Antiviral dibenzothiazepinone derivatives
| Title: | Antiviral dibenzothiazepinone derivatives |
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| Patent Number: | 5,607,929 |
| Publication Date: | March 04, 1997 |
| Appl. No: | 08/140,120 |
| Application Filed: | December 06, 1993 |
| Abstract: | Compounds of formula (I) wherein n is 0, 1 or 2; and R.sup.1 and R.sup.2, which may be the same or different, each represent one or more ring substituent(s) selected from: hydrogen, hydroxy, halogen, cyano, nitro, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl or C.sub.1-6 alkoxy (where the alkyl or cycloalkyl moiety may be optionally substituted by one or more substituents selected from halogen atoms and hydroxyl groups); --NR.sup.4 R.sup.5 where R.sup.4 and R.sup.5, which may be the same or different, each represent hydrogen or C.sub.1-6 alkyl; --S(O).sub.m R.sup.6, where m is 0, 1, 2 or 3 and R.sup.6 represents hydrogen, C.sub.1-6 alkyl or C.sub.3-6 cycloakyl; --SO.sub.2 NR.sup.4 R.sup.5 where R.sup.4 et R.sup.5 are each as defined above; phenyl, phenylC.sub.1-3 alkoxy or phenylC.sub.1-3 alkyl where the phenyl group may be optionally substituted by one or more substituents independently selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxy, nitro, halogen and amino; and --CO.sub.2 H or --COR.sup.7 where R.sup.7 is C.sub.1-6 alkyl or C.sub.3-6 cycloalkyl; R.sup.3 represents hydrogen or C.sub.1-4 alkyl; and esters, salts and other physiologically functional derivatives thereof; show activity as antiviral agents, for example against HIV. Certain of the compounds are novel. |
| Inventors: | Nicol, Robin H. (London, GB2); Slater, Martin J. (Beckenham, GB2); Hodgson, Simon T. (Beckenham, GB2) |
| Assignees: | Glaxo Wellcome Inc. (Research Triangle Park, NC) |
| Claim: | We claim |
| Claim: | 1. A method for treating a viral infection comprising administering to a subject in need of same an antiviral effective amount of a compound of formula (I) ##STR11## wherein: n is 0, 1 or 2; and |
| Claim: | R.sup.1 and R.sup.2, which may be the same or different, each represent one or more ring substituent(s) selected from |
| Claim: | halogen; nitro; C.sub.1-6 alkyl; haloC.sub.1-6 alkyl; C.sub.1-6 alkoxy; |
| Claim: | --NR.sup.4 R.sup.5 where R.sup.4 and R.sup.5, which may be the same or different, each represent hydrogen or C.sub.1-6 alkyl; |
| Claim: | --SO.sub.3 H; |
| Claim: | phenyl; phenylC.sub.1-3 alkoxy; and |
| Claim: | --CO.sub.2 H; |
| Claim: | R.sup.3 represents hydrogen or C.sub.1-4 alkyl; or an ester, salt or salt of such an ester thereof. |
| Claim: | 2. A method according to claim 1 wherein R.sup.3 is hydrogen. |
| Claim: | 3. A method according to claim 1 wherein the compound of formula (I) is selected from the group consisting of |
| Claim: | 3-trifluoromethyldibenzothiazepin-11(10H)-one; |
| Claim: | 3-trifluoromethyldibenzothiazepin-11(10H)-one-5,5-dioxide; |
| Claim: | 4-trifluoromethyldibenzothiazepin-11(10H)-one; |
| Claim: | 4-trifluoromethyldibenzothiazepin-11(10H)-one-5-oxide; |
| Claim: | 4-trifluoromethyldibenzothiazepin-11(10H)-one-5,5-dioxide; |
| Claim: | 7-methoxydibenzothiazepin-11(10H)-one; |
| Claim: | 7-methoxydibenzothiazepin-11(10H)-one-5,5-dioxide; |
| Claim: | 8-trifluoromethyldibenzothiazepin-11(10H)-one; |
| Claim: | 8-trifluoromethyldibenzothiazepin-11(10H)-one-5,5-dioxide; |
| Claim: | 4-trifluoromethyl-9-methyldibenzothiazepin-11(10H)-one; |
| Claim: | 4-trifluoromethyl-9-methyldibenzothiazepin-11(10H)-one-5,5-dioxide; |
