Patent Grant
8618163
The present invention relates generally to compounds and methods for treating ocular disorders. The invention relates specifically to the use of certain well-defined compounds having formyl peptide receptor like-1 (FPRL-1) agonist or antagonist activity.
FPRL-1 (N-formyl peptide receptor like-1) is a G protein-coupled receptor that is expressed on inflammatory cells such as monocytes and neutrophils, as well as T cells and has been shown to play a critical role in leukocyte trafficking during inflammation and human pathology. FPRL-1 is an exceptionally promiscuous receptor that responds to a large array of exogenous and endogenous ligands, including Serum amyloid A (SAA), chemokine variant sCKβ8-1, the neuroprotective peptide humanin, anti-inflammatory eicosanoid lipoxin A4 (LXA4) and glucocotricoid-modulated protein annexin A1. FPRL-1 transduces anti-inflammatory effects of LXA4 in many systems, but it also can mediate the pro-inflammatory signaling cascade of peptides such as SAA. The ability of the receptor to mediate two opposite effects is proposed to be a result of different receptor domains used by different agonists.
Activation of FPRL-1 by lipoxin A4 or its analogs and by Annexin I protein has been shown to result in anti-inflammatory activity by promoting active resolution of inflammation which involves inhibition of polymorphonuclear neutrophils (PMNs) and eosinophils migration and also stimulate monocyte migration enabling clearance of apoptotic cells from the site of inflammation in a nonphlogistic manner. In addition, FPRL1 has been shown to inhibit NK cytotoxicity and promote activation of T cells which further contributes to down regulation of tissue damaging inflammatory signals. FPRL-1/LXA4 interaction has been shown to be beneficial in experimental models of ischemia reperfusion, angiogenesis, dermal inflammation, chemotherapy-induced alopecia, ocular inflammation such as endotoxin-induced uveitis, corneal wound healing, re-epithelialization etc. FPRL-1 thus represents an important novel pro-resolutionary molecular target for the development of new therapeutic agents in diseases with excessive inflammatory responses.
The invention provides well defined compounds having FPRL-1 agonist or antagonist activity. As such, the compounds of the invention are useful for treating a variety of ocular disorders.
In one embodiment of the invention, there are provided methods for treating a disorder associated with mediation of a FPRL-1 receptor. Such methods can be performed, for example, by administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of at least one compound of the structure:
In another embodiment of the invention there provided methods for treating a disorder associated with mediation of a FPRL-1 receptor. Such methods can be performed, for example, by administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of at least one compound of the structure:
In still another embodiment of the invention, there are provided compounds of the structure:
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention claimed. As used herein, the use of the singular includes the plural unless specifically stated otherwise. As used herein, “or” means “and/or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “includes,” and “included,” is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
Unless specific definitions are provided, the nomenclatures utilized in connection with, and the laboratory procedures and techniques of analytical chemistry, synthetic organic and inorganic chemistry described herein are those known in the art. Standard chemical symbols are used interchangeably with the full names represented by such symbols. Thus, for example, the terms “hydrogen” and “H” are understood to have identical meaning Standard techniques may be used for chemical syntheses, chemical analyses, and formulation.
As used herein, “alkyl” refers to straight or branched chain hydrocarbyl groups having from 1 up to about 100 carbon atoms. Whenever it appears herein, a numerical range, such as “1 to 100” or “C1-C100”, refers to each integer in the given range; e.g., “C1-C100 alkyl” means that an alkyl group may comprise only 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 100 carbon atoms, although the term “alkyl” also includes instances where no numerical range of carbon atoms is designated. “Substituted alkyl” refers to alkyl moieties bearing substituents including alkyl, alkenyl, alkynyl, hydroxy, oxo, alkoxy, mercapto, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, halogen, haloalkyl, cyano, nitro, nitrone, amino, lower alkylamino, lower alkyldiamino, amido, azido, —C(O)H, —C(O)R7, —CH2OR7, —C(O)—, —C(O)—, —S—, —S(O)2, —OC(O)—O—, wherein R7 is H or lower alkyl, acyl, oxyacyl, carboxyl, carbamate, sulfonyl, sulfonamide, sulfuryl, and the like. As used herein, “lower alkyl” refers to alkyl moieties having from 1 to about 6 carbon atoms.
As used herein, “alkenyl” refers to straight or branched chain hydrocarbyl groups having at least one carbon-carbon double bond, and having in the range of about 2 up to about 100 carbon atoms, and “substituted alkenyl” refers to alkenyl groups further bearing one or more substituents as set forth above. As used herein, “lower alkenyl” refers to alkenyl moieties having from 2 to about 6 carbon atoms.
As used herein, “alkynyl” refers to straight or branched chain hydrocarbyl groups having at least one carbon-carbon triple bond, and having in the range of about 2 up to about 100 carbon atoms, and “substituted alkynyl” refers to alkynyl groups further bearing one or more substituents as set forth above. As used herein, “lower alkynyl” refers to alkynyl moieties having from 2 to about 6 carbon atoms.
As used herein, “cycloalkyl” refers to cyclic (i.e., ring-containing) alkyl moieties typically containing in the range of about 3 up to about 8 carbon atoms, and “substituted cycloalkyl” refers to cycloalkyl groups further bearing one or more substituents as set forth above.
As used herein, “aryl” refers to aromatic groups having in the range of 6 up to 14 carbon atoms and “substituted aryl” refers to aryl groups further bearing one or more substituents as set forth above.
As used herein, “heteroaryl” refers to aromatic moieties containing one or more heteroatoms (e.g., N, O, S, or the like) as part of the ring structure and having in the range of 5 up to 14 total atoms in the ring structure (i.e., carbon atoms and heteroatoms). “Substituted heterocyclic” refers to heterocyclic groups further bearing one or more substituents as set forth above.
As used herein, “heterocyclic” refers to non-aromatic cyclic (i.e., ring-containing) groups containing one or more heteroatoms (e.g., N, O, S, or the like) as part of the ring structure, and having in the range of 3 up to 14 carbon atoms and “substituted heterocyclic” refers to heterocyclic groups further bearing one or more substituents as set forth above.
As used herein, “halogen” or “halide” refers to fluoride, chloride, bromide or iodide.
It will be readily apparent to those skilled in the art that some of the compounds of the invention may contain one or more asymmetric centers, such that the compounds may exist in enantiomeric as well as in diastereomeric forms. Unless it is specifically noted otherwise, the scope of the present invention includes all enantiomers, diastereomers and racemic mixtures. Some of the compounds of the invention may form salts with pharmaceutically acceptable acids or bases, and such pharmaceutically acceptable salts of the compounds described herein are also within the scope of the invention. In addition, since certain compounds of the invention contain a norbornyl or norbornenyl moiety, all exo and endo isomers are contemplated for use in the practice of the invention.
A “pharmaceutically acceptable salt” is any salt that retains the activity of the parent compound and does not impart any additional deleterious or untoward effects on the subject to which it is administered and in the context in which it is administered compared to the parent compound. A pharmaceutically acceptable salt also refers to any salt which may form in vivo as a result of administration of an acid, another salt, or a prodrug which is converted into an acid or salt.
Pharmaceutically acceptable salts of acidic functional groups may be derived from organic or inorganic bases. The salt may comprise a mono or polyvalent ion. Of particular interest are the inorganic ions, lithium, sodium, potassium, calcium, and magnesium. Organic salts may be made with amines, particularly ammonium salts such as mono-, di- and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules. Hydrochloric acid or some other pharmaceutically acceptable acid may form a salt with a compound that includes a basic group, such as an amine or a pyridine ring.
The invention provides methods for treating a disorder associated with mediation of a FPRL-1 receptor. Such methods are performed, for example, by administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of at least one compound of the structure:
In some embodiments of the invention, the compounds used in the methods of the invention are compounds wherein E2 is NR7
In some embodiments, the compounds used in the methods of the invention have the structure
In certain embodiments, R1 is H, methyl, or Cl. In other embodiments of the invention, R2 and R3 are each independently H.
In some embodiments of the invention, the compounds used in the methods of the invention are compounds
wherein Y is CH2, O, NR7, or S.
Compounds contemplated for use in the methods of the invention include, but are not limited to, compounds having the structures set forth below:
In another embodiment of the invention, there are provided methods for treating a disorder associated with mediation of a FPRL-1 receptor. Such methods can be performed for example, by administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of at least one compound of the structure:
In some embodiments of the invention, the compounds used in the methods of the invention are compounds wherein E2 is NR7.
In some embodiments of the invention, the compounds used in the methods of the invention are compounds having the structures
In some embodiments of the invention, the compounds used in the methods of the invention are compounds wherein R5 is H, C1-C6 alkyl, halide, or trifluoromethyl
In certain embodiments of the invention, the compounds used in the methods of the invention are compounds wherein each X taken together forms a cyclopropyl moiety.
Compounds contemplated for use according to this aspect of the invention include, but are not limited to, compounds having the structures set forth below:
In a further embodiment of the invention there are provided compounds of the structure:
In certain embodiments, E2 is NR7.
