| PATENT ASSIGNEE'S COUNTRY | USA |
| UPDATE | 08.00 |
| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 29.08.00 |
| PATENT TITLE |
Carbocyclic heterocyclic fused-ring quinolinecarboxylic acids useful as immunosuppressive agents |
| PATENT ABSTRACT |
This invention relates to carbocyclic and heterocyclic fused-ring quinolinecarboxylic acid compounds, to pharmaceutical compositions comprising such compounds, and to methods of using such compounds for the treatment and/or prevention of organ transplantation rejection, graft versus host disease, autoimmune diseases, chronic inflammatory diseases, including but not limited to psoriasis and rheumatoid arthritis, and cancer in a mammal. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | 18.11.98 |
| PATENT REFERENCES CITED |
Jadwign Schoen and Krystynn Bogdanowicz-Szwed., Chemical Abstracts 61:1827g. E. Noelting and A. Herzbaum., Chem. Ber. vol. 44, 2585, 1991. N. P. Buu-Hoi, V. Bellavita, A. Ricci, J. P. Hoeffinger and D. Balucani., J. Chem. Soc. (C), 47, 1966. Kamane Takagi et Takeo Ueda., Chem. Pharm. Bull, vol. 19, 1218, 1971. Kamane Takagi et Takeo Ueda., Chem. Pharm. Bull, vol. 20, 2051, 1972. Ng. Ph. Buu-Hoi., J. C. S., 2418, 1958. par Paul Cagniant, Alfred Reisse (**) et Denise Cagniant., Bulletin Se La Societe Chimique de France, 991, (1969). [Bull. Soc. Chem. France, 991, (1969)]. par Paul Cagniant, Guy Merle (**) et Denise Cagniant., Bulletin Se La Societe Chimique De France, 322, (1970). [Bull. Soc. Chem. France, 322 (1970)]. Von Rolf Huisgen, Ivar Ugi., Liebigs Ann. Chem. Bd., 610, 57, (1957). Kinoshita Yukihiko, Ajisawa Yukiyoshi, Ikeguchi Seiichi, Ujiie Shinsei amd Tsutsimi Naoyuki., 1-Pharmacology, vol. 111:187618h, (1989). Seiji Yamaguchi, Kunihiro Tsuzuki, Yoshie Sannomiya, Yutaka Oh-hira and Yoshiyuki Kawase., J. Heterocyclic Chem., 26, 285, (1989). Degutis J, Ezerskaite A., Chemical Abstracts vol. 107:39658y, (1987). Ezerskaite A, Degutis J, Undzenas A, Kalcheva V., Chemical Abstracts vol. 112: 66492z, (1990). Ezerkaite A, Kalcheva V, Peshakova L., 28-Heterocycles vol. 113:58979u, (1990). Fravolini Arnaldo, Rodriguez Salazar Carlos., Chemical Abstracts vol. 70:47334x, (1969). Fravolini Arnaldo, Rodriguez Salazar Carlos., Ann. Chim. (Rome) vol. 58, 1155-62, (1968). Wang Jinjun, Yin Bingzhu, Jiang Guiji., Chemical Abstracts vol. 115:49457m, (1991). Wang Jinjun, Jiang Guiji, Fang Wenlong, Jin Jingji., Chemical Abstracts vol. 115:183138m, (1991). Odette Roussel, N.P. Buu-Hoi and P. Jacquignon., J. Chem. Soc., 5458, (1965). Antonio Da Settimo, Giampaolo Primofiore, Orsete Livi, Pier Luigi Ferrarini and Silvano Spinelli., J. Heterocyclic Chemistry, vol. 16, 169-174, (1979). John T. Brauholtz and Fredrick G. Mann., J. Chem. Soc., 3377, (1958). George R. Procter and Brian M.L.Smith., J.C.S. Perkin I, 862-870, (1978). S. J. Holt and V. Petrow., J.C.S., 607-611, (1947). John T. Brauholtz and Fredrick G. Mann., J. C. S., 381-392, (1955). Fredrick G. Mann., J.C.S., 2816-2824, (1949). Julius V. Brown and Karl Weissbach., Chem. Ber. vol. 62, 2416-2425, (1929). A. K. Kiang and Fredrick G. Mann., J.C.S. 1909-1914, (1951). N.P. Buu-Hoi and G Saint-Ruf., 38-Heterocyclic Compounds 11998, (1964). D. Huckle, I. M. Lockhart and N.E. Webb., J. Chem. Soc. (C), 2252-2260, (1971). Hoi Jirul. Wang Jinjun, Jiang Guiji, Li Jingahu., 29-Heterocycles vol. 116:128709u, (1992). |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A compound of Formula 3 or 4: ##STR27## or a pharmaceutically acceptable salt form thereof, wherein: R.sup.1 and R.sup.2 are independently H, F, Cl, Br, CF.sub.3, or alkyl of 1-4 carbons; R.sup.3 is selected from: phenyl, phenoxy, phenylthio, phenylsulfinyl, phenyl-N(R.sup.4)--, furyl, thienyl, pyridyl, thiazolyl, or oxazolyl; wherein said phenyl, phenoxy, phenylthio, phenylsulfinyl, phenyl-N(R.sup.4)--, furyl, thienyl, pyridyl, thiazolyl, or oxazolyl is substituted with 0-2 groups independently selected from: F, Cl, Br, CF.sub.3, alkyl of 1-4 carbons, alkoxy of 1-4 carbons, alkylthio of 1-4 carbons or alkylsulfinyl of 1-4 carbons; R.sup.4 is H, alkyl of 1-4 carbons or acyl of 1-4 carbons; X is --Y--, --CH.sub.2 Y--, --YCH.sub.2 --, --CH.sub.2 CH.sub.2 Y--, --YCH.sub.2 CH.sub.2 --, --CH.sub.2 YCH.sub.2 --, --CR.sup.5 =C(R.sup.6)--, --CR.sup.6 =N--, or --N=C(R.sup.6)-- (the first atom of X as listed being attached to the quinoline ring); wherein each methylene group in X may be optionally substituted with one or two groups independently selected from alkyl of 1-4 carbons; Y is --CH.sub.2 -- (said --CH.sub.2 -- being optionally and independently substituted with one or two alkyl groups of 1-4 carbons), --O--, --S--, or --N(R.sup.7)--; R.sup.5 and R.sup.6 are independently H or alkyl of 1-4 carbons; R.sup.7 is H, alkyl of 1-4 carbons, or acyl of 1-4 carbons; wherein, in compounds of Formula 3: one of Q.sup.1 and Q.sup.2 is NR.sup.9 and the other is CR.sup.10 or N, provided that the ring which contains Q.sup.1 and Q.sup.2 contains an additional double bond placed so as to generate an aromatic ring; R.sup.9 is H or alkyl of 1-4 carbons; R.sup.10 is H, F, Cl, Br, CF.sub.3, or alkyl of 1-4 carbons; wherein, in compounds of Formula 4: one of Q.sup.3 and Q.sup.4 is N and the other is C, provided that the ring of Formula 4 which contains Q.sup.3 and Q.sup.4 contains an additional double bond placed so as to generate an aromatic pyrrole ring; and R .sup.11 is H, F, Cl, Br, CF.sub.3, or alkyl of 1-4 carbons; subject to the following provisos: 1) X is not NR.sup.7 ; 3) in compounds of Formula 3, or of Formula 4 where Q.sup.4 is N, X must form a bridge of at least two atoms, and the atom of X attached to the ring containing Q.sup.1 and Q.sup.2 or Q.sup.3 and Q.sup.4 must be carbon; 4) in compounds of Formula 4 where Q.sup.3 is N, X must consist of either --CH.sub.2 CH.sub.2 -- or --CH.sub.2 CH.sub.2 CH.sub.2 --, with each methylene group of X optionally and independently substituted as described above; and 5) in compounds of Formula 4 where Q.sup.4 is N, then R.sup.3 must not be phenoxy, phenylthio, phenylsulfinyl, or phenyl-N(R.sup.4)--. 2. A compound of claim 1 of Formulas 3 or 4, or a pharmaceutically acceptable salt form thereof, wherein: R.sup.1 is 6-F or 6-CF.sub.3 ; R.sup.2 is H; R.sup.3 is phenyl, thienyl or furyl; said phenyl, thienyl or furyl being substituted with 0-2 groups independently selected from: F, Cl, Br, CF.sub.3, alkyl of 1-4 carbons, alkoxy of 1-4 carbons, alkylthio of 1-4 carbons or alkylsulfinyl of 1-4 carbons; X is --CH.sub.2 CH.sub.2 --, --CH.sub.2 S--, --SCH.sub.2 --, --CH.sub.2 O--, or --OCH.sub.2 --; wherein, in compounds of Formula 3 Q.sup.2 is CH; wherein, in compounds of Formula 4, Q.sup.3 is C and Q.sup.4 is N. 3. A compound of claim 2, or a pharmaceutically acceptable salt form thereof, wherein: R.sup.3 is phenyl, 2-fluorophenyl, 3-methoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, or thienyl. 4. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. 5. A pharmaceutical composition comprising a compound of claim 2 and a pharmaceutically acceptable carrier. 6. A pharmaceutical composition comprising a compound of claim 3 and a pharmaceutically acceptable carrier. 7. A method of treating organ transplantation rejection, graft versus host disease, psoriasis, rheumatoid arthritis, autoimmune diseases, or chronic inflammatory diseases in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of claim 1. 8. A method of treating organ transplantation rejection, graft versus host disease, psoriasis, rheumatoid arthritis, autoimmune diseases, or chronic inflammatory diseases in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of claim 2. 9. A method of treating organ transplantation rejection, graft versus host disease, psoriasis, rheumatoid arthritis, autoimmune diseases, or chronic inflammatory diseases in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of claim 3. 10. A method of treating organ transplantation rejection or graft versus host disease in a mammal comprising administering in combination to a mammal in need of such treatment a therapeutically effective amount of: (i) a compound of claim 1; and (ii) at least one additional immunosuppressive agent. 11. The method of claim 10 wherein the additional immunosuppressive agent (ii) is selected from the group consisting of cyclosporin A, azathioprine, a corticosteriod, OKT3, FK506, mycophenolic acid or the 2-(N-morpholino)ethyl ester thereof, mycopheolate mofetil, 15-dioxyspergualin, rapamycin, mizoribine, leflunomide, misoprostol, methotrexate, cyclophosphamide, anti-lymphocyte/thymocyte serums or an anti-interleukin-2 receptor antibody. 12. A method of treating rheumatoid arthritis, systemic lupus erthematosus, multiple sclerosis, myasthenia gravis, organ transplantation rejection, graft versus host disease, or a chronic inflammatory disease in a mammal comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a nonsteroidal antiinflammatory drug in combination with a compound of claim 1. 13. A method of treating a skin or mucoepithelial disease in a mammal comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a compound of claim 1. 14. A method of claim 13 wherein the compound of claim 1 is administered in combination with a steroid drug. 15. A topical pharmaceutical composition comprising a carrier suitable for topical formulation and a therapeutically effective amount of a compound of claim 1. 16. A method of treating a solid tumor, lymphoma, or a leukemia in a mammal comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a compound of claim 1. |
| PATENT DESCRIPTION |
