United States Patent [19]
`Shirasawa et al.
`
`US005886035A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,886,035
`Mar 23, 1999
`
`[54] DIFLUOROPROSTAGLANDIN DERIVATIVES
`AND THEIR USE
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`[75] Inventors: Eiichi Shirasawa; Masaaki
`Kageyama; Tadashi Nakajima, all of
`Ikoma; Takashi Nakano, Yokohama;
`Nobuaki Mori, Yokohama; Hideshi
`Sasakura, Yokohama; Yasushi
`Matsumura, Yokohama; Yoshitomi
`Morizawa, Yokohama, all of Japan
`[73] Assignees: Asahi Glass Company Ltd., Tokyo,
`Japan; Santen Pharmaceutical Co.,
`Ltd., Osaka, Japan
`
`[21] Appl. No. 993,017
`[22] Filed:
`Dec. 18, 1997
`[30]
`Foreign Application Priority Data
`Dec. 26, 1996 |JP]
`Japan .................................... 8–348614
`Mar. 26, 1997 [JP]
`Japan ....
`--
`Jun. 27, 1997 |JP]
`Japan .................................... 9–172477
`[51] Int. Cl." ....................... C07C 405/00; A61K 31/557
`[52] U.S. Cl. .......................... 514/330; 514/573; 510/121;
`56.2/503
`[58] Field of Search ............................ 560/121; 502/503;
`514/530, 573
`
`5,166,178 11/1992 Ueno ....................................... 514/573
`Primary Examiner—Robert Gerst!
`Attorney, Agent, or Firm—Oblon, Spivak, McClelland,
`Maier & Neustadt, P.C.
`[57]
`ABSTRACT
`A fluorine-containing prostaglandin derivative of the for
`mula (1) (or a salt thereof) and a medicine containing it,
`particularly, a preventive or therapeutic medicine for an eye
`disease:
`
`
`
`(1)
`
`wherein A is a vinylene group or the like, R' is an aryloxy
`alkyl group or the like, Rº and R are hydrogen atoms or the
`like, and Z is OR" (wherein OR" is a hydrogen atom or an
`alkyl group) or the like.
`
`14 Claims, No Drawings
`
`Micro Labs Exhibit 1001
`
`

`

`1
`DIFLUOROPROSTAGLANDIN DERIVATIVES
`AND THEIR USE
`
`5,886,035
`
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`The present invention relates to fluorine-containing pros
`taglandin derivatives having two fluorine atoms at the
`15-position (or their salts) and medicines containing the
`compounds as an active ingredient, particularly, preventive
`or therapeutic medicines for eye diseases.
`The naturally occurring prostaglandins (PGs) are a class
`of biologically active substances synthesized in the body and
`cellular functions in various tissues of the body as local
`hormones having various biological activities. The PGs F, a
`group of naturally occurring PGs, are known to lower
`intraocular pressure when topically applied to the eye and
`are expected to find applications as therapeutic medicines
`for ocular hypertension or glaucoma (U.S. Pat. No. 4,599,
`353). However, they are irritant to the eye and have a
`problem of their inflammatory side effects such as conges
`tion and damage to the cornea. Therefore, research for
`development of PGF derivatives which do not have such
`side effects is extensively conducted both at home and
`abroad. PGF derivatives having a cyclic structure in the
`co-chain are also known. Shielnshantz et al. reported specific
`PGA, PGB, PGD, PGE and PGF derivatives modified by
`introduction of a cyclic structure are less irritant and con
`gestive to the eye (Japanese Unexamined Patent Publication
`JP-A-8-109132). Ophthalmic compositions for local thera
`peutic medicines for glaucoma and ocular hypertension
`containing a chloprostenol or fluprostenol analog have been
`also reported (Japanese Unexamined Patent Publication
`JP-A-7-165703).
`Among the above-mentioned compounds disclosed in
`the literature, the compound 13,14-dihydro-17-phenyl-18,
`19,20-trinor-PGF2, isopropyl ester (Latanoprost) has an
`excellent pharmacological effect, and ophthalmic solutions
`containing Latanoprost as an active ingredient are used for
`treatment of glaucoma and ocular hypertension at actual
`medical sites. Although Latanoprost is less irritant and
`congestive to the eye, there is still room for improvement in
`the melanogenesis-stimulating property and the duration of
`efficacy. In particular, Latanoprost stimulates
`melanogenesis, and its side effect of causing iridal pigmen
`tation (A. Alm, et al, Ophthalmology, Vol. 102, No. 12,
`1743–1752 (1995)) remains a problem to be solve.
