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`Micro Labs v. Santen Pharm. and Asahi Glass
`IPR2017-01434
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`

`

`5,977,173
`
`2
`naturally occurring prostaglandin are characterized by their
`activity against a particular prostaglandin receptor,
`they
`generally are not specific tor any one prostaglandin receptor.
`Therefore, naturally-occurring prostaglandin are known to
`cause side effects such as inflammation, as well as surface
`irritation when administered systemically. It is generally
`believed that the rapid metabolism of the naturally occurring
`prostaglandin following their release in ihe body limits some
`of the effects of the prostaglandin to a local area. This
`effectively prevents the prostaglandin from stimulating pros-
`taglandin receptors throughout the body and causing the
`effects seen with the systemic administration of naturally
`occurring prostaglandin.
`Prostaglandin, especially prostaglandin of the E series
`(PGE), are known to be potent stimulators of bone resorp-
`tion. PGF,,, has also been shown to be a stimulator of bone
`resorption but not as potent as PGE,. Also,
`it has been
`demonsirated the PGF,,, haslittle effect on bone formation.
`Tt has heen suggested that someofthe effects of PGF,,, on
`bone resorption, formation and cell replication may be
`mediated by an increase in endogenous PGE, production.
`In view of both the wide range of pharmacological
`properties of naturally occurring prostaglandin and of the
`side effects scen with the systemic administration of these
`naturally occurring prostaglandin, attempts have been made
`to prepare analogs to the naturally occurring prostaglandin
`thal are selective for a specific receptor or receptors. A
`number of such analogs have been disclosed in the art.
`Though a variety of prostaglandin analogs have been
`disclosed, there is a continuing need for potent, selective
`prostaglandin analogs for the treatment of a variety diseases
`and conditions.
`
`SUMMARY OF THE INVENTION
`
`The invention provides novel PGF analogs.In particular,
`the present invention relates to compounds having a struc-
`ture according to the following formula:
`HQ4
`
`%
`
`wherein R,, R5, R;, Ry, X, Y, and Z are defined below.
`This invention also includes optical isomers, diastere-
`omers and enantiomers of the formula above, and
`pharmaceutically-acceptable salts, bichydrolyzable amides,
`esters, and imides thereof.
`The compounds ofthe present invention are useful for the
`treatment of a variety of diseases and conditions, such as
`bone disorders and glaucoma. Accordingly,
`the invention
`further provides pharmaceutical compositions comprising
`these compounds. The invention still further provides meth-
`ods of treatment for bone disorders and glaucoma using
`theses compounds or the compositions containing them.
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Terms and Definitions
`“Acyl”is a group suitable for acylating a nitrogen atom to
`form an amide or carbamate or an oxygen atom to form an
`ester group. Preferred acyl groups include benzoyl, acetyl,
`
`a
`
`10
`
`35
`
`40
`
`pea
`
`60
`
`1
`AROMATICC,¢-C29-SUBSTITUTED
`TETRAHYDRO PROSTAGLANDINS USEFUL
`AS FP AGONISTS
`
`CROSS REFERENCE
`
`This application claims priority under Title 35, United
`States Code 119(¢) from Provisional Application Ser. No.
`60/058,217, filed Sep. 9, 1997.
`TECHNICAL FIELD
`
`The subject invention relates to certain novel analogs of
`the naturally occurring prostaglandin. Specifically, the sub-
`ject invention relates to novel Prostaglandin F analogs. The
`subject invention further relates to methods of using said
`novel Prostaglandin F analogs. Preferred uses include meth-
`ods of treating bone disorders and glaucoma.
`BACKGROUND OF THE INVENTION
`
`Naturally occurring prostaglandin (PGA, PGB, PGE,
`PGF, and PGI) are C-20 unsaturated fatty acids. PGF.,,, the
`naturally occurring Prostaglandin F in humans, is charac-
`terized by hydroxyl groupsat the C, and C,, positions on the
`alicyclic ring, a cis-double bond between C, and Cy, and a
`trans-double bond between C,, and C,,. Thus PGF,,, has the
`following formula:
`
`PGPoy
`
`
`
`Analogsof naturally occurring Prostaglandin F have been
`disclosed in the art. For example, see U.S. Pat. No. 4,024,
`179 issued to Bindra and Johnson on May 17, 1977; German
`Patent No. DT-002,460,990 issued to Beck, Lerch, Seeger,
`and Teufel published on Jul. 1, 1976; U.S. Pat. No. 4,128,
`720 issued to Hayashi, Kori, and Miyake on Dec. 5, 1978;
`US. Pat. No. 4,011,262 issued to Hess, Johnson, Bindra, and
`Schaaf on Mar. 8, 1977; U.S. Pat. No. 3,776,938 issued to
`Bergstrom and Sjovall on Dec. 4, 1973; P. W. Collins and S.
