IPR Page 1/28
`
`Santen/Asahi Glass Exhibit 2033
`Micro Labs v. Santen Pharm. and Asahi Glass
`IPR2017-01434
`
`

`

`(19) Japan Patent Office (JP)
`
`(12) Japanese Unexamined Patent
`Application Publication (A)
`
`(11) Japanese Unexamined Patent
`Application Publication
`H07-70054
`(43) Publication date: March 14, 1995
`Technical indications
`
`
`(51) Int. Cl.6
`
`
`Identification codes
`
`JPO file numbers
`
`FI
`
`
`
`
`
`
`
`
`
`
`
`
`Request for examination: Not yet requested Number of claims: 6; FD (Total of 27 pages) Continued on the last page
`(21) Application number
`Japanese Patent Application
`(71) Applicant
`592060271
`
`H5-235903
`
`R-Tech Ueno, Ltd.
`2-4-8 Koraibashi, Chuo-ku. Osaka-shi,
`
`
`
`Osaka-fu
`(22) Date of application
`August 30, 1993
`
`Takashi UENO
`
`(72) Inventor
`7-29 Misakucho, Nishinomiya, Hyogo
`
`(72) Inventor
`Tomio ODA
`
`1-29-B-203 Suzukakedai, Sanda, Hyogo
`(74) Agent
`Hiroyoshi ODASHIMA, Patent Attorney
`(one other agent)
`
`(54) (TITLE OF THE INVENTION) BIOLOGICAL ANTAGONIST AND DISEASE-TREATING PREPARATION
`
`(57) Abstract (with amendment)
`(CONSTITUTION) A prostaglandin
`represented by a general formula
`
`compound
`
`[for example, 13,14-dehydro-15-dehydroxy-17,17-
`difluoro-PGE1 methyl ester].
`(EFFECT) This compound is useful as a preparation
`to
`treat allergic disease, a preparation
`to
`treat
`inflammatory disease, an antihistamine agent, and a
`bronchodilator.
`
`
`
`
`
`
`
`IPR Page 2/28
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`

`

`(2) Japanese Unexamined Patent Application Publication H7-70054
`
`(Scope of Patent Claims)
`(Claim 1) A preparation for treating allergy and
`inflammatory diseases, having a 15-dehydroxy-
`prostaglandin compound as an active ingredient.
`(Claim 2) An antihistamine agent, having a 15-
`dehydroxy-prostaglandin compound as an active
`ingredient.
`(Claim 3) A bronchodilator, having a 15-dehydroxy-
`prostaglandin compound as an active ingredient.
`(Claim 4) A preparation as recited in any one of
`claims 1-3, wherein a 15-dehydroxy-prostaglandin
`compound
`is
`a
`15-dehydroxy-prostaglandin
`compound [sic, repeated] represented by formula (I)
`(Chemical formula 1)
`
`
`
`[in the formula, X and Y represent hydrogen,
`hydroxy, halogen, lower alkyl, hydroxy (lower) alkyl,
`or oxo (provided that at least one of the group of X
`and Y is a group other than hydrogen, and the five-
`membered ring may have at least one double bond);
`A is -CH2OH, -COH2OH, -COOH, or a functional
`derivative thereof; R1 represents a saturated or
`unsaturated bivalent lower or medium aliphatic
`hydrocarbon residue; R2 represents a saturated or
`unsaturated lower or medium aliphatic hydrocarbon
`residue unsubstituted or substituted with halogen
`(provided that the end of lower or medium aliphatic
`hydrocarbon residue may be substituted with lower
`alkoxy, cyclo (lower) alkyl, aryl, or aryloxy)].
`(Claim 5) A compound or salts thereof when R3 is a
`hydrogen atom, represented by a general formula
`(Chemical formula 2)
`
`
`[in the formula, L and M represent hydrogen,
`hydroxy, halogen, lower alkyl, hydroxy (lower) alkyl,
`or oxo (provided that at least one of the groups of L
`and M is a group other than hydrogen, and the five-
`membered ring may have at least one double bond);
`Z1 and Z2 represent hydrogen atom, halogen, or lower
`alkyl (provided that at least one of Z1 and Z2 is
`halogen); R3 represents a hydrogen atom, lower alkyl
`group, lower cycloalkyl group, monocyclic aryl
`group, monocyclic aryl
`lower alkyl group, or
`monocyclic aroyl lower alkyl group; R4 represents a
`saturated
`or
`unsaturated
`bivalent
`aliphatic
`hydrocarbon residue having from 4 to 8 carbon
`atoms; R5 represents a saturated or unsaturated
`bivalent lower aliphatic hydrocarbon residue; R6
`represents a saturated or unsaturated, single bond or
`bivalent lower aliphatic hydrocarbon residue; and R7
`represents a lower alkyl group, unsubstituted or lower
`group,
`cycloalkyl
`alkyl-substituted
`lower
`unsubstituted or halogen or halo
`lower alkyl-
`substituted monocyclic aryl group, unsubstituted or
`halogen or halo lower alkyl-substituted monocyclic
`aryloxy group].
`(Claim 6) The compound as recited in claim 5,
`
`(α chain)
`
`
`wherein Z1 and/or Z2 are fluorine atoms.
`(Detailed Description of the Invention)
`(0001)
`invention
`(Industrial Application) The present
`pertains to a novel use of and a specific new 15-
`dehydroxy-prostaglandin compound.
`(0002)
`(Prior Art) In allergy and inflammatory diseases,
`histamine has been known widely as one of the
`chemical mediators, and the so-called antihistamine
`is widely used today as the treatment for allergy and
`inflammatory diseases.
`(hereinafter,
`(0003) Meanwhile, prostaglandins
`prostaglandin will be referred to as PG,) contained in
`the tissues and organs of humans and other mammals,
`is a group of organic carboxylic acids showing a wide
`range of physiological activities. As a general
`structural characteristic, PGs that exist naturally have
`a prostanoic acid skeleton.
`(0004)
`(Chemical formula 3)
`
`(ω chain)
`
`
`
`
`
`IPR Page 3/28
`
`

