Field of the Invention

The present invention relates to polar C-l esters of prostaglandins. More particularly, the present invention concerns C-l ester derivatives of naturally occurring and synthetic prostaglandins bearing polar groups in the alcohol portion. Such compounds are potent ocular hypotensives, and are particularly suitable for the management of glaucoma.

Due to their increased water solubility, they can be readily formulated in aqueous ophthalmic solutions.

Background of the Invention

Ocular hypotensive agents are useful in the treatment of a number of various ocular hypertensive conditions, such as post-surgical and post-laser trabeculectomy ocular hypertensive episodes, glaucoma, and as presurgical adjuncts.

Glaucoma is a disease of the eye characterized by increased intraocular pressure. On the basis of its etiology, glaucoma has been classified as primary or secondary. For example, primary glaucoma in adults (congenital glaucoma) may be either open-angle or acute or chronic angle-closure.

Secondary glaucoma results from pre-existing ocular diseases such as uveitis, intraocular tumor or an enlarged cataract.

The underlying causes of primary glaucoma are not yet known. The increased intraocular tension is due to the obstruction of aqueous humor outflow. In chronic open-angle glaucoma, the anterior chamber and its anatomic structures appear normal, but drainage of the aqueous humor is impeded. In acute or chronic angle-closure glaucoma, the anterior chamber is shallow, the filtration angle is narrowed, and the iris may obstruct the trabecular meshwork at the entrance of the canal of Schiemm. Dilation of the pupil may

push the root of the iris forward against the angle, and may produce pupillary block and thus precipitate an acute attack. Eyes with narrow anterior chamber angles are predisposed to acute angle-closure glaucoma attacks of various degrees of severity.

Secondary glaucoma is caused by any interference with the flow of aqueous humor from the posterior chamber into the anterior chamber and subsequently, into the canal of Schiemm. Inflammatory disease of the anterior segment may prevent aqueous escape by causing complete posterior synechia in iris bombe and may plug the drainage channel with exudates. Other common causes are intraocular tumors, enlarged cataracts, central retinal vein occlusion, trauma to the eye, operative procedures and intraocular hemorrhage.

Considering all types together, glaucoma occurs in about

2% of all persons over the age of 40 and may be asymptotic for years before progressing to rapid loss of vision. In cases where surgery is not indicated, topical β-adrenoreceptor antagonists have traditionally been the drugs of choice for treating glaucoma.

Prostaglandins were earlier regarded as potent ocular hypertensives; however, evidence accumulated in the last decade shows that some protaglandins are highly effective ocular hypotensive agents and are ideally suited for the long- term medical management of glaucoma (see, for example, Bito, L. Z. Biological Protection with Prostaglandins Cohen, M. M., ed., Boca Raton, Fla, CRC Press Inc., 1985, pp. 231-252; and

Bito, L. Z., Applied Pharmacology in the Medical Treatment of Glaucomas Drance, S. M. and Neufeld, A. H. eds., New York,

Grune & Stratton, 1984, pp. 477-505). Such prostaglandins include PGF2 _α , PGF^ _α , PGE2, and certain lipid-soluble esters, such as C^ to C5 alkyl esters, e.g. l-isopropyl ester, of such compounds.

In the United States Patent No. 4,599,353 certain prostaglandins and their derivatives, in particular PGE2 and

PGF2 _α and the Cj to C5 alkyl esters of the latter compound, were reported to possess ocular hypotensive activity and were recommended for use in glaucoma management. It was suggested that the Cj to C5 alkyl esters of PGF2 _α , such as its methyl and isopropyl esters, would be particularly advantageous due to their lipid-solubility which would permit more ready penetration through the cornea and would lower the effective amounts of these compounds.

Although the precise mechanism is not yet known, recent experimental results indicate that the prostaglandin- induced reduction in intraocular pressure results from increased uveoscleral outflow [Nilsson et al., I n v e s t .

Ophthalmol. Vis. Sci. 28(suppD. 284 (1987)].

