SUBSTITUTED l-ARY -3-BENZY AMINOPYRROLIDINE: DOPAMINE RECEPTOR SUBTYPE SPECIFIC LIGA DS
BACKGROUND OF THE INVENTION Field of the Invention
This invention relates to l-aryl-3-benzylaminopyrrolidines and pharmaceutical compositions containing such compounds. It also relates to the use of such compounds in the treatment or prevention of psychotic disorders such as schizophrenia and other central nervous system diseases.
Description of the Related Art
The therapeutic effect of conventional antipsychotics, known as neuroleptics, is generally believed to be exerted through blockade of dopamine receptors. However, neuroleptics are frequently responsible for undesirable extrapyramidal side effects (EPS) and tardive dyskinesias, which are attributed to blockade of D2 receptors in the striatal region of the brain. The dopamine D4 receptor subtype has been identified (Nature, 347: 146 (Sokoloff et al . , 1990)). Its unique localization in limbic brain areas and its differential recognition of various antipsychotics suggest that the D4 receptor may play a major role in the etiology of schizophrenia. Selective D„ antagonists are considered effective antipsychotics free from the neurological side effects displayed by conventional neuroleptics .
Summary of the Invention This invention provides novel compounds which interact with dopamine receptor subtypes. Accordingly, in a broad aspect, the invention provides compounds of Formula I.
or the pharmaceutically acceptable addition salts thereof wherein:
Rl and R2 are the same or different and represent hydrogen,
halogen, Ci-Cβ alkyl , C1-C4 alkoxy, C1-C4 alkylthio,
hydroxy, amino, mono- or di (Ci-Cβ) alkylamino, cyano, C3.-C4
alkoxycarbonyl , trifluoromethoxy, SO
2NH
2 or trifluoromethyl ; R
3 is hydrogen or
alkyl; X represents N or CR
4;
Y and Y' independently represent CR5, nitrogen, or oxygen; and R4 and R5 independently represent hydrogen or Cx-C6 alkyl.
Dopamine D4 receptors are concentrated in the limbic system (Science, 265 : 1034 (Taubes, 1994)) which controls cognition and emotion. Therefore, compounds that interact with these receptors are useful in the treatment of cognitive disorders. Such disorders include cognitive deficits
which are a significant component of the negative symptoms (social withdrawal and unresponsiveness) of schizophrenia. Other disorders include those involving memory impairment or attention deficit disorders. Compounds of the present invention demonstrate high affinity and selectivity in binding to the D4 receptor subtype. These compounds are therefore useful in treatment of a variety of neuropsychological disorders, such as, for example, schizophrenia, psychotic depression and mania. Other dopamine- mediated diseases such as Parkinsonism and tardive dyskinesias can also be treated directly or indirectly by modulation of D4 receptors .
Compounds of this invention are also useful in the treatment of depression, memory- impairment or Alzheimer's disease by modulation of D4 receptors since they exist selectively in areas known to control emotion and cognitive functions .
Thus, in another aspect, the invention provides methods for treatment and/or prevention of neuropsychochological or affective disorders including, for example, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, memory impairment, cognitive deficits, Parkinson-like motor disorders, e.g., Parkinsonism and dystonia, and motion disorders related to the use of neuroleptic agents. In addition, the compounds of
the invention are useful in treatment of depression, memory- impairment or Alzheimer's disease. Further, the compounds of the present invention are useful for the treatment of other disorders that respond to dopaminergic blockade, e.g., substance abuse and obsessive compulsive disorder. These compounds are also useful in treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents .
In yet another aspect, the invention provides pharmaceutical compositions comprising compounds of Formula I. In another aspect, the invention provides intermediates useful in the preparation of compounds of Formula I.
DETAILED DESCRIPTION OF THE INVENTION In addition to the compounds of Formula I, the invention provides compounds of Formula II:
II or the pharmaceutically acceptable addition salts thereof wherein:
Ri and R2 are the same or different and represent hydrogen,
halogen, Ci-Cζ alkyl, C1-C4 alkoxy, C1-C4 alkylthio,
hydroxy, amino, mono- or di (Ci-Cς) alkylamino, cyano, C1-C4
alkoxycarbonyl, trifluoromethoxy, SO2NH2 or
trifluoromethyl ; and X represents N or CR4;
Y and Y' independently represent CR5, nitrogen, or oxygen; and
R4 and R5 are as defined above for Formula I.
