United States Patent [19J
`Goulet et al.
`
`[54] O·ARYL, 0-ALKYL, 0-ALKEl'.'YL AND
`O·ALKYNYLRAP AMYCIN DERIVATIVES
`
`[75]
`
`Inventors: Mark Goulet, Westfield; William H.
`Parsons, Edison; Peter J. Sinclair,
`Highland Park; Frederick Wong,
`Glen Ridge; Matthew J. Wyuatt,
`Mountainside, all of N.J.
`[73] Assignee: Merck&: Co., Inc., Rahway, N.J.
`[21] Appl. No.: 973,807
`[22] Filed:
`Nov. 9, 1992
`[51]
`Int. Cl.s ................... A61K 31/395; C07D 498/16
`[52] U.S. Cl •..................................... 514/291; 540/456
`[58] Field of Search ......................... 540/456; 514/291
`[56]
`References Cited
`U.S. PATENT DOCUMENTS
`3,929,992 12/1975 Sehgal et al. ....................... 424/122
`4,650,803 3/1987 Stella et al. ......................... 514/291
`5,100,883 3/1992 Schiehser ............................ 514/183
`5,102,876 4/1992 Caufield .............................. 514/183
`5,118,677 6/1992 Caufield .............................. 514/183
`5,118,678 6/1992 Kao et al. ............................ 514/183
`5,120,725 6/1992 Kao et al. ............................ 514/183
`5,120,727 6/1992 Kao et al. ............................ 514/183
`5,120,842 6/1992 Failli et al. .......................... 540/452
`5,138,051 8/1992 Hughes et al. ...................... 540/456
`5,151,413 9/1992 Caufield et al. ...................... 514/63
`5,162,333 11/1992 Failli et al. .......................... 514/291
`5,162,334 11/1992 Goulet et al. ....................... 514/291
`5,169,851 12/1992 Hughes et al. ...................... 514/291
`
`FOREIGN PATENT DOCUMENTS
`0227355 7/1987 European Pat. Off ............. 540/456
`0516347 12/1992 European Pat. Off ............. 540/456
`2245891 1/1972 United Kingdom ................ 540/456
`W089/05304 6/1989 World Int. Prop. 0 ........... 540/456
`W091/02736 3/1991 World Int. Prop. 0 ........... 540/456
`W091/13889 9/1991 World Int. Prop. 0 ........... 450/456
`W092/05179 4/1992 World Int. Prop. 0 ........... 450/456
`W092/14737 9/1992 World Int. Prop. 0 ........... 450/456
`W092/20688 11/1992 World Int. Prop. 0 ........... 540/456
`
`I lllll llllllll Ill lllll lllll lllll lllll lllll lllll lllll lllll llllll Ill lllll llll
`US005258389A
`S,258,389
`[11] Patent Number:
`[45] Date of Patent:
`Nov. 2, 1993
`
`W092/21341 11/1992 World Int. Prop. 0 ........... 450/456
`
`OTHER PUBLICATIONS
`Findlay, et al., Can. J. Chem., 58, 579-590 (1980).
`
`Primary Examiner-Robert T. Bond
`Attorney, Agent, or Firm-Charles M. Caruso; J. Eric
`Thies
`
`[57]
`ABSTRACT
`0-Aryl, 0-alkyl, 0-alkenyl and 0-alkynylrapamycin
`derivatives of the general structural Formula I:
`
`MeO
`
`r:;e .. ,,,......_ H
`
`lhl~o
`N H II
`
`0
`
`Me
`
`Me
`
`Me
`
`Me
`
`have been prepared from suitable precursors by alkyla(cid:173)
`tion and/or arylation at C-42 and/or C-31. These com(cid:173)
`pounds are useful in a mammalian host for the treatment
`of autoimmune diseases and diseases of inflammation,
`infectious diseases, the prevention of rejection of for(cid:173)
`eign organ transplants and the treatment of solid tu(cid:173)
`mors.
`
`12 Claims, No Drawings
`
`Breckenridge Exhibit 1032
`Breckenridge v. Novartis AG
`
`

`
`1
`
`5,258,389
`
`O·ARYL, O·ALKYL, O·ALKENYL AND
`O·ALKYNYLRAPAMYCIN DERIVATIVES
`
`ci:"
`
`N H
`
`MeO
`
`Me
`
`5
`
`Me
`
`Meo'''''
`
`II
`
`Me
`
`Me
`
`SUMMARY OF THE INVENTION
`The present invention is related to 0-aryl, 0-alkyl,
`0-alkenyl and 0-alkynylrapamycin derivatives which
`are useful in a mammalian host for the treatment of
`autoimmune diseases (such as juvenile-onset or recent(cid:173)
`onset diabetes mellitus, multiple sclerosis, rheumatoid
`arthritis, liver disease, posterior uveitis, allergic enceph(cid:173)
`alomyelitis, and glomerulonephritis), diseases of inflam(cid:173)
`mation, infectious diseases (particularly fungal infec(cid:173)
`tions), the prevention of rejection of foreign organ
`transplants, e.g. bone marrow, kidney, liver, heart, skin,
`small-bowel, and pancreatic-islet-cell transplants, and
`the treatment of solid tumors.
`More particularly, this invention relates to com(cid:173)
`pounds of the general structural Formula I:
`
`2
`tive as immunosuppressive agents, therefore useful in
`preventing transplant rejection (FASEB 3, 3411 (1989);
`FASEB 3, 5256 (1989); and Lancet 1183 (1978)).
