The present invention relates to the use of 6-keto PGF1xcex1 and analogs thereof to stimulate mucin secretion to treat dry eye, keratoconjunctivitis, Sjogren""s syndrome and related ocular surface diseases.
Dry eye is a common ocular surface disease afflicting millions of people in the U.S. each year, especially the elderly (Schein et. al., Prevalence of dry eye among the elderly. American J. Ophthalmology, 124:723-738, (1997)). 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, the common end result is the breakdown of the tear film, which results in dehydration of the exposed outer surface of the eye. (Lemp, Report of the Nation Eye Institute/Industry Workshop on Clinical Trials in Dry Eyes, The CLAO Journal, 21(4):221-231 (1995)). Four events have been identified which singly or in combination are believed to result in the dry eye condition: a) decreased tear production or increased tear evaporation; b) decreased conjunctival goblet-cell density; c) increased corneal desquamation; and d) destabilization of the cornea-tear interface (Gilbard, Dry eye: pharmacological approaches, effects, and progress. The CLAO Journal, 22:141-145 (1996)). Another major problem is the decreased mucin production by the conjunctival cells and/or corneal epithelial cells of mucin, which protects and lubricates the ocular surface (Gipson and Inatomi, Mucin genes expressed by ocular surface epithelium. Progress in Retinal and Eye Research, 16:81-98 (1997)).
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. Another approach has been the use of ocular inserts that provide a tear substitute or to stimulate 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. Examples of these treatment approaches 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.) and 5,294,607 (Glonek et. al.).
United States Patents directed to the use of ocular inserts in the treatment of dry eye include U.S. Pat. No. 3,991,759 (Urquhart). 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 recent approach involves the provision of lubricating substances in lieu of artificial tears. U.S. Pat. No. 4,818,537 (Guo) discloses the use of a lubricating, liposome-based composition.
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 tear film; 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.
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.
In view of the foregoing, there is a clear need for an effective treatment for dry eye that is capable of alleviating symptoms, as well as treating the underlying physical and physiological deficiencies of dry eye, and that is both convenient and inexpensive to administer.
Mucins are proteins which are heavily glycosylated with glucosarnine-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 conjuctival epithelium of human eyes (Greiner et. al., Mucus Secretory Vesicles in Conjunctival Epithelial Cells of Wearers of Contact Lenses, Archives of Ophthalmology, 98:1843-1846 (1980); and Dilly et. al., Surface Changes in the Anaesthetic Conjunctiva in Man, with Special Reference to the Production of Mucus from a Non-Goblet-Cell Source, British Journal of Ophthalmology, 65:833-842 (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 Conjuctival Epithelia Produce a Mucin-Like Glycoprotein for the Apical Surface, Investigative Ophthalmology and Visual Science (IOVS), 36(2):337-344 (1995)). Recently, a new mucin was reported to be secreted via the cornea apical and subapical cells as well as the conjunctival epithelium of the human eye (Watanabe et. al., IOVS, 36(2):337-344 (1995)). These mucins provide lubrication, and additionally attract and hold moisture and sebacious 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 (xe2x80x9cHETExe2x80x9d) derivatives (Yanni et. al., Effect of Intravenously Administered Lipoxygenase Metabolites on Rat Trachael Mucous Gel Layer Thickness, International Archives of Allergy And Applied Immunology, 90:307-309 (1989)).
The conventional treatment for dry eye, as discussed above, includes administration of artificial tears to the eye several times a day. Other agents claimed for increasing ocular mucin and/or tear production include vasoactive intestinal polypeptide (Dartt et. al., Vasoactive intestinal peptide-stimulated glycocongfugate secretion from conjunctival goblet cells. Experimental Eye Research, 63:27-34, (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, 65:569-574 (1997)), and the use of 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), retinoids (U.S. Pat. No. 5,455,265) and hydroxyeicosatetraenoic acid derivatives (U.S. Pat. No. 5,696,166). 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. Thus, there remains a need for an efficacious therapy for the treatment of dry eye and related diseases.
Prostaglandins are metabolite derivatives of arachidonic acid. Arachidonic acid in the body is converted to prostaglandin G2, which is subsequently converted to prostaglandin H2. Other naturally occurring prostaglandins are derivatives of prostaglandin H2. A number of different types of prostaglandins are known in the art including A, B, C, D, E, F, G, I and J-Series prostaglandins (U.S. Pat. No. 5,151,444; EP 0 561 073 A1; Coleman et. al., VIII International Union of Pharmacology classification of prostanoid receptors: Properties, distribution, and structure of the receptors and their subtypes, Pharmacological Reviews, 45:205-229 (1994)). Depending on the number of double-bonds in the xcex1-(top chain) and/or the xcfx89-chain (bottom chain), the prostaglandins are further classified with subscripts such as PGD2, PGE1, PGE2, PGF2xcex1, etc. (U.S. Pat. No. 5,151,444; Coleman et. al., VIII International Union of Pharmacology classification of prostanoid receptors: Properties, distribution, and structure of the receptors and their subtypes, Pharmacological Reviews, 45:205-229 (1994)). Whilst these classes of prostaglandins interact preferably with the designated major classes of receptors (e.g. DP, EP, FP) and subclasses of receptors (e.g. EP2, EP3, EP4), the subscripts associated with the prostaglandin does not necessarily correspond with the subclass of the receptor(s) with which they interact. Furthermore, it is well known that these endogenous prostaglandins are non-specific in terms of interacting with the various classes of prostaglandin receptors. Thus, the natural prostaglandin PGE2 not only interacts with EP2 receptors, but can also activate EP1, EP3 and EP4 receptors (Coleman et. al., VIII International Union of Pharmacology classification of prostanoid receptors: Properties, distribution, and structure of the receptors and their subtypes, Pharmacological Reviews, 45:205-229 (1994)).