FIELD OF THE INVENTION This invention relates to carbocyclic and heterocyclic fused-ring quinolinecarboxylic acid compounds, to pharmaceutical compositions comprising such compounds, and to methods of using such compounds for the treatment and/or prevention of organ transplantation rejection, graft versus host disease, autoimmune diseases, and chronic inflammatory diseases, including but not limited to psoriasis and rheumatoid arthritis, in a mammal. BACKGROUND OF THE INVENTION 2-Phenyl-4-quinolinecarboxylic acids are disclosed as tumor-inhibiting agents by U.S. Pat. No. 4,680,299, issued to Hesson on Jul. 14, 1987. Utility of these compounds for the treatment of skin and epithelial diseases is disclosed by U.S. Pat. No. 4,861,783, issued to Ackerman et al. on Aug. 29, 1989. Utility of these compounds as immunomodulatory or immunosuppressive agents is disclosed by U.S. Pat. No. 4,968,701, issued to Ackerman et al. on Nov. 6, 1990. U.S. Pat. No. 5,204,329, issued to Ackerman et al. on Apr. 20, 1993, describes the use of these compounds in combination with a second immunosuppressive agent for the treatment of transplantation rejection and other disease conditions. Additional examples of 2-phenyl-4-quinolinecarboxylic acids are disclosed as useful in the treatment of arthritis and for inducing immunosuppression in U.S. Pat. No. 4,847,381, issued to Sutherland et al. on Jul. 11, 1989; and in U.S. Pat. No. 4,968,702, issued to Poletto et al. on Nov. 6, 1990. Benz[c]acridine-7-carboxylic acids and 5,6-dihydrobenz[c]acridine-7-carboxylic acids are known in the chemical literature. They are generally synthesized by the Pfitzinger reaction of an appropriate isatin with an appropriate 3,4-dihydro-1(2H)-naphthalenone. U.S. Pat. No. 4,918,077, issued to Behrens on Apr. 17, 1990, discusses a number of references dealing with these compounds, and also discloses tumor-inhibiting 3-phenyl-5,6-dihydrobenz[c]acridine-7-carboxylic acids of the formula: ##STR1## where R.sup.1 is, inter alia, COOH, COONa or COOK; R.sup.2 and R.sup.3 are independently H, F, Cl, Br, I, methyl, ethyl, CF.sub.3, alkylthio, alkylsulfinyl, or alkylsulfonyl; and R.sup.4 and R.sup.5 independently are H or taken together are S. U.S. Pat. No. 5,135,934, issued to Behrens et al. on Aug. 4, 1992, discloses the utility of these compounds as immunosuppressive and anti-inflammatory agents. The synthesis of ring-fused quinolinecarboxylic acids of the formula: ##STR2## where n is 1-4, and R is H or methyl, has also been reported by Huisgen et al. [Ann. Chem. (1957) 610:57] and Schoen et al. [Rocz. Chem. (1964) 38:425; Chem. Abstr. 61, 1827g]. Noelting et al. [Chem. Ber. (1911) 44:2585] reported the synthesis of these compounds also, as well as of the compound where R is H and where (CH.sub.2).sub.n has been replaced by S. The same compound, but where R is methyl and (CH.sub.2).sub.n is replaced by S, was synthesized by Buu-Hoi [J. Chem. Soc. C (1966) 47] as an intermediate to potential carcinogens. The synthesis of 4,5-dihydrofuro[2,3-c]acridine-6-carboxylic acids of the formula: ##STR3## where R is methyl, phenyl, or 4-bromophenyl, has been reported by Takagi et al. [Chem. Pharm. Bull. (1971) 19:1218, and Chem. Pharm. Bull. (1972) 20:2051]. Buu-Hoi et al. [J. Chem. Soc. (1958) 2418] reported the synthesis of the compound shown below as an intermediate for potential carcinogens. ##STR4## Cagniant et al. [Bull. Soc. Chim. Fr. (1969) 991, and Bull. Soc. Chim. Fr. (1970) 322] reported the synthesis of other thienoacridine analogs of the formula: ##STR5## where R is H or methyl and n is 1 or 2. The compound shown below was reported by Braunholtz et al. [J. Chem. Soc. (1962) 4346] as a synthetic intermediate. ##STR6## Benzofuro[3,2-b]quinolines of the formula: ##STR7## where R is lower alkyl or carboxy are disclosed in Jpn. Kokai Tokkyo Koho 63,295,579, issued to Kinoshita et al. on Dec. 1, 1988 [Chem. Abstr. 111, 187618], with utility in the treatment of osteoporosis. Analogous carboxylic acids substituted with a single halogen atom, as well as the corresponding N-oxides, were synthesized by Yamaguchi et al. [J. Heterocyclic Chem. (1989) 26:285] as intermediates to potential carcinogens, mutagens and antitumor substances. An additional compound of the same formula, where R is COOH, where a methoxy substituent is present on the benzofuran ring, and where the O has been replaced by S, has also been synthesized by Buu-Hoi et al. [Israel J. Chem. (1963) 1:369; Chem. Abstr. 60, 11998f]. Degutis et al. [Khim. Geterotsikl. Soedin. (1986) 1375; Chem. Abstr. 107, 39658] and Ezerskaite et al. [Izv. Khim. (1989) 22:113; Chem. Abstr. 112, 66492, and Izv. Khim. (1989) 22:232; Chem. Abstr. 113, 58979] synthesized indoloquinoline carboxylic acids of the formula: ##STR8## where R.sup.1 and R.sup.2 are H or alkyl and R.sup.3 is H or bromo, and disclosed utility as sensitizers for electrophotography. Holt et al. [J. Chem. Soc. (1947) 607] also discuss the synthesis of this type of compound. Fravolini et al. [Ann. Chim. (1968) 58:1155; Chem. Abstr. 70, 47334] synthesized the fluorinated benzothiopyranoquinoline carboxylic acids shown below. ##STR9## Hou et al. [Youji Huaxue (1991) 11:615; Chem. Abstr. 116, 128709] reported the synthesis of the compounds shown below, where R is H or halogen. ##STR10## Wang et al. [Gaodeng Xuexiao Huaxue Xuebao (1991) 12:59; Chem. Abstr. 115, 49457, and Zhongguo Yiyao Gongye Zashi (1991) 22:103; Chem. Abstr. 115:183138] disclosed the synthesis and anti-inflammatory activity of 7-carboxyisochromano[4,3-b]quinolines of the formula: ##STR11## where R is H, halogen or methyl. A compound of this formula, but lacking the R group and with O replaced by S, was synthesized by Braun et al. [Chem. Ber. (1929) 62:2416] and by Kiang et al. [J. Chem. Soc. (1951) 1909]. No utility was reported for this latter compound. Roussel et al. [J. Chem. Soc. (1965) 5458] reported the synthesis of dibenzonaphthyridine derivatives of the formula: ##STR12## where R.sup.1 is H, methyl or chloro; R.sup.2 is H, methoxy or chloro, and R.sup.3 is H or methyl, as potential carcinogens. The quinolinonaphthyridine derivatives show below (R=H, acetyl) were reported by Settimo et al. [J. Heterocyclic Chem. (1979) 16:169]. ##STR13## Synthesis of similar compounds, lacking the methyl substituent shown above but where R is methyl or phenyl, have been reported by Braunholtz et al. [J. Chem. Soc. (1955) 381] and Mann [J. Chem. Soc. (1949) 2816], respectively. The benzoquinolinoazepine derivatives of the formula: ##STR14## where R is methyl or tosyl have been synthesized by Braunholtz et al. [J. Chem. Soc. (1958) 3377] and by Proctor et al. [J. Chem. Soc. Perkin Trans. I (1978) 862], respectively. Another compound of this formula, but with NR replaced by S, was synthesized by Huckle et al. [J. Chem. Soc. C (1971) 2252]. There are no literature references disclosing the ring-fused quinolinecarboxylic acids or derivatives thereof of the present invention, or their use in treating and/or preventing immunologic disorders. Presently, cyclosporin A, an immunosuppressive agent, used in combination with other adjunctive therapies, such as azathioprine and corticosteroids, is the treatment of choice for the prevention of organ transplantation rejection. Other immunosuppressive agents such as azathioprine, corticosteroids (such as prednisone), OKT3, FK506, mycophenolic acid or the 2-(N-morpholino)ethyl ester thereof, 15-deoxyspergualin, rapamycin, mizoribine, misoprostol and anti-interleukin-2 receptor antibodies, have been used or have been suggested to be useful in the treatment and/or prevention of organ transplantation rejection. Use of any of these known immunosuppressive compounds, either alone or in combination, is associated with a high incidence of side effects such as nephrotoxicity and/or hepatoxicity. Thus, there presently exists a need for improved therapies for the treatment of cancer and for the treatment and/or prevention of organ transplantation rejection, graft versus host disease, autoimmune diseases, and chronic inflammatory diseases, including but not limited to psoriasis and rheumatoid arthritis. It has now been found that the carbocyclic and heterocyclic fused-ring quinolinecarboxylic acid compounds described herein are useful for the treatment and/or prevention of organ transplantation rejection, graft versus host disease, autoimmune diseases, and chronic inflammatory diseases, including but not limited to psoriasis and rheumatoid arthritis, in a mammal. The carbocyclic and heterocyclic fused-ring quinolinecarboxylic acid compounds of this invention can be used alone or in combination with one or more additional known immunosuppressive agents, such as cyclosporin A (CSA or CsA) and analogs thereof, FK506 (or FK-506) and analogs thereof, corticosteroids, azathioprine (AZA), mycophenolic acid or the 2-(N-morpholino)ethyl ester thereof, mycophenolate mofetil, rapamycin, 15-deoxyspergualin, mizoribine, leflunomide, OKT3, anti-interleukin-2 receptor antibodies, misoprostol, methotrexate, cyclophosphamide, and anti-lymphocyte/thymocyte serums, thereby to reduce the dosage required and associated adverse effects of these immunosuppressive agents. SUMMARY OF THE INVENTION This invention relates to carbocyclic and heterocyclic fused-ring quinolinecarboxylic acid compounds of Formulas 1-4 described below, to pharmaceutical compositions comprising such compounds, and to methods of using such compounds for the treatment and/or prevention of organ transplantation rejection, graft versus host disease, autoimmune diseases, and chronic inflammatory diseases, including but not limited to psoriasis and rheumatoid arthritis, in a mammal. The compounds of Formulas 1-4 of the present invention are also useful for the treatment of tumors in a mammal. The compounds of Formulas 1-4 described herein have been discovered to be immunosuppressive or immunomodulatory agents which are useful for the treatment and/or prevention in a mammal of organ transplantation rejection, graft versus host disease, and autoimmune diseases, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, psoriasis, multiple sclerosis, and myasthenia gravis. The