The isopropyl ester of PGF2 _α has been shown to have significantly greater hypotensive potency than the parent compound, which was attributed to its more effective penetration through the cornea. In 1987 this compound was described as "the most potent ocular hypotensive agent ever reported" [see, for example, Bito, L. Z., Arch. Ophthalmol. 105.

1036 (1987), and Siebold et al., Prodru g 5 . 3 (1989)]. However, the use of PGF2 _α l-isopropyl ester or other C-l alkyl esters in the clinical practice, is considerably limited by formulation difficulties due to their hydrophobic nature. Their ophthalmic formulations can only be made with oily carriers, such as sterile anhydrous peanut oil.

Also, whereas prostaglandins appear to be devoid of significant intraocular side effects, ocular surface (conjunctival) hyperemia and foreign-body sensation have been consistently associated with the topical ocular use of such compounds, in particular PGF2 _α and its prodrugs, e.g. its l-isopropyl ester, in humans. The clinical potential of

prostaglandins in the management of conditions associated with increased ocular pressure, e.g. glaucoma, is greatly limited by these side effects.

In a series of co-pending United States patent applications assigned to Allergan, Inc. prostaglandin esters with increased ocular hypotensive activity accompanied with no or substantially reduced side-effects are disclosed. The co-pending USSN 386,835 (filed 27 July 1989), relates to certain 11-acyl-prostaglandins, such as 11-pivaloyl, 11 - acetyl, 11-isobutyryl, 11-valeryl, and 11-isovaleryl PGF2 _α .

Intraocular pressure reducing 15-acyl prostaglandins are disclosed in the co-pending application USSN 357,394 (filed

25 May 1989). Similarly, 11,15- 9,15- and 9,11-diesters of prostaglandins, for example 11,15-dipivaloyl PGF2 are known to have ocular hypotensive activity. See the co- pending patent applications USSN Nos. 385,645, 386,312 and 386,834 (all filed 27 July 1989). PGF l-alcohols and their use as ocular hypotensives are disclosed in co-pending patent application USSN 07/538,204 (filed 14 June 1990). Other prostaglandin derivatives for ocular use are, for example, disclosed in USSN 07/611,029 (filed 9 November 1990), USSN 07/624,659 (filed 10 December 1990) and USSN 07/623,234 (filed 6 December 1990). The disclosures of these patent applications are hereby expressly incorporated by reference.

Summary of the Tnvention

Surprisingly, it has been found that water-soluble C-l esters of prostaglandin compounds exhibit essentially the same ocular hypotensive activity as the 1 -alkyl esters of the same parent compound, and cause significantly lower ocular surface hyperemia. These compounds differ from the known C-l alkyl esters of prostaglandins in that they carry a polar group which dramatically increases their water-solubility. As a result, they can be readily formulated in water-based

solutions which greatly facilitates their use in glaucoma management.

In one aspect, the present invention relates to a method of treating ocular hypertension which comprises applying to the eye an amount sufficient to treat ocular hypertension of a compound of formula (I)

wherein the wavy line attachments indicate either alpha (α) or beta (β) configuration; hatched lines indicate α configuration, solid triangles are used to indicate β configuration; the dashed bonds represent a single bond or a double bond which can be in the cis or trans configuration; X is selected from the group consisting of O, S and NR, where R is hydrogen or an aliphatic hydrocarbon group of about 1 to about 6 carbon atoms; Y is a polar functional group; one of R _j and R2 is =0, -OH or a -0(CO)R4 group, and the other one is -OH or a -0(CO)R4 group or R _j is =0 and R2 is H; R3 is -OH or

-0(C0)R4, wherein R4 is a saturated or unsaturated acyclic hydrocarbon group having from 1 to about 20 carbon atoms, or -(CH2) _n R5 wherein n is 0-10, and R5 is an aliphatic ring from about 3 to about 7 carbon atoms, or an aromatic or heteroaromatic ring, wherein said heteroatom is O, S or N; or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method for increasing the water-solubility of prostaglandin compounds by converting them into their polar C-l esters, as hereinabove defined.

