United States Patent [19J
`Klein et al.
`
`[54] 9-DEOXOTAXANE COMPOUNDS
`[75]
`
`Inventors: Larry L. Klein, Lake Forest; Clinton
`M. Yeung, Skokie; Leping Li,
`Gurnee, all of Ill.
`
`[73] Assignee: Abbott Laboratories, Abbott Park,
`Ill.
`[21] Appl. No.: 208,509
`
`[22] Filed:
`
`Mar. 9, 1994
`
`Related U.S. Application Data
`[63] Continuation-in-part of Ser. No. 46,678, Apr. 14, 1993,
`Pat. No. 5,352,806, which is a continuation-in-part of
`Ser. No. 914,720, Jul. 16, 1992, abandoned, which is a
`continuation-in-part of Ser. No. 870,509, Apr. 17, 1992,
`abandoned.
`Int. CI.6 ............................................ C07D 305/14
`[51]
`[52] U.S. Cl. ..................................... 549/510; 514/449
`[58] Field of Search ......................... 549/510; 514/449
`References Cited
`[56]
`U.S. PATENT DOCUMENTS
`4,876,399 10/1989 Holton et al. ....................... 549/510
`
`I lllll llllllll Ill lllll lllll lllll lllll lllll 111111111111111111111111111111111
`US005440056A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,440,056
`Aug. 8, 1995
`
`Assistant Examiner-John Peabody
`Attorney, Agent, or Firm-Andreas M. Danckers
`ABSTRACT
`[57]
`Compounds having the formula
`
`(!)
`
`wherein -ORI comprises alkanoyl or the C-13 side(cid:173)
`chain of taxol; R2, R3, and R6 can be oxygenated or
`hydrogen in various combinations; and R4 and R5 are
`acyl groups,
`as well as a process for the preparation thereof, pharma(cid:173)
`ceutical compositions containing the above compounds,
`and a method for their use in inhibiting tumor growth.
`
`Primary Examiner-Johann Richter
`
`10 Claims, No Drawings
`
`Actavis - IPR2017-01100, Ex. 1007, p. 1 of 12
`
`

`

`1
`
`5,440,056
`
`9-DEOXOTAXANE COMPOUNDS
`
`This application is a continuation-in-part of U.S. pa(cid:173)
`tent application Ser. No. 08/046,678, filed Apr. 14, 1993
`now U.S. Pat. No. 5,352,806, which is a continuation-in(cid:173)
`part of U.S. patent application Ser. No. 07/914,720,
`filed Jul. 16, 1992 and now abandoned, which is a con(cid:173)
`tinuation-in-part of U.S. patent application Ser. No.
`07/870,509, filed Apr. 17, 1992 and now abandoned.
`
`2
`7-Deoxybaccatin or 7-deoxytaxol derivatives have been
`described in the international (PCT) application publi(cid:173)
`cation No. WO 93/02064, published Feb. 4, 1993 and J.
`Org. Chem. 58:3798-3799 (1993). 10-Desacetoxytaxol
`5 derivatives have been described in the international
`(PCT) application publication No. WO 93/06093, pub(cid:173)
`lished Apr. 1, 1993; U.S. Pat. No. 5,248,796, published
`Sep. 28, 1993; European Patent Application EP 558959,
`published Sep. 8, 1993; J. Org. Chem. 58:2927-2928
`10 (1993); and Tetrahedron Lett. 34(31):4921-24 (1993).
`7, 10-Dideoxytaxol derivatives have been described in J.
`Org. Chem. 58:5028-5029 (1993) and Tetrahedron Lett.
`34(43):6845-6848 (1993).
`Certain patents and patent applications also purport
`to generically disclose 9-deoxotaxanes, namely, U.S.
`Pat. Nos. 4,876,399, 5,015,744 and 5,175,315 and inter(cid:173)
`(PCT) application publication No. WO
`national
`93/20036. While these disclosures refer generically to
`9-deoxo compounds, they contain no teaching as to
`how to prepare these compounds and contain no spe-
`cific examples, prophetic or actual, of 9-deoxo taxanes.
`Consequently, these disclosures provide no more than a
`motivation to attempt the preparation of such com(cid:173)
`pounds.
`In fact, the ability to synthesize 9-deoxygenated com(cid:173)
`pounds having potentially superior biological or phar(cid:173)
`macologic properties may offer significant advantages
`to the chemist and pharmacologist. It is therefore an
`object of the present invention to provide such com(cid:173)
`pounds and the means for their preparation.