`Fujisawa United States patents (U.S. Pat. No.
`4,929,611, issued May 29, 1990 and U.S. Pat. No.
`4,956,352, issued Sept. 11, 1990) disclose the use of
`FK-506-type compounds in treating resistance to trans(cid:173)
`plantation. A Sandoz European patent application
`10 (EPO Publication No. 0,315,978) discloses the use of
`FR-900506 and related compounds in the topical treat(cid:173)
`ment of inflammatory and hyperproliferative skin dis(cid:173)
`eases and of cutaneous manifestations of immunologi(cid:173)
`cally-mediated illness. A Fisons World patent applica-
`15 tion (PCT Publication WO 90/14826) discloses the use
`of FR-900506 and related compounds in the treatment
`of reversible obstructive airways disease, particularly
`asthma. A Fujisawa European patent application (EPO
`20 Publication No. 0,423,714) discloses the use of FK-506
`and derivatives as hair revitalizing agents. Various stud(cid:173)
`ies have suggested the efficacy of FK-506 in the treat(cid:173)
`ment of a number of ailments, including rheumatoid
`arthitis (C. Arita, et al., C/incial exp. lmmunol .• 1990, 82,
`25 456-461; N. Inamura, et al., Clin. lmmunol. lmmunopa(cid:173)
`thol. 1988, 46, 82-90), recent-onset diabetes (N. Murase,
`et al., Diabetes., 1990, 39, 1584-86; N. Murase, et al.,
`Lancet, 1990, 336, 373-74), posterior uveitis (H. Kawa-
`30 shima, Invest. Ophthalmul, Vis. Sci., 1988, 29, 1265-71),
`hepatic injury associated with ischemia (M. Sake, et al.,
`Life Sci., 1990, 47, 687-91) allergic encephalomyelitis
`(K, Deguchi, et al., Brain Nerve, 1990, 42, 391-97),
`glomerulonephritis (J. McCauley, et al., Lancet, 1990,
`35 335, 674), systemic lupus erythematosus (K. Takabaya(cid:173)
`shi, et al., Clin. lmmunol, lmmunopathol., 1989, 51,
`110-117), multidrug resistance (M. Naito, et al., Cancer
`Chemother, Pharmacol., 1992, 29, 195-200), inflamma-
`40 tion of mucosa and blood vessels (PCT Publication WO
`wherein RI and R2 are hereinafter defined.
`91/17754), cytomegalovirus infection (UK Publication
`This invention also relates to pharmaceutical compo-
`GB 2,247,620A), and idiopathic thrombocytophenic
`sitions containing the compounds, and to a method of
`purpura and Basedow's disease (PCT Publication WO
`use of the present compounds and other agents for the
`91/19495).
`treatment and prevention of certain affiictions, diseases
`45 Mono- and diacylated derivatives of rapamycin (es-
`and illnesses.
`terified at the 31and42 positions) have been shown to
`BACKGROUND OF THE INVENTION
`be useful as antifungal agents (U.S. Pat. No. 4,316,885)
`.
`. Rapa~ycm characterized by Fi~dla~ and coworkers
`and used to make water soluble prodrugs of ra amycin
`p
`m 1978 is a 35-membered macrohde isolated from S.
`.
`hygroscopicus (Can. J. Chem., 1978, 56, 2491, J. Antibiot- 50 (U.S: Pat. No. 4,650,803). Reduction products of rapa-
`ics, 1975, 28, 721, U.S. Pat. No. 3,929,992, issued Dec.
`mycm have been prepared (U.S. Pat. Nos. 5,102,876 and
`30, 1975, U.S. Pat. No. 3,993,749, issued Nov. 23, 1975.
`5,138,051). Derivatives of rapamycin at the 31 and 42
`Rapamycin has been found to have antifungal activity,
`positions which have been disclosed include: carboxylic
`particularly against Candida albicans, both in vitro and
`acid esters (PCT Patent Publication W092/05179);
`in vivo (J. Antibiotics, 1978, 31, 539).
`55 carbamates (U.S. Pat. No. 5.118.678); amide esters (U.S.
`Rapamycin alone (U.S. Pat. No. 4,885,171) or in com-
`Pat. No. 5,118,677); fluorinated esters (U.S. Pat. No.
`bination with picibanil (U.S. Pat. No. 4,401,653) has
`5,100,883); acetals (U.S. Pat. No. 5,151,413); and silyl
`been shown t? have antitumor activity. R. ;Martel et al.
`ethers (U.S. Pat. No. 5,120,842). In addition, bicyclic
`(Can, J. Phys1ol. Pharmacol, 55, 48 (1977) disclosed that
`derivatives ofrapamycin connected via the 31 42 posi-
`rapamycin is. ~ffective in an experimen.tal allergi~ e~- 60 tions (U.S. Pat. No. 5,120,725) and rapamyci~ dimers
`cephalomyeht1s model, a model for multiple sclerosis; m
`t d
`· ·
`(U S N p
`5 120 727)
`· th 42
`0 · at. •
`connec e vi~ e
`posiu~n
`an adjuvant arthritis model, a model for rheumatoid
`· ·
`•
`have been disclosed. Vanous aryl(lower alkyl) and
`arthritis· and effectively inhibited the formation of IgE-
`like antlbodies.