| Claim: | 10-ethyl-3-trifluoromethyldibenzothiazepin-11(10H)-one; |
| Claim: | 4-fluorodibenzothiazepin-11(10H)-one; |
| Claim: | 4-fluorodibenzothiazepin-11(10H)-one-5,5-dioxide; |
| Claim: | 10-methyl-4-fluorodibenzothiazepin-11-one; |
| Claim: | 10-methyl-4-trifluoromethyldibenzothiazepin-11-one; |
| Claim: | 4-methylthiodibenzothiazepin-11(10H)-one; |
| Claim: | 4-methylthiodibenzothiazepin-11(10H)-one-5,5-dioxide; |
| Claim: | 2-aminodibenzothiazepin-11(10H)-one; |
| Claim: | 2-nitrodibenzothiazepin-11(10H)-one; |
| Claim: | 2-nitrodibenzothiazepin-11(10H)-one-5,5-dioxide; |
| Claim: | 4,8-bistrifluoromethyldibenzothiazepin-11(10H)-one; |
| Claim: | 4,8-bistrifluoromethyldibenzothiazepin-11(10H)-one-5,5-dioxide; |
| Claim: | 1-methoxydibenzothiazepin-11(10H)-one; |
| Claim: | 1-methoxydibenzothiazepin-11(10H)-one-5,5-dioxide; |
| Claim: | 1-fluorodibenzothiazepin-11(10H)-one; |
| Claim: | methyl dibenzothiazepin-11(10H)-one-3-carboxylate; |
| Claim: | dibenzothiazepin-11(10H)-one-3-carboxylic acid; |
| Claim: | and esters, salts and salts of such an ester thereof. |
| Claim: | 4. A compound of formula (I) ##STR12## wherein: R.sup.3 is C.sub.1-4 alkyl; and |
| Claim: | or an ester, salt or salt of such an ester thereof. |
| Claim: | 5. A compound according to claim 4 selected from a group consisting of |
| Claim: | 4-methylthiodibenzothiazepin-11(10)-one-5,5-dioxide; |
| Claim: | and esters, salts and salts of such esters thereof. |
| Claim: | 6. A pharmaceutical composition which comprises at least one compound of claim 4 together with at least one physiologically acceptable carrier or excipient. |
| Current U.S. Class: | 514/211; 540/488 |
| Current International Class: | A01N 4300; A61K 3155; C07D28116 |
| Patent References Cited: | 3367930 February 1968 Schmuts et al. 3541085 November 1970 Sheeley et al. 3853882 December 1974 Szmuskovicz 3887575 June 1975 Hester, Jr. et al. 4002639 January 1977 Vogt 4163785 August 1979 Hoffmann et al. 4263207 April 1981 Rokach et al. 4728735 March 1988 Belanger et al. |
| Other References: | R. Pauwls, Nature, vol. 343, pp. 470-473, "Potent and Selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivative," (1990). N. Rasanu, Rev. Chim, vol. 20(3), pp. 175-176, "Chimia tioxantonei. Transpozitia Beckman a oximei tioxantonei si oximei tioxanton-5,5-dioxidului," 1969. A. H. Corwin, A. B. Chivvis, and C. B. Storm, Chemical Abstract, vol. 62, pp. 14681-14684, "Seven- and Higher-Membered Rings," (1965). J. Schmutz, F. Kunzle, F. Hunziker and A. Burki, Helvetica Chimica Acta, vol. 48, No. 38, pp. 336-347, "Neue Synthese von Lactamen der Dibenz[v,f]-1, 4-thiazepin-, -oxazepin und Dibenz[b,e]-azepin-Reihe," (1965). P. Catsoulacos, Bulletin de la Societe Chimique de France, No. 6, pp. 2136-2137, "Synthese de derives du dibenzo[b, f] thiazein-1,4 one-10 dioxyde-5,5," (1973). D. Besanty, J. Mayrargue, G. E. Moussa, M. E. Shaaban, P. Gayral, M. Miocque, Eur. J. Med. Chem, vol. 23, pp. 403-405, "Synthese de benzo et dibenzothiazepines nitrees a visee anti-parasitaire," (1988). D. Hellwinkel, R. Lenz and F. Lammerzahl, Tetrahedron, vol. 39, No. 12, pp. 2073-2084, "Heterocyclic Syntheses via Carbanionically Induced Rearrangement Reactoins" (1983). N. Kamigata, S. Hashimoto, M. Kobayashi and H. Nakanishi, The Chemical Society of Japan, No. 58, pp. 3131-3136, "Photochemical Ring-expansion Reaction of 1,2-Benzisothiazolinones," (1985). Z. Polivka, J. Holubek, E. Svatek, A. Dlabac, D. Pucek, Z. Z. Sedivy