`
`BACKGROUND OF THE INVENTION
`The present invention relates to plant-derived chemo(cid:173)
`therapeutic compounds. More particularly, the inven(cid:173)
`tion is directed to deoxygenated taxol compounds pre- 15
`pared from a natural product which is isolated from
`Taxus canadensis, as well as novel analogs of taxol pre(cid:173)
`pared therefrom.
`Taxol, a member of the taxane family of terpenes, is
`of interest as a chemotherapeutic agent against a broad 20
`range of cancers. Derived primarily from the Pacific
`yew Taxus brevifolia, taxol has been shown to be active
`against advanced breast and ovarian cancers in clinical
`trials, and has exhibited promising activity against a
`number of other tumor types in preliminary investiga- 25
`tions. A summary of the current state of taxol research,
`development and clinical testing may be found in Ro(cid:173)
`therberg, Curr. Opin. Invest. Drugs, 2(12): 1269-1277
`(1993); a review of synthetic efforts in the taxol field is
`provided by D.G.I. Kingston in Prag. Chem. Org. Nat. 30
`Prod., 61:1-206 (1993).
`Although taxol, which possesses the structural for(cid:173)
`mula
`
`SUMMARY OF THE INVENTION
`In one aspect of the present invention are disclosed
`35 9-deoxygenated taxane compounds having the follow(cid:173)
`ing structural formula (I):
`
`40
`
`R 10""
`
`(I)
`
`has shown considerable therapeutic potential, its scar- 45
`city in nature and the need for more potent cytostatic
`agents have led researchers to pursue alternative
`sources as well as analogs of the compound. Some ef(cid:173)
`forts have been made to produce taxol in tissue and cell
`culture. Total chemical synthesis of the compound and 50
`its related analogs has been attempted but has not yet
`been achieved. The chemical conversion of naturally
`occurring taxol precursors such as baccatin III and
`cephalomannine to taxol itself or its analogs has been
`reported; however, additional routes for the production 55
`of potentially active taxanes are still needed.
`One line of inquiry has focused on a more abundant
`taxane precuror,
`13-acetyl-9-dihydrobaccatin
`III,
`which can be obtained from the widely distributed Ca(cid:173)
`nadian yew Taxus canadensis as described in published 60
`international application No. PCT /US93/03532, pub(cid:173)
`lished on Oct. 28, 1993 as publication No. WO 93/21173
`and incorporated herein by reference. This 9-dihydro
`modication makes possible the preparation of a new
`series of taxol analogs.
`Modifications of the C-7 and C-10 positions of the
`baccatin moiety, including 7-deoxy, 10-desacetoxy and
`7, 10-dideoxytaxol derivatives, have also been described.
`
`as well as prodrugs thereof. It is expected that these
`compounds will be useful in connection with the treat(cid:173)
`ment, or in the preparation oftaxol derivatives for use in
`treatment, of cancers and leukemias.
`RI in formula (I) is alkanoyl or a radical of the for(cid:173)
`mula:
`
`.0
`
`II R7/'-1: Jl,
`Rs· y
`
`7'
`
`OR9
`
`in which R7 is hydrogen, alkyl, phenyl, substituted
`65 phenyl, alkoxy, substituted alkoxy, amino, substituted
`amino, phenoxy or substituted phenoxy; R 8 is hydrogen,
`alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, phenyl,
`substituted phenyl, a-naphthyl, or .8-naphthyl; and R9 is
`
`Actavis - IPR2017-01100, Ex. 1007, p. 2 of 12
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`

`

`5,440,056
`
`s
`
`7-thiocar- 20
`
`3
`hydrogen, alkanoyl, substituted alkanoyl or aminoal(cid:173)
`kanoyl.
`R2, R3 and R6 in formula (I) are independently hy(cid:173)
`droxyl, hydrogen, alkoxyl, alkanoyloxy or aminoalk(cid:173)
`anoyloxy.
`R 4 in formula (I) is alkyl, alkanoyl, aminoalkanoyl or
`aroyl.
`RS in formula (I) is alkyl, alkanoyl, aminoalkanoyl or
`aroyl.
