lllllllllllllllllllllllllllIlllllllllllllllllllllllllllllllllllllllllllllll
`US005143918A
`[11] Patent Number:
`5,143,918
`[45'] Date of Patent:
`Sep.1,1992
`
`Bierer, et al., Science, 1990, 250, 556-559.
`Donald, et al., Tetrahedron Lett., 1991, 32, 1375-1378.
`C. Arita, et al., Clin. exp Immunol, 1990, 82, 456-461.
`N. Murase, et al., Diabetes, 1990, 39, 1584-86.
`J. McCauley, et al., Lancet, 1990, 335, 674.
`K. Takabayashi, et al., Clin. Immunol. Immunopathol.,
`1989, 51, 110-117.
`M. Sakr, et al., Life Science, 1990, 47, 687-691.
`Primary Examiner-Robert T. Bond
`Attorney, Agent, or Firm-Charles M. Caruso; Robert J.
`North; J. Eric Thies
`[57]
`ABSTRACT
`Novel C-3" and C-4" halogen-substituted macrolides of
`FK-506 type structural Formula I:
`
`R2 4..
`
`1
`
`United States Patent [191
`Bochis et al.
`
`[54] HALOMACROLIDES AND DERIVATIVES
`HAVING IMMUNOSUPPRESSIVE
`ACTIVITY
`[75] Inventors: Richard J. Bochis, East Brunswick;
`Matthew J. Wyvratt, Jr.,
`Mountainside, both of NJ.
`[73] Assignee: Merck & Co., Inc., Rahway, NJ.
`[21] Appl. No.: 759,747
`[22] Filed:
`Sep. 12, 1991
`
`[63]
`
`Related US. Application Data
`Continuation of Ser. No. 596,177, Oct. 11, 1990, aban
`cloned.
`
`[51] Int. Cl.5 ............... .. A61K 31/695; A61K 31/395;
`C07D 498/16
`[52] US. Cl. .................................. .. 514/291; 514/183;
`514/411; 540/456
`[58] Field of Search .............. .. 540/456; 514/183, 411;
`314/29
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`4,650,803 3/1987 Stella et a1. ....................... .. 514/291
`4,894,366 1/1990 Okuhara et a1.
`.. 540/456
`
`4,916,138 4/1990 Ueda et a1. . . . . . . . . .
`
`. . . . .. 514/294
`
`4,929,611 5/1990 Okuhara et a].
`4,956,352 9/1990 Okuhara et a].
`4,981,792 l/l99l Inamine et a1.
`
`. 514/183
`514/63
`.. 435/119
`
`4,987,139 1/1991 Chen et al. . . . . .
`
`. . . . .. 514/321
`
`5,011,844 4/1991 Fehr . . . . . . . .
`
`. . . . .. 514/291
`
`5,064,835 11/1991 Bochis et a1. ..................... .. 514/291
`
`FOREIGN PATENT DOCUMENTS
`
`0315978 5/1989 European Pat. Off. .
`0323042 7/1989 European Pat. Off. .
`0349061 1/ 1990 European Pat. Off. .
`0353678 2/1990 European Pat. Off. .
`0356399 2/ 1990 European Pat. Off. .
`0388152 9/ 1990 European Pat. Off. .
`0388153 9/1990 European Pat. Off. .
`0402931 12/1990 European Pat. Off. .
`0413532 2/1991 European Pat. Off. .
`0423714 4/ 1991 European Pat. Off. .
`0427680 5/1991 European Pat. Off. .
`0428169 5/ 1991 European Pat. Off. .
`0428365 5/ 1991 European Pat. Off. .
`0444659 9/ 1991 European Pat. Off. .
`0444829 9/ 1991 European Pat. Off. .
`WO89/05304 6/1989 World Int. Prop. 0. .
`WO90/ 14826 12/ 1990 World Int. Prop. 0. .
`\VO9l/02736 3/1991 World Int. Prop. 0. .
`\VO9l/04025 4/ 1991 World Int. Prop. 0. .
`WO9l/l3889 9/1991 World Int. Prop. 0. .
`W09l/ 13899 9/ 1991 World Int. Prop. 0. .
`
`OTHER PUBLICATIONS
`Tanaka, et al., J. Am. Chem. Soc., 1987, 109 5031-5033.