`For this reason, extensive research has been conducted
`both at home and abroad for development of long-lasting
`PGF derivatives having much the same biological activities
`as the naturally occurring one and few side effects.
`Meanwhile, Bezglov et al. reported 15-fluoro-15-deoxy
`PGF2, which is derived from naturally occurring PGF20 by
`introducing fluorine at the 15-position and retains the skel
`eton of its origin. 15-Fluoro-15-deoxy-PGF2, is reported to
`have remarkable pharmacological actions such as the 100
`fold greater contraction action and the 1000-fold relaxation
`action on smooth muscle in the respiratory system as com
`pared with those of the naturally occurring PGF2, and the
`55
`action on the smooth muscle in the digestive and circulatory
`systems comparable to that of the naturally occurring PGF2,
`(Izv. Akad. Nauk SSSR, Ser. Biol., 6,831 (1989). However,
`no report has been made on any pharmacological actions of
`the compound on any eye disease, particularly on glaucoma.
`No prostaglandin F derivatives that have a fluorine atom
`at the 15-position have been known except 15-fluoro-15
`deoxy-PGF2, Especially, no report has been made on
`derivatives having two fluorine atoms at the 15-position,
`15,15-difluoro-15-deoxy PGs F2, per se or their synthesis.
`The present inventors synthesized 15,15-difluoro-15
`deoxy-PGF2, and its novel derivatives and measured their
`
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`2
`biological activities to assess their usefulness as medicines.
`The present inventors also measured the biological activities
`of derivatives of 15,15-difluoro-15-deoxy-PGF2, which
`have a substituted or unsubstituted aryloxy group on the
`co-chain and are prepared by modifying the carboxyl group
`or the hydroxyl group of the prostaglandin to assess their
`usefulness as medicines. As a result, the present inventors
`have found that 15,15-difluoro-15-deoxy-PGF2, and its
`derivatives are superior to the known natural PGF2, in the
`effect of lowering intraocular pressure are scarcely irritant to
`the eye, scarcely affect the ocular tissues such as the cornea,
`the iris and the conjunctive, and have long-lasting efficacy.
`They are characterized in that they stimulates melanogenesis
`much less as well as in that their efficacy lasts longer than
`Latanoprost.
`The present invention relates to the compound 15,15
`difluoro-15-deoxy-PGF2, and its derivatives and their use as
`medicines, in particular, as medicines for eye diseases, and
`provides a fluorine-containing prostaglandin derivative of
`the following formula (1) or a salt thereof:
`
`
`
`(1)
`
`wherein A is an ethylene group, a vinylene group, an
`ethynylene group, —OCH2— or —SCH2—,
`R’ is a substituted or unsubstituted Cas alkyl group, a
`substituted or unsubstituted Csis alkenyl group, a sub
`stituted or unsubstituted Csis alkynyl group, a substi
`tuted or unsubstituted Csis cycloalkyl group, a substi
`tuted or unsubstituted aralkyl group or a substituted or
`unsubstituted aryloxyalkyl group,
`each of Rº and R' which are independent of each other,
`is a hydrogen atom or an acyl group, or forms a single
`bond together with Z,
`X is —CH2—, -O- or —S—, Z is —OR*,
`—NHCOR’, -NHSO.R" or —SR’, or forms a single
`bond together with Rº or Rº,
`each of R", Rº, Rº and R7 which are independent of one
`another, is a hydrogen atom, an alkyl group, an alkenyl
`group, an alkynyl group, a cycloalkyl group, an aryl
`group or an aralkyl group,
`and a dual line consisting of solid and broken lines is a
`single bond, a cis-double bond or a trans-double bond,
`a medicine containing the above compound as an active
`ingredient; and a preventive or therapeutic medicine for
`an eye disease containing the above compound as an
`active ingredient.
`The fluorine-containing prostaglandin derivatives of the
`present invention may be the same as the naturally occurring
`type except for the two fluorine atoms at the 15-position
`(namely, compounds wherein A is a vinylene group, R' is a
`n-pentyl group, both Rº and Rº are hydrogen atoms, X is
`—CH2—, Zis–OH, and the dual line is a cis-double bond).