compounds of Formulas 1-4 of the present invention are also useful for the treatment and/or prevention in a mammal of chronic inflammatory diseases, including but not limited to Crohn's disease, inflammatory bowel disease, rheumatoid arthritis, psoriasis, and primary biliary cirrhosis. The compounds of Formulas 1-4 of the present invention are also useful for the treatment of tumors in a mammal, including leukemias and solid tumors, including tumors of the breast, colon, and lung. The present invention also provides pharmaceutical compositions comprising a compound of Formulas 1-4 and a pharmaceutically acceptable carrier. Also provided in the present invention are methods of treatment and/or prevention of organ transplantation rejection, graft versus host disease, autoimmune diseases, or chronic inflammatory diseases comprising administering to a mammal in need of such treatment and/or prevention, a therapeutically effective amount of a compound of Formulas 1-4 of the present invention. The present invention also provides methods of treatment and/or prevention of organ transplantation rejection, graft versus host disease, psoriasis, autoimmune diseases, and chronic inflammatory diseases in a mammal comprising administering to the mammal in a therapeutically effective amount for the treatment of a desired aforesaid disease a combination of: (i) a compound of Formulas 1-4 as described below and (ii) at least one additional immunosuppressive agent. Such additional immunosuppressive agent may be selected from the group including but not limited to cyclosporin A (CSA or CsA) and analogs thereof, FK506 and analogs thereof, corticosteroids, azathioprine (AZA), mycophenolic acid or the 2-(N-morpholino)ethyl ester thereof, mycophenolate mofetil, rapamycin, 15-deoxyspergualin, mizoribine, leflunomide, OKT3, antiinterleukin-2 receptor antibodies, misoprostol, methotrexate, cyclophosphamide, and antilymphocyte/thymocyte serums. The compounds of Formulas 1-4 of the present invention may also be administered in combination with a non-steroidal anti-inflammatory agent, selected from the group including but not limited to, aspirin, ibuprofen, naproxen, indomethacin, diclofenac, sulindac, piroxicam, etodolac, ketoprofen, meclofenamate, suprofen, and tolmetin, for the treatment and/or prevention of organ transplantation rejection, graft versus host disease, psoriasis, autoimmune diseases, and chronic inflammatory diseases in a mammal. Compounds of Formulas 1-4 of the present invention may also be administered in combination with other tumor inhibiting agents, including but not limited to, 5-fluorouracil, for the treatment of tumors in a mammal. DETAILED DESCRIPTION OF THE INVENTION This invention relates to carbocyclic and heterocyclic fused-ring quinolinecarboxylic acid compounds of Formulas 1-4 described below, to pharmaceutical compositions comprising such compounds, and to methods of using such compounds for the treatment and/or prevention of immunologic disorders, including organ transplantation rejection, graft versus host disease, autoimmune diseases, and chronic inflammatory diseases, including but not limited to psoriasis and rheumatoid arthritis, in a mammal. The compounds of Formulas 1-4 of the present invention are also useful for the treatment of tumors in a mammal. The compounds of Formulas 1-4 described herein have been discovered to be immunosuppressive or immunomodulatory agents which are useful for the treatment and/or prevention in a mammal of organ transplantation rejection, graft versus host disease, and autoimmune diseases, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, psoriasis, multiple sclerosis, and myasthenia gravis. The compounds of Formulas 1-4 of the present invention are also useful for the treatment and/or prevention in a mammal of chronic inflammatory diseases, including but not limited to Crohn's disease, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, psoriasis, and primary biliary cirrhosis. The compounds of Formulas 1-4 of the present invention are also useful for the treatment of tumors in a mammal, including leukemias and solid tumors, including tumors of the breast, colon, and lung. The carbocylic and heterocyclic fused-ring quinolinecarboxylic acid compounds of the present invention are selected from compounds of Formulas 1, 2, 3, or 4 (1-4): ##STR15## or pharmaceutically acceptable salts thereof, wherein: R.sup.1 and R.sup.2 are independently selected from H, F, Cl, Br, CF.sub.3, or alkyl of 1-4 carbons; R.sup.3 is selected from: phenyl, phenoxy, phenylthio, phenylsulfinyl, phenyl-N(R.sup.4)-, furyl, thienyl, pyridyl, thiazolyl, or oxazolyl; wherein said phenyl, phenoxy, phenylthio, phenylsulfinyl, phenyl-N(R.sup.4)-, furyl, thienyl, pyridyl, thiazolyl, or oxazolyl is substituted with 0-2 groups independently selected from: F, Cl, Br, CF3,alkyl of 1-4 carbons, alkoxy of 1-4 carbons, alkylthio of 1-4 carbons or alkylsulfinyl of 1-4 carbons; R.sup.4 is selected from H, alkyl of 1-4 carbons or acyl of 1-4 carbons; X is selected from --Y--, --CH.sub.2 Y--, --YCH.sub.2 --, --CH.sub.2 CH.sub.2 Y--, --YCH.sub.2 CH.sub.2 --, --CH.sub.2 YCH.sub.2 --, --CR.sup.5 =C(R.sup.6)--, --CR.sup.6 =N--, or N=C(R.sup.6)--, (the first atom of X as listed being attached to the quinoline ring); wherein each methylene group in X may be optionally substituted with one or two groups independently selected from alkyl of 1-4 carbons; Y is --CH.sub.2 -- (said --CH.sub.2 -- group being optionally substituted with one or two alkyl groups of 1-4 carbons), --O--, --S--, or --N(R.sup.7)--; R.sup.5 and R.sup.6 are independently H or alkyl of 1-4 carbons; R.sup.7 is selected from H, alkyl of 1-4 carbons or acyl of 1-4 carbons; wherein, in compounds of Formula 1 and Formula 2: Z.sup.1, Z.sup.2 and Z.sup.3 are independently CR.sup.8 or N, with the proviso that at least one of Z.sup.1, Z.sup.2 and Z.sup.3 is not nitrogen; R.sup.8 is independently selected from H, F, Cl, Br, CF.sub.3, or alkyl of 1-4 carbons; wherein, in compounds of Formula 3: one of Q.sup.1 and Q.sup.2 is S or NR.sup.9 and the other is CR.sup.10 or N, with the stipulation that the ring which contains Q.sup.1 and Q.sup.2 contains an additional double bond placed so as to generate an aromatic ring; R.sup.9 is selected from H or alkyl of 1-4 carbons; R.sup.10 is selected from H, F, Cl, Br, CF.sub.3, or alkyl of 1-4 carbons; wherein, in compounds of Formula 4: one of Q.sup.3 and Q.sup.4 is N and the other is C, with the stipulation that the ring of Formula 4 which contains Q.sup.3 and Q.sup.4 contains an additional double bond placed so as to generate an aromatic pyrrole ring; and R.sup.11 is H, F, Cl, Br, CF.sub.3, or alkyl of 1-4 carbons; subject to the following provisos: 1) X is not NR.sup.7 ; 2) in compounds of Formula 1, when X is CH.sub.2 CH.sub.2 and each of Z.sup.1, Z.sup.2 and Z.sup.3 is CH, then R.sup.3 is not unsubstituted phenyl; 3) in compounds of Formula 3, or of Formula 4 where Q.sup.4 is N, X must form a bridge of at least two atoms, and the atom of X attached to the ring containing Q.sup.1 and Q.sup.2 or Q.sup.3 and Q.sup.4 must be carbon; 4) in compounds of Formula 4 where Q.sup.3 is N, X must consist of either --CH.sub.2 CH.sub.2 -- or --CH.sub.2 CH.sub.2 CH.sub.2 --, with each methylene group of X optionally substituted as described above; and 5) in compounds of Formuala 4 where Q.sup.4 is N, then R.sup.3 must not be phenoxy, phenylthio, phenylsulfinyl, or phenyl-N(R.sup.4)--. Preferred carbocyclic and heterocyclic fused-ring quinolinecarboxylic acid compounds of the present invention are those compounds described above of Formulas 1-4 wherein R.sup.1 and R.sup.2 are substituted at the 5- and/or 6-position on the quinoline ring. Preferred carbocyclic and heterocyclic fused-ring quinolinecarboxylic acid compounds of the present invention are those compounds described above of Formulas 1-4 wherein: R.sup.1 is 6-F or 6-CF.sub.3 ; and/or R.sup.2 is H; and/or R.sup.3 is phenyl, thienyl or furyl; said phenyl, thienyl or furyl being substituted with 0-2 groups independently selected from: F, Cl, Br, CF.sub.3, alkyl of 1-4 carbons, alkoxy of 1-4 carbons, alkylthio of 1-4 carbons or alkylsulfinyl of 1-4 carbons; and/or X is --CH.sub.2 CH.sub.2 --, --CH.sub.2 S--, --SCH.sub.2 --, --CH.sub.2 O--, or --OCH.sub.2 --; and/or wherein, in compounds of Formula 1 or Formula 2, Z.sup.1 is CH; and/or wherein, in compounds of Formula 3, Q.sup.1 is S and Q.sup.2 is CH; and/or wherein, in compounds of Formula 4, Q.sup.3 is C and Q.sup.4 is N. More preferred carbocyclic and heterocyclic fused-ring quinolinecarboxylic acid compounds of Formulas 1-4 of the present invention are those preferred compounds described above wherein: R.sup.3 is phenyl, 2-fluorophenyl, 3-methoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, or thienyl. Specifically preferred compounds of Formulas 1-4 of the present invention are compounds selected from the following, or a pharmaceutically acceptable salt form thereof: (a) the compound of Formula 1 where R.sup.1 is 6-F; R.sup.2 is H; R.sup.3 is phenyl; Z.sup.1, Z.sup.2 and Z.sup.3 are all CH; and X is CH.sub.2 S; or a sodium salt; (b) the compound of Formula 1 where R.sup.1 is CF.sub.3 ; R.sup.2 is H; R.sup.3 is phenyl; Z.sup.1, Z.sup.2 and Z.sup.3 are all CH; and X is CH.sub.2 S, or a sodium salt; (c) the compound of Formula 1 where R.sup.1 is 6-F; R.sup.2 is H; R.sup.3 is 2-fluorophenyl; Z.sup.1, Z.sup.2 and Z.sup.3 are all CH; and X is CH.sub.2 S, or a sodium salt; (d) the compound of Formula 1 where R.sup.1 is 6-F; R.sup.2 is H; R.sup.3 is 3-methoxyphenyl; Z.sup.1, Z.sup.2 and Z.sup.3 are all CH; and X is CH.sub.2 S, or a sodium salt; (e) the compound of Formula 1 where R.sup.1 is 6-F; R.sup.2 is H; R.sup.3 is phenyl; Z.sup.1, Z.sup.2 and Z.sup.3 are all CH; and X is CH.sub.2 O, or a sodium salt; (f) the compound of Formula 1 where R.sup.1 