In a further aspect, the present invention relates to a pharmaceutical composition comprising an effective amount of a compound of formula (I) as hereinabove defined, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, such pharmaceutical compositions are in the form of ophthalmic solutions for the treatment of ocular hypertension, comprising an amount sufficient to treat ocular hypertension of a compound of formula (I) as hereinabove defined, or a pharmaceutically acceptable salt thereof.

The present invention further relates to pharmaceutical products comprising such ophthalmic solutions in a container adapted to dispense its contents in metered form.

In another aspect, the present invention relates to new polar prostaglandin C-l esters of the formula (I), in which the

Y polar functional group is a lower hydroxyalkyl or aminoalkyl group which may be optionally substituted in the alkyl moiety, a carboxyl or aminocarbonyl group, or a -SO3H or -PO3H group, and the other symbols and substituents are as hereinabove defined, and pharmaceutically acceptable salts of these compounds.

Detailed Description of the Invention

The present invention relates to polar C-l esters of prostaglandins.

Prostaglandins can be described as derivatives of prostanoic acid which has the following structural formula:

Various types of prostaglandins are known, depending on the structure and substituents carried on the alicyclic ring of the prostanoic acid skeleton. Further classification is based on the number of unsaturated bonds in the side chains indicated by numerical subscripts after the generic type of prostaglandin [e.g., prostaglandin E _j (PGE _j ), prostaglandin E2 (PGE2)], and on the configuration of the substituents on the alicyclic ring indicated by α or β [e.g. prostaglandin F2 _α (PGF _2α )].

The prostaglandin derivatives according to the present invention are encompassed by the formula (I)

wherein the wavy line attachments indicate either alpha (α) or beta (β ) configuration; hatched lines indicate α configuration, solid triangles are used to indicate β configuration; the dashed bonds represent a single bond or a double bond which can be in the cis or trans configuration; X is selected from the group consisting of O, S and NR, where R is hydrogen or an aliphatic hydrocarbon group of about 1 to about 6 carbon atoms; Y is a polar functional group; one of R _j and R2 is =0, -OH or a -0(CO)R4 group, and the other one is

-OH or a -0(CO)R4 group or Rj is =0 and R2 is H; R3 is -OH or

-0(CO)R4, wherein R4 is a saturated or unsaturated acyclic hydrocarbon group having from 1 to about 20 carbon atoms,

or -(CH2) _n R5 wherein n is 0-10, and R5 is an aliphatic ring from about 3 to about 7 carbon atoms, or an aromatic or heteroaromatic ring wherein said heteroatom is O, S or N; or a pharmaceutically acceptable salt thereof.

The above formula includes C-l polar esters of prostaglandins of the F, D, E, A and B series. A preferred group of the compounds of the present invention is encompassed by the following formula (II)

wherein Rχ/R2 is -OH/-OH, =0/-OH, -OH/=0 (the -OH groups may be esterified) and the other symbols and substituents are as defined hereinabove. This definition includes PGF, PGE, and PGD derivatives.

Particularly preferred are the PGF2 _α derivatives of the formula (III)

CH OH

and their 9- and/or 11- and/or 15 -esters.

In all of the above formulae, as well as in those provided hereinafter, the dotted lines on bonds between carbons 5 and 6 (C-5), between carbons 13 and 14 (C-13), between carbons 8 and 12 (C-8), between carbons 10 and 11 (C-10) and between carbons 17 and 18 (C-l 7) indicate a

single or a double bond which can be in the cis or trans configuration. If two solid lines are used that indicates a specific configuration for that double bond. Hatched lines at positions C-9, C-l l and C-15 indicate the α configuration. If one were to draw the β configuration, a solid triangular line would be used.

The naturally occurring stereochemistry of PGF2 _α includes the C-9, C-l l, and C-15 hydroxyl groups in the α configuration. In the compounds used in accorance with the present invention, however, prostaglandins having the C-9 or C-l l or C-15 substituents in β configuration are also contemplated. As hereinabove mentioned, in all formulas provided herein broken line attachments to the cyclopentane ring indicate substituents in the α configuration. Thickened solid line attachments to the cyclopentane ring indicate substituents in the α configuration. For instance, 9β- P G F compounds have the same structure as PGF _α compounds, except that the hydroxyl at the C-9 position is in the β configuration. Also, the broken line attachment of the hydroxyl group or other substituent to the C-l l and C-15 carbon atoms signifies the β configuration; therefore, com¬ pounds with the epi configuration for the hydroxyl group at C-15 are designated by using 15β and if there is no indication of the β configuration, the configuration is assumed α.