In other embodiments, there are provided compounds of the structure
In some embodiments of the invention, R5 is H, C1-C6 alkyl, halide, or trifluoromethyl
In certain embodiments, each X taken together forms a cyclopropyl moiety.
Compounds contemplated in this aspect of the invention include, but are not limited to, compounds having any one of the structures
The compounds of the invention may be prepared in a variety of ways. One method for preparing invention compounds is set forth in the schematic set forth below:
Biological activity of compounds according to Formula 1 and Formula 2 is set forth in Table 1 below. CHO-Gal6 cells stably expressing FPRL1 were cultured in (F12, 10% FBS, 1% PSA, 400 μg/ml geneticin and 50 μg/ml hygromycin) and HEK-Gqi5 cells stable expressing FPR1 were cultured in (DMEM high glucose, 10% FBS, 1% PSA, 400 μg/ml geneticin and 50 μg/ml hygromycin). In general, the day before the experiment, 18,000 cells/well were plated in a 384-well clear bottom poly-d-lysine coated plate. The following day the screening compound-induced calcium activity was assayed on the FLIPRTetra. The drug plates were prepared in 384-well microplates using the EP3 and the MultiPROBE robotic liquid handling systems. Compounds were tested at concentrations ranging from 0.61 to 10,000 nM. Results are expressed as EC50 (nM) and efficacy values.
The compounds and methods of the invention are useful in treating disorders associated with agonism or antagonism of FPRL-1 receptors. As such, the compounds and methods of the invention are useful for treating disorders such, for example, wet and dry age-related macular degeneration (ARMD), diabetic retinopathy (proliferative), retinopathy of prematurity (ROP), diabetic macular edema, uveitis, retinal vein occlusion, cystoid macular edema, glaucoma, branch vein occlusion, Best's vitelliform macular degeneration, retinitis pigmentosa, proliferative vitreoretinopathy (PVR), or any other degenerative disease of either the photoreceptors or the RPE.
Those skilled in the art will readily understand that for administration or the manufacture of medicaments the compounds disclosed herein can be admixed with pharmaceutically acceptable excipients which per se are well known in the art. Specifically, a drug to be administered systemically, it may be confected as a powder, pill, tablet or the like, or as a solution, emulsion, suspension, aerosol, syrup or elixir suitable for oral or parenteral administration or inhalation.
For solid dosage forms or medicaments, non-toxic solid carriers include, but are not limited to, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, the polyalkylene glycols, talcum, cellulose, glucose, sucrose and magnesium carbonate. The solid dosage forms 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 monostearate or glyceryl distcarate may be employed. They may also be coated by the technique described in the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release. Liquid pharmaceutically administrable dosage forms can, for example, comprise a solution or suspension of one or more of the presently useful compounds and optional pharmaceutical adjutants in a carrier, such as for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like. Typical examples of such auxiliary agents are sodium acetate, sorbitan monolaurate, triethanolamine, sodium acetate, triethanolamine oleate, etc. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 16th Edition, 1980. The composition of the formulation to be administered, in any event, contains a quantity of one or more of the presently useful compounds in an amount effective to provide the desired therapeutic effect.
Parenteral administration is generally characterized by injection, either subcutaneously, intramuscularly or intravenously. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol and the like. In addition, if desired, the injectable pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like.
The amount of the presently useful compound or compounds administered is, of course, dependent on the therapeutic effect or effects desired, on the specific mammal being treated, on the severity and nature of the mammal's condition, on the manner of administration, on the potency and pharmacodynamics of the particular compound or compounds employed, and on the judgment of the prescribing physician. The therapeutically effective dosage of the presently useful compound or compounds is preferably in the range of about 0.5 or about 1 to about 100 mg/kg/day.
A liquid which is ophthalmically acceptable is formulated such that it can be administered topically to the eye. The comfort should be maximized as much as possible, although sometimes formulation considerations (e.g. drug stability) may necessitate less than optimal comfort. In the case that comfort cannot be maximized, the liquid should be formulated such that the liquid is tolerable to the patient for topical ophthalmic use. Additionally, an ophthalmically acceptable liquid should either be packaged for single use, or contain a preservative to prevent contamination over multiple uses.
For ophthalmic application, solutions or medicaments are often prepared using a physiological saline solution as a major vehicle. Ophthalmic solutions should preferably be maintained at a comfortable pH with an appropriate buffer system. The formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
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 useful surfactant is, for example, Tween 80. Likewise, various useful 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 ophthalmically 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. A useful chelating agent is edetate 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:
For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compound disclosed herein are employed. Topical formulations may generally be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.
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 following examples are intended only to illustrate the invention and should in no way be construed as limiting the invention.
To a solution of maleic anhydride (0.20 g, 2.0 mmol) in chloroform (5.0 mL) at 0° C. under Argon atmosphere was added dropwise spiro[2,4]hepta-4,6-diene (0.20 mL, 2.0 mmol), and the reaction was allowed to warm up slowly to ambient temperature and stirred for 18 h in the dark. The solvent was then removed, and the residue was recrystallized from methanol to afford the title compound as a white solid
1HNMR (300 MHz, CDCl3): δ ppm 0.40-0.52 (m, 2H), 0.53-0.61 (m, 2H), 2.81 (ddd, J=4.47, 2.12, 1.90 Hz, 2H), 3.66 (dd, J=2.93, 1.47 Hz, 2H), 6.30 (t, J=1.90 Hz, 2H).
A mixture of Compound 1 (0.10 g, 0.53 mmol) and a catalytic amount of 10% Pd—C in 1,4-dioxane (5.0 mL) was stirred under a hydrogen atmosphere for 18 h, and then the solution was filtered through Celite. The solvent was removed under vacuum, and the residue was recrystallized from methanol to produce the title compound as a white solid.
1HNMR (300 MHz, CDCl3): δ ppm 0.63 (s, 4H), 1.53 (d, J=8.50 Hz, 2H), 1.90 (d, J=1.76 Hz, 2H), 2.0-2.09 (m, 2H), 3.57 (d, J=1.76 Hz, 2H).
A flask containing a mixture of Compound 1 (0.1562 g, 0.82 mmol) and PtO2 (catalytic amount) in glacial acetic acid was evacuated and filled with dry nitrogen three times. The resulting suspension was stirred at 60° C. under a hydrogen atmosphere for 18 h. The reaction was cooled to room temperature, and the solution was filtered through Celite with the aid of glacial acetic acid. The solvent was removed under reduced pressure, and the residue was recrystallized in MeOH/H2O to afford the title compound as a white solid.
1HNMR (300 MHz, CDCl3): δ ppm 1.08 (s, 6H), 1.37 (s, 1H), 1.40 (s, 1H), 1.90 (d, J=2.05 Hz, 1H), 1.93 (d, J=1.47 Hz, 1H), 2.11-2.20 (m, 2H), 3.52-3.60 (m, 2H).
General Procedure A
To a solution of Compound 1 (95 mg, 0.5 mmol) in CHCl3 (3 mL) was added 4-trifluoromethylthioaniline (96 mg, 0.5 mmol) in CHCl3 (1 mL). The mixture was stirred for 16 h at ambient temperature. The resulting precipitate was filtered and washed with cold (0° C.) CHCl3 (3 mL) to give the title compound as a white solid.
1HNMR (300 MHz, CD3OD): δ 0.42-0.60 (m, 4H), 2.45-2.55 (m, 2H), 3.71 (dq, J=3.3, 9.9 Hz, 2H), 6.22-6.38 (m, 2H), 7.53-7.68 (m, 4H).
Following General Procedure A, Compound 1 (39 mg, 0.2 mmol) and 4-t-butyl aniline (29 mg, 0.2 mmol) in THF (2 mL) were converted into the title compound, which was isolated as a white solid.
1HNMR (300 MHz, CD3COCD3): δ 0.44-0.58 (m, 4H), 1.27 (s, 9H), 2.53 (d, J=9.5 Hz, 2H), 3.43 (dd, J=3.0, 9.9 Hz, 1H), 3.61 (dd, J=3.0, 9.9 Hz, 1H), 6.22 (d, J=3.0 Hz, 1H), 6.32 (d, J=3.0 Hz, 1H), 7.28 (dd, J=2.1, 6.6 Hz, 2H), 7.50 (dd, J=2.1, 6.6 Hz, 2H).
Following General Procedure A, Compound 1 (41 mg, 0.22 mmol) and 4-isopropyl aniline (45 mg, 0.33 mmol) in THF (3 mL) were converted into the title compound, which was isolated as a white solid after purification by silica gel chromatography.
1HNMR (300 MHz, CD3COCD3): δ 0.42-0.55 (m, 4H), 1.20 (d, J=6.9 Hz, 6H), 2.49 (s, 1H), 2.55 (s, 1H), 2.84 (sept, J=6.9 Hz, 1H), 3.43 (dd, J=3.3, 10.2 Hz, 1H), 3.61 (dd, J=3.3, 10.2 Hz, 1H), 6.20 (d, J=3.0 Hz, 1H), 6.32 (d, J=3.0 Hz, 1H), 7.12 (dd, J=1.8, 6.6 Hz, 2H), 7.50 (dd, J=1.8, 6.6 Hz, 2H).
