2,2-difluoro 15-hydroxyeicosatetraenoic acid analogs and methods of use

2,2-Difluoro HETE derivatives and methods of their use for treating dry eye are disclosed.

The present invention is directed to novel hydroxyeicosatetraenoic acid
 related compounds, compositions and methods of use. The compounds are
 particularly useful in treating dry eye.
 BACKGROUND OF THE INVENTION
 Dry eye, also known generically as Keratoconjunctivitis sicca, is a common
 ophthalmological disorder affecting millions of Americans each year. The
 condition is particularly widespread among post-menopausal women due to
 hormonal changes following the cessation of fertility. Dry eye may afflict
 an individual with varying severity. In mild cases, a patient may
 experience burning, a feeling of dryness, and persistent irritation such
 as is often caused by small bodies lodging between the eye lid and the eye
 surface. In severe cases, vision may be substantially impaired. Other
 diseases, such as Sjogren's disease and Cicatricial pemphigoid manifest
 dry eye complications.
 Although it appears that dry eye may result from a number of unrelated
 pathogenic causes, all presentations of the complication share a common
 effect, that is the breakdown of the pre-ocular tear film, which results
 in dehydration of the exposed National Eye Institute/Industry Workshop on
 Clinical Trials in Dry Eyes, The CLAO Journal, volume 21, number 4, pages
 221-231 (1995)).
 Practitioners have taken several approaches to the treatment of dry eye.
 One common approach has been to supplement and stabilize the ocular tear
 film using so-called artificial tears instilled throughout the day. Other
 approaches include the use of ocular inserts that provide a tear
 substitute or stimulation of endogenous tear production.
 Examples of the tear substitution approach include the use of buffered,
 isotonic saline solutions, aqueous solutions containing water soluble
 polymers that render the solutions more viscous and thus less easily shed
 by the eye. Tear reconstitution is also attempted by providing one or more
 components of the tear film such as phospholipids and oils. Phospholipid
 compositions have been shown to be useful in treating dry eye; see, e.g.,
 McCulley and Shine, Tear film structure and dry eye, Contactologia, volume
 20(4), pages 145-49 (1998); and Shine and McCulley, Keratoconjunctivitis
 sicca associated with meibomian secretion polar lipid abnormality,
 Archives of Ophthalmology, volume 116(7), pages 849-52 (1998). Examples of
 phospholipid compositions for the treatment of dry eye are disclosed in
 U.S. Pat. Nos. 4,131,651 (Shah et al.), 4,370,325 (Packman), 4,409,205
 (Shively), 4,744,980 and 4,883,658 (Holly), 4,914,088 (Glonek), 5,075,104
 (Gressel et al.), 5,278,151 (Korb et al.), 5,294,607 (Glonek et al.),
 5,371,108 (Korb et al.) and 5,578,586 (Glonek et al.) U.S. Pat. No.
 5,174,988 (Mautone et al.) discloses phospholipid drug delivery systems
 involving phospholipids, propellants and an active substance.
 U.S. Pat. No. 3,991,759 (Urquhart) discloses the use of ocular inserts in
 the treatment of dry eye. Other semi-solid therapy has included the
 administration of carrageenans (U.S. Pat. No. 5,403,841, Lang) which gel
 upon contact with naturally occurring tear film.
 Another approach involves the provision of lubricating substances in lieu
 of artificial tears. For example, U.S. Pat. No. 4,818,537 (Guo) discloses
 the use of a lubricating, liposome-based composition, and U.S. Pat. No.
 5,800,807 (Hu et al.) discloses compositions containing glycerin and
 propylene glycol for treating dry eye.
 Aside from the above efforts, which are directed primarily to the
 alleviation of symptoms associated with dry eye, methods and compositions
 directed to treatment of the dry eye condition have also been pursued. For
 example, U.S. Pat. No. 5,041,434 (Lubkin) discloses the use of sex
 steroids, such as conjugated estrogens, to treat dry eye condition in
 post-menopausal women; U.S. Pat. No. 5,290,572 (MacKeen) discloses the use
 of finely divided calcium ion compositions to stimulate pre-ocular tear
 film production; and U.S. Pat. No. 4,966,773 (Gressel et al.) discloses
 the use of microfine particles of one or more retinoids for ocular tissue
 normalization.
