interest are embodi(cid:173)
`ments in which -Q-A- is O, especially in cases in which J is
`one of the currently preferred J moieties noted just above
`(although preferably not —P03H2). Of special interest too
`are any of the foregoing compounds in which in which JQA-
`is (R2Y)(Me)(P=0)0— in which R2Y— contains 15 or
`fewer carbon atoms, preferably 10 or fewer carbon atoms,
`and in some embodiments 6 or fewer carbon atoms.
`This new family of compounds includes a number of
`classes of compounds of particular interest.
`For instance, one such class is illustrated by formula (a):
`
`(a)
`
`RU
`P — Q — A,
`
`J-Q-A- is not (HO)2(PO)—O— or the dimethyl phosphate
`ester thereof (and preferably not another di-lower alkyl
`ester thereof). Wavy bonds, e.g., as shown in FIG. 1 at
`positions 28 and 43 indicate that the substituent may be in
`either orientation.
`J moieties of special interest in various embodiments of
`this invention include those shown in Series 1:
`
`\'
`
`||
`P
`
`R5R2N
`
`R\
`
`R5G
`
`R5(X
`
`R5R2N
`
`R5R2N
`
`- - R5Ov
`
`R^O,
`
`R^O
`
`/
`~ - - ~ R5
`
`^
`
`,/
`.R50
`K
`
`•RTt^N^
`
`f R ^N fr
`!fr
`
`30
`
`35
`
`p
`
`In this class, each R5 is an independently selected, aliphatic,
`40 heteroaliphatic, aryl, or heteroaryl moiety (which moiety
`may be substituted or unsubstituted), especially a lower (i.e.
`from 1 to 6 carbons) aliphatic moiety, e.g., a lower alkyl,
`which may be optionally substituted (e.g. with a halo,
`hydroxyl, —O-acyl (i.e., acyloxy), alkoxyl, haloalkyl-,
`hydroxyalkoxyl, aryl, or heteroaryl moiety, etc.). In several
`examples of this class, the compounds of formula (a) com(cid:173)
`prise a moiety, J, selected from the following:
`
`45
`
`50
`
`55
`
`60
`
`HO'
`
`65
`
`, R^O
`
`- R ^N
`
`/RTMSr
`
`R^CX
`
`.leR-Tsr
`
`where K, R2, R5 and R6 are as defined above. J moieties
`currently of special interest are those in which K is oxygen,
`as are illustrated in numerous exemplary compounds
`depicted below, including among others, any of the follow(cid:173)
`ing:
`
`0
`PH—
`, /
`R50
`
`0
`?-\—
`/
`5
`R5R2N^J|
`O
`1
`
`R5R2N
`
`r
`
`/-
`
`0
`P—
`, /
`R50
`O
`R 5 o- J'
`R ^N
`
`o
`P—
`«, / .
`R ^N
`-<-->--
`O
`RH^W
`II
`P-
`/
`G—POfOR^j
`
`in which each occurrence of R5 is an independently chosen
`lower aliphatic or aryl moiety, which may be substituted or
`
`West-Ward Pharm.
`Exhibit 1049
`Page 004
`
`