Following General Procedure A, Compound 1 (36 mg, 0.18 mmol) and aniline (24 mg, 0.26 mmol) in CHCl3 (2 mL) were converted into the title compound, which was isolated as a white solid.
1HNMR (300 MHz, CD3OD): δ 0.42-0.60 (m, 4H), 2.49 (d, J=3.0 Hz, 2H), 3.48 (dd, J=3.0, 12.0 Hz, 1H), 3.59 (dd, J=3.0, 9.0 Hz, 1H), 6.24 (dd, J=3.0, 6.0 Hz, 1H), 6.37 (dd, J=3.0, 6.0 Hz, 1H), 7.03 (2, J=6.0 Hz, 2H), 7.25 (t, J=6.0 Hz, 2H), 7.47 (d, J=6.0 Hz, 1H).
Following General Procedure A, Compound 1 (28 mg, 0.15 mmol) in CHCl3 (2 mL) and 4-aminobenzenesulfonamide (26 mg, 0.15 mmol) in MeOH (2 mL) were mixed together at ambient temperature for 16 h to produce the title compound, which was isolated as a white solid.
1HNMR (300 MHz, CD3CN): δ 0.42-0.60 (m, 4H), 2.57 (d, J=9.0 Hz, 2H), 3.49 (dd, J=3.0, 12.0 Hz, 1H), 3.55 (dd, J=3.0, 9.0 Hz, 1H), 6.27 (dd, J=3.0, 6.0 Hz, 1H), 6.33 (dd, J=3.0, 6.0 Hz, 1H), 7.68 (d, J=9.0 Hz, 2H), 7.79 (t, J=6.0 Hz, 2H).
Following General Procedure A, Compound 2 (0.084 g, 0.44 mmol) and 4-iodoaniline (0.090 g, 0.44 mmol) in chloroform (6 mL) were converted into the title compound, which was isolated as a white solid.
1HNMR (300 MHz, acetone-d6): δ ppm 0.45-0.71 (m, 4H), 1.66 (d, J=18.46 Hz, 4H), 1.78-1.93 (m, 1H), 2.18-2.34 (m, 1H), 3.17 (dd, J=8.08, 1.90 Hz, 1H), 3.45 (dd, J=11.43, 4.40 Hz, 1H), 7.43-7.54 (m, 2H), 7.55-7.67 (m, 2H), 9.21 (br. s., 1H).
Following General Procedure A, Compound 2 (0.090 g, 0.47 mmol) and 4-bromoaniline (0.080 g, 0.47 mmol) in chloroform (3.0 mL) were converted into the title compound, which was isolated as a white solid.
1HNMR (300 MHz, acetone-d6): δ ppm 0.45-0.70 (m, 4H), 1.53-1.76 (m, 4H), 1.76-1.93 (m, 1H), 2.18-2.36 (m, 1H), 3.15 (ddd, J=11.43, 3.52, 1.76 Hz, 1H), 3.46 (dd, J=11.43, 3.52 Hz, 1H), 7.42 (d, J=5.08 Hz, 2H), 7.62 (d, J=9.08 Hz, 2H), 9.23 (br. s., 1H).
Following General Procedure A, Compound 2 (0.042 g, 0.22 mmol) and 4-chloroaniline (0.028 g, 0.22 mmol) in chloroform (1.5 mL) were converted into the title compound, which was isolated as a white solid.
1HNMR (300 MHz, acetone-d6): δ ppm 0.42-0.66 (m, 4H), 1.51-1.75 (m, 4H), 1.78-1.91 (m, 1H), 2.20-2.35 (m, 1H), 3.15 (ddd, J=11.43, 3.66, 1.90 Hz, 1H), 3.46 (ddd, J=11.43, 4.69, 1.17 Hz, 1H), 7.28 (d, J=5.27 Hz, 2H), 7.66 (d, J=5.27 Hz, 2H), 9.22 (br. s., 1H), 10.31 (br. s., 1H).
Following General Procedure A, Compound 3 (0.019 g, 0.10 mmol) and 4-iodoanline (0.020 g, 0.10 mmol) in chloroform (2 mL) were converted into the title compound, which was isolated as a white solid.
1HNMR (300 MHz, acetone-d6) δ ppm 1.08 (s, 3H), 1.15 (s, 3H), 1.53-1.70 (m, 2H), 1.81 (t, J=3.37 Hz, 2H), 1.95 (t, J=8.96 Hz, 1H), 2.23 (dd, J=8.94, 7.47 Hz, 1H), 3.17 (ddd, J=11.57, 3.66, 2.05 Hz, 1H), 3.49 (ddd, J=11.65, 4.47, 1.47 Hz, 1H), 7.43-7.54 (m, 2H), 7.57-7.66 (m, 2H), 9.23 (br. s., 1H)
Following General Procedure A, Compound 3 (0.047 g, 0.24 mmol) and 4-bromoaniline (0.041 g, 0.24 mmol) in chloroform (4 mL) were converted into the title compound, which was isolated as a white solid.
1HNMR (300 MHz, acetone-d6): 6 ppm 0.92-0.23 (m, 6H), 1.50-1.88 (m, 4H), 1.95 (br. s., 1H), 2.22 (br. s., 1H), 3.19 (br. s., 1H), 3.48 (br. s., 1H), 7.42 (d, J=7.33 Hz, 2H), 7.61 (d, J=7.91 Hz, 2H), 9.25 (br. s., 1H)
Following General Procedure A, Compound 3 (0.047 g, 0.24 mmol) and 4-chloroaniline (31 mg, 0.24 mmol) in chloroform (4 mL) was converted into the title compound, which was isolated as a white solid.
1HNMR (300 MHz, acetone-d6): δ ppm 1.08 (br. s., 3H), 1.16 (br. s., 3H), 1.52-1.87 (m, 4H), 1.9 (br. s., 1H), 2.23 (br. s., 1H), 3.19 (br. s., 1H), 3.48 (br. s., 1H), 7.28 (d, J=8.20 Hz, 2H), 7.66 (d, J=8.20 Hz, 2H), 9.26 (br. s., 1H).
Following General Procedure A, Compound 1 (0.20 g, 1.05 mmol) and 4-iodoaniline (229 mg, 1.05 mmol) in chloroform (25 mL) were mixed together at ambient temperature for 16 h to produce the title compound, which was isolated as a white solid.
1HNMR (300 MHz, acetone-d6): δ ppm 0.34-0.57 (m, 4H), 2.42-2.61 (m, 2H), 3.37-3.50 (m, 1H), 3.53-3.65 (m, 1H), 6.14-6.26 (m, 1H), 6.31 (dd, J=6.01, 2.49 Hz, 1H), 7.44 (q, J=4.79 Hz, 2H), 7.53-7.65 (m, 2H), 9.16 (br. s., 1H), 10.37 (br. s., 1H).
A mixture of Compound 15 (0.020 g, 0.049 mmol), methyl iodide (6.0 μL, 0.098 mmol), and sodium bicarbonate (0.02 g, 0.245 mmol) in DMF (2.0 mL) was stirred at ambient temperature for 18 h. The solution was filtered and the solvent was removed in vacuo. The residue was purified by preparative TLC using ethyl acetate (30%) and hexane (70%) as eluent to afford the title compound as a white solid.
1HNMR (300 MHz, CDCl3): δ ppm 0.39-0.54 (m, 2H), 0.59 (d, J=7.03 Hz, 2H), 2.58 (br. s., 2H), 3.51 (d, J=1.47 Hz, 2H), 3.55 (s, 3H), 6.35 dt, J=2.98, 1.47 Hz, 1H) 6.62 (dt, J=2.93, 1.47 Hz, 1H), 7.21-7.27 (d, J=8.79 Hz, 2H), 7.32 (br. s., 1H), 7.58 (d, J=8.79 Hz, 2H).
Following General Procedure B, Compound 15 (0.031 g, 0.076 mmol) and ethyl iodide (12.2 μL, 0.152 mmol) were converted into the title compound, which was isolated as a white solid.
1HNMR (300 MHz, CDCl3): δ ppm 0.37-0.51 (m, 2H), 0.57 (d, J=7.03 Hz, 2H), 1.08 (t, J=7.18 Hz, 3H), 2.58 (br. s., 2H), 3.51 (d, J=1.76 Hz, 2H), 3.99 (m, 2H), 6.36 (dd, J=3.37, 2.20 Hz, 1H), 6.61 (dd, J=3.52, 2.34 Hz, 1H), 7.19-7.31 (m, 2H), 7.38 (s, 1H), 7.57 (d, 2H).
Following General Procedure B, Compound 15 (0.045 g, 0.11 mmol) and 2-iodopropane (22.0 μL, 0.22 mmol) were converted into the title compound, which was isolated as a white solid.