The compound 6-keto-PGF1xcex1(1) is a known stable hydrolysis product of PGI2 in mammals, and is frequently used as a marker for the determination of PGI2 in blood and urine (Prostaglandins and Related Substances: A Practical Approach; C. Benedetto, R. G. McDonald-Gibson, S. Nigam, and T. F. Slater, Eds.; IRL Press: Oxford, 1987, pp. 13-16). Recently, it has been found that 6-keto PGF1xcex1 is a potent chloride secretagogue released by intestinal epithelial cells in response to hypoxia [Colgan et. al., J. Clin. Invest., 102:1161(1998)]. Of interest in the present invention are 1 and its structural analogs. 
The present invention is directed to compositions and methods for the treatment of dry eye and other disorders requiring the wetting of the eye. More specifically, the present invention discloses compositions containing 6-keto PGF1xcex1 and its analogs, and methods of their use for treating dry eye type disorders.
Preferred compositions include an effective amount of 6-keto PGF1xcex1 or an analog thereof for the production of mucins. The compositions are administered topically to the eye for the treatment of dry eye.
It has now been discovered that 6-keto PGF1xcex1and its analogs stimulate mucin production in human conjuctival epithelium and are therefore believed to be useful in treating dry eye. Specifically included are compounds of the following formula I: 
wherein:
R1 is (CH2)pCO2R, (CH2)pOR2, (CH2)pCOT, or (CH2)pT, where:
R is H or pharmaceutically acceptable cationic salt moiety, or CO2R forms a pharmaceutically acceptable ester moiety;
OR2 forms a free or functionally modified hydroxy group, where R2 is preferably H, alkyl, acyl, or aryl;
T comprises a free or functionally modified amino group and is preferably NR3R4 
where R3 and R4, are the same or different and are selected from the group consisting of H, alkyl, aryl, acyl, alkoxycarbonyl, alkoxy, aminocarbonyl, and hydroxy; and
p is 0 or 2;
Q9 and Q11 form a free or functionally modified hydroxy group and are preferably R9O and R11O, respectively, where R9 and R11 are the same or different and are preferably H, alkyl, acyl, or aryl;
Xxe2x80x94Y is CH2CH2, trans-CHxe2x95x90CH, or Cxe2x89xa1C;
one of A, B is H and the other comprises a free or functionally modified hydroxy group, or A-B together are the oxygen of a carbonyl group; and
D is cycloalkyl, C5-8 alkyl, (CH2)qAr or (CH2)qOAr; where q is 1-6; and
Ar is a phenyl ring optionally substituted with alkyl, halo, trihalomethyl, alkoxy, acyl, acyloxy, amino, alkylamino, acylamino, or hydroxy; or
D is (CH2)pAr1; where p is 0-6; and 
wherein:
W is CH2, O, S(O)m, NR10, CH2CH2, CHxe2x80x94CH, CH2O, CH2S(O)m, CHxe2x80x94N, or CH2NR10; where m is 0-2, and R10 is H, alkyl, or acyl; Z is H, alkyl, alkoxy, acyl, acyloxy, halo, trihalomethyl, amino, alkylamino, acylamino, or hydroxy; and 
is single or double bond.
It is believed that the compounds of formula I wherein D is selected from the group consisting of (CH2)qAr, (CH2)qOAr, (CH2)pAr1, and cycloalkyl, where p, q, Ar, and Ar1 are as defined above, are novel.
It is appreciated that those compounds of formula I wherein R9 is H (i.e., where a hydroxyl group is present at carbon 9) exist as an equilibrium mixture of ketoalcohol i and hemiketal ii isomers, with the latter usually being the predominant or even exclusive isomer. Both forms are included within the scope of the invention. For convenience, only the ketoalcohol form is depicted in the specification and claims. 
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 xe2x80x9cpharmaceutically acceptable saltxe2x80x9d and xe2x80x9cpharmaceutically acceptable ester/pharmaceutically acceptable thioesterxe2x80x9d 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 xe2x80x9cophthalmically acceptable saltxe2x80x9d, xe2x80x9cophthalmically acceptable esterxe2x80x9d, and xe2x80x9cophthalmically acceptable thioesterxe2x80x9d 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 xe2x80x9cfree hydroxy groupxe2x80x9d means an OH. The term xe2x80x9cfunctionally modified hydroxy groupxe2x80x9d 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, OCH2C(O)CH3,OCH2C(O)C2H5, OCH3, OCH2CH3, OC(O)CH3, and OC(O)C2H5.