In all of the above groups preferred are compounds in which the Y polar functional group is a lower hydroxyalkyl or aminoalkyl group which may be optionally substituted in the alkyl moiety, a carboxyl or aminocarbonyl group, or a -SO3H or -PO3H group, and the other symbols and substituents are as hereinabove defined, and pharmaceutically acceptable salts of these compounds. Particularly preferred are such derivatives of PGF2 _α compounds. The optional substituents of the "alkyl" moiety include, for example, hydroxyl, nitro, chloro, fluoro, etc., and other substituents which do not affect

the therapeutic utility of the prostaglandin derivatives of this invention.

In the substituent definitions, the "aliphatic hydrocarbon groups" have from 1 to about 6, most preferably

1 to about 4 carbon atoms. The aliphatic hydrocarbon groups may be straight or branched chained, saturated or unsaturated, such as straight or branched chained alkyl, alkenyl, alkynyl groups. Typical representatives of the alkyl groups include, for example, methyl, ethyl, n_- and isopropyl, n_-, s ec -, iso- and tert-butyl, n_- and isopentyl, n_- and neohexyl, etc. groups. Typical alkenyl and alkynyl groups are vinyl, allyl, propenyl, ethynyl and propargyl.

The definition of R4 may include a cyclic component,

-(CH2) _n R5, wherein n is 0-10, R5 is an aliphatic ring from about 3 to about 7 carbon atoms, or an aromatic or heteroaromatic ring. The "aliphatic ring" may be saturated or unsaturated, and preferably is a saturated ring having 3-7 carbon atoms, inclusive. As an aromatic ring, R5 preferably is a monoaromatic, e.g., phenyl, and the heteroaromatic rings, which are also preferably monoaromatic, have oxygen, nitrogen or sulfur as a heteroatom and most preferably the heteroatom is sulfur, as in R5 is thienyl. Preferably n is 0-4.

In the definition of Y, the term "polar functional group" is used in the broadest sense and includes any groups comprising elements with different electronegativities and therefore having covalent bonds of polar nature.

The most preferred compounds are those PGF2 _α derivatives in which Y is a lower hydroxyalkyl or aminoalkyl group which may be optionally substituted in the alkyl moiety, a carboxyl or aminocarbonyl group, or a -SO3H or -PO3H group.

The term "lower alkyl" alone or in combination with other moieties refers to alkyl groups having from one to about 6 carbon atoms. Preferred are the alkyl groups containing 1 to about 4, more preferably, 1 or 2 carbon atoms.

Particularly preferred are the following compounds:

PGF _2α l-(2-hydroxy)ethyl ester, PGF2 _α 1 -aminocarbonylmethyl ester, and

PGF2 _α 1-glycolamide.

The compounds of the present invention can be pre¬ pared by methods known in the art. The synthesis of PGF2 _α l-(2-hydroxy)ethyl ester and PGF2 _α 1 -aminocarbonylmethyl ester is illustrated in the Examples and in the synthesis described in Figure 1 , where the reagents and reaction conditions employed are as follows:

Reaction a: ICH ₂ CH ₂ OH, iPr ₂ NEt, DMF, 70° C, 3 hours;

Reaction b: ICH ₂ CONH ₂ , iPr ₂ NEt, DMF, 25° C, 16 hours.

Other compounds of formula (I) can be made in an analogous manner or by other reactions well known in organic chemistry.

A pharmaceutically acceptable salt is any salt which retains the activity of the parent compound and does not impart any deleterious or undesirable effect on the subject to whom it is administered and in the context in which it is administered. Of particular interest are the acid addition salts of the amine compounds of the present invention. Within this group, ophthalmically acceptable salts are those which do not impart any deleterious or undesirable effect when applied to the eye.