`heteroaryl derivatives of FK-506 type compounds have
`The immunosuppressive effects of rapamycin have 65 also been disclosed (UK Patent Publication No. GB
`2,245,891A). 0-Aryl, 0-alkyl, 0-alkenyl and 0-alkynyl
`been disclosed (FASEB 3, 3411 (1989); Med. Sci. Res.,
`1989, 17, 877). Cyclosporin A and FK-506, other mac-
`derivatives of FK-506 type compounds will have been
`rocyclic molecules, also have been shown to be effec-
`disclosed (EPO Patent Publication No. 0,515,071).
`
`

`
`5,258,389
`
`3
`DETAILED DESCRIPTION OF THE
`INVENTION
`A. Scope of the Invention
`The novel compound of this invention has structural
`Formula I:
`
`4
`
`(b')-OH,
`(c') C1-6alkoxy,
`(d') C02H,
`(e') -C02-C1-6alkyl,
`(f) -C3_7cycloalkyl, and
`(g')-ORll,
`(iv) or where R6and R' and the N to which they
`are attached can form an unsubstituted or sub(cid:173)
`stituted 3-7-membered saturated heterocyclic
`ring which can include one or two additional
`heteroatoms independently selected from the
`group consisting of 0 S(O)p. NR 14, wherein
`R 14 is hydrogen or C1-6 alkyl unsubstituted or
`substituted by phenyl, and p is 0, 1 or 2, the
`ring being selected from the group consisting
`of: aziridine, morpholine,
`thiomorpholine,
`thiomorpholine-oxide,
`thiomorpholine-diox(cid:173)
`ide, piperidine, pyrrolidine, and piperazine,
`(h) -NR6CO-C1-6alkyl-R', wherein R6 is as de-
`fined above,
`(i) -NR6C02-C1-6lllkyJ-R7,
`G) -NR6CONR6R7,
`(k) -OCONR R6R7,
`(l)-CQOR6,
`(m)-CHO,
`(n) phenyl,
`(o) substituted phenyl in which the substituents are
`X, Y and Z,
`(p) phenyloxy,
`(q) substituted phenyloxy in which the substituents
`are X, Y and Z,
`(r) 1- or 2- naphthyl,
`(s) substituted 1- or 2- naphthyl in which the sub(cid:173)
`stituents are X, Y and Z,
`(t) Diphenyl
`(u) substituted biphenyl in which the substituents
`are X, Y and Z.
`(v) -OR11 , and
`(w) -S(O)p-C1-6lllkyl;
`·
`(IO) C3-10 alkenyl;
`(11) substituted C3_10 alkenyl in which one or more
`substituent(s) is(are) selected from:
`(a) hydroxy,
`(b) oxo,
`(c) C1-6alkoxy,
`(d) phenyl-C1-3alkoxy,
`(e) substituted phenyl-C1-3alkoxy, in which the
`substituents on phenyl are X, Y and Z,
`(f) -OCO-C1-681kyl,
`(g) -NR6R7, wherein R6 and R' are as defined
`above
`(h)-NR6CO-C1-68lkyl, wherein R6is as defined
`above,
`(i) -CQOR6, wherein R6 is as defined above,
`G)-CHO,
`(k) phenyl,
`(1) substituted phenyl in which the substituents are
`X, Yand Z,
`(m) 1- or 2-naphthyl,
`(n) substituted 1- or 2-naphthyl in which the sub(cid:173)
`stituents are X, Y and Z,
`(o) biphenyl,
`(p) substituted biphenyl in which the substituents
`are X, Y and Z,
`(q)-ORll, and
`(r) -S(O)p-C1-6lllkyl;
`(12) C3-1oalkyl;
`
`s
`
`10
`
`IS
`
`20
`
`2S
`
`30
`
`3s
`
`or a pharmaceutically acceptable salt thereof, wherein:
`RI and R2 are independently selected from:
`(1) hydrogen;
`(2) phenyl;
`(3) substituted phenyl in which the substituents are X,
`Y and Z;
`(4) 1- or 2- naphthyl;
`(5) substituted 1- or 2- naphthyl in which the substitu-
`ents are X, Y and Z;
`(6) biphenyl;
`(7) substituted biphenyl in which the substituents are
`X, Yand Z;
`(8) C1-10 alkyl;
`(9) substituted C1-10 alkyl in which one or more sub(cid:173)
`stituent(s) is(are) selected from:
`(a) hydroxy,
`(b) oxo,
`(c) C1-6 -alkoxy,
`(d) phenyl-C1-3alkoxy,
`(e) substituted phenyl-C1_3alkoxy, in which the
`substituents on phenyl are X, Y and Z,
`(f) -OCO-C1-6lllkyl,
`(g) -NR 6R 7, wherein R 6 and R 7 are independently so
`selected from
`(i) hydrogen,
`(ii) C1-1oalkyl unsubstituted or substituted with
`one or more of the substituent(s) selected
`from:
`(a') phenyl, which is unsubstituted or substi~
`tuted with X, Y and Z,
`(b')-OH,
`(c') C1-6lllkoxy,
`(d')-C02H,
`(e') -C02-C1-6lllkyl,
`(f) -C3_7cycloalkyl, and
`(g') -ORll,
`(iii)C3-1oalkenyl unsubstituted or substituted
`with one or more of the substituent(s) selected 65
`from:
`(a') phenyl, which is unsubstituted or substi(cid:173)
`tuted with X, Y and Z,
`
`40
`
`45
`
`SS
`
`60
`
`

`
`5,258,389
`
`6
`(n) -CH(OR12)(QR13), wherein R12 and Rl3 are
`C1-3alkyl or taken together form an ethyl or propyl
`bridge,
`(o)
`
`5
`
`15
`
`wherein R9 and m are as defined above, and
`(p)
`
`wherein R9 and m are as defined above, and
`(q)-ORll;
`or any two of adjacent X, Y and Z can be joined to
`form a ring having 5, 6 or 7 ring atoms, said ring
`atoms comprising 1 or 2 oxygen atoms, the remaining
`ring atoms being carbon, selected from the group
`consisting of: dioxolanyl, dihydrofuranyl, dihy(cid:173)
`dropyranyl, and dioxanyl.