`

`(3) Japanese Unexamined Patent Application Publication H7-70054
`
`(0005) On the other hand, some synthetic analogues
`have modified skeletons. Natural PGs are classified to
`PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs,
`PGIs, and PGJs according to the structural characteristic
`of the five-membered ring, and the chains are further
`classified under the presence and absence of unsaturation
`and oxidation to
`Subscript 1 … 13,14-unsaturated-15-OH
`Subscript 2 … 5,6- and 13,14-diunsaturated-15-OH
`Subscript 3 … 5,6-, 13,14-, and 17,18-triunsaturated-15-
`OH.
`(0006) PGFs are further classified into α (the hydroxyl
`group is of an alpha configuration) and β (the hydroxyl
`group is of a beta configuration) according to the
`configuration of the hydroxyl group at the 9-position.
`(0007) A group of 15-dehydroxy-PG compound with no
`hydroxyl group at the 15-position of naturally occurring-
`type PGs has been known to have an ocular hypotensive
`activity (WO91/13869.) The 15-dehydroxy-16-oxo-PG
`compound having no hydroxyl group at the 15-position
`but having an oxo group at the 16-position has been
`disclosed to be effective in allergy, inflammation, and so
`forth.
`(Japanese Unexamined Patent Application
`Publication No. H4-330015.)
`(0008)
`(Problems to be Solved by the Invention) The inventors
`of this invention continued their research about a novel
`use of the 15-dehydroxy-PG compound having neither
`hydroxyl group nor oxo group at the 15-position and the
`16-position including a new compound, and as the result
`thereof, the inventors found that these compounds have
`an outstanding antagonistic action
`to histamine;
`therefore, the compound is useful in the treatment of
`allergy or inflammatory diseases, and the present
`invention was completed.
`(0009)
`(Constitution of the Invention) That is, the present
`invention is to provide a preparation for treating allergy,
`a preparation for treating inflammatory disease, an
`antihistamine, a bronchodilator, and a new 15-
`dehydroxy-PG compound using a 15-dehydroxy-PG
`compound as an active ingredient.
`(0010) Allergic disease is an allergic reaction, that is, a
`body develops antibodies against unique substances
`(antigen or allergen; for example, pollen, grains, dust,
`animal-transported airborne substances, food, drugs,
`curative serums, bacteria, and substances produced by
`bacteria) in certain cells, and the next time the body
`encounters such substances,
`it reacts as
`if such
`substances were harmful instead of defensively. This
`includes hay fever (seasonal nasal catarrh, vasomotor
`rhinitis,) bronchial asthma, serum sickness, serum shock,
`allergic dermatitis, allergic gastritis, allergic arthritis,
`allergic
`conjunctivitis,
`allergic diarrhea,
`allergic
`laryngitis, allergic purpura, allergic neuritis, allergic
`granuloma, allergic encephalomyelitis, allergic alveolitis,
`allergic nephritis, allergic rhinitis, allergic asthma, and
`allergic eczema.
`(0011) Furthermore, the present invention includes the
`so-called autoimmune diseases that cause tissue injury to
`one’s own cells by producing antibodies to react against
`the components that constitute one’s own tissues. The
`
`
`
`disease includes rheumatoid arthritis (RA,) systemic