A first set of preferred compounds of Formula II are those where X is CH and Y and Y' are both CR5. Such compounds are referred to hereinafter as compounds of Formula IIA. More preferred compounds of Formula IIA are where X is carbon, Y and
Y' are both CH, and Rx is 4-halo or 4- (C1-C4) alkyl .
Particularly preferred Rx groups in IIA are chloro,
bromo, and methyl. In other preferred compounds of Formula IIA, R2 is hydrogen, X is carbon, Y and Y' are both CH, and Rx is 4-halo or 4- (C1-C4) alkyl .
A second set of preferred compounds of Formula II are those where X is CR4 and Y and Y' are both oxygen. Such compounds are referred to hereinafter as compounds of Formula IIB. More preferred compounds of Formula IIB are where X is CH, Y and Y' are both oxygen, and Rx is 4-halo or 4- (Cι~
C4) alkyl. Particularly preferred R1 groups in compounds of
Formula IIB are chloro, bromo, and methyl. In other preferred compounds of Formula IIB, R2 is hydrogen, X is CH, Y and Y' are both oxygen, and Rx is 4-halo or 4- (C1-C4) alkyl .
A third set of preferred compounds of Formula II are those where X is CR4 and Y and Y' are both nitrogen. Such compounds are referred to hereinafter as compounds of Formula IIC. More preferred compounds of Formula IIC are where X is CH, Y and Y' are both nitrogen, and Rx is 4-halo or 4- (C1-C4) alkyl .
Particularly preferred Rx groups in compounds of Formula IIC are chloro, bromo, and methyl. In other preferred compounds of Formula IIC, R2 is hydrogen, X is CH, Y and Y' are both nitrogen, and Rλ is 4-halo or 4 - (C1-C4) alkyl .
Another set of preferred compounds of Formula II are those where X is nitrogen and Y and Y' are both CH. Such compounds are referred to hereinafter as compounds of Formula IID. More preferred compounds of Formula IID are where X is nitrogen, Y and Y' are both CH, and Rλ is 4-halo or 4- (C1-C4) alkyl .
Particularly preferred Rx groups in compounds of Formula IID are chloro, bromo, and methyl. In other preferred compounds of Formula IID, R2 is hydrogen, X is nitrogen, Y and Y' are both CH, and R is 4-halo or 4- (C1-C4) alkyl .
The invention also provides intermediates useful in preparing compounds of Formula I . These intermediates have Formulae III -V.
Ill where R
e is hydrogen or
alkyl, and R
2 , X, Y' and Y are as defined above for Formula I .
IV
where R2, X, Y' and Y are as defined above for Formula I.
v where R
λ , R
2, X, Y' and Y are as defined above for Formula I.
In certain situations, the compounds of Formula I may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. In these situations, the single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.
Representative compounds of the present invention, which are encompassed by Formula I, include, but are not limited to the compounds in Table I and their pharmaceutically acceptable acid addition salts. In addition, if the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt.
Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds .
Non-toxic pharmaceutical salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC- (CH2)n-COOH where n is 0-4, and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.
The present invention also encompasses the acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I . Where a compound exists in various tautomeric forms, the invention is not limited to any one of the specific tautomers . The invention includes all tautomeric forms of a compound.
By
alkyl" or "lower alkyl" in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, such as, for example, methyl, ethyl,
propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2- pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3- methylpentyl . Preferred Ci-Cβ alkyl groups are methyl, ethyl,
propyl, butyl, cyclopropyl and cyclopropylmethyl . By "Ci-Cj alkoxy" or "lower alkoxy" in the present invention is meant straight or branched chain alkoxy groups having 1-6 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2 -pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3- hexoxy, and 3-methylpentoxy.
By the term "halogen" in the present invention is meant fluorine, bromine, chlorine, and iodine.
Representative l-aryl-3-benzylaminopyrrolidines of the present invention are shown in Table 1. The number under each compound is its compound number.
Table 1
The invention also pertains to the use of compounds of general Formula I in the treatment of neuropsychological disorders. The interaction of compounds of the invention with dopamine receptors is shown in the examples. This interaction results in the pharmacological activity of these compounds.