`However, among the fluorine-prostaglandin derivatives of
`the present invention, those having an oo-chain which is not
`of the naturally occurring type (namely, wherein A is a
`vinylene group, and R' is a n-pentyl group) are preferred. In
`particular, those having wherein R’ is one of the above
`mentioned groups except an alkyl group are preferred.
`In the present invention, the eye disease as the target for
`prevention or therapy is preferably glaucoma or ocular
`hypertension.
`
`Micro Labs Exhibit 1001-2
`
`

`

`5,886,035
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`In the following description, the term “lower” for an
`organic group corresponds to a carbon number of from 1 to
`6. A preferred lower organic group is an organic group
`having from 1 to 4 carbon atoms.
`An “alkyl group” may be linear or branched, and unless
`otherwise noted, a lower alkyl group is preferred. Specific
`examples include a methyl group, an ethyl group, a propyl
`group, an isopropyl group, a butyl group, an isobutyl group,
`a sec-butyl group, a t-butyl group, a pentyl group and a hexyl
`grOup.
`An “alkenyl group” is preferably a lower alkenyl group,
`unless otherwise noted, and more preferably a linear or
`branched alkenyl group having from 2 to 6 carbon atoms and
`one unsaturated group. Specific examples include a vinyl
`group, an allyl group, a 1-propenyl group, an isopropenyl
`group, a 3-butenyl group, a 3-pentenyl group and a
`4-hexenyl group.
`An “alkynyl group” is preferably a lower alkynyl group,
`unless otherwise noted, more preferably a linear or branched
`alkynyl group having from 2 to 6 carbon atoms and one
`unsaturated group. Specific examples include a 1-propynyl
`group, a 2-propynyl group, a 3-butynyl group, a 3-pentynyl
`group and a 4-hexynyl group.
`As an “alkoxy group”, although a wide variety of com
`mon alkoxy groups may be used, a lower alkoxy group is
`25
`preferred, and more preferred is a linear or branched alkoxy
`group having from 1 to 4 carbon atoms. Specific examples
`include a methoxy group, an ethoxy group, a propoxy group
`and a butoxy group.
`A “halogen atom” means a fluorine atom, a chlorine atom,
`a bromine atom or an iodine atom.
`An “aryl group” means a monovalent aromatic hydrocar
`bon group which may have a substituent (such as a lower
`alkyl group, a halogen atom, a haloalkyl group, a lower
`alkoxy group or a lower alkylamino group), preferably a
`phenyl group or its derivative. For example, a phenyl group,
`a tolyl group, a halophenyl group (such as a chlorophenyl
`group, a fluorophenyl group or a bromophenyl group), a
`dihalophenyl group (such as a dichlorophenyl group, a
`difluorophenyl group or a dibromophenyl group), a trih
`alophenyl group (such as a trichlorophenyl group, a trifluo
`rophenyl group or a tribromophenyl group), a haloalkylphe
`nyl group (such as a trifluoromethylphenyl group), an
`alkoxyphenyl group (such as a methoxyphenyl group or an
`ethoxyphenyl group), a dialkoxyphenyl group (such as a
`dimethoxyphenyl group or a diethoxyphenyl group) or a
`trialkoxyphenyl group (such as a trimethoxyphenyl group or
`a triethoxyphenyl group) may be mentioned.
`An “aralkyl group” means an aryl-substituted alkyl group,
`in which the aryl group as the substituent may be as
`described above, and the carbon number of the alkyl group
`is preferably from 1 to 4. Specific examples include a benzyl
`group, a benzhydryl group, a trityl group and a phenethyl
`grOup.
`A “cycloalkyl group” means an unsubstituted or substi
`tuted 3 to 8-membered cycloalkyl group, and when
`substituted, may have a lower alkyl group, a halogen atom
`or an alkoxy group as a substituent. For example, a cyclo
`propyl group, a cyclobutyl group, a cyclopentyl group, a
`cyclohexyl group, a cycloheptyl group, a methylcyclohexyl
`group, a dimethylcyclopentyl group, a dimethylcyclohexyl
`group, a chlorocyclohexyl group or a dichlorocyclohexyl
`group may be mentioned.
`A “haloalkyl group” means a lower haloalkyl group
`having at least one halogen atom. A fluoromethyl group, a
`difluoromethyl group, a trifluoromethyl group, a trifluoro
`ethyl group, a pentafluoroethyl group, a chloromethyl group,
`
`35
`
`4
`a dichloromethyl group, a trichlromethyl group or a bro
`momethyl group may be mentioned.