`[lupus] erythematosus (SLE,) diffuse scleroderma (PSS,)
`Hashimoto's
`disease,
`Sjogren's
`syndrome,
`hyperthyroidism, myasthenic syndrome, and Behçet’s
`disease.
`(0012) Inflammatory disease is a group of lesions
`consisting
`of
`circulatory
`disorders,
`exudation,
`degeneration, and hyperplasia that occur caused by an
`inflammatory reaction, that is, when a stimulus (whether
`it is a physical or chemical stimulus, or a stimulus
`caused by microorganisms and other parasites) is added
`that can break the dynamic equilibrium of the function or
`the structure of local organs or tissues in a living body,
`and the signs of this disease include suffusion, fever,
`pain, swelling, and dysfunction. This disease includes
`conjunctivitis,
`iritis, uveitis, central retinitis, otitis
`externa, acute suppurative otitis media, mastoiditis, otitis
`interna, chronic
`rhinitis, acute
`rhinitis, sinusitis,
`laryngitis,
`tonsillitis,
`chronic
`bronchitis,
`acute
`bronchiolitis,
`lobar pneumonia, bronchopneumonia,
`primary atypical pneumonia, dry pleurisy, wet pleurisy,
`mediastinitis, acute rheumatism endocarditis, bacterial
`endocarditis,
`thrombophlebitis, polyarteritis,
`acute
`nephritis, chronic nephritis, cystitis, perinephritis,
`stomatitis, esophagitis, acute gastritis, chronic gastritis,
`ulcerative colitis, acute appendicitis, chronic hepatitis,
`acute hepatitis, cholangiolitic hepatitis, inflammation of
`the gallbladder, chronic pancreatitis, acute pancreatitis,
`chronic peritonitis, acute peritonitis, thyroiditis, contact
`dermatitis, acute hemorrhagic encephalitis, purulent
`meningitis, optic nerve myelitis, alcoholic polyneuritis,
`diabetic polyneuritis, polymyositis, myositis ossificans,
`degenerative arthritis, rheumatoid arthritis, periarthritis
`scapulohumeralis, osteitis deformans, etc.
`(0013) Histamine is a substance that is present in various
`tissues, but the majority thereof is contained in mast
`cells and basophils, released in response to non-immune
`stimulation
`(traumatic or
`toxic
`stimulation, or
`stimulation by a certain compound, for example,
`compound 48/80) or
`immune stimulation, causing
`allergic symptoms, such as itching, edema, redness, and
`bronchoconstriction, and
`stimulating gastric acid
`secretion.
`(0014) A bronchial smooth muscle is contracted by
`stimulus of a histamine receptor and a leukotriene
`receptor. Stimulating the parasympathetic nerve releases
`acetylcholine from the periphery, binding it with a
`cholinergic receptor on the surface of a smooth muscle,
`causing it to contract. Stimulating the sympathetic nerve
`releases noradrenaline from the periphery and adrenaline
`from the adrenal medulla, stimulating the β- receptor to
`relax smooth muscles; however, a stimulus of α receptor
`causes muscle contraction. All drugs having activity of
`directly or
`indirectly
`inhibiting
`the constriction
`mechanism are included as a bronchodilator.
`(0015) In the present invention, the term “treatment”
`includes a management of all diseases
`including
`prevention,
`therapy, mitigation, prevention
`from
`aggravation, or mitigation of aggravation.
`(0016) In the present invention, a 15-dehydroxy-PG
`compound includes all prostaglandin derivatives having
`neither hydroxyl group nor oxo group at the 15- and 16-
`
`IPR Page 4/28
`
`