is 6-F; R.sup.2 is H; R.sup.3 is 3-methylphenyl; Z.sup.1, Z.sup.2 and Z.sup.3 are all CH; and X is SCH.sub.2, or a sodium salt; (g) the compound of Formula 1 where R.sup.1 is 6-F; R.sup.2 is H; R.sup.3 is phenyl; Z.sup.1 and Z.sup.2 are CH; Z.sup.3 is N; and X is CH.sub.2 CH.sub.2, or a sodium salt; (h) the compound of Formula 1 where R.sup.1 is 6-F; R.sup.2 is H; R.sup.3 is phenyl; Z.sup.1, Z.sup.2 and Z.sup.3 are all CH; and X is OCH.sub.2, or a sodium salt; (i) the compound of Formula 1 where R.sup.1 is 6-F; R.sup.2 is H; R.sup.3 is phenyl; Z.sup.1 and Z.sup.2 are CH; Z.sup.3 is N; and X is SCH.sub.2, or a sodium salt; (j) the compound of Formula 1 where R.sup.1 is 6-F; R.sup.2 is H; R.sup.3 is 2-fluorophenyl; Z.sup.1, Z.sup.2 and Z.sup.3 are CH; and X is CH.sub.2 CH.sub.2, or a sodium salt; (k) the compound of Formula 1 where R.sup.1 is 6-F; R.sup.2 is H; R.sup.3 is 3-trifluoromethylphenyl; Z.sup.1, Z.sup.2 and Z.sup.3 are CH; and X is CH.sub.2 CH.sub.2, or a sodium salt; (l) the compound of Formula 1 where R.sup.1 is 6-F; R.sup.2 is H; R.sup.3 is 3-methoxyphenyl; Z.sup.1, Z.sup.2 and Z.sup.3 are CH; and X is CH.sub.2 CH.sub.2, or a sodium salt. The present invention also provides pharmaceutical compositions comprising a compound of Formulas 1-4 and a pharmaceutically acceptable carrier. Also provided in the present invention are methods of treatment and/or prevention of organ transplantation rejection, graft versus host disease, autoimmune diseases, or chronic inflammatory diseases comprising administering to a mammal in need of such treatment and/or prevention, a therapeutically effective amount of a compound of Formulas 1-4 of the present invention. The compounds of the present invention are also useful for the treatment of skin and muco-epithelial diseases in a mammal, such as psoriasis (in all its forms), lichen (including lichen planus), chronic eczema, icthyosis, pityriasis and chronic uticaria. Pharmaceutical compositions comprising a compound of Formulas 1-4 formulated for topical administration are particularly useful for the treatment of such skin and muco-epithelial diseases. The present invention also provides methods of treatment and/or prevention of immunological disorders including organ transplantation rejection, graft versus host disease, psoriasis, autoimmune diseases, and chronic inflammatory diseases in a mammal comprising administering to the mammal in a therapeutically effective amount for the treatment of a desired aforesaid disease a combination of: (i) a compound of Formulas 1-4 as described below and (ii) at least one additional immunosuppressive agent. Such additional immunosuppressive agent may be selected from the group including but not limited to cyclosporin A (CSA or CsA) and analogs thereof, FK506 and analogs thereof, corticosteroids, azathioprine (AZA), mycophenolic acid or the 2-(N-morpholino)ethyl ester thereof, mycophenolate mofetil, rapamycin, 15-deoxyspergualin, mizoribine, leflunomide, OKT3, anti-interleukin-2 receptor antibodies, misoprostol, methotrexate, cyclophosphamide, and anti-lymphocyte/thymocyte serums. The compounds of Formulas 1-4 of the present invention may also be administered in combination with a non-steroidal anti-inflammatory agent, selected from the group including but not limited to, aspirin, ibuprofen, naproxen, indomethacin, diclofenac, sulindac, piroxicam, etodolac, ketoprofen, meclofenamate, suprofen, and tolmetin, for the treatment and/or prevention of organ transplantation rejection, graft versus host disease, psoriasis, autoimmune diseases, and chronic inflammatory diseases in a mammal. Compounds of Formulas 1-4 of the present invention may also be administered in combination with other tumor inhibiting agents, including but not limited to, 5-fluorouracil, for the treatment of tumors in a mammal. The compounds of Formulas 1-4 of the present invention are potent inhibitors of dihydroorotate dehydrogenase, the fourth enzyme in the de novo pyrimidine nucleotide biosynthesis pathway. Current recommended therapy for the prevention of organ transplantation rejection and related disorders, including graft versus host disease, traditionally involves patient treatment with cyclosporin A and adjunctive therapy with corticosteroids and other immunosuppressive drugs (Jacobs and Elgin, "Cyclosporin A, Current Status, Including the Cape Town Experience" in Immune Modulation Agents and Their Mechanisms, ISBN 0-8247-7178-8, 1984, pp 191-228; Transplantation and Clinical Immunology, Volume XX Combined Immuno-suppressive Therapy in Transplantation ISBN 0-444-81068-4, 1989). In view of the significant clinically observed toxicities associated with cyclosporin A (nephrotoxicity) and AZA (hepatoxicity), there is a need for improved therapies to replace or to be used in combination with cyclosporin A or AZA. The present results indicate that the compounds of Formulas 1-4 of the present invention will be useful as single therapy agents as well as agents to be used in combination with other compounds currently used in these clinical regimens such as cyclosporin A. The compounds of Formulas 1-4 of the present invention have a unique mechanism of action (inhibition of dihydroorotate dehydrogenase) which is distinct from other available immunosuppressive agents. The compounds of Formulas 1-4 should be useful to permit the administration of reduced doses of other immunosuppressive agents (such as CsA and AZA) used in combination therewith, thereby reducing the adverse effects of these agents. The isolation of FK506 is described in European Patent Application publication number 240,773, published Oct. 14, 1987 and the chemical synthesis of FK506 is described in Jones et al. (1989) J. Am. Chem. Soc. 111:1157-1159. The preparation of azathioprine is described in U.S. Pat. No. 3,056,785 issued to Burroughs Wellcome. Azathioprine is available as Imuran.RTM., for which the product information, including dosage and administration, is given in Physicians' Desk Reference 44th Edition, 1990, pp 777-778. The preparation of cyclosporin A is described in U.S. Pat. No. 4,117,118 issued to Sandoz. Cyclosporin A is available as Sandimmune.RTM., for which the product information, including dosage and information, is given in Physicians' Desk Reference 44th Edition, 1990, pp 1950-1952. The preparation of prednisone is described in U.S. Pat. Nos. 2,897,216 and 3,134,718 issued to Schering. Prednisone is available commercially from several manufacturers as are other corticosteroids (see generally, Physicians' Desk Reference, supra). Murine monoclonal antibody to the human T3 antigen (herein referred to as OKT3) is available as Orthoclone OKT.RTM.3, for which the product information, including dosage and administration and references to methods of preparation, is given in Physicians' Desk Reference, 1990, pp 1553-1554. The preparation of mycophenolic acid is described in British patents 1,157,099; 1,157,100; and 1,158,387 issued to ICI. 15-Deoxyspergualin is a derivative of spergualin discovered in culture filtrates of the bacterial strain BGM162-aFZ as reported in Ochiai et al. Prolongation of Rat Heart Allograft Survival by 15-deoxyspergualin, J..sub.-- Antibiot (Tokyo) 1987; 40:249. Mizoribine is described in U.S. Pat. No. 3,888,843 issued to Toyo Jozo. Misoprostol, a prostaglandin (PGE1) analog, is described in U.S. Pat. No. 3,965,143 assigned to Searle and U.S. Pat. No. 4,132,738 assigned to Miles. Rapamycin is described in U.S. Pat. Nos. 4,650,803; 4,316,885; 4,885,171; 3,993,749 and 3,929,992, all assigned to Ayerst. Antibodies to the IL-2 receptor protein are described in U.S. Pat. Nos. 4,578,335 and 4,845,198 (Immunex) and U.S. Ser. No. 7/341,361 and U.S. Pat. No. 4,892,827 issued to Pastan et al. There is also provided by this invention methods of treating cancer in a mammal, including leukemia, lymphoma, and solid tumors, including pancreatic, mammary, colon, breast, lung, epithelial, and melanoma tumors, comprising the administration to a mammal bearing such a tumor a therapeutically effective tumor-inhibiting amount of a compound of Formulas 1-4 as described above. The compounds of Formulas 1-4 of the present invention can be administered in combination with a second immunosuppressive agent, thereby to reduce the doses of each drug required to achieve the desired therapeutic effect. Thus, the combination treatment of the present invention permits the use of lower doses of each component, with reduced adverse, toxic effects of each component. A lower dosage minimizes the potential of side effects of the compounds, thereby providing an increased margin of safety relative to the margin of safety for each component when used as a single agent. By "therapeutically effective amount" it is meant an amount of a compound of Formulas 1-4 that when administered alone or in combination with a second additional immunosuppressive agent to a cell or mammal is effective to prevent or ameliorate the disease condition or the progression of the disease. By "administered in combination" or "combination" when referring to component (i) and component (ii) of the present invention, it is meant that the components are administered concurrently to the cell or mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, component (i) and component (ii) may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect. This invention also includes pharmaceutical kits comprising or consisting essentially of: a pharmaceutical composition comprising a compound of Formulas 1-4; or a compound of Formulas 1-4 together with a pharmaceutical composition comprising at least one additional immunosuppressive agent. This invention also provides methods of using such pharmaceutical kits for the treatment of organ transplantation rejection, graft versus host disease, psoriasis and autoimmune diseases, including but not limited to rheumatoid