| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | May 4, 2004 |
| PATENT TITLE |
Chlorinated heterocyclic compounds and methods of synthesis |
| PATENT ABSTRACT | Compositions of the present invention comprise chlorinated heterocyclic compounds, including racemic monochloroflosequinan, purified enantiomers of monochloroflosequinan and the sulfone derivative of monochloroflosequinan. The methods of the present invention comprise the synthesis of racemic monochloroflosequinan and derivatives thereof, including the sulfone derivative. Intermediates in the synthesis are also provided. The methods further comprise the synthesis of enantiomers of monochloroflosequinan |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | October 28, 2002 |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
We claim: 1. A composition comprising racemic 3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone. 2. A composition comprising (S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone in enantiomeric excess. 3. A composition according to claim 2, wherein said (S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone is at least 90% of the enantiomeric excess. 4. A composition according to claim 2, wherein said (S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone is at least 95% of the enantiomeric excess. 5. A composition comprising (R)-(-)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone in enantiomeric excess. 6. A composition according to claim 5, wherein said (R)-(-)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone; is at least 90% of the enantiomeric excess. 7. A composition according to claim 5, wherein said (R)-(-)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone is at least 95% of the enantiomeric excess. 8. A composition comprising 3-chloromethylsulfonyl-7-fluoro-1-methyl-4-quinolone. 9. A composition comprising 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone. 10. A method for the synthesis of chlorodesoxyflosequinan, comprising: a) providing: i) flosequinan, and ii) triphenyl phosphine; and b) reacting said flosequinan and triphenyl phosphine in an organic solvent under conditions such that desoxyflosequinan (7-fluoro-1-methyl-3-methylthio-4-quinolone) is produced; and c) further reacting said desoxyflosequinan with N-chlorosuccinimide and 2,2'-azobisisobutyronitrile in an organic solvent under conditions such that chlorodesoxyflosequinan (3-chloromethylthio-7-fluoro-1-methyl-4-quinolone) is produced. 11. The method of claim 10, wherein said organic solvent in said reacting step b) is selected from the group consisting of carbon tetrachloride, xylene and toluene. 12. The method of claim 10, wherein said providing step a) optionally provides iii) a catalyst, and said reacting step b) occurs in the presence of said catalyst. 13. The method of claim 12, wherein said organic solvent in said reacting step b) is selected from the group consisting of xylene and toluene. 14. The method of claim 12, wherein said catalyst is tetrabromomethane. 15. The method of claim 10, wherein said organic solvent in step c) is selected from the group consisting of carbon tetrachloride and benzene. 16. A method for the synthesis of chlorodesoxyflosequinan, comprising: a) providing: i) flosequinan, ii) thionyl chloride, and iii) pyridine; and b) reacting said flosequinan, thionyl chloride and pyridine in an organic solvent under conditions such that chlorodesoxyflosequinan (3-chloromethylthio-7-fluoro-1-methyl-4-quinolone) is produced. 17. A method for the synthesis of monochloroflosequinan, comprising: a) providing: i) chlorodesoxyflosequinan (3-chloromethylthio-7-fluoro-1-methyl-4-quinolone), ii) hydrogen peroxide, and iii) potassium carbonate; and b) reacting said chlorodesoxyflosequinan, hydrogen peroxide and potassium carbonate in a solvent under conditions such that monochloroflosequinan (3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone) is produced. 18. A methods for the synthesis of monochloroflosequinan, comprising: a) providing: i) flosequinan, and ii) N-chlorosuccinimide; and b) reacting said flosequinan and N-chlorosuccinimide in an organic solvent under conditions such that monochloroflosequinan (3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone) is produced. 19. The method of claim 18, wherein said organic solvent is selected from the group consisting of carbon tetrachloride and benzene. 20. The method of claim 19, wherein when said organic solvent is carbon tetrachloride, said reacting step b) additionally includes 2,2'-azobisisobutyronitrile. 21. A method for the synthesis of monochloroflosequinan, comprising: a) providing: i) chlorodesoxyflosequinan (3-chloromethylthio-7-fluoro-1-methyl-4-quinolone), and ii) a camphor based reagent; and b) reacting said chlorodesoxyflosequinan and camphor based reagent in an organic solvent under conditions such that an enantiomer of monochloroflosequinan is produced in enantiomeric excess. 22. The method of claim 21, wherein said camphor based reagent is (R)-(-)-(10-camphorsulfonyl) oxaziridine. 