`
`25
`
`5
`(13) substituted C3_10alkynyl in which one or more
`substituent(s) is(are) selected from:
`(a) hydroxy,
`(b) oxo,
`(c) C1-6lllkoxy,
`(d) phenyl-C1_3alkoxy,
`(e) substituted phenyl-C1_3alkoxy, in which the
`substituents on phenyl are X, Y and Z,
`(f) -OCO-C1-6lllkyl,
`(g) -NR6R7, wherein R6 and R7 are as defined 10
`above,
`(h)-NR6CO-C1-6lllkyl, wherein R6is as defined
`above,
`(i) -COOR6 is as defined above,
`G)-CHO,
`(k) phenyl,
`(I) substituted phenyl in which the substituents are
`X, Yand Z,
`(m) 1- or 2-naphthyl,
`(n) substituted 1- or 2-naphthyl in which the sub- 20
`stituents are X, Y and Z,
`(o) biphenyl,
`(p) substituted biphenyl in which the substituents
`are X, Y and Z, and
`(q) -QRll;
`with the proviso that Rl and R2 are not simulta(cid:173)
`neously hydrogen;
`R 11 is selected from:
`(a) -PO(OH)Q-M+, wherein M+is a positively 30
`charged inorganic or organic counterion,
`(b) -S03-M+.
`(c) -CO(CH2)qC02-M+, wherein q is 1-3, and
`(d)-CO-C1-6lllkyl-NR6R7·wherein R6and R7are
`as defined above and the alkyl is unsubstituted or 35
`substituted with one or more substituents selected
`from:
`(i) hydroxy,
`(ii) C1-6lllkoxy,
`(iii) -NR16Rl7, wherein Rl6 and Rl 7 are indepen- 40
`dently selected from:
`(a') hydrogen, and
`(b') C1-6lllkyl,
`(iv) -COQR6, wherein R6 is as defined above,
`(v) phenyl,
`(vi) substituted phenyl in which the substituents are
`X, Y and Z,
`(vii) -SH, and
`(viii) -S-C1-6lllkyl;
`X, Y and Z independently are selected from:
`(a) hydrogen,
`(b) C1-7 alkyl,
`(c) C2-6 alkenyl,
`(d) halogen,
`(e) -(CH2)m-NR6R7, wherein R6 and R7 are as 55
`defined above, and m is 0 to 2,
`(f)-CN,
`(g)-CHO,
`(h)-CF3,
`(i) -SR8, wherein RS is hydrogen, Ci-6alkyl, trifluo- 60
`romethyl, or phenyl,
`G) -SOR8, wherein R8 is as defined above,
`(k) -S02R8, wherein RS is as defined above,
`(I) -CONR6R7, wherein R6 and R7 are as defined
`above,
`(m) R9Q(CH2)m· wherein R9 is hydrogen, C1-3 alkyl,
`hydroxy-C2_3alkyl,
`trifluoromethyl, phenyl or
`naphthyl and m is as defined above,
`
`The compounds of the present invention have asym(cid:173)
`metric centers and this invention includes all of the
`optical isomers and mixtures thereof.
`In addition compounds with carbon-carbon double
`bonds may occur in Z- and E- forms with all isomeric
`forms of the compounds being included in the present
`invention.
`When any variable (e.g., alkyl, aryl, R6, R7, RS, R9,
`RIO, Rll, etc.) occurs more than one time in any vari(cid:173)
`able or in Formula I, its definition on each occurrence is
`independent of its definition at every other occurrence.
`As used herein, the term "alkyll" includes those alkyl
`groups of a designated number of carbon atoms of either
`a straight, branched, or cyclic configuration. Examples
`of "alkyl" include methyl, ethyl, propyl, isopropyl,
`butyl, sec-and tert-butyl, pentyl, hexyl, heptyl, cyclo-
`propyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohep(cid:173)
`tyl, norbornyl, and the like. "Alkoxy" represents an
`alkyl group of indicated number of carbon atoms at(cid:173)
`tached through an oxygen bridge, such as methoxy,
`ethoxy, propoxy, butoxy and pentoxy.
`"Alkanoyl" is intended to include those alkylcarbo(cid:173)
`nyl groups of specified number of carbon atoms, which
`are exemplified by formyl, acetyl, propanoyl and buty-
`50 ryl; "alkanoyloxy" is intended to include those alkylcar(cid:173)
`bonyl groups of specified number of carbon atoms at(cid:173)
`tached through an oxygen bridge, which are exempli(cid:173)
`fied by formyloxy, acetoxy, propionoyloxy, and butyry-
`loxy. "Alkenyl" is intended to include hydrocarbon
`chains of a specified number of carbon atoms of either a
`straight- or branched-configuration and at least one
`unsaturation, which may occur at any point along the
`chain, such as ethenyl, propenyl, butenyl, pentenyl,
`dimethyl pentenyl, and the like, and includes E and Z
`forms, where applicable; and "arylalkyl" represents aryl
`groups as herein defined which are attached through a
`straight or branched chain alkyl group of from one to
`six carbon atoms, such as, for example, benzyl, phen(cid:173)
`ethyl, 3,3-diphenylpropyl, and the like. "Halogen", as
`used herein, means fluoro, chloro, bromo and iodo.