The compounds of general formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general formula I and a pharmaceutically acceptable carrier. One or more compounds of general formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents
and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay
material such as glyceryl monosterate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more
preservatives, for example ethyl, or n-propyl p- hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures
of these. Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1 , 3-butanediol . Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or
diglycerides . In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of general formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
Compounds of general formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day) . The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
A representative synthesis of the l-aryl-3- benzylaminopyrrolidines of the invention is presented in Scheme I . Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention.
Scheme 1
wherein Ri, R2 , X, Y' and Y are as defined above for Formula 1.
As shown, a properly substituted arylamine may be condensed with maleic anhydride to provide acid III. Acid III may then be cyclized to produce a maleimide of structure IV. Reaction of IV with properly substituted benzyl amine produces amino succinimide V. Succinimide V may be reduced with borane to provide the desired l-aryl-3-benzylaminopyrrolidines of Formula I . Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention.
The disclosures of all articles and references mentioned in this application, including patents, are incorporated herein by reference.
The preparation of the compounds of the present invention is illustrated further by the following examples which are not to be construed as limiting the invention in scope or spirit to the specific procedures and compounds described in them. The starting materials and various intermediates may be obtained from commercial sources, prepared from commercially available organic compounds, or prepared using well known synthetic methods.
Example 1 1. 1- (2 -Naphthyl) maleimide
Maleic anhydride (3.8 g, 38.8 mmol) is dissolved in 100 mL ether and cooled to 0°C. 2 -Naphthylamine (5.0 g, 35.0 mmol) in 100 mL ether is added dropwise to the above solution with stirring. The resulting mixture is then warmed to room temperature and stirred for another hour. The mixture is then vacuum filtered and the resulting solid washed with ether. The solid is resuspended in 30 g acetic anhydride with 0.3 g sodium acetate. The resulting mixture is heated at 100 °C for 3 hr. and then cooled to room temperature. The acetic anhydride and acetic acid are removed by evaporation under reduced pressure.
The residue is redissolved in dichloromethane and the sodium acetate is removed by filtration. Dichloromethane is then removed under reduced pressure. The remaining solid recrystallized from hexane and acetone to yield 1- (2-
naphthyl) maleimide as a tannish crystal (6.5 g, 84%) H NMR (CDCI3) 7.91 (d, J = 8.5 Hz, 1H) , 7.88-7.84 (m, 3H) , 7.54-7.51
(m, 2H) , 7.45 (dd, J = 8.5, 1.8 Hz, 1H) , 6.90 (s, 2H) .
2. 3- (4-Chlorobenzyl) amino- 1- (2 -naphthyl) succinimide 1- (2 -Naphthyl) maleimide (223 mg, 1.0 mmol) and 4- chlorobenzylamine (142 mg, 1.0 mmol) are combined and stirred in 10 mL THF at room temperature overnight. Most of the THF is subsequently evaporated after which 30 mL ether is added
to cause crystallization of 3- (4-chlorobenzyl) amino-1- (2- naphthyl) succinimide. The product was collected by vacuum filtration. This yielded the product as a gray crystal (300
mg, 82%) ^H NMR (CDCI3) 7.91 (d, J = 8.5 Hz, 1H) , 7.87 (m,
2H) , 7.80 (d, J = 1.8 Hz, 1H) , 7.54-7.52 (m, 3H) , .7.38-7.26 (m, 5H) , 3.98 (dd, J = 8.5, 5.5 Hz, 1H) , 3.95 (s, 2H) , 3.20 (dd, J = 18.3, 8.5 Hz, 1H) , 2.75 (dd, J = 18.3, 5.5 Hz, 1H) .
3. 3- (4-Chlorobenzyl) amino-1- (2 -naphthyl ) pyrrolidine 3- (4-Chlorobenzyl) amino-1- (2-naphthyl) succinimide (300 mg, 82.3 mmol) is refluxed in 20 mL THF. Borane-dimethylsulfide (1.0 mL, 10 M) is added and the resulting mixture refluxed overnight. After evaporation of solvent and any remaining borane, 20 mL of methanol is added and the resulting mixture refluxed for 4 hr. The solvent is evaporated under reduced pressure. The hydrochloride salt of the clear residue is made and recrystallized from isopropanol to give the title compound
(Compound 3, 200 mg, 72%). ^H NMR (DMSO) 9.78 (d br, 2H) , 7.75 (d, J = 9.2 Hz, 1H) , 7.71-7.63 (m, 4H),.7.51 (d, J = 9.5 Hz, 2H) , 7.34 (t, J = 6.5 Hz, 1H) , 7.15 (t, J = 6.7 Hz, 1H) , 7.05 (dd, J = 8.6, 2.0 Hz, 1H) , 6.81 (s, 1H) , 4.25 (t, J = 5.5 Hz, 2H) , 3.98 (m, 1H) , 3.70-3.58 (m, 3H) , 3.37 (q, J = 9.2 Hz, 1H) , 2.42-2.34 (m, 2H) . (m.p. 207-209°C) .