23. The method of claim 21, wherein said camphor based reagent is (S)-(+)-(10-camphorsulfonyl) oxaziridine. 24. The method of claim 22, wherein said enantiomer of monochloroflosequinan is (S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone. 25. The method of claim 23, wherein said enantiomer of monochloroflosequinan is (R)-(-)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone. 26. A method for the synthesis of Monochloroflosequinan sulfone, comprising: a) providing: i) monochloroflosequinan (3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone), and ii) m-chloroperoxybenzoic acid; and b) reacting said monochloroflosequinan and m-chloroperoxybenzoic acid in an organic solvent under conditions such that monochloroflosequinan sulfone (3-chloromethylsulfonyl-7-fluoro-1-methyl-4-quinolone) is produced |
| PATENT DESCRIPTION |
FIELD OF THE INVENTION The present invention teaches the synthesis of chlorinated racemic heterocyclic compounds. Purified enantiomers of chlorinated heterocyclic compounds, and the synthesis of the same, are also taught in the present invention. BACKGROUND A variety of heterocyclic compounds have been described as having various pharmaceutical applications. However, the synthesis of such compounds, especially on a large scale, is often labor-intensive, expensive and time consuming. For compounds with a chiral center (i.e. compounds which have enantiomers), it is often desirable to be able to obtain a composition which is significantly enriched for one enantiomer over another enantiomer of the same compound, as enantiomers, while identical with respect to certain physical properties, such as melting and boiling points, may differ in their chemical, biological or biochemical properties. In view of the different chemical, biological or biochemical properties associated with different enantiomers, chemists have explored many approaches for acquiring enantiomerically pure compounds including the resolution of the racemates using chiral stationary phases, structural modifications of naturally occurring chiral substances (as reagents for running stereospecific reactions) and asymmetric catalysis using chiral catalysts or enzymes. Optically active catalysts or enzymes have limited application in multiple step and kilo scale processes due to their high prices. Similarly the use of chiral stationary phases, for optical resolution, is a very expensive means for kilo scale production. What is needed, therefore, is a simplified and economical method for the stereospecific synthesis of heterocyclic compounds and acquisition of purified enantiomers for those compounds with chiral centers. SUMMARY OF THE INVENTION The present invention relates to heterocyclic compositions and methods for their synthesis. The compositions comprise a racemic mixture of monochloroflosequinan, and derivatives (e.g. the sulfone) thereof. Other compositions comprise enantiomers of monochloroflosequinan. The compositions also comprise chlorodesoxyflosequinan. In one embodiment, the present invention contemplates compositions comprising racemic monochloroflosequinan (i.e. racemic 3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone). In another embodiment, the present invention contemplates compositions comprising the sulfone derivative of racemic monochloroflosequinan (i.e. 3-chloromethylsulfonyl-7-fluoro-1-methyl-4-quinolone). In one embodiment, the present invention contemplates compositions comprising a purified enantiomer of monochloroflosequinan, including derivatives thereof. In one embodiment, said purified enantiomer of monochloroflosequinan is a (+)-enantiomer (i.e. (S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone). In another embodiment, said composition is substantially free of the (-)-enantiomer of monochloroflosequinan. In yet another embodiment, said purified enantiomer of monochloroflosequinan is a (-)-enantiomer (i.e. (R)-(-)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone). In another embodiment, said composition is substantially free of the (+)-enantiomer of monochloroflosequinan. In some embodiments, a composition comprising a substantially purified enantiomer of monochloroflosequinan is contemplated. In some embodiments, the purified enantiomer (i.e. the (+)- or the (-)-enantiomer of monochloroflosequinan) represents at least 80% of the purified enantiomer preparation, more preferably at least 90%, more preferably at least 95% and even more preferably, at least 98% of the preparation. Likewise, the other enantiomer represents less than 20%, 10%, 5% or 2% of the preparation. In some embodiments, a composition comprising an enantiomer of monochloroflosequinan (i.e. (S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone or (R)-(-)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone) in enantiomeric excess is contemplated. In some embodiments, the major enantiomer in the composition is in at least 90% enantiomeric excess, and more preferably, 95% enantiomeric excess. In some embodiments, a composition comprising (S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone having an optical purity of at least 85% is contemplated. In other embodiments, a composition comprising (S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone having an optical purity of at least 95% is contemplated. In other embodiments, a composition comprising (R)-(-)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone having an optical purity of at least 85% is contemplated. In yet other embodiments, a composition comprising (R)-(-)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone having an optical purity of at least 95% is contemplated. In one embodiment, the present invention contemplates compositions comprising chlorodesoxyflosequinan (i.e. 