`An “acyl group” means a monovalent or polyvalent group
`derived from a carboxylic acid by removing hydroxyl group
`(s) from all the carboxyl group(s). As the carboxylic acid, a
`saturated or unsaturated aliphatic carboxylic acid, a carbocy
`clic carboxylic acid or a heterocyclic carboxylic acid may be
`mentioned. As the carbocyclic carboxylic acid, a saturated or
`unsaturated alicyclic carboxylic acid or an aromatic car
`oboxylic acid may be mentioned.
`Among the fluorine-containing prostaglandin derivatives
`of the formula (1) (hereinafter referred to as the fluorine
`containing prostaglandin derivatives (1)), the following
`compounds are preferred from the standpoint of biological
`activities and physical properties.
`As A, a vinylene group or an ethylene group is preferred,
`and the vinylene group induces cis- or trans-vinylene
`groups. A trans-vinylene group is particularly preferred. In
`the case of —OCH2—or —SCH2—, the oxygen atom or the
`sulfur atom is preferably linked to the ring.
`As X, -CH2— is particularly preferred.
`The dual line consisting of solid and broken lines is
`preferably a cis-double bond.
`R’ is preferably an organic group corresponding to the
`Go-chain moiety of the naturally occurring PGF2, (when the
`rest is not of the naturally occurring type) or an organic
`group corresponding to the co-chain moiety of any of various
`synthetic PGs F2. Such organic groups include, for
`example, a Cas alkyl group, a Cas alkenyl group, a Cs-s
`alkynyl group, a Cs-s cycloalkyl group, an aralkyl group, an
`aryloxy group having an aryl group such as a phenyl group,
`and such groups having various substituents.
`The alkyl group may have a cyclic organic group such as
`a cycloalkyl group as a substituent, and the alkenyl group
`and the alkynyl group may have a cyclic organic group such
`as an aryl group or a cycloalkyl group as a substituent. For
`example, R' may be a cycloalkyl group-substituted alkyl
`group, a cycloalkyl group-substituted alkenyl group, or an
`aryl group-substituted alkenyl group. Further, it may be an
`organic group having an oxygen atom or a sulfur atom
`introduced to replace a carbon atom of a linear organic group
`such as an alkyl group, or an organic group having a cyclic
`organic group such as a cycloalkylene group or an arylene
`group introduced between two carbon atoms of a linear
`organic group. Further, a cycloalkyl group, an aralkyl group,
`an aryloxy group and an organic group having such a group
`as a substituent may have a linear organic group such as an
`alkyl group as a substituent on the ring moiety. Substituents
`in R* include, in addition to the above-mentioned
`substituents, a halogen atom, an oxygen atom-containing
`substituent, a sulfur atom-containing substituent, a nitrogen
`atom-containing substituent, and others.
`When R’ is a linear substituted or unsubstituted group, a
`linear Cs-g alkyl group, a linear Cs-g alkenyl group and a
`linear Cs-g alkynyl group and such groups substituted with
`one or two methyl group are particularly preferred. Specific
`linear groups as R' include the following groups. Among
`them, preferred are a n-pentyl group, a 2-methylhexyl group,
`a 1-methyl-3-pentynyl group, a 1-methyl-3-hexynyl group,
`and a 1,1-dimethyl-3-hexynyl group.
`A n-propyl group, a n-butyl group, a n-pentyl group, a
`n-hexyl group, a n-heptyl group, a n-Octyl group, a n-decyl
`group, a 1-methylpentyl group, a 1,1-dimethylpentyl group,
`a 1-methylhexyl group, a 2-methylpentyl group, a
`2-methylhexyl group, a 3-pentenyl group, a 1-methyl-3
`pentenyl group, a 1-methyl-3-hexenyl group, a 1,1
`dimethyl-3-pentenyl group, a 1,1-dimethyl-3-hexenyl
`
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`
`Micro Labs Exhibit 1001-3
`
`

`

`5,886,035
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`group, a 2-methyl-3-pentenyl group, a 2-methyl-3-hexenyl
`group, a 3-pentynyl group, a 1-methyl-3-pentynyl group, a
`1-methyl-3-hexynyl group, a 2-methyl-3-pentynyl group, a
`2-methyl-3-hexynyl group, a 1,1-dimethyl-3-pentynyl
`group, and a 1,1-dimethyl-3-hexynyl group.