`In a second aspect of the present invention are dis- 10
`closed synthetic processes for the preparation of the
`above compounds, as well as novel intermediates useful
`therein which have the formulae:
`Methyl 13-Acetyl-9-dihydrobaccatin III 9-0-xan(cid:173)
`thate;
`9-Deoxobaccatin III;
`13-{ (2R,3S)-N-Benzyloxycarbonyl-N,O-( l-methyle(cid:173)
`thylidene )-3-phenylisoserine}-9-deoxobaccatin III;
`7-0-T rieth ylsil yl-9-deoxobaccatin III;
`13-Acetyl-9-deoxobaccatin
`III
`bonylimidazolide;
`7-deoxy-9-deoxobaccatin III;
`l 3-{(2R,3S)-N-Benzyloxycarbonyl-N ,0-( 1-methyle-
`th y lidene )-3-phen ylisoserine }-7-deoxy-9-deoxobaccatin
`III;
`7-Deoxy-9-deoxobaccatin
`bony limidazolide;
`10-Desacetoxy-7-deoxy-9-deoxobaccatin III; and
`13-{(2 R,3S )-N-Benzyloxycarbonyl-N,0-(1-methyle(cid:173)
`thylidene )-3-phenylisoserine}-10-desacetoxy-7-deoxy-
`9-deoxobaccatin III.
`Such intermediates (compounds 2, 3, 4, 8, 9, 10,12, 13,
`14 and 16) are shown in Schemes I. II and III.
`
`4
`The term .. alkoxyalkyl" as used herein refers to 2.n
`alkoxy group, as previously defined, appended to the
`parent molecular moiety through an alkyl group, as
`previously defined.
`The term "aroyl" as used herein refers to a phenyl
`ring attached to the parent molecular moiety through a
`carbonyl (-C(O)-) or thiocarbonyl group (-C(S)-).
`The phenyl ring may be unsubstituted or substituted
`with one to five substituents independently selected
`from halo, haloalkyl, alkyl, amino, and alkoxy.
`The term "aminoalkanoyl" as used herein refers to an
`alkanoyl function as defined above substituted with
`between one and three amino groups including, but not
`limited to, 2-aminopropanoyl, 4-aminobutanoyl and
`IS 6-aminohexanoyl. Additionally, the amino groups op(cid:173)
`tionally may be substituted with peptidyl residues of the
`naturally occurring amino acids, as well as di- and tri(cid:173)
`peptide residues formed therefrom.
`The term "aminoalkyl" as used herein refers to an
`alkyl function as defined above substituted with amino
`or substituted amino, as defined below.
`The term "halogen" as used herein refers to a substit(cid:173)
`uent selected from bromo (Br), chloro (Cl), fluoro (F)
`and iodo (I).
`The term "haloalkyl" as used herein refers to an alkyl
`group as defined above substituted with between one
`and three halogen atoms including, but not limited to,
`fluoromethyl, trifluoromethyl and 2-fluoroethyl.
`The term "hydroxyalkyl" as used herein refers to 2.11
`alkyl group as defined above substituted with a hydrrn~y
`group.
`The terms "N-protected" and "N-protecting" as used
`herein refer to the use of a group intended to protect an
`amino function or the N-terminus of an amino acid or
`3S peptide against undesirable reactions during a synthetic
`procedure or to prevent the attack of exopeptidases on
`the compound or to increase the solubility of the com(cid:173)
`pound and include, but are not limited to, the use in the
`same of such groups as sulfonyl; acyl, such as acetyl,
`pivaloyl and benzoyl; alkoxycarbonyl, such as tert(cid:173)
`butyloxycarbonyl
`(BOC)
`and benzyloxycarbonyl
`(Cbz); and L- or D-aminoacyl residues, which may
`themselves be N-protected. Other examples may be
`found in The Peptides, E. Gross and J. Meienhofer, 'lo!.
`45 3, Academic Press (1981), incorporated herein by refer··
`ence.
`The term "prodrug" as used herein refers to com(cid:173)
`pounds that are rapidly transformed in vivo to yield the
`parent compounds of Formula (I)~ as for example by
`SO hydrolysis in blood. T. Higuchi and V. Stella provide a
`thorough discussion of the prodrug concept in "Pro··
`drugs as Novel Delivery Systems'', A.C.S. Symposium
`Series, Vol. 14, American Chemical Society (1975),
`incorporated herein by reference. Examples of esters
`SS useful as prodrugs for compounds containing carboxyl
`groups can be found on pages 14-21 of "Bioreversib!e
`Carriers in Drug Design: Theory and Application", ed.