1HNMR (300 MHz, CDCl3): δ ppm 0.37-0.51 (m, 2H), 0.57 (d, J=7.03 Hz, 2H), 1.08 (t, J=7.18 Hz, 3H), 2.58 (br. s., 2H), 3.51 (d, J=1.76 Hz, 2H), 3.99 (m, 2H), 6.36 (dd, J=3.37, 2.20 Hz, 1H), 6.61 (dd, J=3.52, 2.34 Hz, 1H), 7.19-7.31 (m, 2H), 7.38 (s, 1H), 7.57 (d, 2H).
To a cold (0° C.) mixture of ether (40 mL) and maleic anhydride (4.4 g, 44.9 mmol) was added dimethylfulvene (4.4 g, 41.51 mmol). The solution was stirred for 8 h at 0° C. A solid separated, which was recrystallized from diethyl ether to obtain the pure exo product (Compound 19-exo). The eluent, which contained a mixture of endo and exo isomers, was concentrated to dryness in vacuo. The residue was purified, and the isomers were separated, by silica gel chromatography (hexane:ethyl acetate::4:1) to produce the endo isomer (Compound 19-endo) as a white solid.
Compound 19-exo: 1HNMR (300 MHz, CDCl3): δ 1.59 (s, 6H), 3.04 (s, 2H), 3.87 (t, J=3.0 Hz, 2H), 6.45 (t, J=3.0 Hz, 2H).
Compound 19-endo: 1HNMR (300 MHz, CDCl3): δ 1.58 (s, 6H), 3.52 (dd, J=3.0, 4.5 Hz, 2H), 3.92 (dd, J=3.0, 4.6 Hz, 2H), 6.44 (t, J=3.0 Hz, 2H).
Following General Procedure A, Compound 19-endo (0.114 g, 0.56 mmol) and 4-bromoaniline (96.3 mg, 0.56 mmol) in THF (4 mL) were mixed together at ambient temperature for 16 h to produce the title compound, which was isolated as a white solid.
1HNMR (300 MHz, CDCl3): δ 1.59 (s, 3H), 1.60 (s, 3H), 3.23 (dd, J=3.0, 9.0 Hz, 1H), 3.29 (dd, J=3.0, 9.0 Hz, 1H), 3.61 (br s, 1H), 3.67 (br s, 1H), 6.25 (dd, J=3.0, 6.0 Hz, 1H), 6.39 (dd, J=3.0, 6.0 Hz, 1H), 7.45 (d, J=3.0 Hz, 4H).
Following General Procedure A, Compound 19-exo (0.068 g, 0.35 mmol) and 4-bromoaniline (60.2 mg, 0.35 mmol) in THF (2 mL) were mixed together at ambient temperature for 16 h to produce the title compound, which was isolated as a white solid after recrystallization from acetonitrile.
1HNMR (300 MHz, CD3OD): δ 1.61 (s, 3H), 1.70 (s, 3H), 2.64 (d, J=9.9 Hz, 1H), 2.76 (d, J=9.9 Hz, 1H), 3.47 (br s, 1H), 3.61 (br s, 1H), 6.39 (t, J=2.1 Hz, 2H), 7.40 (s, 4H).
Following General Procedure A, Compound 19-endo (86 mg, 0.42 mmol) and 4-iodo-aniline (92 mg, 0.42 mmol) in THF (3 mL) were mixed together at ambient temperature for 16 h to produce the title compound, which was isolated as a white solid.
1HNMR (300 MHz, CD3OD): δ 1.59 (s, 3H), 1.60 (s, 3H), 3.30 (dd, J=3.0, 9.0 Hz, 2H), 3.60 (m, 2H), 6.27 (dd, J=3.0, 6.0 Hz, 1H), 6.39 (dd, J=3.0, 6.0 Hz, 1H), 7.31 (d, J=9.0 Hz, 2H), 7.57 (d, J=9.0 Hz, 2H).
To a solution of Compound 19-exo (300 mg, 1.6 mmol) in EtOAC (10 mL) was added 10% Pd—C (16 mg) under argon. The flask was evacuated and refilled with hydrogen gas from a balloon, and the reaction was stirred for 2 h. The reaction was diluted with ethyl acetate (20 mL) and hexane (20 mL), and filtered through a short column of Celite. The product (Compound 23) was collected as white solid after removing the solvent under vacuum.
1HNMR (300 MHz, CDCl3): δ 1.42-1.52 (m, 2H), 1.66 (s, 6H), 1.70-1.80 (m, 2H), 2.69 (s, 2H), 3.20 (t, J=2.4 Hz, 2H).
Following General Procedure A, Compound 23 (100 mg, 0.49 mmol) and 4-bromoaniline (89 mg, 0.51 mmol) in THF (4 mL) were mixed together at ambient temperature for 16 h to produce the title compound, which was isolated as a white solid.
1HNMR (300 MHz, CDCl3): δ 1.42-1.52 (m, 2H), 1.66 (s, 6H), 1.70-1.80 (m, 2H), 2.69 (s, 2H), 3.20 (t, J=2.4 Hz, 2H).
Compound 1 (41 mg, 0.22 mmol) and 2-amino-5-bromopyridine (46 mg, 0.27 mmol) in THF (3.0 mL) were heated in an oil bath at 70° C. for 24 h to produce the title compound, which was isolated as a white solid.
1HNMR (300 MHz, CD3SOCD3): δ 0.40-0.48 (m, 4H), 2.40-2.49 (m, 1H), 3.30 (d, J=6.0 Hz, 1H), 3.38 (d, J=12.0 Hz, 1H), 3.60 (d, J=12.0 Hz, 1H), 6.16 (d, J=6.0 Hz, 1H), 6.21 (d, J=6.0 Hz, 1H), 7.92 (d, J=9.0 Hz, 1H), 7.97 (d, J=9.0 Hz, 1H), 8.38 (brs, 1H).
Additional Compounds that were Prepared by General Procedure A
1HNMR (300 MHz, CD3CN): δ 0.44-0.60 (m, 4H), 2.58 (d, J=12.0 Hz, 2H), 3.48 (dd, J=3.3, 10.2 Hz, 1H), 3.56 (dd, J=3.3, 10.2 Hz, 1H), 6.26 (dd, J=3.0, 5.7 Hz, 1H), 6.37 (dd, J=3.0, 5.7 Hz, 1H), 7.35 (t, J=8.4 Hz, 1H), 7.46 (t, J=8.4 Hz, 2H), 7.58-7.68 (m, 6H).
1HNMR (300 MHz, acetone-d6): δ 0.33-0.66 (m, 4H), 2.52 (br.s., 1H), 2.58 (br.s., 1H), 3.48 (dd, J=9.96, 3.52 Hz, 1H), 3.63 (dd, J=9.96, 3.52 Hz, 1H), 6.17-6.29 (m, 1H), 6.29-6.37 (m, 1H), 7.32 (d, J=7.62 Hz, 1H), 7.47 (t, J=7.91 Hz, 1H), 7.72. (d, J=7.91 Hz, 1H), 8.13 (s, 1H), 9.38 (br.s., 1H).
1HNMR (300 MHz, acetone-d6): δ 0.47 (br.s., 4H), 2.51 (d, J=11.13 Hz, 2H), 3.46 (br.s., 1H), 3.55 (br.s., 1H), 6.25 (d, J=12.60 Hz, 2H), 7.38 (br.s., 2H), 7.98 (br.s., 1H), 9.31 (br.s., 1H).
1HNMR (300 MHz, acetone-d6): δ 0.41-0.56 (m, 4H), 2.51 (br.s., 1H), 2.58 (br.s., 1H), 3.41-3.57 (m, 1H), 3.73 (dd, J=10.11, 3.37 Hz, 1H), 3.86 (s, 3H), 6.25 (dd, J=5.57, 2.93 Hz, 1H), 6.40 (dd, J=5.57, 2.64 Hz, 1H), 6.77-6.91 (m, 1H), 6.92-7.01 (m, 2H), 8.24 (d, J=8.20 Hz, 1H), 8.42 (br.s., 1H).
1HNMR (300 MHz, CD3CN): δ 0.45-0.60 (m, 4H), 2.57 (d, J=11.7 Hz, 2H), 3.49 (dd, J=3.0, 6.0 Hz, 1H), 3.56 (dd, J=3.0, 6.0 Hz, 1H), 6.25 (d, J=6.0 Hz, 1H), 6.35 (d, J=6.0 Hz, 1H), 7.64 (s, 4H), 7.79 (s, 4H).
1HNMR (300 MHz, CD3SOCD3): δ 0.45-0.62 (m, 4H), 1.50-1.65 (m, 2H), 1.70-1.82 (m, 2H), 2.05-2.20 (m, 1H), 3.05 (d, J=11.4 Hz, 1H), 3.28 (d, J=6.9 Hz, 1H), 3.39 (dd, J=4.8, 11.4 Hz, 1H), 7.34 (t, J=7.5 Hz, 1H), 7.43 (t, J=7.5 Hz, 2H), 7.64 (d, J=8.1 Hz, 1H), 8.00 (t, J=8.1 Hz, 2H), 8.10 (s, 1H).