`The substituted or unsubstituted cycloalkyl group as R' is
`preferably a Cas cycloalkyl group, or such a cycloalkyl
`group substituted by at least one lower alkyl group. Particu
`larly preferred is an unsubstituted cyclopentyl group, an
`unsubstituted cyclohexyl group, a C1-1 alkyl group
`substituted cyclopentyl group, or a C-4 alkyl group
`substituted cyclohexyl group.
`The substituted or unsubstituted aralkyl group as R' is
`preferably an aralkyl group which contains, for example, a
`benzene ring, a furan ring, a thiophene ring or a naphthalene
`ring and may be substituted by, for example, a halogen atom,
`a haloalkyl group, an alkoxy group or a hydroxyl group. The
`carbon number of the alkyl moiety (i.e. the alkylene group)
`of the aralkyl group is preferably from 1 to 4. A particularly
`preferred aralkyl group is a C1-2 alkyl group substituted with
`a phenyl group or a C1-2 alkyl group substituted with a
`phenyl group substituted with one or two lower alkyl groups.
`Specifically, a phenylmethyl group, a 2-phenylethyl
`group, a 3-methylphenylmethyl group, a 2-(3-methylphenyl)
`ethyl group, a 3-trifluoromethylphenylmethyl group, a 2-(3
`trifluoromethylphenyl)ethyl group, a 3-chlorophenylmethyl
`group, a 2-(3-chlorophenyl)ethyl group, a 2-(3,5
`dichlorophenyl)ethyl group and a 2-(3,4-dichlorophenyl)
`ethyl group are preferred.
`The substituted or unsubstituted aryloxyalkyl group as R'
`is preferably an aryloxyalkyl group which contains, for
`example, a benzene ring, a furan ring, a thiophene ring or a
`naphthalene ring and may have, for example, a halogen
`atom, a haloalkyl group, an alkoxy group or a hydroxyl
`group as a substituent on the aryl moiety. The aryl moiety is
`preferably a phenyl group which is not substituted or sub
`stituted with from 1 to 3 halogen atoms or haloalkyl groups.
`The carbon number of the alkyl moiety substituted with an
`aryloxy group is preferably from 1 to 3.
`Specific preferred aryloxyalkyl groups as a phenoxym
`ethyl group, a 3-chlorophenoxymethyl group, a
`3-fluorophe noxy methyl
`group,
`&l
`3-trifluoromethylphenoxymethyl group, a 3,5
`dichlorophen oxy methyl
`grO up,
`&l
`3,4
`dichlorophen oxy methyl
`grO up,
`&l
`3,5
`45
`difluorophenoxymethyl group, a 3,4-difluorophenoxymethyl
`group, a 3,5-bis(trifluoromethyl)phenoxymethyl group and a
`3,4-bis(trifluoromethyl)phenoxymethyl group.
`As R', in addition to those described above, a C-, alkyl
`group substituted by the above-mentioned cycloalkyl group
`is preferred as a type of substituted alkyl group. As such a
`cycloalkyl group, a cyclopentyl group or a cyclohexyl group
`is preferred, and as such an alkyl group, a C1-2 alkyl group
`is preferred. Specific examples include a cyclopentylmethyl
`group, a 2-cyclopentylethyl group and a cyclohexylmethyl
`grOup.
`As R', more preferred are the above-mentioned substi
`tuted or unsubstituted aryloxyalkyl groups. Among them, a
`substituted or unsubstituted phenoxymethyl group such as a
`phenoxymethyl group, a 3-chlorophenoxymethyl group, a
`3,5-dichlorophe noxymethyl group or a 3,4
`dichlorophenoxymethyl group is preferred.
`Each of Rº and Rº' which are independent of each other,
`is a hydrogen atom or an acyl group, or forms a single bond
`as described later. It is preferred that both Rº and R are
`hydrogen atoms, or that either R or R is an acyl group and
`the other is a hydrogen atom. When only one of them is an
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`6
`acyl group, it is preferred that R is an acyl group. Com
`pounds wherein at least one of Rº and R is an acyl group
`are useful as prodrugs because they hydrolyze in vivo to
`biologically active compounds. As the acyl group, a C2 2.0
`acyl group, particularly, an aliphatic hydrocarbon type C2-20
`acyl group is preferred. In particular, fluorine-containing
`prostaglandin derivatives wherein either R or R is an
`aliphatic linear hydrocarbon type acyl group having a carbon
`number of at least 4 are useful as prodrugs having improved
`lipid solubility.