arthritis, systemic lupus erythematous, multiple sclerosis, myasthenia gravis, insulin dependent diabetes, as well as chronic inflammatory disease including but not limited to Crohn's disease and primary biliary cirrhosis, in a mammal. This invention also includes combination products comprising pharmaceutical compositions comprising a compound of Formulas 1-4 in physical combination or in a single dosage form with a second immunosuppressive agent, to pharmaceutical kits containing these combination products, and to methods of using these combination products for the treatment of organ transplantation rejection, graft versus host disease, psoriasis and autoimmune diseases, including but not limited to rheumatoid arthritis, systemic lupus erythematous, multiple sclerosis, insulin dependent diabetes, myasthenia gravis, as well as chronic inflammatory disease including but not limited to Crohn's disease and primary biliary cirrhosis, in a mammal. The compounds of Formulas 1-4 herein described may have asymmetric centers. All chiral, diastereomeric, and racemic forms are included in the present invention. All chiral, diastereomeric, and racemic forms are intended for a given compound unless the specific stereochemistry for the compound is specifically indicated. All stable geometric isomers present in the compounds described herein are contemplated in the present invention and all geometric isomeric forms of a structure are intended, unless the specific isomer form is specifically indicated. When any variable occurs more than one time in any constituent or in formula 1, 2, 3, or 4, or any other formula herein, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R.sup.8, then said group may optionally be substituted with up to three R.sup.8 and R.sup.8 at each occurrence is selected independently from the defined list of possible R.sup.8. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. As used herein, "acyl of 1-4 carbons" is intended to include an alkyl group of 1-3 carbons attached through a carbonyl bridge (i.e. --C(=O)-(C.sub.1 -C.sub.3 alkyl)). As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; "alkylthio" represents an alkyl group of indicated number of carbon atoms attached through an sulfur bridge; "alkylsulfinyl" represents an alkyl group of indicated number of carbon atoms attached through a sulfinyl bridge. The term "substituted", as used herein, means that any one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. By "stable compound" or "stable structure" is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds that are modified by making acid or base salts. Examples include, but are not limited to, mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts of the compounds of this invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference. The disclosures of all of the references cited herein are hereby incorporated herein by reference in their entirety. Synthesis Compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference. In the discussion below, compounds of Formula 1 are used in the schemes and accompanying text, and starting materials and intermediates appropriate to the preparation of compounds of Formula 1 are described. However, it is to be understood that the methods discussed are not limited to the preparation of compounds of Formula 1, but rather may be used for the preparation of compounds of Formulas 2, 3 and 4 as well, by substitution of the appropriate, analogous starting materials and intermediates. Although the structures shown in the schemes below are related to compounds of Formula 1, it will be understood that analogous schemes are applicable for the synthesis of compounds of Formulas 2, 3 and 4. Compounds of Formulas 1, 2, 3 and 4 may be prepared by the reaction shown in Scheme 1 (which represents this reaction for the preparation of compounds of Formula 1). An appropriately substituted isatin of Formula 5 is condensed with an appropriately substituted cyclic ketone of Formula 6. This condensation, commonly called the Pfitzinger condensation, is well known in the chemical literature (for example, see Buu-Hoi et al., J. Org. Chem. (1953) 18:1209, and Jones, Quinolines Part I, 1977, Wiley, pp 197-207). The reaction is usually carried out in a suitable solvent, such as ethanol or a mixture of ethanol and water, in the presence of a suitable base, such as sodium hydroxide or potassium hydroxide, at a temperature in the range of about 5.degree. C. to the boiling point of the solvent, preferably at the boiling point of the solvent. Acidification of the reaction mixture with a mineral acid such as hydrochloric acid or an organic acid such as acetic acid provides the compounds of Formula 1, 2, 3, or 4. Alternatively, the compound of Formula 1, 2, 3, or 4 may be directly isolated from the reaction mixture as a salt, such as the sodium salt or potassium salt. ##STR16## Alternatively, compounds of Formulas 1, 2, 3 and 4 may be prepared by a two-reaction sequence as shown in Scheme 2 (which represents this reaction sequence for the preparation of compounds of Formula 1). This alternative two-reaction sequence is preferred when the ketone of Formula 6 is unstable to the reaction conditions required for the reaction of Scheme 1, or is unreactive under these conditions. In this alternative reaction sequence, an appropriately substituted isatin of Formula 5 is reacted with an appropriately substituted cyclic ketone of Formula 6, in a suitable solvent such as ethanol, in the presence of a suitable base such as diethylamine or pyrrolidine, at a temperature in the range of about 5.degree. C. to the boiling point of the solvent, to provide an intermediate aldol condensation product of Formula 7. The product of Formula 7 is then reacted further in a suitable solvent such as ethylene glycol dimethyl ether or dioxane, in the presence of a mineral acid such as aqueous hydrochloric acid or an organic acid such as methanesulfonic acid, in an amount which represents about 25-100% of the volume of the solvent. The temperature of the reaction is in the range of about 5.degree. C. to the boiling point of the solvent. Removal of the solvent and treatment with water provides the compound of Formula 1, 2, 3, or 4. ##STR17## Alternatively, the compounds of Formulas 1, 2, 3 and 4 where R.sup.3 is phenyl, furyl, thienyl, pyridyl, thiazolyl, or oxazolyl (wherein said phenyl, furyl, thienyl, pyridyl, thiazolyl, or oxazolyl is optionally substituted) may be prepared according to the reaction sequence shown in Scheme 3 (which represents this reaction sequence for the preparation of compounds of Formula 1). In this sequence, a ketone of Formula 8 (where the R.sup.3 substituent of the ketone of Formula 6 has been replaced by an appropriate substituent such as bromo) is condensed with an isatin of Formula 5, using the Pfitzinger condensation analogous to that shown in Scheme 1 or the two-step reaction sequence analogous to that shown in Scheme 2, to provide the compound of Formula 9. This compound is then coupled with an arylboronic acid or heteroarylboronic acid R.sup.3 -B(OH).sub.2 using a standard coupling reaction such as that described by Miyara et al. [Synth. Comm. (1981) 11:513], commonly referred to as a Suzuki coupling, to provide the compound of Formula 1, 2, 3, or 4. The use of this reaction sequence requires that R.sup.1 and R.sup.2 are not Br. ##STR18## Certain substituents on compounds of Formulas 5 and/or 6 may be incompatible with the reaction conditions to prepare the compounds of Formulas 1, 2, 3 or 4. In these cases, the substituents may be replaced with suitable protected forms of the desired substituents, or with suitable precursors to the desired substituents. After isolation of the product of the reaction sequences shown in Schemes 1, 2 or 3, the desired substituents may be elaborated by suitable deprotection or other manipulations to provide the compound of Formula 1, 2, 3 or 4. Cases where this may be necessary will be evident to one skilled in the art, as will the methods to be used for conversion to the desired compounds. Compounds of Formulas 1, 2, 3 and 4 wherein X is CR.sup.5 =CR.sup.6, CR.sup.6 =N or N=CR.sup.6 may be prepared from the corresponding compounds where X is CHR.sup.5 CHR.sup.6, CHR.sup.6 NH or NHCHR.sup.6, respectively, by methods well known in the art. Examples are treatment with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in a solvent such as benzene or toluene, as described by Pataki et al. [J. Org. Chem. (1987) 52:2226], and treatment with palladium on charcoal as described by Garrett et al. [Tetrahedron Lett. (1969) 191]. Compounds of Formula 1, 2, 3, or 4 which contain an acyl group as R.sup.4 and/or R.sup.7 may be prepared from the corresponding compound where R.sup.4 and/or R.sup.7 is H, using methods well known in the art, such as acylation with an acid chloride or anhydride. Isatins of Formula 5 used as starting materials for the compounds of Formula 1, 2, 3 and 4 are either commercially available, or may be prepared using methods as described by Papp and references given therein [Adv. Heterocyclic Chem. (1975) 18:1]. Ketones of Formula 6 (which may be used to prepare compounds of Formula 1, and which in the following discussions are meant to represent also the ketones which may be used to prepare compounds of Formulas 2, 3, and 4) may be prepared using a variety of standard methods well known in the literature. Several applicable methods are herein described, but these methods are meant as illustrative examples only and do not constitute a limitation to the present invention. In cases of suitable reactivity which will be apparent to one skilled in the art, the ketones of Formula 6 may be prepared by a Friedel-Crafts acylation reaction as illustrated in Scheme 4. A suitable carboxylic acid precursor of Formula 10 may either be cyclized directly to 6 using an