 Although these approaches have met with some success, problems in the
 treatment of dry eye nevertheless remain. The use of tear substitutes,
 while temporarily effective, generally requires repeated application over
 the course of a patient's waking hours. It is not uncommon for a patient
 to have to apply artificial tear solution ten to twenty times over the
 course of the day. Such an undertaking is not only cumbersome and time
 consuming, but is also potentially very expensive. Transient symptoms of
 dry eye associated with refractive surgery have been reported to last in
 some cases from six weeks to six months or more following surgery.
 The use of ocular inserts is also problematic. Aside from cost, they are
 often unwieldy and uncomfortable. Further, as foreign bodies introduced in
 the eye, they can be a source of contamination leading to infections. In
 situations where the insert does not itself produce and deliver a tear
 film, artificial tears must still be delivered on a regular and frequent
 basis.
 Mucins are proteins which are heavily glycosylated with glucosamine-based
 moieties. Mucins provide protective and lubricating effects to epithelial
 cells, especially those of mucosal membranes. Mucins have been shown to be
 secreted by vesicles and discharged on the surface of the conjunctival
 epithelium of human eyes (Greiner et al., Mucous Secretory Vesicles in
 Conjunctival Epithelial Cells of Wearers of Contact Lenses, Archives of
 Ophthalmology, volume 98, pages 1843-1846 (1980); and Dilly et al.,
 Surface Changes in the Anaesthetic Conjunctiva in Man, with Special
 Reference to the Production of Mucous from a Non-Goblet-Cell Source,
 British Journal of Ophthalmology, volume 65, pages 833-842 (1981)). A
 number of human-derived mucins which reside in the apical and subapical
 corneal epithelium have been discovered and cloned (Watanabe et al., Human
 Corneal and Conjunctival Epithelia Produce a Mucin-Like Glycoprotein for
 the Apical Surface, Investigative Ophthalmology and Visual Science, volume
 36, number 2, pages 337-344 (1995)). Recently, Watanabe discovered a new
 mucin which is secreted via the cornea apical and subapical cells as well
 as the conjunctival epithelium of the human eye (Watanabe et al., IOVS,
 volume 36, number 2, pages 337-344 (1995)). These mucins provide
 lubrication, and additionally attract and hold moisture and sebaceous
 material for lubrication and the corneal refraction of light.
 Mucins are also produced and secreted in other parts of the body including
 lung airway passages, and more specifically from goblet cells interspersed
 among tracheal/bronchial epithelial cells. Certain arachidonic acid
 metabolites have been shown to stimulate mucin production in these cells.
 Yanni reported the increased secretion of mucosal glycoproteins in rat
 lung by hydroxyeicosatetraenoic acid ("HETE") derivatives (Yanni et al,
 Effect of Intravenously Administered Lipoxygenase Metabolites on Rat
 Trachael Mucous Gel Layer Thickness, International Archives of Allergy And
 Applied Immunology, volume 90, pages 307-309 (1989)). Similarly, Marom has
 reported the production of mucosal glycoproteins in human lung by HETE
 derivatives (Marom et al., Human Airway Monohydroxy- eicosatetraenoic Acid
 Generation and Mucous Release, Journal of Clinical Investigation, volume
 72, pages 122-127 (1983)).
 Agents claimed for increasing ocular mucin and/or tear production include
 vasoactive intestinal polypeptide (Dartt et. al., Vasoactive intestinal
 peptide-stimulated glycocongjugate secretion from conjunctival goblet
 cells, Experimental Eye Research, volume 63, pages 27-34, (1996)),
 gefarnate (Nakmura et. al., Gefarnate stimulates secretion of mucin-like
 glycoproteins by corneal epithelium in vitro and protects corneal
 epithelium from dessication in vivo, Experimental Eye Research, volume 65,
 pages 569-574 (1997)), liposomes (U.S. Pat. No. 4,818,537), androgens
 (U.S. Pat. No. 5,620,921), melanocycte stimulating hormones (U.S. Pat. No.