Pharmaceutical compositions may be prepared by combining a therapeutically effective amount of at least one compound according to the present invention, or a pharmaceutically acceptable salt thereof, as an active ingredient, with conventional ophthalmically acceptable pharmaceutical excipients, and by preparation of unit dosage forms suitable for topical ocular use. The therapeutically efficient amount typically is between about 0.0001 and about 5% (w/v), preferably about 0.001 to about 1.0% (w/v) in liquid formulations.

For ophthalmic application, preferably solutions are prepared using a physiological saline solution as a major vehicle. The pH of such ophthalmic solutions should preferably be maintained between 6.5 and 7.2 with an appropriate buffer system, a substantially neutral pH being preferred. The formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.

Preferred preservatives that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate. A preferred surfactant is, for example, Tween 80.

Likewise, various preferred vehicles may be used in the ophthalmic preparations of the present invention. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.

Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable opthalmically acceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant for use in the present invention includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmic preparations are chelating agents. The preferred chelating agent is edentate disodium, although other chelating agents may also be used in place or in conjunction with it.

The ingredients are usually used in the following amounts:

Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative 0-0.10 vehicle 0-40 tonicity adjustor 0- 1 0 buffer 0.01 - 10 pH adjustor q.s. pH 4.5-7.5 antioxidant as needed surfactant as needed purified water as needed to make

100%

The actual dose of the active compounds of the present invention depends on the specific compound, and on the

condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.

The ophthalmic formulations of the present invention are conveniently packaged in forms suitable for metered application, such as in containers equipped with a dropper, to facilitate application to the eye. Containers suitable for dropwise application are usually made of suitable inert, non- toxic plastic material, and generally contain between about 0.5 and about 15 ml solution.

Especially preservative-free solutions are often formulated in non-resealable containers containing up to about ten, preferably up to about five units doses, where a typical unit dose is from one to about 8 drops, preferably one to about 3 drops. The volume of one drop usually is about 20-35 μl.

The invention is further illustrated by the following non-limiting Examples.

Example 1

PGF2 _α l-(2-hvdroxy )ethyl ester

Diisopropylethylamine (45 μl, 02.6 mmol) was added to a solution of PGF2 _α (45.3 mg, 0.128 mmol) and 2-iodoethanol

(30 μl, 0.38 mmol) in dry dimethylformamide (0.5 ml). The clear solution was heated under argon at 70° C for 3 h. The solvent and volatiles were evaporated in vacuo and the residue was partitioned between 10% citric acid and ethyl acetate. The crude product was extracted into ethyl acetate and the organic extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated to give 46 mg crude product. Purification was achieved by column chromatography (silica gel, 15: 1 methylene chloride/

methanol, Rf 0.26) to give 34.3 mg (67% yield) of pure PGF2 _α -l(2-hydroxy) ethyl ester.

1H NMR (300 MHz, CDCI ₃ ): 55.40 (2H, ABX, J _AB =15.2, JAX= ⁸ - ^{7 HZ} ) _> 5.33-5.48 (2H, m), 4.15-4.30 (2H, m), 4.14 (1H, t,

J=4 Hz), 4.04 (1H, q, J=7 Hz), 3.85-3.9 (1H, m), 3.81 (2H, t, J=4.6 Hz), 3.1 (4H, br s). 2.0-2.4 (9H, m), 1.2-1.8 (15H, M), 0.88 ppm (3H, distorted t, J=6.5 Hz); ^{1 3} C NMR (75 MHz, CDCI ₃ ):δl72.20, 135.54, 132.90, 129.67, 129.34, 77.63, 73.19, 72.51, 66.05, 60.81, 55.48, 49.72, 42.71, 37.09, 33.33, 31.74,

26.46, 25.56, 25.26, 24.62, 22.64, 14.07 ppm;

MS (El, TMS derivative):m/z 687 (M ⁺ , 0.8%), 597 (M- TMSOH, 6), 191 (25), 173 (16), 147 (14), 117 (20) 75 (39), 73 (100),

HRMS (El, TMS derivative): calculated for C3 H ₇ o0 ₆ Si: 686.4250, found; 685.4255.