`

`US 7,091,213 B2
`
`0
`
`
`
`-c jmmuea
`
`0
`
`^'U
`^ P-
`/
`Me
`
`—
`
`^
`
`n
`
`Me
`
`0
`
`^ JJ
`\^
`'
`/ . Me
`
`P-
`
`This class is further illustrated in the synthetic examples that
`follow, through members of its subclass in which J-Q-A- is
`(R5)2PO—O—. Furthermore, note that all of the R2, R5, R6
`and J moieties disclosed or exemplified herein in connection
`with a given compound, subclass or class of compounds are
`equally applicable in other cases unless otherwise specified.
`Thus, the disclosure of a R2, R5, R6 or J moiety in one case
`is intended to be extrapolated to all other cases except as
`otherwise noted.
`Another class of compounds of this invention which is
`also of interest is illustrated by formula (b):
`
`HO
`
`HO
`
`Me- y yy
`
`Me-
`
`(b)
`
`30
`
`HO
`
`35
`
`This class is further illustrated in the synthetic examples that
`follow, through members of its subclass in which J-Q-A- is
`(R5)(R50)PO—O—.
`Another class of compounds of this invention which is
`also of interest is illustrated by formula (c), with the proviso
`40 noted at the outset:
`
`45
`
`(<=)
`
`R^O^
`
`P -Q
`
`R^O
`
`In this class, each R5 is an independently selected, aliphatic,
`heteroaliphatic, aryl, or heteroaryl moiety (which moiety
`may be substituted or unsubstituted), especially a lower
`aliphatic moiety, e.g. a lower alkyl, which may be optionally
`substituted (e.g. with a hydroxyl, alkoxyl, hydroxyalkoxyl,
`acyloxy-, aryl, or heteroaryl moiety, etc.). In the case of 55
`—OR5, the R5 moiety may additionally be H. Illustrative
`examples include compounds of formula (b) in which J is
`selected from the following:
`
`50
`
`Me-
`
`Me-
`
`Me-
`
`60
`
`65
`
`West-Ward Pharm.
`Exhibit 1049
`Page 005
`
`

`

`US 7,091,213 B2
`
`In this class, each R5 is independently selected, and is H or
`an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety
`(which moiety may be substituted or unsubstituted), espe(cid:173)
`cially lower aliphatic moiety, including lower alkyl, which
`may be optionally substituted (e.g. with a hydroxyl, alkoxyl,
`hydroxyalkoxyl, acyloxy-, aryl, or heteroaryl moiety, etc.).
`Illustrative examples include compounds of formula (c) in
`which J is selected from the following:
`
`10
`This class is further illustrated in the synthetic examples that
`follow, including members of its subclass in which J-Q-A-
`is (R50)(R50)PO—O—.
`Another class of compounds of this invention which is
`also of interest is illustrated by formula (d):
`
`(d)
`
`HO
`
`In this class, each R5 is an independently selected, aliphatic,
`heteroaliphatic, aryl, or heteroaryl moiety (which moiety
`may be substituted or unsubstituted), especially lower (i.e.
`from 1 to 6 carbons) aliphatic moiety including lower alkyl,
`which may be optionally substituted (e.g. with a hydroxyl,
`alkoxyl, hydroxyalkoxyl, acyloxy-, aryl, or heteroaryl moi(cid:173)
`ety, etc.). In some embodiments —NHR5 is —NH2. Illus(cid:173)
`trative examples include compounds of formula (d) in which
`J is selected from the following:
`
`M e-
`
`- P-
`/
`•NH
`
`M e-
`
`-P.
`/
`•NH
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`West-Ward Pharm.
`Exhibit 1049
`Page 006
`
`

`

`US 7,091,213 B2
`
`11
`This class is further illustrated by its subclass in which
`J-Q-A- is (R5)(R5N)PO—O—.
`Another class of compounds of this invention which is
`also of interest is illustrated by formula (e):
`
`12
`This class is further illustrated in the synthetic examples that
`follow, through members of its subclass in which J-Q-A- is
`(R5N)(R5N)PO—O—.
`Another class of compounds of this invention also of
`interest is illustrated by formula (f):
`
`O
`||
`P - Q -A
`
`R5NH
`
`R5NH
`
`(e)
`
`15
`
`O
`
`^ - Q -A
`
`R5NH
`
`(f)
`
`In this class, each R5 is independently selected and is H or
`an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety
`(which moiety may be substituted or unsubstituted), espe(cid:173)
`cially lower (i.e. from 1 to 6 carbons) aliphatic moiety
`including lower alkyl, which may be optionally substituted
`(e.g. with a hydroxyl, alkoxyl, hydroxyalkoxyl, acyloxy-,
`aryl, or heteroaryl moiety, etc.). Illustrative examples
`include compounds of formula (e) in which J is selected
`from the following:
`
`H2NV
`
`HjN
`
`HN-
`
`Ph-
`
`HN-.
`
`HjN
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`In this class, each R5 is independently selected and is H or
`an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety
`(which moiety may be substituted or unsubstituted), espe(cid:173)
`cially lower (i.e. from 1 to 6 carbons) aliphatic moiety
`including lower alkyl, which may be optionally substituted
`(e.g. with a hydroxyl, alkoxyl, hydroxyalkoxyl, acyloxy-,
`aryl, or heteroaryl moiety, etc.). Illustrative examples
`include compounds of formula (!) in which J is selected from
`the following:
`
`In classes (d), (e) and (f), "QA" is preferably —O— or
`—OVO—.
`Another class of compounds of this invention which is
`also of interest is illustrated by formula (g):
`
`West-Ward Pharm.
`Exhibit 1049
`Page 007
`
`