`W.Djuric, “Synthesis of Therapeutically Useful Prostaglan-
`din and Prostacyclin Analogs”, Chem. Rev. Vol. 93 (1993),
`pp. 1533-1564; G. L. Bundy and F. 1. Lincoln, “Synthesis
`of 17-Phenyl-18,19,20-Trinorprostaglandins:
`I. The PG,
`Series”, Prostaglandin, Vol. 9 No. 1 (1975), pp. 1-4; W.
`Bartman, G. Beck, U. Lerch, H. Teufel, and B. Scholkens,
`“Luteolytic Prostaglandin: Synthesis and Biological
`Activity”, Prostaglandin, Vol. 17 No. 2 (1979), pp. 301-311;
`C.
`liljebris, G. Selen, B. Resul, J. Sternschantz, and U.
`Hacksell, “Derivatives of 17-Phenyl-18, 19,20-
`trinorprostaglandin Fc Isopropyl Ester: Potential Antiglau-
`coma Agents”, Journal ofMedicinal Chemistry, Vol. 38 No.
`2 (1995), pp. 289-304.
`Naturally occurring prostaglandin are known to possess a
`wide range of pharmacological properties. For cxample,
`prostaglandin have been shown to: relax smooth muscle,
`which results in vasodilatation and bronchodilatation,
`to
`inhibit gastric acid secretion, to inhibit platelet aggregation,
`to reduce intraocular pressure, and to induce labor. Although
`
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`5,977,173
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`10
`
`20
`
`30
`
`40
`
`3
`tert-butyl acetyl, para-phenyl benzoyl, and trifluoroacetyl.
`More preferred acyl groups include accty] and benzoyl. The
`most preferred acyl group is acetyl.
`“Alkyl”is a saturated or unsaturated hydrocarbon chain
`having 1 to 18 carbon atoms, preferably 1 to 12, more
`preferably 1 to 6, more preferablystill 1 to 4 carbon atoms.
`Alkyl chains may be straight or branched. Preferred
`branched alkyl have one or two branches, preferably one
`branch.Preferred alkyl are saturated. Unsaturated alkyl have
`one or more double bonds and/or one or moretriple bonds.
`Preferred unsaturated alkyl have one or two double bonds or
`one triple bond, more preferably one double bond. Alkyl
`chains may be unsubstituted or substituted with from 1 to
`about4 substituents. Preferred alkyl are unsubstituted. Pre-
`ferred substituted alkyl are mono-, di-, or trisubstituted.
`Preferred alkyl substituents include halo, hydroxy,aryl (e.g.,
`phenyl,
`tolyl, alkyloxphenyl, alkyloxycarbonylphenyl,
`halophenyl), heterocyclyl, and heteroaryl.
`“Aromatic ring” is an aromatic hydrocarbon ring system.
`Aromatic rings are monocyclic or fused bicyclic ring sys-
`tems. Monocyclic aromatic rings contain from about 5 to
`about 10 carbon atoms, preferably from 5 to 7 carbon atoms,
`and most preferably from S to 6 carbon atomsin the ring.
`Bicyclic aromatic rings contain from 8 to 12 carbon atoms,
`preferably 9 or 10 carbon atomsin the ring. Aromatic rings
`may be unsubstituted or substituted with from 1 to about 4
`substituents on the ring. Preferred aromatic ring substituents
`include: halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl,
`phenoxy or any combination thereof. More preferred sub-
`stituents include halo and haloalkyl. Preferred aromatic
`rings include naphthyl and phenyl. The most preferred
`aromatic ring is phenyl.
`“Bone disorder” means the necd for bone repair or
`replacement. Conditions in whichthe need for bone repair or
`replacement mayarise include: osteoporosis (including post
`menopausal osteoporosis, male and female senile ostcoporo-
`sis and corticosteroid induced osteoporosis}, osteoarthritis,
`Paget’s disease, osteomalacia, multiple myeloma and other
`forms of cancer, prolonged bed rest, chronic disuse of a
`limb, anorexia, microgravity, exogenous and endogenous
`gonadal
`insufficiency, bone fracture, non-union, defect,
`prosthesis implantation and the like.
`“Carbocyclic aliphatic ring” is a saturated or unsaturated
`hydrocarbon ring. Carbocyclic aliphatic rings are not aro-
`matic, Carbocyclic aliphatic rings are monocyclic, or are
`fused, spiro, or bridged bicyclic ring systems. Monocyclic
`carbocyclic aliphatic rings contain from about 4 to about 10
`carbon atoms, preferably from 4 to 7 carbon atoms, and most
`preferably from 5 to 6 carbon atoms in the ring. Bicyclic
`carbocyclic aliphatic rings contain from 8 to 12 carbon ;
`atoms, preferably from 9 to 10 carbon atomsin the ring.