Example 2 The following compounds are prepared essentially according to the procedures set forth above in Example 1 :
(a) 3- (4-chlorobenzyl) amino-1- ( 6 -quinoxalinyl) pyrrolidine hydrochloride (Compound 1, m.p. 168-170°C)
(b) 3- (4-chlorobenzyl) amino-1- (benzo [1.4] dioxan-6- yl) pyrrol idine hydrochloride (Compound 2, m.p. 237-239°C)
(c) 3- (4-chlorobenzyl) amino-1- (2 -quinolinyl) pyrrolidine hydrochloride (Compound 4, m.p. 170-172°C)
(d) 3- (4-methylbenzyl) amino-1- (6 -quinoxalinyl) pyrrolidine hydrochloride (Compound 5, m.p. 180-182°C)
(e) 3- (4-methylbenzyl) amino-1- (benzo [1.4] dioxan-6- yl) pyrrolidine hydrochloride (Compound 6, m.p. 143-145°C)
(f) 3- (4-methylbenzyl) amino-1- (2 -naphthyl) pyrrolidine hydrochloride (Compound 7, m.p. 218-220°C )
(g) 3- (4-methylbenzyl) amino-1- (2 -quinolinyl) pyrrolidine hydrochloride (Compound 8, m.p. 188-190°C)
Example 3 Assay for D^ and D Receptor Binding Activity
The pharmaceutical utility of compounds of this invention is indicated by the assays for dopamine receptor subtype affinity described below.
Pellets of COS cells containing recombinantly produced D2
or D4 receptors from African Green Monkey are used for the
assays. The sample is homogenized in 100 volumes (w/vol) of 0.05 M Tris HCl buffer at 4° C and pH 7.4. The sample is then centrifuged at 30,000 x g and resuspended and rehomogenized. The sample is then centrifuged as described and the final tissue sample is frozen until use. The tissue is resuspended 1:20 (wt/vol) in 0.05 M Tris HCl buffer containing 100 mM NaCl . Incubations are carried out at 48°C and contain 0.4 ml of
tissue sample, 0.5 nM 3H-YM 09151-2 (Nemonapride, cis-5-Chloro- 2-methoxy-4- (methylamino) -N- (2 -methyl -2- (phenylmethyl) -3- pyrrolidinyl) benzamide) and the compound of interest in a total incubation of 1.0 ml. Nonspecific binding is defined as that binding found in the presence of 1 mM spiperone; without further additions, nonspecific binding is less than 20% of total binding. Binding characteristics for examples of compounds encompassed within Formula I for the D2 and D4
receptor subtypes are shown in Table 2 for rat striatal homogenates .
TABLE 2
Compound Number1 D4 Ki (nM) D2 Ki (nM)
1 11 ND 2 18 ND 3 209 1800 4 135 670 5 16 ND 6 34 ND 7 245 ND 8 101 ND
Compounds of the invention possess a Ki value for the
displacement of [3H] YM-09151-2 from the dopamine D4 receptor
subtype of below 500 nM.
The binding characteristics of compounds of Formula I for the D4 receptor, expressed in nM, generally range from about 5 nanomolar (nM) to about 250 nanomolar (nM) . These compounds typically have binding constants for the D2 receptor of from about 500 nM to at least 1800 nM. Thus, the compounds of the invention are generally at least about 5 time more selective for the D4 receptor than the D2 receptor.
The invention and the manner and process of making and using it, are now described in such full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains, to make and use the same. It is to be understood
that the foregoing describes preferred embodiments of the present invention and that modifications may be made therein without departing from the spirit or scope of the present invention as set forth in the claims. To particularly point out and distinctly claim the subject matter regarded as invention, the following claims conclude this specification.