`
`are described. These macrolide immunosuppressants
`are useful in a mammalian host for the treatment of
`autoimmune diseases (such as juvenile-onset diabetes
`melitus, multiple sclerosis and rheumatoid arthritis),
`infectious diseases and/or the prevention of rejection of
`foreign organ transplants, e.g. bone marrow and heart
`transplants. In addition, these macrolide immunosup
`pressants are useful in the topical treatment of in?am
`matory and hyperproliferative skin diseases and cutane
`ous manifestations of immunologically-mediated ill
`nesses such as: psoriasis, atopical dermatitiis, contact
`dermatitis and further eczematous dermatitises, seborr
`hoeic dermatitis, Lichen planus, Pemphigus, bullous
`Pemphigoid, Epidermolysis bullosa, urticaria, angio
`edemas, vasulitides erythemas, cutaneous eosinophilias,
`Lupus erythematosus or Alopecia areata.
`
`9 Claims, No Drawings
`
`NOVARTIS EXHIBIT 2015
`Par v Novartis, IPR 2016-00084
`Page 1 of 27
`
`

`
`1
`
`5,143,918
`
`2
`23,25-dimethoxy-13,19,21,27-tetramethyl-l 1,28-dioxa
`4-azatricyclo[22.3. l .O4v9]octacos‘ l 8-ene-2,3, l0, 1 6-tetr
`aone (FR-900520) and related compounds which are the
`starting materials for the preparation of the compounds
`described. The synthetic preparation of the aforemen
`tioned starting material (FR-900506) has recently been
`reported (J. Am. Chem. Soc., 1989, 111, 1157).
`
`HALOMACROLIDES AND DERIVATIVES
`HAVING IMMUNOSUPPRESSIVE ACI'IVITY
`
`This is a continuation of application Ser. No.
`07/596,177, ?led on Oct. 11, 1990 now abandoned.
`The present invention is related to compounds which
`are useful in a mammalian host for the treatment of
`autoimmune diseases (such as juvenile-onset diabetes
`melitus, multiple sclerosis and rheumatoid arthritis),
`infectious diseases and/or the prevention of rejection of
`foreign organ transplants, e.g. bone marrow and heart
`transplants and are also useful in the topical treatment of
`in?ammatory and hyperproliferative skin diseases and
`cutaneous manifestations of immunologically-mediated
`illnesses.
`More particularly, this invention relates to the intro
`duction of a halogen substituent at G3" or C-4" of the
`cyclohexyl ring in compounds of the general structural
`Formula I:
`
`25
`
`BACKGROUND OF THE INVENTION
`
`Immunoregulatory abnormalities have been shown to
`exist in a wide variety of “autoimmune” and chronic
`in?ammatory diseases, including systemic lupus ery
`thematosis, chronic rheumatoid arthritis, type 1 diabetes
`mellitus, in?ammatory bowel disease, biliary cirrhosis,
`uveitis, multiple sclerosis and other disorders such as
`Chrons disease, ulcerative colitis, bullous pemphigoid,
`sarcoidosis, psoriasis, ichthyosis, and Graves ophthal
`mopathyi Although the underlying pathogenesis of
`each of these conditions may be quite different, they
`have in common the appearance of a variety of autoan
`tibodies and self-reactive lymphocytes. Such self-reac
`tivity may be due, in part, to a loss of the homeostatic
`controls under which the normal immune system oper
`ates.
`Similarly, following a bone'marrow or an organ
`transplantation, the host lymphocytes recognize the
`foreign tissue antigens and begin to produce antibodies
`which lead to graft rejection.
`One end result of an autoimmune or a rejection pro
`cess is tissue destruction caused by in?ammatory cells
`and the mediators they release. Antiflammatory agents
`such as NSAID’s and corticosteroids act principally by
`blocking the effect or secretion of these mediators but
`do nothing to modify the immunologic basis of the
`disease. On the other hand, cytotoxic agents such as
`cyclophosphamide, act in such a nonspeci?c fashion
`that both the normal and autoimmune responses are
`shut off. Indeed, patients treated with such nonspeci?c
`immuno-suppressive agents are as likely to succumb
`from infection as they are from their autoimmune dis
`ease.
`Cyclosporin A which was approved by the US.
`FDA in 1983 is currently the leading drug used to pre
`vent rejection of transplanted organs. The drug acts by
`inhibiting the body’s immune system from mobilizing its
`vast arsenal of natural protecting agents to reject the
`transplant’s foreign protein. Though cyclosporin A is
`effective in ?ghting transplant rejection, it is nephro
`toxic and is known to cause several undesirable side
`effects including kidney failure, abnormal liver function
`and gastro-intestinal discomfort.
`Newer, safer drugs exhibiting less side effects are
`constantly being searched for in the ?eld.