`Carbocyclic aliphatic rings may be unsubstituted or substi-
`tuted with from 1
`to about 4 substituents on the ring.
`Preferred carbocyclic aliphatic ring substituents include:
`halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy
`or any combmation thereof. More preferred substituents
`include halo and haloalkyl. Preferred carbocyclic aliphatic
`rings include cyclopentyl, cyclohexyl, cyclohexenyl,
`cycloheptyl, and cyclooctyl. More preferred carbocyclic
`aliphatic rings include cyclohexyl, cyclohepiyl, and
`cyclooctyl. The most preferred carbocyclic aliphatic ring is
`cycloheptyl.
`,
`“Halo”is fluoro, chloro, bromooriodo. Preferred halo are
`fluoro, chloro and bromo; more preferred are chloro and
`fluoro, especially fluoro.
`“Haloalkyl”is a straight, branched, or cyclic hydrocarbon
`substituted with one or more halo substituents. Preferred
`
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`4
`haloalkyl are C,-C,,; more preferred are C,-C,; more
`preferred still are C,-C,. Preferred halo substituents are
`fluoro and chloro. ‘The most preferred haloalkyl is trifluo-
`romethyl.
`“Heteroalkyl”is a saturated or unsaturated chain contain-
`ing carbon and at least one heteroatom, wherein no two
`heteroatomsare adjacent. Heteroalkyl chains contain from J
`to 18 member atoms (carbon and hetcroatoms) in the chain,
`preferably 1 to 12, more preferably 1 to 6, more preferably
`still 1 to 4. Heteroalkyl chains may bestraight or branched.
`Preferred branched heteroalkyl have one or two branches,
`preferably one branch. Preferred heteroalkyl are saturated.
`Unsaturated heteroalkyl have one or more double bonds
`and/or one or more triple bonds. Preferred unsaturated
`heteroalkyl have one or two double bonds or onetriple bond,
`more preferably one double bond. Heteroalkyl chains may
`be unsubstituted or substituted with from 1
`to about 4
`substituents. Preferred heteroalkyl are unsubstituted. Pre-
`ferred hetcroalkyl substituents include halo, hydroxy, aryl
`(c.g., phenyl, tolyl, alkyloxphenyl, alkyloxycarbonylphenyl,
`halophenyl), heterocyclyl, heteroaryl. For example, alkyl
`substituted with the following substituents are heteroalkyl:
`alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy),
`aryloxy (e.g., phenoxy, chlorophenoxy,
`tolyloxy,
`methoxyphenoxy, benzyloxy, alkyloxycarbonylphenoxy,
`acyloxyphenoxy), acyloxy (e.g., propionyloxy, benzoyloxy,
`acetoxy), carbamoyloxy, carboxy, mercapto, alkylthio,
`acylthio, arylthio (e.g., phenylthio, chlorophenylthio,
`alkylphenylthio, alkoxyphenylthio, benzylthio,
`alkyloxycarbonylphenylthio), amino (¢.g., amino, mono-
`and di- C,-C,; alkanylamino, methylphenylamino,
`methylbenzylamino, C,-C, alkanylamido, carbamamido,
`ureido, guanidino).
`“Heteroalom” is a nitrogen, sulfur, or oxygen atom.
`Groups containing more than one heteroatom may contain
`different heteroatoms.
`“Heterocyclic aliphatic ring”is a saturated or unsaturated
`ring containing carbon and from 1 to about 4 heteroatomsin
`the ring, wherein no two heteroatoms are adjacentin the ring
`and no carbonin the ring that has a heteroatom attached to
`it also has a hydroxyl, amino, orthiol group attachedto it.
`Heterocyclic aliphatic rings are not aromatic. Heterocyclic
`aliphatic rings are monocyclic, or are fused or bridged
`bicyclic ring systems. Monocyclic heterocyclic aliphatic
`rings contain from about 4 to about 10 member atoms
`(carbon and heteroatoms), preferably from 4 to 7, and most
`preferably from 5 to 6 member atomsin the ring. Bicyclic
`heterocyclic aliphatic rings contain from 8 to 12 member
`aloms, preferably 9 or 10 member atorns in the ring. Het-
`erocyclic aliphatic rings may be unsubstituted or substituted
`with from 1 to about 4 substituents on the ring. Preferred
`heterocyclic aliphatic ring substituents include: halo, cyano,
`alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any com-
`bination thereof. More preferred substituents include halo
`and haloalkyl. Preferred heterocyclic aliphatic rings include
`piperzyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl
`and piperdyl.
`“Heteroaromatic ring” is an aromatic ring system con-
`taining carbon and from 1 to about4 heteroatomsin thering.
