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United States Patent (19) 11 Patent Number: 5,952,334 Gomez Et Al

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United States Patent (19) 11 Patent Number: 5,952,334 Gomez Et Al USOO5952334A United States Patent (19) 11 Patent Number: 5,952,334 Gomez et al. (45) Date of Patent: Sep. 14, 1999 54 CARBOCYCLIC COMPOUNDS Primary Examiner Amelia Owens Attorney, Agent, or Firm Nixon & Vanderhye 75 Inventors: Jose Ruiz Gomez, Jose Marie Bueno Calderon; Silvestre Garcia-Ochoa 57 ABSTRACT Dorado; Maria T. Fraile Gabaldon; Julia C. Pichel; Jose Fiandor Roman; Domingo Gargallo Viola; Juan C. A compound of formula Cuevas Zurita; Jose L. Lavandera Diaz, Sophie Huss, all of Madrid, (I) Spain 73 Assignee: GlaxoWellcome S.A., Spain 21 Appl. No.: 09/081,090 22 Filed: May 19, 1998 Related U.S. Application Data 63 Continuation of application No. 08/669,441, filed as appli cation No. PCT/EP95/04331, Nov. 6, 1995, Pat. No. 5,854, 280. 30 Foreign Application Priority Data (a) Nov. 8, 1994 EP European Pat. Off. .............. 945.00173 Nov. 8, 1994 EP European Pat. Off. .............. 945OO175 51) Int. Cl. .......................... A01N 43/54; AO1N 43/02; AO1N 43/64 52 U.S. Cl. .......................... 514/269; 514/149; 514/183; 514/383; 514/430; 514/456; 514/450 58 Field of Search ................... 549/90, 396; 514/430, 514/456, 183, 149, 269, 450, 383 (b) 56) References Cited FOREIGN PATENT DOCUMENTS WO 98/10782 3/1998 WIPO. OTHER PUBLICATIONS Patent Abstracts of Japan vol. 18, No. 485 (C-1248), 1994 JPA,06 157582 Banyu Pharmaceut. Co. Ltd. Jun. 1994. Patent Abstracts of Japan vol. 11, No. 119 (C-436), 1987 having antifungal activity in combination with other anti JPA,62040292 Sankyo Co. Ltd. Feb. 1987. fungal agents. Helvetica Chimcia Acta, vol. 54, No. 119, Basel, CH pp. 1178–1190, XP002000182 Hauser D. and Sigg H.P.: “Iso lierung und Abbau von Sordarin'. 6 Claims, No Drawings 5,952,334 1 CARBOCYCLIC COMPOUNDS (I) This a continuation of application Ser. No. 08/669,441, filed Oct. 18, 1996, now U.S. Pat. No. 5,854,280, which is a 371 of PCT/EP95/04331, filed Nov. 6, 1995. This invention relates to novel Sordarin derivatives hav ing antifungal activity, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine, more particularly in the prevention or treatment of diseases in animals, including humans, caused by fungal infection. British Patent Specification No. 1,162,027 describes the preparation of an antibiotic, SL2266, by the cultivation of the strain NRRL 3196 of the fungus species Sordaria araneosa. SL 2266, later named Sordarin, is reported to have 15 (a) fungistatic activity. The same research group also described in Helvetica Chimica Acta (1971), 51, 119-120 the degra dation of Sordarin to Sordaricin. Published Japanese Patent Application No. J6 2040292A describes the preparation of an antibiotic, Zofimarin, which is reported to have antifungal activity. Sordarin, Sordaricin and Zofimarin may be represented by formula (A) below (b) (A) 25 and pharmaceutically acceptable Salts and Solvates (e.g. hydrates) or metabolically labile derivatives thereof, wherein 35 R" represents hydrogen, halogen, hydroxyl, Calkoxy or where acyloxy; OR as R° and R may each independently represent hydrogen, Cigalkyl or Calkoxy Calkyl or R and R may OH together with the carbon atom to which they are 40 attached represent C=O, C=S or Cascycloalkyl, HO NOCH3 R" represents hydrogen or CHR" (where R is hydrogen, hydroxyl, Calkoxy or a group OCOR in which R is Calkyl or aryl); CH R and R may each independently represent hydrogen, 45 Calkyl or Calkoxy C1-alkyl or R and R may describes Sordarin, together with the carbon atom to which they are OR as OH describes Sordaricin; and attached represent C=O, C=S or Cascycloalkyl, OR as in represents Zero or 1; 50 X and Y may each independently represent oxygen, sulphur or CRR' (where R and R' may each OCOCH=7CH-CH=CHCH independently represent hydrogen, C-alkyl, Calkoxy or CalkoxyC, alkyl or R and R' may HO SOCH3 together with the carbon atom to which they are 55 attached represent C=O C=S, C-cycloalkyl or C=CHR'' where R'' represents hydrogen or CH Calkyl); or when X or Y is oxygen and n is Zero then -Y-CRR or -X-CRR-respectively may also describes Zofimarin. represent-N=CR- or -NR'-CRR- (where Although Sordarin and Zofimarin exhibit antifungal 60 CR and R are C=O and R is Calkyl an acyl activity, both compounds are only moderately active and group COR' where R' is Calkyl) or when Y is have limited Spectra of action when tested against a battery Oxygen and n is Zero X may be represent the group of fungal organisms. We now describe hereinafter a novel CR' (wherein R' has the meanings defined above) group of fungicidal Sordarin derivatives which exhibit excel which is attached to the pyran ring by a double