`As will be understood by those skilled in the art,
`pharmaceutically acceptable salts include, but are not
`limited to salts with inorganic acids such as hydrochlo-
`
`45
`
`65
`
`

`
`5,258,389
`
`7
`ride, sulfate, phosphate, diphosphate, hydrobromide,
`and nitrate or salts with an organic acid such as malate,
`maleate, fumarate, tartrate, succinate, citrate, acetate,
`lactate, methanesulfonate, p-toluenesulfonate or palmo(cid:173)
`ate, salicylate and stearate. Similarly pharmaceutically s
`acceptable cations include, but are not limited to so(cid:173)
`dium, potassium, calcium, aluminum, lithium and am(cid:173)
`monium (especially ammonium salts with -amines of the
`formula HNR 6R 7). One embodiment of the present
`invention encompasses the compounds of Formula I 10
`wherein:
`Rl and R2 are independently selected from:
`(1) hydrogen;
`(2) methyl;
`(3) phenyl;
`(4) substituted phenyl in which the substituents are X,
`Y and Z;
`(5) 1- or 2- naphthyl;
`(6) substituted 1- or 2- naphthyl in which the substitu-
`ents are X, Y and Z;
`(7) biphenyl; and
`(8) substituted and biphenyl in which the substituents
`are X, Y and Z;
`with the proviso that RI and R2 are not simulta-
`neously hydrogen;
`X, Y and Z are independently, selected from:
`(a) hydrogen,
`(b) C1-1 alkyl,
`(c) C2-6 alkenyl,
`(d) halogen,
`(e) -(CH2)m-NR6R7, wherein R6 and Rare, inde-
`pendently selected from
`(i) hydrogen, or
`(ii) C1-6 alkyl unsubstituted or substituted with
`phenyl, and m is 0 to 2,
`(f)-CN,
`(g)-CHO,
`(h)-CF3,
`(i) -SR 8, wherein R 8 is hydrogen, C1-68lkyl, trifluo-
`romethyl, or phenyl,
`G) -SQR8, wherein R8 is as defined above,
`(k) -S02R8, wherein R8 is as defined above,
`(I) -CONR6R7, wherein R6 and R7 are as defined
`above,
`(m) R9Q(CH2)m- wherein R9 is hydrogen, C1-3 alkyl, 4s
`hydroxy-C2.3alkyl,
`trifluoromethyl, phenyl or
`naphthyl and m is as defined above,
`(n) -CH(OR12)(QR13), wherein R12 and R13 are
`C1-3 alkyl or taken together form an ethyl or pro-
`pyl bridge,
`(o)
`
`15
`
`20
`
`2s
`
`30
`
`3S
`
`40
`
`8
`ing of: dioxolanyl, dihydrofuranyl, dihydropyranyl,
`and dioxanyl.
`
`Another embodiment of the present invention en(cid:173)
`compasses the compounds of Formula I wherein:
`RI and R2 are independently selected from:
`(1) hydrogen;
`(2) C1-10 alkyl; (3) substituted C1-10 alkyl in which
`one or more substituent(s) is(are) selected from:
`(a) hydroxy,
`(b) oxo,
`(c) C1-6-alkoxy,
`(d) phenyl-C1.3alkoxy,
`(e) substituted phenyl-C1.3alkoxy, in which the
`substituents on phenyl are X, Y and Z,
`(f) -OCO-C1-681kyl,
`(g)-NR6R7, wherein R6and R7 are independently
`selected from
`(i) hydrogen,
`(ii) C1-10alkyl unsubstituted or substituted with
`one or more of the substituent(s) selected
`from:
`(a') phenyl, which is unsubstituted or substi-
`tuted with X, Y and Z,
`(b')-OH,
`(c') C1-68lkoxy,
`(d')-C02H,
`(e') -C02-C1-68lkyl,
`(f) -C314 7cycloalkyl, and
`(g')-ORll,
`(iii)C3.10alkenyl unsubstituted or substituted
`with one or more of the substituent(s) selected
`from:
`(a') phenyl, which is unsubstituted or substi-
`tuted with X, Y and Z,
`(b')-OH,
`(c') C1-68lkoxy,
`(d')-C02H,
`(e') -C02-C1-68lkyl,
`(f) -C3_7cycloalkyl, and
`(g')-ORll,
`(iv)or where R6 and R7 and the N to which they
`are attached can form an unsubstituted or sub(cid:173)
`stituted 3-7-membered saturated heterocyclic
`ring which can include one or two additional
`heteroatoms independently selected from the
`group consisting of 0 S(O)p, NR14, wherein
`R 14 is hydrogen or C1-6 alkyl unsubstituted or
`substituted by phenyl, and p is 0, 1 or 2, the
`ring being selected from the group consisting
`of: aziridine, morpholine,
`thiomorpholine,
`thiomorpholine-oxide,
`thiomorpholine-diox(cid:173)
`ide, piperidine, pyrrolidine, and piperazine,
`(h) -NR6CO-Ct-68lkyl-R7, wherein R6 is as de-
`fined above,
`(i) -NR6C02-C1-68lkyl-R7,
`G) -NR6CONR6R7,
`(k) -OCONR6R7,
`(l)-COOR6,
`(m)-CHO,
`(n) phenyl,
`(o) substituted phenyl in which the substituents are
`X, Y and Z,
`(p) phenyloxy,
`(q) substituted phenyloxy in which the substituents