acid catalyst such as sulfuric acid, methanesulfonic acid, or polyphosphoric acid, optionally in an appropriate solvent, or the acid may first be activated by conversion to the corresponding acid chloride or acid anhydride using standard methods, after which it may be cyclized by use of an appropriate Lewis acid catalyst such as aluminum chloride or boron trifluoride, in an appropriate solvent. The Friedel-Crafts acylation reaction is well known in the chemical literature, and has been extensively reviewed, for example by Gore [Chapter 31 in Olah, Friedel-Crafts and Related Reactions, vol. 3, 1964, Interscience Publishers]. This method will be limited to cases in which the ring onto which the acylation is to occur is sufficiently reactive toward Friedel-Crafts acylation conditions, such as for example a benzene or thiophene ring. The carboxylic acids of Formula 10 may in turn be prepared using reactions and methods well known in the chemical literature. ##STR19## Ketones of Formula 6 may also be prepared using the reaction sequence shown in Scheme 5. A suitable starting material of Formula 11, where G.sup.1 and G.sup.2 are suitable functional groups such as carboxylate esters, nitriles, or carboxylic acids, may be cyclized using conditions appropriate to the substituents G.sup.1 and G.sup.2 to give an intermediate of Formula 12, which may then be further converted to the ketone of Formula 6. In the case where G.sup.1 and G.sup.2 are carboxylate esters, the cyclization is commonly known as the Dieckmann condensation. In the case where G.sup.1 and G.sup.2 are nitriles, the cyclization is commonly known as the Thorpe-Ziegler condensation. These reactions are well known in the chemical literature (see, for example, Schaefer et al. [Org. Reactions (1967) 15:1]), and may be carried out in an appropriate solvent using a basic catalyst, such as sodium methoxide, sodium ethoxide, or potassium t-butoxide. In the case where G.sup.1 and G.sup.2 are carboxylic acids, the reaction may be carried out by treatment with acetic anhydride and acetic acid, according to the procedure of Normant-Chefnay et al. [Compt. Rend. Acad. Sci. (C) (1968) 267:547]. The cyclized intermediate of Formula 12 may then be further reacted under appropriate conditions to cause removal of the group G.sup.2, providing the desired ketone of Formula 6. Such conditions are well known in the chemical literature, and usually involve acid- or base-catalyzed hydrolysis of a nitrile or an ester to the corresponding carboxylic acid, which is then decarboxylated using well-known methods to provide the compound of Formula 6. In the case where G.sup.1 and G.sup.2 are carboxylic acids, the intermediate compound of Formula 12 is not isolated, but undergoes decarboxylation in the reaction to provide the compound of Formula 6 directly. ##STR20## Ketones of Formula 6 wherein X is CH.sub.2 O or CH.sub.2 S may also be prepared by the reaction sequence shown in Scheme 6. An appropriate methyl ketone of Formula 13, where Y is O or S, may be converted to a compound of Formula 14, where the wavy line represents either a single or double bond, and where either R is an alkyl group such as methyl or ethyl, or NR.sub.2 is a cyclic amino group such as pyrrolidine, piperidine, or morpholine. In the case where the wavy line is a single bond, this reaction is called the Mannich reaction, and is very well known in the chemical literature (see, for example, Blicke [Org. Reactions (1942) 1:303, and Cox et al. [Synthesis (1989) 709]). In the case where the wavy line is a double bond, this reaction may be achieved, for example, by condensation of 13 with a compound such as N,N-dimethylformamide dimethyl acetal, as reported by Lin et al. [J. Heterocyclic Chem. (1977) 14:345]. In some cases, the compound of Formula 14 may spontaneously cyclize to provide the desired compound of Formula 15 (which is equivalent to the ketones of Formula 6 where X is CH.sub.2 O or CH.sub.2 S), while in other cases the cyclization may be induced by treatment with an appropriate reagent, such as an acidic or a basic catalyst. In the case where the wavy bond of 14 is a double bond, then the keto ring of 15 will contain a double bond, which may be reduced using standard methods known in the literature to provide the desired compound of Formula 15. ##STR21## In cases where R.sup.3 is phenyl, furyl, thienyl, pyridyl, thiazolyl, or oxazolyl (wherein said phenyl, furyl, thienyl, pyridyl, thiazolyl, or oxazolyl is optionally substituted), ketones of structure 6 may also be synthesized from a suitable precursor ketone 16, where G is bromo or hydroxy, by a coupling reaction with an arylboronic acid or a heteroarylboronic acid as shown in Scheme 7. In the case where G is bromo, the coupling reaction may be performed using the Suzuki coupling mentioned earlier, in reference to Scheme 3. Alternatively, in the case where G is hydroxy, the hydroxy group may be activated by conversion to the corresponding trifluoromethanesulfonate, using standard methods and techniques. The resulting trifluoromethanesulfonate may be coupled with an arylboronic acid or heteroarylboronic acid, for example using the procedure described by Oh-e et al. [Synlett (1990) 221]. ##STR22## Examples of the preparation of ketone starting materials of Formula 6 and related ketones which may be used to synthesize compounds of Formulas 1, 2, 3, and 4 are given below. All melting points are uncorrected. All reactions were conducted under a nitrogen atmosphere except where otherwise noted. All commercial chemicals were used as received. Chromatography was performed with Merck silica gel 60 (230-400 mesh). The chromatography eluents are given as ratios by volume. Organic phases from solvent-solvent extractions were generally dried over magnesium sulfate, unless otherwise noted. Solvents were generally removed by evaporation under reduced pressure on a rotary evaporator unless otherwise noted. Peak positions for .sup.1 H NMR spectra are reported as parts per million (.delta.) downfield from the internal standard tetramethylsilane. Abbreviations for .sup.1 H NMR spectra are as follows: s=singlet, d=doublet, m=multiplet, dd=doublet of doublets, dm=doublet of multiplets. Mass spectra were obtained using chemical ionization with ammonia as the reagent gas. Preparation of 6-(4-methylphenyl)-1-tetralone a. 6-Methoxytetralone (50 g, 280 mmol) was suspended in glacial acetic acid (250 mL). Hydrobromic acid (47%; 500 mL) was added and the mixture was heated at reflux for 6 h, cooled to room temperature, and poured onto 500 g of crushed ice. After 1 h the precipitate was collected and recrystalized from ethanol to provide 32 g of 6-hydroxytetralone. Concentration of the mother liquor provided an additional 9 g of product, mp 149-152.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.7.80 (d, 1H), 6.78 (d, 1H), 6.68 (s, 1H), 2.90 (t, 2H), 2.55 (t, 2H), 2.05 (m, 2H). b. A portion of the product of part a (9.0 g, 55.5 mmol) was dissolved in dimethoxyethane (100 mL). Pulverized potassium carbonate (16.88 g, 122 mmol) was added and the reaction mixture heated at reflux under nitrogen for 10 minutes, then cooled to room temperature. N-Phenyltrifluoromethanesulfonimide (19.85 g, 55.5 mmol) was added and the mixture heated at reflux for 0.5 h, then cooled to room temperature. The solvent was decanted from the solid, which was washed with additional dimethoxyethane. The washings were added to the decanted solution and the combined solvents evaporated to yield an oil. Purification by column chromatography on silica gel using 5:1 hexane/ethyl acetate as eluant provided 15.7 g (96%) of 6-trifluoromethanesulfonyloxy-1-tetralone as an off-white solid; .sup.1 H NMR (CDCl.sub.3) .delta.8.15 (d, 1H), 7.25-7.15 (m, 2H), 3.02 (t, 2H), 2.65 (t, 2H), 2.18 (m, 2H). c. A portion of the product of part b (8.0 g, 27.2 mmol), 4-methylphenylboronic acid (4.07 g, 29.9 mmol), and pulverized tribasic potassium phosphate (8.65 g, 40.7 mmol) were suspended in anhydrous dioxane. The reaction mixture was degassed by bubbling nitrogen through the suspension for 10 minutes. Tetrakis(triphenylphosphine)palladium (943 mg, 0.8 mmol) was added and the mixture was heated at reflux for 5 h, allowed to cool to room temperature, diluted with diethyl ether, filtered and evaporated. Purification by chromatography on silica gel using dichloromethane as eluant provided 2.2 g (34%) of 6-(4-methylphenyl)-1-tetralone as an off-white solid; .sup.1 H NMR (CDCl.sub.3) .delta.8.05 (d, 1H), 7.58-7.25 (m, 6H), 3.05 (t, 2H), 2.64 (t, 2H), 2.40 (s, 3H); Mass spectrum (methane chemical ionization) m/z 265 (M+C.sub.2 H.sub.5), 237 (M+H). Preparation of 2-phenyl-7,8-dihydroquinolin-5(6H)-one 3-Aminocyclohexenone (5.55 g, 50 mmol) and 3-dimethylaminopropiophenone hydrochloride (10.65 g, 50 mmol) were suspended in glacial acetic acid (15 mL) and heated at reflux for 1 h. The mixture was cooled to room temperature and cautiously poured into 20% aqueous sodium carbonate. After gas evolution ceased the residue was extracted with chloroform, dried over anhydrous sodium carbonate, filtered and evaporated. Purification by chromatography on silica gel using 1:1 chloroform/dichloromethane as eluant provided 2.95 g (26%) of 2-phenyl-7,8-dihydroquinolin-5(6H)-one as an off-white solid, mp 128-130.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.8.32 (d, 1H), 8.05 (dd, 2H), 7.66 (d, 2H), 7.55-7.42 (m,3H), 3.21 (t, 2H), 2.72 (t, 2H), 2.22 (m, 2H). Preparation of 2-phenyl-7,8-dihydro-1,3-quinazolin-5-(6H)-one a. 1,3-Cyclohexanedione (11.2 g, 100 mmol) was suspended in dimethylformamide dimethylacetal (28 mL) and the mixture was heated at reflux for 1 h. The mixture was cooled to room temperature and the solvent was evaporated to provide an orange solid, which was recrystalized from ethyl acetate to provide 12 g (72%) of 2-dimethylaminomethylene-1,3-cyclohexanedione as light orange needles, mp 116-118.