 4,868,154), phosphodiesterase inhibitors (U.S. Pat. No 4,753,945), and
 retinoids (U.S. Pat. No. 5,455,265). However, many of these compounds or
 treatments suffer from a lack of specificity, efficacy and potency and
 none of these agents have been marketed so far as therapeutically useful
 products to treat dry eye and related ocular surface diseases.
 U.S. Pat. No. 5,696,166 (Yanni et al.) discloses compositions containing
 naturally occurring HETEs, or derivatives thereof, and methods of use for
 treating dry eye. Yanni et al. discovered that compositions comprising
 HETEs increase ocular mucin secretion when administered to a patient and
 are thus useful in treating dry eye.
 In view of the foregoing, there is a need for an effective, convenient
 treatment for dry eye that is capable of alleviating symptoms, as well as
 treating the underlying physical and physiological deficiencies of dry
 eye.
 SUMMARY OF THE INVENTION
 The present invention is directed to compositions and methods for the
 treatment of dry eye and other disorders requiring the wetting of the eye,
 including symptoms of dry eye associated with refractive surgery such as
 LASIK surgery. More specifically, the present invention discloses
 2,2-difluoro derivatives of (5Z,8Z, 11Z,
 13E)-15-hydroxyeicosa-5,8,11,13-tetraenoic acid (15-HETE). The
 compositions are preferably administered topically to the eye.
 The compounds of the present invention are believed to be more stable than
 the naturally occurring HETE-related compounds.
 DETAILED DESCRIPTION OF THE INVENTION
 The present invention is directed to novel 2,2-difluoro, 15-HETE
 derivatives, compositions and methods of use. It is believed that, among
 other utilities, the compounds stimulate ocular mucin production and/or
 secretion following topical ocular application and are therefore believed
 to be useful in treating dry eye. These compounds are of formula I:
 ##STR1##
 wherein:
 R.sup.1 is CO.sub.2 R, CONR.sup.2 R.sup.3, CH.sub.2 OR.sup.4, CH.sub.2
 NR.sup.5 R.sup.6, CH.sub.2 N.sub.3, CH.sub.2 Hal, CH.sub.2 NO.sub.2,
 CH.sub.2 SR.sup.20, COSR.sup.21 or 2,3,4,5-tetrazol-1-yl, wherein:
 R is H or CO.sub.2 R forms a pharmaceutically acceptable salt or a
 pharmaceutically acceptable ester;
 NR.sup.2 R.sup.3 and NR.sup.5 R.sup.6 are the same or different and
 comprise a free or functionally modified amino group, e.g., R.sup.2,
 R.sup.3, R.sup.5 and R.sup.6 are the same or different and are H, alkyl,
 cycloalkyl, aralkyl, aryl, OH, or alkoxy, with the proviso that at most
 only one of R.sup.2 and R.sup.3 are OH or alkoxy and at most only one of
 R.sup.5 and R.sup.6 are OH or alkoxy;
 OR.sup.4 comprises a free or functionally modified hydroxy group, e.g.,
 R.sup.4 is H, acyl; alkyl, cycloalkyl, aralkyl, or aryl;
 Hal is F, Cl, Br or I;
 SR.sup.20 comprises a free or functionally modified thiol group;
 R.sup.21 is H or COSR.sup.21 forms a pharmaceutically acceptable salt or a
 pharmaceutically acceptable thioester;
 A, B, C and D are the same or different and are C.sub.1 -C.sub.5 alkyl,
 alkenyl, or alkynyl or a C.sub.3 -C.sub.5 allenyl group;
 X is C(O) (i.e. a carbonyl group) or X is
 ##STR2##
 wherein R.sup.9 O constitutes a free or functionally modified hydroxy
 group.