`

`US 7,091,213 B2
`
`13
`
`14
`
`J —Q-O,
`
`(g)
`
`J-O,,
`
`(g)(i)(a)
`
`where J, Q, n and the various R groups are as previously
`defined, and with the proviso noted previously. This class
`encompasses a number of subclasses of interest, including
`the following:
`
`where J is selected from:
`P(0)(OMe)(Me),
`P(0)Me2,
`P(0)Ph2,
`P(0)(OnPr)(Me),
`P(0)(OiPr)(Me),
`P(0)(OnBu)(Me),
`P(0)(Me)(OCH2CH20Me),
`P(0)(Me)(OCH2CH20Et),
`P(0)(Me)(OCH2CH20CH2CH20H),
`P(0)(OMe)(Et),
`P(0)(CH2CH2CH20H)2,
`P(0)(OEt)2,
`P(0)(NH2)2,
`P(0)(OH)
`CH2 — PO(OH)2,
`
`J-O,
`
`(g)(i)
`
`30 In compounds of the structure shown in "(g)(i)(a)", J is a
`moiety other than —P03H2, a salt thereof, or —P03Me2.
`Those choices for the subsituent, J, are permitted only in
`combination with one or more additional structural changes
`35 relative to rapamycin, e.g. altered stereochemistry at one or
`more sites including C43 or C28, modification in the sub-
`stituent or stereochemistry at C7, reduction of one or more
`of the ketone functionalities, demethylation at one or more
`sites, etc. Thus the following compounds, among others, are
`of interest:
`
`45
`
`50
`
`55
`
`60
`
`65
`
`in which Q is absent, i.e., in which J is linked (i.e.,
`covalently bonded) to the cyclohexyl ring via an oxygen.
`This subclass (which excludes O-phosphorylated rapamycin
`itself and the salts or methyl phosphodiester
`thereof)
`includes compounds comprising any moiety, J, as previously
`defined, including all of the types of J moieties illustrated
`elsewhere in this document, including those shown in the
`various compounds, types of compounds and illustrative J
`moieties disclosed herein, including among others the fol(cid:173)
`lowing illustrative examples:
`
`West-Ward Pharm.
`Exhibit 1049
`Page 008
`
`