`Z is —OR", -NHCOR*, —NHSO.R.", —SR’ or repre
`sents a single bond together with Rº or Rº, which means
`cyclization of a compound wherein Z is OH and either R or
`R’ is a hydrogen atom (a compound having a carboxyl group
`at the end of the Cº-chain and a hydroxyl group either at the
`9-position or at the 11-position) by esterification of the
`carboxyl group and the hydroxyl group to form an ester bond
`between the end of the Cº-chain and the 9- or 11-position.
`Such cyclic compounds having an ester bond hydrolyze in
`vivo into biologically active compounds, and therefore are
`useful as prodrugs.
`As R*—R7 in the groups represented by —OR",
`—NHCOR’, -NHSO.R." and —SR’, a hydrogen atom, an
`alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl
`group, an aryl group and an aralkyl group may be men
`tioned. The alkyl group, the alkenyl group, the alkynyl group
`and the alkyl moiety of the aralkyl group may be linear or
`branched and may have various substituents such as halogen
`atoms. The cycloalkyl group, the aryl group and the aralkyl
`group may have an alkyl group or other substituents on the
`ring. As such substituents, the substituents described above
`for R' may be mentioned.
`The alkyl group, the alkenyl group and the alkynyl group
`as R*-R" preferably have a carbon number of at most 20,
`particularly, at most 8. Specific examples of these linear
`hydrocarbon groups include the following groups. As the
`alkyl group, a methyl group, an ethyl group, a n-propyl
`group, an isopropyl group, a n-butyl group, a n-pentyl group,
`a n-hexyl group, a n-heptyl group, a n-Octyl group, a n-decyl
`group, a 1-methylpentyl group, a 1,1-dimethylpentyl group,
`a 1-methylhexyl group, a 2-methylpentyl group and
`2-methylhexyl group may be mentioned.
`As the alkenyl group, an allyl group, a 2-butenyl group,
`a 3-pentenyl group, 1-methyl-3-pentenyl group, 1-methyl
`3-hexenyl group, 1,1-dimethyl-3-pentenyl group and a 1,1
`dimethyl-3-hexenyl group may be mentioned.
`As the alkenyl group, a propargyl group, a 3-pentynyl
`group, a 1-methyl-3-pentynyl group, a 1-methyl-3-hexynyl
`group, a 1,1-dimethyl-3-pentynyl group and a 1,1-dimethyl
`3-hexynyl group may be mentioned.
`As the substituted alkyl group, a halogen atom-substituted
`alkyl group or a cycloalkyl group-substituted alkyl group
`may be mentioned. The carbon number of the halogen
`atom-substituted alkyl group is preferably at most 6, and the
`carbon number of the alkyl moiety of the cycloalkyl group
`substituted alkyl group is preferably from 1 to 2. As the
`halogen atom-substituted alkyl group, for example, a trif
`luoromethyl group or a pentafluoroethyl group may be
`mentioned. As the cycloalkyl group-substituted alkyl group,
`for example, a cyclobutylmethyl group, a cyclopentylmethyl
`group or a cyclohexylmethyl group may be mentioned.
`The carbon number of the cycloalkyl group is preferably
`at most 10. Specific examples include a cyclopropyl group,
`a cyclobutyl group, a cyclopentyl group, a cyclohexyl group,
`a 2,2-dimethylcyclopropyl group, a 3-cyclopentenyl group,
`a 3-cyclohexynyl group and a cyclooctanyl group.
`As the aryl group, a substituted or unsubstituted phenyl
`group is preferred. As the substituent, an alkyl group
`
`Micro Labs Exhibit 1001-4
`
`

`

`5,886,035
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`The fluorine-containing prostaglandin derivatives of the
`present invention can be synthesized by a process similar to
`a general process for producing prostaglandin F2. For
`example, first of all, the Go-chain is introduced into the
`starting material, a Corey lactone, and the resulting enone is
`converted by fluorination into an o-chain-containing Corey
`lactone having two fluorine atoms at the 15-position. Sub
`sequent reduction of the lactone is to a lactol followed by
`introduction of the Cº-chain unit by the Wittig reaction, and,
`if necessary, acylation or of a hydroxyl group or removal of
`the protecting group for a hydroxyl group, gives fluorine
`containing prostaglandin derivatives of the present inven
`tion. The introduction of the Cº-chain unit may be followed
`by conversion of a carboxyl group into an ester, an acyl
`amide, a sulfonamide or a thioester and, if necessary,
`removal of the protecting group for a hydroxyl group or
`acylation of a hydroxyl group to produce fluorine-containing
`prostaglandin derivatives of the present invention.