`

`(4) Japanese Unexamined Patent Application Publication H7-70054
`
`
`positions of a prostanoic acid skeleton regardless of the
`presence or the absence of an unsaturated bond (double or
`triple bond.) The number of prostanoic acid shown in
`formula (A) is used in the naming convention of a 15-
`dehydroxy-PG compound of the present invention.
`(0017) Although the above-mentioned formula (A) is a C-
`20 basic skeleton, the number of carbon atoms in the
`present invention is not limited thereto. That is, the
`number of carbon atoms that constitute the basic skeleton
`starts at the carboxylic acid with the number 1, the
`number of carbon atoms in the α-chain is from 2 to 7
`towards the five-membered ring, the number of carbon
`atoms in the five-membered ring is from 8 to 12, and the
`number of carbon atoms in the ω-chain is from 13 to 20;
`however, when the number of carbon atoms is decreased
`in the α-chain, the subsequent number starting from the 2-
`position is deleted, and when the number is increased in
`the α-chain, compounds are named as substituents at the
`2-position in place of a carboxyl group (the 1-position.)
`Similarly, when the number of carbon atoms is decreased
`in the ω-chain, the number of carbon atoms is deleted
`starting from the 20-position, and when the number is
`increased in the ω-chain, the carbon atoms at the 21-
`position henceforth are named as a substituent. Unless
`specified otherwise, the configuration shall be according
`to the configuration having the above-mentioned basic
`skeleton.
`(0018) Therefore, when the ω-chain has five carbon
`atoms, and the end thereof is substituted with a phenyl,
`those
`are named 15-dehydroxy-18,19,20-trinor-17-
`phenyl-PGs; when the ω-chain has ten carbon atoms;
`those are named 15-dehydroxy 20-ethyl-PGs.
`(0019) Although the above-mentioned formula shows a
`specific configuration, which
`is
`the most
`typical
`coordination, unless
`specified otherwise,
`in
`this
`Specification, a compound shall have
`the above-
`mentioned configuration.
`(0020) Generally, PGDs, PGEs, and PGFs have a hydroxy
`group on the carbon atom at the 9-position and/or the 11-
`position; however, in the present invention, a 15-
`dehydroxy-16-oxo PG compound contains PGs having a
`group other than hydroxy at the 9-position and/or the 11-
`position. Such PGs are named 9-dehydroxy-9-substituted
`PGs or 11-dehydroxy-11-substituted PGs. When it has a
`hydrogen atom instead of a hydroxy group, they are
`simply named 9-dehydroxy-PGs or 11-dehydroxy-PGs.
`(0021) As mentioned above, although naming of the
`compound of the present invention is performed based on
`
`
`a prostanoic acid skeleton, the naming is also possible
`based on IUPAC. Examples of naming of the compound
`by both nomenclatures will be described as examples of
`embodiment. The 15-dehydroxy-PG compound used in
`the present invention may be all PG derivatives having
`neither hydroxyl group nor oxo group at the 15- and the
`16-position, these may be a saturated object, and they
`may further have a double bond in the 5- to 6-position,
`the 13- to 14-position, or the 18- to 19-position.
`Furthermore, 13,14-dihydro compounds in which the 13-
`to 14-position is saturated are also included. 13,14-
`dihydro compounds having a double bond at the 14- and
`15-position are also further included. Typical examples of
`the compounds that can be used in the present invention
`include 15-dehydroxy-PGA, 15-dehydroxy-PGD, 15-
`dehydroxy-PGE, 15-dehydroxy-PGF, the 13,14-dihydro
`compounds thereof, or 14,15-dihydro compounds thereof,
`and substituents and derivatives thereof.
`(0022) A preferable compound used in the present
`invention has formula (I.)
`(0023)
`(Chemical formula 4)
`
`
`(0024) [In the formula, X and Y represent hydrogen,
`hydroxy, halogen, lower alkyl, hydroxy (lower) alkyl, or
`oxo (provided that at least one of groups of X and Y
`represents the group other than hydrogen, and the five-
`membered ring may have at least one double bond); A
`represents -CH2OH, -COH2OH, -COOH, or the functional
`represents a
`saturated or
`thereof; R1
`derivative
`unsaturated bivalent
`lower or medium
`aliphatic
`hydrocarbon residue; R2 represents a saturated or
`unsaturated lower or medium aliphatic hydrocarbon
`residue unsubstituted or substituted by halogen (provided
`that the end of lower or medium aliphatic hydrocarbon
`residue may be substituted with lower alkoxy, cyclo
`(lower) alkyl group, aryl group, or aryloxy group)].
`(0025) The present invention is a compound, or salts
`thereof when R3 represents a hydrogen atom, represented
`by a general formula.
`(0026)
`(Chemical formula 5)
`
`(0027) [In the formula, L and M represent hydrogen,
`hydroxy, halogen, lower alkyl, hydroxy (lower) alkyl, or
`oxo (provided that at least one of the groups of L and M
`represents a group other than hydrogen, and the five-
`membered ring may have at least one double bond); Z1
`
`
`and Z2 represents hydrogen atom, halogen, or lower alkyl
`(provided that at least one of Z1 and the Z2 is halogen); R3
`represents a hydrogen atom, lower alkyl group, lower
`cycloalkyl group, monocyclic aryl group, monocyclic aryl
`lower alkyl group, or monocyclic aroyl lower alkyl group;
`
`
`
`
`
`IPR Page 5/28
`
`