`The 23-membered tricyclo-macrolide immunosup
`pressant, FR-900506,
`
`'30
`
`35
`
`OCH}
`
`wherein R is methyl, ethyl, propyl or allyl; R1 and R2
`are independently halo, hydroxy, and C1-C3 alkoxy,
`with the proviso that at least one R1 or R2 is halogen;
`R3 is hydrogen or hydroxy and R4 is hydrogen; or R3
`and R4 can be taken together to form a double bond;
`X=O or (HO, H) and n is 1 or 2. It also relates to phar
`maceutical compositions containing the compounds and
`to a method of use of the present compounds and other
`agents for the treatment of autoimmune diseases, infec
`tious diseases, the rejection of foreign organ transplants,
`in?ammatory and hyperproliferative skin diseases and
`/or cutaneous manifestations of immunologically
`mediated illnesses.
`
`BRIEF DESCRIPTION OF DISCLOSURES IN
`THE ART
`Fujisawa European and Japanese and US. patents
`(EPO Publication No. 0,184,162 and PB] Disclosure
`63-17884 US. Pat. No. 4,894,366) and publications (J.
`Am. Chem. Soc., 1987, 109, 5031 and J. Antibiotics 1987,
`40,
`1249) disclose
`17-allyl-l,14-dihydroxy-12-[2’-(
`4"-hydroxy-3"-methoxycyclohexyl)-l'-methylvinyl]
`23,25-dimethoxy-13,19,21,27-tetramethyl-l1,28-dioxa
`4-azatricyclo-[22.3.l.04’9]octacos-18-ene-2,3,l0,16-tetr
`aone (FR-900506),
`l7-ethyl-1,l4-dihydroxy-l2-[2'
`(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]
`
`45
`
`50
`
`55
`
`65
`
`NOVARTIS EXHIBIT 2015
`Par v Novartis, IPR 2016-00084
`Page 2 of 27
`
`

`
`5,143,918
`
`R2
`
`10
`
`15
`
`20
`
`25
`
`35
`
`40
`
`and related compounds which were isolated and char
`acterized by Tanaka, Kuroda, and co-workers at
`Fujisawa Pharmaceutical Co. in Japan, see J. Am.
`Chem. S0c., 1987, 109, 5031, and EPO Pub. No.
`0,184,162 have been shown to possess exceptional im
`munosuppressive activity. The compound FR-900506
`has been reported to be 100 times more effective than
`cyclosporin in the suppression of in vitro immune sys
`tems (J. Antibiotics 1987, 40, 1256). In addition, these
`compounds are reputed to possess topical activity in the
`treatment of in?ammatory and hyperproliferative skin
`diseases and cutaneous manifestations of immunologi
`cally-mediated illnesses (EPO Pub. No. 0,315,978).
`Accordingly, an object of the present invention is to
`provide new analogs of these tricyclomacrolides which
`will (1) restore the balance of the help-and-suppression
`mechanism of the immune system by acting at an earlier
`point than the anti-in?ammatory agents and (2) induce
`speci?c long-term transplantation tolerance through a
`suppressor cell circuit without increasing the body’s
`susceptibility to infection.
`Another object of the present invention is to provide
`analogs of these tricyclo-macrolides which possess topi
`cal activity in the treatment of in?ammatory and hyper
`proliferative skin diseases and cutaneous manifestations
`of immunologically-mediated illnesses.
`An additional object of the present invention is to
`provide pharmaceutical compositions for administering
`to a patient in need of the treatment one or more of the
`active immunosuppressive agents of the present inven
`tron.
`Still a further object of this invention is to provide a
`method of controlling graft rejection, autoimmune and
`chronic in?ammatory dieases by administering a suffi
`cient amount of one or more of the novel immunosup
`pressive agents in a mammalian species in need of such
`treatment.
`Finally, it is the object of this invention to provide
`processes for the preparation of the active compounds
`of the present invention.
`
`50
`
`55
`
`CH 30
`
`OCH 3
`
`wherein:
`R is methyl, ethyl, propyl or allyl; R1 and R2 are
`independently halo, hydroxy, C1-C3 alkoxy, with
`the proviso that at least one R1 or R2 is halogen; R3
`is hydrogen or hydroxy and R4 is hydrogen; or R3
`and
`R4 can be taken together to form a double bond;
`X=O or (HO, H) and n is 1 or 2;
`In the present invention, compounds with asymmet
`ric centers may occur as racemates, racemic mixtures
`and as individual diastereomers, with all isomeric forms
`of the compounds being included in the present inven
`tron.
`In addition compounds with carbon-carbon double
`bonds may occur in Z— and E— forms with all iso
`meric forms of the compounds being included in the
`present invention.
`When any variable (e.g., alkyl, R, R1, R2, R3, R4, etc.)
`occurs more than one time in any variable or in For
`mula I, its de?nition on each ocurrence is independent
`of its de?nition at every other occurrence.