 The compounds of formula (I) may also be incorporated into phospholipids as
 glyceryl esters or sphingomyelin amides. Phospholipid sphingomyelin amides
 of the compounds of formula (I) will typically comprise a formula (I)
 compound amidated via its carbon 1 carboxylate to the amino group of the
 sphingomyelin backbone. The phospholipid formula (I) esters will comprise
 various phospholipids. Phospholipid esters of the compounds of formula (I)
 will typically comprise a formula (I) compound esterified via its carbon 1
 carboxylate to the sn-1 or sn-2 position alcohol, or both, of the glycerol
 backbone of the phospholipid. If the sn-1 or sn-2 position of the glyceryl
 ester class does not contain an ester of a compound of formula (I), then
 such carbon positions of the glycerol backbone will comprise a methylene,
 ether or ester moiety linked to a substituted or unsubstituted C.sub.12-30
 alkyl or alkenyl (the alkenyl group containing one or more double bonds);
 alkyl(cycloalkyl)alkyl; alkyl(cycloalkyl); alkyl(heteroaryl);
 alkyl(heteroaryl)alkyl; or alkyl-M-Q; wherein the substitution is alkyl,
 halo, hydroxy, or functionally modified hydroxy; M is O or S; and Q is H,
 alkyl, alkyl(cycloalkyl)alkyl, alkyl(cycloalkyl), alkyl(heteroaryl) or
 alkyl(heteroaryl)alkyl. However, at least one of the sn-1 or sn-2 position
 alcohols of the glycerol backbone must form an ester with a compound of
 formula (I) via the carbon 1 carboxylate of the latter. Preferred
 phospholipid-formula (I) esters will be of the phosphatidylethanolamine,
 phosphatidylcholine, phosphatidylserine, and phospatidylinositol type. The
 most preferred phospholipid-formula (I) esters will comprise a formula (I)
 compound esterified via its carbon 1 carboxylate to the alcohol at the
 sn-2 position of phosphatidylcholine, phosphatidylethanolamine or
 phosphatidylinositol. The phospholipid-formula (I) esters and
 sphingomyelin amides may be synthesized using various phospholipid
 synthetic methods known in the art; see for example, Tsai et al.,
 Biochemistry, volume 27, page 4619 (1988); and Dennis et al.,
 Biochemistry, volume 32, page 10185 (1993).
 Included within the scope of the present invention are the individual
 enantiomers of the compounds of the present invention, as well as their
 racemic and non-racemic mixtures. The individual enantiomers can be
 enantioselectively synthesized from the appropriate enantiomerically pure
 or enriched starting material by means such as those described below.
 Alternatively, they may be enantioselectively synthesized from
 racemic/non-racemic or achiral starting materials. (Asymmetric Synthesis;
 J. D. Morrison and J. W. Scott, Eds.; Academic Press Publishers: New York,
 1983-1985, volumes 1-5; Principles of Asymmetric Synthesis; R. E. Gawley
 and J. Aube, Eds.; Elsevier Publishers: Amsterdam, 1996). They may also be
 isolated from racemic and non-racemic mixtures by a number of known
 methods, e.g. by purification of a sample by chiral HPLC (A Practical
 Guide to Chiral Separations by HPLC; G. Subramanian, Ed.; VCH Publishers:
 New York, 1994; Chiral Separations by HPLC; A. M. Krstulovic, Ed.; Ellis
 Horwood Ltd. Publishers, 1989), or by enantioselective hydrolysis of a
 carboxylic acid ester sample by an enzyme (Ohno, M.; Otsuka, M. Organic
 Reactions, volume 37, page 1 (1989)). Those skilled in the art will
 appreciate that racemic and non-racemic mixtures may be obtained by
 several means, including without limitation, nonenantioselective
 synthesis, partial resolution, or even mixing samples having different
 enantiomeric ratios. Departures may be made from such details within the
 scope of the accompanying claims without departing from the principles of
 the invention and without sacrificing its advantages. Also included within
 the scope of the present invention are the individual isomers
 substantially free of their respective enantiomers.
 As used herein, the terms "pharmaceutically acceptable salt",
 "pharmaceutically acceptable ester" and "pharmaceutically acceptable
 thioester" means any salt, ester or thioester, respectively, that would be
 suitable for therapeutic administration to a patient by any conventional
 means without significant deleterious health consequences; and
 "ophthalmically acceptable salt", "ophthalmically acceptable ester" and
 "ophthalmically acceptable thioester" means any pharmaceutically
 acceptable salt, ester or thioester, respectively, that would be suitable
 for ophthalmic application, i.e. non-toxic and non-irritating.