and M. Protiva, Collection Czechoslovak Chem Commun., vol. 48, pp. 1465-1476, "3-(4-Methyliperazino)Dibenzo[b,f]-1,2,4-Triazolo[4,3-d]-1,4-Thiazepine and its 6-Chloro and 12-Chloro Derivatives"; Synthesis and Pharmacology, (1983). J. Joshi, B. C. Joshi and F. S. K. Barar, Pharmazie, No. 44, pp. 265-267, "Synthesis and Pharmacological evaluation of triazolo derivatives of 8-amino-10, 11-dihydro-dibenzo[b,e]1,4-thiazepin-11-one," (1989). O. F. Bennett, J. Johnson and J. Tramondozzi, Organic Preparations and Procedures, Int., 6(6), pp. 287-293, "Synthesis of 2-Methoxydibenzo [b,f] (1,4)-Thiazepin-11 (10H) -One-5, 5-Dioxide," (1974). N. Kamigata, S. Hashimoto and M. Kobayashi, Sulfur Letters, vol. 2(1), pp. 17-22, "On Direct Photo-Oxidation of Benzisothiazol-3 (2H)-Ones in the Presence of Oxygen," (1984). G. P. Dhareshwar and B. D. Hosangadi, Indian J. Chem, vol. 15B, pp. 963-964, "Studies in Amination & Intramolecular Amidation Reactions with Polyphosphoric Acid: Synthesis of 2-Aminodiphenyl Sulphone, Dibenzo [b,f][1,4]thiazepin-11(10H)-one-5,5-dioxide & Dibenz[b,f][1,4]oxazepin-11(10H)-one," (1977). N. Kamigata, S. Hashimoto, S. Fujie, and M. Kobayashi, J. Chem. Soc., Chem. Commun., pp. 765-766, "Photoisomerization of 2-Aryl-1,2-benzisothiazol-3(2H)-ones," (1983). O. F. Bennett, J. Johnson and S. Galletto, Journal of Heterocyclic Chemistry, vol. 12, pp. 1211-1213, "A Novel Synthesis of Dibenzo [b,f][1,4]thiazepin-11(10H)one 5,5-Dioxides," (1975). B. C. Joshi and J. Pande, Chemistry and Industry, pp. 825-826, "Synthesis and structural studies of 9-amino-10,11-dihydro-5H-dibenzo(b,e)(1,4)thiazepine 11-one," (1985). K. Nagarajan, C. L. Kulkarni, A. Venkateswarlu and R. K. Shah, Indian Journal of Chemistry, vol. 12, pp. 258-262, "Condensed Heterotricycles: Dibenz [b,f][1,4]oxazepines-11(10H)-thiones, 11-Substituted Dibenze[b,f][1,4]oxazepines & Dibenz[b,f][1,4]thiazepin Analogues," (1974). K. Nagarajan, C. L. Kulkarni, and A. Venkateswarlu, Indian Journal of Chemistry, vol. 12, pp. 247-251, "Condensed Heterotricycles: Beckmann Rearrangement of Xanthone & Thioxanthone Oximes as a Route to Dibenz[b,f][1,4]-oxazepines & Thiazepines," (1974). K. Nagarajan, A. Venkateswarlu, C. L. Kulkarny and R. K. Shah, Indian Journal of Chemistry, vol. 12, pp. 227-235, "Condensed Heterotricycles: Synthesis of Dibenz[b,f][1,4]oxazepines, Dibenz[b,f][1,4]thiazepins and Dibenz[b,f][1,4]diazepines by Cyclization of 2-Halo-2'-hydroxy(mercato/amino)benzanilides," (1974). J. Schmutz, F. Kunzle, F. Hunziker and R. Gauch, Helvetica Chimica Acta, vol. 50(1), pp. 245-254, "Uber in 11-Stellung amino-substituierte Dibenzo[b,f]-1,4-thiazepine und -oxazepine," (1967). P. Catsoulacos, Journal of Heterocyclic Chemistry, vol. 7(2), pp. 409-411, "Synthesis of Substituted Dihydrodibenzothiazepines and Related Compounds," (1970). S. Palazzo, L. I. Giannola and S. Curonna, Journal of Heterocyclic Chemistry, vol. 11(5), pp. 839-841, "The Behaviour of some Thioxanthene and Thiathrene Derivatives with Hydrazoic Acid," (1974). N. R. Shete, Indian J. Chem., vol. 21B, pp. 581-582, "Synthesis of 11-Oxo & 11, 11-Diphenyl Derivatives of Dibenzo [b,f][1,4] thiazepines, Dibenzo[b,f][1,4]-oxazepines & Dibenzo[b,e][1,4]diazepines," (1982). |
| Primary Examiner: | Bond, Robert T. |
| Attorney, Agent or Firm: | Nixon & Vanderhye |
| Accession Number: | edspgr.05607929 |
| Database: | USPTO Patent Grants |
| Language: | English |
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