`are X, Y and Z,
`(r) 1- or 2- naphthyl,
`
`so
`
`wherein R9 and mare as defined above, and
`(p)
`
`SS
`
`60
`
`wherein R9 and m are as defined above, and
`(q)-ORll;
`or any two of adjacent X, Y and Z can be joined to 6S
`form a ring having 5,6 or 7 ring atoms, said ring atoms
`comprising 1 or 2 oxygen atoms, the remaining ring
`atoms being carbon, selected from the group consist-
`
`

`
`5
`
`10
`
`25
`
`30
`
`35
`
`40
`
`45
`
`9
`(s) substituted 1- or 2- naphthyl in which the sub(cid:173)
`stituents are X, Y and Z,
`(t) biphenyl
`(u) substituted biphenyl in which the substituents
`are X, Y and Z;
`(v) -ORll, and
`(w) -S(O)p-C1-6lllkyl;
`(4) C3_10 alkenyl;
`(5) substituted C3-tO alkenyl in which one or more
`substituent(s) is(are) selected from:
`(a) hydroxy,
`(b) oxo,
`(c) C1-6alkoxy,
`(d) phenyl-C1-3alkoxy,
`(e) substituted phenyl-C1_3alkoxy, in which the 15
`substitucnts on phenyl are X, Y and Z,
`(f) -OCO-C1-6alkyl,
`(g) -NR6R7, wherein R6 and R7 are as defined
`above
`(h)-NR6CO-C1-6lllkyl, wherein R6is as defined 20
`above,
`(i) -COOR6, wherein R6 is as defined above,
`(j)-CHO,
`(k) phenyl,
`(1) substituted phenyl in which the substituents are
`X, Yand Z,
`(m) 1- or 2-naphthyl,
`(n) substituted 1- or 2-naphthyl in which the sub-
`stituents are X, Y and Z,
`(o) biphenyl,
`(p) substituted biphenyl in which the substituents
`are X, Y and Z,
`(q)-QRll, and
`(r) -S(O)p-C1-6lllkyl;
`(6) C3-10alkynyl;
`(7) substituted C3-10alkynyl in which one or more
`substituent(s) is(are) selected from:
`(a) hydroxy,
`(b) oxo,
`(c) C1-6lllkoxy,
`(d) phenyl-C1_3alkoxy,
`(e) substituted phenyl-C1_3alkoxy, in which the
`substituents on phenyl are X, Y and Z,
`(f) -OCO-C1-6lllkyl,
`(g) -NR6R7, wherein R6 and R7 are as defined
`above,
`(h) -NR6CO-Ct-6lllkyl, wherein R6 is as defined
`above,
`(i) -COOR6, wherein R6 is as defined above,
`(j)-CHO,
`(k) phenyl,
`(1) substituted phenyl in which the substituents are
`X, Y and Z,
`(m) 1- or 2-naphthyl,
`(n) substituted 1- or 2-naphthyl in which the sub(cid:173)
`stituents are X, Y and Z,
`(o) biphenyl,
`(p) substituted biphenyl in which the substituents
`are X, Y and Z, and
`(q)-QRll;
`with the proviso that RI and R2 are not simulta(cid:173)
`neously hydrogen;
`R II is selected from:
`(a) -PO(OH)Q-M+, wherein M+is a positively 65
`charged inorganic or organic counterion,
`(b) -S03-M+,
`(c) -CO(CH2)qC02-M+, wherein q is l-3, and
`
`5,258,389
`
`10
`(d)-CO-Ct-6lllkyl-NR6R7, wherein R6and R7 are as
`defined above and the alkyl is unsubstituted or
`substituted with one or more substituents selected
`from:
`(i) hydroxy,
`(ii) C1-6alkoxy,
`(iii) -NRl6R17, wherein R16 and Rl7 are indepen(cid:173)
`dently selected from:
`(a') hydrogen, and
`(b') C1-6alkyl,
`(iv) -COOR6, wherein R6 is as defined above,
`(v) phenyl,
`(vi) substituted phenyl in which the substituents are
`X, Y and Z,
`(vii) -SH, and
`(viii) -S-C1-6alkyl;
`X, Y and Z independently are selected from:
`(a) hydrogen,
`(b) C1-1 alkyl,
`(c) C2-6 alkenyl,
`(d) halogen,
`(e) -(CH2)m-NR6R7, wherein R6 and R7 are as
`defined above, and m is 0 to 2,
`(f)-CN,
`(g)-CHO,
`(h)-CF3,
`(i)-SR8, wherein R8 is hydrogen, C1-6lllkyl, trifluo-
`romethyl, or phenyl,
`(j) -SQR8, wherein R8 is as defined above,
`(k) -S02R8, wherein R8.is as defined above,
`(l) -CONR6R7, wherein R6 and R7 are as defined
`above,
`(m) -R_9Q(CH2)m- wherein R9 is hydrogen, C1-3 alkyl,
`hydroxy-C2_3alkyl,
`trifluoromethyl, phenyl or
`naphthyl and m is as defined above,
`(n) -CH(QR12)(QRl3), wherein R12 and Rl3 are
`C1_3alkyl or taken together form an ethyl or propyl
`bridge,
`(o)
`
`50
`
`55
`
`60
`
`wherein R9 and m are as defined above, and
`(p)
`
`wherein R9 and m are as defined above, and
`(q)-QRll;
`or any two of adjacent X, Y and Z can be joined to
`form a ring having 5, 6 or 7 ring atoms, said ring
`atoms comprising 1 or 2 oxygen atoms, the remaining
`ring atoms being carbon, selected from the group
`consisting of: dioxolanyl, dihydrofuranyl, dihy(cid:173)
`dropyranyl, and dioxanyl.