 The term "free hydroxy group" means an OH. The term "functionally modified
 hydroxy group" means an OH which has been functionalized to form: an
 ether, in which an alkyl, aryl, cycloalkyl, heterocycloalkyl, alkenyl,
 cycloalkenyl, heterocycloalkenyl, alkynyl, or heteroaryl group is
 substituted for the hydrogen; an ester, in which an acyl group is
 substituted for the hydrogen; a carbamate, in which an aminocarbonyl group
 is substituted for the hydrogen; or a carbonate, in which an aryloxy-,
 heteroaryloxy-, alkoxy-, cycloalkoxy-, heterocycloalkoxy-, alkenyloxy-,
 cycloalkenyloxy-, heterocycloalkenyloxy-, or alkynyloxy-carbonyl group is
 substituted for the hydrogen. Preferred moieties include OH, OCH.sub.2
 C(O)CH.sub.3,OCH.sub.2 C(O)C.sub.2 H.sub.5, OCH.sub.3, OCH.sub.2 CH.sub.3,
 OC(O)CH.sub.3, and OC(O)C.sub.2 H.sub.5.
 The term "free amino group" means an NH.sub.2. The term "functionally
 modified amino group" means an NH.sub.2 which has been functionalized to
 form: an aryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-,
 heterocycloalkoxy-, alkenyl-, cycloalkenyl-, heterocycloalkenyl-,
 alkynyl-, or hydroxy-amino group, wherein the appropriate group is
 substituted for one of the hydrogens; an aryl-, heteroaryl-, alkyl-,
 cycloalkyl-, heterocycloalkyl-, alkenyl-, cycloalkenyl-,
 heterocycloalkenyl-, or alkynyl-amino group, wherein the appropriate group
 is substituted for one or both of the hydrogens; an amide, in which an
 acyl group is substituted for one of the hydrogens; a carbamate, in which
 an aryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-, heterocycloalkoxy-,
 alkenyl-, cycloalkenyl-, heterocycloalkenyl-, or alkynyl-carbonyl group is
 substituted for one of the hydrogens; or a urea, in which an aminocarbonyl
 group is substituted for one of the hydrogens. Combinations of these
 substitution patterns, for example an NH.sub.2 in which one of the
 hydrogens is replaced by an alkyl group and the other hydrogen is replaced
 by an alkoxycarbonyl group, also fall under the definition of a
 functionally modified amino group and are included within the scope of the
 present invention. Preferred moieties include NH.sub.2, NHCH.sub.3,
 NHC.sub.2 H.sub.5, N(CH.sub.3).sub.2, NHC(O)CH.sub.3, NHOH, and
 NH(OCH.sub.3).
 The term "free thiol group" means an SH. The term "functionally modified
 thiol group" means an SH which has been functionalized to form: a
 thioether, where an alkyl, aryl, cycloalkyl, heterocycloalkyl, alkenyl,
 cycloalkenyl, heterocycloalkenyl, alkynyl, or heteroaryl group is
 substituted for the hydrogen; or a thioester, in which an acyl group is
 substituted for the hydrogen. Preferred moieties include SH,
 SC(O)CH.sub.3, SCH.sub.3, SC.sub.2 H.sub.5, SCH.sub.2 C(O)C.sub.2 H.sub.5,
 and SCH.sub.2 C(O)CH.sub.3.
 The term "acyl" represents a group that is linked by a carbon atom that has
 a double bond to an oxygen atom and a single bond to another carbon atom.
 The term "alkyl" includes straight or branched chain aliphatic hydrocarbon
 groups that are saturated and have 1 to 15 carbon atoms. The alkyl groups
 may be interrupted by one or more heteroatoms, such as oxygen, nitrogen,
 or sulfur, and may be substituted with other groups, such as halogen,
 hydroxyl, aryl, cycloalkyl, aryloxy, or alkoxy. Preferred straight or
 branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and
 t-butyl.
 The term "cycloalkyl" includes straight or branched chain, saturated or
 unsaturated aliphatic hydrocarbon groups which connect to form one or more
 rings, which can be fused or isolated. The rings may be substituted with
 other groups, such as halogen, hydroxyl, aryl, aryloxy, alkoxy, or lower
 alkyl. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl,
 cyclopentyl and cyclohexyl.