`As used herein, “alkyl” is intended to include both
`branched, straight chain and cycloalkyl saturated ali
`phatic hydrocarbon groups having the speci?ed num
`ber of l-8 carbon atoms, representative examples being
`methyl, ethyl, isopropyl, tert-butyl, sec-butyl, isopentyl,
`n-hexyl, n-heptyl, n-octyl, iso-octyl, and the like;
`“halo”, as used herein, means ?uoro, chloro, bromo or
`iodo.
`In the present invention it is preferred that in com
`pounds of Formula I:
`R is ethyl, propyl or allyl;
`R1 is ?uoro, chloro, bromo, or iodo and R2 is hydroxy
`or methoxy; or R2 is ?uoro, chloro, bromo or iodo
`and R1 is hydroxy or methoxy;
`R3 is hydrogen or hydroxy;
`R4 is hydrogen;
`n is l or 2.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`A. Scope of the Invention
`This invention relates to compounds of the general
`Formula I:
`
`65
`
`B. Preparation of Compounds Within the Scope of the
`Present Invention
`The starting materials for the preparation of the 3"
`halo and 4"-halo compounds of this invention are repre
`sented by Formula II:
`
`NOVARTIS EXHIBIT 2015
`Par v Novartis, IPR 2016-00084
`Page 3 of 27
`
`

`
`5,143,918
`
`6
`duced to a hydrogen or eliminated to form a double
`bond with R4 (by methods similar to those disclosed in
`EPO Publication 0,323,042). The carbonyl of X may be
`reduced to a hydroxy by methods disclosed in EPO
`Publication 0,323,042 also U.S. Ser. No. 07/486,700
`?led Mar. 1, 1990. The methoxy of R1 as produced may
`be replaced with hydroxy or demethylated and subse
`quently protected as desired, if necessary. This demeth
`ylation of R1 may be carried out in a fermentation reac
`tion using the compounds of Formula II as a feedstock.
`For instance, compound B named under Formula II
`above may be demethylated at R1 above by using the
`microorganism Actinomycetales ATCC No. 53771 (as
`taught in U.S. Ser. No. 213,025 ?led Jun. 29, 1988 and
`hereby incorporated by reference) or produced directly
`by a mutant organism (as taught in U.S. Ser. No.
`323,653 ?led Mar. 15, 1989 and hereby incorporated by
`reference). Similarly, compound A may be deme
`thylated (as taught in U.S. Ser. No. 213,063 also ?led
`Jun. 29, 1988).
`Suitable protecting groups for hydroxyl include those
`groups well known in the art which are: l-(lower alkyl
`thio) (lower)alkyl, wherein “lower alkyl” indicates a
`straight, cyclic or branched chain of one to six carbon
`atoms, such as lower alkylthiomethyl (e.g. methylthi
`omethyl, ethylthiomethyl, propylthiomethyl, isopropyl
`thiomethyl, butylthiomethyl, isobutylthiomethyl, hex
`ylthiomethyl, etc.), and the like, in which the preferred
`one may be C1-C4 alkylthiomethyl and the most pre
`ferred one may be methylthiomethyl; trisubstituted silyl
`such as tri(lower)alkylsilyl (e.g. trimethylsilyl, triethyl
`silyl, tributysilyl, tri-isopropylsilyl (TIPS), t-butyldime
`thylsilyl, (TBDMS) tri-t-butylsilyl, etc.), lower alkyl
`diarylsilyl (e.g. methyl-diphenylsilyl, ethyl-diphenylsi
`lyl, propyl-diphenylsilyl, t-butyldiphenylsilyl, etc.), and
`the like, in which the preferred one may be tri(C1-C4_
`)alkylsilyl and C1-C4 alkyldiphenylsilyl, and the most
`preferred one may be tert-butyl-dimethylsilyl, tri-i
`propylsilyl and tert-butyldiphenylsilyl; acyl such as
`aliphatic acyl, aromatic acyl and aliphatic acyl substi
`tuted with aromatic group, which are derived from
`carboxylic acids; and the like.
`Compounds A, B, C and D of Formula II, organisms
`to produce the same, conditions of fermentation, separa
`tion techniques, and chemical modi?cation of the prod
`ucts are fully described in EPO Publication No.
`0,184,162. This document is hereby incorporated by
`reference.
`The compounds of the present invention which are
`represented by Formula I are prepared by the methods
`shown in the following Reaction Schemes wherein R,
`R1, R2, R3, R4, X and n are as de?ned above unless
`otherwise indicated. It will be readily apparent to one of
`ordinary skill in the art reviewing the synthetic route
`depicted below that other compounds within Formula I
`can be synthesized by substitution of appropriate reac
`tants and agents in the synthesis shown below.