1HNMR (300 MHz, acetone-d6): δ 0.51 (br.s., 4H), 2.51 (s, 4H), 2.58 (br.s., 1H), 3.49 (d, J=2.93 Hz, 1H), 3.55-3.69 (m, 1H), 6.18-6.29 (m, 1H), 6.31 (br.s., 1H), 7.70 (d, J=8.20 Hz, 2H), 7.90 (d, J=7.62 Hz, 2H), 9.38 (br.s., 1H).
1HNMR (300 MHz, CD3OH): δ 0.40-0.60 (m, 4H), 2.48 (s, 2H), 3.46 (dd, J=3.0, 10.2 Hz, 1H), 3.55 (dd, J=3.0, 10.2 Hz, 1H), 6.24 (s, 1H), 6.36 (s, 1H), 6.68 (d, J=9.0 Hz, 2H), 7.24 (d, J=9.0 Hz, 2H).
1HNMR (300 MHz, acetone-d6): δ 0.37-0.59 (m, 4H), 2.51 (br.s., 1H), 2.57 (br.s., 1H), 3.46 (dd, J=9.96, 3.52 Hz, 1H), 3.53-3.67 (dd, J=9.96, 3.52 Hz, 1H), 6.24 (m, 1H), 6.28-6.40 (m, 1H), 7.21 (d, J=8.79 Hz, 2H), 7.70 (d, J=9.08 Hz, 2H), 9.27 (br.s., 1H).
1HNMR (300 MHz, acetone-d6): δ 0.36-0.60 (m, 4H), 2.44 (s, 3H), 2.50 (br.s., 1H), 2.55 (br.s., 1H), 3.44 (dd, J=9.96, 3.22 Hz, 1H), 3.55-3.65 (dd, J=9.96, 3.22 Hz, 1H), 6.22 (dd, J=5.57, 2.93 Hz, 1H), 6.32 (dd, J=5.42, 2.78 Hz, 1H), 7.20 (d, J=8.50 Hz, 2H), 7.55 (d, J=8.79 Hz, 2H), 9.08 (br.s., 1H).
1HNMR (300 MHz, acetone-d6): δ 0.35-0.57 (m, 4H), 1.17 (t, J=7.47 Hz, 3H), 2.46-2.65 (m, 4H), 3.42 (dd, J=9.96, 3.52 Hz, 1H), 3.60 (dd, J=9.96, 3.52 Hz, 1H), 6.21 (dd, J=5.57, 2.93 Hz, 1H), 6.33 (dd, J=5.71, 2.78 Hz, 1H), 7.09 (d, J=8.20 Hz, 2H), 7.49 (d, J=8.50 hz, 2H), 8.99 (br.s., 1H).
1HNMR (300 MHz, CD3OD): δ 0.46-0.73 (m, 4H), 1.71 (d, J=3.81 Hz, 4H), 1.77-1.94 (m, 2H), 2.11-2.26 (m, 1H), 3.16-3.27 (dd, J=11.43, 4.40 Hz, 1H), 3.45 (dd, J=11.43, 4.40 Hz, 1H), 7.26-7.37 (m, 1H), 7.45 (t, J=7.91 Hz, 1H), 7.69 (d, J=7.91 Hz, 1H), 7.98 (s, 1H).
1HNMR (300 MHz, acetone-d6): δ 0.36-0.70 (m, 4H), 1.44-1.75 (m, 4H), 1.81 (br.s., 1H), 2.20 (br.s., 1H), 3.16 (d, J=10.84 Hz, 1H), 3.41 (d, J=10.84 Hz, 1H), 7.43 (br.s., 2H), 8.06 (br.s., 1H), 9.34 (br.s., 1H)
1HNMR (300 MHz, acetone-d6): δ 0.47-0.70 (m, 4H), 1.55-1.74 (m, 4H), 1.81-1.83 (m, 2H), 2.23-2.38 (m, 1H), 2.81 (br.s., 1H), 3.16 m, 1H), 3.58-3.69 (m, 1H), 3.84 (s, 3H), 6.83-6.93 (m, 1H), 6.95-7.06 (m, 2H), 8.31 (d, J=8.20 Hz, 1H), 8.47 (br.s., 1H).
1HNMR (300 MHz, CDCl3): δ 0.50-0.70 (m, 4H), 1.20 (t, J=7.5 Hz, 3H), 1.62-1.90 (m, 5H), 2.02-2.20 (m, 1H), 2.57 (q, J=7.5 Hz, 2H), 3.20-3.38 (m, 2H), 7.12 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H).
1HNMR (300 MHz, CD3OD): δ 0.50-0.70 (m, 4H), 1.62-1.90 (m, 5H), 2.12-2.22 (m, 1H), 3.21 (d, J=10.8 Hz, 1H), 3.43 (d, J=10.8 Hz, 1H), 7.17 (d, J=8.4 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H).
1HNMR (300 MHz, CD3OD): δ 0.50-0.65 (m, 4H), 1.60-1.85 (m, 5H), 2.18-2.24 (m, 1H), 2.43 (s, 3H), 3.18 (d, J=11.4 Hz, 1H), 3.43 (d, J=11.4 Hz, 1H), 7.22 (d, J=9.0 Hz, 2H), 7.43 (d, J=9.0 Hz, 2H).
1HNMR (300 MHz, CD3OD): δ 0.50-0.70 (m, 4H), 1.60-1.88 (m, 5H), 2.18 (brs, 1H), 2.54 (s, 3H), 3.21 (d, J=10.8 Hz, 1H), 3.45 (d, J=10.8 Hz, 1H), 7.65 (d, J=7.8 Hz, 2H), 7.92 (d, J=7.8 Hz, 2H).
1HNMR (300 MHz, CD3OD): δ 0.51-0.73 (m, 4H), 1.72 (br.s., 4H), 1.76-1.91 (m, 2H), 2.12-2.26 (m, 1H), 2.77 (s, 3H), 3.22 (d, J=10.84 Hz, 1H), 3.45 (d, J=10.84 Hz, 1H), 7.63 (d, 2H), 7.77 (d, J=8.79 Hz, 2H), 7.89 (s, 1H).
(1R,2S,3R,4S)-3-((4-(Methylsulfonyl)phenyl)carbamoyl)spiro[bicyclo[2.2.1]heptane-7,1′-cyclopropane]-2-carboxylic Acid (Compound 45).
1HNMR (300 MHz, CD3OD): δ 0.61 (m, 4H), 1.70 (br.s., 4H), 1.81 (br.s., 1H), 1.86-1.93 (m, 1H), 3.08 (s, 3H), 3.37-3.50 (m, 2H), 7.70-7.93 (m, 4H).
To a solution of starting material (0.30 g, 0.83 mmol) in THF (15.0 mL) at ambient temperature was added 1,1′-carbonyl bis-1H-imidazole (0.15 g, 0.91 mmol), and the reaction was stirred for 2 h. NH4OH 28-30% (1.50 mL) was added, and the reaction was stirred for 10 min, then acidified with 2N HCl to pH=1. The mixture was extracted with EtOAc, dried over MgSO4, and filtered. The solvent was removed, and the residue was purified by preparative TLC (MeOH/CH2Cl2=5/95) to afford 0.0658 g (22%) of the desired product as a white solid.
1HNMR (300 MHz, CD3OD): δ 0.61 (br.s., 4H), 1.61-1.83 (m, 4H), 1.96-2.12 (m, 2H), 3.31 (br.s., 2H), 7.32-7.41 (m, 2H), 7.42-7.51 (m, 2H).
Additional Compounds that were Prepared by General Procedure C
1HNMR (300 MHz, CD3OD): δ 0.39-0.63 (m, 4H), 2.50 (s, 2H), 3.52 (s, 2H), 6.27-6.34 (m, 1H), 6.38-6.47 (m, 1H), 7.29-7.52 (m, 4H).
1HNMR (300 MHz, CDCl3): δ 0.46 (d, J=5.86 Hz, 2H), 0.58 (d, J=7.33 Hz, 2H), 1.05-1.34 (m, 3H), 2.41-2.71 (m 4H), 3.54 (d, J=8.50 Hz, 2H), 6.54 (br.s., 1H), 6.59 (br.s., 1H), 7.11 (d, J=8.20 Hz, 2H), 7.33 (d, J=7.62 Hz, 2H), 7.86 (br.s., 1H).
1HNMR (300 MHz, CD3OD): δ 0.41-0.63 (m, 4H), 2.42 (s, 3H), 2.51 (br.s., 2H), 3.52 (br.s., 2H), 6.32 (br.s., 1H), 6.36-6.48 (m, 1H), 7.19 (d, J=8.50 Hz, 2H), 7.42 (d, J=8.50 Hz, 2H).
1HNMR (300 MHz, CD3OD): δ 0.42-0.60 (m, 4H), 2.50 (br.s., 2H), 3.51 (s, 2H), 6.31 (m, 1H), 6.40 (m, 1H), 7.30 (d, J=8.50 Hz, 2H), 7.56 (d, J=8.50 Hz, 2H).