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone). In one embodiment, the present invention contemplates methods for the synthesis of racemic monochloroflosequinan. In another embodiment, the present invention contemplates methods for the synthesis of the sulfone derivative of racemic monochloroflosequinan. In yet other embodiments, the present invention contemplates methods for the stereopreferred synthesis (e.g. the preferential synthesis of one enantiomer) and separation of enantiomers of monochloroflosequinan. In one embodiment, a method for the synthesis of the (+)- enantiomer of monochloroflosequinan (i.e. (S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone) in enantiomeric excess is contemplated. The method further provides additional separation steps. In another embodiment, a method for the synthesis of the (-)-enantiomer of monochloroflosequinan (i.e. (R)-(-)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone) in enantiomeric excess is contemplated. The method further provides additional separation steps. In some embodiments, the present invention provides methods of synthesis of chlorodesoxyflosequinan (i.e. 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone). In some embodiments, the present invention provides a method, comprising: a) providing: i) flosequinan, and ii) triphenyl phosphine; and b) reacting said flosequinan and triphenyl phosphine in an organic solvent under conditions such that desoxyflosequinan (7-fluoro-1-methyl-3-methylthio-4-quinolone) is produced; and c) further reacting said desoxyflosequinan with N-chlorosuccinimide and 2,2'-azobisisobutyronitrile in an organic solvent under conditions such that chlorodesoxyflosequinan (3-chloromethylthio-7-fluoro-1-methyl-4-quinolone) is produced. A variety of solvents can be used in this reaction. In some embodiments, said organic solvent in said reacting step b) is selected from the group consisting of carbon tetrachloride, xylene and toluene. In some embodiments, said providing step a) optionally provides iii) a catalyst, and said reacting step b) occurs in the presence of said catalyst. In some embodiments, said organic solvent in said reacting step b) is selected from the group consisting of xylene and toluene. A variety of solvents can be used in this reaction. A variety of catalysts are contemplated for this reaction. In some embodiments, said catalyst is tetrabromomethane. In some embodiments, said organic solvent in step c) is selected from the group consisting of carbon tetrachloride and benzene. In another embodiment, the present invention provides a method, comprising: a) providing: i) flosequinan, ii) thionyl chloride, and iii) pyridine; and b) reacting said flosequinan, thionyl chloride and pyridine in an organic solvent under conditions such that chlorodesoxyflosequinan (3-chloromethylthio-7-fluoro-1-methyl-4-quinolone) is produced. In another embodiment, the present invention provides a method, comprising: a) providing: i) chlorodesoxyflosequinan (3-chloromethylthio-7-fluoro-1-methyl-4-quinolone), ii) hydrogen peroxide, and iii) potassium carbonate; and b) reacting said chlorodesoxyflosequinan, hydrogen peroxide and potassium carbonate in a solvent under conditions such that monochloroflosequinan (3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone) is produced. In yet other embodiments, the present invention provides a method, comprising: a) providing: i) flosequinan, and ii) N-chlorosuccinimide; and b) reacting said flosequinan and N-chlorosuccinimide in an organic solvent under conditions such that monochloroflosequinan (3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone) is produced. A variety of solvents are contemplated. In some embodiments, said organic solvent is selected from the group consisting of carbon tetrachloride and benzene. In other embodiments, when said organic solvent is carbon tetrachloride, said reacting step b) additionally includes 2,2'-azobisisobutyronitrile. In another embodiment, the present invention provides a method, comprising: a) providing: i) chlorodesoxyflosequinan (3-chloromethylthio-7-fluoro-1-methyl-4-quinolone), and ii) a camphor based reagent; and b) reacting said chlorodesoxyflosequinan and camphor based reagent in an organic solvent under conditions such that an enantiomer of monochloroflosequinan is produced