`As shown in Reaction Scheme A for preparing the
`4"-halogen derivatives, the C-14-oxygen-protected
`macrolide (V protected with TIPS or TBDMS) is pre
`pared from the 4",14-dihydroxy macrolide (III) by
`treating III with silylating agents TIPSX or TBDMSX
`(where X=ch1oride or trifluoromethane sulfonate) to
`form IV and hydrolyzing off the C-4" protecting group
`to give V, and reacted with o-nitrobenzene sulfonyl
`chloride to form VI, which is then reacted with LiX,
`where X=Cl, Br, I, in an aprotic solvent, e.g., N,N
`
`10
`
`15
`
`20
`
`OCH 3
`
`25
`
`30
`
`35
`
`wherein R is methyl, ethyl, propyl or allyl; R1 and R2
`are, independently, hydroxy or methoxy; R3 is hydro
`gen or hydroxy; R4 is hydrogen or R3 and R4 can be
`taken together to form a double bond. X is 0; and n is l
`or 2.
`The production and characterization of compounds
`of Formula II is well known in the literature (see EPO
`Publication No. 0,323,042, EPO Publication No.
`0,184,162, PBJ Disclosure 63-17884, J. Am. Chem. Soc.,
`1987, 109, 5031 and J. Antibiotics, 1987, 40, 1249). Both
`biological fermentation and synthetic processes may be
`found. A synthetic route to compounds of Formula II
`can involve modi?cations of a route described in J. Am.
`Chem. 500., 1989, 111, 1157.
`Biological fermentation followed by synthetic modi
`?cation is presently favored in the art as the method to
`produce compounds of Formula II. Organisms belong
`ing to the genus Streptomyces such as Streplomyces tsu
`kubaensis, No. 9993 placed in an aqueous nutrient me
`dium will produce desired compounds in isolable
`amounts. The nutrient medium contains sources of as
`similable carbon and nitrogen, preferably under aerobic
`conditions. Produced in fermentation are four com
`pounds of Formula II, (A) where R is allyl, R1 is me
`thoxy, R2 and R3 are hydroxyl, R4 is hydrogen, X is 0
`and n is 2; (B) where R is ethyl, R1 is methoxy, R2 and
`R3 are hydroxyl, R4 is hydrogen, X is 0 and n is 2; (C)
`where R is methyl, R1 is methoxy, R2 and R3 are hy
`droxyl, R4 is hydrogen, X is 0 and n is 2; and (D) where
`R is allyl, R1 is methoxy, R2 and R3 are hydroxyl, R4 is
`hydrogen, X is 0 and n is l.
`-
`A lyophilized sample of the isolated Streptomyces
`tsukubaensis, No. 9993 was deposited with the Fermen
`tation Research Institute, Agency of Industrial Science
`and Technology (No. 1-3, Higashi l-chome, Yatabema
`chi Tsukuba-gun, Ibaraki Prefecture, Japan) under the
`deposit number of FERM P-7886 (deposit date: Oct.
`5th, 1984), and then converted to Budapest Treaty route
`of the same depository on Oct. 19, 1985 under the new
`deposit number of FERM BP-927.
`Using the four compounds produced in fermentation
`above, the remaining compounds of Formula II may be
`easily produced. The allyl of R may be conveniently
`reduced to propyl by well known methods. The R2 or
`R3 hydroxyls may be protected by well known meth
`ods, for example as disclosed in EPO Publication
`0,323,042. In addition, the hydroxy of R3 may be re
`
`45
`
`50
`
`55
`
`65
`
`NOVARTIS EXHIBIT 2015
`Par v Novartis, IPR 2016-00084
`Page 4 of 27
`
`

`
`5,143,918
`7
`8
`Oxygen
`dimethylformamide, to introduce the halo substituent at
`oxygen-protected derivatives. The C-4"
`the C4" position to produce VIII. The protecting
`protected derivative (XI) is separated and puri?ed by
`chromatography.
`group at GM is then removed to produce IX. Com
`Following the analogous procedure for the C-4" halo
`pound V can be treated with DAST at 0° C. in CHzClz
`and after the removal of protecting groups, if any, to 5 derivatives, the C-3" hydroxy is reacted with ortho
`give compound IX where R2=F.
`nitrobenzene-sulfonyl chloride to form XII, which is
`A route to C-3” halo substituted compounds is shown
`then reacted with LiX (where X=Cl, Br, I) to form the
`in Reaction Scheme B. The procedure is analogous to
`C-3" halo derivative XIII. In addition, C-3" and 04"
`that for forming the C-4” halo derivatives.
`halo substituted compounds can be alternatively pre
`The macrolide III is treated with the demethylating 1O pared as shown in Scheme C. Treatment of the deme
`microorganism ATCC No. 53771 or ATCC No. 53828
`thylated
`natural
`product ' (R=CH2CH=CH2,
`to produce the C-4" and C-3" dihydroxy macrolide X.