The term xe2x80x9cfree amino groupxe2x80x9d means an NH2. The term xe2x80x9cfunctionally modified amino groupxe2x80x9d means an NH2 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 NH2 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 NH2, NHCH3, NHC2H5, N(CH3)2, NHC(O)CH3, NHOH, and NH(OCH3).
The term xe2x80x9cacylxe2x80x9d 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 xe2x80x9calkylxe2x80x9d 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 xe2x80x9ccycloalkylxe2x80x9d 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 xe2x80x9cheterocycloalkylxe2x80x9d 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 xe2x80x9calkenylxe2x80x9d includes straight or branched chain hydrocarbon groups having 1 to 15 carbon atoms with at least one carbonxe2x80x94carbon 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 alkeny groups include, allyl, 1-butenyl, 1-methyl-2-propenyl and 4-pentenyl.
The term xe2x80x9ccycloalkenylxe2x80x9d includes straight or branched chain, saturated or unsaturated aliphatic hydrocarbon groups which connect to form one or more non-aromatic rings containing a carbonxe2x80x94carbon 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 xe2x80x9cheterocycloalkenylxe2x80x9d 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 xe2x80x9ccarbonyl groupxe2x80x9d represents a carbon atom double bonded to an oxygen atom, wherein the carbon atom has two free valencies.
The term xe2x80x9caminocarbonylxe2x80x9d 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 xe2x80x9clower alkylxe2x80x9d represents alkyl groups containing one to six carbons (C1-C6).
The term xe2x80x9chalogenxe2x80x9d represents fluoro, chloro, bromo, or iodo.
The term xe2x80x9carylxe2x80x9d 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 xe2x80x9cheteroarylxe2x80x9d 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 xe2x80x9caryloxyxe2x80x9d, xe2x80x9cheteroaryloxyxe2x80x9d, xe2x80x9calkoxyxe2x80x9d, xe2x80x9ccycloalkoxyxe2x80x9d, xe2x80x9cheterocycloalkoxyxe2x80x9d, xe2x80x9calkenyloxyxe2x80x9d, xe2x80x9ccycloalkenyloxyxe2x80x9d, xe2x80x9cheterocycloalkenyloxyxe2x80x9d, and xe2x80x9calkynyloxyxe2x80x9d represent an aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, or alkynyl group attached through an oxygen linkage.
The terms xe2x80x9calkoxycarbonylxe2x80x9d, xe2x80x9caryloxycarbonylxe2x80x9d, xe2x80x9cheteroaryloxycarbonylxe2x80x9d, xe2x80x9ccycloalkoxycarbonylxe2x80x9d, xe2x80x9cheterocycloalkoxycarbonylxe2x80x9d, xe2x80x9calkenyloxycarbonylxe2x80x9d, xe2x80x9ccycloalkenyloxycarbonylxe2x80x9d, xe2x80x9cheterocycloalkenyloxycarbonylxe2x80x9d, and xe2x80x9calkynyloxycarbonylxe2x80x9d represent an alkoxy, aryloxy, heteroaryloxy, cycloalkoxy, heterocycloalkoxy, alkenyloxy, cycloalkenyloxy, heterocycloalkenyloxy, or alkynyloxy group 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 for purposes of the present invention are those compounds of formula I wherein:
R1 is CO2R, wherein R is H, or CO2R forms an ophthalmically acceptable salt or an ophthalmically acceptable ester moiety;
R9 and R11 are H;
Xxe2x80x94Y is CH2CH2, trans-CHxe2x95x90CH, or Cxe2x89xa1C;
one of A, Bxe2x95x90H, and the other is OH; and
D is n-C5H11, CH2CH2Ar, CH2OAr, or cyclohexyl, where Ar is a phenyl ring optionally substituted with halo or trihalomethyl.
Preferred novel compounds are those of formula I wherein:
R1 is CO2R, wherein R is H, or CO2R forms an ophthalmically acceptable salt or an ophthalmically acceptable ester moiety;
R9 and R11 are H;
Xxe2x80x94Y is CH2CH2, trans-CHxe2x95x90CH, or Cxe2x89xa1C;
one of A, Bxe2x95x90H, and the other is OH; and
D is CH2CH2Ar, CH2OAr, or cyclohexyl, where Ar is a phenyl ring optionally substituted with halo or trihalomethyl.
Among the most preferred of the foregoing compounds are the following compounds 1-6: 
Compound 1 is commercially available from Cayman Chemical Co., Ann Arbor, Mich. The syntheses of compounds 2 and 3 are disclosed in U.S. Pat. Nos. 4,205,178 and 4,158,667. Compounds 4-6 can be prepared as detailed in examples 1-3 (below).
USPTO Backgrounds
USPTO Backgrounds