`
`B. Preparation of Compounds Within the Scope of the
`Present Invention
`The starting material for the preparation of the com(cid:173)
`pounds of this invention is rapamycin:
`
`

`
`11
`
`5,258,389
`
`12
`
`-continued
`
`REACTION SCHEME A
`
`Me
`
`ci:"
`
`N H
`
`II
`0
`
`Me
`
`REACTION SCHEME B
`
`Me
`
`MeO
`
`(i::
`
`N H II
`0
`
`Mc
`
`MeO
`
`5
`
`10
`
`15
`
`Me
`
`Mc
`
`Me
`
`20
`
`25
`
`The production and characterization of rapamycin is
`well know in the literature (see U.S. Pat. No. 3,929,992
`issued Dec. 30, 1975; U.S. Pat. No. 3,993,749 issued
`Nov. 23, 1976). Analogs of rapamycin, such as 30-
`desmethylrapamycin (see PCT Patent Publication WO
`92/14737) may also be employed as starting material to
`give analagous derivatives. The novel processes for 30
`preparing the novel compounds of the present invention
`are illustrated as follows, wherein RI and R2 are as
`defined above unless otherwise indicated. It will be
`readily apparent to one of ordinary skill in the art re- 35
`viewing the synthetic route depicted below that other
`compounds within Formula I can be synthesized by
`substitution of appropriate reactants and agents in the
`synthesis shown below.
`
`40 Me
`
`MeO
`
`Me
`
`ci:"
`
`N
`
`H:
`
`11
`0
`
`REACTION SCHEME A
`
`Me
`
`MeO
`
`cL:
`
`N H II
`0
`
`Me
`
`45
`
`50
`
`55
`
`Me
`
`Me
`
`Me
`
`60
`
`Me
`
`I) TBDMS triflate
`lutidine
`CH2Cl2
`
`2) 10% TsOH
`MeOH
`CH3CN
`
`Me
`
`65
`
`Me
`
`Me
`
`

`
`13
`
`REACTION SCHEME C
`
`5,258,389
`
`14
`-continued
`REACTION SCHEME C
`
`HO
`
`MeO
`
`Me
`
`Me
`
`cL"
`
`N H II
`0
`
`MeO
`
`5
`
`10
`
`15
`
`Me
`
`Me
`
`H a::
`
`N
`
`iI
`
`11
`0
`
`Me
`
`Mea"'''
`
`Me
`
`Me
`
`20
`
`Me
`
`Me
`
`NH
`II
`R10 ............. cc13
`CF3S03H(cat.)
`cyclohexane/
`CH2Cl2
`
`REACTION SCHEME E
`
`MeO
`
`cL"
`
`N
`
`iI
`
`11
`
`Me
`
`Me
`
`Me
`
`pyridine
`Et20
`
`1l)Os04
`
`2) Nal04
`THF/H20
`
`

`
`15
`-continued
`REACTION SC
`HEMEE
`
`5,258,389
`
`16
`
`Me
`
`o,,,,
`HOiC
`'\./
`A
`
`Me
`
`NaCI02
`NaH2P04 (aq.)
`2-methyl-2-
`
`butene J
`
`t-BuOH
`
`Me
`
`~o
`
`~o
`
`Me
`
`45
`
`I
`0
`R6
`,,,,-.....A
`\
`N
`17 R
`
`55
`
`60
`
`65
`
`Me
`
`Me
`
`-;_Me
`
`

`
`5,258,389
`
`17
`
`-continued
`REACTION SCHEME F
`
`5
`
`0
`II
`0
`R6
`\,....,,_I
`N
`A
`~7
`
`10
`
`15
`
`Me
`
`18
`-continued
`REACTION SCHEME G
`
`Me
`
`Me
`
`I ~(Ph)3BH
`tTHF
`
`H
`
`Me
`
`/
`Hc)""A
`
`0
`
`,,,,
`
`20
`
`Me
`
`Me
`
`Me
`
`REACTION SCHEME H
`
`25
`
`0
`/
`II
`H"A
`
`0
`
`,,,,
`
`Me
`
`Me
`
`Me
`
`REACTION SCHEME G
`
`H
`
`Me
`
`0
`0
`A/,,,,
`HO
`A
`
`MeO
`
`N H
`
`II
`0
`
`o:::
`
`Me
`
`Me
`
`Me
`
`HOBt
`EDC
`CH2CI2/DMF
`
`JR6R7NH
`
`OH
`0 A/,,,,
`Rla
`A
`
`45
`
`50
`
`55
`
`Me
`
`60
`
`65
`
`Me tR1°MgBr
`
`THF
`-78° c.
`
`Me
`
`NMO
`4A sieves
`CH2Cl2
`
`JTPAP(cat.)