`CH2CI-I2CH3, CI-IZCH3, or CH3; R1:OH; RZZOH;
`This is treated with one molar equivalent of protecting
`R3=OH, OTBDMS, OTIPS or H; R4=H) with 0
`group reagent, such as tert-butyldimethylsilyl chloride
`nitrobenzenesulfony] chloride followed by base gives a
`or tri-isopropylsilyl tri?uoromethanesulfonate, in 15 mixture of epoxides which can be separated (XIV).
`CHZCIZ with imidazole or 2,6-lutidine as an acid sca-
`Nucleophilic ring opening with LiX or TiCl4/I‘MSN3
`vanger to produce a mixture of C-4" and C-3" mono-
`affords the G3" or C-4" halo derivative (XIII).
`
`REACTION SCHEME A
`
`RZQ
`
`CH3O
`
`H3
`
`TBDMS h] 'd
`or
`c on e
`
`. “3C
`
`1) TIPStn'llate
`lutjdine
`CHzClz
`—->
`
`(Cl-‘11),.
`N
`
`:
`
`5
`O
`
`\\O
`
`R3
`
`Q
`4
`
`MR
`
`0
`
`H3C
`
`CH3O
`
`OCH;
`
`1) 10% TsOH R3 = OTIPS, OTBDMS or H
`McOI-I
`R2 = OTIPS or OTMBDS
`CH3CN
`
`v
`
`CH3O
`R3 = H or OH
`n = l or 2
`
`OCH3
`
`E o-nitro benzene
`sulfonyl chloride,
`(i-PrhNET,
`DMAP CHgClz
`
`OCH;
`
`OCH3
`
`NOVARTIS EXHIBIT 2015
`Par v Novartis, IPR 2016-00084
`Page 5 of 27
`
`

`
`NOVARTIS EXHIBIT 2015
`Par v Novartis, IPR 2016-00084
`Page 6 of 27
`
`

`
`11
`
`5,143,918
`
`continued
`
`REACTION SCHEME A
`
`12
`
`CH3O
`
`OCH3
`
`R3 = OH or H
`R; = Cl, Br, or I
`n = l or 2
`
`REACTION SCHEME B
`
`111,,
`
`HO
`
`where
`
`XIII
`
`CH3O
`
`OCH3
`
`R1 = F and R2 = OH
`or
`R1 = OH and R2 = F
`R3 = OH or H
`
`CH3O
`
`OCH3
`
`3
`l. DAST R = OTBDMS, OTIPS
`2. Deblock
`or H
`
`NOVARTIS EXHIBIT 2015
`Par v Novartis, IPR 2016-00084
`Page 7 of 27
`
`

`
`NOVARTIS EXHIBIT 2015
`Par v Novartis, IPR 2016-00084
`Page 8 of 27
`
`

`
`15
`
`5,143,918
`
`REACTION SCHEME C
`
`R2
`
`16
`
`CH3O
`R3 = OTBDMS, OTIPS or H
`
`XIII
`
`0
`
`H3C
`
`(XII-Is
`
`c1130
`R3 = OH or H
`R1 = OH and R2 = Cl, Br, orI
`R1= Cl; Br, or I and R2 = OH
`
`where
`
`Et 3N
`
`((3112),,
`
`E1) LiX or
`TiCl4/I‘MSN3
`then
`2) Acid Deblock
`(If Necessary)
`
`0CH3
`c1130
`R3 = OTBDMS, OTIPS or H
`
`The object compounds of Formula I obtained ac
`cording to the reactions as explained above can be iso
`lated and puri?ed in a conventional manner, for exam
`ple, extraction, precipitation, fractional crystallization,
`recrystallization, chromatography, and the like.
`It is to be noted that in the aforementioned reactions
`and the post-treatment of the reaction mixture therein,
`the stereoisomer(s) of starting and object compounds
`due to asymmetric carbon atom(s) or double bond(s) of
`the object compounds of Formula I may occassionally
`be transformed into the other stereo isomer(s), and such
`cases are also included within the scope of the present
`invention.
`In the present invention, compounds with asymmet
`ric centers may occur as racemates, racemic mixtures
`and as individual diastereomers, with all isomeric forms
`
`55
`
`65
`
`of the compounds being included in the present inven
`tion. These may be prepared by methods such as those
`disclosed in publications which describe synthetic
`routes to fragments of the macrolide FR-900506 and the
`total synthesis of the macrolide FR-900506 itself (Tetra
`hedron Lett., 1988, 29, 277; Tetrahedron Lett., 1988, 29,
`281,‘ Tetrahedron Lett., 1988, 29, 4481; J. Org. Chem,
`1989, 54, 9; J. Org. Chem, 1989, 54, 11,- J. Org. Chem,
`1989, 54, 15;]. Org. Chemzl, 1989, 54, 17;]. Am. Chem.