in enantiomeric excess. In some embodiments said camphor based reagent is (R)-(-)-(10-camphorsulfonyl) oxaziridine. In such embodiments, said enantiomer of monochloroflosequinan is (S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone. In yet other embodiments, said camphor based reagent is (S)-(+)-(10-camphorsulfonyl) oxaziridine. In such embodiments, said enantiomer of monochloroflosequinan is (R)-(-)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone. In some embodiments, a one-step method of synthesis of 3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone is contemplated. The method comprises: a) providing: i) flosequinan, and ii) N-chlorosuccinimide; and b) reacting, in an organic solvent, said flosequinan with said N-chlorosuccinimide under conditions such that 3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone is produced. A variety of solvents are contemplated. In some embodiments, said organic solvent is selected from the group consisting of carbon tetrachloride and benzene. In embodiments wherein the solvent is carbon tetrachloride, the reaction additionally includes 2,2'-azobisisobutyronitrile (AIBN). In other embodiments, a three-step method of synthesis of 3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone is contemplated. The method comprises: a) providing: i) racemic flosequinan, and ii) triphenyl phosphine; and b) reacting said racemic flosequinan and said triphenylphosphine in an organic solvent under conditions such that 7-fluoro-1-methyl-3-methylthio-4-quinolone is produced; and c) further reacting said 7-fluoro-1-methyl-3-methylthio-4-quinolone with N-chlorosuccinimide and 2,2'-azobisisobutyronitrile in an organic solvent under conditions such that 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone is produced; and d) reacting said 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone with hydrogen peroxide under conditions such that 3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone is produced. A variety of solvents are contemplated. In some embodiments, the solvent in step b) is carbon tetrachloride. In some embodiments, the solvent in step c) is carbon tetrachloride. In some embodiments, potassium carbonate is included in said reacting step d). In other embodiments, alternative methods for the synthesis of 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone are contemplated. In one embodiment, the method comprises: a) providing: i) racemic flosequinan, ii) thionyl chloride, and iii) pyridine; and b) reacting said racemic flosequinan, thionyl chloride and pyridine under conditions such that 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone is produced. In yet other embodiments, methods for the synthesis of the sulfone derivative of monochloroflosequinan are contemplated. In one embodiment, the method comprises: a) providing: i) monochloroflosequinan (3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone), and ii) m-chloroperoxybenzoic acid; and b) reacting said monochloroflosequinan and said m-chloroperoxybenzoic acid under conditions such that monochloroflosequinan sulfone (3-chloromethylsulfonyl-7-fluoro-1-methyl-4-quinolone) is produced. In other embodiments, 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone is used in stereopreferred oxidation reactions to produce (S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone or (R)-(-)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone. The mixture of enantiomers produced may then be subjected to further separation procedures. In one embodiment, the 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone used in the subsequent synthesis and separation of enantiomers of monochloroflosequinan is synthesized by a method comprising: a) providing: i) racemic flosequinan, ii) triphenylphosphine, and iii) a catalyst; and b) reacting, in a solvent, said racemic flosequinan and said triphenylphosphine in the presence of said catalyst under conditions such that 7-fluoro-1-methyl-3-methylthio-4-quinolone is produced; and c) further reacting said 7-fluoro-1-methyl-3-methylthio-4-quinolone in a solvent with N-chlorosuccinimide and 2,2'-azobisisobutyronitrile under conditions such that 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone is produced. Again, a variety of solvents are contemplated. In some embodiments, said solvent in step b) is toluene and said catalyst is tetrabromomethane (CBr.sub.4). In some embodiments, the method further provides the synthesis of (R)-(-)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone. The method further comprises d) reacting said 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone with (S)-(+)-(10-camphorsulfonyl)oxaziridine under conditions such that (R)-(-)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone is produced in enantiomeric excess. In other embodiments, the method further provides the synthesis of (S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone. The method further comprises d) reacting said 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone with (R)-(-)-(10-camphorsulfonyl)oxaziridine under conditions such that (S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone is produced in enantiomeric excess. In some embodiments, racemic flosequinan is reacted with triphenyl phosphine and a catalyst in anhydrous xylene to produce 7-fluoro-1-methyl-3-methylthio-4-quinolone. In some embodiments, the catalyst is tetrabromomethane (CBr.sub.4). Thus, in one embodiment, a method of synthesis of 7-fluoro-1-methyl-3-methylthio-4-quinolone is provided, comprising: a) providing: i) racemic flosequinan, ii) anhydrous xylene, iii) a catalyst, and iv) triphenyl phosphine; and b) reacting said racemic flosequinan and said triphenyl phosphine in said anhydrous xylene in the presence of said catalyst under conditions such that 7-fluoro-1-methyl-3-methylthio-4-quinolone is produced. In one embodiment, said catalyst is tetrabromomethane (CBr.sub.4). DESCRIPTION OF THE DRAWINGS FIG. 1 depicts a one-step chemical synthesis of racemic monochloroflosequinan. Racemic flosequinan is chlorinated as described to produce monochloroflosequinan. FIG. 2 depicts the first step in a three step protocol for the synthesis of racemic monochloroflosequinan. Triphenylphosphine reduction of flosequinan to 7-fluoro-1-methyl-3-methylthio-4-quinolone (desoxyflosequinan) is depicted. FIG. 3 depicts the second step in a three step protocol for the synthesis of racemic monochloroflosequinan. The chlorination of desoxyflosequinan with N-chlorosuccinimide to yield 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone is depicted. FIG. 4 depicts the third step in a three step protocol for the synthesis of racemic monochloroflosequinan. The hydrogen peroxide oxidation of chlorodesoxyflosequinan to monochloroflosequinan is depicted. FIG. 5 depicts the synthesis of racemic monochloroflosequinan in an alternative solvent. Flosequinan is reacted as described to produce monochloroflosequinan. FIG. 6 depicts an alternative protocol for the synthesis of 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone. Racemic flosequinan is reacted as described to produce 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone. FIG. 7 depicts a protocol for the synthesis of monochloroflosequinan sulfone. Monochloroflosequinan is reacted as described to produce monochloroflosequinan sulfone. FIG. 8 depicts the first step in the synthesis of e.e. (S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone and (R)-(-)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone. In this step, flosequinan is reacted as described to produce 7-fluoro-1-methyl-3-methylthio-4-quinolone. FIG. 9 depicts the second step in the synthesis of e.e.(S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone and (R)-(-)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone. In this step, 7-fluoro-1-methyl-3-methylthio-4-quinolone is chlorinated as described to produce 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone. FIG. 10 depicts the stereopreferred oxidation of 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone to produce (R)-(-)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone. FIG. 11 depicts the stereopreferred oxidation of 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone to produce (S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone. FIG. 12 depicts the use of an alternative solvent (anhydrous xylene) in the reduction of flosequinan to 7-fluoro-1-methyl-3-methylthio-4-quinolone (desoxyflosequinan). FIG. 13 outlines the various chemical reactions described in the description and examples. FIG. 14 depicts the results of in vitro phosphodiesterase inhibition assays using monochloroflosequinan sulfone. FIG. 15 shows the PDE3 inhibition curves for monochloroflosequinan sulfone (circles) and the reference compound, IBMX (squares). FIG. 16 depicts the results of in vitro phosphodiesterase inhibition assays using monochloroflosequinan. FIG. 17 shows the PDE1 inhibition curves for monochloroflosequinan (circles) and the reference compound, IBMX (squares). FIG. 18 shows the PDE3 inhibition curves for monochloroflosequinan (circles) and the reference compound, IBMX (squares). FIG. 19 depicts the results of in vitro phosphodiesterase inhibition assays using the (-)-enantiomer of monochloroflosequinan (i.e. (R)-(-)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone). FIG. 20 depicts the results of in vitro phosphodiesterase inhibition assays using the (+)-enantiomer of monochloroflosequinan (i.e. (S)-(+)-3-chloromethyl sulfinyl-7-fluoro-1-methyl-4-quinolone). DEFINITIONS As used herein, "R and S" are used to denote the absolute configuration of the molecule about its chiral center(s). As used herein, the prefixes "(+) and (-)" are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) meaning that the compound is levorotatory (rotates to the left). A compound prefixed with (+) is dextrorotatory (rotates to the right). As used herein, the terms "enantiomer" or "enantiomeric isomer" refer to stereoisomers of molecules that are non-superimposable mirror images of each other. Enantiomers