`E. B. Roche, Pergamon Press (1987), incorporated
`herein by reference.
`The term "prodrug ester group" as used herein refers
`to any of several ester-forming groups that are hydro(cid:173)
`lyzed under physiological conditions. Examples of pro(cid:173)
`drug ester groups include phosphates, pivaloylo;;(cid:173)
`ymethyl, acetoxymethyl, phthalidyl, indanyl and me-
`65 thoxymethyl, as well as other such groups known in the
`art.
`The term "protecting group" as used herein is a term
`well-known in the art and refers to substituents on func-
`
`III
`
`10-thiocar-
`
`25
`
`30
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`The compounds of the present invention compose
`9-deoxotaxanes as well as derivatives thereof having the
`structural formula (I) wherein groups RI through R9 are
`as described above. Specifically included among the 40
`compounds of the invention are those wherein -RI is
`the C-13 side-chain of taxol or a radical having the
`formula
`
`Ph
`
`H
`\
`
`,.
`PhC(O(~ or
`
`HO
`
`0
`
`Ph
`
`,.
`H
`~ \
`O_JN~
`!
`~ .
`~
`OHO
`0
`
`The following definitions apply to these compounds
`and throughout the present disclosure:
`The term "alkyl" as used herein refers to a monova(cid:173)
`lent group derived by the removal of a single hydrogen
`atom from a straight- or branched-chain saturated hy(cid:173)
`drocarbon containing one to six carbon atoms includ(cid:173)
`ing, but not limited to, methyl, ethyl, n- and iso-propyl,
`n-, sec-, iso- and tert-butyl, pentyl and hexyl.
`The term "alkanoyl" as used herein refers to an alkyl 60
`function as defined above attached to the parent molec(cid:173)
`ular moiety via a carbonyl group including, but not
`limited to, acetyl, propionyl, butanoyl and isobutanoyl.
`The term "alkoxy" as used herein refers to an alkyl
`function as defined above attached to the parent molec(cid:173)
`ular moiety via an oxygen atom including, but not lim(cid:173)
`ited to, methoxy, ethoxy, iso-propoxy, butoxy and tert(cid:173)
`butoxy.
`
`Actavis - IPR2017-01100, Ex. 1007, p. 3 of 12
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`

`5,440,056
`
`45
`
`5
`tional groups of compounds undergoing chemical trans(cid:173)
`formation which prevent undesired reactions and deg(cid:173)
`radations during a synthesis; see, for example, T. H.
`Greene, "Protective Groups in Organic Synthesis,"
`John Wiley & Sons (1981), incorporated herein by ref- 5
`erence.
`The term "substituted alkanoyl" as used herein refers
`to an alkanoyl group as defined above substituted with
`between one and three groups such as hydroxyl, sulfhy(cid:173)
`dryl, alkoxyl, carboxyl and halogen.
`The term "substituted alkoxy" as used herein refers to
`an alkoxy group as defined above substituted with be(cid:173)
`tween one and three groups such as hydroxyl, sulfhy(cid:173)
`dryl, alkoxyl, thioalkoxyl, carboxyl, amino and halogen.
`The term "substituted amino" as used herein refers to 15
`an amino group substituted with one or two alkyl
`groups including, but not limited to, t-butylamino, ben(cid:173)
`zylamino, and N,N-dimethylamino.
`The term "substituted phenyl" as used herein refers
`to a phenyl group substituted with between one and 20
`three substituents independently selected from alkyl,
`halogen, haloalkyl, alkoxy, benzyloxy, thioalkoxy, hy(cid:173)
`droxy, alkanoyl, carboxy, amino, alkylamino, dialkyl(cid:173)
`amino, nitro and -OS03H.
`The term "substituted phenoxy" as used herein refers 25
`to a phenoxy group substituted with between one and
`three substituents independently selected from alkyl,
`halogen, haloalkyl, alkoxy, benzyloxy, thioalkoxy, hy(cid:173)
`droxy, alkanoyl, carboxy, amino, alkylamino, dialkyl(cid:173)
`amino, nitro and -OS03H.
`The term "thioalkoxy" as used herein refers to an
`alkoxy group as defined above wherein a sulfur atom is
`substituted for the oxygen atom.