`Heteroaromatic rings are monocyclic or fused bicyclic ring
`systems. Monocyclic heteroaromatic rings contain from
`about 5 to about 10 member atoms (carbon and
`heteroatoms), preferably from 5 to 7, and most preferably
`from 5 to 6 member atomsin the ring. Bicyclic heteroaro-
`matic rings contain from 8 to 12 memberatoms, preferably
`9 or 10 memberatomsin the ring. Heteroaromatic rings may
`be unsubstituted or substituted with from 1 to about 4
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`

`5,977,173
`
`5
`substituents on the ring. Preferred heteroaromatic ring sub-
`stituents include: halo, cyano, alkyl, heteroalkyl, haloalkyl,
`phenyl, phenoxy or any combination thereof. More preferred
`substituenis include halo, haloalkyl, and phenyl. Preferred
`heteroaromatic rings include thienyl,
`thiazolo, purinyl,
`pyrimidyl, pyridyl, and furanyl. More preferred heteroaro-
`malic rings include thienyl, furanyl, and pyridyl. The most
`preferred heteroaromatic ring is thienyl.
`“Loweralkyl”is an alkyl chain radical comprised of1 10
`6, preferably 1 to 4 carbon atoms.
`
`“Phenyl” is a six-membered monocyclic aromatic ring
`which may or may not be substituted with from about 1 to
`about 4 substituents. The substituents may be substituted at
`the ortho, meta or para position on the phenyl ring, or any
`combination thereof. Preferred phenyl substituents include:
`halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy
`or any combination thereof. More preferred substituents on
`the phenyl ring include halo and haloalkyl. The most pre-
`ferred substituent is halo. The preferred substitution pattern
`on the phenyl ring is ortho or meta. The most preferred
`substitution pattern on the phenyl ring is ortho.
`Compounds
`The subject invention involves compounds having the
`following structure:
`Ho%t
`%,
`
`
`
`In the above structure, R, is CO,H, C(O)NHOH, CO.R,,
`CH.OH, S(O),R;, C(O)NHR,, C(O)NHS(O).Rs, or tetra-
`zole; wherein R, is alkyl, hetcroalkyl, carbocyclic aliphatic
`ring, heterocyclic aliphatic ring, aromatic ring, or heteroaro-
`matic ring. Preferred R; is CH;, C,Hs, C,H,. Preferred R,
`is CO,H, C(O)NHOH, CO.CH,;, CO,C,H;, CO.CIL,
`CO.,C,He, CO,C3H;0., and C(O)NHS(O).R,. More pre-
`ferred R, is CO,H, C(O)NHOH, CO.CH3, and CO,C;Hs.
`Most preferred R, is CO,H and CO.CH,.
`In the above structure, R, is H or loweralkyl. Preferred
`R, is H and CH,. Most preferred R, is H.
`In the above structure, X is NRgR;, ORs, SRo, S(O)Ro, or
`S(O),R.; wherein R,,R,, and Rg are independently selected
`from the group consisting of H, acyl, alkyl, heteroalkyl,
`carbocyclic aliphatic ring, heterocyclic aliphatic ring, aro-
`matic ring, and heteroaromatic ring; and wherein R, is alkyl,
`heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic
`ring, aromaticring, or heteroaromatic ring. Preferred R, and
`R, are H, CH, and C,H,. Preferred R, is H, CH,, C,H, and
`C3H,. Preferred Rg is CH, and C,H. Preferred X is NRR,
`and OR,. Most preferred X is OH.
`In the above structure, R, and R, are independently
`selected from the group consisting of H, CH,, and C,H.
`Preferred R, and R, are H.
`
`In the above structure, Y is NR,8, S(O), or S(O),;
`wherein R,, is H, acyl, alkyl, hetcroalkyl, carbocyclic
`
`6
`aliphatic ring, heterocyclic aliphatic ring, aromatic ring, or
`heteroaromatic ring. Preferred R,) is H and CH. Preferred
`Y is NH and S.
`
`In the above structure, Z is carbocyclic aliphatic ring,
`heterocyclic aliphatic ring, aromatic ring, or heteroaromatic
`ring. Preferred Z is monocyclic carbocyclic aliphatic ring,
`monocyclic heterocyclic aliphatic ring, monocyclic aro-
`matic ring, and monocyclic heteroaromatic ring. More pre-
`ferred Z is monocyclic aromatic ring or monocyclic het-
`eroaromatic ring. The most preferred Z is thienyl or phenyl.
`
`isomers, diastere-
`The invention also includes optical
`omers and enantiomers of the above structure. Thus, at all
`stereocenters where stereochemistry is not defined (C,,, Cy.,
`C,,, and C,,), both epimers are envisioned. Preferred ste-
`reochemistry at all such stereocenters of the compounds of
`the invention mimic that of naturally occurring PGF,,.