`

`(5) Japanese Unexamined Patent Application Publication H7-70054
`
`
`
`R4 represents a saturated or unsaturated bivalent
`aliphatic hydrocarbon residue having from 4 to 8
`carbon atoms; R5 represents a saturated or
`unsaturated bivalent lower aliphatic hydrocarbon
`residue; R6 represents saturated or unsaturated,
`single bond or bivalent lower aliphatic hydrocarbon
`residue; and R7 represents a lower alkyl group,
`unsubstituted or
`lower alkyl-substituted
`lower
`cycloalkyl
`group, monocyclic
`aryl
`group
`unsubstituted or substituted with halogen or halo
`lower alkyl, or monocyclic aryloxy group
`unsubstituted or substituted with halogen or halo
`lower alkyl].
`(0028) The term “unsaturated” in R1, R2, R4, R5,
`and R6 in the formula described above refers to the
`inclusion of, as the bond between carbon atoms in
`the main chain or the side chain, at least one double
`bond and/or triple bond independently, separately,
`or continuously. In accordance with the usual
`nomenclature,
`the unsaturation between
`two
`continuous positions is shown by displaying the
`position number of the younger one, and the
`unsaturation between two non-continuous positions
`is shown by displaying both position numbers.
`Those unsaturated are preferably a double bond at
`the 2-position, a double bond or triple bond at the
`5-position, a double bond at the 13-position, and a
`double bond at the 14-position.
`(0029) The term “lower or medium aliphatic
`hydrocarbon” refers to hydrocarbons having a
`straight or branched chain having from 1 to 14
`carbon atoms [provided that the side chain is
`preferably those having from 1 to 3 carbon atoms],
`preferably hydrocarbons having from 2 to 8 carbon
`atoms in case of R1 and hydrocarbons having from
`2 to 12 carbon atoms in case of R2.
`(0030) The term “halogen” includes fluorine,
`chlorine, bromine, and iodine.
`(0031) The term “lower” includes the groups
`having from 1 to 6 carbon atoms, unless especially
`specified otherwise.
`(0032) The term “lower alkyl” includes saturated
`hydrocarbon groups of a straight or branched chain
`having from 1 to 6 carbon atoms, for example,
`contains methyl, ethyl, propyl, isopropyl, butyl,
`isobutyl, t-butyl, pentyl, and hexyl.
`(0033) The term “lower alkoxy” refers to lower
`alkyl -O- whose lower alkyls have the same
`meaning as described above.
`(0034) The term “hydroxy (lower) alkyl” refers to
`the alkyls described above substituted with at least
`one hydroxy group, for example, hydroxymethyl,
`1-hydroxyethyl, 2-hydroxyethyl, and 1-methyl-1-
`hydroxyethyl.
`(0035) The term “lower alkanoyloxy” refers to the
`group represented by formula RCO-O- (the RCO-
`here represents acyl that is produced by oxidizing
`the lower alkyls as described above, for example,
`acetyl.)
`
`(0036) The term “cyclo (lower) alkyl” refers to the
`group produced by the cyclization of the lower
`alkyl groups as described above.
`(0037) The
`term “aryl”
`includes aromatic
`carbocyclic or heterocyclic group (preferably
`monocyclic groups) which may be substituted, for
`example, phenyl,
`tolyl, xylyl, and
`thienyl.
`Examples of substituents include halogen and
`halogen-substituted lower alkyl group (here, a
`halogen atom and a lower alkyl group refer to those
`described above.)
`(0038) The term “aryloxy” refers to the group
`represented by formula ArO- (here, Ar represents
`the aryl groups described above.)
`(0039) The term “functional derivatives” of the
`carboxyl group represented by A includes salts
`(preferably pharmaceutically acceptable salts,)
`esters, and amides.
`(0040) Nontoxic salts commonly used are included
`as the suitable “pharmaceutically acceptable salts,”
`with examples including salts with inorganic bases,
`for example, alkaline metal salts (sodium salt,
`potassium salt, and the like,) alkaline earth metal
`salts (calcium salt, magnesium salt, and the like,)
`ammonium salts, salts with organic bases, for
`example, amine salts (for example, methylamine,
`dimethylamine
`salt,
`cyclohexylamine
`salt,
`benzylamine salt, piperidine salt, ethylenediamine
`salt, ethanolamine
`salt, diethanolamine
`salt,
`triethanolamine salt, tris(hydroxy methylamino)
`ethane salt, monomethyl-monoethanolamine salt,
`lysine salt, procaine salt, and caffeine salt, and the
`like,) basic amino acid salts (for example, arginine
`salt,
`lysine
`salt, and
`the
`like,)
`tetra-alkyl
`ammonium salt, and the like. These salts can be
`manufactured by conventional methods from the
`corresponding acids and bases, for example, or by
`salt exchange.
`(0041) Examples of esters include aliphatic esters
`including lower alkyl esters, such as methyl ester,
`ethyl ester, propyl ester, isopropyl ester, butyl ester,
`isobutyl ester,
`t-butyl ester, pentyl ester, 1-
`cyclopropyl ethyl ester, and the like; lower alkenyl
`esters, such as vinyl ester, allyl ester, and the like;
`lower alkynyl esters, such as ethynyl ester,
`propynyl ester, and the like; hydroxy (lower) alkyl
`ester such as hydroxy ethyl ester, and the like;
`lower alkoxy
`(lower) alkyl ester, such as
`methoxymethyl ester, 1-methoxy ethyl ester, and
`the like; and for example, optionally substituted
`aryl ester such as phenyl ester, tosyl ester, t-
`butylphenyl
`ester,
`salicyl
`ester,
`3,4-
`dimethoxyphenyl ester, benzamide phenyl ester,
`and the like; aryl (lower) alkyl ester, such as benzyl
`ester, trityl ester, benzhydryl ester, and the like.
`(0042) Examples of amide include mono- or di-
`lower
`alkylamides
`such
`as methylamide,
`ethylamide, dimethylamide, and the like; aryl
`amides, such as anilide, toluidide, and the like;
`alkyl or aryl sulfonylamides, such as
`
`
`
`IPR Page 6/28
`
`