`Representative examples of the compounds of the
`present invention include the following:
`13-Acetyl-9-deoxobaccatin III;
`9-Deoxotaxol;
`13-Acetyl-7-deoxy-9-deoxobaccatin III;
`7- Deoxy-9-deoxotaxol;
`13-Acetyl-10-desacetoxy-7-deoxy-9-deoxobaccatin
`III; and
`10-Desacetoxy-7-deoxy-9-deoxotaxol.
`Preferred among these compounds are 9-deoxotaxol,
`7-deoxy-9-deoxotaxol, and 10-desacetoxy-7-deoxy-9-
`deoxotaxol.
`Pharmaceutical compositions of the present invention
`comprise one or more of the above compounds in com(cid:173)
`bination with a pharmaceutically acceptable carrier. By
`"pharmaceutically acceptable" is meant within the
`scope of sound medical judgement, suitable for use in 50
`contact with the tissues of humans and lower animals
`without undue toxicity, irritation, allergic response and
`the like, and are commensurate with a reasonable bene(cid:173)
`fit/risk ratio. As used herein, the term "pharmaceuti(cid:173)
`cally acceptable carrier" means a non-toxic, inert solid, 55
`semi-solid or liquid filler, diluent, encapsulating mate(cid:173)
`rial or formulation auxially of any type. Some examples
`of materials which can serve as pharmaceutically ac(cid:173)
`ceptable carriers are sugars such as lactose, glucose and
`sucrose; starches such as com starch and potato starch; 60
`cellulose and its derivatives such as sodium carboxy(cid:173)
`methyl cellulose, ethyl cellulose and cellulose acetate;
`powdered tragacanth; malt; gelatin; talc; excipients
`such as cocoa butter and suppository waxes; oils such as
`peanut oil, cottonseed oil; safflower oil; sesame oil; olive 65
`oil; com oil and soybean oil; glycols; such a propylene
`glycol; esters such as ethyl oleate and ethyl laurate;
`agar; buffering agents such as magnesium hydroxide
`
`6
`and aluminun hydroxide; alginic acid; pyrogen-free
`water; isotonic saline; Ringer's solution; ethyl alcohol,
`and phosphate buffer solutions, as well as other non-
`toxic compatible lubricants such as sodium lauryl sul(cid:173)
`fate and magnesium stearate, as well as coloring agents,
`releasing agents, coating agents, sweetening, flavoring
`and perfuming agents, preservatves and antioxidants
`can also be present in the composition, according to the
`judgement of the formulator. The pharmaceutical com-
`10 positions of this invention can be administered to hu(cid:173)
`mans and other animals orally, rectally, parenterally,
`intracistemally, intravaginally, intraperitoneally, topi(cid:173)
`cally (as by powders, ointments, or drops), bucally, or
`as an oral or nasal spray.
`Liquid dosage forms for oral administration include
`pharmaceutically acceptable emulsions, microemul(cid:173)
`sions, solutions, suspensions, syrups and elixirs. In addi(cid:173)
`tion to the active compounds, the liquid dosage forms
`may contain inert diluents commonly used in the art
`such as, for example, water or other solvents, solubiliz(cid:173)
`ing agents and emulsifiers such as ethyl alcohol, isopro-
`pyl alcohol, ethyl carbonate, ethyl acetate, benzyl alco(cid:173)
`hol, benzyl benzoate, propylene glycol, 1,3-butylene
`glycol, dimethylformamide, oils (in particular, cotton(cid:173)
`seed, groundnut, corn, germ, olive, castor, and sesame
`oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
`glycols and fatty acid esters of sorbitan, and mixtures
`thereof. Besides inert diluents, the oral compositions
`can also include adjuvants such as wetting agents, emul-
`30 sifying and suspending agents, sweetening, flavoring,
`and perfuming agents.
`Injectable preparations, for example, sterile injectable
`aqueous or oleaginous suspensions may be formulated
`according to the known art using suitable dispersing or
`35 wetting agents and suspending agents. The sterile injec(cid:173)
`table preparation may also be a sterile injectable solu(cid:173)
`tion, suspension or emulsion in a nontoxic parenterally
`acceptable diluent or solvent, for example, as a solution
`in 1,3-butanediol. Among the acceptable vehicles and
`40 solvents that may be employed are water, Ringer's
`solution, U.S.P. and isotonic sodium chloride solution.
`In addition, sterile, fixed oils are conventionally em(cid:173)
`ployed as a solvent or suspending medium. For this
`purpose any bland fixed oil can be employed including
`synthetic mono- or diglycerides. In addition, fatty acids
`such as oleic acid are used in the preparation of injecta-
`bles.