`Soc, 1989, 111, 1157).
`
`NOVARTIS EXHIBIT 2015
`Par v Novartis, IPR 2016-00084
`Page 9 of 27
`
`

`
`20
`
`25
`
`17
`C. Utility of the Compounds within the Scope of the
`Invention
`The compounds of Formula I may be employed as
`immunosuppressants by methods and in dosages known
`in the prior art for compounds of Formula II. These
`compounds possess pharmacological activity, i.e., im
`munosuppressive activity, and the like, and therefore
`are useful for the treatment and prevention of the resis
`tance to transplantation or transplantation rejection of
`organs or tissues such as heart, kidney, liver, medulla
`ossium, skin, etc., graft-versus-host diseases by medulla
`ossium transplantation, autoimmune diseases such as
`rheumatoid arthritis, systemic lupus erythematosis,
`Hashimoto’s thyroiditis, multiple sclerosis, myasthenia
`gravis, type I diabetes, uveitis, etc. The compounds of
`Formula I are also useful for treating in?ammatory and
`hyperproliferative skin diseases and cutaneous manifes
`tations of immunologically-mediated illnesses such as:
`psoriasis, atopical dermatitiis, contact dermatitis and
`further eczematous dermatitises, seborrhoeic dermatitis,
`Lichen planus, Pemphigus, bullous Pemphigoid, Epi
`dermolysis bullosa, urticaria, angioedemas, vasculitides,
`erythemas, cutaneous eosinophilias or Alopecia areata.
`The pharmaceutical compositions of this invention
`can be used in the form of a pharmaceutical preparation,
`for example, in solid, semisolid or liquid form, which
`contains one or more of the compounds of the present
`invention, as an active ingredient, in admixture with an
`organic or inorganic carrier or excipient suitable for
`external, enteral or parenteral applications. The active
`ingredient may be compounded, for example, with the
`usual non-toxic, pharmaceutically acceptable carriers
`for tablets, pellets, capsules, suppositories, solutions,
`emulsions, suspensions, and any other form suitable for
`use. The carriers which can be used are water, glucose,
`lactose, gum acacia, gelatin, mannitol, starch paste,
`magnesium trisilicate, talc, corn starch, keratin, colloi
`dal silica, potato starch, urea and other carriers suitable
`for use in manufacturing preparations, in solid, semi
`solid, or liquid form, and in addition auxiliary, stabiliz
`ing, thickening and coloring agents and perfumes may
`be used. The active object compound is included in the
`pharmaceutical composition in an amount sufficient to
`produce the desired effect upon the process or condi
`tion of diseases.
`This invention also relates to a method of treatment
`for patients suffering from immunoregulatory abnor
`malities involving the administration of a compound of
`Formula I as the active constituent.
`For the treatment of these conditions and diseases
`caused by immmunoirregularity a compound of formula
`I may be administered orally, topically, parenterally, by
`inhalation spray or rectally in dosage unit formulations
`containing conventional non-toxic pharmaceutically
`acceptable carriers, adjuvants and vehicles. The term
`parenteral as used herein includes subcutaneous injec
`tions, intravenous, intramuscular, intrasternal injection
`or infusion techniques.
`The pharmaceutical compositions containing the ac
`tive ingredient may be in a form suitable for oral use, for
`example, as tablets, troches, lozenges, aqueous or oily
`suspensions, dispersible powders or granules, emulsions,
`hard or soft capsules, or syrups or elixers. Compositions
`intended for oral use may be prepared according to any
`method known to the art for the manufacture of phar
`maceutical compositions and such compositions may
`contain one or more agents selected from the group
`
`5,143,918
`18
`consisting of a sweetening agents, ?avoring agents,
`coloring agents and preserving agents in order to pro
`vide pharmaceutically elegant and palatable prepara
`tion. Tablets containing the active ingredient in admix‘
`ture with non-toxic pharmaceutically acceptable excipi
`ents may also be manufactured by known methods. The
`excipients used may be, for example, (l) inert diluents
`such as calcium carbonate, lactose, calcium phosphate
`or sodium phosphate; (2) granulating and disintegrating
`agents such as corn starch, or alginic acid; (3) binding
`agents such as starch, gelatin or acacia, and (4) lubricat
`ing agents such as magnesium stearate, stearic acid or
`talc. The tablets may be uncoated or they may be coated
`by know techniques to delay disintegration and absorp
`tion in the gastrointestinal tract and thereby provide a
`sustained action over a longer period. For example, a
`time delay material such as glyceryl monostearate or
`glyceryl distearate may be employed. They may also be
`coated by the techniques described in the US. Pat. Nos.