`

`(6) Japanese Unexamined Patent Application Publication H7-70054
`
`
`methylsulfonyl amide, ethylsulfonyl amide, tolyl
`sulfonylamide, and the like.
`(0043) In the above-mentioned formulae (I) and (II,)
`the configuration of the ring, α-, and/or ω-chain may
`be the same as or different from the configuration of
`natural PGs. However, the present invention also
`includes the mixture of the compound having a
`natural configuration and a compound having an
`unnatural configuration. The examples of the typical
`compounds of the present invention include 15-
`dehydroxy-PGEs,
`13,14-dihydro-15-dehydroxy-
`PGEs, and 2 derivatives
`thereof, 3-methyl
`derivative,
`derivatives, 5
`11-dehydroxy
`derivatives, 11-dehydroxy 11-methyl derivatives,
`13 derivatives, 14 derivatives, 15-mono- or di-
`methyl
`derivatives,
`15-mono-
`or
`difluoro
`derivatives, 16-mono- or di-methyl derivatives, 16-
`mono- or difluoro derivatives, 17-mono- or di-
`methyl
`derivatives,
`17-mono-
`or
`difluoro
`derivatives, 18-mono- or dimethyl derivatives, 18-
`mono- or difluoro derivatives, 19-mono- or di-
`methyl
`derivatives,
`19-mono-
`or
`difluoro
`17,18,19,20-tetranol
`derivatives,
`derivatives,
`17,18,19,20-tetranol-16-ethoxy
`derivatives,
`17,18,19,20-tetranol-16-cyclopentyl
`derivatives,
`17,18,19,20-tetranol-16-phenyl
`derivatives,
`17,18,19,20-tetranol-16-phenoxy
`derivatives,
`18,19,20-trinor derivatives, 18,19,20-trinor- 17-
`
`
`
`
`
`methoxy derivatives, 18,19,20-trinor-17-cyclohexyl
`derivatives, 18,19,20-trinor-17-phenyl derivatives,
`18,19,20-trinor-17-phenoxy derivatives, 19,20-dinor
`derivatives, 19,20-dinor-18-methoxy derivatives,
`19,20-dinor-18-cyclopentyl derivatives, 19,20-dinor-
`18-phenyl
`derivatives,
`19,20-dinor-18-phenoxy
`derivatives, 20-nor derivatives, 20-nor-19-methoxy
`derivatives, 20-nor-19-phenyl derivatives, 20-
`methoxy derivatives, 20-methyl derivatives, 20-ethyl
`derivatives,
`20-propyl
`derivatives,
`20-butyl
`derivatives, 20-phenyl derivatives, and the like.
`(0044) In the present invention, each tautomer, the
`mixture thereof, or an optical isomer, the mixture
`thereof, racemic isomers, and other steric isomers,
`can also be used for the same objective.
`(0045)
`(Manufacturing method) The compound of the
`present invention can be manufactured, for example,
`based on the description disclosed in WO 91/13869.
`It can also be manufactured according to the
`following reaction formula. In the reaction formula,
`P1, P2, P3, P4, and P5 represent protective groups, D
`represents a leaving group, B represents -CH2-CH2-
`or -CH=CH-, and A and X have the same meanings
`as the described above.
`(0046)
`(Chemical formula 6)
`
`
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`IPR Page 7/28
`
`