Example 2

PGF2 1 -aminocarbonylmethyl ester

Diisopropylethylamine (19 μl, 0.11 mmol) was added to a solution of PGF2 _α (31 mg, 0.088 mmol) and iodoacetamide

(24.5 mg, 0.13 mmol) in dry dimethylformamide (0.25 ml) at 25° C. The clear solution was stirred at 25° C for 16 h. The solvent and volatiles were evaporated in vacuo and the residue was partitioned between 10% citric acid and ethyl acetate. The crude product was extracted into ethyl acetate and the organic extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated to give 35.8 mg crude product. Purification was achieved by column chromatography (silica gel, 10% methanol in ethyl acetate, Rf 0.25) to give 28.4 mg (79% yield) of pure PGF _{2 α} 1- aminocarbonylmethyl ester.

^l R NMR (300 MHz, CDCI ₃ ):δ6.25 (1H, br s), 5.91 (1H, br s), 5.54 (2H, ABX J _AB =15.4, J _A χ=6-2, Jβχ=8.1 Hz), 5.33-5.48 (2H, m), 4.58 (2H, AB, J=15.7 Hz), 4.17 (1H, br s), 4.08 (1H, q, J=6.2 Hz), 3.98 (1H, br s), 2.77 (1H, br s), 2.44 (2H, t, J=6.9 Hz),

2.05-2.5 (7H, m), 1.78-1.81 (3H, m), 1.2-1.75 (10H, m), 0.89 ppm (3H, distorted t, J=6.5Hz);

¹³ C NMR (75 MHz, CDCI ₃ ): 5172.79, 170.56, 135.61, 133.01, 129.61, 129.21, 77.36, 73.19, 72.16, 62.40, 55.27,

49.67, 42.86, 37.06, 32.93, 31.71, 26.35, 25.44, 25.27, 24.39, 22.63, 14.05 ppm;

IR (neat):3100-3600, 2930, 2860, 1745, 1680, 1430, 970 cm ^"1 .

Example 3

Intraocular Pressure Reducing Activity

Experimental quantities of the test compounds were prepared in an ophthalmic formulation containing 0.1% polysorbate (Tween 80) - lOmM TRIS. One eye of each experimental animal was treated by applying one 25 μl drop of the drug formulation to the ocular surface, the contralateral eye received 25 μl of vehicle as a control. Intraocular pressure was measured by applanation pneumatonometry immediately before drug administration and at subsequent, predetermined times thereafter. New Zealand albino/dutch belted cross rabbits were employed as experimental animals.

The results are shown in Table I where the ocular hypotensive effects of water soluble PGF2 _α -l-esters are compared to the activity of PGF2 _α -l-isopropyl ester. At a

0.1% concentration, the ocular hypotensive activity reaches a

virtually identical maximum (about 10 mmHg) for PGF2 _α - l - (2-hydroxy)ethyl ester and PGF2 _α -l -isopropyl ester. A transient hypertensive response also occurred which is typical for rabbits. The PGF2 _α -l -glycolamide ester also exhibited pronounced ocular hypotensive activity. The results clearly show that PGF2 _α can be esterified at the 1- carboxyl group by polar ester groups without loss of activity compared to 1 -alkyl acyl esters.

TABLE I

EFFECT ON INTRAOCULAR PRESSURE (mmHg) CHANGES AT PREDETERMINED TIMES tH

The foregoing description details specific methods and compositions that can be employed to practice the present invention, and represents the best mode contemplated. However, it is apparent from one of ordinary skill in the art that further compounds with the desired pharmacological properties can be prepared in an analogous manner, and that the disclosed compounds can also be obtained from different starting compounds via different chemical reactions. Similarly, different pharmaceutical compositions may be prepared and used with substantially the same results. Thus,

however detailed the foregoing may appear in text, it should not be construed as limiting the overall scope hereof; rather, the ambit of the present invention is to be governed only by the lawful construction of the appended claims.