`The injectable formulations can be sterilized, for
`example, by filtration through a bacterial-retaining fil(cid:173)
`ter, or by incorporating sterilizing agents in the form of
`sterile solid compositions which can be dissolved or
`dispersed in sterile water or other sterile injectable me(cid:173)
`dium prior to use.
`In order to prolong the effect of a drug, it is often
`desirable to slow the absorption of the drug from subcu(cid:173)
`taneous or intramuscular injection. This may be accom(cid:173)
`plished by the use of a liquid suspension of crystalline or
`amorphous material with poor water solubility. The
`rate of absorption of the drug then depends upon its rate
`of dissolution which, in turn, may depend upon crystal
`size and crystalline form. Alternatively, delayed absorp-
`tion of a parenterally administered drug form is accom(cid:173)
`plished by dissolving or suspending the drug in an oil
`vehicle. Injectable depot forms are made by forming
`microencapsule matrices of the drug in biodegradable
`polymers such as polylactide-polyglycolide. Depending
`upon the ratio of drug to polymer and the nature of the
`particular polymer employed, the rate of drug release
`
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`

`5,440,056
`
`7
`can be controlled. Examples of other biodegradable
`polymers include poly(orthoesters) and poly(anhy(cid:173)
`drides) Depot injectable formulations are also prepared
`by entrapping the drug in liposomes or microemulsions
`which are compatible with body tissues.
`Compositions for rectal or vaginal administration are
`preferably suppositories which can be prepared by mix(cid:173)
`ing the compounds of this invention with suitable non(cid:173)
`irritating excipients or carriers such as cocoa butter,
`polyethylene glycol or a suppository wax which are IO
`solid at ambient temperature but liquid at body tempera(cid:173)
`ture and therefore melt in the rectum or vaginal cavity
`and release the active compound.
`Solid compositions of a similar type may also be em(cid:173)
`ployed as fillers in soft and hard-filled gelatin capsules 15
`using such excipients as lactose or milk sugar as well as
`high molecular weight polethylene glycols and the like.
`The active compounds can also be in micro-encap(cid:173)
`sulated form with one or more excipients as noted
`above. The solid dosage forms of tablets, dragees, cap- 20
`sules, pills, and granules can be prepared with coatings
`and shells such as enteric coatings, release controlling
`coatings and other coatings well known in the pharma(cid:173)
`ceutical formulating art. In such solid dosage forms the
`active compound may be admixed with at least one inert 25
`diluent such as sucrose, lactose or starch. Such dosage
`forms may also comprise, as is normal practice, addi(cid:173)
`tional substances other than inert diluents, e.g., tableting
`lubricants and other tableting aids such a magnesium
`stearate and microcrystalline cellulose. In the case of 30
`capsules, tablets and pills, the dosage forms may also
`comprise buffering agents. They may optionally contain
`opacifying agents and can also be of a composition that
`they release the active ingredient(s) only, or preferen(cid:173)
`tially, in a certain part of the intestinal tract, optionally, 35
`in a delayed manner. Examples of embedding composi(cid:173)
`tions which can be used include polymeric substances
`and waxes.
`Dosage forms for topical or transdermal administra(cid:173)
`tion of a compound of this invention include ointments, 40
`pastes, creams, lotions, gels, powders, solutions, sprays,
`inhalants or patches. The active component is admixed
`under sterile conditions with a pharmaceutically ac(cid:173)
`ceptable carrier and any needed preservatives or buffers
`as may be required. Ophthalmic formulation, ear drops, 45
`eye ointments, powders and solutions are also contem(cid:173)
`plated as being within the scope of this invention.
`The ointments, pastes, creams and gels may contain,
`in addition to an active compound of this invention,
`excipients such as animal and vegetable fats, oils, waxes, 50
`paraffins, starch, tragacanth, cellulose derivatives, poly(cid:173)
`ethylene glycols, silicones, bentonites, silicic acid, talc
`and zinc oxide, or mixtures thereof.
`Powders and sprays can contain, in addition to the
`compounds of this invention, excipients such as lactose, 55
`talc, silicic acid, aluminum hydroxide, calcium silicates
`and polyamide powder, or mixtures of these substances.
`Sprays can additionally contain customary propellants
`such as chlorofluorohydrocarbons.