`

`
`
`(7) Japanese Unexamined Patent Application Publication H7-70054
`
`(0047)
`
`
`(Chemical formula 7)
`
`
`
`
`
`IPR Page 8/28
`
`

`

`
`
`(8) Japanese Unexamined Patent Application Publication H7-70054
`
`
`(0048)
`
`
`
`
`(Chemical formula 8)
`
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`
`IPR Page 9/28
`
`

`

`
`
`(9) Japanese Unexamined Patent Application Publication H7-70054
`
`
`lactone (1) having a suitable
`(0049) Corey
`protective group is oxidized (for example, Collins
`oxidation)
`to prepare (2,) and (2-oxo alkyl)
`phosphonic acid ester having R, which is the object,
`is made to react thereto to obtain (3.) For example,
`when a 16,16-difluoro compound is the object,
`(3,3-difluoro-2-oxo alkyl)-phosphonic acid ester
`may be used; when a 16,16-dimethyl compound is
`the object, (3,3-dimethyl-2-oxo alkyl)-phosphonic
`acid ester may be used; and when a 17-phenyl
`
`
`
`compound is the object, (4-phenyl-2-oxo alkyl)-
`phosphonic acid ester may be used. When a 13,14-
`dihydro compound is the object, an oxo group is
`reduced to prepare (4) and further reduced to
`prepare (5.) The hydroxyl group of compound (5)
`is detached (for example, imidazole thiocarbonyl
`esterification) to prepare (6,) and this leaving group
`is reduced (for example, hydrogenated tri-n-butyl
`tin) to prepare (7.) This protective group at the 11-
`
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`IPR Page 10/28
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`