 The term "heterocycloalkyl" refers to cycloalkyl rings that contain at
 least one heteroatom such as O, S, or N in the ring, and can be fused or
 isolated. The rings may be substituted with other groups, such as halogen,
 hydroxyl, aryl, aryloxy, alkoxy, or lower alkyl. Preferred
 heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl,
 piperazinyl, and tetrahydropyranyl.
 The term "alkenyl" includes straight or branched chain hydrocarbon groups
 having 1 to 15 carbon atoms with at least one carbon-carbon double bond,
 the chain being optionally interrupted by one or more heteroatoms. The
 chain hydrogens may be substituted with other groups, such as halogen.
 Preferred straight or branched alkenyl groups include, allyl, 1-butenyl,
 1-methyl-2-propenyl and 4-pentenyl.
 The term "cycloalkenyl" includes straight or branched chain, saturated or
 unsaturated aliphatic hydrocarbon groups which connect to form one or more
 non-aromatic rings containing a carbon-carbon double bond, which can be
 fused or isolated. The rings may be substituted with other groups, such as
 halogen, hydroxyl, alkoxy, or lower alkyl. Preferred cycloalkenyl groups
 include cyclopentenyl and cyclohexenyl.
 The term "heterocycloalkenyl" refers to cycloalkenyl rings which contain
 one or more heteroatoms such as O, N, or S in the ring, and can be fused
 or isolated. The rings may be substituted with other groups, such as
 halogen, hydroxyl, aryl, aryloxy, alkoxy, or lower alkyl. Preferred
 heterocycloalkenyl groups include pyrrolidinyl, dihydropyranyl, and
 dihydrofuranyl.
 The term "carbonyl group" represents a carbon atom double bonded to an
 oxygen atom, wherein the carbon atom has two free valencies.
 The term "aminocarbonyl" represents a free or functionally modified amino
 group bonded from its nitrogen atom to the carbon atom of a carbonyl
 group, the carbonyl group itself being bonded to another atom through its
 carbon atom.
 The term "lower alkyl" represents alkyl groups containing one to six
 carbons (C.sub.1 -C.sub.6).
 The term "halogen" represents fluoro, chloro, bromo, or iodo.
 The term "aryl" refers to carbon-based rings which are aromatic. The rings
 may be isolated, such as phenyl, or fused, such as naphthyl. The ring
 hydrogens may be substituted with other groups, such as lower alkyl,
 halogen, free or functionalized hydroxy, trihalomethyl, etc. Preferred
 aryl groups include phenyl, 3-(trifluoromethyl)phenyl, 3-chlorophenyl, and
 4-fluorophenyl.
 The term "heteroaryl" refers to aromatic hydrocarbon rings which contain at
 least one heteroatom such as O, S, or N in the ring. Heteroaryl rings may
 be isolated, with 5 to 6 ring atoms, or fused, with 8 to 10 atoms. The
 heteroaryl ring(s) hydrogens or heteroatoms with open valency may be
 substituted with other groups, such as lower alkyl or halogen. Examples of
 heteroaryl groups include imidazole, pyridine, indole, quinoline, furan,
 thiophene, pyrrole, tetrahydroquinoline, dihydrobenzofuran, and
 dihydrobenzindole.
 The terms "aryloxy", "heteroaryloxy", "alkoxy", "cycloalkoxy",
 "heterocycloalkoxy", "alkenyloxy", "cycloalkenyloxy",
 "heterocycloalkenyloxy", and "alkynyloxy"represent an aryl, heteroaryl,
 alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl,
 heterocycloalkenyl, or alkynyl group, respectively, attached through an
 oxygen linkage.
 The terms "alkoxycarbonyl", "aryloxycarbonyl", "heteroaryloxycarbonyl",
 "cycloalkoxycarbonyl", "heterocycloalkoxycarbonyl", "alkenyloxycarbonyl",
 "cycloalkenyloxycarbonyl", "heterocycloalkenyl oxycarbonyl", and
 "alkynyloxycarbonyl" represent an alkoxy, aryloxy, heteroaryloxy,
 cycloalkoxy, heterocycloalkoxy, alkenyloxy, cycloalkenyloxy,
 heterocycloalkenyloxy, or alynyloxy group, respectively, bonded from its
 oxygen atom to the carbon of a carbonyl group, the carbonyl group itself
 being bonded to another atom through its carbon atom.