`Transdermal patches have the added advantage of 60
`providing controlled delivery of a compound to the
`body. Such dosage forms can be made by dissolving or
`dispensing the compound in the proper medium. Ab(cid:173)
`sorption enhancers can also be used to increase the flux
`of the compound across the skin. The rate can be con- 65
`trolled by either providing a rate controlling membrane
`or by dispersing the compound in a polymer matrix or
`gel.
`
`8
`The methods of the present invention include a
`method for treating tumors in a human or lower mam(cid:173)
`mal, comprising administering to a patient in need oi
`such treatment a therapeutically effective amount o[ a
`5 compound of the invention, in such amounts and for
`such time as is necessary to achieve a therapeutic effect.
`By a "therapeutically effective amount" of the com(cid:173)
`pound of the invention is meant a sufficient amount of
`the compound to treat a tumor, at a reasonable benefit/··
`risk ratio applicable to any medical treatment. It will be
`understood, however, that the total daily usage of the
`compounds and compositions of the present invention
`will be decided by the attending physician within the
`scope of sound medical judgement. The specific thera(cid:173)
`peutically effective dose level for any particular patient
`will depend upon a variety of factors including the
`disorder being treated and the severity of the disorder;
`the activity of the specific compound employed; the
`specific composition employed; the age, body weight,
`general health, sex and diet of the patient; the time of
`administration, route of administration, and rate of ex-
`cretion of the specific compound employed; the dura(cid:173)
`tion of the treatment; drugs used in combination or
`coincidental with the specific compound employed; and
`like factors well known in the medical arts.
`The total daily dose of the compounds of this inven(cid:173)
`tion administered to a human or other mammal in single
`or in divided doses can be in amounts, as for example
`from 0.001 to 50 mg/kg body weight or more usually
`from 0.01 to 25 mg/kg body weight. Single dose com(cid:173)
`positions may contain such amounts or submultiples
`thereof to make up the daily dose. In general, treatment
`regimens according to the present invention compose
`administration to a human patient in need of such treat(cid:173)
`ment from about 10 mg to about 1000 mg of the com(cid:173)
`pound(s) of this invention per day in single or multiple
`doses.
`More generally, the methods of the present invention
`include the inhibition of growth of a mammalian tumor
`by exposing the tumor to a compound of the invention,
`in such concentration and for such time as is necessary
`to obtain the desired inhibition.
`The processes of the present invention, in which the
`above compounds of formula (I) are prepared from
`9-dihydro-13-acetylbaccatin III (compound 1), com(cid:173)
`prise the steps of:
`(a) thioacylating 9-dihydro-13-acetylbaccatin IE to
`give a 9-thioacyl compound;
`(b) deoxygenating the product of step (a);
`(c) deacetylating in the 13-position;
`(d) adding a suitable side-chain to the C-13 position of
`the product of step (c); and
`(e) selectively deprotecting of the product of step (d).
`A process for preparing a 7-deoxy--9-deoxota;;ane
`compound comprises the steps of:
`(a) thioacylating 9-dihydro-13-acetylbaccatin III to
`give a 9-thioacyl compound;
`(b) deoxygenating the product of step (a);
`(c) repeating steps (a) and (b) in the 7-position;
`(d) deacetylating in the 13-position;
`(e) adding a suitable side-chain to the C-13 position of
`the product of step (d); and
`(f) selectively deprotecting of the product of step (e).
`for preparing a 7-dexoy9-deo;;o-10-
`A process
`desacetoxytaxane compound comprises the steps of:
`(a) thioacylating 9-dihydro-13-acetylbaccatin EI to
`give a 9-thioacyl compound;
`(b) deoxygenating the product of step (a);
`
`Actavis - IPR2017-01100, Ex. 1007, p. 5 of 12
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`25
`
`9
`(c) repeating steps (a) and (b) in the 7-position;
`(d) deacetylating in the IO-position;
`(e) repeating steps (a) and (b) in the IO-position;
`(f) deacetylating in the 13-position;
`(g) adding a suitable side-chain to the C-13 position of 5
`the product of step (f); and
`(h) selectively deprotecting of the product of step (g).
`More specifically, it has been found that compound 1
`of the present invention may be obtained by alcoholic
`extraction from crushed needles and twigs of Taxus IO
`canadensis. This extract is then purified using customary
`separatory techniques, beginning with partitioning be(cid:173)
`tween solvent systems consisting of acetone, methanol,
`hexane, heptane and water to remove fats and lipids.