`

`US 7,091,213 B2
`
`16
`Another class of compounds of this invention which is
`also of interest is illustrated by the compounds in which A
`is —NR2— as depicted in formula (h):
`
`(h)
`
`.0
`
`15
`
`wherein R5 is H or lower alkyl, including, among others,
`methyl.
`Also of particular interest is the subclass of compounds,
`(g)(ii), which differs from subclass (g)(i)(a) in one or more
`of the following respects: (a) the substituent at position 28
`is epimerized (relative to the orientation of rapamycin's C28
`—OH), (b) one or both ketones at positions 24 and 30 are
`reduced to hydroxyl groups, (c) the methoxyl group at
`position 7 is replaced by H or by one of the various C7
`substituents listed elsewhere, and (d) the substituent J-O—
`at position 43 is in the epimeric orientation (relative to the
`orientation of rapamycin's C43 —OH). Again, J is any of the
`phosphorus-containing moieties as previously described.
`Another subclass of interest is depicted below in (g)(iii) to
`illustrate compounds with an O-linked J moiety in which Q
`is present. This subclass illustrates the case in which Q is
`—OV— where V is an aliphatic moiety.
`
`30
`
`35
`
`40
`
`(g)(iii)
`
`This class includes the subclass in which Q is absent, i.e., in
`which J is linked (i.e., covalently bonded) to the cyclohexyl
`ring via a nitrogen as illustrated below:
`
`, NH
`
`(h)(i)
`
`where J is selected from:
`P(0)(OMe)(Me),
`P(0)Me2,
`P(0)Ph2,
`P(0)(OnPr)(Me),
`P(0)(OiPr)(Me),
`P(0)(OnBii)(Me),
`PlPXMeXOCHjCHjOMe),
`PfOXMeJfOCHjCHjOEt),
`P(0)(Me)(OCH2CH20CH2CH20H),
`P(0)(OMe)(Et),
`P(0)(CH2CH20H)2,
`P(0)(OEt)2,
`P(0)(NH2)2.
`
`where J is selected from:
`P(0)(OMe)(Me),
`P(0)Me2,
`P(0)Ph2,
`P(0)(OnPr)(Me),
`P(0)(OiPr)(Me),
`P(0)(OnBii)(Me),
`PlPXMeXOCHjCHjOMe),
`PlpjlMeXOCHjCHjOEt),
`P(0)(Me)(OCH2CH20CH2CH20H),
`P(0)(OMe)(Et),
`P(0)(CH2CH20H)2,
`P(0)(OEt)2,
`P(0)(NH2)2,
`
`65
`
`West-Ward Pharm.
`Exhibit 1049
`Page 009
`
`

`

`US 7,091,213 B2
`
`17
`Another subclass of class (h) of interest is illustrated
`below by rapamycin derivatives in which Q is present and
`comprises an aliphatic or heteroaliphatic moiety, V, which
`may be substituted or unsubstituted, where each of the
`variable moieties are as previously defined or otherwise
`exemplified herein:
`
`18
`
`J—s,
`
`(i)(i)
`
`J.
`
`^ N H„
`
`(h)(ii)
`
`in which Q is absent, i.e., in which J is linked (i.e.,
`25 covalently bonded) to the cyclohexyl ring via a sulfur atom.
`This subclass includes compounds comprising any moiety, J,
`as previously defined, including the following illustrative
`examples:
`
`where JQ-is J — O C H J C H J N H— > J — C H J C H J N H —>
`J — O C H J C H J O C H J C H J N H— or
`J—OCHfCHjJCHjNH-
`
`Another class of compounds of this invention which is
`also of interest is illustrated by formula (i):
`
`30
`
`35
`
`40
`
`J
`
`S
`
`(i)(i) (examples)
`
`J — Q -S
`
`(i)
`
`45
`
`50
`
`55
`
`60
`
`where J is selected from:
`P(0)(OMe)(Me),
`P(0)Me2,
`P(0)Ph2,
`P(0)(OnPr)(Me),
`P(0)(OiPr)(Me),
`P(0)(OnBii)(Me),
`PlPXMeXOCHjCHjOMe),
`PlpjlMeXOCHjCHjOEt),
`PlPXMeXOCHjCHjOCHjCHjOH),
`P(0)(OMe)(Et),
`PlPXCHjCHjOHh,
`P(0)(OEt)2,
`P(0)(NH2)2,
`
`Another subclass of interest is depicted below in (i)(ii)
`where J, Q, n and the various R groups are as previously 65 which illustrates some compounds with an O-linked J moi-
`defined. This class encompasses a number of subclasses of
`ety in which Q is present. This subclass illustrates the case
`interest, including the following:
`in which Q is —SV— where V is an aliphatic moiety.
`
`West-Ward Pharm.
`Exhibit 1049
`Page 010
`
`