1HNMR (300 MHz, CD3OD): δ 0.61 (br.s., 4H), 1.76 (m, 4H), 1.96-2.12 (m, 2H), 3.31 (br.s., 2H), 7.33 (d, 8.79 Hz, 2H), 7.57 (d, J=8.79 Hz, 2H).
1HNMR (300 MHz, CD3OD): δ 0.52-0.69 (m 4H), 1.19 (m, 3H), 1.61-1.84 (m, 4H), 2.04 (d, J=8.20 Hz, 2H), 2.58 (d, J=7.62 Hz, 2H), 3.30 (br.s., 2H), 7.10 (d, J=8.20 Hz, 2H), 7.39 (d, J=8.50 Hz, 2H).
1HNMR (300 MHz, CD3OD): δ 0.53-0.70 (m, 4H), 1.64-1.84 (m, 4H), 1.96-2.08 (m, 2H), 2.43 (s, 3H), 3.16-3.28 (m, 2H), 7.20 (d, J=8.79 Hz, 2H), 7.45 (d, J=8.50 Hz, 2H).
1HNMR (CDCl3): δ 1.12 (d, J=14.36 Hz, 6H), 1.69-2.08 (m, 6H), 3.23 (br.s., 1H), 3.27-3.41 (m, 1H), 5.70 (br.s., 2H), 7.32-7.42 (m, 2H), 7.42-7.53 (m, 2H), 9.12 (br.s., 1H).
1HNMR (300 MHz, CDCl3): δ 1.09 (d, J=7.62 hz, 6H), 1.51-2.05 (m, 6H), 3.13-3.27 (m, 1H), 3.32 (br.s., 1H), 5.84 (br.s., 2H), 7.33 (d, J=8.20 Hz, 2H), 7.54 (d, J=8.20 Hz, 2H), 9.11 (br.s., 1H).
1HNMR (300 MHz, CDCl3): δ 1.09 (d, J=10.84 Hz, 6H), 1.61-2.06 (m, 6H), 2.44 (s, 3H), 3.21 (m, 1H), 3.34 (m, 1H), 5.93 (br.s., 1H), 7.19 (d, J=8.20 Hz, 2H), 7.49 (d, J=8.20 Hz, 2H), 8.80-9.01 (m, 1H).
1HNMR (300 MHz, CDCl3): δ 1.03-1.32 (m, 9H), 1.75 (br.s., 2H), 2.00 (br.s., 4H), 2.60 (q, J=7.52 Hz, 2H), 3.24 (m., 1H), 3.28-3.42 (m, 1H), 7.12 (d, J=8.20 Hz, 2H), 7.44 (d, J=7.91 Hz, 2H).
To a solution of Compound 1 (760 mg, 4 mmol) in THF (10 mL) was added LiBH4 (99 mg, 4.5 mmol) at ambient temp. The mixture was stirred for 16 h, then quenched with 5% H2SO4 in water (15 mL), and the product was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with brine, and dried (MgSO4), and concentrated under vacuum. The residue was purified by flash chromatrography on silica gel using 30% EtOAc in hexane as the eluent. The title compound, Intermediate A, was isolated as a white solid.
1HNMR (300 MHz, CDCl3): δ 0.40-0.60 (m, 4H), 2.45 (brs, 1H), 2.70 (brs, 1H), 3.20-3.31 (m, 1H), 3.40 (dd, J=4.5, 9.6 Hz, 1H), 3.85 (dd, J=3.6, 9.6 Hz, 1H), 4.31 (t, J=9.0 Hz, 1H), 6.38 (brs, 2H).
To a solution of 4-bromoaniline (390 mg, 2.3 mmol) in THF (5 mL) at ambient temperature was added n-BuLi (2.5M solution in hexane, 0.72 mL, 1.8 mmol). After 30 min at ambient temperature, a solution of Intermediate A (190 mg, 1.1 mmol) in THF (5 mL) was added. The reaction mixture was stirred for 3 h, and then quenched by the addition of EtOAc (25 mL) and water (5 mL). This mixture was washed with brine, the layers separated and the organic layer was dried (MgSO4), and concentrated under reduced pressure. The residue was titutrated with CCl4 (5 mL) to give the title compound as a solid.
1HNMR (300 MHz, CD3OD): δ 0.40-0.60 (m, 4H), 2.35 (s, 1H), 2.43 (s, 1H), 2.80-2.92 (m, 1H), 3.30-3.58 (m, 3H), 6.21 (d, J=5.7 Hz, 1H), 6.37 (d, J=5.7 Hz, 1H), 7.40 (d, J=7.8 Hz, 2H), 7.44 (d, J=7.8 Hz, 2H).
To a solution of Compound 2 (450 mg, 2.3 mmol) in THF (10 mL) was added LiBH4 in THF (2M soln. 1.4 mL, 2.8 mmol) at ambient temperature. The mixture was stirred for 1 h, and the reaction was quenched with 5% H2SO4 in water (10 mL). The solution was diluted with 25 mL of EtOAc, the layers separated, and the product was extracted from the aqueous layer with EtOAc (2×25 mL). The combined organic layers were washed with brine, and dried (MgSO4), and the solvents were concentrated under vacuum. The residue was purified by flash chromatrography on silica gel using 25% EtOAc in hexane as the eluent. The title compound, Intermediate B, was isolated as a white solid after removal of the solvent under vacuum.
1HNMR (300 MHz, CDCl3): δ 0.52-0.64 (m, 4H), 1.50-1.65 (m, 2H), 1.65-1.95 (m, 4H), 3.10-3.22 (m, 2H), 4.22-4.38 (m, 2H).
Compound 59 was prepared from Intermediate B by using the same procedure used to prepare Compound 58.
1HNMR (300 MHz, CD3OD): δ 0.50-0.70 (m, 4H), 1.55-1.75 (m, 4H), 1.80 (t, J=8.1 Hz, 1H), 2.04 (t, J=8.1 Hz, 1H), 2.42-2.60 (m, 1H), 3.16 (dd, J=3.9, 11.4 Hz, 1H), 3.80-3.95 (m, 2H), 7.40 (d, J=7.8 Hz, 2H), 7.46 (d, J=7.8 Hz, 2H).
Bicyclo[2.2.2]oct-2-ene-2,3-dicarboxylic anhydride (Alfa Aesar Co., 212 mg, 1.2 mmol), 4-bromoaniline (172 mg, 1.0 mmol) and 4.8 mL of chloroform were stirred overnight at room temperature. The solid that formed was separated by filtration and washed 3 times with cold chloroform. The solid was dried to yield the title compound as a white solid.
1HNMR (300 MHz, acetone-d6): δ 1.31-1.49 (m, 4H), 1.60-1.72 (m, 4H), 3.06 (s, 1H), 3.23 (s, 1H), 7.48 (d, 2H, J=8.8 Hz), 7.66 (d, 2H, J=8.8 Hz), 9.67 (s, 1H), 11.45 (s, 1H).
Additional Compounds that were Prepared by General Procedure C
1HNMR (300 MHz, CDCl3): δ 1.09 (s, 6H), 1.51-2.05 (m, 6H), 3.13-3.27 (m, 1H), 3.32 (br. s., 1H), 7.33 (d, J=8.2 Hz, 2H), 7.54 (d, J=8.2 Hz, 2H).
1HNMR (300 MHz, CD3OD): δ 0.61 (br.s, 4H), 1.74-1.85 (m, 4H), 1.98-2.05 (m, 2H), 3.25-3.34 (m, 2H), 7.33 (d, J=8.2 Hz, 2H), 7.57 (d, J=8.2 Hz, 2H).
1HNMR (300 MHz, CD3OD): δ 0.45-60 (m, 4H), 2.42 (s, 3H), 2.51 (s, 2H), 3.50-3.58 (m, 2H), 6.32 (s, 1H), 6.45 (s, 1H), 7.19 (d, J=6.0 Hz, 2H), 7.42 (d, J=6.0 Hz, 2H).
1HNMR (300 MHz, CDCl3): δ 1.07 (s, 3H), 1.11 (s, 3H), 1.67-2.05 (m, 6H), 2.44 (s, 3H), 3.10-3.40 (m, 2H), 7.19 (d, J=8.2 Hz, 2H), 7.49 (d, J=8.2 Hz, 2H).
1HNMR (300 MHz, CDCl3): δ 1.09 (s, 3H), 1.15 (s, 3H), 1.20 (t, J=7.5 Hz, 3H), 1.50-1.80 (m, 2H), 1.80-2.02 (m, 4H), 2.60 (q, J=7.52 Hz, 2H), 3.22-3.40 (m, 2H), 7.12 (d, J=8.20 Hz, 2H), 7.44 (d, J=8.20 Hz, 2H).