`4,256,108; 4,160,452; and 4,265,874 to form osmotic
`therapuetic tablets for controlled release.
`In some cases, formulations for oral use may be in the
`form of hard gelatin capsules wherein the active ingre
`dient is mixed with an inert solid diluent, for example,
`calcium carbonate, calcium phosphate or kaolin. They
`may also be in the form of soft gelatin capsules wherein
`the active ingredient is mixed with water or an oil me
`dium, for example peanut oil, liquid paraffin, or olive
`oil.
`Aqueous suspensions normally contain the active
`materials in admixture with excipients suitable for the
`manufacture of aqueous suspensions. Such excipients
`may be:
`(1) suspending agents such as sodium carboxymethyl
`cellulose, methylcellulose, hydroxypropylmethylcel
`lulose, sodium alginate, polyvinylpyrrolidone, gum
`tragacanth and gum acacia;
`(2) dispersing or wetting agents which may be
`(a) a naturally-occurring phosphatide such as lecithin,
`(b) a condensation product of an alkylene oxide with
`a fatty acid, for example, polyoxyethylene stearate,
`(c) a condensation product of an ethylene oxide with
`a long chain aliphatic alcohol, for example, hep
`tadecaethyleneoxycetanol,
`(d) a condensation product of ethylene oxide with a
`partial ester derived from a fatty acid and a hexitol
`such as polyoxyethylene sorbital monooleate, or
`(e) a condensation product of ethylene oxide with a
`partial ester derived from a fatty acid and a hexitol
`anhydride, for example polyoxyethylene sorbitan
`monooleate.
`The aqueous suspensions may also contain one or
`more preservatives, for example, ethyl or n-propyl p
`hydroxybenzoate; one or more coloring agents; one or
`more ?avoring agents; and one or more sweetening
`agents such as sucrose or saccharin.
`Oily suspension may be formulated by suspending the
`active ingredient in a vegetable oil, for example, arachis
`oil, olive oil, sesame oil or coconutoil, or in a mineral oil
`such as liquid paraffin. The oily suspensions may con
`tain a thickening agent, for example, beeswax, hard
`paraffin or cetyl alcohol. Sweetening agents and ?avor
`ing agents may be added to provide a palatable oral
`preparation. These compositions may be prepared by
`the addition of an antioxidant such as ascorbic acid.
`Dispersible powders and granules are suitable for the
`preparation of an aqueous suspension. They provide the
`active ingredient in admixture with a dispersing or wet
`
`45
`
`60
`
`65
`
`NOVARTIS EXHIBIT 2015
`Par v Novartis, IPR 2016-00084
`Page 10 of 27
`
`

`
`20
`
`5,143,918
`19
`ting agent, a suspending agent and one or more preser
`vatives. Suitable dispersing or wetting agents and sus
`pending agents are exempli?ed by those already men
`tioned above. Additional excipients, for example, those
`sweetening, ?avoring and coloring agents described
`above may also be present.
`The pharmaceutical compositions of the invention
`may also be in the form of oil-in-water emulsions. The
`oily phase may be a vegetable oil such as olive oil or
`arachis oils, or a mineral oil such as liquid paraffin or a
`mixture thereof. Suitable emulsifying agents may be (1)
`naturally, occurring gums such as gum acacia and gum
`tragacanth, (2) naturally-occurring phosphatides such
`as soy bean and lecithin, (3) esters or partial esters de
`rived from fatty acids and hexitol anhydrides, for exam
`ple, sorbitan monooleate, (4) condensation products of
`said partial esters with ethylene .oxide, for example,
`polyoxyethylene sorbitan monooleate. The emulsions
`may also contain sweetening and ?avoring agents.
`Syrups and elixirs may be formulated with sweeten
`ing agents, for example, glycerol, propylene glycol,
`sorbitol or sucrose. Such formulations may also contain
`a demulcent, a preservative and ?avoring and coloring
`agents.
`The pharmaceutical compositions may be in the form
`of a sterile injectable aqueous or oleagenous suspension.
`This suspension may be formulated according to known
`methods using those suitable dispersing or wetting
`agents and suspending agents which have been men
`tioned above. The sterile injectable preparation may
`30
`also be a sterile injectable solution or suspension in a
`non-toxic parenterally-acceptable diluent or solvent, for
`example, as a solution in 1,3-butane diol. Among the
`acceptable vehicles and solvents that may be employed
`are water,‘Ringer’s solution and isotonic sodium chlo
`ride solution. In addition, sterile, ?xed oils are conven
`tionally employed as a solvent or suspending medium.
`For this purpose any bland ?xed oil may be employed
`includin