`The defatted crude extract is further partitioned, in !5
`several stages, between solvent systems consisting of
`methanol, methylene chloride, chloroform, ethyl ace(cid:173)
`tate and water. Those fractions of the extract which are
`soluble in a solvent system consisting either of methy(cid:173)
`lene chloride or of chloroform and ethyl acetate contain 20
`compound 1.
`The above fractions may be further purified by planet
`coil countercurrent chromatography (PCCC), using
`solvent systems consisting of hexane, methanol, methy-
`lene chloride, chloroform, toluene, and water or suit(cid:173)
`able aqueous buffers. The various fractions contain
`several taxane derivatives, including taxol, cephaloman(cid:173)
`nine and baccatin III. The solvent is removed from the
`fraction containing compound 1, which is recrystallized 30
`from methanol or ethanol and water to afford the pure
`compound as white crystals. If desired, taxol, baccatin,
`and other related compounds may also be isolated from
`the various chromatographic fractions.
`Asymmetric centers may exist in the compounds of 35
`the present invention. The present invention contem(cid:173)
`plates the various stereoisomers and mixtures thereof.
`Starting compounds of particular stereochemistry are
`either commercially available or are made by the meth(cid:173)
`ods detailed below and resolved by techniques well 40
`known in the organic chemical arts.
`In general, the compounds of formula (I) may then be
`synthesized from compound 1 by treatment with a thi(cid:173)
`oacylating agent at C-9, followed by tin hydride reduc(cid:173)
`tion to give compounds shown in Scheme I. Further 45
`thioacyl/reduction steps can be carried out on 3 for the
`other hydroxyls at C-7, C-10 and C-1, as for 9, 14, etc.
`These deoxy compounds can also be deacetylated at
`C-13 as for IO and 12; the C-13 hydroxyl treated as
`above with lactams or acetonide forms of the appropri- 50
`ate side chain; the side chain protecting groups re(cid:173)
`moved; and the side chain nitrogen acylated to afford
`the final 9-deoxo analogs.
`As a particular example of the process illustrated
`below in Scheme I, 13-acetyl-9-dihydrobaccatin III (1) 55
`is treated with lithium hexamethyldisilazide, carbon
`disulfide, and methyl iodide to give the C-9 methyl
`xanthate 2. Compound 2 is treated with tributyltin or
`tris(trimethylsilyl)silane or other
`trisubstituted
`tin
`agents to effect a deoxygenation giving compound 3, 60
`followed by methyllithium to remove the acetyl group
`in the 13-position giving compound 4, which is shown
`with a hydroxy-protecting group in the 7-position.
`Compound 4 is then reacted with an appropriate pro(cid:173)
`tected side-chain derivative (as for example (3R,4S)-N- 65
`acyl-3-0-(1-ethoxyethyl)-4-phenyl-2-azetidinone (5) or
`(2R,3S)-N-protected-N,O-(l-methylethylidene)-3-
`phenylisoserine (6)). The protecting groups may then be
`
`5,440,056
`
`10
`removed with a mild acid when intermediate 5 is used,
`as for example 1 % HCl in ethanol or methanol, or cata(cid:173)
`lytically hydrogenated when intermediate 6 is used.
`When intermediate 6 is used, deprotection is followed
`3'-aminoacylation (as for example treatment with ben(cid:173)
`zoic anhydride) to produce the desired 9-deoxotaxanes
`of formula (I), in this case, 9-deoxotaxol (7). (When
`intermediate 5 is used, R is the desired acyl group, i.e.
`benzoyl in the case of the taxol analogs.) Alternatively,
`the deoxygenation steps can be repeated on compound
`3 to give the 9-deoxo-7-deoxy compound 9.
`The further elaboration of compound 9 is shown in
`Scheme II. Treatment of compound 9 with methylli(cid:173)
`thium to remove the 13-acetyl protecting group gives
`compound IO. Compound IO may then be reacted with
`an appropriate protected side-chain derivative (as for
`example (3R,4S)-N-acyl-3-0-(1-ethoxyethyl)-4-phenyl-
`(2R,3S)-N-protected-N,O-(l(cid:173)
`(5), or
`2-azetidinone
`methylethylidene)-3-phenylisoserine (6)). The protect(cid:173)
`ing groups are then removed with a mild acid (as for
`example 1 % HCl in ethanol or methano