`
`Me
`
`Me
`
`

`
`19
`-continued
`REACTION SCHEME H
`
`5,258,389
`
`20
`silyl trifluoromethanesulfonate in a solution of methy(cid:173)
`lene chloride; 2,6-lutidine and t-butyldimethylsilyl tri(cid:173)
`fluoromethanesulfonate in a solution of methylene chlo(cid:173)
`ride; pyridine and acetic anhydride in a solution of
`5 methylene chloride; pyridine and benzoyl chloride in a
`solution of methylene chloride; pyridine and p-nitro(cid:173)
`benzoyl chloride in a solution of methylene chloride;
`imidazole and t-butyldiphenylsilyl chloride in a solution
`of methylene chloride; and the like. For example, as
`shown in Reaction Scheme A, rapamycin may be pro(cid:173)
`tected at C-42 as the t-butyldimethylsilyl ether by treat(cid:173)
`ment with one equivalent oft-butyldimethylsilyl trifluo(cid:173)
`romethanesulfonate in methylene chloride to give the
`15 C-42-di-O-TBDMS macrolide. Treatment with two
`equivalents of TBDMS triflate followed by treatment
`with acetic acid or toluene-sulfonic acid in methanol
`results in selective removal of the C-42 ether to give the
`C-31-0-TBDMS macrolide.
`
`10
`
`Me
`
`Me
`
`Me
`
`REACTION SCHEME I
`
`Me
`
`Me tAcylation
`
`or
`Phosphorylation
`
`Meo
`
`~e,,,,,......._H
`
`Me
`
`" ~ ~ 0
`N H II
`
`0
`
`Me
`
`Me
`
`Me
`
`20
`
`55
`
`Reaction Scheme B
`As shown in Reaction Scheme B, a solution of rapa(cid:173)
`mycin in an inert organic solvent such as methylene
`chloride, benzene, toluene, chloroform, or the like or
`25 mixtures thereof may be treated with a triarylbismuth
`diacetate reagent (wherein RI is aryl) (prepared imme(cid:173)
`diately prior to use by the addition of acetic acid to a
`suspension of a triarylbismuth carbonate in an inert
`organic solvent such as methylene chloride, chloroform
`30 or the like or mixtures thereof) in the presence of a
`catalytic amount of copper(II) acetate at a temperature
`of 20° -50° C., preferably room temperature, for a per(cid:173)
`iod of one hour to seven days, preferably one day, to
`35 give the 42-0-aryl rapamycin and/or the 31, 42-di-O(cid:173)
`aryl rapamycin. Alternatively, the triarylbismuth(V)
`reagent may be prepared by treatment of a triarylbismu(cid:173)
`thine with a suitable oxidant such as peracetic acid,
`iodobenzene diacetate, bis(trifluoroacetoxy)iodoben-
`40 zene and the like in an inert solvent such as methylene
`chloride, chloroform, benzene, toluene and the like.
`The triarylbismuth(V) reagent may be used without
`purification or may be purified by silica gel chromatog(cid:173)
`raphy. Triarylbismuthines may be prepared by the reac-
`45 tion of an appropriate aryl Grignard reagent with bis(cid:173)
`muth trichloride in an inert organic solvent such as
`tetrahydrofuran, diethyl ether, or 1,4-dioxane, or mix(cid:173)
`tures thereof, at or near room temperature for a period
`of 1 to 48 hours. General procedures for the preparation
`50 and use of triaryl bismuth reagents may be found in
`Barton, D.H.E., et al., J. Chem. Soc. Chem. Commun.,
`1986, 65 and references cited therein.
`Similarly, the 31-0-aryl compounds may be prepared
`by protecting the 42-alcohol of rapamycin with a pro(cid:173)
`tecting group, such as with a tert-butyl dimethylsilyl
`group, followed by arylation of the 31-position with a
`triaryl bismuth reagent. Removal of the protecting
`group provides the 31-0-aryl compounds. In the case of
`60 the tert-butyl dimethylsilyl protecting group, deprotec(cid:173)
`tion can be accomplished under mildly acidic condi(cid:173)
`tions.
`If desired, the 31-hydroxy-42-0-aryl rapamycin, or
`31-0-aryl-42-hydroxy rapamycin may be treated with a
`different triarylbismuth diacetate reagent (prepared
`immediately prior to use by procedures analogous to
`those disclosed above), to give mixed 31-0-aryl-42-0-
`aryl macrolides.
`
`Reaction Scheme A
`Protection of the C-31 and/or the C-42 hydroxy 65
`group may be accomplished by methods known in the
`prior art for rapamycin (see e.g. U.S. Pat. No. 5, 120,842)
`such as by treatment with: 2,6-lutidine and triisopropyl-
`
`

`
`21
`Reaction Scheme C
`As shown in Reaction Scheme C, a solution of the
`rapamycin in an inert organic solvent such as methylene
`chloride, chloroform, pentane, hexane, cyclohexane, 5
`heptane or the like or mixtures thereof is treated with an
`alkyl, alkenyl or alkynyl trichloroacetimidate reagent
`(prepared by the reaction of an appropriate sodium
`alkoxide with trichloroacetonitrile, such as described by
`Wessel, H.P., Iversen, T., Bundle, D.R., J. Chem. Soc., 10
`Perkin Trans. L 1985, 224 7) in the presence of a mild
`acid catalyst such as trifluoromethanesulfonic acid,
`p-toluenesulfonic acid, methane-sulfonic acid, benzene(cid:173)
`sulfonic acid, p-nitrobenzene-sulfonic acid, p-bromo(cid:173)
`benzenesulfonic acid, p-chlorobenzenesulfonic acid, or 15
`p-methoxybenzenesulfonic acid, or mixtures thereof at a
`temperature of 20• -50° C.,preferably room tempera(cid:173)
`ture, for a period of one hour to seven days, preferably
`one day, to give the 31- and/or 42-0-alkyl, -alkenyl or
`-alkynyl rapamycin derivative.
`In addition, the procedure of Reaction Scheme