have identical physical properties, such as melting points and boiling points, and also have identical spectroscopic properties. Enantiomers differ from each other with respect to their interaction with plane-polarized light and with respect to biological activity. As used herein, the term "stereoisomer" refers to compounds that have their atoms connected in the same order but differ in the arrangement of their atoms in space. (e.g. L-alanine and D-alanine). As used herein, the terms "racemic", "racemic mixture", or "racemate" refers to a mixture of the two enantiomers of one compound. An ideal racemic mixture is one wherein there is a 50:50 mixture of both enantiomers of a compound such that the optical rotation of the (+) enantiomer cancels out the optical rotation of the (-) enantiomer. As used herein, the phrase "enantiomeric excess" or "e.e." refers to a reaction product wherein one enantiomer is produced in excess of the other and the percentage of the excess enantiomer is calculated using either (or both) of the following algorithms: Algorithm No. 1: enantiomeric excess=(specific rotation of the reaction product/specific rotation of the pure enantiomer in excess).times.100. Algorithm No. 2: enantiomeric excess=[(moles of major enantiomer--moles of other enantiomer/total moles of both enantiomers)].times.100. As an example (the values in this example are offered for illustration only and do not represent data subsequently expressed in the "Experimental" section of this application), the observed rotation of a reaction product +8.52 degrees of rotation and the specific rotation of the R-configured enantiomer is reported as +15.00 degrees of rotation. The sign of the specific rotation of the reaction product indicates which enantiomer is in excess (e.g. in this example the R-configured isomer is in excess). If these values are inserted into Algorithm No. 1, the enantiomeric excess=(+8.52/+15.00)(100)=56.8% in excess of the R-isomer. As used herein, the terms "purified enantiomer" and "purified enantiomer preparation" are meant to indicate a preparation (e.g. derived from non-optically active starting material, substrates or intermediates) wherein one enantiomer (for example, the (+) enantiomer) is enriched over the other, and more preferably, wherein the other enantiomer (for example the (-) enantiomer) represents less than 20%, more preferably less than 10% [e.g. in this particular instance, the (+) enantiomer is substantially free of the (-) enantiomer], and more preferably less than 5% and still more preferably, less than 2% of the preparation. A purified enantiomer may be synthesized substantially free of the other enantiomer, or a purified enantiomer may be synthesized in a stereopreferred procedure, followed by separation steps, or a purified enantiomer may be derived from a racemic mixture. Whether expressed as a "purified enantiomer" or "a compound in enantiomeric excess", the terms are meant to indicate that the amount of one enantiomer exceeds the amount of the other. Thus, when referring to an enantiomer preparation, both (or either of) the percent of the major enantiomer (e.g. by weight) and (or) the percent enantiomeric excess of the major enantiomer may be used to determine whether the preparation represents a purified enantiomer preparation. As used herein, the term "optical purity" refers to the ratio of the observed optical rotation of a sample consisting of a mixture of enantiomers to the optical rotation of one pure enantiomer. As used herein, the term "camphor based reagent" refers to a reagent (or reagents) comprising a camphor moiety, as shown below: ##STR1## Camphor based reagents include, but are not limited to the following: (R)-(-)-(10-camphorsulfonyl)oxaziridine: ##STR2## (S)-(+)-(10-camphorsulfonyl)oxaziridine: ##STR3## and (-)-(8,8-dichlorocamphorylsulfonyl)oxaziridine: ##STR4## As used herein, the phrase "flosequinan" refers to 7-fluoro-1-methyl-3-(methylsulphinyl)-4(1H)-quinolinone which may also be described as 7-fluoro-1-methyl-3-(methylsulfinyl)-4(1H)-quinolone) and as 7-fluoro-1-methyl-3-methylsulfinyl-4-quinolone having the chemical structure of: ##STR5## As used herein, the phrase "racemic flosequinan" or "flosequinan racemate" refers to a mixture of the two enantiomers of flosequinan. An ideal racemic mixture of the enantiomers of flosequinan refers to a 1:1 mixture of the S-(-)- and R-(+)-enantiomers of flosequinan, such that the optical rotation of the (+)-enantiomer cancels out the optical rotation of the (-)-enantiomer. As used herein, "desoxyflosequinan" refers to 7-fluoro-1-methyl-3-methylthio-4-quinolone having the chemical structure of: ##STR6## As used herein, "monochloroflosequinan" refers to the chemical composition designated as 3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone having the chemical structure corresponding to: ##STR7## As used herein, the phrase "racemic monochloroflosequinan" or "monochloroflosequinan racemate" refers to a mixture of the two enantiomers of monochloroflosequinan. An ideal