`Specifically speaking, the fluorine-containing prostaglan
`din derivatives (1) can be prepared, for example, by a
`process comprising fluorination of a ketone (2) having an
`Go-chain to give an Go-chain-containing Corey lactone (3)
`having two fluorine atoms at the 15-position, reduction of
`the lactone (3) to a lactol (4) and reaction of the lactol (4)
`with a phosphorane (5) to introduce an O-chain unit. The
`phosphorane (5) is obtainable from a phosphonium salt (6).
`Because it is not necessary for the starting compound to have
`the same configuration as the resulting fluorine-containing
`prostaglandin derivative (1), the following formulae (2) to
`(4) do not specify the configurations of the substituents
`bonded to the cyclopentane rings. In the formulae (5) and
`(6), Rº is a substituted or unsubstituted alkyl group, a
`substituted or unsubstituted aryl group, a substituted or
`unsubstituted aralkyl group or a dialkylamino group, and Y
`is a halogen atom such as a chlorine atom, a bromine atom
`or an iodine atom.
`
`25
`
`7
`(preferably having a carbon number of at most 4), a halom
`ethyl group, a halogen atom, an alkoxy group, an acyl group,
`an acylamino group or a nitro group is preferred. Specific
`examples of the aryl group include a phenyl group, a
`4-methylphenyl group, a 4-(t-butyl)phenyl group, a
`3-trifluoromethylphenyl group, a 4-trifluoromethylphenyl
`group, a 4-chlorophenyl group, a 4-acetylphenyl group, a
`4-benzoylphenyl group, a 4-acetylaminophenyl group, a
`4-benzoylaminophenyl group, a 3-nitrophenyl group and a
`4-nitrophenyl group.
`As the aralkyl group, an aralkyl group consisting of an
`alkyl moiety having a carbon number of at most 4
`(preferably a carbon number of 1 or 2) and a phenyl group
`is preferred. The phenyl group may be substituted with an
`alkyl group (preferably having a carbon number of at most
`4), a halomethyl group, a halogen atom, an alkoxy group, an
`acyl group, an acylamino group, a nitro group or the like.
`The alkyl moiety of the aralkyl group may be branched.
`Specific examples include:
`a benzyl group, a phenethyl group, a diphenylmethyl
`group, a 3-methylphenylmethyl group, a
`3-chlorophe nyl methyl
`group,
`&l
`3-fluoro me thyl phenylmethyl group, a
`3-bro mop he nyl methyl
`group,
`&l
`3-trifluoromethylphenylmethyl group, a 1-(3
`methylphenyl)ethyl group, a 1-(3-chlorophenyl)ethyl
`group, a 1-(3-trifluoromethylphenyl)ethyl group, a
`1-(3-fluorophenyl)ethyl group, a 1-(3-bromophenyl)
`ethyl group, a 2-(3-methylphenyl)ethyl group, a 2-(3
`chlorophenyl)ethyl
`group,
`a
`2-(3
`trifluoromethylphenyl)ethyl group, a 2-(
`30
`3-fluorophenyl)ethyl group, a 2-(3-bromophenyl)ethyl
`group, a 1-methyl-2-(3-methylphenyl)ethyl group, a
`1-methyl-2-(3-chlorophenyl)ethyl group, a 1-methyl-2
`(3-trifluoromethylphenyl)ethyl group, a 1-methyl-2-(3
`fluorophenyl)ethyl group and a 1-methyl-2-(3
`bromophenyl)ethyl group.
`Each of R"—R’ is preferably a substituted or unsubstituted
`alkyl, cycloalkyl or aralkyl group. As the substituent, a
`halogen atom or an alkyl group having a carbon number of
`at most 4 which is bonded to a ring is preferred. Particularly
`preferred R'-R" are alkyl groups, and a haloalkyl is par
`ticularly preferred as R*.