`

`19
`
`US 7,091,213 B2
`
`(i)(ii)
`
`20
`(o) Compounds of the invention that retain at least 0.01,
`preferably 0.1 and more preferably at least 0.5 times the
`potency of rapamycin in a T cell proliferation assay (e.g.,
`which have an IC50 value less than 100-fold, preferably less
`than 10-fold, and more preferably less than 2-fold worse
`than that of rapamycin).
`(p) Compounds of the formula:
`
`J Q - A.
`
`where J is selected from:
`P(0)(OMe)(Me),
`P(0)Me2,
`P(0)Ph2,
`P(0)(OnPr)(Me),
`P(0)(OiPr)(Me),
`P(0)(OnBii)(Me),
`PlPXMeXOCHjCHjOMe),
`PlpjlMeXOCHjCHjOEt),
`P(0)(Me)(OCH2CH20CH2CH20H),
`P(0)(OMe)(Et),
`P I P X C H J C H J O H X,
`P(0)(OEt)2,
`P(0)(NH2)2,
`
`Additional classes of compounds of the invention of
`particular interest are noted below:
`(j) Compounds of FIG. 1, in which JQA- replaces the
`C-43 hydroxyl group of rapamycin, with conservation of
`stereochemistry at C43 relative to rapamycin, where JQA is
`as defined above, with the proviso noted at the outset. Such
`compounds can be prepared from rapamycin as disclosed in
`detail below.
`(k) Compounds as in class (j), but with one or more
`additional structural modifications relative to rapamycin.
`Numerous such modifications are known in the art and are
`alluded to elsewhere herein, including replacement of the
`—OMe substituent at C7, or alteration of its stereochemis(cid:173)
`try; epimerization at one or both of C28 and C43; reduction
`of one or more of the ketone functionalities e.g. at one or
`both of ring positions 24 and 30; desmethylation at one or
`more sites; reduction of one or more of the double bonds
`between CI and C6; and/or use of the prolyl analog instead
`of the pipicolate structure of rapamycin. Compounds of this
`invention may be prepared in some cases by starting with the
`appropriate rapamycin analog in place of rapamycin itself
`and in other cases by effecting the desired additional trans(cid:173)
`formation on the appropriate JQA-containing rapalog.
`(1) Compounds of this invention in which J is other than
`—P03H2, a salt thereof, or a dialkyl phosphate (such as
`—P03Me2, for example).
`(m) Compounds of the invention with a molecular weight
`below 1700, preferably below 1400, and more preferably
`below 1200 mass units (not counting the contribution of a
`counter ion in cases in which the compound is in a salt
`form).
`(n) Compounds of the invention which are chemically
`linked to a polyethylene glycol moiety or other solubility-
`enhancing group. Examples include glycinate (or other
`aminocarboxylate) esters or PEGylated esters (see e.g. WO
`02/24706, the contents of which are incorporated herein by
`reference) of any free —OH moiety of a rapalog of this
`invention.
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`thereof,
`and pharmaceutically acceptable derivatives
`wherein A is —O—, —S— or —NR2— or is absent (i.e., or
`is a covalent bond linking JQ to C-43); Q is absent (i.e., is
`a covalent bond) or (if A is —O—, —S— or —NR2—) Q
`may be —V—, —OV—, —SV—, or —NR2V—, where V
`is an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety,
`such that J is linked to the cyclohexyl ring directly, through
`A or through VA, OVA, SVA or NR2VA; K is O or S;
`
`J=
`
`K
`R5Y\I| '
`P-
`
`R5Y
`
`R'Yv
`
`R^Y
`
`R'Y^
`
`R^G
`
`each occurrence of Y is independently —O—, —S—,
`—NR2—, or a bond linking a R moiety to P; each occur(cid:173)
`rence of R2 and R5 is independently an aliphatic, het(cid:173)
`eroaliphatic, aryl, or heteroaryl moiety, or H; and each
`occurrence of R6 is independently —PK(YR5)(YR5), —SO2
`(YR5) or —C(0)(YR5); so long as any R2 or R5 moiety
`linked directly to P is not H; wherein two R2, R5 and/or R6
`moieties may be chemically linked to one another to form a
`ring; each occurrence of G is independently —O—, —S—,
`—NR2—, or (M)x; each occurrence of M is independently a
`substituted or unsubstituted methylene moiety, and any
`M-M' moiety may be saturated or unsaturated; each occur(cid:173)
`rence of x is independently an integer from 1-6; wherein
`each of the foregoing aliphatic and heteroaliphatic moieties
`is independently linear or branched, or cyclic or acyclic, and
`substituted or unsubstituted, and each of the aryl, heteoraryl,
`acyl, aroyl or heteroaroyl moieties is independently substi(cid:173)
`tuted or unsubstituted;
`
`West-Ward Pharm.
`Exhibit 1049
`Page 011
`
`