1HNMR (300 MHz, CDCl3): δ 0.46 (d, J=5.86 Hz, 2H), 0.58 (d, J=5.86 Hz, 2H), 1.19 (t, J=8.50 Hz, 3H), 2.41-2.71 (m, 4H), 3.54 (q, J=8.50 Hz, 2H), 6.54 (s, 1H), 6.59 (s, 1H), 7.11 (d, J=8.20 Hz, 2H), 7.33 (d, J=8.20 Hz, 2H).
1HNMR (300 MHz, CD3OD): δ 0.53-0.70 (m, 4H), 1.64-1.84 (m, 4H), 1.96-2.08 (m, 2H), 2.43 (s, 3H), 3.16-3.28 (m, 2H), 7.20 (d, J=8.50 Hz, 2H), 7.45 (d, J=8.50 Hz, 2H).
1HNMR (300 MHz, CD3OD): δ 0.52-0.69 (m, 4H), 1.19 (t, J=7.62 Hz, 3H), 1.61-1.84 (m, 4H), 2.04 (d, J=8.20 Hz, 2H), 2.58 (q, J=7.62 Hz, 2H), 3.20-3.35 (m, 2H), 7.10 (d, J=8.20 Hz, 2H), 7.39 (d, J=8.20 Hz, 2H).
1HNMR (300 MHz, CDCl3): δ 0.42-0.60 (m, 4H), 2.50 (br. s., 2H), 3.51 (s, 2H), 6.31 (dd, J=3.81, 1.76 Hz, 1H), 6.40 (dd, J=3.81, 1.76 Hz, 1H), 7.30 (d, J=8.50 Hz, 2H), 7.56 (d, J=8.50 Hz, 2H).
Additional Compounds that were Prepared by General Procedure A
1HNMR (300 MHz, CD3SOCD3): δ 0.51-0.73 (m, 4H), 1.72 (br.s., 4H), 1.76-1.91 (m, 2H), 2.12-2.26 (m, 1H), 2.77 (s, 3H), 3.22 (d, J=10.84 Hz, 1H), 3.45 (dd, J=10.84, 4.40 Hz, 1H), 7.63 (d, J=8.79 Hz, 2H), 7.77 (d, J=8.79 Hz, 2H).
1HNMR (300 MHz, CD3SOCD3): δ 0.61 (t, J=8.94 Hz, 4H), 1.70 (br.s., 4H), 1.76-1.91 (m, 2H), 3.40 (s, 3H), 3.30 (br.s., 1H), 3.45 (br.s., 1H), 7.70-7.93 (m, 4H).
1HNMR (300 MHz, CD3COCD3): δ 0.44-0.061 (m, 4H), 3.34 (d, J=8.5 Hz, 2H), 6.50-6.70 (m, 2H), (7.01 (d, J=8.2 Hz, 2H), 7.36 (d, J=8.2 Hz, 2H).
1HNMR (300 MHz, CD3COCD3): δ 0.70-0.85 (m. 4H), 1.66 (br.s., 4H), 1.65-1.55 (s, 6H), 3.18 (d, J=3H), 3.30 (br.s., 1H), 3.60 (br.s., 1H), 7.25 (br. s., 4H).
1HNMR (300 MHz, CD3OD): δ 0.55-0.70 (m. 4H), 1.63 (br.s., 3H), 1.75-1.92 (m, 2H), 2.05-2.25 (m, 2H), 3.20 (dd, J=4.5.0, 2.0 Hz, 1H), 3.45 (dd, J=4.5, 2.0 Hz, 1H), 7.60 (d, J=8.00 Hz, 2H), 7.80 (m, 4H).
1HNMR (300 MHz, CD3OD): δ 0.55-0.72 (m, 4H), 1.70 (br.s., 3H), 1.80-1.92 (m, 2H), 2.05 (s, 3H), 2.20-2.25 (m, 1H), 3.20 (dd, J=4.5, 2.0 Hz, 1H), 3.45 (dd, J=4.5, 2.0 Hz, 1H), 7.45 (s, 4H).
To compound (CAS #359434-59-6) (260 mg, 0.74 mmol), CH2Cl2 (5 mL) was added Et3N (231 mg, 2.29 mmol). This solution was cooled to −30° C. and a solution of ClCO2Et (124 mg, 1.15 mmol) in CH2Cl2 (3 mL) was added via canula. The mixture was stirred for 15 min, then dimethylamine in THF (2M solution, 1 mL) was added to the reaction. After warming to ambient temperature the solid formed was collected by filtration. This solid was partially dissolved in EtOAC (5 mL), MeOH (2 mL), and water (2 mL) and mixed well in a separatory funnel. The product (Compound 62) was the insoluble solid and was collected by filtration as a white solid.
1HNMR (300 MHz, CD3SOCD3): δ 0.44 (s, 4H), 2.35 (s, 1H), 2.53 (s, 1H), 2.64 (s, 3H), 2.82 (s, 3H), 3.42 (d, J=7.2 Hz, 1H), 3.55 (d, J=7.2 Hz, 1H), 5.87 (s, 1H), 6.35 (s, 1H), 7.41 (s, 4H).
Additional Compounds that were Prepared by General Procedure D
1HNMR (300 MHz, CD3OD): δ 0.55-0.70 (m, 4H), 1.62-1.80 (m, 4H), 1.95-2.05 (m, 2H), 2.68 (s, 3H), 3.15-3.38 (m, 2H), 7.38 (d, J=8.2 Hz, 2H), 7.47 (d, J=8.2 Hz, 2H).
1HNMR (300 MHz, CD3OD): δ 0.55-0.70 (m, 4H), 1.06 (t, J=7.2 Hz, 3H), 1.65-1.80 (m, 4H), 1.95-2.05 (m, 2H), 3.15 (q, J=8.2 Hz, 2H), 3.20-3.35 (m, 2H), 7.38 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.2 Hz, 2H).
1HNMR (600 MHz, CD3OD): δ 0.55-0.70 (m, 4H), 1.05 (d, J=6.6 Hz, 3H), 1.09 (d, J=6.6 Hz, 3H), 1.65-1.80 (m, 4H), 1.95-2.00 (m, 1H), 2.10-2.15 (m, 1H), 3.21 (dd, J=3.6, 7.2 Hz, 1H), 3.26 (dd, J=3.60, 7.2 Hz, 1H), 3.91 (sept, 1H), 7.38 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.2 Hz, 2H).
1HNMR (600 MHz, CD3SOD3): δ 0.50-0.75 (m, 4H), 1.50-1.75 (m, 4H), 1.98 (br.s., 2H), 3.01 (br.s., 1H), 3.20 (br.s., 1H), 3.50 (s, 3H), 7.41 (d, J=8.2 Hz, 2H), 7.52 (d, J=8.2 Hz, 2H).
1HNMR (600 MHz, CDCl3): δ 0.01 (s, 6H), 0.45-0.70 (m, 4H), 0.83 (s, 9H), 1.55-1.80 (m, 5H), 2.05-2.15 (m, 1H), 3.01-3.08 (m, 1H), 3.32-3.45 (m, 3H), 3.60-3.70 (m, 2H), 7.19 (d, J=8.8 Hz, 2H), 7.32 (d, J=78.8 Hz, 2H).
To a cold (0° C.) solution of compound 81 (46 mg, 0.084 mmol) in THF (5 mL) was added HF-pyridine (0.5 mL). The reaction mixture was warmed to ambient temperature and stirred for 2 h. After which time aq. NaHCO3 (1 M, 10 mL) was added and extracted with CH2Cl2 (2×20 mL). The organic layer was washed with brine and dried with MgSO4. The solid was filtered and from the filtrate solvent was removed under reduced pressure. The crude product was purified by silicagel prep. TLC. The product (compound 82) was isolated as a white solid.
1HNMR (600 MHz, CD3OD): δ 0.45-0.70 (m, 4H), 1.65-1.80 (m, 4H), 1.95-2.15 (m, 2H), 3.20-3.40 (m, 4H), 3.56 (t, J=6.0 Hz, 2H), 7.38 (d, J=9.0 Hz, 2H), 7.46 (d, J=9.0 Hz, 2H).
To compound 10 (200 mg, 0.55 mmol), CH2Cl2 (5 mL) was added Et3N (231 mg, 2.29 mmol). This solution was cooled to −30° C. and a solution of ClCO2Et (124 mg, 1.15 mmol) in CH2Cl2 (3 mL) was added via canula. The mixture was stirred for 15 min, then MeOH (0.5 mL) was added to the reaction. After warming to ambient temperature the solvent was removed and the crude product was purified by silicagel chromatography. The pure product (Compound 83) was isolated as a white solid.
1HNMR (300 MHz, CDCl3): δ 0.44-0.65 (m, 4H), 1.60-1.80 (m, 5H), 2.10-2.28 (m, 1H), 3.15 (d, J=7.2 Hz, 1H), 3.30 (dd, J=7.2, 3.6 Hz, 1H), 7.40 (s, 4H).
Additional Compounds that were Prepared by General Procedure E
1HNMR (300 MHz, CDCl3): δ 0.50-0.65 (m, 4H), 1.09 (t, J=7.2 Hz, 3H), 1.50-1.85 (m, 5H), 2.20-2.31 (m, 1H), 3.10 (d, J=7.8 Hz, 1H), 3.45 (dd, J=7.2, 3.6 Hz, 1H), 3.99 (q, J=7.2 Hz, 2H), 7.42 (d, J=8.2 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H).