`Z is preferably a group represented by —OR". R* in Z is
`preferably a hydrogen atom or a C1-20 hydrocarbon group
`such as an alkyl group, a cycloalkyl group or an aralkyl
`group. Compounds wherein R* is a hydrocarbon group are
`useful as prodrugs because they hydrolyze in vivo into
`biologically active compounds. It is possible to improve the
`lipid solubility of compounds by proper selection of hydro
`carbon groups. As Z, particularly preferred are a hydroxyl
`group, a methoxy group, an ethoxy group, an isopropoxy
`group, an isobutoxy group, a cyclohexyloxy group and a
`benzyloxy group.
`A fluorine-containing prostaglandin derivative of the
`present invention having an acidic group such as a carboxy
`group, for example like those wherein Z is a hydroxyl group,
`may take the form of a salt with a base. Similarly, when a
`compound of the present invention has a basic group such as
`an amino group, it may take the form of a salt with an acid.
`Salts with bases include alkali metal salts such as sodium
`salts and potassium salts, alkaline earth metal salts such as
`calcium salts and magnesium salts and ammonium salts such
`as unsubstituted ammonium salts and alkyl-substituted
`ammonium salts. Salts with acids include inorganic acid
`salts such as hydrochlorides, sulfates and phosphates and
`organic acid salts such as acetates, oxalates, citrates, succi
`nates and p-toluenesulfonates.
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Micro Labs Exhibit 1001-5
`
`

`

`5,886,035
`
`...~
`
`-continued
`COZ
`
`(5)
`
`(6) 5
`
`The ketones shown above are known compound except
`those having specific substituents as R'. The novel ketones
`having specific substituents as R' can be prepared by a
`process similar to that for the other known ketones. For
`example, these ketones can be prepared by reaction of a
`dialkyl 3-substituted-2-oxopropylphosphonate with a Corey
`lactone having a formyl group.
`The conversion of a ketone into an Go-chain-containing
`Corey lactone having two fluorine atoms at the 15-position
`by fluorination can be achieved by various known fluorina
`tion processes, for example, by using various nucleophilic
`fluorinating agents in inert solvents.
`When a ketone as the starting material has a functional
`group liable to fluorinate during the fluorination, it is pre
`ferred to preliminarily protect the functional group by a
`protecting group. For example, when R’ is a hydrogen atom,
`R’ is preferably protected by a protecting group during the
`fluorination of the carbonyl group at the 15-position and
`then the protection group is removed.
`The protecting groups include, for example, a triorganosi
`lyl group, an acyl group, an alkyl group, an aralkyl group
`and a cyclic ether group. An acyl group to protect a hydroxyl
`group at the 11-position of a ketone used as the starting
`material may be the same as or different from the acyl group
`as R* of a fluorine-containing prostaglandin derivative (1).
`A fluorine-containing prostaglandin derivative (1) having an
`acyl group which is different from the acyl group used as the
`protecting group can be obtained by removing the protecting
`group and then introducing a different acyl group.
`The triorganosilyl group is a group having three organic
`groups such as alkyl groups, aryl groups, aralkyl groups or
`alkoxy groups bonded to a silicon atom. Particularly pre
`ferred is a triorganosilyl group having three groups of at
`least one kind selected from the group consisting of lower
`alkyl groups and aryl groups. Specifically, a
`t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, a
`triethylsilyl group, a triphenylsilyl group or a triisopropyl
`silyl group may, for example, be preferred.
`As the acyl group, an acetyl group, a trifluoroacetyl group,
`a pivaloyl group, a benzoyl group or a p-phenylbenzoyl
`group is preferred, and as the cyclic ether group, a tetrahy
`dropyranyl group or a tetrahydrofuranyl group is preferred.
`As the alkyl group or the aralkyl group which may have a
`substituent, an alkoxyalkyl group such as a methoxymethyl
`group, a 1-ethoxyethyl group or a 2-methoxyethoxymethyl
`group as well as a benzyl group, a methoxybenzyl group or
`a trityl group may, for example, be mentioned.
`The protecting group for a hydroxyl group as mentioned
`above, can be converted to a hydroxyl group by a conven
`tional method. For example, it can readily be converted to a
`hydroxyl group by methods disclosed in publications e.g.
`“Shinjikken Kagaku Koza 14 Syntheses and Reactions of
`Organic Compounds (I), (II) and (V)”, published by
`Maruzen, and “Protective Groups in Organic Synthesis”
`written by T. W. Greene, published by J. Wiley & Sons.
`The p