`
`It has been discovered thal the novel PGF analogs of the
`subject
`invention are useful for treating bone disorders,
`especially those that require a significant increase in bone
`mass, bone volume, or bone strength. Surprisingly,
`the
`compounds of the subject invention have been found to
`provide the following advantages over known bone disorder
`therapies: (1) An increase trabecular number through for-
`mation of new trabeculae; (2) An increase in bone mass and
`bone volume while maintaining a more normal bone turn-
`over rate; and (3) An increase in bone formation at the
`endosteal surface without increasing cortical porosity.
`
`In order to determine and assess pharmacologicalactivity,
`testing of the subject compounds in animals is carried out
`using, various assays known to those skilled in the art. For
`example, the bone activity of the subject compoundscan be
`conveniently demonstrated using an assay designed to test
`the ability of the subject compounds to increase bone
`volume, mass, or density. An cxamplc of such assays is the
`ovariectomized rat assay.
`
`In the ovariectomized rat assay, six-month old rats are
`ovariectomized, aged 2 months, and then dosed once a day
`subcutaneously with a test compound. Upon completion of
`the study, bone mass and/or density can be measured by dual
`energy x-ray absorptometry (DXA) or peripheral quantita-
`tive computed tomography (pQCT), or micro computed
`tomography (mCT). Alternatively, static and dynamic his-
`tomorphometry can be used to measure the increase in bone
`volume or formation.
`
`Pharmacological activity for glaucoma can be demon-
`strated using assays designed to test the ability of the subject
`compounds to decrease intraocular pressure. Examples of
`such assays are described in the following reference, incor-
`porated herein: C.
`liijebris, G. Selen, B. Resul, J.
`Sternschantz, and U. Hacksell, “Derivatives of 17-Phenyl-
`18,19,20-trinorprostaglandin F,0 Isopropyl Ester: Potential
`Antiglaucoma Agents’, Journal of Medicinal ChemistrY,
`Vol. 38 No. 2 (1995), pp. 289-304.
`
`Compounds useful in the subject invention can be made
`using conventional organic syntheses. A particularly pre-
`ferred synthesis is the following general reaction scheme:
`
`15
`
`tea
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`45
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`whS
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`5,977,173
`
`Scheme 1
`
`NH,OH Formula H
`
`R;0H
`
`NH2S(O)2R5
`
`Ry = C(O)oRs
`C(O)NOOH
`C(O) NHS(O)}2Rs5
`C(CYNHRs
`
`NNN
`R3
`
`R2 X
`Formula I
`X=0OH8
`Ry = C(O)aRs
`
`NworTh,0
`
`PO
`
`X = OMs, OT
`
`
`Ry Y—7.
`C(O} Formula [V
` Formula V
`NNON Ry PO
`
`Ry
`
`HO
`
`1) protect
`2) conjugate additiion
`
`NUNN Ry
`
`
`
`PO
`
`1) reduce/protect
`2) epoxidation
`
`
`
`PSN Ri
`
`PO
`
`Sic
`
`1) oxidation
`2) HNR,Ry
`3) ROM,CeCiy
`
`
` Formula HL
`
`X=NReR7
`
`when X = SRg, Nero
`
`PO,
`
`X = ORg, SRo
`
`Formula VI
`X= S(O), n=12
`
`In Scheme 1, R,, R,, R,, R,, X, ¥, and Z are as defined
`above. The Methyl 7|3-(R)-hydroxy-5-oxo-1 -cyclopent-1-
`yl] heptanoate (Sla) depicted as starting material
`for
`Scheme 1 is commercially available (such as from Sumi-
`tomo Chemical or Cayman Chemical).
`In the above Scheme 1, Methyl 7-[3-(R)-hydroxy-5-oxo-
`1-cyclopent-1-yi] heptanoate (S1a) is reacted with a silylat-
`ing agent and basein a solventthatwill allow the silylation
`to proceed. Preferred silylating agents include tert-
`butyldimethylsilyl chloride and tert-butyldimethylsilyl trif-
`luoromethanesulphonate. The most preferred silylating
`agentis tert-butyidimethylsily1 trifluoromethanesulphonate.
`Preferred bases include triethylamine, trimethylamine, and
`2,6-lutidine. More preferred bases includetriethylamine and
`
`IPR Page 5/20
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`60
`
`ss 2,6-lutidine. The most preferred base is 2,6-lutidine. Pre-
`ferred solvents include halocarbon solvents with dichlo-
`romethane being the most preferred solvent. The reaction is
`allowed to proceed at a temperature preferably between
`-100° C. and 100° C., more preferably between —80° C. and
`80° C., and most preferably between -70° C. and 23° C.