racemic mixture of the enantiomers of monochloroflosequinan refers to a 1:1 mixture of the (+)- and (-)-enantiomers of monochloroflosequinan, such that the optical rotation of the (+)-enantiomer cancels out the optical rotation of the (-)-enantiomer. As used herein, "chlorodesoxyflosequinan" refers to the chemical composition designated as 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone having the chemical structure corresponding to: ##STR8## As used herein the "sulfone derivative of monochloroflosequinan" or "monochloroflosequinan sulfone" refers to the chemical composition designated as 3-chloromethylsulfonyl-7-fluoro-1-methyl-4-quinolone having the chemical structure corresponding to: ##STR9## As used herein, the "(+)-enantiomer of monochloroflosequinan" or "(S)-(+)-monochloroflosequinan" refers to the chemical composition designated as (+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone or (S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone having the structure corresponding to: ##STR10## As used herein, the "(-)-enantiomer of monochloroflosequinan" or "(R)-(-)-monochloroflosequinan" refers to the chemical composition designated as (-)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone or (R)-(-)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone having the structure corresponding to: ##STR11## As used herein, "room temperature", "RT" or "ambient temperature" is approximately 18.degree. C. to 21.degree. C. As used herein, "overnight" is approximately 8 hours, more preferably 12 hours, more typically 17 hours, but can be up to approximately 30 hours. As used herein, the term "heterocyclic compound" refers to a compound comprising a ring composed of atoms of more than one kind. As used herein, "optical activity" refers to the property of certain substances to rotate plane polarized light. A compound or mixture of compounds which is "optically inactive" produces no net rotation of plane polarized light. As used herein, a "catalyst" refers to a substance that, when added to a reaction mixture, changes (e.g. speeds up) the rate of attainment of equilibrium in the system without itself undergoing a permanent chemical change. Examples of suitable catalysts contemplated for use in the present invention include, but are not limited to, tetrabromomethane (CBr.sub.4), carbon tetraiodide and iodide. As used herein, an "organic solvent" refers to an organic substance that will dissolve other substances. Examples of organic solvents suitable for use in embodiments of the present invention include, but are not limited to carbon tetrachloride (CCl.sub.4), xylene, toluene, benzene and methylene dichloride. As used herein, the term "IBMX" corresponds to the structure having the chemical formula: 3-isobutyl-1-methylxanthine (available from Sigma). DETAILED DESCRIPTION OF THE INVENTION The present invention relates to heterocyclic compositions and methods for their synthesis. The methods of the present invention comprise the synthesis of heterocyclic compounds and the separation of enantiomers. In some embodiments, the compositions comprise a racemic mixture of monochloroflosequinan, including derivatives thereof. In a preferred embodiment, said monochloroflosequinan derivative is the sulfone derivative of monochloroflosequinan. In other embodiments, the compositions comprise a purified enantiomer of monochloroflosequinan, including derivatives thereof. In one embodiment, said purified enantiomer is the (+)-enantiomer of monochloroflosequinan (i.e. (S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone). In one embodiment, said (+)-enantiomer of monochloroflosequinan is substantially free of the (-)-enantiomer of monochloroflosequinan. In other embodiments, said purified enantiomer is the (-)-enantiomer of monochloroflosequinan (i.e. (R)-(-)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone). In some embodiments, said (-)-enantiomer of monochloroflosequinan is substantially free of the (+)-enantiomer of monochloroflosequinan. It is not intended that the present invention be limited to complete separation of enantiomers, or 100% percent purity. It is sufficient that the preparation is enriched for one enantiomer (e.g. a 50:50 mixture becomes a 60:40 mixture). Methods of producing a racemic mixture of flosequinan, as set out in U.S. Pat. Nos. 5,079,264 and 5,011,931 to MacLean et al., are hereby incorporated by reference. In one embodiment, racemic flosequinan is prepared according to the protocol set out in Example 8. Without limiting the invention to any particular mechanism, racemic monochloroflosequinan, the enantiomers of monochloroflosequinan, and the sulfone derivatives of monochloroflosequinan are enzyme inhibitors. In specific examples, these compounds differentially inhibit various phosphodiesterases (e.g. PDE 1-6). The enzyme inhibition of racemic monochloroflosequinan, the enantiomers of monochloroflosequinan, and the sulfone derivatives of monochloroflosequinan has utility, for example, in therapeutics. Therefore, the present invention