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.8.05 (s, 1H), 3.40 (s, 3H), 3.19 (s, 3H), 2.26 (t, 4H), 1.95 (m, 1H). b. Sodium (1.09 g 47 mmol) was cautiously added in small portions to anhydrous ethanol over 15 minutes, and the mixture was stirred until all of the sodium dissolved. Benzamidine hydrochloride (7.80 g, 49 mmol) was added, followed by a portion of the material from part a (8.31 g, 50 mmol) dissolved in ethanol (30 mL). The mixture was heated at reflux for 1 h and cooled to room temperature. The solvent was evaporated and the residue treated with water (100 mL), and the product filtered. The product was recrystallized from ethyl acetate to provide 5.2 g (42%) of 2-phenyl-7,8-dihydro-1,3-quinazolin-5(6H)-one as light yellow cubes, mp 122-124.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.9.25 (s, 1H), 8.55 (dd, 2H), 7.58-7.48 (m, 3H), 3.18 (t, 2H), 2.74 (t, 2H), 2.24 (m, 2H); Mass spectrum m/z 225 (M+H). Preparation of 7-phenylthiochroman-4-one a. 3-Bromothiophenol (10 g, 52.9 mmmol) was dissolved in acrylonitrile (11.28 g, 213 mmol). Triton B (1 mL) was added, at which time the reaction mixture became exothermic and began to reflux without added heat. The mixture was allowed to cool to room temperature, poured into cold aqueous sodium hydroxide (2%; 200 mL), and extracted with diethyl ether. The organic layer was dried, filtered and evaporated to provide 12 g (93%) of 3-[(3-bromophenyl)thio]propionitrile as a tan oil; .sup.1 H NMR (CDCl.sub.3) .delta.7.54 (s, 1H), 7.42 (d, 1H), 7.32 (d, 1H), 7.25-7.15 (m, 2H), 3.15 (t, 2H), 2.62 (t, 2H); Mass spectrum m/z 261, 259 (M+NH.sub.4). b. The product of part a (12.0 g, 50 mmol) was dissolved in glacial acetic acid (10 mL). Concentrated hydrochloric acid (250 mL) was added and the reaction mixture was heated at reflux for 4 h. The mixture was cooled to room temperature and poured onto 250 g of crushed ice. After the ice melted the precipitate was filtered and dissolved in a saturated aqueous solution of sodium bicarbonate (250 mL), and the solution was washed with ethyl acetate. The aqueous layer was cautiously acidified with concentrated hydrochloric acid and extracted with ethyl acetate The organic phase was dried, filtered and evaporated to provide 7.4 g (54%) of 3-[(3-bromophenyl)thio]propanoic acid as a white powder, mp 87-88.degree. C. .sup.1 H NMR (DMSO-d.sub.6) .delta.7.52 (s, 1H), 7.40-7.25 (m, 3H), 3.18 (t, 2H), 2.53 (t, 2H); Mass spectrum m/z 280, 278 (M+NH.sub.4), 262, 260 (m+H). c. A portion of the product of part b (2.61 g, 10 mmol) was pulverized and added to concentrated sulfuric acid (8 mL), and the mixture was stirred at room temperature for 3 h. The mixture was poured onto ice. After the ice melted the mixture was extracted with ethyl acetate. The organic extract was cautiously washed with a saturated aqueous solution of sodium bicarbonate, then with brine. The organic phase was dried, filtered and evaporated. The product was recrystalized from benzene/hexane to provide 1.6 g (66%) of 7-bromothiochroman-4-one as a white powder, mp 55-57.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.7.94 (d, 1H), 7.45 (s, 1H), 7.30 (dd, 1H), 3.25 (t, 2H), 2.97 (t, 2H); Mass spectrum m/z 262, 260 (M+NH.sub.4), 245, 243 (M+H). d. The product of part c (15.00 g, 61.47 mmol), phenylboronic acid (7.52 g, 61.67 mmol), and tetrabutylammonium bromide (0.99 g, 3.07 mmol) were dissolved in toluene (200 mL), aqueous sodium carbonate (2M; 60 mL) and ethanol (30 mL). The mixture was degassed by passing a stream of nitrogen through the vigourously stirred mixture for 0.5 h. Tetrakis(triphenylphosphine)palladium (2.14 g, 1.8 mmol) was added and the mixture was heated at reflux overnight (approx 16 h). The mixture was cooled to room temperature, and the layers separated. The aqueous layer was extracted with ethyl acetate (2.times.50 mL). The combined organic layers were dried, filtered through a plug of silica gel, and evaporated to a white solid which was recrystalized from benzene/hexane to provide 10.9 g (74%) of 7-phenylthiochroman-4-one as an off-white powder, mp 85-87.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.8.17 (d, 1H), 7.60-7.36 (m, 7H), 3.24 (t, 2H), 2.98 (t, 2H); Mass spectrum m/z 258 (M+NH.sub.4) 241 (M+H). Preparation of 7-(4-methylphenyl)chroman-4-one a. 3-Bromophenol (100 g, 580 mmol) and triethylamine (104 mL, 750 mmol) were dissolved in dichloromethane (500 mL), and the solution was cooled in an ice bath. Acetyl chloride (49.7 g, 630 mmol) was added dropwise. After 1 h the cooling bath was removed and the mixture was stirred overnight (approx 16 h) at room temperature. The mixture was washed with hydrochloric acid (1N, 250 mL), water (250 mL), 5% NaHCO.sub.3 (250 mL), and brine (250 mL). The organic layer was dried and evaporated to provide 124 g (99%) of 3-bromophenyl acetate as a light brown liquid; .sup.1 H NMR (CDCl.sub.3) .delta.7.36 (d, 1H), 7.32-7.20 (m, 2H), 7.05 (d, 1H), 2.28 (s, 3H). b. The product of part a (60 g, 280 mmol) was added to aluminum chloride (120 g, 890 mmol) and placed in an oil bath at 160.degree. C. for 3 h. The mixture was allowed to cool to rooom temperature and poured onto 300 g of an ice/hydrochloric acid (iN) mixture. After the ice melted the mixture was extracted with ethyl acetate. The organic layer was dried, filtered through a pad of silica gel and evaporated to yield a light yellow oil which solidified under vacuum to provide 53 g (88%) of 4-bromo-2-hydroxyacetophenone; .sup.1 H NMR (CDCl.sub.3) .delta.12.32 (s, 1H), 7.58 (d, 1H), 7.18 (s, 1H), 7.05 (d, 1H), 3.60 (s, 3H). c. The product of part b (53 g, 250 mmol) was dissolved in dimethylformamide dimethyl acetal (98 mL) and heated at reflux under nitrogen for 1 h, during which time a precipitate formed. The mixture was cooled to room temperature, glacial acetic acid (100 mL) was cautiously added and the mixture was heated at reflux for 1 h. Analysis of an aliquot of the reaction mixture by thin-layer chromatography and .sup.1 H NMR showed the reaction had not gone to completion, so additional acetic acid (100 mL) was added and the mixture was refluxed for an additional 2 h, and allowed to stand at room temperature overnight (approx 16 h). The precipitate was filtered, dried and recrystallized from ethanol to provide 37 g (68%) of 7-bromochromen-4-one. Concentration of the mother liquor provided an additional 12 g of product, mp 154-155.degree. C.; .sup.1 H NMR (CDCl.sub.3) 88.05 (d, 1H), 7.82 (d, 1H), 7.62 (s, 1H), 7.55 (d, 1H), 6.35 (d, 1H); Mass spectrum m/z 244, 242 (M+NH.sub.4), 225, 227 (M+H). d. The product of part c (4.5 g, 20 mmol), 4-methylphenylboronic acid (3.26 g, 24 mmol) and tetrabutylammonium bromide (322 mg, 1 mmol) were dissolved in a mixture of toluene (40 mL), ethyl alcohol (10 mL) and 2 M aqueous sodium carbonate, and degassed by passing a stream of nitrogen through the vigorously stirred mixture for 0.5 h. Tetrakis(triphenylphosphine)palladium (139 mg, 0.12 mmol) was added and the mixture was heated at reflux overnight (approx 16 h.). The mixture was cooled to room temperature and filtered through celite. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were filtered through a pad of silica gel and evaporated to provide 3.2 g (68%) of 7-(4-methylphenyl)chromen-4-one as a light tan powder, mp 159-160.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.8.35 (d, 1H), 7.95 (d, 1H), 7.72 (m, 1H), 7.65 (d, 2H), 7.38 (d, 2H), 6.42 (d, 1H), 2.50 (s, 3H); Mass spectrum m/z 237 (M+H). e. The product of part d (1.80 g, 7.62 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL) and cooled in a dry ice-acetone bath. Potassium tri-secbutylborohydride, (1.0 M in tetrahydrofuran; 7.6 mL, 7.6 mmol) was added dropwise and the mixture was stirred for 1 h, at the cooling bath temperature. The reaction mixture was poured into a 20% aqueous solution of monobasic potassium phosphate, and extracted with ethyl acetate. The organic layer was dried, filtered and evaporated. Purification by column chromatography on silica gel using 1:1 chloroform/dichloromethane provided 1.46 g (81%) of 7-(4-methylphenyl)chroman-4-one as an off-white solid; .sup.1 H NMR (CDCl.sub.3) .delta.7.85 (d, 1H), 7.52 (d, 2H), 7.35-7.18 (m, 4H), 4.58 (t, 2H), 2.82 (t, 2H), 2.40 (s, 3H). Preparation of 7-phenylisochroman-4-one a. Methyl iodide (10.0 mL, 160 mmol) was added to a mixture of 4-bromo-2-methylbenzoic acid (25.0 g, 116 mmol) and potassium carbonate (20.0 g, 145 mmol) in anhydrous dimethylformamide (75 mL) at room temperature under a nitrogen atmosphere and stirred for 18 h. The mixture was poured into water and extracted with ethyl acetate (3.times.50 mL). The organic phases were combined, washed with copper sulfate solution (50 mL) and brine (50 mL), dried and evaporated. Purification by column chromatography on silica gel using 9:1 hexane/ethyl acetate as eluant provided 21.0 g (79%) of methyl 4-bromo-2-methylbenzoate as a clear liquid: .sup.1 H NMR (CDCl.sub.3) .delta.7.85 (d, 1H), 7.42-7.47 (m, 2H), 3.95 (s, 3H), 2.64 (s, 3H); IR (neat) 1726 cm.sup.-1 ; Mass spectrum m/z 197, 199 (M+H-OCH.sub.3). b. A mixture of the product of part a (20.0 g, 87 mmol), N-bromosuccinimide (15.54 g, 87 mmol), and benzoyl peroxide (0.21 g, 1 mole %) in carbon tetrachloride (75 mL) was heated to reflux under a nitrogen atmosphere for 3 h. The solution was cooled to room temperature and filtered. The filtrate was concentrated to give an orange oil which formed crystals upon standing. A white solid was collected by suction filtration and recrystallized from hexane to provide 15.23 g (56%) of methyl 2-bromomethyl-4-bromobenzoate as a white powder, mp 78-79.degree. C.: .sup.1 H NMR (CDCl.sub.3) .delta.7.84 (d, 1H), 7.63 (s, 1H), 7.50(d of d, 1H), 4.89 (s, 2H), 3.94 (s, 3H); IR (KBr) 1722 cm.sup.