`The resulting silylated compound is isolated by methods
`known to those of ordinary skill in the art. Such methods
`include, but are not
`limited to, extraction, solvent
`evaporation, distillation, and crystallization. Preferably, the
`silyl ether is purified after isolation by distillation under
`vacuum.
`
`65
`
`The silylated compound is then reacted with the cuprate
`generated via Grignard formation of the appropriate alkenyl
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`5,977,173
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`9
`bromide as disclosed, for example, in the following refer-
`ences: H. O. House et. al., “The Chemistry of Carbanions:
`A Convenient Precursor for the Generation of Lithium
`Organocuprates”, J. Org, Chem. Vol. 40 (1975) pp. 1460-69
`and P. Knochel ct. al., “Zinc and Copper Carbenoids as
`Efficient and Selective a'/d' Multicoupling Reagents”, J.
`Amer.Chem. Soc. Vol. 111 (1989) p. 6474-76. Preferred
`alkenyl bromides include 4-bromo-i-butene, 4-bromo-1-
`butyne, 4-bromo-2-methyl-1-butene, and 4-bromo-2-ethyl-
`1-butene. The most preferred alkenyl bromide is 4-bromo-
`1-butene. Preferred solvents include ethereal solvents, of
`which diethyl ether and tetrahydrofuran are preferred. The
`most preferred solvent is tetrahydrofuran. The Grignard
`reagent is allowed to form at a temperature between 100° C.
`and 23° C., more preferably between 85° C. and 30° C., and
`most preferably between 75° C. and 65° C. The reaction time
`is preferably between 1 hour and 6 hours, with a more
`preferred reaction time beimg between 2 hours and 5 hours,
`and the most preferred reaction time being between 3 hours
`and 4 hours.
`the cuprate is
`is formed,
`Once the Grignard reagent
`generated from the alkenyl magnesium species. The tem-
`perature range for cuprate formation is between -100° C.
`and 0° C. The preferred temperature range is between ~80°
`C. and -20° C. The more preferred temperature range is
`between -75° C. and -50° C. ‘The preferred reaction time is
`between 30 minutes and 6 hours. ‘The more preferred reac-
`tion time is between 45 minutes and 3 hours. The most
`preferred reaction lime is between 1 hours and 1.5 hours.
`The compound depicted as S1b is isolated by methods
`known to one of ordinary skill in the art. Such methods
`include, but are not
`limited to, extraction, solvent
`evaporation,distillation, and crystallization. Preferably, S1b
`is purified by flash chromatography onsilica gel (Merck,
`230-400 mesh) using 10% EtOAc/hexanesas the eluent.
`S1b is then reacted with a hydride reducing agent anda 3
`polar, protic solvent
`to give the Cg alcohol. Preferred
`reducing agents include lithium aluminumhydride, sodium
`borohydride, and [.-selectride. More preferred reducing
`agents include sodium borohydride, and L-selectride. The
`most preferred reducing agent is sodium borohydride. Pre-
`ferred solvents include methanol, ethanol, and butanol. The
`most preferred solvent is methanol. The reduction is carried
`out at a temperature between -100° C. and 23° C. The
`preferred temperature range is between -60° C. and 0° C.
`The most preferred temperature range is between —45° C.
`and -20° C.
`The resulting alcohol of S1b is isolated by methods
`known to one of ordinary skill in the art. Such methods
`include, but are not
`limited to, extraction, solvent
`evaporation, distillation, and crystallization. Preferably, the
`alcohol is purified by flash chromatography on silica gel
`(Merck, 230-400 mesh) using 20% EtOAc/hexanes as the
`eluent.
`The alcohol can be protected as described previously
`herein. The protected or unprotected alcohol is then treated
`with meta-chloroperbenzoic acid in a halocarbon solvent to
`provide the novel epoxide intermediate depicted as Sic.
`Preferred halocarbon solvents include dichloromethane,
`dichloroethane, and chloroform. More preferred halocarbon
`solvents are dichloromethane and dichloroethane. The most
`preferred halocarbon solvent is dichloromethane.
`The compound depicied as Sic is isolated by methods
`known to one of ordinary skill in the art. Such methods
`include, but are not
`limited to, extraction, solvent
`evaporation,distillation, and crystallization. Preferably, S1b
`is purified by flash chromatography on silica gel (Merck,
`230-400 mesh) using 20% EtOAc/hexanes as the eluent.
`
`50
`
`60
`
`IPR Page 6/20
`
`10
`The intermediate epoxide depicted as Sic can be reacted
`with a variety of oxygen, sulfur and nitrogen containing
`nucleophiles as disclosed, for example,
`in J. G. Smith,
`“Synthetically Useful Reactanis of Epoxides”, Synthesis
`(1984) p. 629-656,
`to provide the C,,-protected 13,14-
`dihydro-15-substituted-16-tetranor Prostaglandin F, o
`derivatives of Formula I.