bond; lent antifungal activity and a broad Spectrum of action. Thus, 65 R" represents hydrogen, halogen, azido, Calkyl, according to a first aspect of the present invention, we hydroxy, Calkoxy (optionally Substituted by 1 or 2 provide compounds of formula (I) hydroxy or a ketal thereof or 1 or 2 C- alkoxy groups), 5,952,334 3 4 arylCaalkoxy, Cs, alkenyloxy, a group OCOR' Examples of suitable Y groups include oxygen or CR'R'' (where R is arylCalkoxy or a Coalkyl group wherein R is hydrogen, Calkoxy or C-alkyl and R' is optionally containing one or two double bonds) or hydrogen or Calkyl. Cigalkoxycarbonyl Calkoxy, and R' represents When R is an unsaturated Coalkyl group it may hydrogen or R' and R' may together with the carbon particularly represent a Straight or branched chain Cssalkyl atom to which they are attached represent C=O or group containing two double bonds, for example C=CH; -CH=^CH-CH=CHCH R7 represents CHR' where R' is hydrogen, hydroxyl, When R is a C- alkoxy group substituted by hydroxy Calkoxy or a group OCOR' in which R' is or alkoxy, this may be for example 2,3-dihydroxy propoxy Calkyl); and and the acetone ketal derived therefrom or a 2,3-dimethoxy W represents an oxygen or Sulphur atom or a CH group; propoxy group. and the dotted line in group (a) indicates the optional R" is preferably a hydrogen atom with R' sited in the presence of an additional bond; C-configuration. Suitable pharmaceutically acceptable Salts of the com 15 R" may represent, for example, a hydrogen atom or a pounds of formula (I) include inorganic base Salts. Such as hydroxyl group. alkali metal salts (for example Sodium and potassium salts) R may represent, for example, hydrogen or C-alkyl and ammonium Salts and organic base Salts. Suitable organic (e.g. methyl), and R may represent, for example, hydrogen, base salts include amine salts such as trialkylamine (e.g. Calkyl (e.g. methyl, ethyl or n-propyl) or CalkoxyC. triethylamine), dialkylamine (e.g. dicyclohexylamine), alkyl (e.g. methoxyethyl), or CRR may represent C=O, optionally Substituted benzylamine (e.g. phenylbenzylamine C=S or Cascycloalkyl (e.g. cyclopentyl). or p-bromobenzylamine), procaine, ethanolamine, R" may represent, for example, methyl or die thanolamine, N-methylglucosamine and tri Calkoxymethyl (e.g. methoxymethyl). (hydroxymethyl)methylamine Salts and amino acid Salts 25 (e.g. lysine and arginine Salts). R and R may each independently represent, for References hereinafter to a compound of formula (I) example, hydrogen or Calkyl (e.g. methyl). includes that compound and its pharmaceutically acceptable Examples of ring Systems represented by Salts. Other Salts which are not pharmaceutically acceptable R2 R3 R2 R3 R2 R3 may be useful in the preparation of compounds of formula X X R5 (I) and these form a further aspect of the invention. X (CRR)n include O O.s O R6 s Metabolically labile derivatives of compounds of formula (I) are compounds which are converted in the body to Null \ / O compounds of formula (I). Examples of Such derivatives 35 include conventional metabolically labile esters formed R2 R3 R2 R3 R2 from the free carboxylic acid in the molecule. R9 R9 R1 It is to be understood that the present invention encom O, O. O and passes any individual isomers, including optical isomers, of 40 R10 R10, \ compounds represented by formula (I) above as well as mixtures thereof, including wholly or partially racemic R2 R3 mixtures thereof. AS used herein, “alkyl as a group or part of a Calkoxy R11N O group may be a Straight or branched chain. Suitable 45 examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, S-butyl and t-butyl, n-hexyl and n-octyl. AS used herein, the term “aryl” as a group or part of a Examples of particular R' groups include halogen (e.g. group means phenyl or heteroaryl each optionally Substi fluorine), azido hydroxyl, Calkoxy, benzyloxy, tuted by one or more (e.g. 1, 2 or 3) atoms or groups selected 50 benzyloxycarbonyloxy, Calkoxycarbonyloxy and from halogen, hydroxyl, C-alkyl, Calkoxy or Calkoxy Calkoxy (e.g. methoxyethoxy), C. Calkoxy carbonyl. The heteroaryl group may be a 5- or alkoxycarbonyl-Calkoxy, Calkylcarbonyloxy, 2,3- 6-membered heteroaromatic ring containing one or more heteroatoms Selected from nitrogen, oxygen and Sulphur. dihydroxy propoxy, and the acetone ketal thereof, Suitable examples of heteroaryl groups include pyridyl, 55 2,3dimethoxy propoxy, C. alkenyloxy e.g. allyloxy or furyl, thienyl and pyrrolyl. 3methylallyloxy or R' and R'' and the carbon atom to The term “halogen” means herein fluorine, chlorine, bro which they are attached represents C=O or C=CH2. mine or iodine. R" may represent, for example, methyl or When R is an acyloxy group it may represent, for Calkoxymethyl (e.g. methoxymethyl) or hydroxy methyl.
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