-1 ; Mass spectrum m/z 325 (M+NH.sub.4); Anal. calcd. for C.sub.9 H.sub.8 Br.sub.2 O.sub.2 : C 35.10, H 2.62, Br 51.89; Found: C 35.09, H 2.63, Br 51.67. c. Sodium hydride (1.43 g; 60% in oil, 36 mmol) was suspended in anhydrous tetrahydrofuran (10 mL) under a nitrogen atmosphere. A solution of the product of part b (10.0 g, 32 mmol) and methyl glycolate (2.76 mL, 36 mmol) in anhydrous tetrahydrofuran (40 mL) was added at room temperature and the mixture was heated at reflux for 3 h. After cooling to room temperature, the solution was quenched with methanol (2 mL), poured into water (200 mL), and extracted with ethyl acetate (50 mL). The organic phase was washed with brine, dried and evaporated to give a white residue. Purification by column chromatography on silica gel using 4:1 hexane/ethyl acetate as eluant provided 7.10 g (69%) of methyl 2-[(2-methoxy-2-oxoethoxy)methyl]-4-bromobenzoate as a white solid, mp 60-62.degree. C.: .sup.1 H NMR (CDCl.sub.3) .delta.7.93 (s, 1H), 7.83 (d, 1H), 7.48 (dd, 1H), 5.01 (s, 2H), 4.25 (s, 2H), 3.88 (s, 3H), 3.79 (s, 3H); IR (KBr) 1758, 1720 cm.sup.-1 ; Mass spectrum m/z 334 (M+NH.sub.4); Anal. calcd. for C.sub.12 H.sub.13 BrO.sub.5 : C 45.45, H 4.13, Br 25.20; Found: C 45.42, H 4.03, Br 25.17. d. A mixture of the product of part c (6.77 g, 21 mmol) and sodium hydroxide (50% aqueous solution, excess) in 50% aqueous ethanol (200 mL) was heated at reflux for 5 h. The solution was cooled to room temperature, poured into water (400 mL), and acidified with concentrated hydrochloric acid to give a white precipitate which was collected by filtration and air dried to provide 6.04 g (98%) of 2-[(2-hydroxy-2-oxoethoxy)methyl]-4-bromobenzoic acid as a white solid, mp 194-196.degree. C.: .sup.1 H NMR (DMSO-d.sub.6) .delta.7.84 (m, 2H), 7.62 (d, 1H), 4.90 (s, 2H), 4.19 (s, 2H); IR (KBr) 1704 cm.sup.-1 ; Mass spectrum m/z 230 (M-CH.sub.2 COOH); Anal. calcd. for C.sub.10 H.sub.9 O.sub.5 Br: C 41.55, H 3.14, Br 27.64; Found: C 41.33, H 3.08, Br 27.42. e. A mixture of the product of part d (5.48 g, 19 mmol) and potassium acetate (3.0 g, 31 mmol) in acetic anydride (10.0 mL) was heated at reflux under a nitrogen atmosphere for 18 h. The reaction solution was cooled to room temperature and concentrated. Aqueous sodium hydroxide (1N; 100 mL) was added carefully, and the aqueous solution was extracted with diethyl ether (3.times.50 mL). The organic extracts were combined, dried and evaporated. The residue was taken up in aqueous sodium hydroxide (1N; 100 mL) and stirred for 5 min at room temperature. The mixture was poured into water (400 mL) and the solid was collected by filtration. Purification by column chromatography on silica gel using 5:1 hexane/ethyl acetate as eluant provided 1.15 g (27%) of 7-bromoisochroman-4-one as a white solid, mp 144-146.degree. C.: .sup.1 H NMR (CDCl.sub.3) .delta.7.91 (d, 1H), 7.57 (dd, 1H), 7.41 (s, 1H), 4.86 (s, 2H), 4.36 (s, 2H); IR (KBr) 1688 cm.sup.-1 ; Mass spectrum m/z 226 (M+H); Anal. calcd. for C.sub.9 H.sub.7 O.sub.2 Br: C 47.61, H 3.11, Br 35.19; Found: C 47.65, H 3.10, Br 35.04. f. Nitrogen gas was bubbled through a mixture of the product of part e (0.611 g, 27 mmol) and phenylboric acid (0.36 g, 29 mmol) in 5:2 toluene/ethanol(30 mL) for 4 hours. Sodium carbonate (0.57 g, 5.38 mmol) was added followed by tetrabutylammonium bromide (0.049 g, 0.13 mmol) and tetrakis(triphenylphosphine)palladium (0.012 g, 0.04 mmol). The solution was heated at reflux for 18 h, cooled to room temperature, and evaporated. The residue was taken up in water (50 mL) and extracted with ethyl acetate (3.times.20 mL). The organics were combined, washed with brine, dried and evaporated. The solid was recrystallized from hexane to provide 0.429 g (70%) of 7-phenylisochroman-4-one as a gold-colored solid, mp 127-128.degree. C.: .sup.1 H NMR (CDCl.sub.3) .delta.8.12 (d, 1H), 7.60-7.66 (m, 3H), 7.39-7.51 (m, 4H), 4.96 (s, 2H), 4.41 (s, 2H); IR (KBr) 1688 cm.sup.-1 ; Mass spectrum m/z=225 (M+H); Anal. calcd. for C.sub.15 H.sub.12 O.sub.2 : C 80.34, H 5.39; Found: C 80.03, H 5.45. Preparation of 7-phenylisothiochroman-4-one a. To a solution of 3-bromobenzyl bromide (23.75 g, 90 mmol) and thioglycolic acid (11.42 g, 120 mmol) in ethanol (150 mL) was added potassium hydroxide (14.24 g, 250 mmol) in water (50 mL). The reaction was heated at reflux for 3.5 h, cooled and the ethanol was evaporated. The residue was quenched with water (100 mL) and the mixture was extracted with ether (50 mL). The aqueous layer was acidified to pH 1 with concentrated hydrochloric acid, extracted with ethyl acetate (2.times.100 mL) and the organic phase was dried. Evaporation of the solvent followed by washing of the residue with hexane afforded 3-bromophenylmethylthioacetic acid as a white solid (92%), mp 90-91.degree. C.: .sup.1 H NMR (CDCl.sub.3) .delta.3.10 (s, 2H), 3.82 (s, 2H), 7.20-7.29 (m, 2H), 7.39-7.42 (dd, 1H), 7.52 (d, 1H); IR (KBr) 1706 cm.sup.-1 ; Mass spectrum m/z 280 (M+NH.sub.4); Anal. calcd. for C.sub.9 H.sub.9 O.sub.2 SBr: C 41.39, H 3.47, S 12.28; Found C 41.43, H 3.49, S 12.10. b. To a cold (0.degree. C.) solution of the product of part a (22.00 g, 80 mmol) in methylene chloride (200 mL) was added oxalyl chloride (11.81 g, 90 mmol) dropwise followed by four drops of dimethylformamide. The reaction mixture was stirred vigorously at 0.degree. C. and then at room temperature for 5 h. The mixture was concentrated to a yellow oil which was redissolved in fresh methylene chloride (100 mL). The solution was added dropwise at 0.degree. C. to a slurry of aluminum chloride (11.30 g, 80 mmol) in methylene chloride (150 mL). The mixture was warmed to room temperature and stirred for 48 h, then was poured into crushed ice (150 g). The organic layer was separated and washed with water (50 mL), saturated sodium bicarbonate (50 mL) and brine (50 mL), dried and evaporated to a dark brown solid. Chromatography on silica gel using 20:1 hexane:ethyl acetate as eluant afforded 7-bromoisothiochroman-4-one (88%) as a brown solid, mp 81.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.3.54 (s, 2H), 3.88 (s, 2H), 7.26 (s, 1H), 7.50 (d, 1H), 7.95 (d, 1H); IR (KBr) 1676 cm.sup.-1 ; Mass spectrum m/z 245 (M+H); Anal. calcd. for C.sub.9 H.sub.7 BrOS: C 44.46, H 2.90, S 13.19; Found C 44.28, H, 2.77, S 13.09. c. 7-Phenylisothiochroman-4-one was prepared in 62% yield via the procedure used in part f of the preparation of 7-phenylisochroman-4-one, and was recrystallized from benzene/hexanes, mp 87-89.degree. C.: .sup.1 H NMR (CDCl.sub.3) .delta.3.59 (s, 2H), 3.99 (s, 2H), 7.38-7.47 (m, 4H), 7.49-7.60 (m, 3H), 8.17 (d, 1H); IR (KBr) 1674, cm.sup.-1 ; Mass spectrum m/z 241 (100); Anal. calcd. for C.sub.15 H.sub.12 O.sub.5 : C 74.97, H 5.03, S 13.34; Found C 75.06, H 5.00, S 13.20. Preparation of 7-phenyl-8-aza-isothiochroman-4-one To a solution of ethyl 2-methyl-6-phenylnicotinate (prepared according to Spath et al. [Monatsh. Chem. (1928) 49:265]) (1.00 g, 4.10 mmol) in carbon tetrachloride (10 mL) was added N-bromosuccinimide (0.81 g, 4.60 mmol) and benzoyl peroxide (0.05 g). The reaction was heated at reflux for 18 h, cooled and filtered. The filtrate was concentrated and redissolved in anhydrous tetrahydofuran (10 mL). Methyl thioglycolate (0.37 mL, 4.10 mmol) was added, followed by sodium hydride (80%, 0.12 g, 4.1 mmol). The reaction mixture was allowed to stir at room temperature for 3 h. Additional sodium hydride (80%, 0.14 g, 4.6 mmol) was added and the solution was heated to gentle reflux for 18 h. The reaction was cooled to 0.degree. C. and quenched with water (20 mL). The mixture was washed with ethyl acetate (50 mL). The aqueous layer was acidified to pH 5 with acetic acid and the product extracted with ethyl acetate (3.times.40 mL). The organic extract was washed with brine (10 mL), dried and evaporated to provide an orange oil. Chromatography on silica gel using 6:1 hexane:ethyl acetate as eluant afforded a mixture of uncyclised compound as a yellow oil (20%) and the desired methyl 7-phenyl-8-aza-isothiochroman-4-one-3-carboxylate (23%) as a yellow solid, mp 78-81.degree. C. This material was heated at reflux in 3N aqueous hydrochloric acid (30 mL) for 12 h, then cooled and made basic. Extraction with ethyl acetate (4.times.50 mL) afforded a semi-solid mass after drying and evaporation. Chromatography on silica gel using 7:1 hexane/ethyl acetate as eluant afforded 7-phenyl-8-azaisothiochroman-4-one as a yellow solid (68%), mp 97-99.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.3.58 (s, 2H), 4.14 (s, 2H), 7.48 (m, 4H), 7.78 (d, 1H), 8.04-8.07 (m, 2H), 8.40 (d, 1H); IR (KBr) 1680 cm.sup.-1 ; Mass spectrum m/z 242 (M+H); Anal. calcd. for C.sub.14 H.sub.11 NOS: C 69.68 H 4.54 N 5.80; Found C 69.39 H 4.58 N 5.69. The compounds of the present invention and their preparation can be further understood by the following representative Examples, which do not constitute in any way a limitation of the present invention. All melting points are uncorrected. All reactions were conducted under a nitrogen atmosphere except where otherwise noted. All commercial chemicals were used as received. Chromatography was performed with Merck silica gel 60 (230-400 mesh). The chromatography eluents are given as ratios by volume. Organic phases from solvent-solvent extractions were generally dried over magnesium sulfate, unless otherwise noted. Solvents were generally removed by evaporation under reduced pressure on a rotary evaporator unless otherwise noted. Peak positions for .sup.1 H NMR spectra are reported as parts per million (.delta.) downfield from the internal standard tetramethylsilane. Abbreviations for .sup.1 H NMR spectra are as follows: s=singlet, d=doublet, m=multiplet, dd=doublet of doublets, dm=doublet of multiplets. Mass spectra were obtained using chemical ionization with ammonia as the reagent gas unless otherwise noted. |
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