`With sulfur nucleophiles, the reaction is carried out pref-
`erably at between 150° C. and 0° C., more preferably
`between 120° C. and 20° C., and most preferably between
`80° C. and 50° C. Preferred bases for the reaction include
`triethylamine, N,N diisopropylethylamine, and trimethy-
`lamine. The most preferred base is triethylamine. Preferred
`solvents for the reaction are aromatic hydrocarbon solvents.
`Preferred solvents include xylenes, toluene, and benzene.
`The most preferred solvent is benzene. With nitrogen and
`oxygen nucleophiles, preferred solvents include ethereal
`solvents and polar, protic solvents. More preferred ethereal
`solvents include diethyl ether, dibutyl ether and tetrahydro-
`furan. The most preferred ethereal solvent is tetrahydrotu-
`ran. More preferred polar, protic solvents include ethyl
`alcohol, methyl alcohol, and tert-butyl aleohol. The most
`preferred polar, protic solvent is ethyl alcohol.
`The ring-opening process with nitrogen and oxygen
`nucleophiles can be catalyzed with Lewis acids. Preferred
`Lewis acids include magnesium perchlorate, trimethylsilyl
`triflucromethanesulphonate, and trimethylaluminum. The
`most preferred Lewis acid is magnesium perchlorate. The
`reaction is carried out at a temperature between 150° C. and
`23° C., preferably between 125° C. and 40° C., and more
`prefcrably between 100° C. and 75° C.
`The resulting compounds can be isolated, but are gener-
`ally deprotected using techniques knownto one of ordinary
`skill in the art, and isolated as the final 13,14-dihydro-15-
`substituted-16-tetranor prostaglandin F,,, derivative. Com-
`pounds depicted by Formula I are exemplified in Examples
`2-28.
`Compounds depicted by Formula II can be made directly
`from those described in Formula I by methods known to one
`of ordinary skill in the art. For example, the condensation of
`methyl esters of Formula I with amines or hydroxylamine
`provides compounds depicted by Formula IT. Compounds
`depicted by Formula IT are exemplified in Examples 29-32.
`Compounds depicted by Formula III] can be made directly
`from those described in Formula I by methads known to one
`of ordinary skill
`in the art.
`‘The appropriately protected
`derivative from Formula I is oxidized to the ketone follow-
`ing the process described in the following references: A.
`McKillop and D. W. Young, “Organic Synthesis Using
`Supported Reagents—Part 1”, Synthesis (1979) p. 401-22;
`G. Piancatelli et al., “Pyridium Chlorochromate: A Versatile
`Oxidation Organic Synthesis”, Synthesis (1982) p. 245-58;
`E. J. Corey and J. W. Suggs, “Pyridinitum Chlorochromate:
`An Efficient Reagent for Oxidation of Primary and Second-
`ary Alcohols to Carbonyl Compounds”, Tetrahedron Lett.
`Vol. 31 (1975) p. 2647-50; and references cited therein. The
`ketone is then condensed with N-methylamine to give the
`imine. Addition of the methylcerium nucleophile (~1.5
`equiv.), as described for example in T. Imamoto, ct al.,
`“Carbon-Carbon Bond Forming Reactions Using Cerium
`Metal or Organcerium (Ill) Reagents”, J. Org. Chem. Vol. 49
`(1984) p. 3904-12; T. Imamoto, et al., “Reactions of Car-
`bonyl Compounds with Grignard Reagents in the Presence
`of Cerium Chloride”, J. Am. Chem. Soc. Vol. 111 (1989) p.
`4392-98; and references cited therein, gives the aminom-
`ethyl derivative of Formula IIT. Compounds depicted by
`Formula III are exemplified in Examples 39-42.
`
`IPR Page 6/20
`
`

`

`5,977,173
`
`11
`Compounds depicted by Formula IV and Formula V can
`be made from compounds described in Formula Tf by acti-
`vation and subsequent nucleophilic displacement of the
`appropriately functionalized hydroxyl group. Transforma-
`tions of this type are described in the following references:
`E. J. Corey et al., “Simple Stereospecific Routes to 9-cpi-
`Prostaglandin F,a”, J.C.S. Chem. Comm. (1975) p. 658-9;
`E. J. Corey et al., “Superoxide ion as a Synthetically Useful
`Oxygen Nucleophile”, Fetrahedron Lett. (1975) p. 3183-6;
`E. J. Coreyet al., “Total Synthesis of 5-desoxy Leukotriene
`D. A New and Useful Equivalent of the 4-Formyl-Trans,
`Trans-1,3-Butadienyl Anion’, Tetrahedron Lett. Vol. 23
`(1982) p. 3463-66;and references cited therein. Compounds
`depicted by Formula V are exemplified in Examples 33-36.