`

`(10) Japanese Unexamined Patent Application Publication H7-70054
`
`position is detached to prepare (8,) and another protective
`group (for example, tetrahydropyranyl) is introduced to
`prepare (9,) and lactone is reduced to lactol (10.) An α-chain
`is introduced by a Wittig reaction, or the like, to prepare
`(11,) esterified to prepare (12,) the 9-position is oxidized to
`prepare (13,) and when the 11-position is deprotected, the
`target compound (14) is obtained. Among the above-
`mentioned manufacturing methods, if the reduction that
`obtains (5) from compound (4) is excluded, the compound
`(15) having a double bond at the 13- and 14-position will be
`obtained. If an α-chain introduction agent is properly
`selected, a compound in which B is -CH2-CH2- or -CH=CH-
`will be obtained. A compound in which A is COOH is
`obtained by hydrolyzing compound (14.)
`(0050) Compound (16) in which the carbon of compound
`(1) has been increased is used as the starting compound, and
`performing the same reaction produces compound (18) and
`compound (19) of 14,15-dehydro having a double bond at
`the 14- and 15-position. In this case, using (3,3-difluoro-2-
`oxo alkyl)-phosphonic acid ester as
`(2-oxo alkyl)
`phosphonic acid ester produces a 17,17-difluoro compound,
`using (3,3-dimethylol-2-oxo alkyl)-phosphonic acid ester
`produces a 17,17-dimethyl compound, and using (4-phenyl-
`2-oxo alkyl)-phosphonic acid ester produces a 18-phenyl
`compound.
`(0051) Oxidizing a protective group at the 11-position, for
`example, (20) protected with a monocyclic aryl sulfone
`group (for example, Jones oxidation) produces a PGA
`compound (21.) In case of targeting a compound having X
`being other than OH (for example, lower alkyl) in general
`formula (I,) compound (22) can be obtained by reacting, for
`example, a lower alkyl copper complex with compound
`(21.) A PGF-type compound can be obtained by the
`deprotection of compound (12) at the 11-position. A PGD-
`type compound can be obtained by protecting compound
`(12) at the 9-position and deprotecting at the 11-position to
`prepare (24,) oxidizing it to prepare (25,) and deprotecting it
`at the 9-position to obtain (26.)
`(0052)
`(Effect) The above-mentioned 15-dehydroxy-PG compound
`is useful as a preparation for treating allergy, a preparation
`for treating inflammatory diseases, an antihistamine, and a
`bronchodilator.
`(0053) The compound used in the present invention can be
`used as drugs for animals and humans and is usually used
`systemically or locally by methods including eye drop,
`rhinenchysis, oral administration,
`intravenous
`injection
`(including infusion,) subcutaneous injection, and intrarectal
`administration. The dose changes according to whether it is
`to be administered to an animal or human, according to age,
`weight, symptoms to be treated, a desired curative effect,
`method of administration, treatment periods, and other
`factors; however, usually, doses in the range of 0.05-100
`µg/eye for the usual local administration, or from half to
`quarter doses daily or doses in the range of 0.001-500 mg/kg
`for continuous and systemic administration can usually
`achieve sufficient effects.
`(0054) Eye drops or an ophthalmic ointment is included as
`the ophthalmic solutions according to the present invention.
`
`
`
`Eye drops are prepared by dissolving an active ingredient in
`a sterile aqueous solution, for example, a physiological
`saline, buffer solution, or the like, or combining it for
`dissolution at the time of use. An ophthalmic ointment is
`prepared by mixing an active ingredient with a base.
`(0055) Nasal drops or nasal sprays are included as the nasal
`drop agent according to the present invention. Nasal drops
`are prepared by dissolving an active ingredient in a sterile
`aqueous solution, for example, a physiological saline, a
`buffer solution, or the like, or combining it for dissolution at
`the time of use. Nasal sprays are prepared by blowing an
`active ingredient with a compressed gas or an air pump in
`the form of water droplets or powder.
`(0056) Tablets, troches, sublingual tablets, capsules, pills,
`powder medicine, granules, etc. are included as the solid
`composition for internal use according to the present
`invention. In such a solid composition, at least one active
`substance is mixed with at least one inactive diluent, for
`example, lactose, cellulose, silicic acid anhydride, or the like.
`The composition may contain additives other than an
`inactive diluent, for example, a lubricant, a disintegrant, and
`a stabilizer in accordance with a conventional method. A
`tablet or a pill may be coated with a stomach-soluble film or
`an enteric-coated film as needed, and may be coated with
`two or more layers. It may also be prepared as capsules
`made of substances that can be disintegrated. When a quick
`action is required, it may also be prepared as sublingual
`tablets.
`(0057) Emulsions, liquids and solutions, suspensions, syrups,
`elixirs, and the like, can be exemplified as the liquid
`compositions for internal use. Inactive diluents generally
`used, for example, may include purified water, ethanol, or
`the like. This composition may contain an adjuvant such as a
`wetting agent or a suspending agent, a sweetening agent, a
`flavoring, a fragrance, and an antiseptic in addition to the
`inactive diluent.
`(0058) As other compositions for internal use, sprays
`containing one or more than one active substances and
`prescribed by a publicly known method may be included.
`(0059) Sterile, aqueous or non-aqueous liquids and solutions,
`suspensions, and emulsions are included as the injections for
`the parenteral drug administration according to the present
`invention.
`(0060) Such composition may also contain an adjuvant such
`as an antiseptic, a wetting agent, an emulsifier, and a
`dispersing agent. These are sanitized, for example, by a
`filtration through a bacteria-retaining filter, blending with a
`germicide, gas sterilization, or radiation sterilization. These
`can be manufactured as a sterile solid composition and can
`also be used by dissolving it in aseptic water or a sterile
`solvent for injection before use.
`(0061) Another form
`is a suppository or a vaginal
`