 Preferred compounds of the present invention include those of formula I,
 wherein:
 R.sup.1 is CO.sub.2 R, wherein R is H or CO.sub.2 R forms an ophthalmically
 acceptable salt or an ophthalmically acceptable ester;
 A, B, C, D are the same or different and are CH.dbd.CH or C.ident.C; and
 X is
 ##STR3##
 Among the particularly preferred compounds of formula (I) are compounds
 2-4, whose preparations are detailed in the following examples 1-3:
 ##STR4##

Ingredient Amount (% w/v)
 Compound 1 0.00001-0.01
 Ethanol 0.0505
 Polyoxyl 40 Stearate 0.1
 Boric Acid 0.25
 Sodium Chloride 0.75
 Disodium Edetate 0.01
 Polyquaternium-1 0.001
 NaOH/HCl q.s., pH = 7.5
 Purified Water q.s. 100%
 The above composition is prepared by the following method. The batch
 quantities of polyoxyl 40 stearate, boric acid, sodium chloride, disodium
 edetate, and polyquaternium-1 are weighed and dissolved by stirring in 90%
 of the batch quantity of purified water. The pH is adjusted to 7.5.+-.0.1
 with NaOH and/or HCI. Under yellow light or reduced lighting, the batch
 quantity of Compound 1 as a stock solution in ethanol and the additional
 quantity of ethanol necessary for the batch are measured and added.
 Purified water is added to q.s. to 100%. The mixture is stirred for five
 minutes to homogenize and then filtered through a sterilizing filter
 membrane into a sterile recipient.
 Preferably, the above process is performed using glass, plastic or other
 non-metallic containers or containers lined with such materials.
 EXAMPLE 2

Ingredient Amount (% w/v)
 Compound of formula (I) 0.00001-0.01
 Ethanol 0.005-0.2
 Polyoxyl 40 Stearate 0.1
 Boric Acid 0.25
 Sodium Chloride 0.75
 Disodium Edetate 0.01
 Polyquaternium-1 0.001
 NaOH/HCl q.s., pH = 7.5
 Purified Water q.s. 100%
 The above formulation may be made by a method similar to the method
 described in Example 1.
 EXAMPLE 3

Ingredient Amount (% w/v)
 Compound of formula (I) 0.00001-0.01
 Polyoxyl 40 Stearate 0.1
 Ethanol 0.005-0.2
 Boric Acid 0.25
 Sodium Chloride 0.75
 NaOH/HCl q.s., pH = 7.5
 Purified Water q.s. 100%
 The above formulation may be made by a method similar to the method
 described in Example 1.
 EXAMPLE 4
 The following is an example of an artificial tears carrier-composition of
 the present invention:

Ingredient Amount (% w/v)
 Compound of formula (I) 0.00001-0.01
 HPMC 0.3
 Dextran 70 0.1
 Sodium Chloride 0.8
 Potassium Chloride 0.12
 Dibasic Sodium Phosphate 0.025
 Disodium EDTA 0.01
 Polyquaternium-1 0.001 + 10% excess
 Purified Water Qs
 NaOH/HCl qs to pH 6-8
 The above formulation may be made by a method similar to the method
 described in Example 1.
 EXAMPLE 5
 The following is an example of a phospholipid carrier-composition of the
 present invention:

Ingredient Amount (% w/v)
 Compound of formula (I) 0.00001-0.01
 Ethanol 0.005-0.2
 Polyoxyl 40 Stearate 0.1
 DPPC 0.05
 DPPE 0.05
 Sodium Chloride 0.8
 Potassium Chloride 0.12
 Dibasic Sodium Phosphate 0.025
 Disodium EDTA 0.01
 Polyquaternium-1 0.001 + 10% excess
 Purified Water Qs
 NaOH/HCl qs to pH 6-8
 The above formulation may be made by a method similar to the method
 described in Example 1.
 The invention in its broader aspects is not limited to the specific details
 shown and described above. Departures may be made from such details within
 the scope of the accompanying claims without departing from the principles
 of the invention and without sacrificing its advantages.