`Compounds depicted by Formula VI can be made from
`those described in Formula V (where X is SR, ) by selective
`oxidation procedures as described,
`for example,
`in the
`following references: E.
`J. Corey et al., “Pathways for
`Migration and Cleavage of the S-Peptide Unit of the
`Leukotrienes”, Zetrahedron Lett. Vol. 23 (1982) p. 3467-70;
`Prostaglandin Vol. 24 (1982) p. 801; Y. Girard ct al.,
`“Synthesis of the Sulfones of Leukotrienes C,, D,, and L,”,
`Tetrahedron Lett. Vol. 23 (1982) p. 1023-26; and references
`cited therein. Compounds depicted by Formula VI are
`exemplified in Examples 37-38.
`
`12
`The following non-limiting examples illustrate the
`compounds, compositions, and uses of the present invention.
`
`Examples Compounds are analyzed using 4H and 4C
`NMR, Elemental analysis, mass spectra, high resolution
`mass spectra and/or IR spectra as appropriate.
`
`10
`
`15
`
`inert solvents are used, preferably in dried
`Typically,
`form. For example, tetrahydrofuran (THF)is distilled from
`sodium and benzophenone, diisopropylamine is distilled
`from calcium hydride andall other solvents are purchased as
`the appropriate grade. Chromatography is performed on
`silica gel (70-230 mesh; Aldrich) or (230-400 mesh; Merck)
`as appropriate. Thin layer chromatography analysis is per-
`formed on glass mountedsilica gel plates (200-300 mesh;
`Baker) and visualized using UV, 5% phosphomolybdic acid
`in EtOH, or ammonium molybdate/ccrric sulfate in 10%
`aqueous H,SO,.
`
`Example 1
`
`Preparation of 13,14-dihydro-16-(3-fluorophenylthio) tetra-
`nor prostaglandin F,a (11), and 13,14-dihydro-15-methyl-
`16-(3-fluorophenylihio) tetranor prostaglandin Fy (1j):
`
`Q
`
`HO
`
`la
`
`Q
`
`TBDMSO
`
`Ib
`
`COMe
`
`2, 6 Lutidine
`TBDMSOTE
`
`CO.Me
`
`1) CuB:DMS
`
`R
`
`se
`
`2) NaBHy
`
`HQ
`
`TBDMS
`
`HQ,
`%,
`
`TBDMS
`
`IPR Page 7/20
`
`
`
`
`m-CPBA
`
`F
`
`CO2Me
`
`HS:
`
`1) Eun,
`2) HF/pyridine
`
`IPR Page 7/20
`
`

`

`13
`
`14
`
`5,977,173
`
`-continued
`
` R
`
`
`LiOH, THF/H,0av
`
`OH
`
`ig,R=H
`th, R = CH3
`
`1g,R=H
`Th, R = CH3
`
`a. Methyl 7-(2-oxo-4-(1,1,2,2-tetramethyl-1-silapropoxy)
`cyclopent-1-enyl) heptanoate 1b: To a solution of Methyl-
`7-[3-(R)-hydroxy-5-oxo-1-cyclopenten-1-yl] heptanoate 1a
`(1 equiv.) in CH,CL, at -78° C. is added 2,6 Lutidine (1.3
`equiv.) dropwise over 15 minutes. The solution is kept at
`-78° C., and TBDMS Triflate (1.2 equiv.) in CH,Cl, is
`added dropwise over 15 minutes. The reaction is warmed
`gradually to room temperature and stirred at room tempera-
`ture for 15 hours. Aqueous 10% HClis added and the layers
`are separated. The water layer is extracted with CHCl, and
`the organic layers are combined. The organic layer is washed
`with brine, dried (Na,SO,) and concentrated. The residue is
`distilled under vacuum (10 mm Hg)to providethe silyl ether
`1b as a yellowliquid.
`b. Methyl 7-(5-but-3-enyl-2-hydroxy-4-(1,1,2,2-
`tetramcthyl-1-silapropoxy)cyclopentyl) heptanoate 1c, 1d:
`To a slurry of Mg° powder (2 equiv.) in THF at room
`temperature is added onecrystal of 1, and 1-bromobutene (2
`equiv.) dropwise over 10 minutes. The reaction proceeds to
`exotherm as the addition continues. After the addition is
`complete, the reaction is refluxed for 3 hours and cooled ta
`room temperature. The Grignard is diluted with THF and
`added via cannula to a 3-necked flask equipped with
`mechanical stirring and charged with CuBr.DMS(2 equiv.)
`in a 1:1 solution of THF/DMSat -78° C. After the addition
`of the Grignard (~20 min), the reaction is stirred for 1 hour
`at -78° C. The color of the reactionis dark red at this point.
`A solution of