contemplates formulations an the administration of formulations to patients. GENERAL DESCRIPTION OF CHEMICAL SYNTHETIC PROTOCOLS In one embodiment, the synthesis of racemic monochloroflosequinan (3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone) may be carried out as a one step procedure, involving the direct chlorination of racemic flosequinan. In one embodiment, N-chlorosuccinimide is used in the chlorination. In one embodiment, the solvent is carbon tetrachloride (see Example 1), while in another embodiment the solvent is benzene (see Example 3). In other embodiments, the synthesis of racemic monochloroflosequinan is carried out as a three step procedure, as described in more detail in Example 2. Briefly, in the first step, racemic flosequinan is reduced to desoxyflosequinan (7-fluoro-1-methyl-3-methylthio-4-quinolone). In the second step, desoxyflosequinan is chlorinated using N-chlorosuccinimide, to produce chlorodesoxyflosequinan (3-chloromethylthio-7-fluoro-1-methyl-4-quinolone). In the third step, chlorodesoxyflosequinan is subjected to oxidation to produce 3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone (monochloroflosequinan). Such oxidation may be accomplished using hydrogen peroxide. In other embodiments, chlorodesoxyflosequinan is synthesized by reacting flosequinan with thionyl chloride and pyridine, as described in more detail in Example 4. In yet other embodiments, the synthesis of monochloroflosequinan sulfone (3-chloromethylsulfonyl-7-fluoro-1-methyl-4-quinolone) is contemplated. In one embodiment, the synthesis of monochloroflosequinan sulfone is carried out by m-chloroperoxybenzoic acid oxidation of monochloroflosequinan, as described in Example 5. In other embodiments, the synthesis and separation of enantiomers of monochloroflosequinan is contemplated. The (R)-(-)-enantiomer of monochloroflosequinan is synthesized by the stereopreferred oxidation of 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone, followed by suitable separation procedures (see part C. of Example 6). The (S)-(+)-enantiomer of monochloroflosequinan is synthesized by the stereopreferred oxidation of 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone, followed by suitable separation procedures (see part D. of Example 6). The 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone used as a substrate for the stereopreferred oxidation reactions may be synthesized by chlorination of 7-fluoro-1-methyl-3-methylthio-4-quinolone. In one embodiment, the chlorination is accomplished by the use of N-chlorosuccinimide (see part B. of Example 6). The 7-fluoro-1-methyl-3-methylthio-4-quinolone which serves as a substrate for the chlorination reaction may be produced by the catalytical reduction of 7-fluoro-1-methyl-3-methylsulfinyl-4-quinolone (see part A. of Example 6). A variety of catalysts are contemplated, including but not limited to tetrabromomethane, carbon tetraiodide and iodide. In one embodiment tetrabromomethane is used with toluene as the solvent (see part A. of Example 6). In another embodiment, anhydrous xylene is contemplated as the solvent, with tetrabromomethane as the catalyst (see Example 7). The present invention also contemplates the formulation of comprising a racemic mixture of monochloroflosequinan, the enantiomers of monochloroflosequinan (and derivatives thereof) as a pharmaceutically acceptable salt. In addition, pharmaceutical formulations of a racemic mixture of monochloroflosequinan, the enantiomers of monochloroflosequinan (and derivatives thereof) may also contain binders, fillers, carriers, preservatives, stabilizing agents, emulsifiers, buffers and excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. The present invention also contemplates the administration of a racemic mixture of monochloroflosequinan, the enantiomers of monochloroflosequinan (and derivatives thereof) as a pharmaceutically acceptable salt or formulation. The present invention also contemplates the administration of a racemic mixture of monochloroflosequinan, the enantiomers of monochloroflosequinan (and derivatives thereof) formulations to a subject. EXPERIMENTAL The following examples serve to illustrate certain preferred embodiments and aspects of the present invention and are not to be construed as limiting the scope thereof. In the experimental disclosure which follows, the following abbreviations apply: eq (equivalents); M (Molar); .mu.M (micromolar); N (Normal); mol (moles); mmol (millimoles); .mu.mol (micromoles); nmol (nanomoles); g (grams); mg (milligrams); L (liters); ml (milliliters); .degree. C. (degrees Centigrade). All bracketed numbers [e.g. "(1)"] after the chemical name of a compound, refer to the corresponding chemical structure as designated by the same bracketed number in FIGS. 1 through 12. All NMR spectra were recorded using Varian-Gemini 300 MHz Spectrometer |
| PATENT EXAMPLES | available on request |
| PATENT PHOTOCOPY | available on request |
|
Want more information ? Interested in the hidden information ? Click here and do your request. |