1HNMR (300 MHz, CD3COCD3): δ 0.45-0.65 (m, 4H), 1.60-1.88 (m, 4H), 2.30-2.42 (m, 1H), 3.06-3.22 (m, 2H), 3.52 (dd, J=11.3, 4.5 Hz, 1H), 4.98 (ABq, J=8.5 Hz, 2H), 7.10-7.24 (m, 3H), 7.28 (d, J=6.7 Hz, 2H), 7.46 (d, J=8.2 Hz, 2H), 7.62 (d, J=8.2 Hz, 2H).
A mixture of compound 10 (200 mg, 0.55 mmol), 2-iodopropane (935 mg, 5.5 mmol), NaHCO3 (460 mg, 5.5 mmol) and DMF (5 mL) was stirred at RT for 48 h. Then the solvent was removed by distillation, crude product was crystallized using CH2Cl2 and hexane. The product (compound 86) was isolated as a white solid.
1HNMR (300 MHz, CD3COCD3): δ 0.45-0.60 (m, 4H), 1.05 (d, J=6.3 Hz, 3H), 1.12 (d, J=6.3 Hz, 3H), 1.55-1.70 (m, 3H), 1.75-1.90 (m, 2H), 2.23-2.34 (m, 1H), 3.08 (d, J=11.4 Hz, 1H), 3.44 (dd, J=11.4, 4.4 Hz, 1H), 4.89 (septet, J=6.3 Hz, 1H), 7.43 (d, J=8.8 Hz, 2H), 7.64 (d, J=8.8 Hz, 2H).
To a solution of compound 2 (62 mg, 0.33 mmol), in CH2Cl2 (1 mL) was added 4-bromophenylhydrazine (CAS 41931-18-4) (61 mg, 0.33 mmol) in CH2Cl2 (2 mL). The reaction was stirred for 2 h at RT. The product (compound 87) separated as a white ppt, which was collected by filtration.
1HNMR (300 MHz, CD3OD): δ 0.50-0.70 (m, 4H), 1.60-1.85 (m, 5H), 2.10-2.20 (m, 1H), 3.20 (dd, J=8.4, 2.1 Hz, 1H), 3.40 (dd, J=8.4 Hz, 2.1 Hz, 1H), 6.73 (d, J=6.9 Hz, 2H), 7.24 (d, J=6.9 Hz, 2H).
To a cold (−50° C.) solution of 4-bromo N-methylaniline (564 mg, 3.03 mmol) in THF (5 mL) was added n-BuLi (2.5 M solution in hexane, 0.4 mL, 1 mmol). The reaction was warmed to RT and stirred for 30 min. To this turbid reaction mixture a solution of compound 2 (186 mg, 0.96 mmol) in THF (5 mL) was added and stirred for 2 h. After which time all the solvent was removed under reduced pressure. The crude solid was diluted with ice-cold 10% HCl (10 mL), ether (40 mL) and mixed well in a separatory funnel. The aq. layer was discarded, and the ether layer and the undissolved solid were collected and the solvent was removed under reduced pressure. This crude mixture was purified by reverse phase column chromatography and eluted with CH3CN:H2O:TFA (90:9.9:0.1). The product (compound 86) was collected as colorless crystals.
1HNMR (300 MHz, CD3OD): δ 0.30-0.50 (m, 2H), 0.60-0.80 (m, 2H), 1.20-1.35 (m, 1H), 1.50-1.70 (m, 4H), 1.82 (br. s, 1H), 2.83 (d, J=5.4 Hz, 1H), 3.22 (s, 3H), 3.69 (br. s, 1H), 7.23 (d, J=8.4 Hz, 2H), 7.62 (d, J=8.4 Hz, 2H).
To a solution of compound 46 (50 mg, 0.14 mmol) in DMF (5 mL) was added 4A molecular sieves (100 mg) and stirred for 10 min. Cyanuric chloride (40 mg, 0.21 mmol) was added to the reaction and heated for 18 h at 100° C. Solvent was removed under reduced pressure and the crude mixture was purified by silicagel prep. TLC, MeOH:CH2Cl2 (1:49) was used as eluent. The product (compound 89) was isolated as a pale yellow solid.
1HNMR (300 MHz, CDCl3): δ 0.64 (br. s., 4H), 1.45-1.60 (m, 2H), 1.85-1.95 (m, 2H), 2.08 (br. s., 2H), 3.44 (br. s., 2H), 7.17 (d, J=8.2 Hz, 2H), 7.59 (d, J=8.2 Hz, 2H).
A mixture of compound 10 (200 mg, 0.55 mmol), K2CO3 (110 mg, 0.83 mmol), Me2SO4 (126 mg, 1 mmol), acetone (10 mL) was heated to 80° C. 18 h. The solvent was removed under reduced pressure, and the solid was extracted with CH2Cl2 (40 mL). The CH2Cl2 layer was dried with MgSO4 and solvent removed under reduced pressure. The crude reaction mixture was purified by silicagel column chromatography, using EtOAc:Hexane (3:7). Compound 90 was isolated as a white solid.
1HNMR (300 MHz, CD3OD): δ 0.55-0.75 (m, 4H), 1.47-1.55 (m, 3H), 1.85-2.04 (m, 3H), 3.50 (br. s., 2H), 7.21 (d, J=8.5 Hz, 2H), 7.65 (d, J=8.5 Hz, 2H).
A mixture of compound 90 (108 mg, 0.31 mmol), NaBH4 (60 mg, 1.55 mmol) and MeOH and stirred for 18 h at 45° C. The solvent was removed under reduced pressure and the crude mixture was diluted with CH2Cl2 (40 mL). The organic layer was washed with NaHCO3 in water, dried over MgSO4 and filtered off. The solvent was removed under reduced pressure. The crude mixture was purified by silicagel prep. TLC using MeOH:CH2Cl2 (1:19). The product (compound 91) was isolated as a white solid.
1HNMR (300 MHz, CD3OD): δ 0.55-0.70 (m, 4H), 1.45-1.55 (m, 3H), 1.65-1.90 (m, 4H), 2.72 (dd, J=12.0, 6.0 Hz, 1H), 3.29 (dd, J=12.0, 6.0 Hz, 1H), 7.48 (d, J=8.8 Hz, 2H), 7.57 (d, J=8.8 Hz, 2H).
A mixture of compound 91 (20 mg, 0.06 mmol), K2CO3 (17 mg, 0.12 mmol), NH2OH.HCl (4 mg, 0.06 mmol) and MeOH (5 mL) was heated to 60° C. for 72 h. After which time the solvent was removed under reduced pressure. The crude reaction mixture was purified by silicagel prep. TLC, using MeOH:CH2Cl2 (3:47). Compound 92 was isolated as a white solid.
1HNMR (300 MHz, CD3OD): δ 0.50-0.70 (m, 4H), 1.47-1.55 (m, 1H), 1.65-1.85 (m, 5H), 2.95 (dd, J=12.0, 6.0 Hz, 1H), 3.19 (dd, J=12.0, 6.0 Hz, 1H), 7.41 (d, J=8.8 Hz, 2H), 7.59 (d, J=8.8 Hz, 2H).
A mixture of compound 92 (20 mg, 0.06 mmol), Pd—C (10%) (2 mg), AcOH (75 mg) in MeOH (10 mL) was hydrogenated under 50 psi hydrogen atmosphere for 18 h. After which time the solvent was removed under reduced pressure. The crude reaction was purified by silicagel prep TLC.
The faster moving product (compound 93) was isolated as a pale yellow solid and the slower moving product (compound 94) was isolated as a pale yellow syrup.
Compound 93: 1HNMR (300 MHz, CDCl3): δ 0.45-0.65 (m, 4H), 1.45-1.60 (m, 2H), 1.55-1.80 (m, 3H), 1.85-1.90 (m, 1H), 2.55 (dd, J=10.7, 5.4 Hz, 1H), 3.23 (dd, J=10.7, 5.4 Hz, 1H), 7.17-7.25 (m, 2H), 7.34-7.45 (m, 3H).
Compound 94: 1HNMR (300 MHz, CDCl3): δ 0.50-0.65 (m, 4H), 1.45-1.60 (m, 2H), 1.70-1.80 (m, 3H), 1.93-2.00 (m, 1H), 2.75 (dd, J=10.7, 5.4 Hz, 1H), 3.23 (m, 1H), 7.20-7.27 (m, 1H), 7.40 (t, J=8.2 Hz, 2H), 7.57 (d, J=8.2 Hz, 2H).
While this invention has been described with respect to these specific examples, it is understood that other modifications and variations are possible without departing from the spirit of the invention.
This application claims the benefit of U.S. Provisional Application Ser. No. 61/358,175, filed Jun. 24, 2010, the disclosure of which is hereby incorporated in its entirety herein by reference.
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