`

`US 7,091,213 B2
`
`21
`with the proviso that: J-Q-A- is not (HO)2(P=0)0— or
`(MeO)2(P=0)0—, or (HO)2(P=0)—W—O— (or a
`desmethyl or reduced analog of such (HO)2(P=0)—
`W—O-containing rapamycin derivative, where W com(cid:173)
`prises a substituted or unsubstituted heterocycle compris(cid:173)
`ing
`
`22
`(r) A compound of the formula:
`
`JQ-A,
`
`o
`
`alone or fused to a six-membered aromatic ring, wherein U
`is substituted or unsubstituted amino, O, S, SO or S02; or a 20
`salt of any of the foregoing; and if JQA- is (R2Y)(Me)
`(P=0)0—, then (R2Y) is not an immunogenic carrier
`material, detector carrier material or a solid matrix or salt
`thereof (e.g., as in embodiments in which R2 in that R2Y 25
`group has 15 or fewer, preferably 10 or fewer, and optimally
`6 or fewer carbon atoms).
`(q) Compounds of the formula:
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`J -A
`
`thereof,
`and pharmaceutically acceptable derivatives
`wherein A, J, K and the other variable groups are as defined
`in (p), except in these compounds, with the proviso that (a)
`J-A- is not (HO)2(P=0)0— or (MeO)2(P=0)0—, and (b)
`if JA- is (R2Y)(Me)(P=0)0—, then (R2Y) is not an immu(cid:173)
`nogenic carrier material, detector carrier material or a solid
`matrix matrix or salt thereof (e.g., as in embodiments in
`which R2 in that R2Y group has 15 or fewer, preferably 10
`or fewer, and optimally 6 or fewer carbon atoms) (instead of
`the proviso in the case of (p).
`
`and pharmaceutically acceptable derivatives
`wherein J is chosen from:
`
`thereof,
`
`IW)
`
`R ^N
`O
`R50.J|
`p-
`
`R5R2N
`
`and
`
`R ^ N^
`
`R'R^N
`
`wherein the various variable groups are as otherwise defined
`above in (p) and (q) except that each occurrence of R2 and
`R5 is an independently chosen lower aliphatic or aryl
`moiety, which may be substituted or unsubstituted (except
`that in addition, each —OR5 and —NR2R5 may be —OH
`and —NHR5, respectively);
`and with the proviso that if J-Q-A- is (R2Y)(Me)(P=0)
`O—, then (R2Y) is not an immunogenic carrier material,
`detector carrier material or a solid matrix, or a salt thereof.
`(s) Compounds of the formula:
`
`JQ-A.
`
`West-Ward Pharm.
`Exhibit 1049
`Page 012
`
`

`

`23
`and pharmaceutically acceptable derivatives
`wherein J is chosen from:
`
`thereof,
`
`24
`
`US 7,091,213 B2
`
`0
`
`RMJ p-
`
`/
`R5
`
`_
`
`0
`R^ ! !_
`./
`R^ti
`
`R5R2N
`
`0
`||
`P-
`, - /
`R5R 2N
`
`— and
`
`0
`
`RM
`
`, , /